WO2021154976A1 - Methods of treating brain cancer with panobinostat - Google Patents

Methods of treating brain cancer with panobinostat Download PDF

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Publication number
WO2021154976A1
WO2021154976A1 PCT/US2021/015463 US2021015463W WO2021154976A1 WO 2021154976 A1 WO2021154976 A1 WO 2021154976A1 US 2021015463 W US2021015463 W US 2021015463W WO 2021154976 A1 WO2021154976 A1 WO 2021154976A1
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panobinostat
patient
day
dipg
administering
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PCT/US2021/015463
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French (fr)
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Juan Estruch
Brett LUND
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Secura Bio, Inc.
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Publication of WO2021154976A1 publication Critical patent/WO2021154976A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Panobinostat is currently indicated for the treatment of multiple myeloma in patients that have received at least two prior regimens, including bortezomib and an immunomodulatory agent. It is available as the anhydrous lactate salt under the trade name of FARYDAK ® . Panobinostat is a histone deacetylase inhibitor. Panobinostat is thought to elicit antitumor activity primarily through epigenetic modulation of gene expression and inhibition of protein metabolism.
  • HDACs histone deacetylases
  • Akt protein kinase B
  • hypoxia-inducible factor 1a may help reactivate epigenetically silenced tumor suppressor genes and modify gene expression via inhibition of signal transducer and activator of transcription 3, protein kinase B (Akt), and hypoxia-inducible factor 1a.
  • Brain cancer is one of the deadliest forms of cancer.
  • the five-year survival rate for all brain tumors, including non-cancerous tumors, is 33 %. More than two-thirds of adults with glioblastoma, an aggressive form of brain cancer, will die within two years of diagnosis.
  • Children diagnosed with diffuse intrinsic pontine glioma (DIPG) face the same prognosis as children diagnosed 40 years ago. Only 10 % of children with DIPG survive for two years following their diagnosis, and less than 1 % survive for five years.
  • DIPG diffuse intrinsic pontine glioma
  • a number of factors make brain cancers difficult to treat, including the complexity of brain cancers and the accessibility of tumors.
  • brain tumors are heterogeneous, containing various subpopulations of cancer cells, some of which respond to treatment and some of which do not. Additionally, brain tumors may be difficult to remove surgically because of their proximity to critical structures in the brain. Additionally, many therapeutic agents cannot reach the brain due to the blood-brain barrier. Therefore, there is a medical need for the development of new therapeutics for brain cancer.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering a histone deacetylase inhibitor of Formula I, such as panobinostat.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof.
  • panobinostat or the pharmaceutically acceptable salt thereof, is administered on a 28 day course.
  • panobinostat or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
  • panobinostat, or the pharmaceutically acceptable salt thereof is administered on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
  • panobinostat or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1, 2, and 3 and a rest period on week 4.
  • panobinostat, or the pharmaceutically acceptable salt thereof is administered on a 28 day course, wherein the course has a treatment period on weeks 1 , 2, and 3 and a rest period on week 4, wherein panobinostat or the pharmaceutically acceptable salt thereof is administered up to three times per treatment period.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma (DIPG), ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, and pineal tumor.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administer
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein the DIPG is non-progressed DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein the DIPG is progressed or recurrent DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering an MTD of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is optionally DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the patient exhibits mutations in one or more genes selected from the group consisting of H3F3A, HIST1H3B, HIST1H3C, TP53, ACVR1 , PDGFRA, PPM1 D, PIK3CA, PIK3R1 , MYC, MYCN, and PPM1 D.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, and wherein after administering panobinostat, the patient’s overall survival is improved compared to the median survival for a patient treated with a standard protocol for DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient exhibits a partial response.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, comprising administering a dose of panobinostat selected from the group consisting of 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, and 60 mg.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
  • panobinostat or a pharmaceutically acceptable salt thereof is administered at an MTD of 28 mg/m 2 /day.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4, and wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
  • panobinostat or a pharmaceutically acceptable salt thereof is administered at an MTD of 28 mg/m 2 /day.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 , 2, and 3 and a rest period on week 4.
  • panobinostat or a pharmaceutically acceptable salt thereof is administered at an MTD of 10 mg/m 2 /day.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 , 2, and 3 and a rest period on week 4, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
  • panobinostat or a pharmaceutically acceptable salt thereof is administered at an MTD of 10 mg/m 2 /day.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma (DIPG), ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, and pineal tumor.
  • the brain cancer is selected from the group
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein the DIPG is non-progressed DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein the DIPG is progressed or recurrent DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the patient in need thereof exhibits mutations in one or more genes selected from the group consisting of H9K27M, H3F3A, HIST1H3B, HIST1H3C, TP53, ACVR1, PDGFRA, PPM1 D, PIK3CA, PIK3R1, MYC, MYCN, and PPM1 D.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median survival for a patient treated with a standard protocol for DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient exhibits a partial response.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the dose of panobinostat is selected from the group consisting of 5 mg/m 2 /day, 10 mg/m 2 /day, 16 mg/m 2 /day, 22 mg/m 2 /day, 28 mg/m 2 /day, and 36 mg/m 2 /day.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the dose is selected based on the patient’s body surface area.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the course has a treatment period on weeks 1 , 2, and 3 and a rest period on week 4.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the course has a treatment period on weeks 1, 2, and 3 and a rest period on week 4, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, and pineal tumor.
  • the disclosure provides a method of treating brain cancer in
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, and wherein the DIPG is non-progressed DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, and wherein the DIPG is progressed or recurrent DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the patient in need exhibits mutations in one or more genes selected from the group consisting of H9K27M, H3F3A, HIST1H3B, HIST1 H3C, TP53, ACVR1 , PDGFRA, PPM1 D, PIK3CA, PIK3R1 , MYC, MYCN, and PPM1D.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, comprising administering comprising administering a dose of about 5 mg/m 2 /day to about 36 mg/m 2 /day of panobinostat or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, comprising administering a dose based on the patient in need’s body surface area (BSA).
  • BSA body surface area
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median overall survival for a patient treated with a standard protocol for DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
  • the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient exhibits a partial response.
  • Figs. 1 A -11 show the in vivo and in vitro efficacy of panobinostat.
  • Fig. 1 A shows a decrease in DIPG cell proliferation upon treatment with panobinostat.
  • Fig. 1B shows tumor cell death in tumor cells treated with panobinostat.
  • Fig. 1C shows normalization of histone 3 K27 methylation in H3.3K27M mutant DIPG cells or293T cells expressing an H3.3K27M construct54.
  • Fig. 1D shows a cartoon of an orthotopic model of DIPG.
  • Fig. 1 E shows a tumor on a mouse brain after treatment with panobinostat.
  • Fig. 1 A shows a decrease in DIPG cell proliferation upon treatment with panobinostat.
  • Fig. 1B shows tumor cell death in tumor cells treated with panobinostat.
  • Fig. 1C shows normalization of histone 3 K27 methylation in H3.3K27M mutant DIPG cells or293T cells expressing an H3.3K27M
  • FIG. 1 F shows in vivo bioluminescent images of mice treated with panobinostat (T) and not treated with panobinostat (C).
  • Fig. 1G shows the effect of panobinostat on tumor xenograft growth.
  • Fig. 1 F shows in vivo bioluminescent images of mice treated with panobinostat (T) and not treated with panobinostat (C).
  • Fig. 1G shows the effect of panobinostat on tumor xenograft growth.
  • treat or “treating” means one or more of relieving, alleviating, delaying, reducing, reversing, improving, or managing at least one symptom of a condition in a subject.
  • the term “treating” may also mean one or more of arresting, delaying the onset (i.e. , the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
  • a “maintenance therapy” is treatment administered to prevent cancer after it has disappeared following the initial therapy.
  • TIW administration refers to administration three times per week.
  • the term “maximum tolerated dose” refers to the highest dose of a drug (e.g. a HDAC inhibitor) that does not cause unacceptable side effects.
  • the MTD also displays efficacy (e.g., as described herein, including but not limited to, improving survival, decreasing tumor size, etc.).
  • the HDAC inhibitor is administered at the MTD.
  • the compounds of the present disclosure include alkyl substituents, which include straight and branched-C 1 -C 6 alkyl, unless otherwise noted.
  • alkyl substituents include straight and branched-C 1 -C 6 alkyl, unless otherwise noted.
  • suitable straight- and branched-C 1 -C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl and the like.
  • the alkyl substituents include both unsubstituted alkyl groups and alkyl groups that are substituted by one or more suitable substituents, including unsaturation, i.e.
  • cycloalkyl substituents include C 6 -C 9 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified.
  • cycloalkyl substituents include both unsubstituted cycloalkyl groups and cycloalkyl groups that are substituted by one or more suitable substituents, including C 1 -C 6 alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR 1 s, such as alkoxy.
  • alkyl and cycloalkyl substituents also applies to the alkyl portions of other substituents, such as, without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.
  • the rings are unsubstituted or substituted on the carbon atoms by one or more suitable substituents, including C1-C6alkyl; C4- C9cycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; halo; amino; alkyl amino and OR15, e.g., alkoxy.
  • suitable substituents including C1-C6alkyl; C4- C9cycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; halo; amino; alkyl amino and OR15, e.g., alkoxy.
  • nitrogen heteroatoms are unsubstituted or substituted by H, C1-C4alkyl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; acyl; aminoacyl; alkylsulfonyl; and arylsulfonyl.
  • arylalkyl e.g., benzyl
  • heteroarylalkyl e.g., pyridylmethyl
  • acyl aminoacyl
  • alkylsulfonyl alkylsulfonyl
  • arylsulfonyl arylsulfonyl
  • Suitable alkylcycloalkyl substituents include cyclopentyl methyl, cyclopentylethyl, cyclohexyl methyl and the like. Such substituents are unsubstituted or substituted in the alkyl portion or in the cycloalkyl portion by a suitable substituent, including those listed above for alkyl and cycloalkyl.
  • Aryl substituents include unsubstituted phenyl and phenyl substituted by one or more suitable substituents including C 1 -C 6 alkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; 0(C0)alkyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; aminosulfonyl; arylsulfonyl and OR15, such as alkoxy.
  • Aromatic polycycles include naphthyl, and naphthyl substituted by one or more suitable substituents including C-Calkyl; alkylcycloalkyl, e.g., cyclopropylmethyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkylketones; nitrile; carboxyalkyl; alkylsulfonyl: arylsulfonyl; aminosulfonyl and OR15, such as alkoxy.
  • suitable substituents including C-Calkyl; alkylcycloalkyl, e.g., cyclopropylmethyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkylketones; nitrile; carboxyalkyl; alkylsulfonyl: arylsulfonyl; aminosulfonyl and OR15, such as alk
  • Heteroaryl substituents include compounds with a 5- to 7-membered aromatic ring containing one or more heteroatoms, e.g., from 1-4 heteroatoms, selected from N, O and S.
  • Typical heteroaryl substituents include furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine and the like.
  • heteroaryl substituents are unsubstituted or substituted on a carbon atom by one or more suitable substituents, including alkyl, the alkyl substituents identified above, and another heteroaryl substituent.
  • Nitrogen atoms are unsubstituted or substituted, e.g., by R13; e.g., useful N substituents include H, C 1 - C4alkyl, acyl, aminoacyl and sulfonyl.
  • Arylalkyl substituents include groups of the formula — (CH 2 )ns-aryl, — (CH 2 )ns- 1 — (CH-aryl)-(CH 2 )n5-aryl or — (CH 2 )n5-iCH(aryl)(aryl), wherein aryl and n5 are defined above.
  • Such arylalkyl substituents include benzyl, 2-phenylethyl, 1-phenylethyl, tolyl- 3-propyl, 2-phenylpropyl, diphenylmethyl, 2-diphenylethyl, 5,5-dimethyl-3- phenylpentyl and the like.
  • Arylalkyl substituents are unsubstituted or substituted in the alkyl moiety or the aryl moiety or both as described above for alkyl and aryl substituents.
  • Heteroarylalkyl substituents include groups of the formula — (CH 2 )ns-heteroaryl, wherein heteroaryl and n5 are defined above and the bridging group is linked to a carbon or a nitrogen of the heteroaryl portion, such as 2-, 3- or 4-pyridylmethyl, imidazolylmethyl, quinolylethyl and pyrrolylbutyl. Heteroaryl substituents are unsubstituted or substituted as discussed above for heteroaryl and alkyl substituents.
  • Amino acyl substituents include groups of the formula — C(O) — (CH 2 )n — C(H)(NRI 3 RI4) — (CH 2 )n — R5, wherein n, R13, R and Rs are described above.
  • Suitable aminoacyl substituents include natural and non-natural amino acids, such as glycinyl, D-tryptophanyl, L-lysinyl, D- or L-homoserinyl, 4-aminobutryic acyl and ⁇ -3-amin-4- hexenoyl.
  • Non-aromatic polycycle substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered and each ring can contain zero, one or more double and/or triple bonds.
  • Suitable examples of non-aromatic polycycles include decalin, octahydroindene, perhydrobenzocycloheptene and perhydrobenzo[f]- azulene.
  • Such substituents are unsubstituted or substituted as described above for cycloalkyl groups.
  • Mixed aryl and non-aryl polycycle substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered and at least one ring is aromatic.
  • Suitable examples of mixed aryl and non-aryl polycycles include methylenedioxyphenyl, bis-methylenedioxyphenyl, 1 ,2,3,4-tetrahydronaphthalene, dibenzosuberane, dihdydroanthracene and 9H-fluorene.
  • substituents are unsubstituted or substituted by nitro or as described above for cycloalkyl groups.
  • Polyheteroaryl substituents include bicyclic and tricyclic fused ring systems where each ring can independently be 5- or 6-membered and contain one or more heteroatom, e.g., 1 , 2, 3 or 4 heteroatoms, chosen from O, N or S such that the fused ring system is aromatic.
  • Suitable examples of polyheteroaryl ring systems include quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline and the like.
  • Nitrogen atoms are unsubstituted or substituted, e.g., by
  • R 1 e.g., useful N substituents include H, acyl, aminoacyl and sulfonyl.
  • Non-aromatic polyheterocyclic substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered, contain one or more heteroatom, e.g., 1, 2, 3 or 4 heteroatoms, chosen from O, N or S and contain zero or one or more C — C double or triple bonds.
  • non-aromatic polyheterocycles include hexitol, cis-perhydro-cyclohepta[b]pyridinyl, decahydro- benzo[f][1 ,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octane, hexahydro-thieno[3,2- b]thiophene, perhydropyrrolo[3,2-b]pyrrole, perhydronaphthyridine, perhydro-1H- dicyclopenta[b,e]pyran.
  • non-aromatic polyheterocyclic substituents are unsubstituted or substituted on a carbon atom by one or more substituents, including alkyl and the alkyl substituents identified above.
  • Nitrogen atoms are unsubstituted or substituted, e.g., by R13, e.g., useful N substituents include H, C 1 - C4alkyl, acyl, aminoacyl and sulfonyl.
  • Mixed aryl and non-aryl polyheterocycles substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered, contain one or more heteroatom chosen from O, N or S, and at least one of the rings must be aromatic.
  • Suitable examples of mixed aryl and non-aryl polyheterocycles include 2,3- dihydroindole, 1 ,2,3,4-tetrahydroquinoline, 5,11 -dihydro-10H- dibenz[b,e][1 ,4]diazepine, 5H-dibenzo[b,e][1 ,4]diazepine, 1 ,2-dihydropyrrolo[3,4- b][1 ,5]benzodiazepine, 1 ,5-dihydro-pyrido[2,3-b][1 ,4]diazepin-4-one, 1 ,2, 3, 4, 6, 11- hexahydro-benzo[b]pyrido[2,3-e][1 ,4]diazepin-5-one.
  • Nitrogen atoms are unsubstituted or substituted, e.g., by R13; e.g., useful N substituents include H, C 1 -C4alkyl, acyl, aminoacyl and sulfonyl.
  • amino substituents include primary, secondary and tertiary amines and in salt form, quaternary amines.
  • amino substituents include mono- and di- alkylamino, mono- and di-aryl amino, mono- and di-arylalkyl amino, aryl- arylalkylamino, alkyl-arylamino, alkyl-arylalkylamino and the like.
  • Sulfonyl substituents include alkylsulfonyl and arylsulfonyl, e.g., methane sulfonyl, benzene sulfonyl, tosyl and the like.
  • Acyl substituents include groups of formula — C(O) — W, — OC(O) — W, — C(O) — O — Wor — C(O)NR 13 R 14 , where W is R16, H or cycloalkylalkyl.
  • Acylamino substituents include substituents of the formula — N(R 12 )C(O) — W, — N(RI 2 )C(O)— O— W and — N(R 12 )C(O) — NHOH and R12 and W are defined above.
  • the BBB is a highly selective semipermeable border that separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS).
  • the BBB protects the brain against pathogens (e.g., viruses) and other dangers of the circulatory system, including changes in the composition of the systemic blood supply (e.g., electrolyte levels).
  • the barrier is not complete, however, and permits entry of certain substances, such as small fat-soluble (lipophilic) molecules that can freely diffuse through the barrier.
  • the BBB also permits entry of essential nutrients, such as glucose and amino acids, which are vital to brain function. These nutrients are generally water soluble (hydrophilic), and require more complex mechanisms for crossing the BBB, such as carrier-mediated transport, receptor- mediated transcytosis and absorptive-mediated transcytosis.
  • the BBB While protective under normal circumstances, the BBB frustrates delivery of therapeutic agents to the brain. It has been reported that the BBB blocks delivery of more than 98% of central nervous system (CNS) therapeutic agents.
  • CNS central nervous system
  • panobinostat ability to penetrate the BBB. While efficacy in brain cancers suggests that panobinostat cross the BBB, Applicant’s studies described herein indicate limited penetration of cerebrospinal fluid (CSF), which is a surrogate of CNS tissue penetration and consequently BBB penetration (see, e.g., Example 7). In some embodiments, the methods of the present disclosure are utilized to treat brain cancers.
  • CSF cerebrospinal fluid
  • Non-limiting examples of brain cancers include acoustic neuromas, astrocytomas, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, diffuse pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, and pineal tumors.
  • the methods of the disclosure are used to treat gliomas.
  • Gliomas are tumors that occur in the brain and/or spinal cord.
  • Ependymomas, astrocytomas, and oligodendrogliomas are the three types of gliomas.
  • Glioblastoma, astrocytoma, and anaplastic astrocytoma are examples of astrocytomas.
  • Oligodendroglioma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma are examples of oligodendrogliomas.
  • Anaplastic ependymoma, myxopapillary ependymoma, and subependymoma are examples of ependymomas.
  • Gliomas are diagnosed by biopsy, computed tomography (CT) scan, or magnetic resonance imaging (MRI).
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the methods of the disclosure are used to treat patients with high grade glioma as determined by World Health Organization (WHO) criteria.
  • WHO World Health Organization
  • DIPG Diffuse intrinsic pontine gliomas
  • MRI magnetic resonance imaging
  • the methods of the present disclosure are used to treat patients with pontine lesions that do not exhibit the criteria for radiographically typical DIPG, but have histologic confirmation of malignant glioma as determined by WHO II- IV criteria.
  • DIPG is the leading cause of brain tumor death in children.
  • the median overall survival (OS) is between 8 and 12 months, and an OS of less than 1% at 5 years from diagnosis. Due to the location of the tumor on the brain stem and the tumors infiltrative nature, surgery is not considered as a treatment option.
  • radiation is the only treatment for DIPG with proven efficacy, albeit limited.
  • Current radiotherapy is typically provided over six weeks, and results in limited progression- free survival (PFS) or OS measured in months.
  • PFS progression- free survival
  • alkylating agents e.g. cisplatin, temozolomide, carboplatin
  • DIPG blood-brain barrier
  • HD AC Histone deacetylase
  • histone deacetylase (HDAC) inhibitors are administered to treat brain cancer.
  • HDAC inhibitors are a class of compounds that inhibit the activity of histone deacetylase enzymes. HDAC inhibition leads to an increase in acetylation of lysine residues on histone proteins as well as other nonhistone proteins.
  • a histone deacetylase inhibitor is administered for the treatment of brain cancer.
  • a histone deacetylase inhibitor is administered for the treatment of brain cancer, such as glioma, high grade glioma, or DIPG.
  • the histone deacetylase inhibitor has the following structure: wherein
  • R 1 is H; halo; or a straight-chain C 1 -C 6 alkyl, e.g., methyl, ethyl or n-propyl, in which methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described herein for alkyl substituents;
  • R 3 and R 4 are the same or different and, independently, H, C 1 -C 6 alkyl, acyl or acylamino, or
  • R 2 together with the nitrogen to which it is bound
  • R 3 together with the carbon to which it is bound, can form a C 4 -C 9 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a nonaromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;
  • R 5 is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; acyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; aromatic polycycles; non-aromatic polycycles; mixed aryl and non-aryl polycycles; polyheteroaryl; non-aromatic polyheterocycles; and mixed aryl and non-aryl polyheterocycles; n, n 1 , n 2 and n 3 are the same or different and independently selected from 0-6, when ni is 1-6, each carbon atom can be optionally and independently substituted with
  • X and Y are the same or different and independently selected from H; halo; Ci- C 4 alkyl, such as CH 3 and CF 3 ; NO 2 ; C(O)R 1 ; OR 9 ; SR 9 ; CN; and NR 10 R 11 ;
  • R 6 is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl and 2- phenylethenyl; heteroarylalkyl, e.g., pyridylmethyl; OR 12 ; and NR 13 R 14 ;
  • R 1 is selected from OR15, SR15, S(O)R 1 6. SO2R17, NR13R14 and NR12SO2R6;
  • Rs is selected from H; OR 15 ; NR 13 R 14 ; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 - C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl; R 9 is selected from C 1 - C 4 alkyl, e.g., CH3 and CF3; C(O)-alkyl, e.g., C(O)CH 3 ; and C(O)CF 3 ;
  • R 10 and R 11 are the same or different and independently selected from H, C 1 - C 4 alkyl and -C(O)-alkyl;
  • R 12 is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; C 4 - C 9 heterocycloalkylalkyl; aryl; mixed aryl and non-aryl polycycle; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl;
  • R 13 and R 14 are the same or different and independently selected from H; C 1 - C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; amino acyl, or
  • R 13 and R 14 together with the nitrogen to which they are bound, are C 4 - C 9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle, or mixed aryl and non-aryl polyheterocycle;
  • R 15 is selected from H, C 1 -C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 )mZR 12 ;
  • R 16 is selected from Ci-C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH 2 )mZR 12 ;
  • R 17 is selected from Ci-C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14; m is an integer selected from 0-6; and
  • Z is selected from O, NR 1 , S and S(O).
  • HDAC inhibitors that may be used with the methods disclosed herein may be found in U.S. Pat. No. 6,833,384, which is herein incorporated by reference in its entirety.
  • the compound of formula I is panobinostat.
  • the structure of panobinostat is:
  • Panobinostat is a small molecule chemotherapeutic, currently approved for the treatment of multiple myeloma and sold under the name FARYDAK ® .
  • the chemical name of panobinostat is 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3- yl)ethyl]amino]methyl]phenyl]-2-propenamide.
  • Panobinostat is a potent class I/ll pan- deacetylase inhibitor (DACi) that increases histone acetylation in peripheral blood leukocytes and bone marrow biopsies at low doses.
  • Panobinostat enhances histone acetylation by potently inhibiting deacetylase enzymes involved in reducing the overall acetylation levels.
  • brain cancer patients are treated with panobinostat.
  • DIPG patients are treated with an HDAC inhibitor (e.g. panobinostat).
  • patients with recurrent DIPG are administered an HDAC inhibitor (e.g. panobinostat).
  • patients with non- progressed DIPG are administered an HDAC inhibitor (e.g. panobinostat).
  • patients with progressive DIPG are administered an HDAC inhibitor (e.g. panobinostat).
  • an HDAC inhibitor e.g. panobinostat
  • an HDAC inhibitor e.g. panobinostat
  • an HDAC inhibitor is administered to a DIPG patient at the same time of radiation therapy administration.
  • an HDAC inhibitor is administered to a DIPG patient after the patient has received radiation therapy.
  • an HDAC inhibitor e.g. panobinostat
  • Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts and amino acid addition salts and sulfonate salts.
  • Acid addition salts include inorganic acid addition salts, such as hydrochloride, sulfate and phosphate; and organic acid addition salts, such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate.
  • metal salts are alkali metal salts, such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts, such as magnesium salt and calcium salt, aluminum salt and zinc salt.
  • ammonium salts are ammonium salt and tetramethylammonium salt.
  • organic amine addition salts are salts with morpholine and piperidine.
  • amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine.
  • Sulfonate salts include mesylate, tosylate and benzene sulfonic acid salts.
  • the salt of an HDAC inhibitor e.g. panobinostat
  • the lactate salt e.g. the anhydrous lactate form, described in WO2007/146715, which is herein incorporated by reference in its entirety.
  • an HDAC inhibitor e.g. panobinostat
  • a lactate salt e.g. panobinostat lactate.
  • panobinostat lactate The structure of panobinostat lactate is:
  • panobinostat lactate is C 21 H 23 N 3 O 2 * C 3 H 6 O 3 .
  • an HDAC inhibitor e.g. panobinostat
  • a monohydrate e.g. panobinostat is administered as panobinostat monohydrate.
  • the chemical formula of panobinostat monohydrate is C 21 H 23 N 3 O 2* H 2 O.
  • an HDAC inhibitor e.g. panobinostat
  • a polymorph In some embodiments, the polymorph is an anhydrous lactate salt. Polymorphs of panobinostat are described in US 7,989,494, which is herein incorporated by reference in its entirety. As used herein, panobinostat refers to the free base, any pharmaceutically acceptable salt, or polymorphic form of panobinostat.
  • the HDAC inhibitor may be administered by any suitable method.
  • the HDAC inhibitor e.g., panobinostat
  • parenteral includes subcutaneous, intravenous, intramuscular, intrathecal, intraventricular, and intraarterial injections with a variety of infusion techniques.
  • Intraarterial, intrathecal, intraventricular, and intravenous injection as used herein includes administration through catheters.
  • catheters can be used to facilitate injection of the HDAC inhibitor (e.g., panobinostat) into the spinal canal, or into the subarachnoid space.
  • HDAC inhibitors may be administered in any suitable formulation.
  • suitable formulations include solid oral formulations, such as tablets and gel capsules.
  • panobinostat may be administered in gelatin capsules containing 5, 10, 15, or 20 mg of panobinostat by weight of free base and the following inactive ingredients: magnesium stearate, mannitol, microcrystalline cellulose and pregelatinized starch.
  • the capsules may contain gelatin, FD & C Blue 1 (10 mg capsules), yellow iron oxide (10 mg and 15 mg capsules), red iron oxide (15 mg and 20 mg capsules) and titanium dioxide.
  • panobinostat is administered at the current FDA approved dose as of the filing date of the present application.
  • Panobinostat has been approved at doses of 10 mg, 15 mg, and 20 mg for the treatment of multiple myeloma.
  • a HDAC inhibitor e.g. panobinostat
  • a dose ranging from about 10 mg to about 100 mg, including about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 g, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor is administered at a dose ranging from about 25 mg to about 60 mg.
  • panobinostat is administered at a dose of about 25 mg.
  • panobinostat is administered at a dose of about 30 mg.
  • panobinostat is administered at a dose of about 35 mg.
  • panobinostat is administered at a dose of about 40 mg.
  • panobinostat is administered at a dose of about 45 mg.
  • panobinostat is administered at a dose of about 50 mg.
  • panobinostat is administered at a dose of about 55 mg.
  • a patient is administered a HDAC inhibitor (e.g. panobinostat) or any other therapeutic agent based on the patient’s body surface area (BSA).
  • a patient’s body surface area is calculated according to the following
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor is administered at a dose from about 1 mg/m 2 /day to about 40 mg/m 2 /day.
  • a HDAC inhibitor e.g.
  • panobinostat is administered at about 1 mg/m 2 /day, about 2 mg/m 2 /day, about 3 mg/m 2 /day, about 4 mg/m 2 /day, about 5 mg/m 2 /day, about 6 mg/m 2 /day, about 7 mg/m 2 /day, about 8 mg/m 2 /day, about 9 mg/m 2 /day, about 10 mg/m 2 /day, about 11 mg/m 2 /day, about 12 mg/m 2 /day, about 13 mg/m 2 /day, about 14 mg/m 2 /day, about 15 mg/m 2 /day, about 16 mg/m 2 /day, about 17 mg/m 2 /day, about 18 mg/m 2 /day, about 19 mg/m 2 /day, about 20 mg/m 2 /day, about 21 mg/m 2 /day, about 22 mg/m 2 /day, about 23 mg/m2/day, about 24 mg/m 2 /day, about 25 mg/m 2 /
  • a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 5 mg/m 2 /day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 10 mg/m 2 /day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 16 mg/m 2 /day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 22 mg/m 2 /day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 28 mg/m 2 /day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 36 mg/m 2 /day.
  • patients with a BSA ⁇ 0.80 m 2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 5 mg/m 2 /day.
  • patients with a BSA ⁇ 0.65 m 2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 10 mg/m 2 /day.
  • patients with a BSA ⁇ 0.65 m 2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 16 mg/m 2 /day.
  • patients with a BSA ⁇ 0.65 m 2 are administered a HDAC inhibitor (e.g.
  • panobinostat at a dose of 22 mg/m 2 /day.
  • patients with a BSA ⁇ 0.50 m 2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 28 mg/m 2 /day.
  • patients that are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 36 mg/m 2 /day exhibit a BSA ⁇ 0.50 m 2 .
  • patients are administered a HDAC inhibitor (e.g. panobinostat) at the MTD.
  • the MTD is 28 mg/m 2 /day. In some embodiments, the MTD is 10 mg/m 2 /day. In some embodiments, the MTD is 5 mg/m 2 /day. In some embodiments, the MTD is 16 mg/m 2 /day. In some embodiments, the MTD is 22 mg/m 2 /day. In some embodiments, the MTD is 36 mg/m 2 /day.
  • the dose of panobinostat is increased relative to the approved dose (referred to herein as an “increased dose” or “higher dose”).
  • approved dose refers to the dose that a particular patient would receive for multiple myeloma based on the FDA approved label as of the filing date of this application.
  • the approved dose for treating multiple myeloma is 20 mg.
  • the approved dose for patients with mild hepatic impairment is 15 mg panobinostat, whereas the approved dose for patients with moderate hepatic impairment is 10 mg panobinostat.
  • the approved dose for patients currently receiving treatment with i.e.
  • a strong CYP3A inhibitor e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir
  • a strong CYP3A inhibitor e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir
  • the increased dose is about 5 % higher, about 6 % higher, about 7 % higher, about 8 % higher, about 9 % higher, about 10 % higher, about 11 % higher, about 12 % higher, about 13 % higher, about 14 % higher, about 15 % higher, about 16 % higher, about 17 % higher, about 18 % higher, about 19 % higher, about 20 % higher, about 21 % higher, about 22 % higher, about 23 % higher, about 24 % higher, about 25 % higher, about 26 % higher, about 27 % higher, about 28 % higher, about 29 % higher, about 30 % higher, about 31 % higher, about 32 % higher, about 33 % higher, about 34 % higher, about 35 % higher, about 36 % higher, about 37 % higher, about 38 % higher, about 39 % higher, about 40 % higher, about 41 % higher, about 42 % higher, about 43 % higher, about 44 % higher, about 45 % higher, about 40 %
  • the increased dose of panobinostat ranges from 25-60 mg. In embodiments, the increased dose of panobinostat is 25 mg. In embodiments, the increased dose of panobinostat is 30 mg. In embodiments, the increased dose of panobinostat is 35 mg. In embodiments, the increased dose of panobinostat is 40 mg. In embodiments, the increased dose of panobinostat is 45 mg. In embodiments, the increased dose of panobinostat is 50 mg. In embodiments, the increased dose of panobinostat is 55 mg. In embodiments, the increased dose of panobinostat is 60 mg. In embodiments, the increased dose of panobinostat is 55 mg.
  • the increased dose of panobinostat is 60 mg. In embodiments, the increased dose of panobinostat is 65 mg. In embodiments, the increased dose of panobinostat is 70 mg. In embodiments, the increased dose of panobinostat is 75 mg. In embodiments, the increased dose of panobinostat is 80 mg.
  • the patient is administered an initial dose and then the dose of a HDAC inhibitor (e.g. panobinostat) is increased.
  • the dose is increased in an increment of about 1 mg to about 40 mg, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, or about 40 mg, inclusive of all values and ranges in between.
  • a HDAC inhibitor e.g. panobinostat
  • the dose is increased in an increment of about 1 mg/m 2 /day to about 50 mg/m 2 /day. In some embodiments, the dose is increased in an increment of about 1 mg/m 2 /day, about 2 mg/m 2 /day, about 3 mg/m 2 /day, about 4 mg/m 2 /day, about 5 mg/m 2 /day, about 6 mg/m 2 /day, about 7 mg/m 2 /day, about 8 mg/m 2 /day, about 9 mg/m 2 /day, about 10 mg/m 2 /day, about 11 mg/m 2 /day, about 12 mg/m 2 /day, about 13 mg/m 2 /day, about 14 mg/m 2 /day, about 15 mg/m 2 /day, about 16 mg/m 2 /day, about 17 mg/m 2 /day, about 18 mg/m 2 /day, about 19 mg/m 2 /day, about 20 mg/m 2 /day, about 21 mg/m 2 /day.
  • the dose of HDAC inhibitor is increased in an increment of about 5 mg/m 2 /day. In some embodiments, the dose of HDAC inhibitor (e.g. panobinostat) is increased in an increment of about 6 mg/m 2 /day. In some embodiments, the dose of HDAC inhibitor (e.g. panobinostat) is increased in an increment of about 8 mg/m 2 /day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 5 mg/m 2 /day to 10 mg/m 2 /day. In some embodiments, HDAC inhibitor (e.g.
  • panobinostat is increased from 10 mg/m 2 /day to 16 mg/m 2 /day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 16 mg/m 2 /day to 22 mg/m 2 /day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 22 mg/m 2 /day to 28 mg/m 2 /day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 28 mg/m 2 /day to 36 mg/m 2 /day.
  • the dose increase occurs 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days,
  • Panobinostat pharmacokinetics are linear in the dose range of 10 to 80 mg. Panobinostat pharmacokinetics are also linear in the dose range of 4.8 mg/m 2 to 14 mg/m 2 .
  • the product information for panobinostat describes the pharmacokinetics of panobinostat and is incorporated by reference herein in its entirety: Product information Farydak - Panobinostat lactate - Novartis Pharmaceuticals Australia Pty Ltd - PM-2014-03146-1 -4 - FINAL - 22 October 2018.Therefore, the skilled artisan can determine the pharmacokinetic parameters of panobinostat doses between 10 mg and 80 mg based on known values of 10 mg, 20 mg, and 30 mg, as described herein.
  • dose versus a known pharmacokinetic parameter such as Cmax, tmax, AUC ⁇ , or AUCo-24
  • the patient after administering between about 10 mg and about 100 mg (e.g., 10, 15, 20, 25 ,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg) of panobinostat, the patient has a maximum observed plasma drug concentration (C max ) between 5 ng/mL and 200 ng/mL.
  • C max maximum observed plasma drug concentration
  • the C max is about 5 ng/mL, about 6 ng/mL, about ng/mL 7 ng/mL, about 8 ng/mL, about 9 ng/mL, about 10 ng/mL, about 11 ng/mL, about 12 ng/mL, about 13 ng/mL, about 14 ng/mL, about 15 ng/mL, about 16 ng/mL, about 17 ng/mL, about 18 ng/mL, about 19 ng/mL, about 20 ng/mL, about 21 ng/mL, about 22 ng/mL, about 23 ng/mL, about 24 ng/mL, about 25 ng/mL, about 26 ng/mL, about 27 ng/mL, about 28 ng/mL, about 29 ng/mL, about 30 ng/mL, about 31 ng/mL, about 32 ng/mL, about 33 ng/mL, about 34 ng/mL, about 10 ng/
  • 96 ng/mL about 97 ng/mL, about 98 ng/mL, about 99 ng/mL, about 100 ng/mL, about 101 ng/mL, about 102 ng/mL, about 103 ng/mL, about 104 ng/mL, about 105 ng/mL, about 106 ng/mL, about 107 ng/mL, about 108 ng/mL, about 109 ng/mL, about 110 ng/mL, about 111 ng/mL, about 112 ng/mL, about 113 ng/mL, about 114 ng/mL, about 115 ng/mL, about 116 ng/mL, about 117 ng/mL, about 118 ng/mL, about 119 ng/mL, about 120 ng/mL, about 121 ng/mL, about 122 ng/mL, about 123 ng/mL, about 124 ng/mL,
  • the C max is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values.
  • the C max is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values.
  • after administering between about 10 mg and about 100 mg e.g., 10, 15, 20, 25 ,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg
  • the patient after administering between about 10 mg and about 100 mg (e.g., 10, 15, 20, 25 ,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg) or between about 5 mg/m 2 /day and about 36 mg/m 2 /day (e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, and 36 mg/m 2
  • the C max is reported as geometric mean (% CV).
  • the patient has a C max ranging from 80 % to about 125 % of 12.7 ng/mL (191 %) after administration of 10 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient has a C max ranging from 80 % to about 125 % of 12.6 ng/mL (46 %) after administration of 15 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient has a C max ranging from 80 % to about 125 % of 21.6 ng/mL (83 %) after administration of 20 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a C max ranging from 80 % to about 125 % of 25.3 ng/mL (97 %) after administration of 30 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a C max ranging from 80 % to about 125 % of 28.4 ng/mL (120 %) after administration of 40 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient has a C max ranging from 80 % to about 125 % of 43.4 ng/mL (74 %) after administration of 60 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a C max ranging from 80 % to about 125 % of 66.1 ng/mL (38 %) after administration of 80 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient after administering between about 3 mg/m 2 and about 36 mg/m 2 (e.g., 3, 4, 4.8, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or 5-36 mg/m 2 ) of panobinostat, the patient has a maximum observed plasma drug concentration (C max ) between 5 ng/mL and 200 ng/mL.
  • C max maximum observed plasma drug concentration
  • the C max is about 5 ng/mL, about 6 ng/mL, about ng/mL 7 ng/mL, about 8 ng/mL, about 9 ng/mL, about 10 ng/mL, about 11 ng/mL, about 12 ng/mL, about 13 ng/mL, about 14 ng/mL, about 15 ng/mL, about 16 ng/mL, about 17 ng/mL, about 18 ng/mL, about 19 ng/mL, about 20 ng/mL, about 21 ng/mL, about 22 ng/mL, about 23 ng/mL, about 24 ng/mL, about 25 ng/mL, about 26 ng/mL, about 27 ng/mL, about 28 ng/mL, about 29 ng/mL, about 30 ng/mL, about 31 ng/mL, about 32 ng/mL, about 33 ng/mL, about 34 ng/mL, about 10 ng/
  • ng/mL about 92 ng/mL, about 93 ng/mL, about 94 ng/mL, about 95, about 96 ng/mL, about 97 ng/mL, about 98 ng/mL, about 99 ng/mL, about 100 ng/mL, about 101 ng/mL, about 102 ng/mL, about 103 ng/mL, about 104 ng/mL, about 105 ng/mL, about 106 ng/mL, about 107 ng/mL, about 108 ng/mL, about 109 ng/mL, about 110 ng/mL, about 111 ng/mL, about 112 ng/mL, about 113 ng/mL, about 114 ng/mL, about 115 ng/mL, about 116 ng/mL, about 117 ng/mL, about 118 ng/mL, about 119 ng/mL, about 120 ng/
  • the C max is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values.
  • the patient after administering between about 5 mg/m 2 and about 36 mg/m 2 (e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, or 36 mg/m 2 ) of panobinostat, the patient has a C max of 20 ng/mL.
  • the patient after administering between about 4.8 mg/m 2 and about 14 mg/m 2 (e.g., 4.8, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 mg/m 2 ) of panobinostat, the patient has a C max Of 20 ng/mL.
  • about 4.8 mg/m 2 and about 14 mg/m 2 e.g., 4.8, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 mg/m 2
  • the patient after administering between about 4.8 mg/m 2 and about 14 mg/m 2 (e.g., 4.8, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 mg/m 2 ) of panobinostat, the patient has a C max Of 20 ng/mL.
  • the patient after administering between about 10 mg and about 100 mg of panobinostat, the patient has a time to reach C max (t max ) between 0.1 hours and 2 hours.
  • the t max is about 0.1 hours, about 0.2 hours, about 0.3 hours, about 0.4 hours, about 0.5 hours, about 0.6 hours, about 0.7 hours, about 0.8 hours, about 0.9 hours, about 1.0 hours, about 1.1 hours, about 1.2 hours, about 1.3 hours, about 1.4 hours, about 1.5 hours, about 1.6 hours, about 1.7 hours, about 1.8 hours, about 1.9 hours, or about 2.0 hours.
  • the t max is between about 80 % and about 125 % of any of the aforementioned values or ranges between the aforementioned values.
  • the t max is reported as a median (range).
  • the patient has a t max ranging from 80 % to about 125 % of 1 hour (0.5 hours - 4.0 hours) after administration of 10 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient has a t max ranging from 80 % to about 125 % of 1.0 hours (0.4 hours - 2.0 hours) after administration of 15 mg of panobinosta (or an equivalent dose in terms of BSA)t.
  • the patient has a t max ranging from 80 % to about 125 % of 1.0 hours (0.5 hours - 8 hours) after administration of 20 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a t max ranging from 80 % to about 125 % of 2.0 hours (0.7 hours - 4 hours) after administration of 30 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a t max ranging from 80 % to about 125 % of 1.1 hours (0.5 hours - 4 hours) after administration of 40 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient has a t max ranging from 80 % to about 125 % of 1.1 hours (0.5 hours - 6 hours) after administration of 60 mg of panobinostat. In some embodiments, the patient has a t max ranging from 80 % to about 125 % of 1.5 hours (0.7 hours - 2 hours) after administration of 80 mg of panobinostat (or an equivalent dose in terms of BSA).
  • panobinostat e.g., 10, 15, 20, 25 ,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg
  • the patient has an area under the concentration time curve from zero hours to twenty four hours (AUC 0-24 ) between 25 ng*hr/ mL and 800 ng*hr/ mL.
  • AUC 0-24 is between about 134.9 ng*hr/ mL and about 372.9 ng*hr/ mL.
  • the AUC 0-24 is about 25 ng*hr/ mL, about 50 ng*hr/ mL, about 75 ng*hr/ mL, about 100 ng*hr/ mL, about 125 ng*hr/ mL, about 150 ng*hr/ mL, about 175 ng*hr/ mL, about 200 ng*hr/ mL, about 225 ng*hr/ mL, about 250 ng*hr/ mL, about 275 ng*hr/ mL, about 300 ng*hr/ mL, about 325 ng*hr/ mL, about 350 ng*hr/ mL, about 375 ng*hr/ mL, about 400 ng*hr/ mL, about 425 ng*hr/ mL, about 450 ng*hr/ mL, about 475 ng*hr/ mL, about 500 ng*hr/ m
  • the patient after administering between about 5 mg/m 2 and about 36 mg/m 2 of panobinostat (e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, or 36 mg/m 2 ), the patient has an area under the concentration time curve from zero hours to twenty four hours (AUCo-24) between 25 ng * hr/ mL and 800 ng * hr/ mL. In embodiments, the AUCo-24 is between about 134.9 ng*hr/ mL and about 372.9 ng*hr/ mL.
  • panobinostat e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, or 36 mg/m 2
  • the patient after administering between about 5 mg/m 2 and about 36 mg/m 2 of panobinostat (e.
  • the AUCo-24 is about 25 ng*hr/ mL, about 50 ng*hr/ mL, about 75 ng*hr/ mL, about 100 ng*hr/ mL, about 125 ng*hr/ mL, about 150 ng*hr/ mL, about 175 ng*hr/ mL, about 200 ng*hr/ mL, about 225 ng*hr/ mL, about 250 ng*hr/ mL, about 275 ng*hr/ mL, about 300 ng*hr/ mL, about 325 ng*hr/ mL, about 350 ng*hr/ mL, about 375 ng*hr/ mL, about 400 ng*hr/ mL, about 425 ng*hr/ mL, about 450 ng*hr/ mL, about 475 ng*hr/ mL, about 500 ng*hr/ mL
  • the AUCo-24 is between 80 % and 125 % of the aforementioned values.
  • the patient after administering between about 4.8 mg/m 2 and about 14 mg/m 2 of panobinostat (e.g., 4.8, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg/m 2 ), the patient has an area under the concentration time curve from zero hours to twenty four hours (AUCo- 24) between 25 ng*hr/ mL and 800 ng*hr/ mL.
  • panobinostat e.g., 4.8, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg/m 2
  • the patient after administering between about 4.8 mg/m 2 and about 14 mg/m 2 of panobinostat (e.g., 4.8, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg/m 2 ), the patient has an area under the concentration time curve from zero hours to twenty four hours (AUCo-24) between 134.9 ng*hr/ mL and 372.9 ng*hr/ mL.
  • the AUC 0-24 is reported as a geometric mean (% CV). In some embodiments, the patient has an AUC 0-24 ranging from 80 % to about 125 % of 77 ng*hr/ mL (75 %) after administration of 10 mg of panobinostat. In some embodiments, the patient has an AUC 0-24 ranging from 80 % to about 125 % of 91 ng*hr/ mL (36 %) after administration of 15 mg of panobinostat. In some embodiments, the patient has an AUC 0-24 ranging from 80 % to about 139 ng*hr/ mL (71 %) after administration of 20 mg of panobinostat.
  • the patient has an AUC 0-24 ranging from 80 % to about 125 % of 174 ng*hr/ mL (92 %) after administration of 30 mg of panobinostat. In some embodiments, the patient has an AUC 0-24 ranging from 80 % to about 125 % of 185 ng*hr/ mL (74 %) after administration of 40 mg of panobinostat. In some embodiments, the patient has an AUC 0-24 ranging from 80 % to about 125 % of 222 ng*hr/ mL (48 %) after administration of 60 mg of panobinostat. In some embodiments, the patient has an AUCo-24 ranging from 80 % to about 125 % of 274 ng*hr/ mL (70 %) after administration of 80 mg of panobinostat.
  • the patient after administering between about 10 mg and about 100 mg of panobinostat, the patient has an area under the concentration time curve from zero hours to infinity (AUC ⁇ ) between 25 ng*hr/ mL and 600 ng*hr/ mL.
  • the AUC ⁇ is about 25 ng*hr/ mL, about 50 ng*hr/ mL, about 75 ng*hr/ mL, about 100 ng*hr/ mL, about 125 ng*hr/ mL, about 150 ng*hr/ mL, about 175 ng*hr/ mL, about 200 ng*hr/ mL, about 225 ng*hr/ mL, about 250 ng*hr/ mL, about 275 ng*hr/ mL, about 300 ng*hr/ mL, about 325 ng*hr/ mL, about 350 ng*hr/ mL, about 375 ng*hr/ mL, about 400 ng*hr/ mL, about 425 ng*hr/ mL, about 450 ng*hr/ mL, about 475 ng*hr/ mL, about 500 ng*hr/
  • the AUC ⁇ is reported as a geometric mean (% CV).
  • the patient has an AUC ⁇ ranging from 80 % to about 125 % of 163 ng*hr/ mL (65 %) after administration of 10 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient has an AUC ⁇ ranging from 80 % to about 125 % of 158 ng*hr/ mL (46 %) after administration of 15 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient has an AUC ⁇ ranging from 80 % to about 125 % of 200 ng*hr/ mL (53 %) after administration of 20 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC ⁇ ranging from 80 % to about 125 % of 288 ng*hr/ mL (67 %) after administration of 30 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC ⁇ ranging from 80 % to about 125 % of 322 ng*hr/ mL (67 %) after administration of 40 mg of panobinostat (or an equivalent dose in terms of BSA).
  • the patient has an AUC ⁇ ranging from 80 % to about 125 % of 313 ng*hr/ mL (51 %) after administration of 60 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC ⁇ ranging from 80 % to about 125 % of 303 ng*hr/ mL (96 %) after administration of 80 mg of panobinostat (or an equivalent dose in terms of BSA).
  • a HDAC inhibitor e.g. panobinostat
  • a course comprises a treatment period and a rest period.
  • a HDAC inhibitor e.g., panobinostat
  • Additional therapeutic agents described herein may also be administered during the treatment period.
  • the rest period is a length of time that the patient does not receive treatment with an HDAC inhibitor (e.g., panobinostat).
  • no HDAC inhibitor e.g., panobinostat
  • the rest period enables the patient to recover from the treatment.
  • a HDAC inhibitor e.g. panobinostat
  • a regimen that has a course length of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days or more.
  • the regimen may be repeated for any number of courses to treat brain cancer, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more, as clinically necessary.
  • the course has a rest period.
  • no HDAC inhibitor e.g., panobinostat
  • other therapeutic agent is administered during the rest period.
  • no HDAC inhibitor e.g. panobinostat
  • another therapeutic agent may be administered.
  • the length of the rest period is about 1 day per course, about 2 days per course, about 3 days per course, about 4 days per course, about 5 days per course, about 6 days per course, about 7 days per course, about 8 days per course, about 9 days per course, about 10 days per course, about 11 days per course, about 12 days per course, about 13 days per course, about 14 days per course, about 15 days per course, about 16 days per course, about 17 days per course, about 18 days per course, about 19 days per course, about 20 days per course, about 21 days per course, or more as clinically necessary.
  • the rest period is one week or two weeks or three weeks or four weeks or more.
  • an HDAC inhibitor e.g. panobinostat
  • the length of the treatment period is about 1 day per course, about 2 days per course, about 3 days per course, about 4 days per course, about 5 days per course, about 6 days per course, about 7 days per course, about 8 days per course, about 9 days per course, about 10 days per course, about 11 days per course, about 12 days per course, about 13 days per course, about 14 days per course, about 15 days per course, about 16 days per course, about 17 days per course, about 18 days per course, about 19 days per course, about 20 days per course, about 21 days per course, 22 days per course, about 23 days per course, about 24 days per course, about 25 days per course, about 26 days per course, about 27 days per course, about 18 days per course, about 29 days per course, about 30 days per course, or about 31 days per course, or more.
  • the length of the treatment period is 7 days. In some embodiments, the length of the treatment period is 14 days. In some embodiments, the length of the treatment period is 21 days. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered every day. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered every other day. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered every third day. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered every fourth day. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered one time per week, two times per week, three times per week, four times per week, five times per week, six times per week, or seven times per week.
  • a course may contain more than one treatment period. In some embodiments, a course contains up to five treatment periods. In some embodiments, a course contains one, two, three, four, or five treatment periods. In some embodiments, a course contains one treatment period. In some embodiments, a course contains two treatment periods. In some embodiments, the treatment periods within the course has the same length. In some embodiments, the treatment periods within the course have different lengths.
  • the course contains more than one rest period. In some embodiments, a course contains up to five rest periods. In some embodiments, a course contains one, two, three, four, or five rest periods. In some embodiments, a course contains one rest period. In some embodiments, a course contains two rest periods. In some embodiments, the rest periods within the course has the same length. In some embodiments, the rest periods within the course have different lengths.
  • the HDAC inhibitor e.g., panobinostat
  • the HDAC inhibitor is administered to brain cancer patients according to the approved treatment regimen for panobinostat in multiple myeloma.
  • the currently approved course comprises a course length of 21 days.
  • Panobinostat is administered once every other day for three doses per week (on days 1, 3, 5, 8, 10, and 12) for eight courses.
  • Panobinostat is not administered on days 15-21.
  • Subjects with clinical benefit are administered an additional eight courses of panobinostat after an initial treatment regimen of eight courses unless the subject has unresolved severe or medically significant toxicity.
  • panobinostat is administered in combination with bortezomib and dexamethasone.
  • Bortezomib is administered at a dose of 1.3 mg/m 2 on days 1, 4, 8, and 11 as an injection for courses 1 , 2, 3, 4, 5, 6, 7, and 8, and is administered on days 1 and 8 of courses 9, 10, 11, 12, 13, 14, 15, and 16.
  • Dexamethasone is administered orally at a dose of 20 mg on a full stomach on days 1 , 2, 4, 5, 8, 9, 11, and 12 for courses 1 , 2, 3, 4, 5, 6, 7, and 8, and is administered on days 1 , 2, 8, and 9 for courses 9, 10, 11, 12, 13, 14, 15, and 16.
  • Table 1 and Table 2 illustrate the approved dosing regimen (for multiple myeloma) when panobinostat is administered in combination with Bortezomib and Dexamethasone
  • Table 1 Recommended Dosing Schedule of FARYDAK in combination with Bortezomib and Dexamethasone during courses 1 to 8.
  • the HDAC inhibitor (e.g., panobinostat) is administered in a 14 day course.
  • the HDAC inhibitor (e.g., panobinostat) may be administered at any appropriate frequency during the 14 day course.
  • the HDAC inhibitor (e.g., panobinostat) is administered one or more times during the first week (days 1-7) of the 14 day course.
  • the HDAC inhibitor (e.g., panobinostat) is not administered during the second week (days 8-14) of the 14 day course.
  • the HDAC inhibitor (e.g., panobinostat) is administered 1, 2, 3, 4, 5, 6, or 7 times during the first week (days 1-7) of the 14 day course.
  • the HDAC inhibitor e.g., panobinostat
  • panobinostat is administered three times a week for the first week, and zero times per week in the second week.
  • panobinostat may be administered to the patient on days 1 , 3, and 5 or on days 1 , 4, and 6.
  • the HDAC inhibitor e.g., panobinostat
  • panobinostat is administered in a 14 day course two times a week for the first week and zero times per week for the second week.
  • panobinostat is administered at days 1 and 4 or at days 1 and 5.
  • Panobinostat is not administered on days 8-14 of the course.
  • the HDAC inhibitor e.g., panobinostat
  • the HDAC inhibitor may be administered at any appropriate frequency during the 28 day course.
  • the HDAC inhibitor e.g., panobinostat
  • the HDAC inhibitor e.g., panobinostat
  • the HDAC inhibitor is administered three times a week for the first week (days 1-7), three times a week for the second week (days 8-14) and three times per week in the third week (days 15-21); the fourth week is a rest period.
  • panobinostat is administered on days 2, 4, 6, 9, 11, 14, 16, 18, and 20.
  • the HDAC inhibitor e.g., panobinostat
  • the HDAC inhibitor is administered one or more times the first week (days 1-7) of the 28 day course and one or more times during the third week (days 15-21).
  • panobinostat is administered three times a week for the first week (days 1-7) and three times per week in the third week (days 15-21); the second and fourth week are rest periods.
  • panobinostat is administered on days 2, 4, 6, 16, 18, and 20.
  • a patient is initially administered panobinostat, wherein panobinostat is administered three times a week for the first week (days 1-7), three times a week for the second week (days 8-14) and three times per week in the third week (days 15-21), and the fourth week is a rest period. Subsequently, the patient is administered panobinostat in a 28 day course, wherein panobinostat is administered three or more times on the first week and three or more times in the third week. In some embodiments, the patient initially has recurrent/progressive DIPG. Subsequently, the patient has non-progressed DIPG.
  • a HDAC inhibitor e.g. panobinostat
  • panobinostat is administered as a maintenance therapy.
  • panobinostat is administered one or more times the first week (days 1-7) of a 28 day course and one or more times during the third week (days 15-21).
  • panobinostat is administered three times a week for the first week (days 1-7) and three times per week in the third week (days 15-21); the second and fourth week are rest periods.
  • panobinostat is administered on days 2, 4, 6, 16, 18, and 20.
  • Panobinostat administration may result in adverse events, such as thrombocytopenia, diarrhea, cardiac toxicities, myelosuppression, hemorrhage, infections, hepatotoxicity, and embryo-fetal toxicity.
  • the most common panobinostat toxicities are diarrhea, nausea, vomiting, and myelosuppression, such as thrombocytopenia, neutropenia, and anemia.
  • thrombocytopenia is defined as low platelet count.
  • Neutropenia is defined as a low number of neutrophils in the blood.
  • Anemia is a condition in which there is a lack of healthy red blood cells to carry oxygen to the body’s tissues.
  • the methods of the present disclosure result in a reduction in the percentage of adverse events.
  • equal amounts of panobinostat are administered in the 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4, and in the 28 day course containing treatment periods in weeks 1, 2, and 3, and a rest period in week 4 - and there are less adverse events measured for a 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4.
  • a higher amount of panobinostat is administered on the 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4 compared to the 28 day course containing treatment periods in weeks 1, 2, and 3, and a rest period in week 4.
  • a lower amount of panobinostat is administered on the 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4 compared to the 28 day course containing treatment periods in weeks 1, 2, and 3, and a rest period in week 4.
  • the methods of the present disclosure result in a lower percentage of toxicities.
  • the methods of the present disclosure may result in a lower percentage of thrombocytopenia in brain cancer patients.
  • the methods of the present disclosure may result in a lower percentage of anemia in the patient populations of the present disclosure. In some embodiments, the methods of the present disclosure may result in a lower percentage of diarrhea and/or vomiting. In some embodiments, the methods of the present disclosure may result in a lower percentage of neutropenia. In some embodiments, the present methods reduce the incidence of such adverse events by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%, including all values and ranges therebetween.
  • the methods of the disclosure may reduce the incidence of adverse events that would otherwise be associated with the higher doses described herein.
  • the reduction in adverse events may be achieved with higher doses of panobinostat (e.g., 25-60 mg panobinostat) by increasing the length of time in the rest periods results .
  • panobinostat e.g., 25-60 mg panobinostat
  • panobinostat may be administered for one week, followed by a rest period of one week.
  • panobinostat may be administered for two weeks, followed by a rest period of two weeks.
  • the HDAC inhibitor e.g., panobinostat
  • the panobinostat monotherapy is a first line of treatment. In some embodiments, the panobinostat monotherapy is a second or third line of treatment.
  • the HDAC inhibitor e.g., panobinostat
  • the panobinostat combination therapy is a first line of treatment. In some embodiments, the panobinostat combination therapy is a second or third line of treatment.
  • a HDAC inhibitor e.g. panobinostat
  • the therapeutics can be administered on the same day consecutively or concurrently.
  • the therapeutics can be administered on different days or weeks.
  • panobinostat and the therapeutic are given one day apart, or two days apart, or three days apart, or four days apart, or six days apart, or seven days apart, or 8 days apart, or 9 days apart, or 10 days apart, or 11 days apart, or 12 days apart, or 13 days apart, or 14 days apart, or more.
  • treating according to the disclosed methods leads to a partial response (PR).
  • a PR is ⁇ 50 % reduction in tumor size by bi- dimensional measurement, as compared with baseline measurement on a stable or decreasing dose of corticosteroid, accompanied by a stable or improving neurologic examination.
  • treating according to the disclosed methods leads to a complete response (CR).
  • CR is a complete disappearance on MRI of all evaluable tumor and mass effect, on a stable or decreasing dose of corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination.
  • the patients described exhibit progressive disease (PD).
  • PD is defined as progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression, a greater than 25 % increase in bi-dimensional tumor measurement as compared to the smallest tumor measurement since the start of panobinostat administration, or the appearance of a new lesion.
  • patients with progressive disease have worsening of symptoms as determined from two consecutive visits. In some embodiments, patients with progressive disease have worsening of symptoms in two or more consecutive visits.
  • symptoms of PD include, but not limited to coordination loss, problems with balance and walking, problems with the eyes, double vision, drooping eyelids, uncontrolled eye movements, blurred vision, problems with chewing and swallowing, nausea, vomiting, facial weakness, facial drooping, headaches, tics, and language slurring.
  • treating according to the methods of the disclosure leads to stable disease (SD).
  • SD is a stable neurologic exam and maintenance corticosteroid dose, and magnetic resonance imaging or computed tomography (CT) imaging that neither meets the criteria for PR nor the criteria for PD.
  • CT computed tomography
  • treating according to the methods of the disclosure results in an improvement in overall survival (OS) compared to the median OS of patients administered standard treatment for DIPG.
  • OS is the length of time from diagnosis with DIPG until death.
  • treating according to the methods of the disclosure results in an increase in OS as compared to the median value in overall survival at the time of this disclosure for a particular type of brain cancer.
  • the median overall survival for DIPG patients is between about 8 months and about 12 months.
  • treating according to the methods of the disclosure results in an increase in the OS of about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 5 weeks, or about 6 weeks, or about 7 weeks, or about 8 weeks, or about 9 weeks, or about 10 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or about 12 months, or about 13 months, or about 14 months, or 15 months, or about 16 months, or about 17 months, or about 18 months, or about 19 months, or about 20 months, or about 21 months, or about 22 months, or about 23 months, or about 24 months, or about 3 years, or about 4 years, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years, or more, including all
  • treating according to the methods of the disclosure results in an increase in the OS of about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, about 90 %, about 100 %, about
  • treating according to the methods of the disclosure leads to an increase in progression free survival (PFS) compared to the median PFS of patients administered standard treatment for DIPG.
  • PFS is the length of time between initiation of treatment according to the methods of the disclosure and the date of documented progressive disease or death from any cause.
  • the methods of the disclosure result in an increase in PFS as compared to the median value in progression free survival at the time of this disclosure.
  • the median PFS for DIPG patients is 6 months.
  • treating according to the methods of the disclosure results in an increase in the PFS of about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 5 weeks, or about 6 weeks, or about 7 weeks, or about 8 weeks, or about 9 weeks, or about 10 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or more, or about 12 months, or about 13 months, or about 14 months, or 15 months, or about 16 months, or about 17 months, or about 18 months, or about 19 months, or about 20 months, or about 21 months, or about 22 months, or about 23 months, or about 24 months, or about 3 years, or about 4 years, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years, including all values and ranges in between.
  • treating according to the methods of the disclosure results in an increase in the PFS of about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, about 90 %, about 100 %, about
  • the methods of the disclosure result in a decrease in tumor size.
  • Tumor size is measured according to known methods in the art.
  • tumor size is measured by magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • the MRI sequence is selected from a T1 weighted scan, a T2 weighted scan, and a Fluid Attenuated Inversion Recovery (FLAIR).
  • FLAIR Fluid Attenuated Inversion Recovery
  • the FLAIR sequence is used to measure tumor size.
  • the tumor size decreases by about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 35 %, or about 40 %, or about 45 %, or about 50 %, or about 55 %, or about 60 %, or about 65 %, or about 70 %, or about 75 %, or about 80 %, or about 85 %, or about 90 %, or about 95 %, or about 100 %.
  • panobinostat may be administered in combination with another therapeutic agent.
  • the therapeutic is administered at the current FDA approved dose as of the filing date of the present application.
  • the other therapeutic agent can be administered in a course as described herein.
  • the other therapeutic agent is administered at a dose ranging from about 0.005 mg to about 1 g, including about 0.005 mg, about 0.01 mg, about 0.015 mg, about 0.02 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, about 0.060 mg, about 0.065 mg, about 0.070 mg, about 0.075 mg, about 0.080 mg, about 0.085 mg, about 0.090 mg, about 0.095 mg, about 0.10 mg, about 0.15 mg, about 0.20 mg, about 0.25 mg, about 0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.60 mg, about 0.65 mg, about 0.70 mg, about 0.75 mg, about 0.80 mg, about 0.85 mg, about 0.90 mg, about 0.95 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg,
  • a therapeutic agent is used in combination with an HDAC inhibitor (e.g. panobinostat).
  • the therapeutic agent is a proteasome inhibitor, a BCL-2 inhibitor, a CYP3A inhibitor, another histone deacetylase inhibitor, a checkpoint inhibitor, inhibitors of Tregs, mTOR inhibitors, proteasome inhibitors, a taxane (or other similarly acting microtubule stabilizing or disrupting compounds), a platinum coordinator compound, an epidermal growth factor inhibitor, a vascular endothelial growth factor inhibitor, a vascular endothelial growth factor kinase inhibitor, a MET inhibitor, ABL kinase inhibitor, ALK inhibitor, FLT kinase inhibitor, a MAPK/ERK kinase inhibitor, a RAF kinase inhibitor, a farnesyl transferase inhibitor, an estrogen receptor modulator, an anti-tumor nucleoside deritative, epoth
  • a HDAC inhibitor (e.g. panobinostat) is administered with a proteasome inhibitor.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor (e.g. panobinostat) is administered with marizomib.
  • a HDAC inhibitor e.g. panobinostat
  • bortezomib is administered with carfilzomib.
  • a HDAC inhibitor e.g. panobinostat
  • an antineoplastic agent is selected from the group consisting of: paclitaxel, docetaxel, oxaliplatin, carboplatin, cisplatin, gemcitabine, tamoxifen, trastuzumab, cetuximab, bevacizumab, navelbine, 17- allylamino-17-demothoxy-geldanamycin, lapatinib, erlotinib, gefitinib, IMC-1C11, SU5416, and SU6688.
  • a HDAC inhibitor e.g. panobinostat
  • a hypomethylating agent also known as a demethylating agent
  • Non-limiting examples of hypomethylating agents include decitabine and azacitidine.
  • a HDAC inhibitor e.g. panobinostat
  • BET inhibitors are a class of drugs that reversibly bind to the bromodomains of BET proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein- protein interaction between BET proteins and acetylated histones and transcription factors.
  • BET inhibitors that target both BD1 and BD2 bromodomains include I- BET 151 (GSK1210151A), l-BET 762 (GSK525762), OTX-015, TEN-010, CPI-203, and CPI-0610.
  • a non-limiting example of a BET inhibitor that selectively targets BD1 include olinone.
  • a non-limiting example of BET inhibitor that selectively targets BD2 include RVX-208.
  • a non-limiting example of BET inhibitor that is a dual kinase- bromodomain inhibitor is LY294002.
  • Non-limiting examples of bivalent BET inhibitors include AZD5153, MT-1, and MS645.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor is administered in combination with one more FDA approved therapeutic agents for brain cancer.
  • FDA approved therapeutic agents for brain cancer are: everolimus, bevacizumab, carmustine, lomustine (CCNU), temozolomide, procarbazine hydrochloride, and vincristine sulfate.
  • a HDAC inhibitor e.g. panobinostat
  • chemotherapeutic agent include alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics.
  • Non-limiting examples of alkylating agents include nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, triazenes, uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • panobinostat is administered with temozolomide.
  • Temozolomide is a small molecule chemotherapeutic which crosses the blood-brain barrier. Temozolomide is currently FDA approved for the treatment of adult patients with refractory anaplastic astrocytoma.
  • Non-limiting examples of antimetabolites include methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • Non-limiting examples of natural products and their derivatives include vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, paclitaxel, paclitaxel derivatives (e.g. taxotere), mithramycin, deoxycoformycin, mitomycin c, l-asparaginase, interferons, etoposide, and teniposide.
  • Non-limiting examples of hormones and steroids include: 17a-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, tamoxifen, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, and zoladex.
  • methods of the present disclosure include the administration of microtubule affecting agent (e.g., paclitaxel, a paclitaxel derivative or a paclitaxel-like compound) with panobinostat.
  • microtubule affecting agent e.g., paclitaxel, a paclitaxel derivative or a paclitaxel-like compound
  • a microtubule affecting agent is a compound that interferes with cellular mitosis by affecting microtubule formation and/or action.
  • microtubule affecting agents include allocolchicine, halichondrin B, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel, paclitaxel derivatives, trityl cysteine, vinblastine sulfate, vincristine sulfate, epothilone A, epothilone, discodermolide estramustine, nocodazole, and MAP4.
  • a HDAC inhibitor e.g.
  • a HDAC inhibitor e.g. panobinostat
  • the radiation therapy is external beam radiation.
  • a machine is utilized to aim high-energy rays (or beams) from outside the body into the tumor.
  • the machine is a linear accelator (linac).
  • the external radiation therapy is selected from a group consisting of three-dimensional conformal radiation therapy, image guided radiation therapy, intensity modulated radiation therapy, helical-tomotherapy, photon beam radiation therapy, proton beam radiation therapy, and stereotactic radiosurgery.
  • patients receive between about 40 Gy to about 100 Gy of radiation in combination with a HDAC inhibitor (e.g.
  • panobinostat In some embodiments, patients receive about 40 Gy, or about 45 Gy, 50 Gy, or about 54 Gy, or about 55 Gy, or about 60 Gy, or about 65 Gy, or about 70 Gy, or about 75 Gy, or about 80 Gy, or about 85 Gy, or about 90 Gy, or about 95 Gy, or about 100 Gy of radiation, including all values and ranges in between. In some embodiments, the patient is administered 54 Gy of radiation.
  • a HDAC inhibitor e.g. panobinostat
  • Biological therapies involve the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Some biological therapies for cancer stimulate the body’s immune system to fight cancer cells.
  • Non-limiting examples of biological therapies are: 111 In-labeled DCs, ADV-TK/GCV, ALD-451 , ALECSAT, APX005M , AV-GBM-1, AZD1775, Ad-RTS-hlL-12, Ad5CMV-p53 gene, AdV-tk, Anlotinib, Anti-CD137, Anti-Endoglin Chimeric Monoclonal Antibody TRC105, Anti- HER2 CAR-T, Anti-LAG-3 monoclonal antibody, Anti-PD-1 monoclonal antibody, Anti- PD-L1 CAR T cells, Antigen-specific IgT cells, Autologous Cytomegalovirus-specific Cytotoxic T-lymphocytes, Avelumab, B7-H3 CAR-T, BMS-936558, BTSC mRNA- loaded DCs, Bevacizumab, Biological: DC activated CIK combined with DC, CART- EGFRvlll T cells, anti-CD147 C
  • CD-expressing genetically modified neural stem cells EGFR806-specific chimeric antigen receptor (CAR) T cell, EGFRBi- Armed Autologous T Cells, EGFRvlll CAR T cells, Epidermal growth factor receptor(EGFRv)lll Chimeric antigen receptor (CAR) transduced PBL, Erlotinib, HLA- A2 Restricted Glioma Antigen-Peptides, FPA008, Filgrastim, GAA/TT-peptide vaccine, GBM6-AD, GM-K562 Vaccination, GSC-loaded autologous dendritic cells, GX-I7, Gliolan, Granulocyte-macrophage Colony-stimulating Factor, HBOT, HER.
  • CAR chimeric antigen receptor
  • EGFRBi- Armed Autologous T Cells EGFRvlll CAR T cells
  • CAR CMV-specific CTLs HER2-specific chimeric antigen receptor (CAR) T cell
  • HIV-Gag mRNA-pulsed autologous DCs HSPPC-96, Heat Shock Protein Peptide Complex-96 (HSPPC-96), Hepatitis A Vaccine
  • Human CMV pp65-LAMP mRNA- pulsed autologous DCs Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF, ICT-107, ICT-121 DC vaccine, ID01 Inhibitor BMS-986205, IMA 950, INO-5401 , INO-9012, Ipilimumab, K27M peptide, M032 (NSC 733972), MDV9300, MGMTP140K-encoding retroviral vector, MK-3475, Malignant Glioma Tumor Lysate-Pulsed Autologous Dendritic Cell Vaccine, Modified Measles Virus, Multiple dose
  • biological therapies which are proteins
  • a HDAC inhibitor e.g. panobinostat
  • a targeted therapies e.g. panobinostat
  • Target therapies block the action of certain proteins, enzymes, or molecules involved in cancer cell growth.
  • Chimeric antigen receptor T (CAR T) cells, monoclonal antibodies, antibody drug conjugates, and small molecules are non-limiting examples of targeted therapies.
  • panobinostat is administered in combination with an inhibitor of FLT3.
  • FLT3 inhibitors include anti-FLT3 antibodies, SU5416, midostaurin, SU11248, PKC412, CEP-701, MLN518, and gilteritinib.
  • panobinostat is administered with an inhibitor of IDH.
  • IDH inhibitors include ivosidenib and enasidenib.
  • panobinostat is administered with an inhibitor of CD33, which is found on DIPG cells.
  • a potential CD33 inhibitor can be a small molecule, a monoclonal antibody, or an anti-CD33 CAR T cell.
  • panobinostat is administered with gemtuzumab ozogamicin.
  • panobinostat is administered with an inhibitor of BCL-2.
  • Bcl-2 is an antiapoptotic protein, which promotes cancer growth.
  • Non-limiting examples of BCL-2 include venetoclax, piperlongumine, 2-methoxy-antimycin A3, nilotinib, ABT 737, epigallocatechin gallate, obatoclax mesylate, and ABT 263.
  • panobinostat is administered with an inhibitor of the hedgehog pathway.
  • One protein of the hedgehog pathway is sonic hedgehog, which is active in DIPG.
  • panobinostat is administered with glasdegib, an inhibitor of sonic hedgehog.
  • a HDAC inhibitor e.g. panobinostat
  • a cellular therapy is a therapy in which cells are transplanted into a patient.
  • Non-limiting examples of types of cellular therapies therapies are hematopoietic stem cells, red blood cells, white blood cells, T cells, B cells, natural killer (NK) cells, NKT cells, Tregs, CD4+ T cells, CD8+ T cells, CAR T cells, dendritic cells, neural stem cells, umbilical cord blood, T cell receptor engineered T cells (TCR-T cells), antigen presenting cells, and platelets.
  • the cellular therapy may be autologous or allogeneic.
  • Autologous cellular therapies involve the transplant of cells from one person, which are given back to the same person. Allogeneic cellular therapies involve the transplant of cells from one person to a different person.
  • the cellular therapy may be modified before introduction into a patient. For instance, the cellular therapy may be genetically modified or cultured ex vivo.
  • a HDAC inhibitor e.g. panobinostat
  • An immunomodulatory agent is utilized to enhance the immune response against a tumor.
  • immunomodulatory agents act on macrophages, lymphocytes, neutrophils, natural killer cells, and cytotoxic T lymphocytes.
  • Immunomodulator agents affect cytokine production by immune cells.
  • immunomodulatory agents are small molecules.
  • immunomodulatory agents are CAR T cells.
  • immunomodulatory agents are antibodies.
  • immunomodulatory agents are cytokines.
  • Non-limiting examples of cytokines include IL-2, IL-1, IFN- ⁇ , IL-7, IL-12, IL-6, IL-15, IL-2, TNF ⁇ , and IL-3.
  • immunomodulatory agents are vaccines.
  • Non-limiting examples of vaccines include the GVAX vaccine, galinpepimut-S (GPS), heat shock protein (HSP) vaccine, rindopepimut, dendritic cells, Pep-3-KLH (targets EGFRvlll), and NeoVax.
  • a HDAC inhibitor e.g. panobinostat
  • Bcl-2 is administered with an inhibitor of Bcl-2. Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, schizophrenia, and autoimmunity.
  • Bcl-2 is an oncogene, which results from a translocation between chromosomes 14 and 18.
  • Bcl-2 family proteins regulate apoptosis.
  • a Bcl-2 inhibitor binds to Bcl-2 and prevents cellular signaling.
  • Non-limiting examples of Bcl-2 inhibitors include, oblimersen, navitoclax, ABT-737, and venetoclax.
  • a HDAC inhibitor e.g. panobinostat
  • a therapeutic that penetrates the blood brain barrier have a molecular weight of ⁇ 400 g/mol and high lipid solubility.
  • a therapeutic that crosses the blood brain barrier exhibits less hydrogen bonds with water than a therapeutic that does not cross the blood brain barrier.
  • a therapeutic that crosses the blood-brain barrier forms less than ten hydrogen bonds with water.
  • Non- limiting examples of therapeutics that pass the blood brain barrier include panobinostat, temozolomide, lomustine, and carmustine.
  • a HDAC inhibitor e.g. panobinostat
  • DRD2 dopamine receptor D2
  • DRD2 antagonists have anticancer activity, which is in part derived from the activation of the cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA) pathway.
  • cAMP cyclic adenosine monophosphate
  • PKA protein kinase A
  • panobinostat is administered with the DRD2 antagonist ONC210 (TIC10).
  • a HDAC inhibitor e.g.
  • panobinostat is administered with an inhibitor of regulatory T cells (Tregs).
  • Tregs regulatory T cells are immune cells, which are responsible for the establishment of immune tolerance. Tregs also dampen the functions of anti-neoplastic immune cells and promote cancer progression.
  • Tregs are FOXP3 + , CD25 high , CD4 + T cells.
  • patients with brain cancer exhibit increased Tregs in comparison to healthy patients.
  • an increased percentage of Tregs is correlated with poor prognosis.
  • a HDAC inhibitor e.g. panobinostat
  • Checkpoint inhibitors block immune checkpoint proteins. Examples of checkpoint proteins found on the surface of or secreted by immune cells and cancer cells are PD-1, PD-L1, CTLA-4, B7-1 (CD80), B7-2 (CD86). Immune checkpoint inhibitors prevent the interaction of receptors, such as PD-1 and CTLA-4 from interacting with their ligands PD-L1 , B7-1, and B7-2. In some embodiments, checkpoint inhibitors disrupt cellular signaling and have an anti-cancer effect. In some embodiments, the administration of a checkpoint inhibitors with panobinostat has an anti-cancer effect.
  • the checkpoint inhibitor is an inhibitor of the PD-1/PD-L1 checkpoint.
  • An inhibitor of the PD-1/PD-L1 checkpoint blocks the interaction of PD-1 with PD-L1.
  • a HDAC inhibitor e.g. panobinostat
  • a monoclonal antibody which inhibits the PD-1/PD- L1 checkpoint.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor is administered with an anti-PD-1 antibody.
  • a HDAC inhibitor e.g. panobinostat
  • the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS- 986189.
  • the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, and APT-514.
  • panobinostat is administered with an inhibitor of CTLA-4 selected from the group consisting of ipilimumab and tremelimumab.
  • a HDAC inhibitor e.g. panobinostat
  • B7-1 A non-limiting example of a B7-1 inhibitor is galiximab.
  • a HDAC inhibitor e.g. panobinostat
  • B7-2 A non-limiting example of a B7-2.
  • a HDAC inhibitor e.g. panobinostat
  • mTOR inhibitor is administered with a mammalian target of rapamycin (mTOR inhibitor).
  • mTOR is a conserved serine/threonine kinase, which controls cell growth, proliferation, and survival.
  • mTOR inhibitors block the activity of the mammalian target of rapamycin.
  • Non-limiting examples of mTOR inhibitors include deforolimus, everolimus, sirolimus, temsirolimus, AZD8055, Ku-0063784, PPT242, PP30, Torinl , WYE-354, NVP-BEZ235, PI-103, PKI-179, PKI-587, and XL765.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor is not administered with a strong CYP3A4 inducer.
  • a HDAC inhibitor is not administered with a therapeutic agent that prolongs the QTc interval.
  • methods of the present disclosure are associated with a reduction in drug resistance. Drug resistance in brain cancer patients results from drug resistance-related proteins and enzymes, gene alterations, microRNAs, and erratic signaling pathways.
  • methods of the present disclosure utilize a HDAC inhibitor (e.g. panobinostat) in in combination with other therapies to produce a synergistic effect.
  • HDAC inhibitor e.g. panobinostat
  • a synergistic effect results when the total effect of the therapeutic agents is greater than the sum of the individual effects of each drug.
  • a HDAC inhibitor e.g. panobinostat
  • Wee1 is a checkpoint kinase that prevents cell course progression through phosphorylation of cyclin dependent kinase 1 (CDK1) and cyclic dependent kinase 2 (CDK2).
  • CDK1 and CDK2 are part of the checkpoint kinase 1 (CHK1) pathway.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor e.g.
  • panobinostat downregulates Weel
  • the synergistic effect of dual HDAC inhibitor/Wee1 inhibitor administration allows for a lower dose of panobinostat to be given.
  • the synergistic effect of dual HDAC inhibitor/Wee1 inhibitor administration allows for a lower dose of panobinostat to be given.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor is administered in combination with one or more Wee1 inhibitors for the treatment of brain cancer.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor is synergistic with bisphosphonates.
  • Non-limiting example of bisphosphonates zoledronic acid, alendronate/cholecalciferol, etidronate, umbledronate, ibandronate, pamidronate, alendronate, and tiludronate Coadministration of a HDAC inhibitor (e.g. panobinostat) and bisphosphonates results in induction of the mitochondrial apoptotic pathway and the generation of reactive oxygen species.
  • administration of a HDAC inhibitor (e.g. panobinostat) in combination with a bisphosphonate results in enhanced cancer cell killing.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor e.g. panobinostat
  • topoisomerase inhibitors such as topotecan and/or etoposide.
  • Coadministration of a HDAC inhibitor (e.g. panobinostat) and topoisomerase inhibitors results in induction of the mitochondrial apoptotic pathway and the generation of reactive oxygen species.
  • administration of a HDAC inhibitor (e.g. panobinostat) in combination with a topoisomerase inhibitor results in enhanced cancer cell killing.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor (e.g. panobinostat) is synergistic with a proteasome inhibitor.
  • proteasome inhibitors include bortezomib, ixazomib, marizomib, and carfilzomib.
  • coadministration of panobinostat and a proteasome inhibitor results in synergistic cytotoxicity.
  • combined administration of a HDAC inhibitor (e.g. panobinostat) and a proteasome inhibitor results in downregulation of BCL-2.
  • a HDAC inhibitor (e.g. panobinostat) is administered in combination with one or more proteasome inhibitors for the treatment of brain cancer.
  • a HDAC inhibitor e.g. panobinostat
  • a HIV protease inhibitor is synergistic with a HIV protease inhibitor.
  • combined administration of a HDAC inhibitor (e.g. panobinostat) and a HIV protease inhibitor to enhance histone acetylation include saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir, and darunavir.ln embodiments, a HDAC inhibitor (e.g.
  • panobinostat is synergistic with second generation selective inhibitor of nuclear export (SINE) compounds.
  • SINE compounds second generation selective inhibitor of nuclear export
  • coadministration of a HDAC inhibitor (e.g. panobinostat) and a SINE compound results in a compromised DNA damage response pathway.
  • a compromised DNA damage response pathway leads to destabilization of genomic integrity in cancer cells.
  • panobinostat is administered in combination with one or more SINE compounds for the treatment of brain cancer.
  • a HDAC inhibitor (e.g. panobinostat) is synergistic with ibrutinib.
  • a HDAC inhibitor (e.g. panobinostat) results in downregulation of MyD88. Mutations in MyD88 are responsible for ibrutinib resistance.
  • brain cancer treated according to the present methods has MyD88 mutations.
  • a HDAC inhibitor (e.g. panobinostat) is coadministered with ibrutinib for treatment of brain cancer containing MyD88 mutations.
  • coadministration of a HDAC inhibitor (e.g. panobinostat) and ibrutinib results in decreased resistance of cancer cells to ibrutinib.
  • a HDAC inhibitor e.g. panobinostat
  • a HDAC inhibitor is synergistic with inhibitors of BCL-2. Acquired resistance to BCL-2 inhibitors results from increased MCL-1 and BCL-XL levels, which leads to sequestration of the protein BIM. BIM is a pro-apoptotic protein.
  • panobinostat downregulates the expression of BCL-2, BCL-xl, BCL-w, and MCI-I, resulting in upregulation of BIM.
  • a HDAC inhibitor (e.g. panobinostat) and a BCL-2 inhibitor are administered in combination for the treatment of brain cancer.
  • co-administration of a HDAC inhibitor (e.g. panobinostat) and a BCL-2 inhibitor allows for a lower dose of panobinostat and/or the BCL-2 inhibitor.
  • TP53 is the most frequently mutated gene in human tumors. TP53 is a tumor suppressor gene often inactivated by deletion and/or point mutation in brain cancer. Mutations in p53 are correlated with resistance to chemotherapy. Mutant p53 interacts with histone deacetylases, leading to stabilization of mutant p53 and mutant p53’s aberrant function.
  • a HDAC inhibitor e.g. panobinostat
  • coadministration of a HDAC inhibitor (e.g. panobinostat) and a tyrosine kinase inhibitor has a synergistic effect.
  • coadministration of a HDAC inhibitor (e.g. panobinostat) and a platinum-based therapeutic have a synergistic effect.
  • panobinostat has a synergistic effect with platinum- based therapeutics, tyrosine kinase inhibitors, and BCL-2 inhibitors as a result of panobinostat’s ability to destabilize mutant p53.
  • the methods of the present disclosure comprise treating patients diagnosed with brain cancer.
  • brain cancers include acoustic neuromas, astrocytomas, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, oligoastrocytoma, anaplastic-astrocytoma, pituitary tumors, glioblastoma, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, diffuse midline glioma, and pineal tumors.
  • the brain cancer is a glioma. In some embodiments, the brain cancer is a diffuse infiltrating glioma. In some embodiments, the brain cancer is a high grade glioma. In some embodiments, the brain cancer is classified according to the World Health Organization’s guidelines, which are described by Vigneswaran et al. and Louis et al., which are each incorporated by reference herein in their entireties: Vigneswaran et al. Ann Transl Med. 2015 May;3(7):95. Louis DN et al. (2016) World Health Organization Histological Classification of Tumours of the Central Nervous System. International Agency for Research on Cancer, France.
  • the brain cancer is DIPG.
  • DIPG is a devastating, aggressive brain tumor of childhood arising in the ventral pons, which is part of the brain stem.
  • brainstem tumors are rare among adults, they comprise approximately 10-15% of pediatric brain tumors, with half of all pediatric malignant gliomas occurring in the brainstem.
  • DIPG is the most common tumor subtype in this anatomical region, constituting 80% of brainstem gliomas. With an estimated 200-400 children affected by DIPG annually in the United States, it is the second most common malignant brain tumor of childhood.
  • the prognosis is bleak: the absence of effective therapies makes DIPG uniformly fatal.
  • DIPG is the leading cause of childhood brain tumor death.
  • a patients with DIPG is diagnosed if the patient has a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons.
  • patients with pontine lesions that do not exhibit the criteria for radiographically typical DIPG have histologic confirmation of malignant glioma as determined by WHO ll-IV criteria.
  • the methods of the disclosure are utilized to treat patients with progressive DIPG.
  • patients with progressive DIPG have progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression.
  • patients with progressive DIPG have an increase in the bi-dimensional tumor measurement, taking as a reference the smallest bi-dimensional tumor measurement recorded since diagnosis. Tumor measurements will be conducted via magnetic resonance imaging (MRI).
  • progressive DIPG is associated with the appearance of new tumor lesions, since diagnosis.
  • the methods of the disclosure are utilized to treat patients that have non-progressed DIPG, as determined by clinical or radiographic criteria.
  • patients with DIPG exhibit genetic mutations, which are associated with poor prognosis and resistance to therapeutics.
  • the methods of the present disclosure treat patients with one or more genetic mutations.
  • Non-limiting examples of genetic mutations include mutations in H3F3A, HIST1H3B, HIST1H3C, TP53, ACVR1, PDGFRA, PPM1D, PIK3CA, PIK3R1, MYC, MYCN, and PPM1D. See Lapin et al. Front Oncol. 2017;7:57.
  • patients with DIPG have mutations in genes encoding histones, key chromatin components that play important roles in regulating the epigenome.
  • patients with DIPG have a mutation in H3F3A.
  • H3F3A H3 histone, family 3A
  • H3F3A is a gene encoding histone variant H3.3, which replaces histones as necessary in the event of nucleosome disruption.
  • patients with DIPG have an alteration in histone variant H3.1 , such as an alteration in HIST1 H3B (histone cluster 1 , H3b) or in HIST1 H3C (histone cluster 1, H3c).
  • Histone H3.1 plays a role in packaging newly synthesized DNA during S- phase18.
  • the alteration is a specific missense mutation resulting in the substitution of lysine with methionine at position 27 (K27M). This position is located within the N-terminal tail of the histone; importantly, post- translational modification of histone tails by methylation, acetylation or ubiquitylation of lysine residues is known to mediate the epigenetic regulation of gene expression and alter nucleosome structure.
  • DIPG represents the first identified example of the implication of a histone mutation in oncogenesis and disease.
  • the H3 K27M mutation is heterozygous in 100% of DIPG cells, and remains so in both treatment-naive and treatment-exposed samples, and within low- and high-grade tumor regions. This strongly suggests clonal selection, emphasizing the robust selective advantage that the H3 K27M mutation likely confers.
  • H3 K27M is a gain-of-function mutation that exerts broad transcriptional effects by disrupting lysine trimethylation at position 27.
  • the K27 trimethylation mark (H3K27me3) is necessary for stimulation of methyltransferase activity of Polycomb Repressive Complex 2 (PRC2) via nucleosome interaction with the EZH 2 subunit of PRC230.
  • PRC2 Polycomb Repressive Complex 2
  • PRC2 is known to silence gene transcription in order to regulate stem cell differentiation in development, and mutations in subunits of PRC2 itself have been previously implicated in oncogenesis31.
  • patients with DIPG have a mutation in ACVR1.
  • ACVR1 encodes the type I bone morphogenetic protein (BMP) receptor ALK2.
  • BMP bone morphogenetic protein
  • mutations in ACVR1 lead to amino acid substitutions of R206H, Q207E, R258G, G328E, G328V, G328W, and G356D.
  • patients with DIPG have a mutation in platelet-derived growth factor receptor A (PDGFRA ).
  • PDGFRA is a receptor tyrosine kinase and cell cycle regulatory gene.
  • patients with DIPG have gain-of- function mutations in PDGFRA.
  • patients with DIPG have loss- of-function mutations in PDGFRA.
  • patients with DIPG have a mutation in the protein phosphatase Mg 2+/ Mn 2+ dependent 1D gene ( PPM1D ).
  • PPM1D encodes a serine/threonine phosphatase which dephosphorylates numerous proteins involved in the DNA damage response (DDR) and cellular checkpoint pathway.
  • DDR DNA damage response
  • patients with DIPG experience C-terminal truncations of PPM1D.
  • patients with DIPG have a mutation in the PIK3CA or PIK3R1. PIK3CA and PIK3CA mutations promote tumor angiogenesis and cancer cell sternness.
  • patients with DIPG have mutations in MYC or MYCN.
  • MYC and MYCN are transcriptional regulators.
  • mutations in MYC lead to constitutive expression of the Myc protein.
  • MYC or MYCN mutations enhance gene expression across the whole genome, promoting tumor survival.
  • MYCN amplification is associated with hypermethylation, increased histological grade, and chromothripsis at chromosome
  • TP53 tumor protein 53
  • TP53 is a key tumor suppressor related to the maintenance of genomic stability, including regulation of cellular senescence, apoptosis, metabolism, and DNA repair.
  • the methods of the present disclosure are utilized to treat patients that have increased numbers of Tregs in peripheral blood or in a patient’s brain tumor.
  • Some brain tumors produce CCL22, a chemokine ligand, which recruits Tregs to the tumor.
  • subjects with brain cancer exhibit an increased frequency of PD-L1 on cancer cells or tumor cells.
  • PD-L1 promotes the development, maintenance, and function of Tregs.
  • chemotherapy can promote Treg depletion by tilting the balance from Treg toward effector T cells.
  • cyclophosphamide is administered in combination with panobinostat to reduce Tregs.
  • anti-CCR4 and/or anti CD25 antibodies are utilized to deplete or block Tregs.
  • the anti-CD25 antibody daclizumab depletes Tregs.
  • methods of the present disclosure utilize an anti-CTLA-4 antibody to deplete or block Tregs. CTLA-4 is expressed on Tregs.
  • ipilimumab is administered to deplete or block Tregs.
  • methods of the present disclosure use an anti-GITR antibody to deplete Tregs. GITR is constitutively expressed on Tregs.
  • 0X40 is expressed on Tregs.
  • an anti-OX40 antibody is utilized to deplete or block Tregs.
  • small molecules or antibody antagonists of CCR4 are utilized to block or deplete CCR4.
  • CCR4 is a chemokine receptor found on Tregs that facilitates Treg trafficking.
  • CCR4+ Tregs migrate along a chemokine gradient toward CCL17 or CCL22, which is released by cancer cells or produced by dendritic cells in the lymph nodes. Blockade or depletion of CCR4+ T regs results in disrupted lymph node and tumor homing by T regs.
  • methods of the present disclosure are utilized to treat patients with exhausted T cells. T cell exhaustion is characterized by the loss of T cell function. In embodiments, exhausted T cells display high levels of CD43.
  • exhausted T cells display high levels of CD69. In embodiments, exhausted T cells display high levels of inhibitory receptors, such as PD-1 and CTLA-4. In embodiments, exhausted T cells express LAG-3 and/or TIM-3. In embodiments, exhausted T cells exhibit low expression of CD62. In embodiments, exhausted T cells exhibit low expression of CD127. In embodiments, exhausted effector T cells are PD-1+, LAG3+, CD4+ or PD-1-, TIM3+, CD4+ T cells. In embodiments, increased number of Tregs is associated with increased number of exhausted effector T cells (Teffs).
  • Tregs contribute to suppression of Teffs by the induction of immunosuppression through secretion of cytokines, such as IL-4, IL-10, and TGF ⁇ .
  • the presence of checkpoint proteins is associated with exhausted effector T cells.
  • the frequency of exhausted T cells is increased in patients with brain cancer.
  • the frequency of exhausted T cells is increased in brain cancer patients that relapse.
  • checkpoint inhibitors are utilized in methods of the present disclosure to reverse T cell exhaustion.
  • inhibitors of Tregs are utilized in the present disclosure to reverse T cell exhaustion.
  • the methods of the disclosure are utilized to treat patients from age 0-80. In some embodiments, the methods of the present disclosure are utilized to treat patients from about age 2 to about age 22. In some embodiments, the patients are about 2 years old, about 3 years old, about 4 years old, about 5 years old, about 6 years old, about 7 years old, about 8 years old, about 9 years old, about 10 years old, about 11 years old, about 12 years old, about 13 years old, about 14 years old, about 15 years old, about 16 years old, about 17 years old, about 18 years old, about 19 years old, about 20 years old, about 21 years old, or about 22 years old.
  • the patients are administered panobinostat or another therapeutic agent based on the patient’s body surface area (BSA).
  • BSA body surface area
  • patients exhibit a BSA between about 0.25 and 2.5.
  • patients have a BSA of about 0.25, or about 0.30, or about 0.35, or about 0.40, or about 0.45, or about 0.50, or about 0.55, or about 0.60, or about 0.65, or about 0.70, or about 0.75, or about 0.80, or about 0.85, or about 0.90, or about 0.95, or about 1.0, or about 1.1 , or about 1.2, or about 1.3, or about 1.4, or about 1.5, or about 1.6, or about 1.7, or about 1.8, or about 1.9, or about 2.0, or about 2.1 , or about 2.2, or about 2.3, or about 2.3, or about 2.4, or about 2.5, including all values and ranges in between.
  • compositions may comprise one or more pharmaceutically acceptable excipients or adjuvants.
  • the pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes.
  • the pharmaceutical formulations may comprise a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels.
  • the pharmaceutical compositions may contain additional, compatible, pharmaceutically-active materials such as antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • additional materials useful in physically formulating various dosage forms of the compositions of the present invention such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • such materials when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention.
  • the formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/
  • the therapeutic agents disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the therapeutic agents disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the therapeutic agents disclosed herein can also be formulated as a preparation for implantation or injection.
  • the therapeutic agents can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • the therapeutic agents can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wlkins, Philadelphia, PA.
  • a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • the pharmaceutical compositions comprises a therapeutic agent disclosed herein combined with a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M phosphate buffer or saline (e.g., about 0.8%).
  • Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non- aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
  • Oral carriers can be elixirs, syrups, capsules, tablets and the like.
  • Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, e.g. sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration.
  • the liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
  • a solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet- disintegrating agents; it can also be an encapsulating material.
  • the carrier can be a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets contain up to 99% of the active compound.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
  • the carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.
  • Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle.
  • Diluents for solid compositions and/or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., AVICEL
  • microfine cellulose e.g., lactose, starch, pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • dextrin dextrin
  • dextrose dibasic calcium phosphate dihydrate
  • the pharmaceutical composition may be selected from the group consisting of a solid, powder, liquid and a gel.
  • the pharmaceutical compositions of the present disclosure is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates).
  • the solid pharmaceutical composition comprises one or more excipients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • Solid pharmaceutical compositions that are compacted into a dosage form may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
  • carbomer e.g., carbopol
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach may be increased by the addition of a disintegrant to the composition and/or combination.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.
  • a disintegrant include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.
  • Glidants can be added to improve the flowability of a non-compacted solid composition and/or combination and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition and/or combination to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • Liquid pharmaceutical compositions can be prepared using compounds of the present disclosure and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients to control the release of active compounds.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer.
  • the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent.
  • the compound can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
  • Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • a pharmaceutical compositions of the present invention are formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example an emulsion in an acceptable oil
  • ion exchange resins for example an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • a pharmaceutical composition of the present invention comprises a sustained-release system.
  • a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.
  • Appropriate pharmaceutical compositions of the present disclosure can be determined according to any clinically-acceptable route of administration of the composition to the subject.
  • the manner in which the composition is administered is dependent, in part, upon the cause and/or location.
  • One skilled in the art will recognize the advantages of certain routes of administration.
  • the method includes administering an effective amount of one or more therapeutics of the present disclosure to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., metabolic disorders.
  • the route of administration is systemic, e.g., oral or by injection.
  • the route of administration is intratumoral.
  • the pharmaceutical compositions of the present disclosure are prepared for oral administration.
  • the pharmaceutical compositions are formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical compositions are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate are added.
  • dragee cores are provided with coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to tablets or dragee coatings.
  • compositions for oral administration are push-fit capsules made of gelatin.
  • Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more compounds disclosed herein are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • the therapeutics of the present disclosure are administered by the intravenous route.
  • the parenteral administration may be provided in a bolus or by infusion.
  • the therapeutics of the present disclosure are administered orally (PO).
  • the therapeutics of the present disclosure are administered via intratumoral administration.
  • Patients diagnosed with progressive DIPG were treated with panobinostat after radiation therapy at various doses, including 5 mg/m 2 /day, 10 mg/m 2 /day, 15 mg/m 2 /day, 20 mg/m 2 /day, 25 mg/m 2 /day, 30 mg/m 2 /day, 35 mg/m 2 /day, and 40 mg/m 2 /day.
  • Patients were administered panobinostat Monday, Wednesday, and Friday in a course of four weeks, which included a treatment period of 3 weeks and a rest period of 1 week. Additional courses were administered if the patient obtained a clinical benefit.
  • Panobinostat is administered to patients with progressive DIPG in combination with marizomib or other proteasome inhibitors. Marizomib is administered at a dose of less than 0.8 mg/ m 2 /day at least once a week for three weeks. Panobinostat is administered one hour or more after administration of marizomib. A range of doses of panobinostat is evaluated to determine the lowest dose that panobinostat can be administered at while producing a clinical response and improving tolerability. Panobinostat is administered at doses ranging from 1 mg/m 2 /day to 10 mg/m 2 /day. Panobinostat will be administered for up to five courses of four weeks.
  • panobinostat is administered up to three times per week and a rest period of 1 week. Similar experiments are performed where panobinostat is administered in combination with BET, PI3K, AKT, and MEK inhibitors.
  • Patients with tumors carrying H3F3A mutations have a significant poorer response to radiotherapy than those with HIST1H3B mutations.
  • Patients that have been stratified with these markers are treated with increasing doses of Panobinostat (1 to 10 mg/m 2 ) given once a day for at least 3 times a week, in a four week course, which includes a treatment period of 3 weeks in which panobinostat is administered up to three times per week and a rest period of 1 week.
  • Panobinostat 1 to 10 mg/m 2
  • Example 4 In Vitro Studies of Panobinostat Efficacy against DIPG [0258]The DIPG Preclinical Consortium performed a drug screen using a total of 16 DIPG cell cultures, and found panobinostat to be among the top hits. 12/16 DIPG cell cultures exhibited sensitivity to panobinostat, with an IC50 of -100 nM. Panobinostat was found to decrease DIPG cell proliferation and increase DIPG cell death (Fig. 1A - Fig. 1B). Further, the increase in histone acetylation caused by panobinostat exposure correlated with an unexpected normalization of histone 3 K27 methylation in H3.3K27M mutant DIPG cells or293T cells expressing an H3.3K27M construct54 (Fig. 1C). Accordingly, a normalization of the “K27M” gene expression signature was observed.
  • Panobinostat was profiled for antiproliferative activity in a large panel of solid and hematological malignancy cell lines and subsets of tumor cell types exhibiting sensitivity or relative insensitivity to the drug were identified. All leukemia and lymphoma cell lines tested were highly sensitive to panobinostat (LD50 ⁇ 50 nM). Significant antiproliferative activity was observed with panobinostat in combination with relevant standard of care agents in plasma cells isolated from patients with MM and in leukemia cell lines. Exposure of normal fibroblasts to low nanomolar concentrations of panobinostat inhibited their proliferation; however, treatment with up to micromolar concentrations of the compound for 72 hours did not induce significant cell death.
  • panobinostat-induced apoptosis of bronchial epithelial cells transformed by SV40 large T antigen/telomerase had little effect on normal bronchial epithelial cells, even at greater concentrations. These results provide the basis for a potentially favorable therapeutic window during anticancer therapy with panobinostat. Cultured tumor cells and/or tumors treated with panobinostat exhibit increased levels of acetylated histones, indicating that the anti-tumor activity of panobinostat is accompanied by HDAC inhibition in cell lines and in vivo Example 5.
  • Panobinostat Human xenografts of tumor cell lines growing in athymic nude mice were used to profile panobinostat in vivo in several models. Panobinostat demonstrated single agent and/or combination activity in a range of xenograft models including colon, SCLC, cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM) and other xenografted human primary tumors. Single agent treatment in HCT116 xenograft tumors (colorectal) resulted in dose-related anti-tumor activity with minimal toxicity at panobinostat concentrations, which correlated with persistent histone acetylation.
  • CTCL cutaneous T-cell lymphoma
  • MM multiple myeloma
  • Panobinostat also demonstrated significant anti-tumor activity in androgen-independent prostate cancer xenograft model, in two different types of human plasmacytoma murine models, in combination with trastuzumab in the HER+ BT474 breast cancer tumor xenograft model, in combination with docetaxel in the HID28 hormone independent prostate cancer model.
  • Panobinostat was directly infused into the pons in a pontine orthotopic xenograft model of DIPG (SU-DIPG VI; H3.3K27M subtype) via convection-enhanced delivery (CED).
  • CED convection-enhanced delivery
  • In vivo bioluminescent imaging was performed immediately prior to and 7 days after panobinostat (or vehicle control) administration in order to measure tumor growth by quantitative assessment of photon emission (Fig. 1 D - Fig. 1G). Because panobinostat affects gene expression, we confirmed that panobinostat expression does not down-regulate the luciferase transgene.
  • CED panobinostat
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • panobinostat levels 0.068 ng/mg tissue, equivalent to -200 nM.
  • IC50 for panobinostat was found to be -100 nM, we reasoned that systemic delivery may prove effective.
  • Mice with brainstem orthotopic xenografts of SU-DIPG-VI cells were then treated with 1 mg/kg, 10 mg/kg or 20 mg/kg IP panobinostat.
  • panobinostat Because 20 mg/kg is a relatively high dose and was administered IP, to better model the maximum tolerated dose (MTD), a 10 mg/kg PO dose was administered and measured at 30 min following this PO dose a concentration of -0.053 ng/mg in hindbrain (brainstem plus cerebellum) tissue. While these brain concentrations of panobinostat are only a fraction of what is measured in the serum from the same mice, they are greater than the DIPG cell IC50 for panobinostat of -100 nM.
  • mice bearing patient-derived DIPG orthotopic xenografts were treated with panobinostat systemically 3 times per week (10 mg/kg), a decrease in tumor growth and an increase in survival was measured, albeit the duration of suppressed growth was less than in the mice treated with weekly 20 mg/kg systemic panobinostat.
  • panobinostat penetrates the brain parenchyma, DIPG cells are sufficiently sensitive to it that enough reaches the brain for tumor cell killing to occur.
  • Example 7 Central Nervous System (CNS) Penetration of Panobinostat in a non- human primate model
  • panobinostat was evaluated in a nonhuman primate model known to be predictive of pharmacokinetics in children, using cerebrospinal fluid (CSF) as a surrogate of CNS tissue penetration.
  • CSF cerebrospinal fluid
  • panobinostat penetration into the CSF was limited, with quantifiable CSF concentrations detected in only one sample (animal treated at 1.8 mg/kg).
  • panobinostat like other HDAC inhibitors, has limited CNS penetration. This study suggests that panobinostat would not be effective at treating brain cancers such as DIPG. Needless to say, the efficacy we observed was surprising and unexpected.
  • Example 8 Phase 1 Clinical Trials of Panobinostat in Adults [0264] Several dosing schedules using IV and oral panobinostat were evaluated with pharmacokinetic (PK) assessment. To date, the PK of panobinostat has been characterized in over 700 patients with cancer, of which, over 500 patients used the TIW dosing schedule.
  • Panobinostat Summary In clinical trials of panobinostat administered as a single agent to adults with refractory hematologic malignancies, Cmax and AUC increased proportionally with dose over a dose range of 4.8-14.0 mg/m 2 .
  • Panobinostat ti/2 was 7.8-12 hrs and plasma AUC 0-24 0-24 ranged from 134.9- 372.9 h ⁇ ng/mL.
  • C max was approximately 20 ng/ml, or about 60 nM.
  • Major toxicities included thrombocytopenia, neutropenia, and QTc prolongation that was dose-limiting.
  • Hypokalemia and elevated LFTs (ALT) were reported, as were mild nausea, vomiting and anorexia.
  • panobinostat In a Phase 1 trial of single agent panobinostat administered to adults with solid tumors, patients received oral panobinostat 3 times per week (M-W-F) at doses ranging from 10-20 mg. No DLT was observed. Most common adverse events included thrombocytopenia, nausea and diarrhea. Mean elimination t 1/2 was 9-14 hrs. [0267]A trial of panobinostat for refractory hematological malignancies in children is complete. No dose-limiting toxicities (DLT) have been observed at dose levels up to 34 mg/m 2 /dose, administered 3 days/week x 4 weeks in children with leukemia.
  • DLT dose-limiting toxicities
  • Panobinostat in Combination- Panobinostat has been evaluated in a Phase 1 trial for recurrent adult high-grade glioma (HGG) in combination with bevacizumab.
  • HGG high-grade glioma
  • the combination of panobinostat with bevacizumab was safe and tolerated at a panobinostat dose of 30 mg PO three times per week, every other week and bevacizumab (10 mg/kg every other week).
  • the main DLT was thrombocytopenia; (one case of grade 3 thrombocytopenia was observed at a dose of 20 mg PO three times per week every week, in combination with bevacizumab).
  • Example 9 Phase 1 Clinical Trial of Panobinostat in Children with DIPG [0269] Based on the in vitro and in vivo activity of panobinostat in preclinical models using DIPG cell cultures and orthotopic xenograft model systems, and the potentially important role of histone deacetylases and histone 3 K27M mutations in relation to pontine malignancies, a multicenter Phase 1 trial of panobinostat in children with recurrent/progressive DIPG followed by children with DIPG prior to progression was conducted. [0270] Initially, only patients with recurrent or progressive DIPG were enrolled. These patients occupy “Stratum 1.” Upon completion of the primary objectives for Stratum 1 (see below), patients with DIPG who have received adequate radiation therapy but have not yet progressed were enrolled in “Stratum 2”.
  • the maximum-tolerated dose (MTD) of patients in Stratum 1 was determined to be 10 mg/m 2 /day.
  • the maximum-tolerated dose (MTD) of patients in Stratum 2 was determined to be 28 mg/m 2 /day.
  • MTD maximum-tolerated dose
  • Patient Populations Only patients with recurrent or progressive DIPG (Stratum 1) were enrolled initially. Upon completion of the first primary objectives (see below), patients with DIPG who have received adequate radiation therapy but have not yet progressed were enrolled in Stratum 2. Patients in Stratum 2 follow a different panobinostat dosing regimen than patients in Stratum 1.
  • Panobinostat was administered every other day, 3 times/week, orally, preferably on a Monday/Wednesday/Friday schedule for three weeks, followed by a rest period. Three weeks of therapy plus the one week rest period (total 4 weeks) constituted one course. Treatment continued for up to two years (26 courses) unless the patient experienced progressive disease, unacceptable toxicity or any of the off-study criteria. Table 4 shows the dose levels.
  • the starting dose (dose level 1) was 10 mg/m 2 /day.
  • the table below lists the dose levels that were studied.
  • Table 4 Dose escalation schedule for recurrent/ progressive DIPG treated with three weeks on, one week off schedule (Stratum 1)
  • the starting dose (dose level 1) for Stratum 2 was 1 dose level above the MTD for the ‘3-weeks on, 1 -week off schedule. 10mg/m 2 /day was the MTD for the ‘3-weeks on, 1-week off schedule and thus the initial dose for the ‘every other week’ dosing schedule was16 mg/m 2 /day. Table 5 below listed the proposed dose levels to be studied.
  • panobinostat Rationale for Pharmacokinetic Studies- Hypothesis: The pharmacokinetics and tolerability of panobinostat in pediatric patients with recurrent/progressive DIPG may differ from prior studies of panobinostat in the adult population as well as in children with leukemia, and may be affected by prior treatment, age, body surface area, steroid use or concomitant medications.
  • panobinostat in pediatric patients with DIPG who have received standard radiation therapy, but have received no other systemic therapy and have not yet progressed may differ from the pharmacokinetics and tolerability of panobinostat in pediatric patients with recurrent/progressive DIPG. More likely, the pharmacokinetics and tolerability may differ with an alternative dosing schedule.
  • panobinostat is a substrate of CYP3A4, and dexamethasone is a known inducer of CYP3A4. Thus, one might expect lower exposures of panobinostat when administered concurrently with dexamethasone. It is important to therefore correlate pharmacodynamic effects of panobinostat with PK.
  • the pharmacokinetics of panobinostat may be affected by age, body surface area, steroid use or concomitant medications.
  • Inclusion Criteria- Diagnosis Patients with progressive DIPG, as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since diagnosis, OR the appearance of a new tumor lesion since diagnosis.
  • Inclusion Criteria - Diagnosis (Stratum 2): Patients with DIPG who have not yet progressed by clinical or radiographic criteria.
  • Inclusion Criteria- Age (Stratum 1 and Stratum 2): Patients must be ⁇ 2 but ⁇ 22 years of age at the time of enrollment.
  • Inclusion Criteria- BSA (Stratum 1 and Stratum 2): Patients must have a BSA ⁇ 0.80 m 2 for dose 5mg/m 2 .; patients must have a BSA ⁇ 0.65 m2 for doses of 10mg/m2 - 22 mg/m 2 .; patients must have a BSA ⁇ 0.50 m 2 for doses of 28 mg/m 2 - 36 mg/m 2 .
  • Inclusion Criteria- Ability to Swallow (Stratum 1 and Stratum 2): Patient must be able to swallow capsules whole.
  • Inclusion Criteria- Performance Status (Stratum 1 and Stratum 2): Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ⁇ 16 years of age) assessed within 7 days of enrollment must be ⁇ 50%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, are considered ambulatory for the purpose of assessing the performance score.
  • Inclusion Criteria- Prior Therapy (Stratum 1): Patients must have received a minimum of 54 Gy focal irradiation administered over approximately 42 days prior to enrollment. Patients must have recovered from the acute treatment-related toxicities (defined as ⁇ grade 1) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
  • Inclusion Criteria- Prior Therapy- Myelosuppressive Chemotherapy (Stratum 1): Patients must have received their last dose of known myelosuppressive anticancer therapy or immunotherapy at least 21 days prior to enrollment (42 days if prior nitrosourea).
  • Inclusion Criteria- Prior Therapy- Investigational/Biologic Agent (Stratum 1): Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ⁇ 7 days prior to study enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur, and discussed with the principal investigator.
  • Inclusion Criteria - Prior Therapy- Radiation Therapy (Stratum 2): Patients must have had their last fraction of focal irradiation to the primary site > 14 days prior to enrollment. Patients must not have received local palliative irradiation or craniospinal irradiation.
  • Inclusion Criteria- Growth Factors (Stratum 1 and Stratum 2): Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin). 14 days must have elapsed if patients received PEG formulations.
  • Exclusion Criteria - Prior Therapy (Stratum 2): Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation)
  • Exclusion Criteria - Neurological Status (Stratum 1 and Stratum 2): Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician.
  • Exclusion Criteria - Other malignancy (Stratum 1 and Stratum 2): Patients have a history of any other malignancy.
  • Exclusion Criteria - Transfusions (Stratum 1 and Stratum 2): Patients are known to be refractory to red blood cell or platelet transfusions.
  • Treatment Plan - Agent Administration Patients with recurrent/progressive DIPG were enrolled at the time of progression in Stratum 1. Therapy with panobinostat was administered every other day, 3 times/ week, p.o. preferably on a Monday/Wednesday/Friday schedule for three weeks, followed by one week off of therapy. Three weeks of therapy plus the one week rest period (total 4 weeks) constituted one course. Treatment continued for up to 26 courses (approximately 2 years) barring progressive disease or unacceptable toxicity.
  • Treatment Plan - Panobinostat Dosing was adjusted based on BSA calculated at the beginning of each course of therapy. The dose prescribed was rounded to the nearest deliverable dose based on the BSA adjustment and the available pill sizes. Dosing Tables which reflect this approach are available in Table 17.
  • panobinostat Patients were encouraged to take their dose of panobinostat at the same time each day, preferably in the morning. Each dose of panobinostat was taken with a 4 oz / 120 ml glass of water. Drug must be taken on an empty stomach (either 1 hour before or after meals) on Course 1 , Days 1 and 3, and may be taken with or without food for the remaining doses. Patients were instructed to swallow the capsules whole and not chew them. Patients must avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study.
  • DLT Treatment Plan - Dose-Limiting Toxicity
  • Treatment Plan - Definitions of Dose-Limiting Toxicities (DLTs) Patients who missed more than 2 doses due to toxicity were considered to have experienced a DLT.
  • Treatment Plan - Definitions of Dose-Limiting Toxicities (DLTs) Non- Hematologic DLT: Non-hematologic dose limiting toxicity was any grade 3 or greater non-hematological toxicities with the specific exclusion of the following:
  • Non-hematologic dose limiting toxicity was also any grade 2 non-hematological toxicity that persists for more than 7 days and was considered sufficiently medically significant or sufficiently intolerable by patients as to warrant treatment interruption and/or dose reduction will be considered dose limiting.
  • Non-hematologic dose limiting toxicity was also any panobinostat-related non- hematological toxicity that results in a delay of treatment > 14 days between treatment courses.
  • Treatment Plan Definitions of Dose-Limiting Toxicities (DLTs) — Hematologic DLT: Hematologic dose limiting toxicity was defined as:
  • Treatment Plan Definitions of Dose-Limiting Toxicities (DLTs) —
  • DLTs Dose-Limiting Toxicities
  • Stratum 1 Upon completion of Stratum 1 , patients with DIPG who have received adequate radiation therapy but have not yet progressed were enrolled in Stratum 2. Panobinostat was administered every other day, 3 times/week, every other week p.o. preferably on a Monday/Wednesday/Friday schedule. Total 4 weeks constituted one course. Treatment continued for up to two years (26 courses) unless the patient experienced progressive disease, unacceptable toxicity or any of the off-treatment criteria. The starting dose (dose level 1) for Stratum 2 was 1 dose level above the highest safe dose for the ‘3-weeks on, 1-week off schedule as determined in Stratum 1.
  • Concomitant Medications and Supportive Care Guidelines - Potential QTc prolonging medications Concomitant medications which can prolong the QTc interval were used. Please see Table 7.
  • Ta ble 10 Common Sensitive CYP2D6 Substrates _
  • Concomitant Medications and Supportive Care Guidelines - Febrile Neutropenia Febrile neutropenia was managed according to the local institutional guidelines. Measures include laboratory testing, blood and urine cultures, and institution of broad spectrum antibiotics.
  • medication e.g., Bactrim
  • Table 12 Criteria for dosing delays, dose-reductions, and re-initiation of treatment due to study drug-related non-hematological toxicity (excluding QT prolongation)
  • Dose Modification for Hematological Toxicity If a patient experienced dose- limiting hematological toxicity (i.e. grade 4 thrombocytopenia [ ⁇ 25 x 10 9 /L] or grade 3 thrombocytopenia [ ⁇ 50 and ⁇ 25 x 10 9 /L] with bleeding, or grade 3 twice within 1 treatment course or grade 4, or grade 3 or 4 febrile neutropenia) treatment was withheld. Platelets were transfused to a count of > 100 x 10 9 /L (i.e. a post-transfusion platelet count should be obtained). Counts were checked every 3-4 days (and when medically indicated) during this time.
  • dose- limiting hematological toxicity i.e. grade 4 thrombocytopenia [ ⁇ 25 x 10 9 /L] or grade 3 thrombocytopenia [ ⁇ 50 and ⁇ 25 x 10 9 /L] with bleeding, or grade 3 twice within 1 treatment course or grade 4, or grade 3 or 4 febrile neutropenia
  • QTcF is ⁇ 450 msec or above 60 msec from pre-treatment ECG, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia) were corrected, and triplicate ECGs (5 minutes apart) were conducted and average QTcF was calculated. If the average QTcF from the triplicate ECGs remained ⁇ 450ms, the patient was not be dosed.
  • Pre- dose ECG monitoring was mandatory on days 1 and 5 of course 1 , and day 1 of courses 2 through 4.
  • Post dose ECG (3 hours post dosing) was mandatory only on days land 5 of course 1. On day 5 of course 1, ECG was be performed at a local institution but results were faxed to treating institution within the same day.
  • ECG pre-treatment or post-dose ECG shows a QTcF ⁇ 500ms
  • patient was not eligible for further treatment. If any of these mandatory ECGs show QTcF ⁇ 450 msec or 60 msec above baseline, dosing was held and the above specified measures including follow-up triplicate ECGs and correction of electrolyte abnormalities were performed. If QTcF abnormality resolved, patients resumed treatment and had QTcF checked pre-dose on day 1 of each course for at least the next 3 subsequent courses. Additional QTcF monitoring was performed if clinically indicated. If a patient could not be dosed due to prolonged QTcF for more than 7 days since last dose, the patient was discontinued from study treatment.
  • Ad erse Events and Potential Risks for Panobinostat Very common adverse events occurring in ⁇ 10% of subjects treated with panobinostat are found in Table 14.
  • Table 14 Very Common Adverse Effects in Subjects Treated with Panobinostat
  • Common adverse events occurring in 1 % to 9 % of subjects treated with panobinostat are found in Table 15.
  • Adverse Event Characteristics Adverse events were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
  • Brain Magnetic Resonance with and without gadolinium were obtained on a 1.5 T magnet.
  • Exemplary images include:
  • MRI imaging was also conducted of the spine.
  • Sagittal T1 images were after gadolinium (slice thickness 3 mm skip 0).
  • Axial T 1 images were after gadolinium (slice thickness 3mm skip 0).
  • Axial T2 images were optional.
  • Measurement of Effect Patients with measurable disease were assessed by standard criteria. For the purposes of this study, patients were re-evaluated by MRI after every 2 courses for the first 6 courses, then every 3 courses and when clinically indicated until disease progression or off-study criteria were met. [0360] Definitions - Evaluable for Radiographic Response: Only those patients who had measurable disease present at baseline, had received at least one course of therapy, and had their disease re-evaluated were considered evaluable for response. These patients will have their response classified according to the definitions stated below. Patients who exhibited objective disease progression prior to the first scheduled MRI were considered evaluable.
  • CR Tumor Response Criteria - Complete Response
  • Tumor Response Criteria - Partial Response Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as compared with the baseline measurements, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination. Axial FLAIR images were used for tumor measurements.
  • Tumor Response Criteria - Stable Disease Neurologic exam is at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither the criteria for PR nor the criteria for Progressive Disease.
  • Tumor Response Criteria - Progressive Disease Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a greater than 25% increase in the bi- dimensional measurement, taking as a reference the smallest disease measurement recorded since the start of protocol therapy, OR the appearance of a new tumor lesion.
  • Increasing doses of corticosteroids required to maintain stable neurological status were strongly considered as a sign of clinical progression unless in the context of recent wean or transient neurologic change due e.g. to radiation effects.
  • PFS Tumor Response Criteria - Progressive-Free Survival

Abstract

The present disclosure provides novel methods for treatment of brain cancer. The treatment methods utilize panobinostat as a monotherapy or a combination therapy for treatment of brain cancer. The disclosure further relates to methods for treating diffuse intrinsic pontine glioma (DIPG).

Description

METHODS OF TREATING BRAIN CANCER WITH PANOBINOSTAT
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001]This application claims priority to U.S. Provisional Application No. 62/966,795, filed January 28, 2020, which is incorporated by reference herein in its entirety.
BACKGROUND
[0002] Panobinostat is currently indicated for the treatment of multiple myeloma in patients that have received at least two prior regimens, including bortezomib and an immunomodulatory agent. It is available as the anhydrous lactate salt under the trade name of FARYDAK®. Panobinostat is a histone deacetylase inhibitor. Panobinostat is thought to elicit antitumor activity primarily through epigenetic modulation of gene expression and inhibition of protein metabolism. Inhibition of class I histone deacetylases (HDACs), which target histones and transcription factors such as p53, may help reactivate epigenetically silenced tumor suppressor genes and modify gene expression via inhibition of signal transducer and activator of transcription 3, protein kinase B (Akt), and hypoxia-inducible factor 1a.
[0003] Brain cancer is one of the deadliest forms of cancer. The five-year survival rate for all brain tumors, including non-cancerous tumors, is 33 %. More than two-thirds of adults with glioblastoma, an aggressive form of brain cancer, will die within two years of diagnosis. Children diagnosed with diffuse intrinsic pontine glioma (DIPG) face the same prognosis as children diagnosed 40 years ago. Only 10 % of children with DIPG survive for two years following their diagnosis, and less than 1 % survive for five years. [0004] A number of factors make brain cancers difficult to treat, including the complexity of brain cancers and the accessibility of tumors. Many malignant brain tumors are heterogeneous, containing various subpopulations of cancer cells, some of which respond to treatment and some of which do not. Additionally, brain tumors may be difficult to remove surgically because of their proximity to critical structures in the brain. Additionally, many therapeutic agents cannot reach the brain due to the blood-brain barrier. Therefore, there is a medical need for the development of new therapeutics for brain cancer.
SUMMARY [0005] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering a histone deacetylase inhibitor of Formula I, such as panobinostat.
[0006] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof.
[0007] In some embodiments, panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course.
[0008] In some embodiments, panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
[0009] In some embodiments, panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
[0010] In some embodiments, panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1, 2, and 3 and a rest period on week 4.
[0011] In some embodiments, panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 , 2, and 3 and a rest period on week 4, wherein panobinostat or the pharmaceutically acceptable salt thereof is administered up to three times per treatment period.
[0012] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma (DIPG), ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, and pineal tumor. [0013] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG.
[0014] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein the DIPG is non-progressed DIPG.
[0015] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein the DIPG is progressed or recurrent DIPG.
[0016] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering an MTD of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is optionally DIPG.
[0017] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the patient exhibits mutations in one or more genes selected from the group consisting of H3F3A, HIST1H3B, HIST1H3C, TP53, ACVR1 , PDGFRA, PPM1 D, PIK3CA, PIK3R1 , MYC, MYCN, and PPM1 D.
[0018] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, and wherein after administering panobinostat, the patient’s overall survival is improved compared to the median survival for a patient treated with a standard protocol for DIPG.
[0019] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG. [0020] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient exhibits a partial response.
[0021] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof, comprising administering a dose of panobinostat selected from the group consisting of 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, and 60 mg.
[0022] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof. [0023] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course.
[0024] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4. In some embodiments, panobinostat or a pharmaceutically acceptable salt thereof is administered at an MTD of 28 mg/m2/day. [0025] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4, and wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period. In some embodiments, panobinostat or a pharmaceutically acceptable salt thereof is administered at an MTD of 28 mg/m2/day. [0026] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 , 2, and 3 and a rest period on week 4. In some embodiments, panobinostat or a pharmaceutically acceptable salt thereof is administered at an MTD of 10 mg/m2/day. [0027] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course, wherein the course has a treatment period on weeks 1 , 2, and 3 and a rest period on week 4, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period. In some embodiments, panobinostat or a pharmaceutically acceptable salt thereof is administered at an MTD of 10 mg/m2/day.
[0028] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma (DIPG), ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, and pineal tumor. [0029] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG.
[0030] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein the DIPG is non-progressed DIPG. [0031] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein the DIPG is progressed or recurrent DIPG. [0032] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the patient in need thereof exhibits mutations in one or more genes selected from the group consisting of H9K27M, H3F3A, HIST1H3B, HIST1H3C, TP53, ACVR1, PDGFRA, PPM1 D, PIK3CA, PIK3R1, MYC, MYCN, and PPM1 D.
[0033] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median survival for a patient treated with a standard protocol for DIPG.
[0034] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
[0035] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient exhibits a partial response.
[0036] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the dose of panobinostat is selected from the group consisting of 5 mg/m2/day, 10 mg/m2/day, 16 mg/m2/day, 22 mg/m2/day, 28 mg/m2/day, and 36 mg/m2/day. [0037] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof, wherein the dose is selected based on the patient’s body surface area.
[0038] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course.
[0039] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
[0040] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
[0041] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the course has a treatment period on weeks 1 , 2, and 3 and a rest period on week 4.
[0042] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the course has a treatment period on weeks 1, 2, and 3 and a rest period on week 4, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
[0043] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, and pineal tumor. [0044] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG.
[0045] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, and wherein the DIPG is non-progressed DIPG.
[0046] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, and wherein the DIPG is progressed or recurrent DIPG.
[0047] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the patient in need exhibits mutations in one or more genes selected from the group consisting of H9K27M, H3F3A, HIST1H3B, HIST1 H3C, TP53, ACVR1 , PDGFRA, PPM1 D, PIK3CA, PIK3R1 , MYC, MYCN, and PPM1D.
[0048] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof.
[0049] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, comprising administering comprising administering a dose of about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof.
[0050] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, comprising administering a dose based on the patient in need’s body surface area (BSA).
[0051] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median overall survival for a patient treated with a standard protocol for DIPG.
[0052] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
[0053] In some embodiments, the disclosure provides a method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course, wherein the brain cancer is DIPG, wherein after administering panobinostat, the patient exhibits a partial response.
BRIEF DESCRIPTION OF THE FIGURES
[0054] Figs. 1 A -11 show the in vivo and in vitro efficacy of panobinostat. Fig. 1 A shows a decrease in DIPG cell proliferation upon treatment with panobinostat. Fig. 1B shows tumor cell death in tumor cells treated with panobinostat. Fig. 1C shows normalization of histone 3 K27 methylation in H3.3K27M mutant DIPG cells or293T cells expressing an H3.3K27M construct54. Fig. 1D shows a cartoon of an orthotopic model of DIPG. Fig. 1 E shows a tumor on a mouse brain after treatment with panobinostat. Fig. 1 F shows in vivo bioluminescent images of mice treated with panobinostat (T) and not treated with panobinostat (C). Fig. 1G shows the effect of panobinostat on tumor xenograft growth. Fig. 1 H shows the reduction in tumor growth in panobinostat-treated animals at 1 week in 10 mg/kg and 20 mg/kg treatment groups compared to vehicle- treated controls (n=5 per group and 7 per group; P < 0.05 and 0.01 by two-tailed t test, respectively). Fig. I shows that treatment with panobinostat in a patient-derived DIPG brainstem orthotopic xenograft model (IBs-w0128DIPG, derived from case Ll-F; H3WT subtype) results in significantly prolonged survival in the mice treated with panobinostat compared to controls. DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0055] Any term or expression not expressly defined herein shall have its commonly accepted definition understood by those skilled in the art. To the extent that the following description is of a specific embodiment or a particular use of the invention, it is intended to be illustrative only, and not limiting of the claimed invention. The following description is intended to coverall alternatives, modifications and equivalents that are included in the spirit and scope of the invention, as defined in the appended claims.
[0056] As used herein, “treat” or “treating” means one or more of relieving, alleviating, delaying, reducing, reversing, improving, or managing at least one symptom of a condition in a subject. The term "treating" may also mean one or more of arresting, delaying the onset (i.e. , the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
[0057] As defined herein, “standard treatment” for DIPG is radiation therapy.
[0058]As defined herein, a “maintenance therapy” is treatment administered to prevent cancer after it has disappeared following the initial therapy.
[0059]As defined herein, non-progressed DIPG is DIPG that has not progressed by clinical or radiographic criteria.
[0060] As defined herein, patients with progressive DIPG have progressive disease. [0061]As defined herein, patients with recurrent DIPG have exhibited an initial reduction in tumor size after radiotherapy, but tumor size subsequently increased. [0062]As defined herein, a therapeutic “PO administration” refers to oral administration.
[0063] As defined herein, “TIW administration” refers to administration three times per week.
[0064] As used herein, the term “maximum tolerated dose” (MTD) refers to the highest dose of a drug (e.g. a HDAC inhibitor) that does not cause unacceptable side effects. In some embodiments, the MTD also displays efficacy (e.g., as described herein, including but not limited to, improving survival, decreasing tumor size, etc.). In some embodiments, the HDAC inhibitor is administered at the MTD.
[0065] As used herein, “unsubstituted” means that there is no substituent or that the only substituents are hydrogen. [0066] In some embodiments, the disclosure refers to “halo” substituents, also known as “halogen” substituents. Halo substituents are selected from fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
[0067] In some embodiments, the compounds of the present disclosure include alkyl substituents, which include straight and branched-C1-C6alkyl, unless otherwise noted. Examples of suitable straight- and branched-C1-C6alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl and the like. Unless otherwise noted, the alkyl substituents include both unsubstituted alkyl groups and alkyl groups that are substituted by one or more suitable substituents, including unsaturation, i.e. , there are one or more double or triple C — C bonds; acyl; cycloalkyl; halo; oxyalkyl; alkylamino; aminoalkyl; acylamino; and OR15, e.g., alkoxy.
[0068]As used herein, cycloalkyl substituents include C6-C9cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. Unless otherwise noted, cycloalkyl substituents include both unsubstituted cycloalkyl groups and cycloalkyl groups that are substituted by one or more suitable substituents, including C1-C6alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR1s, such as alkoxy.
[0069] The above discussion of alkyl and cycloalkyl substituents also applies to the alkyl portions of other substituents, such as, without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.
[0070] Heterocycloalkyl substituents include 3- to 9-membered aliphatic rings, such as 4- to 7-membered aliphatic rings, containing from 1-3 heteroatoms selected from nitrogen, sulfur, oxygen. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1,4-diazapane, 1,4-oxazepane and 1,4- oxathiapane. Unless otherwise noted, the rings are unsubstituted or substituted on the carbon atoms by one or more suitable substituents, including C1-C6alkyl; C4- C9cycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; halo; amino; alkyl amino and OR15, e.g., alkoxy. Unless otherwise noted, nitrogen heteroatoms are unsubstituted or substituted by H, C1-C4alkyl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; acyl; aminoacyl; alkylsulfonyl; and arylsulfonyl. [0071]Cycloalkylalkyl substituents include compounds of the formula — (CH2)ns- cycloalkyl, wherein ns is a number from 1-6. Suitable alkylcycloalkyl substituents include cyclopentyl methyl, cyclopentylethyl, cyclohexyl methyl and the like. Such substituents are unsubstituted or substituted in the alkyl portion or in the cycloalkyl portion by a suitable substituent, including those listed above for alkyl and cycloalkyl. [0072] Aryl substituents include unsubstituted phenyl and phenyl substituted by one or more suitable substituents including C1-C6alkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; 0(C0)alkyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; aminosulfonyl; arylsulfonyl and OR15, such as alkoxy.
[0073] Aromatic polycycles include naphthyl, and naphthyl substituted by one or more suitable substituents including C-Calkyl; alkylcycloalkyl, e.g., cyclopropylmethyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkylketones; nitrile; carboxyalkyl; alkylsulfonyl: arylsulfonyl; aminosulfonyl and OR15, such as alkoxy.
[0074] Heteroaryl substituents include compounds with a 5- to 7-membered aromatic ring containing one or more heteroatoms, e.g., from 1-4 heteroatoms, selected from N, O and S. Typical heteroaryl substituents include furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine and the like. Unless otherwise noted, heteroaryl substituents are unsubstituted or substituted on a carbon atom by one or more suitable substituents, including alkyl, the alkyl substituents identified above, and another heteroaryl substituent. Nitrogen atoms are unsubstituted or substituted, e.g., by R13; e.g., useful N substituents include H, C1- C4alkyl, acyl, aminoacyl and sulfonyl.
[0075] Arylalkyl substituents include groups of the formula — (CH2)ns-aryl, — (CH2)ns- 1 — (CH-aryl)-(CH2)n5-aryl or — (CH2)n5-iCH(aryl)(aryl), wherein aryl and n5 are defined above. Such arylalkyl substituents include benzyl, 2-phenylethyl, 1-phenylethyl, tolyl- 3-propyl, 2-phenylpropyl, diphenylmethyl, 2-diphenylethyl, 5,5-dimethyl-3- phenylpentyl and the like. Arylalkyl substituents are unsubstituted or substituted in the alkyl moiety or the aryl moiety or both as described above for alkyl and aryl substituents.
[0076] Heteroarylalkyl substituents include groups of the formula — (CH2)ns-heteroaryl, wherein heteroaryl and n5 are defined above and the bridging group is linked to a carbon or a nitrogen of the heteroaryl portion, such as 2-, 3- or 4-pyridylmethyl, imidazolylmethyl, quinolylethyl and pyrrolylbutyl. Heteroaryl substituents are unsubstituted or substituted as discussed above for heteroaryl and alkyl substituents. [0077]Amino acyl substituents include groups of the formula — C(O) — (CH2)n — C(H)(NRI3RI4) — (CH2)n — R5, wherein n, R13, R and Rs are described above. Suitable aminoacyl substituents include natural and non-natural amino acids, such as glycinyl, D-tryptophanyl, L-lysinyl, D- or L-homoserinyl, 4-aminobutryic acyl and ±-3-amin-4- hexenoyl.
[0078] Non-aromatic polycycle substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered and each ring can contain zero, one or more double and/or triple bonds. Suitable examples of non-aromatic polycycles include decalin, octahydroindene, perhydrobenzocycloheptene and perhydrobenzo[f]- azulene. Such substituents are unsubstituted or substituted as described above for cycloalkyl groups.
[0079] Mixed aryl and non-aryl polycycle substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered and at least one ring is aromatic. Suitable examples of mixed aryl and non-aryl polycycles include methylenedioxyphenyl, bis-methylenedioxyphenyl, 1 ,2,3,4-tetrahydronaphthalene, dibenzosuberane, dihdydroanthracene and 9H-fluorene. Such substituents are unsubstituted or substituted by nitro or as described above for cycloalkyl groups. [0080] Polyheteroaryl substituents include bicyclic and tricyclic fused ring systems where each ring can independently be 5- or 6-membered and contain one or more heteroatom, e.g., 1 , 2, 3 or 4 heteroatoms, chosen from O, N or S such that the fused ring system is aromatic. Suitable examples of polyheteroaryl ring systems include quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline and the like. Unless otherwise noted, polyheteroaryl substituents are unsubstituted or substituted on a carbon atom by one or more suitable substituents, including alkyl, the alkyl substituents identified above and a substituent of the formula — O — (CH2CH=CH(CH3)(CH2))I-3H. Nitrogen atoms are unsubstituted or substituted, e.g., by
R13, e.g., useful N substituents include H, acyl, aminoacyl and sulfonyl.
[0081] Non-aromatic polyheterocyclic substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered, contain one or more heteroatom, e.g., 1, 2, 3 or 4 heteroatoms, chosen from O, N or S and contain zero or one or more C — C double or triple bonds. Suitable examples of non-aromatic polyheterocycles include hexitol, cis-perhydro-cyclohepta[b]pyridinyl, decahydro- benzo[f][1 ,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octane, hexahydro-thieno[3,2- b]thiophene, perhydropyrrolo[3,2-b]pyrrole, perhydronaphthyridine, perhydro-1H- dicyclopenta[b,e]pyran. Unless otherwise noted, non-aromatic polyheterocyclic substituents are unsubstituted or substituted on a carbon atom by one or more substituents, including alkyl and the alkyl substituents identified above. Nitrogen atoms are unsubstituted or substituted, e.g., by R13, e.g., useful N substituents include H, C1- C4alkyl, acyl, aminoacyl and sulfonyl.
[0082] Mixed aryl and non-aryl polyheterocycles substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered, contain one or more heteroatom chosen from O, N or S, and at least one of the rings must be aromatic. Suitable examples of mixed aryl and non-aryl polyheterocycles include 2,3- dihydroindole, 1 ,2,3,4-tetrahydroquinoline, 5,11 -dihydro-10H- dibenz[b,e][1 ,4]diazepine, 5H-dibenzo[b,e][1 ,4]diazepine, 1 ,2-dihydropyrrolo[3,4- b][1 ,5]benzodiazepine, 1 ,5-dihydro-pyrido[2,3-b][1 ,4]diazepin-4-one, 1 ,2, 3, 4, 6, 11- hexahydro-benzo[b]pyrido[2,3-e][1 ,4]diazepin-5-one. Unless otherwise noted, mixed aryl and non-aryl polyheterocyclic substituents are unsubstituted or substituted on a carbon atom by one or more suitable substituents including — N — OH, =N — OH, alkyl and the alkyl substituents identified above. Nitrogen atoms are unsubstituted or substituted, e.g., by R13; e.g., useful N substituents include H, C1-C4alkyl, acyl, aminoacyl and sulfonyl.
[0083]Amino substituents include primary, secondary and tertiary amines and in salt form, quaternary amines. Examples of amino substituents include mono- and di- alkylamino, mono- and di-aryl amino, mono- and di-arylalkyl amino, aryl- arylalkylamino, alkyl-arylamino, alkyl-arylalkylamino and the like.
[0084] Sulfonyl substituents include alkylsulfonyl and arylsulfonyl, e.g., methane sulfonyl, benzene sulfonyl, tosyl and the like.
[0085] Acyl substituents include groups of formula — C(O) — W, — OC(O) — W, — C(O) — O — Wor — C(O)NR13R14, where W is R16, H or cycloalkylalkyl. [0086]Acylamino substituents include substituents of the formula — N(R12)C(O) — W, — N(RI2)C(O)— O— W and — N(R12)C(O) — NHOH and R12 and W are defined above. [0087]The R2 substituent HON — C(O) — CH=C(R1)-aryl-alkyl- is a group of the formula:
Figure imgf000017_0001
Treatment of Brain Cancer
[0088] The BBB is a highly selective semipermeable border that separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS). The BBB protects the brain against pathogens (e.g., viruses) and other dangers of the circulatory system, including changes in the composition of the systemic blood supply (e.g., electrolyte levels). The barrier is not complete, however, and permits entry of certain substances, such as small fat-soluble (lipophilic) molecules that can freely diffuse through the barrier. The BBB also permits entry of essential nutrients, such as glucose and amino acids, which are vital to brain function. These nutrients are generally water soluble (hydrophilic), and require more complex mechanisms for crossing the BBB, such as carrier-mediated transport, receptor- mediated transcytosis and absorptive-mediated transcytosis.
[0089] While protective under normal circumstances, the BBB frustrates delivery of therapeutic agents to the brain. It has been reported that the BBB blocks delivery of more than 98% of central nervous system (CNS) therapeutic agents.
[0090] Without being bound by theory, there is contradictory evidence regarding panobinostat’s ability to penetrate the BBB. While efficacy in brain cancers suggests that panobinostat cross the BBB, Applicant’s studies described herein indicate limited penetration of cerebrospinal fluid (CSF), which is a surrogate of CNS tissue penetration and consequently BBB penetration (see, e.g., Example 7). In some embodiments, the methods of the present disclosure are utilized to treat brain cancers. Non-limiting examples of brain cancers include acoustic neuromas, astrocytomas, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, diffuse pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, and pineal tumors. [0091] In some embodiments, the methods of the disclosure are used to treat gliomas. Gliomas are tumors that occur in the brain and/or spinal cord. Ependymomas, astrocytomas, and oligodendrogliomas are the three types of gliomas. Glioblastoma, astrocytoma, and anaplastic astrocytoma are examples of astrocytomas. Oligodendroglioma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma are examples of oligodendrogliomas. Anaplastic ependymoma, myxopapillary ependymoma, and subependymoma are examples of ependymomas. Gliomas are diagnosed by biopsy, computed tomography (CT) scan, or magnetic resonance imaging (MRI). In some embodiments, the methods of the disclosure are used to treat patients with high grade glioma as determined by World Health Organization (WHO) criteria.
[0092] Diffuse intrinsic pontine gliomas (DIPG) are high grade gliomas affecting children, adolescents, and young adults. They are characterized by infiltrative tumors affecting the brainstem. A DIPG tumor has a pontine epicenter and diffuse involvement of more than 2/3 of the pons, as determined by magnetic resonance imaging (MRI). Warren describes measurement of the pons in her article: Warren. CNS Oncol. 2014 May; 3(3): 181-183, which is incorporated by reference herein in its entirety.
[0093] In some embodiments, the methods of the present disclosure are used to treat patients with pontine lesions that do not exhibit the criteria for radiographically typical DIPG, but have histologic confirmation of malignant glioma as determined by WHO II- IV criteria.
[0094] DIPG is the leading cause of brain tumor death in children. The median overall survival (OS) is between 8 and 12 months, and an OS of less than 1% at 5 years from diagnosis. Due to the location of the tumor on the brain stem and the tumors infiltrative nature, surgery is not considered as a treatment option. At the time of this disclosure, radiation is the only treatment for DIPG with proven efficacy, albeit limited. Current radiotherapy is typically provided over six weeks, and results in limited progression- free survival (PFS) or OS measured in months. There are no proven chemotherapies that have been shown to increase either PFS or OS, despite multiple efforts using alkylating agents (e.g. cisplatin, temozolomide, carboplatin) alone or in combination with radiotherapy. Agents targeting tyrosine kinases (tyrosine kinase inhibitors) and the estrogen receptor (e.g. tamoxifen) alone or in combination with radiotherapy have also been proven ineffective for the treatment of DIPG.
[0095] Examination of magnetic resonance imaging (MRI) scans reveals that patients with DIPG have an absence of irregular contrast enhancements, which is consistent with preservation of the blood-brain barrier (BBB). Because most agents do not cross the BBB, treatment of DIPG poses a significant challenge. Furthermore, DIPG patients exhibit epigenetic changes associated with histone acetylation mutations, resulting in global hypomethylation patterns, a poor response to radiotherapy, relapse, and metastasis. Therefore, there is a need for an improved method to treat DIPG.
Histone deacetylase (HD AC) inhibitors
[0096] In some embodiments, histone deacetylase (HDAC) inhibitors are administered to treat brain cancer. HDAC inhibitors are a class of compounds that inhibit the activity of histone deacetylase enzymes. HDAC inhibition leads to an increase in acetylation of lysine residues on histone proteins as well as other nonhistone proteins. In some embodiments, a histone deacetylase inhibitor is administered for the treatment of brain cancer. In some embodiments, a histone deacetylase inhibitor is administered for the treatment of brain cancer, such as glioma, high grade glioma, or DIPG. In some embodiments, the histone deacetylase inhibitor has the following structure:
Figure imgf000019_0001
wherein
R1 is H; halo; or a straight-chain C1-C6alkyl, e.g., methyl, ethyl or n-propyl, in which methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described herein for alkyl substituents;
R2 is selected from H; C1-C10alkyl, e.g., C1-C6alkyl, e.g., methyl, ethyl or - CH2CH2-OH; C4-C9cycloalkyl; C1-C9heterocycloalkyl; C1-C9heterocycloalkylalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; -(CH2)nC(O)R6 ; -(CH2)nOC(O)R6 ; amino acyl; HON-C(O)-CH=C(R1)-arylalkyl-; and -(CH2)nR7;
R3 and R4 are the same or different and, independently, H, C1-C6alkyl, acyl or acylamino, or
R3 and R4, together with the carbon to which they are bound, represent C=0, C=S or C=NR8 ,or
R2, together with the nitrogen to which it is bound, and R3, together with the carbon to which it is bound, can form a C4-C9heterocycloalkyl, a heteroaryl, a polyheteroaryl, a nonaromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;
R5 is selected from H; C1-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; acyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; aromatic polycycles; non-aromatic polycycles; mixed aryl and non-aryl polycycles; polyheteroaryl; non-aromatic polyheterocycles; and mixed aryl and non-aryl polyheterocycles; n, n1, n2 and n3 are the same or different and independently selected from 0-6, when ni is 1-6, each carbon atom can be optionally and independently substituted with
R3 and/or R4;
X and Y are the same or different and independently selected from H; halo; Ci- C4alkyl, such as CH3 and CF3; NO2; C(O)R1; OR9; SR9; CN; and NR10R11;
R6 is selected from H; C1-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl and 2- phenylethenyl; heteroarylalkyl, e.g., pyridylmethyl; OR12; and NR13R14;
R1 is selected from OR15, SR15, S(O)R16. SO2R17, NR13R14 and NR12SO2R6;
Rs is selected from H; OR15; NR13R14; C1-C6alkyl; C4-C9cycloalkyl; C4- C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl; R9 is selected from C1- C4alkyl, e.g., CH3 and CF3; C(O)-alkyl, e.g., C(O)CH3; and C(O)CF3;
R10 and R11 are the same or different and independently selected from H, C1- C4alkyl and -C(O)-alkyl;
R12 is selected from H; C1-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; C4- C9heterocycloalkylalkyl; aryl; mixed aryl and non-aryl polycycle; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl;
R13 and R14 are the same or different and independently selected from H; C1- C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; amino acyl, or
R13 and R14, together with the nitrogen to which they are bound, are C4- C9heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle, or mixed aryl and non-aryl polyheterocycle;
R15 is selected from H, C1-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R16 is selected from Ci-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12;
R17 is selected from Ci-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14; m is an integer selected from 0-6; and
Z is selected from O, NR1, S and S(O).
[0097] Additional examples of HDAC inhibitors that may be used with the methods disclosed herein may be found in U.S. Pat. No. 6,833,384, which is herein incorporated by reference in its entirety.
Panobinostat
[0098] In some embodiments, the compound of formula I is panobinostat. The structure of panobinostat is:
Figure imgf000021_0001
Panobinostat is a small molecule chemotherapeutic, currently approved for the treatment of multiple myeloma and sold under the name FARYDAK®. The chemical name of panobinostat is 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3- yl)ethyl]amino]methyl]phenyl]-2-propenamide. Panobinostat is a potent class I/ll pan- deacetylase inhibitor (DACi) that increases histone acetylation in peripheral blood leukocytes and bone marrow biopsies at low doses. Panobinostat enhances histone acetylation by potently inhibiting deacetylase enzymes involved in reducing the overall acetylation levels.
[0099] In some embodiments, brain cancer patients are treated with panobinostat. In some embodiments, DIPG patients are treated with an HDAC inhibitor (e.g. panobinostat). In some embodiments, patients with recurrent DIPG are administered an HDAC inhibitor (e.g. panobinostat). In some embodiments, patients with non- progressed DIPG are administered an HDAC inhibitor (e.g. panobinostat). In some embodiments, patients with progressive DIPG are administered an HDAC inhibitor (e.g. panobinostat). In some embodiments, an HDAC inhibitor (e.g. panobinostat) is administered to DIPG patients prior to administration of radiation therapy. In some embodiments, an HDAC inhibitor (e.g. panobinostat) is administered to a DIPG patient at the same time of radiation therapy administration. In some embodiments, an HDAC inhibitor (e.g. panobinostat) is administered to a DIPG patient after the patient has received radiation therapy.
[0100] In some embodiments, an HDAC inhibitor (e.g. panobinostat) is administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts and amino acid addition salts and sulfonate salts. Acid addition salts include inorganic acid addition salts, such as hydrochloride, sulfate and phosphate; and organic acid addition salts, such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate. Examples of metal salts are alkali metal salts, such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts, such as magnesium salt and calcium salt, aluminum salt and zinc salt. Examples of ammonium salts are ammonium salt and tetramethylammonium salt. Examples of organic amine addition salts are salts with morpholine and piperidine. Examples of amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine. Sulfonate salts include mesylate, tosylate and benzene sulfonic acid salts. In some embodiments, the salt of an HDAC inhibitor (e.g. panobinostat) is the lactate salt, e.g. the anhydrous lactate form, described in WO2007/146715, which is herein incorporated by reference in its entirety.
[0101] In some embodiments, an HDAC inhibitor (e.g. panobinostat) is administered a lactate salt (e.g. panobinostat lactate). The structure of panobinostat lactate is:
Figure imgf000022_0001
[0102] The chemical formula of panobinostat lactate is C21H23N3O2 *C3H6O3.
[0103] In some embodiments, an HDAC inhibitor (e.g. panobinostat) is administered as a monohydrate e.g. panobinostat is administered as panobinostat monohydrate. The chemical formula of panobinostat monohydrate is C21H23N3O2*H2O. [0104] In some embodiments, an HDAC inhibitor (e.g. panobinostat) is administered as a polymorph. In some embodiments, the polymorph is an anhydrous lactate salt. Polymorphs of panobinostat are described in US 7,989,494, which is herein incorporated by reference in its entirety. As used herein, panobinostat refers to the free base, any pharmaceutically acceptable salt, or polymorphic form of panobinostat. [0105]The HDAC inhibitor (e.g., panobinostat) may be administered by any suitable method. In some embodiments, the HDAC inhibitor (e.g., panobinostat) can be administered by a variety of means including orally and parenterally. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, intrathecal, intraventricular, and intraarterial injections with a variety of infusion techniques. Intraarterial, intrathecal, intraventricular, and intravenous injection as used herein includes administration through catheters. For example, catheters can be used to facilitate injection of the HDAC inhibitor (e.g., panobinostat) into the spinal canal, or into the subarachnoid space.
[0106] HDAC inhibitors (e.g. panobinostat) may be administered in any suitable formulation. Non-limiting examples of suitable formulations include solid oral formulations, such as tablets and gel capsules. For example, panobinostat may be administered in gelatin capsules containing 5, 10, 15, or 20 mg of panobinostat by weight of free base and the following inactive ingredients: magnesium stearate, mannitol, microcrystalline cellulose and pregelatinized starch. The capsules may contain gelatin, FD & C Blue 1 (10 mg capsules), yellow iron oxide (10 mg and 15 mg capsules), red iron oxide (15 mg and 20 mg capsules) and titanium dioxide.
[0107] In embodiments, panobinostat is administered at the current FDA approved dose as of the filing date of the present application. Panobinostat has been approved at doses of 10 mg, 15 mg, and 20 mg for the treatment of multiple myeloma.
[0108] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose ranging from about 10 mg to about 100 mg, including about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 g, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg, including all values and ranges in between.
[0109] In particular embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose ranging from about 25 mg to about 60 mg. In some embodiments, panobinostat is administered at a dose of about 25 mg. In some embodiments, panobinostat is administered at a dose of about 30 mg. In some embodiments, panobinostat is administered at a dose of about 35 mg. In some embodiments, panobinostat is administered at a dose of about 40 mg. In some embodiments, panobinostat is administered at a dose of about 45 mg. In some embodiments, panobinostat is administered at a dose of about 50 mg. In some embodiments, panobinostat is administered at a dose of about 55 mg.
[0110] In some embodiments, a patient is administered a HDAC inhibitor (e.g. panobinostat) or any other therapeutic agent based on the patient’s body surface area (BSA). In some embodiments, a patient’s body surface area is calculated according to the following formula: BSA= weight (kg)0 425 x height (cm)0 725 x 0.007184. In some embodiments, a patient’s body surface area is calculated according to the following
Figure imgf000024_0001
[0111] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose from about 1 mg/m2/day to about 40 mg/m2/day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at about 1 mg/m2/day, about 2 mg/m2/day, about 3 mg/m2/day, about 4 mg/m2/day, about 5 mg/m2/day, about 6 mg/m2/day, about 7 mg/m2/day, about 8 mg/m2/day, about 9 mg/m2/day, about 10 mg/m2/day, about 11 mg/m2/day, about 12 mg/m2/day, about 13 mg/m2/day, about 14 mg/m2/day, about 15 mg/m2/day, about 16 mg/m2/day, about 17 mg/m2/day, about 18 mg/m2/day, about 19 mg/m2/day, about 20 mg/m2/day, about 21 mg/m2/day, about 22 mg/m2/day, about 23 mg/m2/day, about 24 mg/m2/day, about 25 mg/m2/day, about 26 mg/m2/day, about 27 mg/m2/day, about 28 mg/m2/day, about 29 mg/m2/day, about 30 mg/m2/day, about 31 mg/m2/day, about 32 mg/m2/day, about 33 mg/m2/day, about 34 mg/m2/day, about 35 mg/m2/day, about 36 mg/m2/day, about 37 mg/m2/day, about 38 mg/m2/day, about 39 mg/m2/day, or about 40 mg/m2/day, including all values and ranges in between these values. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 5 mg/m2/day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 10 mg/m2/day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 16 mg/m2/day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 22 mg/m2/day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 28 mg/m2/day. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered at a dose of 36 mg/m2/day.
[0112] In some embodiments, patients with a BSA ≥ 0.80 m2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 5 mg/m2/day. In some embodiments, patients with a BSA ≥ 0.65 m2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 10 mg/m2/day. In some embodiments, patients with a BSA ≥ 0.65 m2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 16 mg/m2/day. In some embodiments, patients with a BSA ≥ 0.65 m2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 22 mg/m2/day. In some embodiments, patients with a BSA ≥ 0.50 m2 are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 28 mg/m2/day. In some embodiments, patients that are administered a HDAC inhibitor (e.g. panobinostat) at a dose of 36 mg/m2/day exhibit a BSA ≥ 0.50 m2.
[0113] In some embodiments, patients are administered a HDAC inhibitor (e.g. panobinostat) at the MTD. In some embodiments, the MTD is 28 mg/m2/day. In some embodiments, the MTD is 10 mg/m2/day. In some embodiments, the MTD is 5 mg/m2/day. In some embodiments, the MTD is 16 mg/m2/day. In some embodiments, the MTD is 22 mg/m2/day. In some embodiments, the MTD is 36 mg/m2/day.
[0114] In some embodiments, the dose of panobinostat is increased relative to the approved dose (referred to herein as an “increased dose” or “higher dose”). As used herein, “approved dose” refers to the dose that a particular patient would receive for multiple myeloma based on the FDA approved label as of the filing date of this application. For example, the approved dose for treating multiple myeloma is 20 mg. For patients with mild hepatic impairment, the approved dose is 15 mg panobinostat, whereas the approved dose for patients with moderate hepatic impairment is 10 mg panobinostat. The approved dose for patients currently receiving treatment with (i.e. , coadministered) a strong CYP3A inhibitor (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir) is 10 mg. In embodiments, the increased dose is about 5 % higher, about 6 % higher, about 7 % higher, about 8 % higher, about 9 % higher, about 10 % higher, about 11 % higher, about 12 % higher, about 13 % higher, about 14 % higher, about 15 % higher, about 16 % higher, about 17 % higher, about 18 % higher, about 19 % higher, about 20 % higher, about 21 % higher, about 22 % higher, about 23 % higher, about 24 % higher, about 25 % higher, about 26 % higher, about 27 % higher, about 28 % higher, about 29 % higher, about 30 % higher, about 31 % higher, about 32 % higher, about 33 % higher, about 34 % higher, about 35 % higher, about 36 % higher, about 37 % higher, about 38 % higher, about 39 % higher, about 40 % higher, about 41 % higher, about 42 % higher, about 43 % higher, about 44 % higher, about 45 % higher, about 46 % higher, about 47 % higher, about 48 % higher, about 49 % higher, about 50 % higher, about 51 % higher, about 52 % higher, about 53 % higher, about 54 % higher, about 55 % higher, about 56 % higher, about 57 % higher, about 58 % higher, about 59 % higher, about 60 % higher, about 61 % higher, about 62 % higher, about 63 % higher, about 64 % higher, about 65 % higher, about 66 % higher, about 67 % higher, about 68 % higher, about 69 % higher, about 70 % higher, about 71 % higher, about 72 % higher, about 73 % higher, about 74 % higher, about 75 % higher, about 76 % higher, about 77 % higher, about 78 % higher, about 79 % higher, about 80 % higher, about 81 % higher, about 82 % higher, about 83 % higher, about 84 % higher, about 85 % higher, about 86 % higher, about 87 % higher, about 88 % higher, about 89 % higher, about 90 % higher, about 91 % higher, about 92 % higher, about 93 % higher, about 94 % higher, about 95 % higher, about 96 % higher, about 97 % higher, about 98 % higher, or about 99 % higher, or about 100 % higher, or about 150 % higher, or about 200 % higher, or about 250 % higher, or about 300 %, or about 400 % higher than the FDA approved dose of panobinostat, including all values and ranges in between these values.
[0115] In embodiments, the increased dose of panobinostat ranges from 25-60 mg. In embodiments, the increased dose of panobinostat is 25 mg. In embodiments, the increased dose of panobinostat is 30 mg. In embodiments, the increased dose of panobinostat is 35 mg. In embodiments, the increased dose of panobinostat is 40 mg. In embodiments, the increased dose of panobinostat is 45 mg. In embodiments, the increased dose of panobinostat is 50 mg. In embodiments, the increased dose of panobinostat is 55 mg. In embodiments, the increased dose of panobinostat is 60 mg. In embodiments, the increased dose of panobinostat is 55 mg. In embodiments, the increased dose of panobinostat is 60 mg. In embodiments, the increased dose of panobinostat is 65 mg. In embodiments, the increased dose of panobinostat is 70 mg. In embodiments, the increased dose of panobinostat is 75 mg. In embodiments, the increased dose of panobinostat is 80 mg.
[0116] In embodiments, the patient is administered an initial dose and then the dose of a HDAC inhibitor (e.g. panobinostat) is increased. In some embodiments, the dose is increased in an increment of about 1 mg to about 40 mg, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, or about 40 mg, inclusive of all values and ranges in between. In some embodiments, the dose is increased in an increment of about 1 mg/m2/day to about 50 mg/m2/day. In some embodiments, the dose is increased in an increment of about 1 mg/m2/day, about 2 mg/m2/day, about 3 mg/m2/day, about 4 mg/m2/day, about 5 mg/m2/day, about 6 mg/m2/day, about 7 mg/m2/day, about 8 mg/m2/day, about 9 mg/m2/day, about 10 mg/m2/day, about 11 mg/m2/day, about 12 mg/m2/day, about 13 mg/m2/day, about 14 mg/m2/day, about 15 mg/m2/day, about 16 mg/m2/day, about 17 mg/m2/day, about 18 mg/m2/day, about 19 mg/m2/day, about 20 mg/m2/day, about 21 mg/m2/day, about 22 mg/m2/day, about 23 mg/m2/day, about 24 mg/m2/day, about 25 mg/m2/day, about 26 mg/m2/day, about 27 mg/m2/day, about 28 mg/m2/day, about 29 mg/m2/day, about 30 mg/m2/day, about 31 mg/m2/day, about 32 mg/m2/day, about 33 mg/m2/day, about 34 mg/m2/day, about 35 mg/m2/day, about 36 mg/m2/day, about 37 mg/m2/day, about 38 mg/m2/day, about 39 mg/m2/day, or about 40 mg/m2/day, about 41 mg/m2/day, about 42 mg/m2/day, about 43 mg/m2/day, about 44 mg/m2/day, about 45 mg/m2/day, about 46 mg/m2/day, about 47 mg/m2/day, about 48 mg/m2/day, about 49 mg/m2/day, or about 50 mg/m2/day, inclusive of all values and ranges in between. In some embodiments, the dose of HDAC inhibitor (e.g. panobinostat) is increased in an increment of about 5 mg/m2/day. In some embodiments, the dose of HDAC inhibitor (e.g. panobinostat) is increased in an increment of about 6 mg/m2/day. In some embodiments, the dose of HDAC inhibitor (e.g. panobinostat) is increased in an increment of about 8 mg/m2/day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 5 mg/m2/day to 10 mg/m2/day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 10 mg/m2/day to 16 mg/m2/day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 16 mg/m2/day to 22 mg/m2/day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 22 mg/m2/day to 28 mg/m2/day. In some embodiments, HDAC inhibitor (e.g. panobinostat) is increased from 28 mg/m2/day to 36 mg/m2/day.
[0117] In embodiments, the dose increase occurs 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 days, 97 days, 98 days, 99 days, or 100 days or more after administration of the initial dose.
[0118] Panobinostat pharmacokinetics are linear in the dose range of 10 to 80 mg. Panobinostat pharmacokinetics are also linear in the dose range of 4.8 mg/m2 to 14 mg/m2. The product information for panobinostat describes the pharmacokinetics of panobinostat and is incorporated by reference herein in its entirety: Product information Farydak - Panobinostat lactate - Novartis Pharmaceuticals Australia Pty Ltd - PM-2014-03146-1 -4 - FINAL - 22 October 2018.Therefore, the skilled artisan can determine the pharmacokinetic parameters of panobinostat doses between 10 mg and 80 mg based on known values of 10 mg, 20 mg, and 30 mg, as described herein. For example, in order to find a pharmacokinetic parameter at an unknown dose, dose versus a known pharmacokinetic parameter, such as Cmax, tmax, AUC~, or AUCo-24, may be plotted. The scatter plot may be fit to a straight line, y= mx + b, where m is the slope of the line, b is the y intercept, and the value of an unknown pharmacokinetic parameter (y) may be calculated by plugging in the dose for x.
[0119] In some embodiments, after administering between about 10 mg and about 100 mg (e.g., 10, 15, 20, 25 ,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg) of panobinostat, the patient has a maximum observed plasma drug concentration (Cmax) between 5 ng/mL and 200 ng/mL. In some embodiments, the Cmax is about 5 ng/mL, about 6 ng/mL, about ng/mL 7 ng/mL, about 8 ng/mL, about 9 ng/mL, about 10 ng/mL, about 11 ng/mL, about 12 ng/mL, about 13 ng/mL, about 14 ng/mL, about 15 ng/mL, about 16 ng/mL, about 17 ng/mL, about 18 ng/mL, about 19 ng/mL, about 20 ng/mL, about 21 ng/mL, about 22 ng/mL, about 23 ng/mL, about 24 ng/mL, about 25 ng/mL, about 26 ng/mL, about 27 ng/mL, about 28 ng/mL, about 29 ng/mL, about 30 ng/mL, about 31 ng/mL, about 32 ng/mL, about 33 ng/mL, about 34 ng/mL, about 35, about 36 ng/mL, about 37 ng/mL, about 38 ng/mL, about 39 ng/mL, about 40 ng/mL, about 41 ng/mL, about 42 ng/mL, about 43 ng/mL, about 44 ng/mL, about 45 ng/mL, about 46 ng/mL, about 47 ng/mL, about 48 ng/mL, about 49 ng/mL, about 50 ng/mL, about 51 ng/mL, about 52 ng/mL, about 53 ng/mL, about 54 ng/mL, about 55 ng/mL, about 56 ng/mL, about 57 ng/mL, about 58 ng/mL, about 59 ng/mL, about 60 ng/mL, about 61 ng/mL, about 62 ng/mL, about 63 ng/mL, about 64 ng/mL, about 65 ng/mL, about 66 ng/mL, about 67 ng/mL, about 68 ng/mL, about 69 ng/mL, about 70 ng/mL, about 71 ng/mL, about 72 ng/mL, about 73 ng/mL, about 74 ng/mL, about 75 ng/mL, about 76 ng/mL, about 77 ng/mL, about 78, ng/mL, about 79 ng/mL, about 80 ng/mL, about 81 ng/mL, about 82 ng/mL, about 83 ng/mL, about 84 ng/mL, about 85 ng/mL, about 86 ng/mL, about 87 ng/mL, about 88 ng/mL, about 89 ng/mL, about 90 ng/mL, about 91 ng/mL, about 92 ng/mL, about 93 ng/mL, about 94 ng/mL, about 95, about
96 ng/mL, about 97 ng/mL, about 98 ng/mL, about 99 ng/mL, about 100 ng/mL, about 101 ng/mL, about 102 ng/mL, about 103 ng/mL, about 104 ng/mL, about 105 ng/mL, about 106 ng/mL, about 107 ng/mL, about 108 ng/mL, about 109 ng/mL, about 110 ng/mL, about 111 ng/mL, about 112 ng/mL, about 113 ng/mL, about 114 ng/mL, about 115 ng/mL, about 116 ng/mL, about 117 ng/mL, about 118 ng/mL, about 119 ng/mL, about 120 ng/mL, about 121 ng/mL, about 122 ng/mL, about 123 ng/mL, about 124 ng/mL, about 125 ng/mL, about 126 ng/mL, about 127 ng/mL, about 128 ng/mL, about 129 ng/mL, about 130 ng/mL, about 131 ng/mL, about 132 ng/mL, about 133 ng/mL, about 134 ng/mL, about 135, about 136 ng/mL, about 137 ng/mL, about 138 ng/mL, about 139 ng/mL, about 140 ng/mL, about 141 ng/mL, about 142 ng/mL, about 143 ng/mL, about 144 ng/mL, about 145 ng/mL, about 146 ng/mL, about 147 ng/mL, about 148 ng/mL, about 149 ng/mL, about 150 ng/mL, about 151 ng/mL, about 152 ng/mL, about 153 ng/mL, about 154 ng/mL, about 155 ng/mL, about 156 ng/mL, about 157 ng/mL, about 158 ng/mL, about 159 ng/mL, about 160 ng/mL, about 161 ng/mL, about 162 ng/mL, about 163 ng/mL, about 164 ng/mL, about 165 ng/mL, about 166 ng/mL, about 167 ng/mL, about 168 ng/mL, about 169 ng/mL, about 170 ng/mL, about 171 ng/mL, about 172 ng/mL, about 173 ng/mL, about 174 ng/mL, about 175 ng/mL, about 176 ng/mL, about 177 ng/mL, about 178, ng/mL, about 179 ng/mL, about 180 ng/mL, about 181 ng/mL, about 182 ng/mL, about 183 ng/mL, about 184 ng/mL, about 185 ng/mL, about 186 ng/mL, about 187 ng/mL, about 188 ng/mL, about 189 ng/mL, about 190 ng/mL, about 191 ng/mL, about 192 ng/mL, about 193 ng/mL, about 194 ng/mL, about 195, about 196 ng/mL, about 197 ng/mL, about 198 ng/mL, about 199 ng/mL, or about 200 ng/mL, including all ranges and values in between. In some embodiments, the Cmax is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values. In some embodiments, after administering between about 10 mg and about 100 mg (e.g., 10, 15, 20, 25 ,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg) or between about 5 mg/m2/day and about 36 mg/m2/day (e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, and 36 mg/m2/day) of panobinostat, the patient has a Cmax of 20 ng/mL.
[0120] In some embodiments, the Cmax is reported as geometric mean (% CV). In some embodiments, the patient has a Cmax ranging from 80 % to about 125 % of 12.7 ng/mL (191 %) after administration of 10 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a Cmax ranging from 80 % to about 125 % of 12.6 ng/mL (46 %) after administration of 15 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a Cmax ranging from 80 % to about 125 % of 21.6 ng/mL (83 %) after administration of 20 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a Cmax ranging from 80 % to about 125 % of 25.3 ng/mL (97 %) after administration of 30 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a Cmax ranging from 80 % to about 125 % of 28.4 ng/mL (120 %) after administration of 40 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a Cmax ranging from 80 % to about 125 % of 43.4 ng/mL (74 %) after administration of 60 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a Cmax ranging from 80 % to about 125 % of 66.1 ng/mL (38 %) after administration of 80 mg of panobinostat (or an equivalent dose in terms of BSA).
[0121] In some embodiments, after administering between about 3 mg/m2 and about 36 mg/m2 (e.g., 3, 4, 4.8, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or 5-36 mg/m2) of panobinostat, the patient has a maximum observed plasma drug concentration (Cmax) between 5 ng/mL and 200 ng/mL. In some embodiments, the Cmax is about 5 ng/mL, about 6 ng/mL, about ng/mL 7 ng/mL, about 8 ng/mL, about 9 ng/mL, about 10 ng/mL, about 11 ng/mL, about 12 ng/mL, about 13 ng/mL, about 14 ng/mL, about 15 ng/mL, about 16 ng/mL, about 17 ng/mL, about 18 ng/mL, about 19 ng/mL, about 20 ng/mL, about 21 ng/mL, about 22 ng/mL, about 23 ng/mL, about 24 ng/mL, about 25 ng/mL, about 26 ng/mL, about 27 ng/mL, about 28 ng/mL, about 29 ng/mL, about 30 ng/mL, about 31 ng/mL, about 32 ng/mL, about 33 ng/mL, about 34 ng/mL, about 35, about
36 ng/mL, about 37 ng/mL, about 38 ng/mL, about 39 ng/mL, about 40 ng/mL, about
41 ng/mL, about 42 ng/mL, about 43 ng/mL, about 44 ng/mL, about 45 ng/mL, about
46 ng/mL, about 47 ng/mL, about 48 ng/mL, about 49 ng/mL, about 50 ng/mL, about
51 ng/mL, about 52 ng/mL, about 53 ng/mL, about 54 ng/mL, about 55 ng/mL, about
56 ng/mL, about 57 ng/mL, about 58 ng/mL, about 59 ng/mL, about 60 ng/mL, about
61 ng/mL, about 62 ng/mL, about 63 ng/mL, about 64 ng/mL, about 65 ng/mL, about
66 ng/mL, about 67 ng/mL, about 68 ng/mL, about 69 ng/mL, about 70 ng/mL, about
71 ng/mL, about 72 ng/mL, about 73 ng/mL, about 74 ng/mL, about 75 ng/mL, about
76 ng/mL, about 77 ng/mL, about 78, ng/mL, about 79 ng/mL, about 80 ng/mL, about
81 ng/mL, about 82 ng/mL, about 83 ng/mL, about 84 ng/mL, about 85 ng/mL, about
86 ng/mL, about 87 ng/mL, about 88 ng/mL, about 89 ng/mL, about 90 ng/mL, about
91 ng/mL, about 92 ng/mL, about 93 ng/mL, about 94 ng/mL, about 95, about 96 ng/mL, about 97 ng/mL, about 98 ng/mL, about 99 ng/mL, about 100 ng/mL, about 101 ng/mL, about 102 ng/mL, about 103 ng/mL, about 104 ng/mL, about 105 ng/mL, about 106 ng/mL, about 107 ng/mL, about 108 ng/mL, about 109 ng/mL, about 110 ng/mL, about 111 ng/mL, about 112 ng/mL, about 113 ng/mL, about 114 ng/mL, about 115 ng/mL, about 116 ng/mL, about 117 ng/mL, about 118 ng/mL, about 119 ng/mL, about 120 ng/mL, about 121 ng/mL, about 122 ng/mL, about 123 ng/mL, about 124 ng/mL, about 125 ng/mL, about 126 ng/mL, about 127 ng/mL, about 128 ng/mL, about 129 ng/mL, about 130 ng/mL, about 131 ng/mL, about 132 ng/mL, about 133 ng/mL, about 134 ng/mL, about 135, about 136 ng/mL, about 137 ng/mL, about 138 ng/mL, about 139 ng/mL, about 140 ng/mL, about 141 ng/mL, about 142 ng/mL, about 143 ng/mL, about 144 ng/mL, about 145 ng/mL, about 146 ng/mL, about 147 ng/mL, about 148 ng/mL, about 149 ng/mL, about 150 ng/mL, about 151 ng/mL, about 152 ng/mL, about 153 ng/mL, about 154 ng/mL, about 155 ng/mL, about 156 ng/mL, about 157 ng/mL, about 158 ng/mL, about 159 ng/mL, about 160 ng/mL, about 161 ng/mL, about 162 ng/mL, about 163 ng/mL, about 164 ng/mL, about 165 ng/mL, about 166 ng/mL, about 167 ng/mL, about 168 ng/mL, about 169 ng/mL, about 170 ng/mL, about 171 ng/mL, about 172 ng/mL, about 173 ng/mL, about 174 ng/mL, about 175 ng/mL, about 176 ng/mL, about 177 ng/mL, about 178, ng/mL, about 179 ng/mL, about 180 ng/mL, about 181 ng/mL, about 182 ng/mL, about 183 ng/mL, about 184 ng/mL, about 185 ng/mL, about 186 ng/mL, about 187 ng/mL, about 188 ng/mL, about 189 ng/mL, about 190 ng/mL, about 191 ng/mL, about 192 ng/mL, about 193 ng/mL, about 194 ng/mL, about 195, about 196 ng/mL, about 197 ng/mL, about 198 ng/mL, about 199 ng/mL, or about 200 ng/mL, including all ranges and values in between. In some embodiments, the Cmax is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values. In some embodiments, after administering between about 5 mg/m2 and about 36 mg/m2 (e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, or 36 mg/m2) of panobinostat, the patient has a Cmax of 20 ng/mL. In some embodiments, after administering between about 4.8 mg/m2 and about 14 mg/m2 (e.g., 4.8, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 mg/m2) of panobinostat, the patient has a Cmax Of 20 ng/mL.
[0122] In some embodiments, after administering between about 10 mg and about 100 mg of panobinostat, the patient has a time to reach Cmax (tmax) between 0.1 hours and 2 hours. In some embodiments, the tmax is about 0.1 hours, about 0.2 hours, about 0.3 hours, about 0.4 hours, about 0.5 hours, about 0.6 hours, about 0.7 hours, about 0.8 hours, about 0.9 hours, about 1.0 hours, about 1.1 hours, about 1.2 hours, about 1.3 hours, about 1.4 hours, about 1.5 hours, about 1.6 hours, about 1.7 hours, about 1.8 hours, about 1.9 hours, or about 2.0 hours. In some embodiments, the tmax is between about 80 % and about 125 % of any of the aforementioned values or ranges between the aforementioned values.
[0123] In some embodiments, the tmax is reported as a median (range). In some embodiments, the patient has a tmax ranging from 80 % to about 125 % of 1 hour (0.5 hours - 4.0 hours) after administration of 10 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a tmax ranging from 80 % to about 125 % of 1.0 hours (0.4 hours - 2.0 hours) after administration of 15 mg of panobinosta (or an equivalent dose in terms of BSA)t. In some embodiments, the patient has a tmax ranging from 80 % to about 125 % of 1.0 hours (0.5 hours - 8 hours) after administration of 20 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a tmax ranging from 80 % to about 125 % of 2.0 hours (0.7 hours - 4 hours) after administration of 30 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a tmax ranging from 80 % to about 125 % of 1.1 hours (0.5 hours - 4 hours) after administration of 40 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has a tmax ranging from 80 % to about 125 % of 1.1 hours (0.5 hours - 6 hours) after administration of 60 mg of panobinostat. In some embodiments, the patient has a tmax ranging from 80 % to about 125 % of 1.5 hours (0.7 hours - 2 hours) after administration of 80 mg of panobinostat (or an equivalent dose in terms of BSA). [0124] In some embodiments, after administering between about 10 mg and about 100 mg of panobinostat (e.g., 10, 15, 20, 25 ,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mg), the patient has an area under the concentration time curve from zero hours to twenty four hours (AUC0-24) between 25 ng*hr/ mL and 800 ng*hr/ mL. In embodiments, the AUC0-24 is between about 134.9 ng*hr/ mL and about 372.9 ng*hr/ mL. In some embodiments, the AUC0-24 is about 25 ng*hr/ mL, about 50 ng*hr/ mL, about 75 ng*hr/ mL, about 100 ng*hr/ mL, about 125 ng*hr/ mL, about 150 ng*hr/ mL, about 175 ng*hr/ mL, about 200 ng*hr/ mL, about 225 ng*hr/ mL, about 250 ng*hr/ mL, about 275 ng*hr/ mL, about 300 ng*hr/ mL, about 325 ng*hr/ mL, about 350 ng*hr/ mL, about 375 ng*hr/ mL, about 400 ng*hr/ mL, about 425 ng*hr/ mL, about 450 ng*hr/ mL, about 475 ng*hr/ mL, about 500 ng*hr/ mL, about 525 ng*hr/ mL, about 550 ng*hr/ mL, about 575 ng*hr/ mL, about 600 ng*hr/ mL, about 625 ng*hr/ mL, about 650 ng*hr/ mL, about 675 ng*hr/ mL, about 700 ng*hr/ mL, about 725 ng*hr/ mL, about 750 ng*hr/ mL, about 775 ng*hr/ mL, about 800 ng*hr/ mL, including all ranges and values in between. In some embodiments, the AUC0-24 is between 80 % and 125 % of the aforementioned values.
[0125] In some embodiments, after administering between about 5 mg/m2 and about 36 mg/m2 of panobinostat (e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, or 36 mg/m2), the patient has an area under the concentration time curve from zero hours to twenty four hours (AUCo-24) between 25 ng*hr/ mL and 800 ng*hr/ mL. In embodiments, the AUCo-24 is between about 134.9 ng*hr/ mL and about 372.9 ng*hr/ mL. In some embodiments, the AUCo-24 is about 25 ng*hr/ mL, about 50 ng*hr/ mL, about 75 ng*hr/ mL, about 100 ng*hr/ mL, about 125 ng*hr/ mL, about 150 ng*hr/ mL, about 175 ng*hr/ mL, about 200 ng*hr/ mL, about 225 ng*hr/ mL, about 250 ng*hr/ mL, about 275 ng*hr/ mL, about 300 ng*hr/ mL, about 325 ng*hr/ mL, about 350 ng*hr/ mL, about 375 ng*hr/ mL, about 400 ng*hr/ mL, about 425 ng*hr/ mL, about 450 ng*hr/ mL, about 475 ng*hr/ mL, about 500 ng*hr/ mL, about 525 ng*hr/ mL, about 550 ng*hr/ mL, about 575 ng*hr/ mL, about 600 ng*hr/ mL, about 625 ng*hr/ mL, about 650 ng*hr/ mL, about 675 ng*hr/ mL, about 700 ng*hr/ mL, about 725 ng*hr/ mL, about 750 ng*hr/ mL, about 775 ng*hr/ mL, about 800 ng*hr/ mL, including all ranges and values in between. In some embodiments, the AUCo-24 is between 80 % and 125 % of the aforementioned values. In some embodiments, after administering between about 4.8 mg/m2 and about 14 mg/m2 of panobinostat (e.g., 4.8, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg/m2), the patient has an area under the concentration time curve from zero hours to twenty four hours (AUCo- 24) between 25 ng*hr/ mL and 800 ng*hr/ mL. In some embodiments, after administering between about 4.8 mg/m2 and about 14 mg/m2 of panobinostat (e.g., 4.8, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg/m2), the patient has an area under the concentration time curve from zero hours to twenty four hours (AUCo-24) between 134.9 ng*hr/ mL and 372.9 ng*hr/ mL.
[0126] In some embodiments, the AUC0-24 is reported as a geometric mean (% CV). In some embodiments, the patient has an AUC0-24 ranging from 80 % to about 125 % of 77 ng*hr/ mL (75 %) after administration of 10 mg of panobinostat. In some embodiments, the patient has an AUC0-24 ranging from 80 % to about 125 % of 91 ng*hr/ mL (36 %) after administration of 15 mg of panobinostat. In some embodiments, the patient has an AUC0-24 ranging from 80 % to about 139 ng*hr/ mL (71 %) after administration of 20 mg of panobinostat. In some embodiments, the patient has an AUC0-24 ranging from 80 % to about 125 % of 174 ng*hr/ mL (92 %) after administration of 30 mg of panobinostat. In some embodiments, the patient has an AUC0-24 ranging from 80 % to about 125 % of 185 ng*hr/ mL (74 %) after administration of 40 mg of panobinostat. In some embodiments, the patient has an AUC0-24 ranging from 80 % to about 125 % of 222 ng*hr/ mL (48 %) after administration of 60 mg of panobinostat. In some embodiments, the patient has an AUCo-24 ranging from 80 % to about 125 % of 274 ng*hr/ mL (70 %) after administration of 80 mg of panobinostat.
[0127] In some embodiments, after administering between about 10 mg and about 100 mg of panobinostat, the patient has an area under the concentration time curve from zero hours to infinity (AUC~) between 25 ng*hr/ mL and 600 ng*hr/ mL. In some embodiments, the AUC~ is about 25 ng*hr/ mL, about 50 ng*hr/ mL, about 75 ng*hr/ mL, about 100 ng*hr/ mL, about 125 ng*hr/ mL, about 150 ng*hr/ mL, about 175 ng*hr/ mL, about 200 ng*hr/ mL, about 225 ng*hr/ mL, about 250 ng*hr/ mL, about 275 ng*hr/ mL, about 300 ng*hr/ mL, about 325 ng*hr/ mL, about 350 ng*hr/ mL, about 375 ng*hr/ mL, about 400 ng*hr/ mL, about 425 ng*hr/ mL, about 450 ng*hr/ mL, about 475 ng*hr/ mL, about 500 ng*hr/ mL, about 525 ng*hr/ mL, about 550 ng*hr/ mL, about 575 ng*hr/ mL, or about 600 ng*hr/ mL, including all ranges and values in between. In some embodiments, the AUC~ is between 80 % and 125 % of any of the aforementioned values or ranges between the aforementioned values.
[0128] In some embodiments, the AUC~ is reported as a geometric mean (% CV). In some embodiments, the patient has an AUC~ ranging from 80 % to about 125 % of 163 ng*hr/ mL (65 %) after administration of 10 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC~ ranging from 80 % to about 125 % of 158 ng*hr/ mL (46 %) after administration of 15 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC~ ranging from 80 % to about 125 % of 200 ng*hr/ mL (53 %) after administration of 20 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC~ ranging from 80 % to about 125 % of 288 ng*hr/ mL (67 %) after administration of 30 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC~ ranging from 80 % to about 125 % of 322 ng*hr/ mL (67 %) after administration of 40 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC~ ranging from 80 % to about 125 % of 313 ng*hr/ mL (51 %) after administration of 60 mg of panobinostat (or an equivalent dose in terms of BSA). In some embodiments, the patient has an AUC~ ranging from 80 % to about 125 % of 303 ng*hr/ mL (96 %) after administration of 80 mg of panobinostat (or an equivalent dose in terms of BSA).
[0129] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in a course. A course comprises a treatment period and a rest period. During the treatment period, a HDAC inhibitor (e.g., panobinostat) is administered. Additional therapeutic agents described herein may also be administered during the treatment period. The rest period is a length of time that the patient does not receive treatment with an HDAC inhibitor (e.g., panobinostat). In some embodiments, no HDAC inhibitor (e.g., panobinostat) is administered during the rest period, but another therapeutic agent may be administered. The rest period enables the patient to recover from the treatment.
[0130] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in a regimen that has a course length of 7 days, 14 days, 21 days, 28 days, 35 days, 42 days or more. The regimen may be repeated for any number of courses to treat brain cancer, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more, as clinically necessary.
[0131] In some embodiments, the course has a rest period. In some embodiments, no HDAC inhibitor (e.g., panobinostat) and/or other therapeutic agent is administered during the rest period. In some embodiments, no HDAC inhibitor (e.g. panobinostat) is administered during the rest period, but another therapeutic agent may be administered. In embodiments, the length of the rest period is about 1 day per course, about 2 days per course, about 3 days per course, about 4 days per course, about 5 days per course, about 6 days per course, about 7 days per course, about 8 days per course, about 9 days per course, about 10 days per course, about 11 days per course, about 12 days per course, about 13 days per course, about 14 days per course, about 15 days per course, about 16 days per course, about 17 days per course, about 18 days per course, about 19 days per course, about 20 days per course, about 21 days per course, or more as clinically necessary. In embodiments, the rest period is one week or two weeks or three weeks or four weeks or more.
[0132] During the treatment period, an HDAC inhibitor (e.g. panobinostat) and, optionally, one or more therapeutic agents disclosed herein are administered. In some embodiments, the length of the treatment period is about 1 day per course, about 2 days per course, about 3 days per course, about 4 days per course, about 5 days per course, about 6 days per course, about 7 days per course, about 8 days per course, about 9 days per course, about 10 days per course, about 11 days per course, about 12 days per course, about 13 days per course, about 14 days per course, about 15 days per course, about 16 days per course, about 17 days per course, about 18 days per course, about 19 days per course, about 20 days per course, about 21 days per course, 22 days per course, about 23 days per course, about 24 days per course, about 25 days per course, about 26 days per course, about 27 days per course, about 18 days per course, about 29 days per course, about 30 days per course, or about 31 days per course, or more. In some embodiments, the length of the treatment period is 7 days. In some embodiments, the length of the treatment period is 14 days. In some embodiments, the length of the treatment period is 21 days. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered every day. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered every other day. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered every third day. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered every fourth day. In embodiments, during the treatment period, the HDAC inhibitor (e.g., panobinostat) is administered one time per week, two times per week, three times per week, four times per week, five times per week, six times per week, or seven times per week.
[0133] In some embodiments, a course may contain more than one treatment period. In some embodiments, a course contains up to five treatment periods. In some embodiments, a course contains one, two, three, four, or five treatment periods. In some embodiments, a course contains one treatment period. In some embodiments, a course contains two treatment periods. In some embodiments, the treatment periods within the course has the same length. In some embodiments, the treatment periods within the course have different lengths.
[0134] In some embodiments, the course contains more than one rest period. In some embodiments, a course contains up to five rest periods. In some embodiments, a course contains one, two, three, four, or five rest periods. In some embodiments, a course contains one rest period. In some embodiments, a course contains two rest periods. In some embodiments, the rest periods within the course has the same length. In some embodiments, the rest periods within the course have different lengths.
[0135] In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered to brain cancer patients according to the approved treatment regimen for panobinostat in multiple myeloma. For multiple myeloma, the currently approved course comprises a course length of 21 days. Panobinostat is administered once every other day for three doses per week (on days 1, 3, 5, 8, 10, and 12) for eight courses. Panobinostat is not administered on days 15-21. Subjects with clinical benefit are administered an additional eight courses of panobinostat after an initial treatment regimen of eight courses unless the subject has unresolved severe or medically significant toxicity. In some embodiments, panobinostat is administered in combination with bortezomib and dexamethasone. Bortezomib is administered at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 as an injection for courses 1 , 2, 3, 4, 5, 6, 7, and 8, and is administered on days 1 and 8 of courses 9, 10, 11, 12, 13, 14, 15, and 16. Dexamethasone is administered orally at a dose of 20 mg on a full stomach on days 1 , 2, 4, 5, 8, 9, 11, and 12 for courses 1 , 2, 3, 4, 5, 6, 7, and 8, and is administered on days 1 , 2, 8, and 9 for courses 9, 10, 11, 12, 13, 14, 15, and 16.
[0136] Table 1 and Table 2 illustrate the approved dosing regimen (for multiple myeloma) when panobinostat is administered in combination with Bortezomib and Dexamethasone
Table 1: Recommended Dosing Schedule of FARYDAK in combination with Bortezomib and Dexamethasone during courses 1 to 8.
Figure imgf000038_0001
Table 2: Recommended Dosing Schedule of FARYDAK in combination with Bortezomib and Dexamethasone during courses 9 to 16
Figure imgf000038_0002
[0137] In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered in a 14 day course. The HDAC inhibitor (e.g., panobinostat) may be administered at any appropriate frequency during the 14 day course. In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered one or more times during the first week (days 1-7) of the 14 day course. In some embodiments, the HDAC inhibitor (e.g., panobinostat) is not administered during the second week (days 8-14) of the 14 day course. In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered 1, 2, 3, 4, 5, 6, or 7 times during the first week (days 1-7) of the 14 day course. In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered three times a week for the first week, and zero times per week in the second week. For example, panobinostat may be administered to the patient on days 1 , 3, and 5 or on days 1 , 4, and 6.
[0138] In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered in a 14 day course two times a week for the first week and zero times per week for the second week. For example, panobinostat is administered at days 1 and 4 or at days 1 and 5. Panobinostat is not administered on days 8-14 of the course.
[0139] In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered in a 28 day course the HDAC inhibitor (e.g., panobinostat) may be administered at any appropriate frequency during the 28 day course. In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered one or more times during the first week (days 1-7), one or more times during the second week (days 8-14), and one or more times during the third week (days 15-21). In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered three times a week for the first week (days 1-7), three times a week for the second week (days 8-14) and three times per week in the third week (days 15-21); the fourth week is a rest period. For example, panobinostat is administered on days 2, 4, 6, 9, 11, 14, 16, 18, and 20.
[0140] In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered one or more times the first week (days 1-7) of the 28 day course and one or more times during the third week (days 15-21). In some embodiments, panobinostat is administered three times a week for the first week (days 1-7) and three times per week in the third week (days 15-21); the second and fourth week are rest periods. For example, panobinostat is administered on days 2, 4, 6, 16, 18, and 20.
[0141] In some embodiments, a patient is initially administered panobinostat, wherein panobinostat is administered three times a week for the first week (days 1-7), three times a week for the second week (days 8-14) and three times per week in the third week (days 15-21), and the fourth week is a rest period. Subsequently, the patient is administered panobinostat in a 28 day course, wherein panobinostat is administered three or more times on the first week and three or more times in the third week. In some embodiments, the patient initially has recurrent/progressive DIPG. Subsequently, the patient has non-progressed DIPG.
[0142] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered as a maintenance therapy. In some embodiments, panobinostat is administered one or more times the first week (days 1-7) of a 28 day course and one or more times during the third week (days 15-21). In some embodiments, panobinostat is administered three times a week for the first week (days 1-7) and three times per week in the third week (days 15-21); the second and fourth week are rest periods. For example, panobinostat is administered on days 2, 4, 6, 16, 18, and 20.
[0143] Panobinostat administration may result in adverse events, such as thrombocytopenia, diarrhea, cardiac toxicities, myelosuppression, hemorrhage, infections, hepatotoxicity, and embryo-fetal toxicity. The most common panobinostat toxicities are diarrhea, nausea, vomiting, and myelosuppression, such as thrombocytopenia, neutropenia, and anemia. Thrombocytopenia is defined as low platelet count. Neutropenia is defined as a low number of neutrophils in the blood. Anemia is a condition in which there is a lack of healthy red blood cells to carry oxygen to the body’s tissues.
[0144] In some embodiments, the methods of the present disclosure result in a reduction in the percentage of adverse events. In some embodiments, there are less adverse events measured for a 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4 compared to a 28 day course containing treatment periods on weeks 1, 2, and 3 and a rest period on week 4. In some embodiments, equal amounts of panobinostat are administered in the 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4, and in the 28 day course containing treatment periods in weeks 1, 2, and 3, and a rest period in week 4 - and there are less adverse events measured for a 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4. In some embodiments, a higher amount of panobinostat is administered on the 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4 compared to the 28 day course containing treatment periods in weeks 1, 2, and 3, and a rest period in week 4. In some embodiments, a lower amount of panobinostat is administered on the 28 day course containing treatment periods on weeks 1 and 3 and rest periods on weeks 2 and 4 compared to the 28 day course containing treatment periods in weeks 1, 2, and 3, and a rest period in week 4. [0145] In some embodiments, the methods of the present disclosure result in a lower percentage of toxicities. For example, the methods of the present disclosure may result in a lower percentage of thrombocytopenia in brain cancer patients. In some embodiments, the methods of the present disclosure may result in a lower percentage of anemia in the patient populations of the present disclosure. In some embodiments, the methods of the present disclosure may result in a lower percentage of diarrhea and/or vomiting. In some embodiments, the methods of the present disclosure may result in a lower percentage of neutropenia. In some embodiments, the present methods reduce the incidence of such adverse events by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%, including all values and ranges therebetween.
[0146] In some embodiments, the methods of the disclosure may reduce the incidence of adverse events that would otherwise be associated with the higher doses described herein. The reduction in adverse events may be achieved with higher doses of panobinostat (e.g., 25-60 mg panobinostat) by increasing the length of time in the rest periods results . For example, in some embodiments, panobinostat may be administered for one week, followed by a rest period of one week. In some embodiments, panobinostat may be administered for two weeks, followed by a rest period of two weeks.
[0147] In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered as a monotherapy at any of the doses described herein. In some embodiments, the panobinostat monotherapy is a first line of treatment. In some embodiments, the panobinostat monotherapy is a second or third line of treatment.
[0148] In some embodiments, the HDAC inhibitor (e.g., panobinostat) is administered in combination with another therapeutic agent described herein. In some embodiments, the panobinostat combination therapy is a first line of treatment. In some embodiments, the panobinostat combination therapy is a second or third line of treatment.
[0149] In embodiments, a HDAC inhibitor (e.g. panobinostat) can be administered in combination with any other therapeutic agent to treat brain cancer. In embodiments, the therapeutics can be administered on the same day consecutively or concurrently. In embodiments, the therapeutics can be administered on different days or weeks. In embodiments, panobinostat and the therapeutic are given one day apart, or two days apart, or three days apart, or four days apart, or six days apart, or seven days apart, or 8 days apart, or 9 days apart, or 10 days apart, or 11 days apart, or 12 days apart, or 13 days apart, or 14 days apart, or more.
Clinical Endpoints
[0150] In some embodiments, treating according to the disclosed methods leads to a partial response (PR). As defined herein, a PR is ≥ 50 % reduction in tumor size by bi- dimensional measurement, as compared with baseline measurement on a stable or decreasing dose of corticosteroid, accompanied by a stable or improving neurologic examination.
[0151] In some embodiments, treating according to the disclosed methods leads to a complete response (CR). As defined herein, CR is a complete disappearance on MRI of all evaluable tumor and mass effect, on a stable or decreasing dose of corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination.
[0152] In some embodiments, the patients described exhibit progressive disease (PD). PD is defined as progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression, a greater than 25 % increase in bi-dimensional tumor measurement as compared to the smallest tumor measurement since the start of panobinostat administration, or the appearance of a new lesion. In some embodiments, patients with progressive disease have worsening of symptoms as determined from two consecutive visits. In some embodiments, patients with progressive disease have worsening of symptoms in two or more consecutive visits. In some embodiments, symptoms of PD include, but not limited to coordination loss, problems with balance and walking, problems with the eyes, double vision, drooping eyelids, uncontrolled eye movements, blurred vision, problems with chewing and swallowing, nausea, vomiting, facial weakness, facial drooping, headaches, tics, and language slurring.
[0153] In some embodiments, treating according to the methods of the disclosure leads to stable disease (SD). As defined herein, SD is a stable neurologic exam and maintenance corticosteroid dose, and magnetic resonance imaging or computed tomography (CT) imaging that neither meets the criteria for PR nor the criteria for PD. [0154] In some embodiments, treating according to the methods of the disclosure results in an improvement in overall survival (OS) compared to the median OS of patients administered standard treatment for DIPG. As defined herein, OS is the length of time from diagnosis with DIPG until death. In some embodiments, treating according to the methods of the disclosure results in an increase in OS as compared to the median value in overall survival at the time of this disclosure for a particular type of brain cancer. For example, the median overall survival for DIPG patients is between about 8 months and about 12 months. In some embodiments, treating according to the methods of the disclosure results in an increase in the OS of about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 5 weeks, or about 6 weeks, or about 7 weeks, or about 8 weeks, or about 9 weeks, or about 10 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or about 12 months, or about 13 months, or about 14 months, or 15 months, or about 16 months, or about 17 months, or about 18 months, or about 19 months, or about 20 months, or about 21 months, or about 22 months, or about 23 months, or about 24 months, or about 3 years, or about 4 years, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years, or more, including all values and ranges in between.
[0155] In some embodiments, treating according to the methods of the disclosure results in an increase in the OS of about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, about 90 %, about 100 %, about
150 %, about 200 %, about 250 %, about 300 %, about 350 %, about 400 %, about
450 %, about 500 %, about 550 %, about 600 %, about 650 %, about 700 %, about
750 %, about 800 %, about 850 %, about 900 %, about 950 %, or about 1000 % or more.
[0156] In some embodiments, treating according to the methods of the disclosure leads to an increase in progression free survival (PFS) compared to the median PFS of patients administered standard treatment for DIPG. As defined herein, PFS is the length of time between initiation of treatment according to the methods of the disclosure and the date of documented progressive disease or death from any cause. [0157] In some embodiments, the methods of the disclosure result in an increase in PFS as compared to the median value in progression free survival at the time of this disclosure. The median PFS for DIPG patients is 6 months. In some embodiments, treating according to the methods of the disclosure results in an increase in the PFS of about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 5 weeks, or about 6 weeks, or about 7 weeks, or about 8 weeks, or about 9 weeks, or about 10 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months, or about 11 months, or more, or about 12 months, or about 13 months, or about 14 months, or 15 months, or about 16 months, or about 17 months, or about 18 months, or about 19 months, or about 20 months, or about 21 months, or about 22 months, or about 23 months, or about 24 months, or about 3 years, or about 4 years, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years, including all values and ranges in between.
[0158] In some embodiments, treating according to the methods of the disclosure results in an increase in the PFS of about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, about 90 %, about 100 %, about
150 %, about 200 %, about 250 %, about 300 %, about 350 %, about 400 %, about
450 %, about 500 %, about 550 %, about 600 %, about 650 %, about 700 %, about
750 %, about 800 %, about 850 %, about 900 %, about 950 %, or about 1000 % or more.
[0159] In some embodiments, the methods of the disclosure result in a decrease in tumor size. Tumor size is measured according to known methods in the art. In some embodiments, tumor size is measured by magnetic resonance imaging (MRI). In some embodiments, the MRI sequence is selected from a T1 weighted scan, a T2 weighted scan, and a Fluid Attenuated Inversion Recovery (FLAIR). In some embodiments, the FLAIR sequence is used to measure tumor size.
[0160] In some embodiments, the tumor size decreases by about 10 %, or about 15 %, or about 20 %, or about 25 %, or about 30 %, or about 35 %, or about 40 %, or about 45 %, or about 50 %, or about 55 %, or about 60 %, or about 65 %, or about 70 %, or about 75 %, or about 80 %, or about 85 %, or about 90 %, or about 95 %, or about 100 %.
Combinations
[0161] As disclosed herein, panobinostat may be administered in combination with another therapeutic agent. In embodiments, the therapeutic is administered at the current FDA approved dose as of the filing date of the present application. The other therapeutic agent can be administered in a course as described herein. [0162] In some embodiments, the other therapeutic agent is administered at a dose ranging from about 0.005 mg to about 1 g, including about 0.005 mg, about 0.01 mg, about 0.015 mg, about 0.02 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.045 mg, about 0.050 mg, about 0.055 mg, about 0.060 mg, about 0.065 mg, about 0.070 mg, about 0.075 mg, about 0.080 mg, about 0.085 mg, about 0.090 mg, about 0.095 mg, about 0.10 mg, about 0.15 mg, about 0.20 mg, about 0.25 mg, about 0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.60 mg, about 0.65 mg, about 0.70 mg, about 0.75 mg, about 0.80 mg, about 0.85 mg, about 0.90 mg, about 0.95 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, and about 1 g, including all values and ranges in between.
[0163] In some embodiments, a therapeutic agent is used in combination with an HDAC inhibitor (e.g. panobinostat). In some embodiments, the therapeutic agent is a proteasome inhibitor, a BCL-2 inhibitor, a CYP3A inhibitor, another histone deacetylase inhibitor, a checkpoint inhibitor, inhibitors of Tregs, mTOR inhibitors, proteasome inhibitors, a taxane (or other similarly acting microtubule stabilizing or disrupting compounds), a platinum coordinator compound, an epidermal growth factor inhibitor, a vascular endothelial growth factor inhibitor, a vascular endothelial growth factor kinase inhibitor, a MET inhibitor, ABL kinase inhibitor, ALK inhibitor, FLT kinase inhibitor, a MAPK/ERK kinase inhibitor, a RAF kinase inhibitor, a farnesyl transferase inhibitor, an estrogen receptor modulator, an anti-tumor nucleoside deritative, epothilones, topoisomerase inhibitor, vinca alkyloid, inhibitor of integrin, folate antagonist, ribonucleotide reductase inhibitor, anthracycline, biological agent, thalidomide, a heat shock protein 90 inhibitor, radiation therapy, steroid, an antineoplastic agent, or an immunomodulatory agent, or a combination thereof.
[0164] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with a proteasome inhibitor. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with a proteasome inhibitor selected from the group consisting of marizomib, carfilzomib, and bortezomib. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with marizomib. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with bortezomib. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with carfilzomib. [0165] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an antineoplastic agent. In some embodiments, the antineoplastic agent is selected from the group consisting of: paclitaxel, docetaxel, oxaliplatin, carboplatin, cisplatin, gemcitabine, tamoxifen, trastuzumab, cetuximab, bevacizumab, navelbine, 17- allylamino-17-demothoxy-geldanamycin, lapatinib, erlotinib, gefitinib, IMC-1C11, SU5416, and SU6688.
[0166] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered combination with one more hypomethylating agents. A hypomethylating agent (also known as a demethylating agent) is a drug that inhibits DNA methylation. Non-limiting examples of hypomethylating agents include decitabine and azacitidine.
[0167] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered combination with one more bromodomain and extraterminal motif (BET) inhibitors. BET inhibitors are a class of drugs that reversibly bind to the bromodomains of BET proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein- protein interaction between BET proteins and acetylated histones and transcription factors. Non-limiting examples of BET inhibitors that target both BD1 and BD2 bromodomains include I- BET 151 (GSK1210151A), l-BET 762 (GSK525762), OTX-015, TEN-010, CPI-203, and CPI-0610. A non-limiting example of a BET inhibitor that selectively targets BD1 include olinone. A non-limiting example of BET inhibitor that selectively targets BD2 include RVX-208. A non-limiting example of BET inhibitor that is a dual kinase- bromodomain inhibitor is LY294002. Non-limiting examples of bivalent BET inhibitors include AZD5153, MT-1, and MS645.
[0168] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in combination with one more FDA approved therapeutic agents for brain cancer. Non- limiting examples of FDA approved therapeutic agents for brain cancer are: everolimus, bevacizumab, carmustine, lomustine (CCNU), temozolomide, procarbazine hydrochloride, and vincristine sulfate.
Table 3: FDA Approved therapeutic agents for Brain Cancer
Figure imgf000047_0001
Figure imgf000048_0001
[0169] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with a chemotherapeutic agent. Classes of chemotherapeutic agents include alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. Non-limiting examples of alkylating agents include nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, triazenes, uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In some embodiments, panobinostat is administered with temozolomide. Temozolomide is a small molecule chemotherapeutic which crosses the blood-brain barrier. Temozolomide is currently FDA approved for the treatment of adult patients with refractory anaplastic astrocytoma.
[0170] Non-limiting examples of antimetabolites, such as folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, include methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine. Non-limiting examples of natural products and their derivatives , such as vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins, include vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, paclitaxel, paclitaxel derivatives (e.g. taxotere), mithramycin, deoxycoformycin, mitomycin c, l-asparaginase, interferons, etoposide, and teniposide.
[0171] Non-limiting examples of hormones and steroids (including synthetic analogs) include: 17a-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, tamoxifen, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, and zoladex. synthetics include cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, and hexamethylmelamine. As used herein, methods of the present disclosure include the administration of microtubule affecting agent (e.g., paclitaxel, a paclitaxel derivative or a paclitaxel-like compound) with panobinostat. A microtubule affecting agent is a compound that interferes with cellular mitosis by affecting microtubule formation and/or action.
[0172] Non-limiting examples of microtubule affecting agents include allocolchicine, halichondrin B, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel, paclitaxel derivatives, trityl cysteine, vinblastine sulfate, vincristine sulfate, epothilone A, epothilone, discodermolide estramustine, nocodazole, and MAP4. [0173] In embodiments, a HDAC inhibitor (e.g. panobinostat) is utilized in combination with one or more therapeutic agents selected from the group consisting of 131-l-TM- 601, 13-cis-retinoicacid, 177Lu-J591 , 18F-DOPA, 18F-FET, 18F-FLT PET Scan, 18F- fluciclovine, 18F-fludeoxyglucose (18F-FDG), 18F-fluoro-dihydroxyphenylalanine, 18F-FMISO, 18F-FPPRGD2, 2B3-101 , 2-hydroxyoleic acid (2-0H0A/20H0A), 2- OHOA, 3'-Deoxy-3'-18f-Fluorothymidine, 5-aminolevulinic acid (5-ALA), 5-Azacytidine (5-AZA), 5-fluorocytosine (5-FC), 5-fluorouracil (5-FU), 6-[F-18]-Fluoro-L-3,4,- dihydroxyphenylalanine, 68Ga-BBN-IRDye800CW, 68Ga-BNOTA-PRGD2, 68Ga- NOTA-Aca-BBN, 6-Thioguanine, 89Zr-J591, 90Y-DOTA-tyr3-Octreotide, 9-ING-41, ABBV-221 , Abemaciclib, ABI-009, ABT 510, ABT-414, ABT-751, ABT-888, ABY-029, AC480, Acetazolamide, acetylcysteine, ACP-196, acridine carboxamide, Adavosertib, ADI-PEG 20, ADV/HSV-tk (gene therapy), AEE788, Afatinib, AG-120, AG-221, AG881, Aldesleukin, aldoxorubicin, Alectinib, Alisertib, alvocidib, AMG 102, AMG 232, AMG 595, AMG 596, AMG-232, Amgen 386, amifostine trihydrate, Aminosyn II, ANG1005, Anlotinib, Antineoplaston therapy (Atengenal + Astugenal), Anti-seizure prophylaxis, AP 12009, AP23573, Apatinib, APG101 , Aprepitant, AQ4N, AR-67 (7-t- butyldimethylsiltyl-10-hydroxy-camptothecin), Armodafinil, Arsenic Trioxide, Ascorbic Acid, Aspirin, Astugenal, ASTX727, Atengenal, Atezolizumab, ATN-161, Atorvastatin, atrasentan hydrochloride, atrial natriuretic peptide (ANP), Auranofin, Avastin, Avelumab, Axitinib, AXL1717, Axumin, AZD1390, AZD2014, AZD4547, AZD7451, AZD8055, Azixa, bafetinib, BAL101553, Basiliximab, , Bavituximab, BBI608, becatecarin, Belinostat, bemcentinib (BGB 324), Bendamustine Hydrochloride, Bevacizumab, BGB-290, BGJ398, BIBF1120, BIBW 2992, Binimetinib, bisulfan, BKM120, BLZ-100, BMS-986016, BMX-001 , Bortezomib, Bosutinib, Boswellia serrata extract, bsi-201 plus temozolomide, Buparlisib, Busulfan, BXQ-350, C225-ILs-dox, Cabazitaxel, Cabozantinib, camptothecin-11 , CAN008, Cannabidiol, Cannabis, Capecitabine, Capivasertib, Captopril, Carboplatin, carboxyamidotriazole, Carmustine (BCNU), Carvedilol, CBL0137, CC-115, CC-122, CC-223, CC-486, CC-8490, CC- 90010, CCNU, CDX-110, Cediranib, Celecoxib (Celebrex), Cemiplimab-Rwlc, Cerebraca wafer, cereport, Ceritinib (LDK378), Cetuximab, Chlorogenic acid, Chloroquine, Cilengitide, cis-diamminedichloroplatinum (CDDP), Cisplatin, cladribine, Cloretazine (VNP40101M), CLR 131 , Combretastatin A4-phosphate (CA4P), Copanlisib, Copper, CpG-ODN, CPT-11 , Crenolanib, Crizotinib, CT-322, CX 4945, Cyclophosphamide, cyclosporine, cyproheptadine hydrochloride, CYT997, Cytarabine, D2C7-IT, Dabrafenib, dacarbazine, dalteparin, Dasatinib, DCC-2618, Defactinib, DeltaRex-G, depatuxizumab mafodotin, depsipeptide, Dexamethasone, Dexamfetamine sulphate, Dexanabinol, Dexmedetomidine, Dianhydrogalactitol, Dichloroacetate (DCA), Dimethyl Fumarate, Disulfiram, DNX-2401, DNX-2440 injection, docetaxel, Donepezil, donepezil hydrochloride, Dovitinib, , Doxorubicin, doxorubicin HCI liposome, doxorubicin hydrochloride, Dronabinol, DS-1001b, DSP- 7888, DTI-015, duloxetine, Durvalumab, E7050, ECO-4601, Edotecarin, EF5, efaproxiral, Eflornithine, eflornithine HCI, EGFR(V)-EDV-Dox, Encorafenib, Ensartinib, Entinostat, Entrectinib, Enzastaurin, Epacadostat, epitinib succinate, ERC1671, Erdafitinib, Erlotinib, Escitalopram, etanidazole, Etirinotecan pegol, Etoposide, Everolimus, exatecan mesylate, F-18 Fluoroethyltyrosine (FET), F-18 RGD-K5, FDOPA PET, Fenofibric acid, fenretinide, Fentanyl sublingual spray, ferumoxytol, FGFR Inhibitor AZD4547, filgrastim, Fimepinostat, Fingolimod, FLT-PET/CT: (3'deoxy-3'-[(18)F] fluorothymidine) PET/CT, Fluciclatide Injection, Fluciclitite, flucytosine, Fludarabine, Fluorescein, fluorouracil, Fluvastatine, FMISO, F-MISO, folinic acid, fotemustine, FPPRGD2, FT-2102, G-202, G207, an oncolytic virus, Gadobenate Dimeglumine, Gadobutrol, Gadolinium, Gadoteridol, Gamma-Secretase Inhibitor RO4929097, gamma-secretase/Notch signalling pathway inhibitor R 04929097, GC1008, GC1118, GDC-0084, Gefitinib, Gemcitabine, Genistein, gimatecan, Gliadel, GLIOLAN, glufosfamide, Glutaminase Inhibitor CB-839 Hydrochloride, Granisetron, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), GX-17, H-1PV, hCRF, HIF-2alpha Inhibitor PT2385, Hiltonol, hrBMP4, Hydroxychloroquine, hydroxyurea, hyperbaric oxygen, I-124-CLR1404, IA Carbon- Radiation, Ibrutinib, Idasanutlin, IDH1 peptide vaccine, IDH1R132H peptide vaccine, IDH305, ID01 inhibitor INCB024360, Ifosfamide, IGF-1R/AS ODN, IL13-PE38QQR, IL-4PE, , IMA950, Imatinib Mesylate, IMC-A12, imetelstat sodium, Imiquimod, IMMU- 132, INC280, Indoximod, INT230-6, Interferon-gamma, Intra-arterial Cetuximab, Intra- arterial Mannitol, Intrathecal methotrexate, Ipatasertib, Ipilimumab, irinotecan, irofulven, Isotretinoin, ispinesib, Itraconazole, ivosidenib, ixabepilone, Ixazomib,
Karenitecin (BNP1350), KB004, Ketoconazole, Keyhole limpet hemocyanin (KLH), KLH, L19TNF, Lacosamide, L-alanosine, Lapatinib, laromustine, Larotrectinib, LB- 100, LBH589, LDE225, LDN, leflunomide, Lenalidomide, Lenvatinib, LEQ506, letrozole, leucovorin, Levetiracetam, Lithium Carbonate, lobradimil, Lomustine,
Lonafarnib, lopinavir, Losartan, LS11 (talaporfin sodium), Lucanthone, LY2157299, LY2228820, LY2940680, Macitentan, Mannitol, Marizomib, MBG453, MDNA55, Mebendazole, Mechlorethamine Hydrochloride, MEDI3617, MEDI-575, Mefloquine, megestrol acetate, MEK162, melphalan, Memantine, mercaptopurine, Mesna, Metformin, methimazole, Methionine, methotrexate, Methoxyamine, methylphenidate hydrochloride, Metronomic Cyclophosphamide, Mibefradil, Microtubule-Targeted Agent BAL101553, Midazolam, Minocycline, Mirtazapine (Remeron), mitolactol, MK - 3475, MK-0752, MK-2206, MK-3475, MK-4827, MK-8628, MLN-518 (Tandutinib), MN- 166, Montanide ISA 51, MOPP Regimen, Motexafin Gadolinium, Motexafin
Gadolinium Injection, MPC-6827 + Carboplatin, MRZ, Nelfinavir, , Neratinib,
Neuradiab, Nifurtimox, Nilotinib, Nimustine, Nivolumab, NM404, NPC-07 for oral administration, NPC-08, NVX-108, 0-(2[18F]FLU0R0ETHYL)-L-TYR0SINE, 06- Benzylguanine (BG), 06-Benzylguanine (06-BG), OKN-007, Olaparib, Olaptesed pegol, Onartuzumab, ONC201 , Ondansetron, Ophthalmic steroid ointment, Ortataxel, Osimertinib, Oxaliplatin, PAC-1 Compound, Paclitaxel, Palbociclib, Palonosetron, Panitumumab, Panzem Nanocrystal Colloidal Dispersion, PARP Inhibitor BGB-290, Patupilone, Pazopanib, PD 0332991, Pegylated interferon alpha-2b, Pegylated Liposomal Doxorubicine, Pemetrexed, penicillamine, pentoxifylline, Perampanel, Perifosine, Perillyl alcohol, PF-00299804, PF-04449913, PF-06840003, PF-299804 (Dacomitinib), phenylacetate, Photofrin (porfimer sodium) , PI3K-beta Inhibitor GSK2636771, Pioglitazone, PLB1001 , Plerixafor, PLX3397, polifeprosan 20 with carmustine implant, Polyinosinic-Polycytidylic acid (Poly-ICLC), PolyMVA, polyvinylpyrrolidone-sodium hyaluronate gel, Pomalidomide, Ponatinib, porfimer sodium, Posaconazole (PCZ), PPX (CT2103), PPX +TMZ+XRT, PQR309, Prednisone, pregabalin, Prexasertib, prinomastat, procarbazine, PRT811, PSMA ADC, PT2977, PTC596, PTK787/ZK 222584, PX-866, R-(-)-gossypol acetic acid, R115777, racotumomab, RAD001 (Everolimus), Ramipril, Rapamycin, Regadenoson, REGN2810, Regorafenib, repotrectinib, Rhenium Liposome Treatment, rhlL-7-hyFc, Ribociclib, Rindopepimut (CDX-110), Ritonavir, RMP-7, R05323441, rofecoxib, Rolapitant, Romidepsin, Romiplostim, Rovalpituzumab tesirine, RRx-001, RTA 744, rubitecan, ruxolitinib, , Sacituzumab Govitecan, sagopilone, Samotolisib, Sapanisertib, SarCNU, Sativex, Savolitinib, SCH 66336, SCH 900105, SCH66336, Selinexor, Selumetinib, semaxanib, Semustine, Sertraline, sildenafil citrate, sirolimus, Siroquine, sodium borocaptate, sodium stibogluconate, Sodium Thiosulfate, Soliramfetol, sonidegib, sorafenib, STAT3 Inhibitor WP1066, Steroid eye drop, Steroids, streptozocin, SU011248 & Irinotecan, SU101, Sulfasalazine, sunitinib, suramin, survivin peptide vaccine, Sym004, TAK-580, talabostat mesylate, Talampanel, talotrexin, Tamoxifen, tandutinib, Taselisib, taurolidine, Tazemetostat, TB-403, Td vaccine, Temferon, temozolomide (TMZ), temsirolimus, terameprocol, Tesevatinib, testosterone, tetanus shot, Tetanus-Diphtheria booster, TG02, TG6002, TH-302, thalidomide, thioguanine, thiotepa, Tinostamustine, tipifarnib, Tivozanib, TLN-4601, TM-601, TN-TC11G, Toca FC, topotecan, TP-38 toxin, TPI287, trabedersen, Trametinib, Tranexamic Acid, Trans Sodium Crocetinate (TSC), Trastuzumab, TRC105, triiodothyronine (T3), Trivax, trofosfamide, TTAC-0001, TVB-2640, Ubidecarenone, Ulixertinib, Ursodiol, USL311, Valacyclovir, Valganciclovir (Valcyte), valproic acid, vandetanib (ZD6474), Vardenafil, vatalanib, VB-111, VEC, VEGF inhibitor PTC299, veledimex, Veliparib, Vemurafenib, verteporfin, Verubulin, Vidaza, Vinblastine, Vincristine, vinorelbine, Vismodegib, Vitamin D3, Vorinostat, VP-16 + Avastin, VXM01, XL147 (SAR245408), XL184, XL765 (SAR245409), Zactima, Zarnestra, ZK 219477, Zotiraciclib (TG02), and ZSP1602.
[0174] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in combination with radiation therapy. In embodiments, the radiation therapy is external beam radiation. In embodiments, a machine is utilized to aim high-energy rays (or beams) from outside the body into the tumor. In embodiments, the machine is a linear accelator (linac). In embodiments, the external radiation therapy is selected from a group consisting of three-dimensional conformal radiation therapy, image guided radiation therapy, intensity modulated radiation therapy, helical-tomotherapy, photon beam radiation therapy, proton beam radiation therapy, and stereotactic radiosurgery. In some embodiments, patients receive between about 40 Gy to about 100 Gy of radiation in combination with a HDAC inhibitor (e.g. panobinostat). In some embodiments, patients receive about 40 Gy, or about 45 Gy, 50 Gy, or about 54 Gy, or about 55 Gy, or about 60 Gy, or about 65 Gy, or about 70 Gy, or about 75 Gy, or about 80 Gy, or about 85 Gy, or about 90 Gy, or about 95 Gy, or about 100 Gy of radiation, including all values and ranges in between. In some embodiments, the patient is administered 54 Gy of radiation.
[0175] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in combination with one or more biological therapies. Biological therapies involve the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Some biological therapies for cancer stimulate the body’s immune system to fight cancer cells. Non-limiting examples of biological therapies are: 111 In-labeled DCs, ADV-TK/GCV, ALD-451 , ALECSAT, APX005M , AV-GBM-1, AZD1775, Ad-RTS-hlL-12, Ad5CMV-p53 gene, AdV-tk, Anlotinib, Anti-CD137, Anti-Endoglin Chimeric Monoclonal Antibody TRC105, Anti- HER2 CAR-T, Anti-LAG-3 monoclonal antibody, Anti-PD-1 monoclonal antibody, Anti- PD-L1 CAR T cells, Antigen-specific IgT cells, Autologous Cytomegalovirus-specific Cytotoxic T-lymphocytes, Avelumab, B7-H3 CAR-T, BMS-936558, BTSC mRNA- loaded DCs, Bevacizumab, Biological: DC activated CIK combined with DC, CART- EGFRvlll T cells, anti-CD147 CAR T cells, anti-CD19 CAR T cells, CIK, CMV Specific Cytotoxic T Lymphocytes (CTL), Carboxylesterase-expressing Allogeneic Neural Stem Cells, Carcinoembryonic Antigen-Expressing Measles Virus, Cemiplimab, Cetuximab, Cixutumumab, DCVax-L, DEC-205/NY-ESO-1 Fusion Protein CDX-1401 , DNX-2401 , Dendritic Cells, Durvalumab, E. coli CD-expressing genetically modified neural stem cells, EGFR806-specific chimeric antigen receptor (CAR) T cell, EGFRBi- Armed Autologous T Cells, EGFRvlll CAR T cells, Epidermal growth factor receptor(EGFRv)lll Chimeric antigen receptor (CAR) transduced PBL, Erlotinib, HLA- A2 Restricted Glioma Antigen-Peptides, FPA008, Filgrastim, GAA/TT-peptide vaccine, GBM6-AD, GM-K562 Vaccination, GSC-loaded autologous dendritic cells, GX-I7, Gliolan, Granulocyte-macrophage Colony-stimulating Factor, HBOT, HER. CAR CMV-specific CTLs, HER2-specific chimeric antigen receptor (CAR) T cell, HIV-Gag mRNA-pulsed autologous DCs, HSPPC-96, Heat Shock Protein Peptide Complex-96 (HSPPC-96), Hepatitis A Vaccine, Human CMV pp65-LAMP mRNA- pulsed autologous DCs, Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF, ICT-107, ICT-121 DC vaccine, ID01 Inhibitor BMS-986205, IMA 950, INO-5401 , INO-9012, Ipilimumab, K27M peptide, M032 (NSC 733972), MDV9300, MGMTP140K-encoding retroviral vector, MK-3475, Malignant Glioma Tumor Lysate-Pulsed Autologous Dendritic Cell Vaccine, Modified Measles Virus, Multiple dose of EO2401 , NK-92/5.28.Z, NT-I7, NeoVax, Neural stem cells loaded with an oncolytic adenovirus, New Castle Disease Virus, Nimotuzumab, Nivolumab, Oncolytic Adenovirus Ad5-DNX-2401 , PEG-interferon alfa-2b, PEP-3 vaccine, PEP- 3-KLH conjugate vaccine, PEP-CMV, PEPIDH1M vaccine, PF-04856884, PVSRIPO, Panitumumab, Pembrolizumab, Pertuzumab, Polio/Rhinovirus Recombinant (PVSRIPO), REOLYSIN, RNA-loaded dendritic cell vaccine, Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO), Research Bloods, Rindopepimut, Ringer's acetate, SL-701 ; poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose), SVN53-67/M57-KLH Peptide Vaccine, Sleeping Beauty Transposed PBL, Suppressor of the PI3K/Akt pathways, TGFa-PE38 immunotoxin, TTRNA dendritic cell vaccine, TTRNA-xALT, Td (tetanus toxoid), Tetanus Toxoid Vaccine, Tetanus-Diphtheria Toxoid (Td), Toca 511 , Trastuzumab, Trebananib, Tremelimumab, Trivalent Influenza Vaccine, V-Boost, VBI-1901 , VXM01, Varlilumab, Vocimagene Amiretrorepvec, Wild-type Reovirus, acoustic coupling fluid, aldesleukin, anti-CTLA-4 antibody, anti-EGFR CAR T, anti-EGFRvlll CAR T cells, anti- MUC1 CAR-T cells, anti-MUC1 CAR-pNK cells, anti-PD-1 antibody, bispecific antibody MDX447, bleomycin, brain mimicking fluid, cintredekin besudotox, daclizumab, delta-24-RGD adenovirus, glioblastoma multiforme multipeptide vaccine IMA950, gp96, interleukin-4 PE38KDEL cytotoxin, lymphokine-activated killer cells, monoclonal antibody Me1-14 F(ab')2, muromonab-CD3, nimotuzumab (anti EGFR humanized monoclonal antibody), olaratumab, oncolytic HSV-1716, peg-filgrastim, pegylated interferon alfa, pp65-LAMP dendritic cell vaccine, ramucirumab, recombinant adenovirus-p53 SCH-58500, recombinant human thrombopoietin, recombinant interferon alfa-2b, 540-548 peptide vaccine, transferrin-CRM107, and ziv-aflibercept.
[0176] In embodiments, biological therapies, which are proteins, may be recombinant or isolated from blood. [0177] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with one or more targeted therapies. Target therapies block the action of certain proteins, enzymes, or molecules involved in cancer cell growth. Chimeric antigen receptor T (CAR T) cells, monoclonal antibodies, antibody drug conjugates, and small molecules are non-limiting examples of targeted therapies. In embodiments, panobinostat is administered in combination with an inhibitor of FLT3. Non-limiting examples of FLT3 inhibitors include anti-FLT3 antibodies, SU5416, midostaurin, SU11248, PKC412, CEP-701, MLN518, and gilteritinib. In embodiments, panobinostat is administered with an inhibitor of IDH. Non-limiting examples of IDH inhibitors include ivosidenib and enasidenib. In embodiments, panobinostat is administered with an inhibitor of CD33, which is found on DIPG cells. A potential CD33 inhibitor can be a small molecule, a monoclonal antibody, or an anti-CD33 CAR T cell. In embodiments, panobinostat is administered with gemtuzumab ozogamicin. In embodiments, panobinostat is administered with an inhibitor of BCL-2. Bcl-2 is an antiapoptotic protein, which promotes cancer growth. Non-limiting examples of BCL-2 include venetoclax, piperlongumine, 2-methoxy-antimycin A3, nilotinib, ABT 737, epigallocatechin gallate, obatoclax mesylate, and ABT 263. In embodiments, panobinostat is administered with an inhibitor of the hedgehog pathway. One protein of the hedgehog pathway is sonic hedgehog, which is active in DIPG. In embodiments, panobinostat is administered with glasdegib, an inhibitor of sonic hedgehog.
[0178] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in combination with a cellular therapy. A cellular therapy is a therapy in which cells are transplanted into a patient. Non-limiting examples of types of cellular therapies therapies are hematopoietic stem cells, red blood cells, white blood cells, T cells, B cells, natural killer (NK) cells, NKT cells, Tregs, CD4+ T cells, CD8+ T cells, CAR T cells, dendritic cells, neural stem cells, umbilical cord blood, T cell receptor engineered T cells (TCR-T cells), antigen presenting cells, and platelets. The cellular therapy may be autologous or allogeneic. Autologous cellular therapies involve the transplant of cells from one person, which are given back to the same person. Allogeneic cellular therapies involve the transplant of cells from one person to a different person. In embodiments, the cellular therapy may be modified before introduction into a patient. For instance, the cellular therapy may be genetically modified or cultured ex vivo.
[0179] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an immunomodulatory agent. An immunomodulatory agent is utilized to enhance the immune response against a tumor. In embodiments, immunomodulatory agents act on macrophages, lymphocytes, neutrophils, natural killer cells, and cytotoxic T lymphocytes. Immunomodulator agents affect cytokine production by immune cells. In embodiments, immunomodulatory agents are small molecules. In embodiments, immunomodulatory agents are CAR T cells. In embodiments, immunomodulatory agents are antibodies. In embodiments, immunomodulatory agents are cytokines. Non-limiting examples of cytokines include IL-2, IL-1, IFN-γ, IL-7, IL-12, IL-6, IL-15, IL-2, TNFα, and IL-3. In embodiments, immunomodulatory agents are vaccines. Non- limiting examples of vaccines include the GVAX vaccine, galinpepimut-S (GPS), heat shock protein (HSP) vaccine, rindopepimut, dendritic cells, Pep-3-KLH (targets EGFRvlll), and NeoVax.
[0180] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an inhibitor of Bcl-2. Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, schizophrenia, and autoimmunity. Bcl-2 is an oncogene, which results from a translocation between chromosomes 14 and 18. Bcl-2 family proteins regulate apoptosis. A Bcl-2 inhibitor binds to Bcl-2 and prevents cellular signaling. Non-limiting examples of Bcl-2 inhibitors include, oblimersen, navitoclax, ABT-737, and venetoclax.
[0181] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with a therapeutic that penetrates the blood brain barrier. In some embodiments, therapeutics that penetrate the blood-brain barrier have a molecular weight of < 400 g/mol and high lipid solubility. In some embodiments, a therapeutic that crosses the blood brain barrier exhibits less hydrogen bonds with water than a therapeutic that does not cross the blood brain barrier. In some embodiments, a therapeutic that crosses the blood-brain barrier forms less than ten hydrogen bonds with water. Non- limiting examples of therapeutics that pass the blood brain barrier include panobinostat, temozolomide, lomustine, and carmustine.
[0182] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with a dopamine receptor D2 (DRD2) antagonist. DRD2 is a G-protein coupled receptor that responds to the neurotransmitter dopamine and inhibits adenylyl cyclase activity. DRD2 antagonists have anticancer activity, which is in part derived from the activation of the cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA) pathway. In some embodiments, panobinostat is administered with the DRD2 antagonist ONC210 (TIC10). [0183] In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an inhibitor of regulatory T cells (Tregs). Regulatory T cells are immune cells, which are responsible for the establishment of immune tolerance. Tregs also dampen the functions of anti-neoplastic immune cells and promote cancer progression. In embodiments, Tregs are FOXP3+, CD25high, CD4+ T cells. In embodiments, patients with brain cancer exhibit increased Tregs in comparison to healthy patients. In embodiments, an increased percentage of Tregs is correlated with poor prognosis.
[0184] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with checkpoint inhibitors. Checkpoint inhibitors block immune checkpoint proteins. Examples of checkpoint proteins found on the surface of or secreted by immune cells and cancer cells are PD-1, PD-L1, CTLA-4, B7-1 (CD80), B7-2 (CD86). Immune checkpoint inhibitors prevent the interaction of receptors, such as PD-1 and CTLA-4 from interacting with their ligands PD-L1 , B7-1, and B7-2. In some embodiments, checkpoint inhibitors disrupt cellular signaling and have an anti-cancer effect. In some embodiments, the administration of a checkpoint inhibitors with panobinostat has an anti-cancer effect. In some embodiments, the checkpoint inhibitor is an inhibitor of the PD-1/PD-L1 checkpoint. An inhibitor of the PD-1/PD-L1 checkpoint blocks the interaction of PD-1 with PD-L1. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with a monoclonal antibody which inhibits the PD-1/PD- L1 checkpoint. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an anti-PD-1 antibody. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an anti-PD-L1 antibody. In some embodiments, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS- 986189. In some embodiments, the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, and APT-514.
[0185] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an inhibitor of the CTLA-4/B7-1 or CTLA-4/B7-2 interaction. An inhibitor of the CTLA-4/B7-1 checkpoint blocks the interaction of CTLA-4 with B7-1. An inhibitor of the CTLA-4/B7-2 checkpoint blocks the interaction of CTLA-4 with B7-2. In some embodiments, the checkpoint inhibitor is an antibody. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an anti-CTLA-4 antibody. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an inhibitor of CTLA-4 selected from the group consisting of ipilimumab and tremelimumab. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an inhibitor of B7-1. A non-limiting example of a B7-1 inhibitor is galiximab. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with an inhibitor of B7-2.
[0186] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is administered with a mammalian target of rapamycin (mTOR inhibitor). mTOR is a conserved serine/threonine kinase, which controls cell growth, proliferation, and survival. mTOR inhibitors block the activity of the mammalian target of rapamycin. Non-limiting examples of mTOR inhibitors include deforolimus, everolimus, sirolimus, temsirolimus, AZD8055, Ku-0063784, PPT242, PP30, Torinl , WYE-354, NVP-BEZ235, PI-103, PKI-179, PKI-587, and XL765.
[0187] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is not administered with a strong CYP3A4 inducer. In some embodiments, a HDAC inhibitor (e.g. panobinostat) is not administered with a therapeutic agent that prolongs the QTc interval. In further embodiments, methods of the present disclosure are associated with a reduction in drug resistance. Drug resistance in brain cancer patients results from drug resistance-related proteins and enzymes, gene alterations, microRNAs, and erratic signaling pathways.
[0188] In further embodiments, methods of the present disclosure utilize a HDAC inhibitor (e.g. panobinostat) in in combination with other therapies to produce a synergistic effect. A synergistic effect results when the total effect of the therapeutic agents is greater than the sum of the individual effects of each drug.
[0189] In embodiments, a HDAC inhibitor (e.g. panobinostat) is synergistic with Wee1 inhibitors, such as MK-1775. Wee1 is a checkpoint kinase that prevents cell course progression through phosphorylation of cyclin dependent kinase 1 (CDK1) and cyclic dependent kinase 2 (CDK2). CDK1 and CDK2 are part of the checkpoint kinase 1 (CHK1) pathway. In embodiments, a HDAC inhibitor (e.g. panobinostat) downregulates the CHK1 pathway. In embodiments, a HDAC inhibitor (e.g. panobinostat) downregulates Weel In embodiments, the synergistic effect of dual HDAC inhibitor/Wee1 inhibitor administration allows for a lower dose of panobinostat to be given. In embodiments, the synergistic effect of dual HDAC inhibitor/Wee1 inhibitor administration allows for a lower dose of panobinostat to be given. In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in combination with one or more Wee1 inhibitors for the treatment of brain cancer. [0190] In embodiments, a HDAC inhibitor (e.g. panobinostat) is synergistic with bisphosphonates. Non-limiting example of bisphosphonates zoledronic acid, alendronate/cholecalciferol, etidronate, reisedronate, ibandronate, pamidronate, alendronate, and tiludronate. Coadministration of a HDAC inhibitor (e.g. panobinostat) and bisphosphonates results in induction of the mitochondrial apoptotic pathway and the generation of reactive oxygen species. In embodiments, administration of a HDAC inhibitor (e.g. panobinostat) in combination with a bisphosphonate results in enhanced cancer cell killing. In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in combination with one or more bisphosphonates for the treatment of brain cancer.
[0191] In embodiments, a HDAC inhibitor (e.g. panobinostat) is synergistic with topoisomerase inhibitors, such as topotecan and/or etoposide. Coadministration of a HDAC inhibitor (e.g. panobinostat) and topoisomerase inhibitors results in induction of the mitochondrial apoptotic pathway and the generation of reactive oxygen species. In embodiments, administration of a HDAC inhibitor (e.g. panobinostat) in combination with a topoisomerase inhibitor results in enhanced cancer cell killing. In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in combination with one or more topoisomerase inhibitors for the treatment of brain cancer.
[0192] In embodiments, a HDAC inhibitor (e.g. panobinostat) is synergistic with a proteasome inhibitor. Non-limiting examples of proteasome inhibitors include bortezomib, ixazomib, marizomib, and carfilzomib. In embodiments, coadministration of panobinostat and a proteasome inhibitor results in synergistic cytotoxicity. In embodiments, combined administration of a HDAC inhibitor (e.g. panobinostat) and a proteasome inhibitor results in downregulation of BCL-2. In embodiments, a HDAC inhibitor (e.g. panobinostat) is administered in combination with one or more proteasome inhibitors for the treatment of brain cancer.
[0193] In some embodiments, a HDAC inhibitor (e.g. panobinostat) is synergistic with a HIV protease inhibitor. In some embodiments, combined administration of a HDAC inhibitor (e.g. panobinostat) and a HIV protease inhibitor to enhance histone acetylation. Non-limiting examples of HIV protease inhibitors include saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir, and darunavir.ln embodiments, a HDAC inhibitor (e.g. panobinostat) is synergistic with second generation selective inhibitor of nuclear export (SINE) compounds. SINE compounds. In embodiments, coadministration of a HDAC inhibitor (e.g. panobinostat) and a SINE compound results in a compromised DNA damage response pathway. A compromised DNA damage response pathway leads to destabilization of genomic integrity in cancer cells. In embodiments, panobinostat is administered in combination with one or more SINE compounds for the treatment of brain cancer.
[0194] In embodiments, a HDAC inhibitor (e.g. panobinostat) is synergistic with ibrutinib. In embodiments, a HDAC inhibitor (e.g. panobinostat) results in downregulation of MyD88. Mutations in MyD88 are responsible for ibrutinib resistance. In some embodiments, brain cancer treated according to the present methods has MyD88 mutations. In embodiments, a HDAC inhibitor (e.g. panobinostat) is coadministered with ibrutinib for treatment of brain cancer containing MyD88 mutations. In embodiments, coadministration of a HDAC inhibitor (e.g. panobinostat) and ibrutinib results in decreased resistance of cancer cells to ibrutinib.
[0195] In embodiments, a HDAC inhibitor (e.g. panobinostat) is synergistic with inhibitors of BCL-2. Acquired resistance to BCL-2 inhibitors results from increased MCL-1 and BCL-XL levels, which leads to sequestration of the protein BIM. BIM is a pro-apoptotic protein. In embodiments, panobinostat downregulates the expression of BCL-2, BCL-xl, BCL-w, and MCI-I, resulting in upregulation of BIM. In embodiments, a HDAC inhibitor (e.g. panobinostat) and a BCL-2 inhibitor are administered in combination for the treatment of brain cancer. In embodiments, co-administration of a HDAC inhibitor (e.g. panobinostat) and a BCL-2 inhibitor allows for a lower dose of panobinostat and/or the BCL-2 inhibitor.
[0196] TP53 is the most frequently mutated gene in human tumors. TP53 is a tumor suppressor gene often inactivated by deletion and/or point mutation in brain cancer. Mutations in p53 are correlated with resistance to chemotherapy. Mutant p53 interacts with histone deacetylases, leading to stabilization of mutant p53 and mutant p53’s aberrant function. In embodiments, a HDAC inhibitor (e.g. panobinostat) decreases the stability of mutant p53 by inhibiting a histone deacetylase.
[0197] In embodiments, coadministration of a HDAC inhibitor (e.g. panobinostat) and a tyrosine kinase inhibitor has a synergistic effect. In embodiments, coadministration of a HDAC inhibitor (e.g. panobinostat) and a platinum-based therapeutic have a synergistic effect. In embodiments, panobinostat has a synergistic effect with platinum- based therapeutics, tyrosine kinase inhibitors, and BCL-2 inhibitors as a result of panobinostat’s ability to destabilize mutant p53. Patient Populations
[0198] In some embodiments, the methods of the present disclosure comprise treating patients diagnosed with brain cancer. Non-limiting examples of brain cancers include acoustic neuromas, astrocytomas, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, oligoastrocytoma, anaplastic-astrocytoma, pituitary tumors, glioblastoma, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, diffuse midline glioma, and pineal tumors.
[0199] In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a diffuse infiltrating glioma. In some embodiments, the brain cancer is a high grade glioma. In some embodiments, the brain cancer is classified according to the World Health Organization’s guidelines, which are described by Vigneswaran et al. and Louis et al., which are each incorporated by reference herein in their entireties: Vigneswaran et al. Ann Transl Med. 2015 May;3(7):95. Louis DN et al. (2016) World Health Organization Histological Classification of Tumours of the Central Nervous System. International Agency for Research on Cancer, France. The World Health Organization grades diffuse infiltrating gliomas on a scale from I to IV. High-grade gliomas are assigned a grade of III or IV. Grade II astrocytomas are found diffusely infiltrating into surrounding neural tissue and exhibit increased hypercellularity and no mitosis. Grade II oligodendrogliomas occur in the white matter and cortex of the cerebral hemispheres and exhibit low mitotic activity and no necrosis. Grade III anaplastic-astrocytomas or oligodendrogliomas are highly infiltrating tumors with increased mitotic activity and no necrosis or vascular proliferation. Grade IV glioblastomas are infiltrating glial neoplasms with necrosis and micro-vascular proliferation; grade IV glioblastomas exhibit a high rate of mitosis.
[0200] In some embodiments, the brain cancer is DIPG. DIPG is a devastating, aggressive brain tumor of childhood arising in the ventral pons, which is part of the brain stem. Though brainstem tumors are rare among adults, they comprise approximately 10-15% of pediatric brain tumors, with half of all pediatric malignant gliomas occurring in the brainstem. DIPG is the most common tumor subtype in this anatomical region, constituting 80% of brainstem gliomas. With an estimated 200-400 children affected by DIPG annually in the United States, it is the second most common malignant brain tumor of childhood. The prognosis is bleak: the absence of effective therapies makes DIPG uniformly fatal. DIPG is the leading cause of childhood brain tumor death. The median age of DIPG diagnosis is 6-7 years, with median survival of 9 months. 90% of children will die from DIPG within 2 years of initial diagnosis, with less than 1% surviving after 5 years. Because DIPG grows diffusely and infiltrates critical brainstem structures, surgical resection is not possible. Radiation therapy has remained the mainstay of treatment for the past three decades since its introduction. At most treatment centers, the standard recommendation is conventionally fractionated local field radiotherapy with dose range of 54-60 Gy for a period of 6 weeks. Radiotherapy provides temporary improvement or stabilization of symptoms and extends overall survival by an average of 3 months; median survival is less than 5 months without radiation. Though both clinical and radiographic responses are initially observed, local recurrence invariably occurs. Chemotherapy has been attempted at time points before, during and after radiation therapy. Despite all efforts, no improvement in overall survival has been demonstrated. Prior to the present disclosure, no therapeutic agent has ever shown significant efficacy for DIPG.
[0201] In some embodiments, a patients with DIPG is diagnosed if the patient has a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons. In some embodiments, patients with pontine lesions that do not exhibit the criteria for radiographically typical DIPG have histologic confirmation of malignant glioma as determined by WHO ll-IV criteria.
[0202] In some embodiments, the methods of the disclosure are utilized to treat patients with progressive DIPG. In some embodiments, patients with progressive DIPG have progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression. In some embodiments, patients with progressive DIPG have an increase in the bi-dimensional tumor measurement, taking as a reference the smallest bi-dimensional tumor measurement recorded since diagnosis. Tumor measurements will be conducted via magnetic resonance imaging (MRI). In some embodiments, progressive DIPG is associated with the appearance of new tumor lesions, since diagnosis.
[0203] In some embodiments, the methods of the disclosure are utilized to treat patients that have non-progressed DIPG, as determined by clinical or radiographic criteria. [0204] In embodiments, patients with DIPG exhibit genetic mutations, which are associated with poor prognosis and resistance to therapeutics. In embodiments, the methods of the present disclosure treat patients with one or more genetic mutations. Non-limiting examples of genetic mutations include mutations in H3F3A, HIST1H3B, HIST1H3C, TP53, ACVR1, PDGFRA, PPM1D, PIK3CA, PIK3R1, MYC, MYCN, and PPM1D. See Lapin et al. Front Oncol. 2017;7:57.
[0205] In some embodiments, patients with DIPG have mutations in genes encoding histones, key chromatin components that play important roles in regulating the epigenome. In some embodiments, patients with DIPG have a mutation in H3F3A. H3F3A (H3 histone, family 3A), is a gene encoding histone variant H3.3, which replaces histones as necessary in the event of nucleosome disruption. In some embodiments, patients with DIPG have an alteration in histone variant H3.1 , such as an alteration in HIST1 H3B (histone cluster 1 , H3b) or in HIST1 H3C (histone cluster 1, H3c). Histone H3.1 plays a role in packaging newly synthesized DNA during S- phase18. In both H3.3 and H3.1, the alteration is a specific missense mutation resulting in the substitution of lysine with methionine at position 27 (K27M). This position is located within the N-terminal tail of the histone; importantly, post- translational modification of histone tails by methylation, acetylation or ubiquitylation of lysine residues is known to mediate the epigenetic regulation of gene expression and alter nucleosome structure. The addition or deletion of such modifications are facilitated by “writers” and “erasers” and result in altered interactions with transcription modifiers, as mediated by “readers.” While mutations in writers, erasers or readers have recently been implicated in other oncogenic pathways, it appears that in DIPG the epigenetic aberrancy directly results from mutation of the histone alone. Indeed, DIPG represents the first identified example of the implication of a histone mutation in oncogenesis and disease. Remarkably, the H3 K27M mutation is heterozygous in 100% of DIPG cells, and remains so in both treatment-naive and treatment-exposed samples, and within low- and high-grade tumor regions. This strongly suggests clonal selection, emphasizing the robust selective advantage that the H3 K27M mutation likely confers.
[0206] In some embodiments, patients with DIPG have a Histone 3 (H3) K27M mutation in the H3F3A gene. H3 K27M is a gain-of-function mutation that exerts broad transcriptional effects by disrupting lysine trimethylation at position 27. The K27 trimethylation mark (H3K27me3) is necessary for stimulation of methyltransferase activity of Polycomb Repressive Complex 2 (PRC2) via nucleosome interaction with the EZH2 subunit of PRC230. PRC2 is known to silence gene transcription in order to regulate stem cell differentiation in development, and mutations in subunits of PRC2 itself have been previously implicated in oncogenesis31. The substitution of lysine with methionine at position 27 interferes with PRC2 stimulation and results in the robust, aberrant derepression of gene transcription normally silenced by PRC2 activity. In DIPG samples, this occurs in the absence of altered EZH2 expression. Strikingly, while the mutant H3 variants represent only a fraction (~3-17%) of the total histone H3 population in DIPG cells, this mutation nonetheless exerts a dominant reprogramming effect and initiates a global pattern of hypomethylation and increased transcriptional activity, with dramatic loss of trimethylation or dimethylation observed across all H3 variants in human DIPG samples as well as in in vivo and in vitro models34,35,30,32; ectopic H3 K27M expression in other cell types similarly leads to global reduction of H3K27me3. Certain trimethylation marks remain, but these were found to associate with certain target genes not usually under H3K27me3 control, possibly signifying further alteration of transcription regulation. Interestingly, there is also an observed increase in H3K27me3 in regions simultaneously trimethylated at H3K4, a mark that usually promotes active gene expression. This contradictory combination of “silent” and “active” marks signifies that the associated target genes are “bivalent” - i.e. , uniquely primed for expression upon H3K27 trimethylation loss — and indeed, these target genes were found to be involved in oncogenic as well as developmental pathways.
[0207] In some embodiments, patients with DIPG have a mutation in ACVR1. ACVR1 encodes the type I bone morphogenetic protein (BMP) receptor ALK2. In some embodiments, mutations in ACVR1 lead to amino acid substitutions of R206H, Q207E, R258G, G328E, G328V, G328W, and G356D.
[0208] In some embodiments, patients with DIPG have a mutation in platelet-derived growth factor receptor A ( PDGFRA ). PDGFRA is a receptor tyrosine kinase and cell cycle regulatory gene. In some embodiments, patients with DIPG have gain-of- function mutations in PDGFRA. In some embodiments, patients with DIPG have loss- of-function mutations in PDGFRA.
[0209] In some embodiments, patients with DIPG have a mutation in the protein phosphatase Mg2+/Mn2+ dependent 1D gene ( PPM1D ). PPM1D encodes a serine/threonine phosphatase which dephosphorylates numerous proteins involved in the DNA damage response (DDR) and cellular checkpoint pathway. In some embodiments, patients with DIPG experience C-terminal truncations of PPM1D. [0210] In some embodiments, patients with DIPG have a mutation in the PIK3CA or PIK3R1. PIK3CA and PIK3CA mutations promote tumor angiogenesis and cancer cell sternness.
[0211] In some embodiments, patients with DIPG have mutations in MYC or MYCN. MYC and MYCN are transcriptional regulators. In some embodiments, mutations in MYC lead to constitutive expression of the Myc protein. In some embodiments, MYC or MYCN mutations enhance gene expression across the whole genome, promoting tumor survival. In some embodiments, MYCN amplification is associated with hypermethylation, increased histological grade, and chromothripsis at chromosome
2p.
[0212] In embodiments, methods of the present disclosure are utilized to treat patients that exhibit mutations or loss of the tumor protein 53 ( TP53 ) tumor suppressor. TP53 is a key tumor suppressor related to the maintenance of genomic stability, including regulation of cellular senescence, apoptosis, metabolism, and DNA repair.
[0213] In embodiments, the methods of the present disclosure are utilized to treat patients that have increased numbers of Tregs in peripheral blood or in a patient’s brain tumor. Some brain tumors produce CCL22, a chemokine ligand, which recruits Tregs to the tumor. In embodiments, subjects with brain cancer exhibit an increased frequency of PD-L1 on cancer cells or tumor cells. PD-L1 promotes the development, maintenance, and function of Tregs. In embodiments, chemotherapy can promote Treg depletion by tilting the balance from Treg toward effector T cells. In embodiments, cyclophosphamide is administered in combination with panobinostat to reduce Tregs. In embodiments, anti-CCR4 and/or anti CD25 antibodies are utilized to deplete or block Tregs. For example, the anti-CD25 antibody daclizumab depletes Tregs. In embodiments, methods of the present disclosure utilize an anti-CTLA-4 antibody to deplete or block Tregs. CTLA-4 is expressed on Tregs. In embodiments, ipilimumab is administered to deplete or block Tregs. In embodiments, methods of the present disclosure use an anti-GITR antibody to deplete Tregs. GITR is constitutively expressed on Tregs. In embodiments, 0X40 is expressed on Tregs. In embodiments, an anti-OX40 antibody is utilized to deplete or block Tregs. In embodiments, small molecules or antibody antagonists of CCR4 are utilized to block or deplete CCR4. CCR4 is a chemokine receptor found on Tregs that facilitates Treg trafficking. CCR4+ Tregs migrate along a chemokine gradient toward CCL17 or CCL22, which is released by cancer cells or produced by dendritic cells in the lymph nodes. Blockade or depletion of CCR4+ T regs results in disrupted lymph node and tumor homing by T regs. [0214] In embodiments, methods of the present disclosure are utilized to treat patients with exhausted T cells. T cell exhaustion is characterized by the loss of T cell function. In embodiments, exhausted T cells display high levels of CD43. In embodiments, exhausted T cells display high levels of CD69. In embodiments, exhausted T cells display high levels of inhibitory receptors, such as PD-1 and CTLA-4. In embodiments, exhausted T cells express LAG-3 and/or TIM-3. In embodiments, exhausted T cells exhibit low expression of CD62. In embodiments, exhausted T cells exhibit low expression of CD127. In embodiments, exhausted effector T cells are PD-1+, LAG3+, CD4+ or PD-1-, TIM3+, CD4+ T cells. In embodiments, increased number of Tregs is associated with increased number of exhausted effector T cells (Teffs). In embodiments, Tregs contribute to suppression of Teffs by the induction of immunosuppression through secretion of cytokines, such as IL-4, IL-10, and TGFβ. In embodiments, the presence of checkpoint proteins is associated with exhausted effector T cells. In embodiments, the frequency of exhausted T cells is increased in patients with brain cancer. In embodiments, the frequency of exhausted T cells is increased in brain cancer patients that relapse. In embodiments, checkpoint inhibitors are utilized in methods of the present disclosure to reverse T cell exhaustion. In embodiments, inhibitors of Tregs are utilized in the present disclosure to reverse T cell exhaustion.
[0215] In some embodiments, the methods of the disclosure are utilized to treat patients from age 0-80. In some embodiments, the methods of the present disclosure are utilized to treat patients from about age 2 to about age 22. In some embodiments, the patients are about 2 years old, about 3 years old, about 4 years old, about 5 years old, about 6 years old, about 7 years old, about 8 years old, about 9 years old, about 10 years old, about 11 years old, about 12 years old, about 13 years old, about 14 years old, about 15 years old, about 16 years old, about 17 years old, about 18 years old, about 19 years old, about 20 years old, about 21 years old, or about 22 years old. [0216] In some embodiments, the patients are administered panobinostat or another therapeutic agent based on the patient’s body surface area (BSA). In some embodiments, patients exhibit a BSA between about 0.25 and 2.5. In some embodiments, patients have a BSA of about 0.25, or about 0.30, or about 0.35, or about 0.40, or about 0.45, or about 0.50, or about 0.55, or about 0.60, or about 0.65, or about 0.70, or about 0.75, or about 0.80, or about 0.85, or about 0.90, or about 0.95, or about 1.0, or about 1.1 , or about 1.2, or about 1.3, or about 1.4, or about 1.5, or about 1.6, or about 1.7, or about 1.8, or about 1.9, or about 2.0, or about 2.1 , or about 2.2, or about 2.3, or about 2.3, or about 2.4, or about 2.5, including all values and ranges in between.
Pharmaceutical formulations
[0217] The therapeutic agents described here may be formulated in any suitable pharmaceutical composition. In some embodiments, pharmaceutical formulations may comprise one or more pharmaceutically acceptable excipients or adjuvants. The pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In some embodiments, the pharmaceutical formulations may comprise a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
[0218] In some embodiments, the pharmaceutical compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the pharmaceutical compositions may contain additional, compatible, pharmaceutically-active materials such as antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation. [0219] For the purposes of this disclosure, the therapeutic agents of the present disclosure can be formulated for administration by a variety of means including orally and parenterally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.
[0220] The therapeutic agents disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the therapeutic agents disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The therapeutic agents disclosed herein can also be formulated as a preparation for implantation or injection. For example, the therapeutic agents can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). Alternatively, the therapeutic agents can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wlkins, Philadelphia, PA.
[0221] In certain embodiments, a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
[0222] In some embodiments, the pharmaceutical compositions comprises a therapeutic agent disclosed herein combined with a pharmaceutically acceptable carrier. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M phosphate buffer or saline (e.g., about 0.8%). Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non- aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
[0223] Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.
[0224] Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
[0225] Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, e.g. sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
[0226] Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet- disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. [0227] Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
[0228] Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.
[0229] Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle. Diluents for solid compositions and/or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
[0230] In various embodiments, the pharmaceutical composition may be selected from the group consisting of a solid, powder, liquid and a gel. In certain embodiments, the pharmaceutical compositions of the present disclosure is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates). In certain of such embodiments, the solid pharmaceutical composition comprises one or more excipients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
[0231] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
[0232] The dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach may be increased by the addition of a disintegrant to the composition and/or combination. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.
[0233]Glidants can be added to improve the flowability of a non-compacted solid composition and/or combination and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
[0234] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition and/or combination to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
[0235] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition and/or combination of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
[0236] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
[0237] In certain embodiments, a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
[0238] Liquid pharmaceutical compositions can be prepared using compounds of the present disclosure and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
[0239] For example, formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients to control the release of active compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
[0240] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
[0241] Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
[0242] Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
[0243] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
[0244] A liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
[0245] In one embodiment, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
[0246] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water. Where the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. [0247] Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
[0248] In certain embodiments, a pharmaceutical compositions of the present invention are formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0249] In certain embodiments, a pharmaceutical composition of the present invention comprises a sustained-release system. A non-limiting example of such a sustained- release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.
[0250] Appropriate pharmaceutical compositions of the present disclosure can be determined according to any clinically-acceptable route of administration of the composition to the subject. The manner in which the composition is administered is dependent, in part, upon the cause and/or location. One skilled in the art will recognize the advantages of certain routes of administration. The method includes administering an effective amount of one or more therapeutics of the present disclosure to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., metabolic disorders. In various embodiments, the route of administration is systemic, e.g., oral or by injection. In embodiments, the route of administration is intratumoral.
[0251] In certain embodiments, the pharmaceutical compositions of the present disclosure are prepared for oral administration. In certain of such embodiments, the pharmaceutical compositions are formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical compositions are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added.
[0252] In certain embodiments, dragee cores are provided with coatings. In certain such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings.
[0253] In certain embodiments, pharmaceutical compositions for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, the pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more compounds disclosed herein are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
[0254] In other embodiments the therapeutics of the present disclosure are administered by the intravenous route. In further embodiments, the parenteral administration may be provided in a bolus or by infusion. In embodiments, the therapeutics of the present disclosure are administered orally (PO). In embodiments, the therapeutics of the present disclosure are administered via intratumoral administration. EXAMPLES
Example 1. Panobinostat Dose Finding Study for DIPG.
[0255] Patients diagnosed with progressive DIPG were treated with panobinostat after radiation therapy at various doses, including 5 mg/m2/day, 10 mg/m2/day, 15 mg/m2/day, 20 mg/m2/day, 25 mg/m2/day, 30 mg/m2/day, 35 mg/m2/day, and 40 mg/m2/day. Patients were administered panobinostat Monday, Wednesday, and Friday in a course of four weeks, which included a treatment period of 3 weeks and a rest period of 1 week. Additional courses were administered if the patient obtained a clinical benefit.
Example 2. Combination Therapy.
[0256] Panobinostat is administered to patients with progressive DIPG in combination with marizomib or other proteasome inhibitors. Marizomib is administered at a dose of less than 0.8 mg/ m2/day at least once a week for three weeks. Panobinostat is administered one hour or more after administration of marizomib. A range of doses of panobinostat is evaluated to determine the lowest dose that panobinostat can be administered at while producing a clinical response and improving tolerability. Panobinostat is administered at doses ranging from 1 mg/m2/day to 10 mg/m2/day. Panobinostat will be administered for up to five courses of four weeks. Each course includes a treatment period of 3 weeks in which panobinostat is administered up to three times per week and a rest period of 1 week. Similar experiments are performed where panobinostat is administered in combination with BET, PI3K, AKT, and MEK inhibitors.
Example 3. Treatment of Progressive DIPG following patient stratification using disease markers.
[0257] Patients with tumors carrying H3F3A mutations have a significant poorer response to radiotherapy than those with HIST1H3B mutations. Patients that have been stratified with these markers are treated with increasing doses of Panobinostat (1 to 10 mg/m2) given once a day for at least 3 times a week, in a four week course, which includes a treatment period of 3 weeks in which panobinostat is administered up to three times per week and a rest period of 1 week. These patients are concomitantly administered radiotherapy or other therapeutic agents as described in this disclosure.
Example 4. In Vitro Studies of Panobinostat Efficacy against DIPG [0258]The DIPG Preclinical Consortium performed a drug screen using a total of 16 DIPG cell cultures, and found panobinostat to be among the top hits. 12/16 DIPG cell cultures exhibited sensitivity to panobinostat, with an IC50 of -100 nM. Panobinostat was found to decrease DIPG cell proliferation and increase DIPG cell death (Fig. 1A - Fig. 1B). Further, the increase in histone acetylation caused by panobinostat exposure correlated with an unexpected normalization of histone 3 K27 methylation in H3.3K27M mutant DIPG cells or293T cells expressing an H3.3K27M construct54 (Fig. 1C). Accordingly, a normalization of the “K27M” gene expression signature was observed.
[0259] Panobinostat was profiled for antiproliferative activity in a large panel of solid and hematological malignancy cell lines and subsets of tumor cell types exhibiting sensitivity or relative insensitivity to the drug were identified. All leukemia and lymphoma cell lines tested were highly sensitive to panobinostat (LD50 < 50 nM). Significant antiproliferative activity was observed with panobinostat in combination with relevant standard of care agents in plasma cells isolated from patients with MM and in leukemia cell lines. Exposure of normal fibroblasts to low nanomolar concentrations of panobinostat inhibited their proliferation; however, treatment with up to micromolar concentrations of the compound for 72 hours did not induce significant cell death. Panobinostat-induced apoptosis of bronchial epithelial cells transformed by SV40 large T antigen/telomerase, but had little effect on normal bronchial epithelial cells, even at greater concentrations. These results provide the basis for a potentially favorable therapeutic window during anticancer therapy with panobinostat. Cultured tumor cells and/or tumors treated with panobinostat exhibit increased levels of acetylated histones, indicating that the anti-tumor activity of panobinostat is accompanied by HDAC inhibition in cell lines and in vivo Example 5. In Vivo Studies of Panobinostat’s Efficacy for DIPG [0260] Human xenografts of tumor cell lines growing in athymic nude mice were used to profile panobinostat in vivo in several models. Panobinostat demonstrated single agent and/or combination activity in a range of xenograft models including colon, SCLC, cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM) and other xenografted human primary tumors. Single agent treatment in HCT116 xenograft tumors (colorectal) resulted in dose-related anti-tumor activity with minimal toxicity at panobinostat concentrations, which correlated with persistent histone acetylation. Inhibition of tumor growth and tumor regression with minimal toxicity, as assessed by animal body weight, was also observed in the HH CTCL xenograft model and the NCI- H146 SCLC xenograft model. Panobinostat also demonstrated significant anti-tumor activity in androgen-independent prostate cancer xenograft model, in two different types of human plasmacytoma murine models, in combination with trastuzumab in the HER+ BT474 breast cancer tumor xenograft model, in combination with docetaxel in the HID28 hormone independent prostate cancer model.
[0261] Panobinostat was directly infused into the pons in a pontine orthotopic xenograft model of DIPG (SU-DIPG VI; H3.3K27M subtype) via convection-enhanced delivery (CED). In vivo bioluminescent imaging was performed immediately prior to and 7 days after panobinostat (or vehicle control) administration in order to measure tumor growth by quantitative assessment of photon emission (Fig. 1 D - Fig. 1G). Because panobinostat affects gene expression, we confirmed that panobinostat expression does not down-regulate the luciferase transgene. We found a marked effect of panobinostat on the rate of tumor xenograft growth; in vehicle-treated control mice, the rate of xenograft growth was approximately 6.5 fold greater than that in mice treated with a single dose of panobinostat by CED (n=4 vehicle controls, 5 treated mice; P<0.05 by two-tailed t test; Fig. 1G). Having shown proof of principle for in vivo efficacy of panobinostat against DIPG, we next investigated the degree to which panobinostat penetrates the pons when administered systemically using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following a single 20 mg/kg intraperitoneal dose, we found pontine panobinostat levels of 0.068 ng/mg tissue, equivalent to -200 nM. As the IC50 for panobinostat was found to be -100 nM, we reasoned that systemic delivery may prove effective. Mice with brainstem orthotopic xenografts of SU-DIPG-VI cells were then treated with 1 mg/kg, 10 mg/kg or 20 mg/kg IP panobinostat. In vivo bioluminescent imaging demonstrated a significant reduction in tumor growth in panobinostat-treated animals at 1 week in 10 mg/kg and 20 mg/kg treatment groups compared to vehicle-treated controls (n=5 per group and 7 per group; P < 0.05 and 0.01 by two-tailed t test, respectively; Fig. 1 H). A second, patient-derived DIPG brainstem orthotopic xenograft model (IBs-w0128DIPG, derived from case Ll-F; H3WT subtype) was also tested using panobinostat 10 mg/kg IP dosed 5 days on, 5 days off, for a total of 9 doses. This resulted in significantly prolonged survival in the mice treated with panobinostat compared to vehicle treated controls (Fig. I, n=10 per group, P < 0.05 by log-rank analysis)
Example 6: Biodistribution of Panobinostat [0262] The brain penetration of panobinostat was tested in rodents. Non-tumor bearing mice were given a dose of panobinostat (20 mg/kg IP or 10 mg/kg PO), and levels of panobinostat were measured in the brain parenchyma (following transcardiac perfusion of saline to avoid sample contamination by blood levels of the drug) 30 minutes later using liquid chromatography-tandem mass spectrometry (LC-MSMS). In the pons, a drug level of panobinostat of about -.068 ng/mg (equivalent to -196 nM) following 20 mg/kg IP dosing was found. Because 20 mg/kg is a relatively high dose and was administered IP, to better model the maximum tolerated dose (MTD), a 10 mg/kg PO dose was administered and measured at 30 min following this PO dose a concentration of -0.053 ng/mg in hindbrain (brainstem plus cerebellum) tissue. While these brain concentrations of panobinostat are only a fraction of what is measured in the serum from the same mice, they are greater than the DIPG cell IC50 for panobinostat of -100 nM. Accordingly, when mice bearing patient-derived DIPG orthotopic xenografts were treated with panobinostat systemically 3 times per week (10 mg/kg), a decrease in tumor growth and an increase in survival was measured, albeit the duration of suppressed growth was less than in the mice treated with weekly 20 mg/kg systemic panobinostat. In summary, the data suggests that while very little panobinostat penetrates the brain parenchyma, DIPG cells are sufficiently sensitive to it that enough reaches the brain for tumor cell killing to occur.
Example 7. Central Nervous System (CNS) Penetration of Panobinostat in a non- human primate model
[0263] We evaluated CNS penetration of panobinostat in a nonhuman primate model known to be predictive of pharmacokinetics in children, using cerebrospinal fluid (CSF) as a surrogate of CNS tissue penetration. Animals were treated with panobinostat doses ranging from 1.0-3.0 mg/kg (3.0 mg/kg is equivalent to human doses of 60 mg/m2). All animals (n=10) tolerated panobinostat well. However, panobinostat penetration into the CSF was limited, with quantifiable CSF concentrations detected in only one sample (animal treated at 1.8 mg/kg). Although this non-human primate model is limited in that it assumes CSF penetration is a surrogate of CNS tissue penetration, and pharmacodynamic markers of HDAC inhibition are not measured in tissue, we conclude that panobinostat, like other HDAC inhibitors, has limited CNS penetration. This study suggests that panobinostat would not be effective at treating brain cancers such as DIPG. Needless to say, the efficacy we observed was surprising and unexpected. Example 8. Phase 1 Clinical Trials of Panobinostat in Adults [0264] Several dosing schedules using IV and oral panobinostat were evaluated with pharmacokinetic (PK) assessment. To date, the PK of panobinostat has been characterized in over 700 patients with cancer, of which, over 500 patients used the TIW dosing schedule.
[0265] Single Agent Panobinostat Summary: In clinical trials of panobinostat administered as a single agent to adults with refractory hematologic malignancies, Cmax and AUC increased proportionally with dose over a dose range of 4.8-14.0 mg/m2. Panobinostat ti/2 was 7.8-12 hrs and plasma AUC0-240-24 ranged from 134.9- 372.9 h·ng/mL. Cmax was approximately 20 ng/ml, or about 60 nM. Major toxicities included thrombocytopenia, neutropenia, and QTc prolongation that was dose-limiting. Hypokalemia and elevated LFTs (ALT) were reported, as were mild nausea, vomiting and anorexia.
[0266] In a Phase 1 trial of single agent panobinostat administered to adults with solid tumors, patients received oral panobinostat 3 times per week (M-W-F) at doses ranging from 10-20 mg. No DLT was observed. Most common adverse events included thrombocytopenia, nausea and diarrhea. Mean elimination t1/2was 9-14 hrs. [0267]A trial of panobinostat for refractory hematological malignancies in children is complete. No dose-limiting toxicities (DLT) have been observed at dose levels up to 34 mg/m2/dose, administered 3 days/week x 4 weeks in children with leukemia. [0268] Panobinostat in Combination- Panobinostat has been evaluated in a Phase 1 trial for recurrent adult high-grade glioma (HGG) in combination with bevacizumab. In adults with HGG, the combination of panobinostat with bevacizumab was safe and tolerated at a panobinostat dose of 30 mg PO three times per week, every other week and bevacizumab (10 mg/kg every other week). The main DLT was thrombocytopenia; (one case of grade 3 thrombocytopenia was observed at a dose of 20 mg PO three times per week every week, in combination with bevacizumab).
Example 9. Phase 1 Clinical Trial of Panobinostat in Children with DIPG [0269] Based on the in vitro and in vivo activity of panobinostat in preclinical models using DIPG cell cultures and orthotopic xenograft model systems, and the potentially important role of histone deacetylases and histone 3 K27M mutations in relation to pontine malignancies, a multicenter Phase 1 trial of panobinostat in children with recurrent/progressive DIPG followed by children with DIPG prior to progression was conducted. [0270] Initially, only patients with recurrent or progressive DIPG were enrolled. These patients occupy “Stratum 1.” Upon completion of the primary objectives for Stratum 1 (see below), patients with DIPG who have received adequate radiation therapy but have not yet progressed were enrolled in “Stratum 2”.
[0271 '[Primary Objectives: Recurrent/Progressive DIPG (Stratum 1)
(a) To describe the toxicity profile and define the dose-limiting toxicities of panobinostat in children with recurrent/progressive DIPG
(b) To estimate the maximum-tolerated dose and/or the recommended- phase 2 dose of panobinostat in children with recurrent/progressive DIPG
(c) To evaluate and characterize the plasma pharmacokinetics of panobinostat in children with recurrent/progressive DIPG
[0272] Secondary Objectives: Recurrent/Progressive DIPG (Stratum 1)
(a) To describe the progression-free survival (PFS) and overall survival (OS) of children with recurrent or progressive DIPG who are treated with panobinostat
(b) To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment
[0273] The maximum-tolerated dose (MTD) of patients in Stratum 1 was determined to be 10 mg/m2/day.
[0274] Primary Objectives: Non-progressed DIPG (Stratum 2)
(a) To describe the toxicity profile and define the dose-limiting toxicities of panobinostat in children with non-progressed DIPG treated with 3 times/week, every other week.
(b) To estimate the maximum-tolerated dose and/or the recommended- phase 2 dose of panobinostat administered 3 times/week, every other week in children with non-progressed DIPG
(c) To evaluate and characterize the plasma pharmacokinetics of panobinostat administered 3 times/week, every other week in children with non- progressed DIPG
[0275] Secondary Objectives: Non-progressed DIPG (Stratum 2)
(a) To describe the progression-free survival (PFS) and overall survival (OS) of children with non-progressed DIPG who are treated with panobinostat
(b) To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment
[0276] The maximum-tolerated dose (MTD) of patients in Stratum 2 was determined to be 28 mg/m2/day. [0277] Patient Populations: Only patients with recurrent or progressive DIPG (Stratum 1) were enrolled initially. Upon completion of the first primary objectives (see below), patients with DIPG who have received adequate radiation therapy but have not yet progressed were enrolled in Stratum 2. Patients in Stratum 2 follow a different panobinostat dosing regimen than patients in Stratum 1.
[0278] Dosing for Stratum 1 Patients: Panobinostat was administered every other day, 3 times/week, orally, preferably on a Monday/Wednesday/Friday schedule for three weeks, followed by a rest period. Three weeks of therapy plus the one week rest period (total 4 weeks) constituted one course. Treatment continued for up to two years (26 courses) unless the patient experienced progressive disease, unacceptable toxicity or any of the off-study criteria. Table 4 shows the dose levels.
[0279] The starting dose (dose level 1) was 10 mg/m2/day. The table below lists the dose levels that were studied.
Table 4: Dose escalation schedule for recurrent/ progressive DIPG treated with three weeks on, one week off schedule (Stratum 1)
Figure imgf000084_0001
[0280] Dosing for Stratum 2 Patients : Upon completion of the first primary objectives, patients with DIPG who have received adequate radiation therapy but have not yet progressed were enrolled in Stratum 2. Panobinostat was administered every other day, 3 times/week, every other week p.o. on a Monday/Wednesday/Friday schedule. Total 4 weeks constituted one course. Treatment continued for up to two years (26 courses) unless the patient experienced progressive disease, unacceptable toxicity or any of the off-treatment criteria.
[0281] The starting dose (dose level 1) for Stratum 2 was 1 dose level above the MTD for the ‘3-weeks on, 1 -week off schedule. 10mg/m2/day was the MTD for the ‘3-weeks on, 1-week off schedule and thus the initial dose for the ‘every other week’ dosing schedule was16 mg/m2/day. Table 5 below listed the proposed dose levels to be studied.
Table 5: Dose escalation schedule for non-progressed DIPG treated every other week (Stratum 2)
Figure imgf000085_0001
[0282] Rationale for Pharmacokinetic Studies- Hypothesis: The pharmacokinetics and tolerability of panobinostat in pediatric patients with recurrent/progressive DIPG may differ from prior studies of panobinostat in the adult population as well as in children with leukemia, and may be affected by prior treatment, age, body surface area, steroid use or concomitant medications.
[0283] The pharmacokinetics and tolerability of panobinostat in pediatric patients with DIPG who have received standard radiation therapy, but have received no other systemic therapy and have not yet progressed may differ from the pharmacokinetics and tolerability of panobinostat in pediatric patients with recurrent/progressive DIPG. More likely, the pharmacokinetics and tolerability may differ with an alternative dosing schedule.
[0284] Rationale for Pharmacokinetic Studies- Preclinical and Clinical Data: Because there are limited pediatric pharmacokinetic (PK) studies of this agent and none in this population, PK information from this study is essential for evaluating toxicity and disease response and for refining dosing in future clinical trials of panobinostat. Mandatory pharmacokinetic studies are needed to characterize the full PK profile of panobinostat in this patient population, correlate PK with toxicities, and evaluate effects of concomitant medications such as dexamethasone. Insights into the biologically active dosage will be gained by relating panobinostat systemic exposure (e.g., AUC) to results of pharmacodynamic studies.
[0285] In vitro studies indicate that panobinostat is a substrate of CYP3A4, and dexamethasone is a known inducer of CYP3A4. Thus, one might expect lower exposures of panobinostat when administered concurrently with dexamethasone. It is important to therefore correlate pharmacodynamic effects of panobinostat with PK. The pharmacokinetics of panobinostat may be affected by age, body surface area, steroid use or concomitant medications.
[0286] Rationale for Pharmacodynamic Studies- Cell-free DNA in peripheral blood or urine: Several tumor suppressor genes associated with the malignant phenotype are repressed by epigenetic mechanisms in sporadic cancers. Thus, therapy with DAC inhibitors may alter tumor phenotype and inhibit growth in such tumors. This method is used to evaluate potential changes after treatment with panobinostat.
[0287] Inclusion Criteria- Diagnosis (Stratum 1): Patients with progressive DIPG, as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since diagnosis, OR the appearance of a new tumor lesion since diagnosis.
(a) Patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation. (b) Patients with pontine lesions that do not meet these radiographic criteria areeligible if there is histologic confirmation of malignant glioma according to the World Health Organization’s classification of brain tumors (Grade ll-IV).
[0288] Inclusion Criteria - Diagnosis (Stratum 2): Patients with DIPG who have not yet progressed by clinical or radiographic criteria.
(a) Patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation.
(b) Patients with pontine lesions that do not meet these radiographic criteria are eligible if there is histologic confirmation of malignant glioma WHO ll-IV.
[0289] Inclusion Criteria- Age (Stratum 1 and Stratum 2): Patients must be ≥ 2 but < 22 years of age at the time of enrollment.
[0290] Inclusion Criteria- BSA (Stratum 1 and Stratum 2): Patients must have a BSA ≥ 0.80 m2 for dose 5mg/m2.; patients must have a BSA ≥ 0.65 m2 for doses of 10mg/m2 - 22 mg/m2.; patients must have a BSA ≥ 0.50 m2 for doses of 28 mg/m2 - 36 mg/m2. [0291] Inclusion Criteria- Ability to Swallow (Stratum 1 and Stratum 2): Patient must be able to swallow capsules whole.
[0292] Inclusion Criteria- Performance Status (Stratum 1 and Stratum 2): Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 7 days of enrollment must be ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, are considered ambulatory for the purpose of assessing the performance score. [0293] Inclusion Criteria- Prior Therapy (Stratum 1): Patients must have received a minimum of 54 Gy focal irradiation administered over approximately 42 days prior to enrollment. Patients must have recovered from the acute treatment-related toxicities (defined as < grade 1) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
[0294] Inclusion Criteria- Prior Therapy- Myelosuppressive Chemotherapy (Stratum 1): Patients must have received their last dose of known myelosuppressive anticancer therapy or immunotherapy at least 21 days prior to enrollment (42 days if prior nitrosourea). [0295] Inclusion Criteria- Prior Therapy- Investigational/Biologic Agent (Stratum 1): Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur, and discussed with the principal investigator.
[0296] Monoclonal antibody treatment and agents with known prolonged half-lives: At least three half-lives must have elapsed prior to enrollment.
[0297] Inclusion Criteria- Prior Therapy- Radiation Therapy (Stratum 1): Patients must have had their last fraction of craniospinal irradiation or radiation to ≥ 50% of pelvis > 3 months prior to enrollment. Patients must have had their last fraction of focal irradiation to the primary site > 42 days prior to enrollment. Patients must have had their last fraction of local palliative irradiation other than previously irradiated primary site (small port) ≥ 14 days.
[0298] Inclusion Criteria - Prior Therapy (Stratum 2): Patients must have received a minimum of 54 Gy focal irradiation administered over approximately 42 days prior to enrollment. Patients must not have received any other prior therapy for treatment of their CNS malignancy besides standard radiation therapy. Patients must have recovered from the acute treatment-related toxicities (defined as < grade 1) of radiotherapy prior to entering this study.
[0299] Inclusion Criteria - Prior Therapy- Radiation Therapy (Stratum 2): Patients must have had their last fraction of focal irradiation to the primary site > 14 days prior to enrollment. Patients must not have received local palliative irradiation or craniospinal irradiation.
[0300] Inclusion Criteria- Organ Function (Stratum 1 and Stratum 2): Patients must have adequate organ and marrow function as defined below:
(a) Absolute neutrophil count ≥ 1 ,000/mm3
(b) Platelets ≥ 100,000/ mm3 (unsupported, defined as no platelet transfusion within 7 days, and recovery from post-transfusion nadir)
(c) Hemoglobin ≥ 8 g/dl (may receive transfusions)
(d) Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN) (e) ALT(SGPT) < 3 x institutional upper limit of normal
(f) Albumin ≥ 3 g/dl
(g) Potassium ≥ lower limit of normal (LLN)
(h) Serum total calcium (correct for serum albumin) or ionized calcium ≥ LLN
(i) Serum creatinine based on age/gender as noted in T able 8. Patients that do not meet the criteria in Table 6 but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible.
Table 6: Serum Creatinine Requirements
Figure imgf000089_0001
[0301] Inclusion Criteria- Cardiac Function (Stratum 1 and Stratum 2):
(a) Left ventricular ejection fraction ≥ 50 by gated radionuclide study OR shortening fraction of ≥ 27% by echocardiogram
(b) Patient has no ventricular arrhythmias except for benign premature ventricular contractions.
(c) Patient has a QTc interval < 450 ms.
[0302] Inclusion Criteria- Growth Factors (Stratum 1 and Stratum 2): Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin). 14 days must have elapsed if patients received PEG formulations.
[0303] Inclusion Criteria- Fruit (Stratum 1 and Stratum 2): Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study.
[0304] Inclusion Criteria- Pregnancy Status (Stratum 1 and Stratum 2): Female patients of childbearing potential must have a negative serum or urine pregnancy test. [0305] Inclusion Criteria- Pregnancy Prevention (Stratum 1 and Stratum 2): Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for 3 months after the last dose of panobinostat.
[0306] Inclusion Criteria- Informed Consent (Stratum 1 and Stratum 2): The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines [0307] Exclusion Criteria - Prior Therapy (Stratum 1):
(a) Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation).
(b) Patients have had prior HDAC, DAC, HSP90 inhibitors for the treatment of their DIPG.
(c) Patients have had valproic acid within 28 days prior to enrollment.
(d) Patients have had prior bone marrow transplant.
[0308] Exclusion Criteria - Prior Therapy (Stratum 2): Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation)
[0309] Exclusion Criteria - Neurological Status (Stratum 1 and Stratum 2): Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician.
[0310 ] Exclusion Criteria - Gastrointestinal (Stratum 1 and Stratum 2):
(a) Patients have impairment of Gl function or Gl disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease.
(b) Patients have diarrhea > CTCAE grade 2.
[0311 ]Exclusion Criteria - Systemic Illness (Stratum 1 and Stratum 2): Patients have any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the ability of the patient to tolerate protocol therapy or put them at additional risk for toxicity or would interfere with the study procedures or results.
[0312] Exclusion Criteria - Other malignancy (Stratum 1 and Stratum 2): Patients have a history of any other malignancy. [0313] Exclusion Criteria - Transfusions (Stratum 1 and Stratum 2): Patients are known to be refractory to red blood cell or platelet transfusions.
[0314 ] Exclusion Criteria - Concurrent Therapy (Stratum 1 and Stratum 2):
(a) Patients who are receiving any other anticancer or investigational drug therapy
(b) Patients who are required to receive any medication which can prolong the QTc interval. Medications that can prolong the QTc interval are found in Table 7.
Table 7: Medications that May Cause QTc Prolongation
Figure imgf000091_0001
[0315 ] Exclusion Criteria - Breast Feeding (Stratum 1 and Stratum 2): Female patient is breastfeeding.
[0316] Exclusion Criteria - Inability to Participate (Stratum 1 and Stratum 2): Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions [0317] Treatment Plan: Treatment could be administered on an outpatient basis. Reported adverse events and potential risks are described in Tables 14-16. Appropriate dose modifications are described in Table 12. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's tumor.
[0318] Treatment Plan - Agent Administration: Patients with recurrent/progressive DIPG were enrolled at the time of progression in Stratum 1. Therapy with panobinostat was administered every other day, 3 times/ week, p.o. preferably on a Monday/Wednesday/Friday schedule for three weeks, followed by one week off of therapy. Three weeks of therapy plus the one week rest period (total 4 weeks) constituted one course. Treatment continued for up to 26 courses (approximately 2 years) barring progressive disease or unacceptable toxicity.
[0319] Patients with DIPG who have not progressed were enrolled after receiving standard radiation therapy in stratum 2, and did not begin treatment until at least 14 days after completion of radiation. Therapy with panobinostat was administered every other day, 3 times/ week, every other week. A minimum of 6 days without drug was required between treatment weeks. Four weeks constituted one course. Treatment continued for up to 26 courses (approximately 2 years) barring progressive disease or unacceptable toxicity.
[0320] Treatment Plan - Panobinostat: Dosing was adjusted based on BSA calculated at the beginning of each course of therapy. The dose prescribed was rounded to the nearest deliverable dose based on the BSA adjustment and the available pill sizes. Dosing Tables which reflect this approach are available in Table 17.
Patients were encouraged to take their dose of panobinostat at the same time each day, preferably in the morning. Each dose of panobinostat was taken with a 4 oz / 120 ml glass of water. Drug must be taken on an empty stomach (either 1 hour before or after meals) on Course 1 , Days 1 and 3, and may be taken with or without food for the remaining doses. Patients were instructed to swallow the capsules whole and not chew them. Patients must avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study.
[0321] If the patient forgot to take his/her dose during the morning on a scheduled treatment day, then he/she should took panobinostat on that same day within 12 hours after the missed dose if possible. After more than 12 hours, that day’s dose was withheld, and the patient waited to take panobinostat until the next scheduled treatment day (i.e. , patients should be instructed not to try to make-up the missed dose after 12 hours). The patient then continued treatment with the original dosing schedule. If vomiting occured within 15 minutes, the dose was repeated. If a dose is missed/ unable to be given, this fact was recorded on the patient diary and the patient continued counting the days of the course, with treatment administered on originally scheduled days.
[0322] Treatment Plan - Dose-Limiting Toxicity (DLT): Management and dose modifications associated with adverse events are outlined in Table 12 and throughout this disclosure. DLT will be defined as any of the events listed in this section that are at least possibly related to panobinostat that occur during the dose-finding period regardless of expectedness. The dose-finding period is defined as the first course of therapy in both strata.
[0323] Management and dose modifications for toxicities which occur outside of the dose-finding period should also follow Table 12 and throughout this disclosure; however, these will not be considered dose limiting for the purpose of dose escalation. [0324] Treatment Plan - Definitions of Dose-Limiting Toxicities (DLTs): Patients who missed more than 2 doses due to toxicity were considered to have experienced a DLT. [0325] Treatment Plan - Definitions of Dose-Limiting Toxicities (DLTs) — Non- Hematologic DLT: Non-hematologic dose limiting toxicity was any grade 3 or greater non-hematological toxicities with the specific exclusion of the following:
(a) Grade 3 nausea/vomiting that is responsive to antiemetics, and that resolves to ≤ Grade 2 within 5 days
(b) Grade 3 electrolyte abnormality that resolves to ≤ Grade 2 within 5 days
(c) Grade 3 rash that is not considered medically significant or intolerable by the patient
(d) Grade 3 diarrhea that resolves to ≤ Grade 1 with optimal use of anti- diarrheal medication
(e) Grade 3 fever that resolves to ≤ Grade 2 within 5 days
(f) Grade 3 infection that resolves to ≤ Grade 2 within 5 days
[0326] Non-hematologic dose limiting toxicity was also any grade 2 non-hematological toxicity that persists for more than 7 days and was considered sufficiently medically significant or sufficiently intolerable by patients as to warrant treatment interruption and/or dose reduction will be considered dose limiting. [0327] Non-hematologic dose limiting toxicity was also any panobinostat-related non- hematological toxicity that results in a delay of treatment > 14 days between treatment courses.
[0328] Treatment Plan - Definitions of Dose-Limiting Toxicities (DLTs) — Hematologic DLT: Hematologic dose limiting toxicity was defined as:
(a) Grade 4 thrombocytopenia (platelet count < 25,000/pL)
(b) Grade 3 thrombocytopenia with bleeding
(c) Grade 3 thrombocytopenia (platelet count ≥ 25,000 but <50,000/mI_) that occurs twice within a treatment course was considered a DLT. (Note: platelet transfusions are recommended for platelet counts <50,000/pL and transfusion should target platelet corrections to >100,000 /pL)
(d) Myelosuppression that caused greater than a 14-day delay between treatment courses
(e) Grade 4 neutropenia
(f) Grade 3 or 4 febrile neutropenia
[0329] Treatment Plan - Definitions of Dose-Limiting Toxicities (DLTs) — Follow-up for toxicities: Patients whose treatment was interrupted or permanently discontinued due to an adverse event or abnormal laboratory value were followed until resolution or stabilization of the event, or initiation of another antitumor treatment, or initiation of hospice/symptomatic care only, whichever comes first. All patients were followed for adverse events and serious adverse events for at least 30 days following the last dose of oral panobinostat, or upon initiation of another antitumor treatment.
[0330] Upon completion of Stratum 1 , patients with DIPG who have received adequate radiation therapy but have not yet progressed were enrolled in Stratum 2. Panobinostat was administered every other day, 3 times/week, every other week p.o. preferably on a Monday/Wednesday/Friday schedule. Total 4 weeks constituted one course. Treatment continued for up to two years (26 courses) unless the patient experienced progressive disease, unacceptable toxicity or any of the off-treatment criteria. The starting dose (dose level 1) for Stratum 2 was 1 dose level above the highest safe dose for the ‘3-weeks on, 1-week off schedule as determined in Stratum 1. The rationale was that 1 week on 1 week off schedule represents a reduction in the amount of drug patients receive per course and thus a dose level that is safe for ‘3- weeks on, 1-week off schedule should also be safe for the every otherweek schedule. We expected that 10 mg/m2 would be the MTD for the ‘3-weeks on, 1-week off schedule and thus expected to start exploring the ‘every other week’ dosing schedule at 16 mg/m2/day. However, if 10 mg/m2 dose level was determined to be unsafe in the ‘3-weeks on, 1-week off schedule, the ‘3-weeks on, 1-week off schedule would be abandoned, and dose escalation for Stratum 2 would be initiated at 10 mg/m2. Table 5 shows the proposed dose levels that were studied.
[0331] Concomitant Medications and Supportive Care Guidelines - Potential QTc prolonging medications: Concomitant medications which can prolong the QTc interval were used. Please see Table 7.
[0332] Concomitant Medications and Supportive Care Guidelines - CYP3A4 and CYP2D6 : Co-administration with medications that were strong CYP3A4 inducers were avoided. Co-administration with medications that were strong CYP3A4 inhibitors and sensitive CYP2D6 substrates was feasible when medically necessary and with close monitoring. See Table 9 and Table 10 for a partial list of common moderate and strong inhibitors of CYP3A4 and common sensitive CYP2D6 substrates.
Table 9: Common and Moderate Strong Inhibitors of CYP3A4
Figure imgf000095_0001
Ta ble 10: Common Sensitive CYP2D6 Substrates
Figure imgf000095_0002
Figure imgf000096_0001
_
[0333] Concomitant Medications and Supportive Care Guidelines - Steroids: Corticosteroids were used at the lowest dose to control symptoms of edema and mass effect, and discontinued, if possible.
[0334] Concomitant Medications and Supportive Care Guidelines - Anticonvulsants: Anticonvulsants drugs were used, if indicated.
[0335] Concomitant Medications and Supportive Care Guidelines - Growth Factors: Routine use of growth factors (i.e. G-CSF, GM-CSF and erythropoietin) was not permitted. However, therapeutic use of G-CSF or GM-CSF in patients with serious neutropenic conditions, such as sepsis, was considered at the investigator’s discretion.
[0336] Concomitant Medications and Supportive Care Guidelines - Anti-emetics: The use of anti-emetics was at the investigator’s discretion. Steroids were not be used as anti-emetics when possible.
[0337] Concomitant Medications and Supportive Care Guidelines - Febrile Neutropenia: Febrile neutropenia was managed according to the local institutional guidelines. Measures include laboratory testing, blood and urine cultures, and institution of broad spectrum antibiotics. [0338] Concomitant Medications and Supportive Care Guidelines - Pneumocystis jiroveci pneumonia (PJP) Prophylaxis: The use of medication (e.g., Bactrim) for PJP prophylaxis in patients on chronic steroids was recommended, but was at the investigator’s discretion.
[0339] Concomitant Medications and Supportive Care Guidelines - Neurosurgical or other surgical procedures: If a neurosurgical procedure or other surgical procedure wasrequired for a reason other than tumor progression (i.e. the onset of hydrocephalus), these procedures were documented, but these events did not constitute criteria for declaring the patient “off therapy”. Panobinostat were held until the patient is clinically stable and had recovered from the acute effects of surgery. [0340] Concomitant Medications and Supportive Care Guidelines - Diarrhea: Patients were advised to drink plenty of water or rehydration fluids to avoid dehydration if diarrhea occurs. Should diarrhea occur, investigators ensured that patients have loperamide on hand and followed the loperamide dosing guidelines in Table L below, at first onset of the symptom. Dehydration prevention and correction of electrolyte disturbances were practiced as per institution’s SOP. Stool count and consistency was noted in the patient diary if treatment for diarrhea was instituted.
[0341] Refer to Table 12 for details of panobinostat dose reduction, and Table 11 below for details of suggested loperamide dosing based on patients body weight. Table 11 : Weight Specific Guidelines for Therapeutic Use of Loperamide
Figure imgf000097_0001
[0342] Duration of Therapy: In the absence of treatment delays due to adverse event(s) or disease progression, treatment continued for 26 courses (approximately 2 years) or until one of the Off Treatment Criteria applied:
(a) Progressive disease (PD)
(b) Development of a medical or psychiatric illness or social issue that in the investigator's judgment renders the patient incapable of further therapy on this protocol or the treating physician determines continuation on this study is not in the patient’s best interest.
(c) The patient, parent or legal guardian refuses further treatment on this protocol. In this case the investigator should clarify if the family also wishes to withdraw consent for continued participation for data collection purposes.
(d) Completion of all protocol defined treatment
(e) Pregnancy
(f) Non-compliance that in the opinion of the investigator does not allow for ongoing participation.
[0343] Dosing Delays/Dose Modification: The criteria for dose modifications for study drug-related toxicity are detailed in Table 12.
Table 12: Criteria for dosing delays, dose-reductions, and re-initiation of treatment due to study drug-related non-hematological toxicity (excluding QT prolongation)
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
[0344] Dose Modification for Hematological Toxicity: If a patient experienced dose- limiting hematological toxicity (i.e. grade 4 thrombocytopenia [< 25 x 109/L] or grade 3 thrombocytopenia [< 50 and ≥ 25 x 109/L] with bleeding, or grade 3 twice within 1 treatment course or grade 4, or grade 3 or 4 febrile neutropenia) treatment was withheld. Platelets were transfused to a count of > 100 x 109/L (i.e. a post-transfusion platelet count should be obtained). Counts were checked every 3-4 days (and when medically indicated) during this time.
[0345] If the toxicity resolved to meet on study parameters within 14 days of drug discontinuation, provided there was no current active bleeding in the case of dose- limiting thrombocytopenia, the patient resumed therapy at one dose level lower. Patients who were dose-reduced for toxicity did not have their dose re-escalated. [0346] If toxicity did not resolve to meet on study parameters within 14 days of drug discontinuation, the patient was removed from protocol therapy.
[0347] Only one dose-reduction per patient was allowed. If any dose-limiting toxicity occured in a patient already dose-reduced for toxicity, the patient was removed from protocol therapy.
[0348] Dose Modification for Prolonged QTc: All cardiac events were treated according to the local standard of care and referred to a cardiologist if clinically indicated. The localized readings of ECGs used the Fridericia correction for QTC interval assessment: QTcF. Any final decisions concerning dose modifications or permanently discontinuing the patient from study drug due to QTcF prolongation were based on the Investigator’s clinical assessment. [0349] Patients must have had QTcF < 450 msec to be eligible for the trial. If QTcF is ≥ 450 msec or above 60 msec from pre-treatment ECG, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia) were corrected, and triplicate ECGs (5 minutes apart) were conducted and average QTcF was calculated. If the average QTcF from the triplicate ECGs remained ≥ 450ms, the patient was not be dosed. Pre- dose ECG monitoring was mandatory on days 1 and 5 of course 1 , and day 1 of courses 2 through 4. Post dose ECG (3 hours post dosing) was mandatory only on days land 5 of course 1. On day 5 of course 1, ECG was be performed at a local institution but results were faxed to treating institution within the same day.
[0350] If a pre-treatment or post-dose ECG shows a QTcF ≥ 500ms, patient was not eligible for further treatment. If any of these mandatory ECGs show QTcF ≥ 450 msec or 60 msec above baseline, dosing was held and the above specified measures including follow-up triplicate ECGs and correction of electrolyte abnormalities were performed. If QTcF abnormality resolved, patients resumed treatment and had QTcF checked pre-dose on day 1 of each course for at least the next 3 subsequent courses. Additional QTcF monitoring was performed if clinically indicated. If a patient could not be dosed due to prolonged QTcF for more than 7 days since last dose, the patient was discontinued from study treatment.
Table 13: Dose Reductions for QTc Prolongation
Figure imgf000102_0001
Figure imgf000103_0002
[0351] Ad erse Events and Potential Risks for Panobinostat: Very common adverse events occurring in ≥ 10% of subjects treated with panobinostat are found in Table 14. Table 14: Very Common Adverse Effects in Subjects Treated with Panobinostat
Figure imgf000103_0001
[0352] Common adverse events occurring in 1 % to 9 % of subjects treated with panobinostat are found in Table 15.
Table 15: Common Adverse Effects in Subjects Treated with Panobinostat
Figure imgf000104_0001
Figure imgf000105_0001
[0353] Uncommon adverse events occurring in less than 1 % of subjects treated with panobinostat are found in Table 16.
Table 16: Uncommon Adverse Effects in Subjects Treated with Panobinostat
Figure imgf000105_0002
[0354] Adverse Event Characteristics: Adverse events were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
[0355] Neuroimaging Studies — Imaging Guidelines: Brain Magnetic Resonance with and without gadolinium were obtained on a 3T magnet. Exemplary images include:
(a) Sagittal T 1 MPRAGE (slice thickness 1.0, 25 cm FOV) (b) Axial T2 images (slice thickness 2mm skip 0, 20 cm FOV)
(c) Axial T2 FLAIR images (slice thickness 4mm skip 0, 20 cm FOV)
(d) Axial DTI images (slice thickness 2.0 mm skip 0, 22 cm FOV); 35 directions, b-values: 0 and 1000 s/mm2
(e) Post gadolinium sagittal T1 SPACE (slice thickness 0.9 mm skip 0, 22 cm FOV)
(f) Axial T 1 post gadolinium images through the whole brain (slice thickness 4mm skip 0, 20 cm FOV)
[0356] Brain Magnetic Resonance with and without gadolinium were obtained on a 1.5 T magnet. Exemplary images include:
(a) Sagittal T1 (slice thickness 5 mm skip 1 mm, 22 cm FOV)
(b) Axial T2 images (slice thickness 4 mm skip 0 mm, 20 cm FOV)
(c) Axial T2 FLAIR images (slice thickness 5 mm skip 0 mm, 20 cm FOV)
(d) Axial DWI, 6 directions (slice thickness 5 mm skip 0 mm, 26 cm FOV)
(e) Post gadolinium sagittal 3DFSPGR images (slice thickness 1.5 mm no skip, 24 cm FOV)
(f) Axial T 1 post gadolinium (slice thickness 3 mm no skip, 16 cm
[0357] MRI imaging was also conducted of the spine. Sagittal T1 images were after gadolinium (slice thickness 3 mm skip 0). Axial T 1 images were after gadolinium (slice thickness 3mm skip 0). Axial T2 images were optional.
[0358] Autopsy Studies: Autopsies were obtained when possible on enrolled patients. Performing pathologists were requested to look for evidence and extent of immune cell infiltration in the specimen. Areas of necrosis were determined and analysis for cause/etiology was attempted. The extent of lymphocyte infiltration particularly in adjacent areas of edema / inflammation was determined. In addition, 15-20 brain tissue slides were requested to perform staining for characterization of infiltrating lymphocyte population and other studies.
[0359] Measurement of Effect: Patients with measurable disease were assessed by standard criteria. For the purposes of this study, patients were re-evaluated by MRI after every 2 courses for the first 6 courses, then every 3 courses and when clinically indicated until disease progression or off-study criteria were met. [0360] Definitions - Evaluable for Radiographic Response: Only those patients who had measurable disease present at baseline, had received at least one course of therapy, and had their disease re-evaluated were considered evaluable for response. These patients will have their response classified according to the definitions stated below. Patients who exhibited objective disease progression prior to the first scheduled MRI were considered evaluable.
[0361] Tumor Response Criteria - Complete Response (CR) Complete disappearance on MR of all evaluable tumor and mass effect, on a stable or decreasing dose of corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination. If CSF was positive, it must be negative.
[0362] Tumor Response Criteria - Partial Response (PR): Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as compared with the baseline measurements, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination. Axial FLAIR images were used for tumor measurements.
[0363] Tumor Response Criteria - Stable Disease (SD): Neurologic exam is at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither the criteria for PR nor the criteria for Progressive Disease.
[0364] Tumor Response Criteria - Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a greater than 25% increase in the bi- dimensional measurement, taking as a reference the smallest disease measurement recorded since the start of protocol therapy, OR the appearance of a new tumor lesion. [0365] Increasing doses of corticosteroids required to maintain stable neurological status were strongly considered as a sign of clinical progression unless in the context of recent wean or transient neurologic change due e.g. to radiation effects.
[0366] Tumor Response Criteria - Progressive-Free Survival (PFS) Interval of time between date of initiation of protocol treatment and minimum date of documentation of PD, death due to any cause, or date of last follow-up.
[0367] Statistical Considerations -Study Design/ Endpoints: Six dose levels were proposed and all may or may not be investigated, primarily dependent upon whether or not toxicity at dose level 1 results in de-escalation to dose level 0. Enrollment commenced at dose level 10mg/m2 for Stratum 1 and at 1 dose level above the Stratum 1 MTD/RP2D in Stratum 2. If the ‘3 weeks on, 1 week off’ schedule was abandoned in Stratum 1 without determining the MTD, we planned to initiate dose escalation in Stratum 2 at 10mg/m2. Dose finding was governed by a two stage continual reassessment method (CRM) which will be applied separately in the two strata. No intra-patient dose escalations were allowed.
Table 17: Dosing Levels
Figure imgf000108_0001
Figure imgf000109_0001
INCORPORATION BY REFERENCE
[0368] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

1. A method of treating brain cancer in a patient in need thereof comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course.
3. The method of claim 2, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
4. The method of claim 3, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
5. The method of claim 1 , wherein the course has a treatment period on weeks 1, 2, and 3 and a rest period on week 4.
6. The method of claim 5, wherein panobinostat or the pharmaceutically acceptable salt thereof is administered up to three times per treatment period.
7. The method of claim 1 , wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, diffuse midline glioma, and pineal tumor.
8. The method of claim 1 , wherein the brain cancer is diffuse intrinsic pontine glioma (DIPG).
9. The method of claim 8, wherein the DIPG is non-progressed DIPG.
10. The method of claim 8, wherein the DIPG is progressed or recurrent DIPG.
11. The method of claim 1 , wherein the patient exhibits mutations in one or more genes selected from the group consisting of H3F3A, HIST1H3B, HIST1H3C, TP53, ACVR1, PDGFRA, PPM1D, PIK3CA, PIK3R1, MYC, MYCN, and PPM1D.
12. The method of claim 11 , wherein the patient exhibits a Histone (H)3 K27M mutation in the H3F3A gene.
13. The method of claim 8, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median survival for a patient treated with a standard protocol for DIPG.
14. The method of claim 8, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
15. The method of claim 8, wherein after administering panobinostat, the patient exhibits a partial response.
16. The method of claim 1 , comprising administering a dose of panobinostat selected from the group consisting of 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg,
55 mg, and 60 mg.
17. A method of treating brain cancer in a patient in need thereof comprising administering about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof.
18. The method of claim 17, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course.
19. The method of claim 18, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
20. The method of claim 19, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
21. The method of claim 17, wherein the course has a treatment period on weeks 1, 2, and 3 and a rest period on week 4.
22. The method of claim 21 , wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
23. The method of claim 17, wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, diffuse midline glioma, and pineal tumor.
24. The method of claim 17, wherein the brain cancer is diffuse intrinsic pontine glioma (DIPG).
25. The method of claim 24, wherein the DIPG is non-progressed DIPG.
26. The method of claim 24, wherein the DIPG is progressed or recurrent DIPG.
27. The method of claim 17, wherein the patient in need thereof exhibits mutations in one or more genes selected from the group consisting of H3F3A, HIST1H3B, HIST1H3C, TP53, ACVR1, PDGFRA, PPM1D, PIK3CA, PIK3R1 , MYC, MYCN, and PPM1 D.
28. The method of claim 27, wherein the patient exhibits a Histone (H)3 K27M mutation in the H3F3A gene.
29. The method of claim 24, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median survival for a patient treated with a standard protocol for DIPG.
30. The method of claim 24, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
31. The method of claim 24, wherein after administering panobinostat, the patient exhibits a partial response.
32. The method of claim 17, comprising administering a dose of panobinostat selected from the group consisting of 5 mg/m2/day, 10 mg/m2/day, 16 mg/m2/day, 22 mg/m2/day, 28 mg/m2/day, and 36 mg/m2/day.
33. The method of claim 32, comprising administering 10 mg/m2/day panobinostat.
34. The method of claim 32, comprising administering 28 mg/m2/day panobinostat.
35. The method of claim 17, comprising administering a dose based on the patient’s body surface area.
36. A method of treating brain cancer in a patient in need thereof comprising administering panobinostat or a pharmaceutically acceptable salt thereof on a 28 day course.
37. The method of claim 36, wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
38. The method of claim 37, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
39. The method of claim 36, wherein the course has a treatment period on weeks 1, 2, and 3 and a rest period on week 4.
40. The method of claim 39, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
41. The method of claim 36, wherein the brain cancer is selected from the group consisting of acoustic neuroma, astrocytoma, chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, diffuse intrinsic pontine glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, oligodendroglioma, pituitary tumors, primitive neuroectodermal, schwannoma, brain stem glioma, craniopharyngioma, juvenile pilocytic astrocytoma, diffuse midline glioma, and pineal tumor.
42. The method of claim 36, wherein the brain cancer is diffuse intrinsic pontine glioma (DIPG).
43. The method of claim 42, wherein the DIPG is non-progressed DIPG.
44. The method of claim 42, wherein the DIPG is progressed or recurrent DIPG.
45. The method of claim 36, wherein the patient in need exhibits mutations in one or more genes selected from the group consisting of H3F3A, HIST 1 H3B, HIST 1 H3C, TP53, ACVR1 , PDGFRA, PPM1 D, PIK3CA, PIK3R1 , MYC, MYCN, and PPM1D.
46. The method of claim 45, wherein the patient exhibits a Histone (H)3 K27M mutation in the H3F3A gene.
47. The method of claim 36, comprising administering about 25 mg to about 60 mg of panobinostat or a pharmaceutically acceptable salt thereof.
48. The method of claim 36, comprising administering comprising administering a dose of about 5 mg/m2/day to about 36 mg/m2/day of panobinostat or a pharmaceutically acceptable salt thereof.
49. The method of claim 48, comprising administering the dose based on the patient in need’s body surface area (BSA).
50. The method of claim 42, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median overall survival for a patient treated with a standard protocol for DIPG.
51. The method of claim 42, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
52. The method of claim 42, wherein after administering panobinostat, the patient exhibits a partial response.
53. The method of claim 48, comprising administering panobinostat at a dose of about 10 mg/m2/day.
54. The method of claim 48, comprising administering panobinostat at a dose of about 28 mg/m2/day.
55. The method of any of the previous claims, wherein panobinostat is a lactate salt.
56. The method of any of the previous claims, wherein panobinostat is a monohydrate.
57. A method of treating progressed or recurrent DIPG in a patient in need thereof comprising administering a 10 mg/m2/day dose of panobinostat or a pharmaceutically acceptable salt thereof.
58. The method of any of the previous claims, wherein panobinostat is a lactate salt.
59. The method of any of the previous claims, wherein panobinostat is a monohydrate.
60. The method of claim 57, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course.
61. The method of claim 60, wherein the course has a treatment period on weeks 1, 2, and 3 and a rest period on week 4.
62. The method of claim 61 , wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
63. The method of claim 57, wherein the patient in need exhibits mutations in one or more genes selected from the group consisting of H3F3A, HIST 1 H3B, HIST 1 H3C, TP53, ACVR1 , PDGFRA, PPM1 D, PIK3CA, PIK3R1 , MYC, MYCN, and PPM1D.
64. The method of claim 63, wherein the patient exhibits a Histone (H)3 K27M mutation in the H3F3A gene.
65. The method of claim 57, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median overall survival for a patient treated with a standard protocol for DIPG.
66. The method of claim 57, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
67. The method of claim 57, wherein after administering panobinostat, the patient exhibits a partial response.
68. A method of treating non-progressed DIPG in a patient in need thereof comprising administering a 28 mg/m2/day dose of panobinostat or a pharmaceutically acceptable salt thereof.
69. The method of any of the previous claims, wherein panobinostat is a lactate salt.
70. The method of any of the previous claims, wherein panobinostat is a monohydrate.
71. The method of claim 68, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered on a 28 day course.
72. The method of claim 71 , wherein the course has a treatment period on weeks 1 and 3 and a rest period on weeks 2 and 4.
73. The method of claim 72, wherein panobinostat, or the pharmaceutically acceptable salt thereof, is administered up to three times per treatment period.
74. The method of claim 68, wherein after administering panobinostat, the patient’s overall survival is improved compared to the median overall survival for a patient treated with a standard protocol for DIPG.
75. The method of claim 68, wherein after administering panobinostat, the patient’s progression free survival is improved compared to the median progression free survival for a patient treated with a standard protocol for DIPG.
76. The method of claim 68, wherein after administering panobinostat, the patient exhibits a partial response.
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