WO2017053823A1 - Traitement à l'aide d'inhibiteurs d'hdac et d'immunothérapie - Google Patents

Traitement à l'aide d'inhibiteurs d'hdac et d'immunothérapie Download PDF

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WO2017053823A1
WO2017053823A1 PCT/US2016/053479 US2016053479W WO2017053823A1 WO 2017053823 A1 WO2017053823 A1 WO 2017053823A1 US 2016053479 W US2016053479 W US 2016053479W WO 2017053823 A1 WO2017053823 A1 WO 2017053823A1
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cancer
inhibitor
abexinostat
immune checkpoint
virus
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PCT/US2016/053479
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Thorsten Graef
Ssucheng Jeff Hsu
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Pharmacyclics Llc
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present invention relates to HDAC inhibitor combinations for the treatment of solid tumors and hematological malignancies.
  • HDACs histone deacetylases
  • hyperacetylation This alters the transcriptional regulation of a subset of genes, including many tumor suppressors, genes involved in cell cycle control, cell division and apopotosis. Further, HDAC inhibitors have been reported to inhibit tumor growth in vivo. The inhibition of tumor growth is accompanied by histone and tubulin hyperacetylation and may involve multiple mechanisms.
  • HDAC inhibitors block cancer cell proliferation both in vitro and in vivo.
  • N- hydroxy-4- ⁇ 2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy ⁇ - benzamide (Compound 1) is a hydroxamate-based HDAC inhibitor for use in the treatment of cancer in a human.
  • a method of treating a cancer includes the step of administering to a subject in need thereof a combination comprising a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is an abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the abexinostat or a salt thereof is a combination of one or more of the following: abexinostat, abexinostat HCl, and abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death- Ligand 1 (PD-Ll). In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1.
  • the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, or a B-cell malignancy. In some embodiments, the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the DLBCL is activated B-cell diffuse large B-cell lymphoma
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof.
  • the B-cell malignancy is a relapsed or refractory B-cell malignancy.
  • the B-cell malignancy is a metastasized B-cell malignancy.
  • the cancer is a solid tumor.
  • the solid tumor is a sarcoma or a carcinoma.
  • the cancer is selected from breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.
  • the cancer is breast cancer.
  • the breast cancer is ductal carcinoma in situ, lobular carcinoma in situ, invasive or infiltrating ductal carcinoma, invasive or infiltrating lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, Paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma.
  • the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is an adenocarcinoma. In some embodiments, the cancer is relapsed or refractory cancer. In some embodiments, the cancer is a metastasized cancer. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody. In some embodiments, the abexinostat or a salt thereof is abexinostat HCl. In some embodiments, the abexinostat or a salt thereof is abexinostat tosylate.
  • the abexinostat or a salt thereof is a combination of one or more of the following: abexinostat, abexinostat HCl, and abexinostat tosylate.
  • the abexinostat or a salt of abexinostat is administered in cycles comprising of 7 days of consecutive administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof.
  • the cycles of 7 consecutive days of daily administration of abexinostat or a salt thereof comprises daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof.
  • the daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises administration of each dosage about 4-6 hours apart.
  • the abexinostat or a salt thereof is administered orally.
  • abexinostat or a salt thereof, and the immune checkpoint inhibitor are administered simultaneously, sequentially or intermittently.
  • the method further comprises administering an additional anticancer agent.
  • the additional anticancer agent is selected from among a
  • the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine,
  • the additional anticancer agent is ibrutinib.
  • a pharmaceutical composition is provided.
  • the pharmaceutical composition comprises an abexinostat or a salt thereof; an immune checkpoint inhibitor; and a pharmaceutically-acceptable excipient.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll).
  • the immune checkpoint inhibitor is an inhibitor of PD-1.
  • the immune checkpoint inhibitor is an antibody.
  • the immune checkpoint inhibitor is a monoclonal antibody.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the combination is in a combined dosage form.
  • the combination is in separate dosage forms.
  • the pharmaceutical combination comprises an additional anticancer agent.
  • the additional anticancer agent is ibrutinib.
  • Fig. 1 illustrates the mean tumor volume from mice treated with the combination of abexinostat (referenced as "PCYC81”) and anti-PDl antibody after implantation with Pan02 cancer cells.
  • the combination of abexinostat and anti-PDl antibody was found to have a combination benefit in reducing tumor volume as compared to treatment with abexinostat or anti-PDl antibody alone.
  • Bioavailability refers to the percentage of ibrutinib dosed that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC(0- ⁇ )) of a drug when administered intravenously is usually defined as 100% bioavailable (F%).
  • Oral bioavailability refers to the extent to which ibrutinib is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.
  • Blood plasma concentration refers to the concentration of Ibrutinib in the plasma component of blood of a subject. It is understood that the plasma concentration of Ibrutinib may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood or plasma concentration of ibrutinib may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(O-oo)) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of ibrutinib may vary from subject to subject.
  • Cmax maximum plasma concentration
  • Tmax time to reach maximum plasma concentration
  • AUC(O-oo) total area under the plasma concentration time curve
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • co-administration refers to administration of both HDAC inhibitor and a checkpoint inhibitor in at least one cycle (but can be administered at the same or a different time in the cycle).
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects.
  • An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.
  • the term "therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • an “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effect amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of ibrutinib, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial.
  • the terms “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect.
  • “enhancing” the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition.
  • An “enhancing- effective amount,” as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • subject refers to an animal.
  • a subject may be, but is not limited to, a mammal including, but not limited to, a human.
  • the terms do not require the supervision (whether continuous or intermittent) of a medical professional.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the terms “treat,” “treating” or “treatment”, include, but are not limited to, prophylactic and/or therapeutic treatments.
  • the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of an HDAC, in an assay that measures such response.
  • EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • cancer recurrence As used herein, “cancer recurrence”, “cancer relapse”, “relapsed or refractory disease” are used interchangeably herein to refer to a return of cancer following treatment, and includes return of cancer in the primary organ, as well as distant recurrence, where the cancer returns outside of the primary organ.
  • salt of abexinostat may refer to abexinostat hydrochloride (abexinostat HC1), abexinostat tosylate (or “tosylate salt of abexinostat"), any other salt of abexinostat, and combinations and/or mixtures thereof.
  • An exemplary salt of abexinostat may be a mixture or combination of abexinostat HC1 and abexinostat tosylate.
  • Other exemplary salts may be disclosed in U.S. Patent Nos. 7,276,612 and 8,026,371, the contents of each of which are herein incorporated by reference in their entireties.
  • reference to the salt of abexinostat can refer to a mixture or a combination of abexinostat with an abexinostat salt.
  • Histone deacetylases including class I histone deacetylases HDAC1 and HDAC2, are overexpressed in many cancers. HDACs remove acetyl groups from histones and other nuclear proteins, and induce chromatin condensation and transcriptional repression. In some embodiments, HDACs are associated with aberrant epigenetic changes associated with cancer and the downregulation of HDACs is associated with a reversal of these aberrant epigenetic changes.
  • HDAC inhibitor refers to histone deacetylase inhibitors, a class of compounds that interfere with the function of histone deacetylase (i.e., they block the activity of histone deacetylases).
  • HDAC inhibitors have shown activity against several types of cancers in clinical trials. HDAC inhibitors promote acetylation of histone proteins, which decondenses chromatin into its active form and reverses the epigenetic silencing of transcription factors and tumor suppressor genes that regulate cell growth. In some embodiments, proteins such as p21, p53, and F-kB have been implicated as targets of HDAC inhibitors.
  • the HDAC inhibitor is a compound of Formula (B):
  • R 1 is hydrogen or alkyl
  • X is -0-, -NR 2 -, or -S(0) n where n is 0-2 and R 2 is hydrogen or alkyl;
  • Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
  • Ar 1 is phenylene or heteroarylene wherein said Ar 1 is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;
  • R 3 is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl;
  • Ar 2 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.
  • the HDAC inhibitor is 3-[(dimethylamino)methyl]-N- ⁇ 2-[4- (hydroxycarbamoyl)phenoxy]ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI- 24781/abexinostat)
  • the HDAC inhibitor is N-hydroxy-4- ⁇ 2-[3-(N,N- dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy ⁇ benzamide tosylate, or a solvate thereof.
  • the HDAC inhibitor may be a tosylate salt as disclosed in U.S. Patent Application Publication No. 2014/0249215, the entire contents of which are herein incorporated by reference in its entirety.
  • the HDAC inhibitor is a tosylate salt of abexinostat (also referred to herein as "abexinostat tosylate”) of formula (I):
  • the HDAC inhibitor is the tosylate salt of abexinostat of formula (II):
  • the HDAC inhibitor is a crystalline form I of N-hydroxy-4-
  • the HDAC inhibitor is a hydrochloride salt of abexinostat
  • the HDAC inhibitor can be a compound as disclosed in U.S. Patent Nos. 7,276,612 and 8,026,371, the contents of each of which are herein incorporated by reference in their entireties.
  • HDAC inhibitor Disclosed herein, in certain embodiments, are pharmaceutical combinations which comprise an HDAC inhibitor and an immunotherapeutic agent.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • immunotherapeutic agent is an immune checkpoint inhibitor.
  • immune checkpoints refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules effectively serve as “brakes” to down-modulate or inhibit an anti-tumor immune response.
  • Immune checkpoint molecules include, but are not limited to, Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, B7H1, B7H4, OX- 40, CD 137, CD40, 2B4, IDOl, ID02, VISTA, CD27, CD28, PD-L2 (B7-DC, CD273), LAG3, CD80, CD86, PDL2, B7H3, HVEM, BTLA, KIR, GAL9, TIM3, A2aR, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), ICOS (inducible T cell costimulator), HAVCR2, CD276, VTCN1, CD70, and CD 160.
  • PD-Ll also known as B7-H1, CD274
  • PD-1 Programmed Death 1
  • CTLA-4 B7H1, B7H4, OX- 40
  • Immune checkpoint inhibitors refer to any modulator that inhibits the activity of the immune checkpoint molecule.
  • Immune checkpoint inhibitors include small molecule inhibitors, antibodies, antibody-derivatives (including Fab fragments and scFvs), antibody-drug conjugates, antisense oligonucleotides, siRNA, aptamers, peptides and peptide mimetics.
  • Inhibitory nucleic acids that decrease the expression and/or activity of immune checkpoint molecules can also be used in the methods disclosed herein.
  • One embodiment is a small inhibitory RNA (siRNA) for interference or inhibition of expression of a target gene.
  • nucleic acid sequences encoding PD-1, PD-L1 and PD-L2 are disclosed in GENBANK® Accession Nos. NM_005018, AF344424, NP_079515, and NP_054862.
  • immunosorbent checkpoint inhibitor(s) and “checkpoint inhibitors” are interchangeable.
  • Immunune checkpoint inhibitors may also be referred to as “immune checkpoints.”
  • the immune checkpoint inhibitor is an inhibitor of PD-L1.
  • the immune checkpoint inhibitor is an inhibitor of PD-1.
  • the immune checkpoint inhibitor is an inhibitor of both PD-L1 and PD-1.
  • HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor are co-administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially.
  • a HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor are co-administered in separate dosage forms.
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are coadministered in combined dosage forms.
  • the co-administration of a HDAC inhibitor (e.g., abexinostat or a salt thereof) and an immune checkpoint inhibitor increases the oral bioavailability of abexinostat or a salt thereof.
  • the co-administration of abexinostat or a salt thereof, and an immune checkpoint inhibitor increases the Cmax of abexinostat or a salt thereof.
  • the co-administration of abexinostat or a salt thereof, and an immune checkpoint inhibitor increases, the AUC of abexinostat or a salt thereof.
  • co-administration of a HDAC inhibitor (e.g., abexinostat or a salt thereof) and an immune checkpoint inhibitor does not significantly affect the Tmax or Tl/2 of abexinostat or a salt thereof, as compared to the Tmax and Tl/2 of abexinostat or a salt thereof, administered without an immune checkpoint inhibitor.
  • the amount of HDAC inhibitor that is given to the patient per administration is from about 10 mg to about 200 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 20 mg to about 100 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 40 mg to about 80 mg.
  • the amount of HDAC inhibitor that is given to the patient per administration is about 40 mg, 60 mg, or 80 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is less than about 10 mg or greater than about 200 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 10 mg/day to about 200 mg/day.
  • the HDAC inhibitor may be abexinostat or a salt thereof.
  • the amount of HDAC inhibitor that is given to the patient per administration is from about 10 mg/m 2 to about 200 mg/m 2 . In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 20 mg/m 2 to about 100 mg/m 2 . In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 40 mg/m 2 to about 80 mg/m 2 . In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is about 40 mg/m 2 , 60 mg/m 2 , or 80 mg/m 2 .
  • the amount of HDAC inhibitor that is given to the patient per administration is less than about 10 mg/m 2 or greater than about 200 mg/m 2 . In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 30 mg/m 2 to about 75 mg/m 2 . In some embodiments, the amount of HDAC inhibitir that is given to the patient per administration is about 30 mg/m 2 , about 45 mg/m 2 , or about 60 mg/m 2 . In some embodiments, the HDAC inhibitor is administered twice a day.
  • the HDAC inhibitor may be abexinostat or a salt thereof.
  • the amount of HDAC inhibitor (e.g., abexinostat or a salt thereof) that is given to the patient per day is from about 10 mg to about 200 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per day is from about 20 mg to about 100 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per day is from about 40 mg to about 80 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per day is about 40 mg, about 60 mg, or about 80 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per day is less than about 10 mg or greater than about 200 mg.
  • the amount of HDAC inhibitor e.g., abexinostat or a salt thereof
  • the amount of HDAC inhibitor that is given to the patient per day is from about 10 mg/day to about 200 mg/day.
  • the HDAC inhibitor may be abexinostat or a salt thereof.
  • the daily dose of abexinostat or a salt thereof may be given in a single administration, or multiple administrations.
  • the HDAC inhibitor is administered in cycles consisting of 1,
  • the HDAC inhibitor is administered in cycles consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 of consecutive administration of HDAC inhibitor followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days with no administration of the HDAC inhibitor. In some embodiments, the HDAC inhibitor is administered in cycles consisting of 1, 2, 3, 4, 5, 6, or 7 days of consecutive administration of the HDAC inhibitor followed by 1, 2, 3, 4, 5, 6, or 7 days with no administration of the HDAC inhibitor.
  • the HDAC inhibitor is not administered on consecutive days, i.e., the HDAC inhibitor may be administered on day 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, and/or day 28, and administered on 1, 2,
  • the HDAC inhibitor is administered once per day, twice per day, three times per day, once daily, every other day, once a week, twice a week, three times a week, every other week, three times a month, once a month, or intermittently.
  • the HDAC inhibitor is administered on 7 consecutive days of daily administration of HDAC inhibitor followed by 7 consecutive says of no administration of HDAC inhibitor.
  • the 7 consecutive days of daily administration of HDAC inhibitor comprises daily administration of about 40 mg to about 80 mg of HDAC inhibitor.
  • the daily administration of about 40 mg to about 80 mg of HDAC inhibitor comprises twice daily administration of about 40 mg to about 80 mg of HDAC inhibitor.
  • the twice daily administration of about 40 mg to about 80 mg of HDAC inhibitor comprises administration of each dosage (or each
  • the HDAC inhibitor is administered on 5 consecutive days, followed by 2 consecutive days of no administration of HDAC inhibitor.
  • the 5 consecutive days of daily administratin of HDAC inhibitor comprises daily administration of about 10 mg/m 2 to about 100 mg/m 2 of HDAC inhibitor. In some embodiments, the 5 consecutive days of daily administration of HDAC inhibitor comprises administration of about 10 mg/m 2 to about 100 mg/m 2 of HDAC inhibitor twice a day.
  • An exemplary dosing regimen includes twice daily administration of about a 20 mg, about a 40 mg, about 60 mg, or about 80 mg tablet or capsule of abexinostat.
  • the first dosage of about a 40 mg, about 60 mg, or about 80 mg is administered at a first time
  • the second dosage of about a 40 mg, about 60 mg, or about 80 mg is administered at a second time, wherein the second time is about 4-6 hours after the first time.
  • the foregoing twice daily administration of abexinostat can continue for 7 consecutive days, which can then be followed by 7 consecutive days of no abexinostat administration.
  • the administration of abexinostat can be initiated at a dosage of, for example, 80 mg per administration (with administrations being, for example, twice a day). That administration can be changed to, for example, 40 mg the next day (per administration). Accordingly, the dosage of abexinostat can be de-escalated. For example, the dosage of abexinostat may start at 80 mg, and may be lowered for subsequent administrations.
  • the HDAC inhibitor may be administered for 14 consecutive days, followed by 7 consecutive days of no administration of the HDAC inhibitor. In some embodiments, less than about 40 mg of HDAC may be administered per administration, or greater than 80 mg of HDAC inhibitor may be administered per administration. In some embodiments, 20 mg of HDAC inhibitor may be administered.
  • Another exemplary dosing regimen includes twice daily administration of about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 75 mg/m 2 or about 80 mg/m 2 tablet or capsule of abexinostat.
  • 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 75 mg/m 2 or about 80 mg/m 2 is administered at a first time
  • the second dosage of about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 75 mg/m 2 or about 80 mg/m 2 is administered at a second time, wherein the second time is about 4-6 hours after the first time (in the same day).
  • the foregoing twice daily administration of abexinostat can continue for 5 consecutive days, which can then be followed by 2 consecutive days of no abexinostat administration.
  • the first dosage at the first time can be different from the second dosage at the second time. In some embodiments, the first dosage at the first time can be the same as the second dosage at the second time.
  • the immune checkpoint inhibitor can be administered daily, and its administration can be continued even during the 7 consecutive day period when abexinostat is not administered (or any other length of time when abexinostat is not administered).
  • the dosing regimen of the checkpoint inhibitor may be determined by the identity of the particular checkpoint inhibitor selected to be administered with the HDAC inhibitor.
  • abexinostat or a salt thereof is administered once per day, twice per day, or three times per day. In some embodiments, abexinostat or a salt thereof is administered once per day. In some embodiments, abexinostat or a salt thereof is
  • abexinostat is administered once per day, twice per day, or three times per day.
  • abexinostat is administered once per day.
  • abexinostat and the immune checkpoint inhibitor are co-administered (e.g., in a single dosage form), once per day.
  • abexinostat and the immune checkpoint inhibitor are administered as a maintenance therapy.
  • the HDAC inhibitor (e.g., abexinostat or a salt thereof) is administered once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • compositions disclosed herein are administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered as a maintenance therapy, for example for a patient in remission.
  • any suitable daily dose of an immune checkpoint inhibitor is contemplated for use with the compositions, dosage forms, and methods disclosed herein.
  • Daily dose of the immune checkpoint inhibitor depends on multiple factors, the determination of which is within the skills of one of skill in the art.
  • the daily dose of the immune checkpoint inhibitor depends of the strength of the immune checkpoint inhibitor. Weak immune checkpoint inhibitors will require higher daily doses than moderate immune checkpoint inhibitors, and moderate immune checkpoint inhibitors will require higher daily doses than strong immune checkpoint inhibitors.
  • the amount of an immune checkpoint inhibitor described herein that is administered in combination with a HDAC inhibitor is from 0.001 mg/kg up to and including 500 mg/kg.
  • the amount of an immune checkpoint inhibitor that is administered is from about 0.01 mg/kg to about 100 mg/kg. In some embodiments, the amount of an immune checkpoint inhibitor that is administered is about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8.5 mg/kg, about 9 mg/kg, about
  • an immune checkpoint inhibitor is administered once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • the immune checkpoint inhibitor is administered once per day, twice per day, or three times per day.
  • the immune checkpoint inhibitor is administered once per day.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered sequentially or simultaneously once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • a HDAC inhibitor is administered following a scheduled regimen while an immune checkpoint inhibitor is administered intermittently. In other instances, a HDAC inhibitor is administered intermittently while an immune checkpoint inhibitor is administered following a scheduled regimen.
  • both a HDAC inhibitor and an immune checkpoint inhibitor are administered intermittently. In some instances, a HDAC inhibitor and an immune checkpoint inhibitor are administered intermittently with an additional anticancer agent.
  • a HDAC inhibitor and the immune checkpoint inhibitor are co-administered (e.g., in a single dosage form) with an additional anticancer agent, once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • a HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor is administered with an additional anticancer agent.
  • the additional anticancer agent is a BTK inhibitor.
  • the BTK inhibitor is ibrutinib.
  • the amount of ibrutinib that is administered in combination with a HDAC inhibitor (e.g., abexinostat or a salt thereof) and an immune checkpoint inhibitor is from about 10 mg/day up to, and including, about 1000 mg/day. In some embodiments, the amount of ibrutinib that is administered is from about 40 mg/day to about 840 mg/day.
  • the amount of ibrutinib that is administered per day is 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 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 480 mg; about 560 mg; about 700 mg; or about 840 mg.
  • the pharmaceutical combination and/or compositions described herein are administered to treatment-naive cancer patients.
  • a treatment-naive cancer patient is a patient who has not received a treatment related to a cancer, a patient who has not received a HDAC inhibitor treatment, a patient who has not received an immune checkpoint inhibitor, or a patient who has not received any combinations of a HDAC inhibitor, immune checkpoint inhibitor, and/or an additional anticancer agent described elsewhere herein.
  • the pharmaceutical combinations and/or combinations described herein are administered to a patient who has not received treatment with a BTK inhibitor, such as ibrutinib.
  • the pharmaceutical combination and/or compositions described herein are administered to cancer patients who have already received one or more prior treatments.
  • the one or more prior treatments include treatments such as surgery, chemotherapy, radiation therapy, and include treatments with one or more of the anticancer agents described elsewhere herein.
  • the pharmaceutical combination and/or compositions disclosed herein are administered to patients for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered as a maintenance therapy, for example for a patient in remission.
  • a HDAC inhibitor and the immune checkpoint inhibitor are administered as a maintenance therapy.
  • the administration of the compounds may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday may be from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, the severity of the disease, a biomarker profile, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of 0.02- 5000 mg per day, or from about 1-1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical combination and/or composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non- reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a HDAC inhibitor is co-administered with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIRl, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments,
  • the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the immune checkpoint inhibitor is an antibody. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody. In some embodiments, the HDAC inhibitor is abexinostat or a salt thereof.
  • abexinostat or a salt thereof is co-administered with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA,
  • PD-Ll also known
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments,
  • the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the immune checkpoint inhibitor is an antibody. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody.
  • any suitable immune checkpoint inhibitor is contemplated for use with the compositions, dosage forms, and methods disclosed herein.
  • the selection of the immune checkpoint inhibitor depends on multiple factors, and the selection of the immune checkpoint inhibitor is within the skills of one of skill in the art. For example, factors to be considered include the desired reduction in the daily dose of abexinostat or a salt thereof, any additional drug interactions of the immune checkpoint inhibitor, and the length for which the immune checkpoint inhibitor may be taken.
  • the immune checkpoint inhibitor is an immune checkpoint inhibitor which may be taken long-term, for example chronically.
  • Immune checkpoint inhibitors refers to any agent that inhibits the immune checkpoint blockade signal that the immune checkpoint molecule in question regulates.
  • Immune checkpoint inhibitors can include, but are not limited to, immune checkpoint molecule binding proteins, antibodies (or fragments or variants thereof) that bind to immune checkpoint molecules, nucleic acids that downregulate expression of the immune checkpoint molecules, or any other molecules that bind to immune checkpoint molecules (i.e. small organic molecules, peptidomimetics, aptamers, etc.).
  • the immune checkpoint inhibitor is an antibody.
  • the antibodies for use in the present invention include, but are not limited to, monoclonal antibodies, synthetic antibodies, polyclonal antibodies, multispecific antibodies (including bi- specific antibodies), human antibodies, humanized antibodies, chimeric antibodies, single- chain Fvs (scFv) (including bi-specific scFvs), single chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments of any of the above.
  • antibodies for use in the present invention include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain a binding site for an immune checkpoint molecule that immunospecifically bind to the immune checkpoint molecule.
  • the immunoglobulin molecules for use in the invention can be of any type ⁇ e.g., IgG, IgE, IgM, IgD, IgA and IgY), class ⁇ e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.
  • the antibodies for use in the invention are IgG, more preferably, IgGl.
  • An antibody against an immune checkpoint molecule suitable for use with the methods disclosed herein may be from any animal origin including birds and mammals ⁇ e.g., human, murine, donkey, sheep, rabbit, goat, guinea pig, camel, horse, shark or chicken).
  • the antibodies are human or humanized monoclonal antibodies.
  • "human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from mice or other animals that express antibodies from human genes.
  • An antibody against an immune checkpoint molecule suitable for use with the methods disclosed herein may be monospecific, bispecific, trispecific or of greater multispecificity.
  • Multispecific antibodies may immunospecifically bind to different epitopes of a polypeptide or may immunospecifically bind to both a polypeptide as well as a heterologous epitope, such as a heterologous polypeptide or solid support material.
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll .
  • the immune checkpoint inhibitor is an antibody against PD-Ll .
  • the immune checkpoint inhibitor is a monoclonal antibody against PD-Ll .
  • the immune checkpoint inhibitor is a human or humanized antibody against PD-Ll .
  • the immune checkpoint inhibitor reduces the expression or activity of one or more immune checkpoint proteins, such as PD-Ll .
  • the immune checkpoint inhibitor reduces the interaction between PD-1 and PD- Ll .
  • Exemplary immune checkpoint inhibitors include antibodies (e.g., an anti-PD-Ll antibody), RNAi molecules (e.g., anti-PD-Ll RNAi), antisense molecules (e.g., an anti-PD- Ll antisense RNA), dominant negative proteins (e.g., a dominant negative PD-Ll protein), and small molecule inhibitors.
  • Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins.
  • An exemplary anti-PD-Ll antibody includes clone EH12.
  • Exemplary antibodies against PD-Ll include: Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX- 1105 (BMS-936559) and BMS-935559 from Bristol -Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; and AstraZeneca's MEDI4736.
  • the anti-PD-Ll antibody is an anti-PD-Ll antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2013079174; CN101104640; WO2010036959; WO2013056716;
  • the PD-Ll inhibitor is a nucleic acid inhibitor of PD-Ll expression.
  • the PD-Ll inhibitor is disclosed in one of the following patent publications (incorporated herein by reference): WO2011127180 or WO2011000841.
  • the PD-Ll inhibitor is rapamycin.
  • a HDAC inhibitor is administered in combination with a PD- Ll inhibitor for the treatment of a cancer.
  • the PD-Ll inhibitor is selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C; mouse anti- PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin.
  • a HDAC inhibitor is administered in combination with a PD-Ll inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C; mouse anti- PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin for the treatment of a cancer.
  • a PD-Ll inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-M
  • abexinostat or a salt thereof is administered in combination with a PD-Ll inhibitor for the treatment of a cancer.
  • the PD-Ll inhibitor is selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BEOlOl) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C; mouse anti- PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin.
  • abexinostat or a salt thereof is administered in combination with a PD-Ll inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BEOlOl) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C; mouse anti- PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a PD-Ll inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of PD-L2. In some embodiments, the immune checkpoint inhibitor is an antibody against PD-L2. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody against PD-L2. In other or additional embodiments, the immune checkpoint inhibitor is a human or humanized antibody against PD-L2. In some embodiments, the immune checkpoint inhibitor reduces the expression or activity of one or more immune checkpoint proteins, such as PD-L2. In other embodiments, the immune checkpoint inhibitor reduces the interaction between PD-1 and PD-L2.
  • Exemplary immune checkpoint inhibitors include antibodies (e.g., an anti-PD-L2 antibody), RNAi molecules (e.g., an anti-PD-L2 RNAi), antisense molecules (e.g., an anti- PD-L2 antisense RNA), dominant negative proteins (e.g., a dominant negative PD-L2 protein), and small molecule inhibitors.
  • Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins.
  • the PD-L2 inhibitor is GlaxoSmithKline' s AMP-224
  • the PD-L2 inhibitor is rHIgM12B7.
  • a HDAC inhibitor is administered in combination with a PD- L2 inhibitor described above and elsewhere for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a PD-L2 inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of PD-1.
  • the immune checkpoint inhibitor is an antibody against PD-1.
  • the immune checkpoint inhibitor is a monoclonal antibody against PD-1.
  • the immune checkpoint inhibitor is a human or humanized antibody against PD-1.
  • the inhibitors of PD-1 biological activity (or its ligands) disclosed in U.S. Pat. Nos. 7,029,674; 6,808,710; or U.S. Patent Application Nos: 20050250106 and 20050159351 can be used in the methods provided herein.
  • Exemplary antibodies against PD-1 include: Anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti-mouse PD-1 antibody Clone RMP1-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as A B011; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP- 514, and AMP-224; and Pidilizumab (CT-011), CureTech Ltd.
  • CT-011 CureTech Ltd.
  • the anti-PD-1 antibody is an anti-PD-1 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO014557; WO2011110604; WO2008156712; US2012023752; WO2011110621; WO2004072286; WO2004056875; WO20100036959; WO2010029434; WO201213548; WO2002078731; WO2012145493; WO2010089411; WO2001014557; WO2013022091; WO2013019906; WO2003011911; US20140294898; and WO2010001617.
  • the PD-1 inhibitor is a PD-1 binding protein as disclosed in WO200914335 (herein incorporated by reference).
  • the PD-1 inhibitor is a peptidomimetic inhibitor of PD-1 as disclosed in WO2013132317 (herein incorporated by reference).
  • the PD-1 inhibitor is a PD-L1 protein, a PD-L2 protein, or fragments, as well as antibody MDX-1 106 (ONO-4538) tested in clinical studies for the treatment of certain malignancies (Brahmer et al., J Clin Oncol. 2010 28(19): 3167-75, Epub 2010 Jun 1).
  • Other blocking antibodies may be readily identified and prepared by the skilled person based on the known domain of interaction between PD-1 and PD-L1/PD-L2, as discussed above. For example, a peptide corresponding to the IgV region of PD-1 or PD- L1/PD-L2 (or to a portion of this region) could be used as an antigen to develop blocking antibodies using methods well known in the art.
  • a HDAC inhibitor is administered in combination with a PD- 1 inhibitor described above and elsewhere for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is an abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with a PD- 1 inhibitor for the treatment of a cancer.
  • the PD-1 inhibitor is selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti-mouse PD- 1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab,
  • lambrolizumab and AnaptysBio's anti-PD-1 antibody, known as ANBOl 1; antibody MDX- 1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP-514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD-L2.
  • CT-011 CureTech Ltd
  • MDX-1 106 ONO-4538
  • PD-L1 and PD-L2.
  • a HDAC inhibitor is administered in combination with a PD-1 inhibitor selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti- mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda,
  • pembrolizumab pembrolizumab, lambrolizumab
  • AnaptysBio's anti-PD-1 antibody known as ANBOl 1; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP-514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD- L2 for the treatment of a cancer.
  • CT-011 CureTech Ltd
  • MDX-1 106 ONO-4538
  • PD-L1 PD-L1
  • PD- L2 for the treatment of a cancer.
  • abexinostat or a salt thereof is administered in combination with a PD-1 inhibitor for the treatment of a cancer.
  • the PD-1 inhibitor is selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti- mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda,
  • pembrolizumab pembrolizumab, lambrolizumab
  • AnaptysBio's anti-PD-1 antibody known as ANBOl 1; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP-514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD- L2.
  • abexinostat or a salt thereof is administered in combination with a PD-1 inhibitor selected from anti -mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANBOl 1; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca' s AMP-514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538
  • the immune checkpoint inhibitor is not a PD-1 inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an antibody against CTLA-4. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody against CTLA-4. In other or additional embodiments, the immune checkpoint inhibitor is a human or humanized antibody against CTLA-4. In one embodiment, the anti-CTLA-4 antibody blocks the binding of CTLA-4 to CD80 (B7-1) and/or CD86 (B7-2) expressed on antigen presenting cells.
  • Exemplary antibodies against CTLA-4 include: Bristol Meyers Squibb's anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); and anti-CTLA4 antibody clone BNI3 from Abeam.
  • Anti-CTLA4 antibody clone BNI3 from Abeam.
  • the anti-CTLA-4 antibody is an anti-CTLA-4 antibody disclosed in any of the following patent publications (herein incorporated by reference) :WO 2001014424; WO 2004035607; US2005/0201994; EP 1212422 B 1; WO2003086459;
  • CTLA-4 antibodies are described in U.S. Patent Nos.
  • the anti-CTLA-4 antibody is an, for example, those disclosed in: WO 98/42752; U.S. Patent Nos. 6,682,736 and 6,207, 156; Hurwitz et al, Proc. Natl. Acad. Sci.
  • the CTLA-4 inhibitor is a CTLA-4 ligand as disclosed in WO1996040915.
  • the CTLA-4 inhibitor is a nucleic acid inhibitor of CTLA-4 expression.
  • anti-CTLA4 RNAi molecules may take the form of the molecules described by Mello and Fire in PCT Publication Nos. WO 1999/032619 and WO 2001/029058; U.S. Publication Nos. 2003/0051263, 2003/0055020, 2003/0056235,
  • the anti-CTLA4 RNAi molecules take the form of double stranded RNAi molecules described by Tuschl in European Patent No. EP 1309726 (incorporated herein by reference).
  • the anti-CTLA4 RNAi molecules take the form of double stranded RNAi molecules described by Tuschl in U.S. Patent Nos. 7,056,704 and 7,078, 196 (incorporated herein by reference).
  • the CRLA4 inhibitor is an aptamer described in PCT Publication No.
  • WO2004081021 such as Del 60 or M9- 14 del 55.
  • the anti-CTLA4 RNAi molecules of the present invention may take the form be RNA molecules described by Crooke in U.S. Patent Nos. 5,898,031, 6,107,094, 7,432,249, and 7,432,250, and European Application No. EP 0928290 (incorporated herein by reference).
  • a HDAC inhibitor is administered in combination with a CTLA-4 inhibitor described above and elsewhere for the treatment of a cancer.
  • a HDAC inhibitor is administered in combination with a CTLA-4 inhibitor for the treatment of a cancer.
  • the CTLA-4 inhibitor is selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55.
  • Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab also known as Yervoy®, MDX-010, BMS-734016 and MDX-101
  • anti-CTLA4 Antibody clone 9H10 from Millipore
  • Pfizer' s tremelimumab CP-675,206,
  • a HDAC inhibitor is administered in combination with a CTLA-4 inhibitor selected from Bristol Meyers Squibb's anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer's tremelimumab (CP-675,206, ticilimumab); anti-CTLA4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55 for the treatment of a cancer.
  • CTLA-4 inhibitor selected from Bristol Meyers Squibb's anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer's tremelimumab (CP-675,206, ticilimumab);
  • abexinostat or a salt thereof is administered in combination with a CTLA-4 inhibitor for the treatment of a cancer.
  • the CTLA-4 inhibitor is selected from Bristol Meyers Squibb's anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer's tremelimumab (CP-675,206, ticilimumab); anti-CTLA4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55.
  • Bristol Meyers Squibb's anti-CTLA-4 antibody ipilimumab also known as Yervoy®, MDX-010, BMS-734016 and MDX-101
  • anti-CTLA4 Antibody clone 9H10 from Millipore
  • Pfizer's tremelimumab CP-675,206,
  • abexinostat or a salt thereof is administered in combination with a CTLA-4 inhibitor selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from
  • Millipore Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55 for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a CTLA-4 inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of LAG3 (CD223). In some embodiments, the immune checkpoint inhibitor is an antibody against LAG3. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody against LAG3. In other or additional embodiments, the immune checkpoint inhibitor is a human or humanized antibody against LAG3. In additional embodiments, an antibody against LAG3 blocks the interaction of LAG3with major histocompatibility complex (MHC) class II molecules.
  • MHC major histocompatibility complex
  • Exemplary antibodies against LAG3 include: anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG-3 chimeric antibody A9H12.
  • the anti-LAG3 antibody is an anti- LAG3 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2010019570; WO2008132601; or WO2004078928.
  • a HDAC inhibitor is administered in combination with a LAG3 inhibitor described above and elsewhere for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with a LAG3 inhibitor for the treatment of a cancer.
  • the LAG3 inhibitor is selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; EVIP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG-3 chimeric antibody A9H12.
  • a HDAC inhibitor is administered in combination with a LAG3 inhibitor selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from
  • Immutep anti-Lag3 antibody BMS-986016
  • LAG-3 chimeric antibody A9H12 for the treatment of a cancer.
  • abexinostat or a salt thereof is administered in combination with a LAG3 inhibitor for the treatment of a cancer.
  • the LAG3 inhibitor is selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG-3 chimeric antibody A9H12.
  • abexinostat or a salt thereof is administered in combination with a LAG3 inhibitor selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; EVIP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG-3 chimeric antibody A9H12 for the treatment of a cancer.
  • a LAG3 inhibitor selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; EVIP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG-3 chimeric antibody A9H12 for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a LAG3 inhibitor.
  • the immune checkpoint inhibitor is an antibody against TEVI3 (also known as HAVCR2). In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody against TEVI3. In other or additional embodiments, the immune checkpoint inhibitor is a human or humanized antibody against TEVI3. In additional embodiments, an antibody against TIM3 blocks the interaction of TIM3 with galectin-9 (Gal9). In some embodiments, the anti-TIM3 antibody is an anti-TEVI3 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2013006490; WO201155607; WO2011159877; or WO200117057. In another embodiment, a ⁇ 3 inhibitor is a ⁇ 3 inhibitor disclosed in WO2009052623.
  • a HDAC inhibitor is administered in combination with a TEVI3 inhibitor described above and elsewhere for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with a TIM3 inhibitor for the treatment of a cancer.
  • abexinostat or a salt thereof is administered in combination with a TIM3 inhibitor for the treatment of a cancer.
  • the immune checkpoint inhibitor is an antibody against B7- H3. In one embodiment, the immune checkpoint inhibitor is MGA271. In some embodiments, the immune checkpoint inhibitor is MGA271.
  • a HDAC inhibitor is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • abexinostat or a salt thereof is abexinostat HC1.
  • abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with a TIM3 inhibitor for the treatment of a cancer.
  • abexinostat or a salt thereof is administered in combination with a TIM3 inhibitor for the treatment of a cancer.
  • a HDAC inhibitor is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for the treatment of a cancer.
  • a B7-H3 inhibitor e.g. MGA271
  • abexinostat or a salt thereof is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a TIM3 inhibitor.
  • the immune checkpoint inhibitor is an antibody against KIR.
  • the immune checkpoint inhibitor is Lirilumab (IPH2101).
  • an antibody against KIR blocks the interaction of KIR with HLA.
  • a HDAC inhibitor is administered in combination with a KIR inhibitor (e.g. Lirilumab) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is not a KIR inhibitor.
  • the immune checkpoint inhibitor is an antibody against CD137 (also known as 4-1BB or TNFRSF9).
  • the immune checkpoint inhibitor is urelumab (BMS-663513, Bristol-Myers Squibb), PF-05082566 (anti-4-lBB, PF- 2566, Pfizer), or XmAb-5592 (Xencor).
  • an anti-CD137 antibody is an antibody disclosed in U.S. Published Application No. US 2005/0095244; an antibody disclosed in issued U.S. Pat. No.
  • 7,288,638 (such as 20H4.9-IgG4 [10C7 or BMS-663513] or 20H4.9-IgGl [BMS-663031]); an antibody disclosed in issued U.S. Pat. No. 6,887,673 [4E9 or BMS-554271]; an antibody disclosed in issued U.S. Pat. No. 7,214,493; an antibody disclosed in issued U.S. Pat. No. 6,303, 121; an antibody disclosed in issued U.S. Pat. No. 6,569,997; an antibody disclosed in issued U.S. Pat. No. 6,905,685; an antibody disclosed in issued U.S. Pat. No. 6,355,476; an antibody disclosed in issued U.S. Pat. No.
  • a HDAC inhibitor is administered in combination with a CD137 inhibitor (e.g. urelumab, PF-05082566, XmAb-5592) for the treatment of a cancer.
  • a CD137 inhibitor e.g. urelumab, PF-05082566, XmAb-5592
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HCl. In some embodiments, the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is not a CD137 inhibitor.
  • the immune checkpoint inhibitor is an antibody against PS.
  • the immune checkpoint inhibitor is Bavituximab.
  • a HDAC inhibitor is administered in combination with a PS inhibitor (e.g. Bavituximab) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HCl.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with a PS inhibitor (e.g. Bavituximab) for the treatment of a cancer.
  • a PS inhibitor e.g. Bavituximab
  • abexinostat or a salt thereof is administered in combination with a PS inhibitor (e.g. Bavituximab) for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a PS inhibitor.
  • the immune checkpoint inhibitor is an antibody against CD52.
  • the immune checkpoint inhibitor is alemtuzumab.
  • a HDAC inhibitor is administered in combination with a CD52 inhibitor (e.g. alemtuzumab) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HCl.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with a CD52 inhibitor (e.g. alemtuzumab) for the treatment of a cancer.
  • abexinostat or a salt thereof is administered in combination with a CD52 inhibitor (e.g.
  • alemtuzumab for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a CD52 inhibitor.
  • the immune checkpoint inhibitor is an antibody against CD30.
  • the immune checkpoint inhibitor is brentuximab vedotin.
  • an antibody against CD30 blocks the interaction of CD30 with CD30L.
  • a HDAC inhibitor is administered in combination with a CD30 inhibitor (e.g. brentuximab vedotin) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is not a CD30 inhibitor.
  • the immune checkpoint inhibitor is an antibody against CD33.
  • the immune checkpoint inhibitor is gemtuzumab ozogamicin.
  • a HDAC inhibitor is administered in combination with a CD33 inhibitor (e.g. gemtuzumab ozogamicin) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is an abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in
  • a CD33 inhibitor e.g. gemtuzumab ozogamicin
  • abexinostat or a salt thereof is administered in combination with a CD33 inhibitor (e.g. gemtuzumab ozogamicin) for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a CD33 inhibitor.
  • the immune checkpoint inhibitor is an antibody against CD20. In one embodiment, the immune checkpoint inhibitor is ibritumomab tiuxetan. In another embodiment, the immune checkpoint inhibitor is ofatumumab. In another
  • the immune checkpoint inhibitor is rituximab. In another embodiment, the immune checkpoint inhibitor is tositumomab. In some embodiments, a HDAC inhibitor is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for the treatment of a cancer.
  • a CD20 inhibitor e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab
  • the HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the abexinostat or a salt thereof is abexinostat HC1. In some embodiments, the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for the treatment of a cancer.
  • a CD20 inhibitor e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab
  • abexinostat or a salt thereof is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a CD20 inhibitor.
  • the immune checkpoint inhibitor is an antibody against CD27 (also known as T FRSF7).
  • the immune checkpoint inhibitor is CDX-1127 (Celldex Therapeutics).
  • an antibody against CD27 blocks the interaction of CD27 with CD70.
  • a HDAC inhibitor is administered in combination with a CD27 inhibitor (e.g. CDX-1127) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1. In some embodiments, the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is not a CD27 inhibitor.
  • the immune checkpoint inhibitor is an antibody against OX40 (also known as T FRSF4 or CD 134). In one embodiment, the immune checkpoint inhibitor is anti-OX40 mouse IgG. In another embodiment, an antibody against OX40 blocks the interaction of OX40 with OX40L.
  • a HDAC is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for the treatment of a cancer.
  • abexinostat or a salt thereof is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for the treatment of a cancer.
  • the immune checkpoint inhibitor is not an OX40 inhibitor.
  • the immune checkpoint inhibitor is an antibody against glucocorticoid-induced tumor necrosis factor receptor (GITR).
  • the immune checkpoint inhibitor is TRX518 (GITR, Inc.).
  • an antibody against GITR blocks the interaction of GITR with GITRL.
  • a HDAC inhibitor is administered in combination with a GITR inhibitor (e.g. TRX518) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with a GITR inhibitor (e.g. TRX518) for the treatment of a cancer.
  • a GITR inhibitor e.g. TRX528
  • abexinostat or a salt thereof is administered in combination with an OX40 inhibitor (e.g. TRX518) for the treatment of a cancer.
  • the immune checkpoint inhibitor is not a GITR inhibitor.
  • the immune checkpoint inhibitor is an antibody against inducible T-cell COStimulator (ICOS, also known as CD278).
  • the immune checkpoint inhibitor is MEDI570 (Medlmmune, LLC) or AMG557 (Amgen).
  • an antibody against ICOS blocks the interaction of ICOS with ICOSL and/or B7-H2.
  • a HDAC inhibitor is administered in combination with an ICOS inhibitor (e.g. MEDI570 or AMG557) for the treatment of a cancer.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • a HDAC inhibitor is administered in combination with an ICOS inhibitor (e.g. MEDI570 or AMG557) for the treatment of a cancer.
  • abexinostat or a salt thereof is administered in combination with an ICOS inhibitor (e.g. MEDI570 or AMG557) for the treatment of a cancer.
  • the immune checkpoint inhibitor is not an ICOS inhibitor.
  • the immune checkpoint inhibitor is an inhibitor against BTLA (CD272), CD 160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM.
  • an immune checkpoint inhibitor can be one or more binding proteins, antibodies (or fragments or variants thereof) that bind to immune checkpoint molecules, nucleic acids that downregulate expression of the immune checkpoint molecules, or any other molecules that bind to immune checkpoint molecules (i.e. small organic molecules, peptidomimetics, aptamers, etc.).
  • an inhibitor of BTLA (CD272) is HVEM.
  • an inhibitor of CD 160 is HVEM.
  • an inhibitor of 2B4 is CD48.
  • an inhibitor of LAIRl is collagen.
  • an inhibitor of TIGHT is CD112, CD113, or CD 155.
  • an inhibitor of CD28 is CD80 or CD86.
  • an inhibitor of LIGHT is HVEM.
  • an inhibitor of DR3 is TL1A.
  • an inhibitor of CD226 is CD155 or CD112.
  • an inhibitor of CD2 is CD48 or CD58.
  • SLAM is self inhibitory and an inhibitor of SLAM is SLAM.
  • a HDAC inhibitor is administered in combination with an inhibitor against BTLA (CD272), CD160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for the treatment of a cancer.
  • a HDAC inhibitor is administered in combination with an inhibitor against BTLA (CD272), CD 160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for the treatment of a cancer.
  • abexinostat or a salt thereof is administered in combination with an inhibitor against BTLA (CD272), CD160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for the treatment of a cancer.
  • a method of treating a cancer in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the combination provides a synergistic therapeutic effect compared to administration of abexinostat or a salt thereof or the immune checkpoint inhibitor alone.
  • the combination provides a benefit compared to administration of abexinostat or a salt thereof or the immune checkpoint inhibitor alone.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations thereof.
  • PD-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • the immune checkpoint inhibitor is an inhibitor of PD-L1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some
  • the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the cancer is a solid tumor. In some embodiments, the cancer is a hematologic cancer.
  • the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma. In some embodiments, the solid tumor is relapsed or refractory solid tumor. In some embodiments, the solid tumor is a treatment naive solid tumor. In some embodiments, the individual has received at least one prior therapy. In some embodiments, the individual has not received at least one prior therapy.
  • the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid
  • hemangioendothelioma hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma;
  • extrarenal rhabdoid tumor extrarenal rhabdoid tumor
  • extraskeletal myxoid chondrosarcoma extraskeletal myxoid chondrosarcoma
  • osteosarcoma osteosarcoma; fibrosarcoma; giant cell tumor; hemangiopericytoma; infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone;
  • liposarcoma liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant mesenchymoma; malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;
  • myxoinflammatory fibroblastic sarcoma myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; P ET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma.
  • the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
  • the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer.
  • the pancreatic cancer is pancreatic ductal adenocarcino
  • the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
  • the carcinoma is pancreatic cancer.
  • the pancreatic cancer is
  • the carcinoma is colorectal (colon) cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the bladder cancer is encompassed by the genitourinary tract cancers.
  • the genitourinary tract cancers also encompass kidney cancer, prostate cancer, and cancers associated with the reproductive organs.
  • the carcinoma is lung cancer.
  • the lung cancer is a non-small cell lung cancer.
  • the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
  • the lung cancer is a small cell lung cancer.
  • the carcinoma is prostate cancer.
  • the prostate cancer is adenocarcinoma or small cell carcinoma.
  • the carcinoma is ovarian cancer.
  • the ovarian cancer is epithelial ovarian cancer.
  • the carcinoma is bile duct cancer.
  • the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
  • the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma,
  • the solid tumor is prostate cancer.
  • the solid tumor is breast cancer.
  • the solid tumor is lung cancer.
  • the solid tumor is colorectal (colon) cancer.
  • the solid tumor is gastroenterological cancer.
  • the solid tumor is melanoma.
  • the solid tumor is lung cancer.
  • the solid tumor is kidney cancer.
  • the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.
  • the breast cancer is ductal carcinoma in situ (intraductal carcinoma), lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, Paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma.
  • the invasive breast carcinoma is further categorized into subtypes.
  • the subtypes include adenoid cystic (or adenocystic) carcinoma, low- grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma or mixed carcinoma.
  • the breast cancer is classified according to stages or how far the tumor cells have spread within the breast tissues and to other portions of the body. In some embodiments, there are five stages of breast cancer, Stage 0-IV. In some embodiments, Stage 0 breast cancer refers to non-invasive breast cancers or that there are no evidence of cancer cells or abnormal non-cancerous cells breaking out of the origin site. In some embodiments, Stage I breast cancer refers to invasive breast cancer in which the cancer cells have invaded into surrounding tissues. In some embodiments, Stage I is subclassified into Stage IA and IB, in which Stage IA describes tumor measures up to 2 cm with no spread of cancer cells.
  • Stage IB describes absence of tumor in breast but have small lumps of cancer cells between 0.2mm to 2mm within the lymph nodes.
  • Stage II breast cancer is further subdivided into Stage IIA and IIB.
  • Stage IIA describes tumor between 2cm to 5 cm in breast only, or absence of tumor in breast but with cancer between 2mm to 2cm in axillary lymph nodes.
  • Stage IIB describes tumor larger than 5cm in breast only, or tumor between 2cm to 5 cm in breast with presence of small tumors from 0.2mm to 2mm in axillary lymph nodes.
  • Stage III breast cancer is further subdivided into Stage IIIA, IIIB, and IIIC.
  • Stage IIIA describes absence of tumor or tumor greater than 5cm in breast with small tumors in 4-9 axillary lymph nodes or small tumors 0.2mm-2mm in size in axillary lymph nodes.
  • Stage IIIB describes tumor spreading into the chest wall or skin of the breast causing swelling or ulcer and with presence of tumor in up to 9 axillary lymph nodes.
  • inflammatory breast cancer is also considered as Stage IIIB.
  • Stage IIIC describes absence of tumor or tumor spreading into the chest wall or to the skin of the breast, with tumor present in 10 or more axillary lymph nodes.
  • Stage IV breast cancer refers to invasive breast cancer that has metastasized into the lymph nodes and other portions of the body.
  • the colon cancer is a colorectal cancer.
  • colon cancer is used interchangeably with colorectal cancer.
  • colorectal (colon) cancer refers to rectal cancer.
  • the colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, or squamous cell- carcinoma.
  • adenocarcinoma is a mucinous adenocarcinoma or a Signet ring cell adenocarcinoma.
  • the colon cancer is classified according to stages or how far they have spread through the walls of the colon and rectum. In some embodiments, there are five stages of colon cancer, Stage 0-IV. In some embodiments, Stage 0 colon cancer refers to the very early stage of cancer. In some embodiments, Stage I colon cancer refers to when the cancer has spread beyond the innermost lining of the colon to the second and third layers and also involves the inside wall of the colon. In some embodiments, Stage II colon cancer refers to when the tumor has extended through the muscular wall but has not yet spread into the lymph nodes. In some embodiments, Stage III colon cancer refers to when the tumor has metastasized the colon into one or more lymph nodes.
  • Stage IV colon cancer refers to when the tumor has metastasized to other parts of the body.
  • Stage 0 rectal cancer refers to when the tumor is located only on the inner lining of the rectum.
  • Stage I refers to when the tumor has advanced through the inner lining of the rectum but not yet reach past the muscular wall.
  • described herein is a method of treating a solid tumor in an individual in need thereof which comprises administering a combination of abexinostat HC1, abexinostat tosylate, or combinations thereof, and an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS
  • the immune checkpoint inhibitor is an inhibitor of PD-L1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some
  • the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the solid tumor is prostate cancer.
  • the solid tumor is breast cancer.
  • the solid tumor is lung cancer.
  • the solid tumor is colorectal (colon) cancer.
  • the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.
  • described herein is a method of treating a solid tumor in an individual in need thereof which comprises administering a combination of abexinostat or a salt thereof and an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of PD-L1.
  • the immune checkpoint inhibitor is an inhibitor of PD-1.
  • the immune checkpoint inhibitor is an inhibitor of CTLA-4.
  • the immune checkpoint inhibitor is an inhibitor of LAG3.
  • the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma,
  • the solid tumor is prostate cancer.
  • the solid tumor is breast cancer.
  • the solid tumor is lung cancer.
  • the solid tumor is colorectal (colon) cancer.
  • the solid tumor is gastroenterological cancer.
  • the solid tumor is melanoma.
  • the solid tumor is lung cancer.
  • the solid tumor is kidney cancer.
  • the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.
  • described herein is a method of treating a pancreatic cancer in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • described herein is a method of treating a pancreatic cancer in an individual in need thereof which comprises administering a combination of abexinostat or a salt thereof and an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, ⁇ 3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of TIM3.
  • a cancer is a treatment-naive cancer.
  • a treatment-naive cancer is a cancer that has not been treated by a therapy, such as for example by an HDAC inhibitor, an immune checkpoint inhibitor, and/or by an additional therapeutic agent disclosed elsewhere herein.
  • a treatment-naive cancer is a solid tumor.
  • a treatment-naive solid tumor is a solid tumor such as bladder, breast, colon, pancreatic, lung, prostate, ovarian, proximal or distal bile duct cancer, or melanoma.
  • described herein is a method of treating a treatment-naive solid tumor in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations thereof.
  • PD-Ll also known as B7-H1, CD274
  • PD-1 Programmed Death 1
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the solid tumor is a relapsed or refractory solid tumor.
  • the relapsed or refractory solid tumor is a sarcoma or carcinoma.
  • the relapsed or refractory solid tumor is a sarcoma.
  • the relapsed or refractory solid tumor is a carcinoma.
  • the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma;
  • angiosarcoma chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;
  • esthesioneuroblastoma Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;
  • hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
  • mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;
  • neoplasms with perivascular epitheioid cell differentiation osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;
  • the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
  • the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer.
  • the carcinoma is breast cancer.
  • the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
  • the carcinoma is pancreatic cancer.
  • the pancreatic cancer is adenocarcinoma, or islet cell carcinoma.
  • the carcinoma is colorectal (colon) cancer.
  • the colorectal cancer is adenocarcinoma.
  • the solid tumor is a colon polyp.
  • the colon polyp is associated with familial adenomatous polyposis.
  • the carcinoma is bladder cancer.
  • the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma.
  • the carcinoma is lung cancer.
  • the lung cancer is a non-small cell lung cancer.
  • the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
  • the lung cancer is a small cell lung cancer.
  • the carcinoma is prostate cancer.
  • the prostate cancer is adenocarcinoma or small cell carcinoma.
  • the carcinoma is ovarian cancer.
  • the ovarian cancer is epithelial ovarian cancer.
  • the carcinoma is bile duct cancer.
  • the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
  • the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer,
  • leiomyosarcoma lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the relapsed or refractory solid tumor is prostate cancer. In some embodiments, the relapsed or refractory solid tumor is breast cancer. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer.
  • the relapsed or refractory solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.
  • the relapsed or refractory solid tumor is a relapsed or refractory breast cancer.
  • the relapsed or refractory breast cancer is ductal carcinoma in situ (intraductal carcinoma), lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, Paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma.
  • the invasive breast carcinoma is further categorized into subtypes.
  • the subtypes include adenoid cystic (or adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma or mixed carcinoma.
  • the relapsed or refractory solid tumor is a relapsed or refractory colon cancer.
  • the relapsed or refractory colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, squamous cell-carcinoma, mucinous adenocarcinoma, or Signet ring cell adenocarcinoma.
  • described herein is a method of treating a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the individual has relapsed or has developed a refractory solid tumor to an existing therapy.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations thereof.
  • PD-Ll also known as B7-H1, CD274
  • PD-1 Programmed Death 1
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma.
  • the relapsed or refractory solid tumor is prostate cancer.
  • the relapsed or refractory solid tumor is breast cancer.
  • the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is
  • the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma.
  • the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.
  • described herein is a method of treating a relapsed or refractory pancreatic cancer in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the abexinostat or a salt thereof is abexinostat HC1. In some embodiments, the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations thereof.
  • PD-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the solid tumor is a metastasized solid tumor.
  • the metastasized solid tumor is a sarcoma or carcinoma.
  • the metastasized solid tumor is a sarcoma.
  • the metastasized solid tumor is a carcinoma.
  • the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma;
  • chondrosarcoma chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;
  • esthesioneuroblastoma Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;
  • hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
  • mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;
  • neoplasms with perivascular epitheioid cell differentiation osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;
  • the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
  • the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer.
  • the carcinoma is breast cancer.
  • the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
  • the carcinoma is pancreatic cancer.
  • the pancreatic cancer is adenocarcinoma, or islet cell carcinoma.
  • the carcinoma is colorectal (colon) cancer.
  • the colorectal cancer is adenocarcinoma.
  • the solid tumor is a colon polyp.
  • the colon polyp is associated with familial adenomatous polyposis.
  • the carcinoma is bladder cancer.
  • the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma.
  • the carcinoma is lung cancer.
  • the lung cancer is a non-small cell lung cancer.
  • the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
  • the lung cancer is a small cell lung cancer.
  • the carcinoma is prostate cancer.
  • the prostate cancer is adenocarcinoma or small cell carcinoma.
  • the carcinoma is ovarian cancer.
  • the ovarian cancer is epithelial ovarian cancer.
  • the carcinoma is bile duct cancer.
  • the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
  • the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.
  • the metastasized solid tumor is breast cancer.
  • the metastasized solid tumor is lung cancer.
  • the metastasized solid tumor is ovarian cancer.
  • the metastasized solid tumor is prostate cancer.
  • the metastasized solid tumor is genitourinary tract cancer. In some embodiments, the metastasized solid tumor is osteosarcoma. In some embodiments, the metastasized solid tumor is leiomyosarcoma. In some embodiments, the metastasized solid tumor is malignant fibrous histiocytoma. In some embodiments, the metastasized solid tumor is alveolar soft part sarcoma. In some
  • the metastasized solid tumor is Ewing's bone sarcomas. In some embodiments, the metastasized solid tumor is melanoma. In some embodiments, the metastasized solid tumor is head and neck cancer. In some embodiments, the metastasized solid tumor is kidney cancer. In some embodiments, the metastasized solid tumor is colorectal cancer. In some embodiments, the metastasized solid tumor is pancreatic cancer. In some embodiments, the metastasized solid tumor is neuroblastoma.
  • a method of treating a metastasized solid tumor in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations thereof.
  • PD-Ll also known as B7-H1, CD274
  • PD-1 Programmed Death 1
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments,
  • the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.
  • a method of treating a hematologic cancer in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the hematologic cancer is leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • the hematologic cancer is a T-cell malignancy.
  • the T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T- cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, or treatment-related T-cell lymphomas.
  • the hematologic cancer is not a T-cell malignancy.
  • the hematologic cancer is a B-cell proliferative disorder.
  • the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • high risk CLL or a non-CLL/SLL lymphoma.
  • the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • FL follicular lymphom
  • DLBCL is further divided into subtypes: activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL.
  • ABC- DLBCL is characterized by a CD79B mutation.
  • ABC-DLBCL is characterized by a CD79A mutation.
  • the ABC-DLBCL is
  • the cancer is acute or chronic myelogenous (or myeloid) leukemia
  • myelodysplastic syndrome or acute lymphoblastic leukemia.
  • the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC- DLBCL). In some embodiments, the cancer is follicular lymphoma (FL). In some
  • the cancer is multiple myeloma.
  • the cancer is chronic lymphocytic leukemia (CLL).
  • the cancer is small lymphocytic lymphoma (SLL).
  • the cancer is non-CLL/SLL lymphoma.
  • the cancer is high risk CLL or high risk SLL.
  • the hematological cancer is not a B-cell proliferative disorder. [00163]
  • described herein is a method of treating a hematologic cancer in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1. In some embodiments, the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidyls), phosphatidyl
  • the immune checkpoint inhibitor is an inhibitor of PD-L1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some
  • the immune checkpoint inhibitor is an inhibitor of TIM3.
  • the hematologic cancer is leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy.
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (CLL), small
  • the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.
  • the hematologic cancer is a relapsed or refractory
  • the relapsed or refractory hematologic cancer is leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, T- cell malignancy, or a B-cell malignancy.
  • the relapsed or refractory hematologic cancer is a T-cell malignancy.
  • the relapsed or refractory T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell
  • leukemia/lymphoma ATLL
  • blastic K-cell lymphoma enteropathy -type T-cell lymphoma
  • hematosplenic gamma-delta T-cell lymphoma hematosplenic gamma-delta T-cell lymphoma
  • lymphoblastic lymphoma nasal K/T-cell lymphomas, or treatment-related T-cell lymphomas.
  • the relapsed or refractory hematologic cancer is a B-cell proliferative disorder.
  • the relapsed or refractory cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non- CLL/SLL lymphoma.
  • the cancer is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's
  • macroglobulinemia multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • PMBL primary mediastinal B-cell lymphoma
  • immunoblastic large cell lymphoma precursor B-lymphoblastic lymphoma
  • B cell prolymphocytic leukemia lymphoplasmacy
  • the relapsed or refractory DLBCL is further divided into subtypes: activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL.
  • ABC- DLBCL is characterized by a CD79B mutation.
  • ABC-DLBCL is characterized by a CD79A mutation.
  • the ABC-DLBCL is
  • the cancer is acute or chronic myelogenous (or myeloid) leukemia
  • the cancer is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is relapsed or refractory activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the cancer is relapsed or refractory follicular lymphoma (FL). In some embodiments, the cancer is relapsed or refractory multiple myeloma. In some embodiments, the cancer is relapsed or refractory chronic lymphocytic leukemia (CLL).
  • DLBCL diffuse large B-cell lymphoma
  • ABS-DLBCL activated B- cell diffuse large B-cell lymphoma
  • FL refractory follicular lymphoma
  • the cancer is relapsed or refractory multiple myeloma. In some embodiments, the cancer is relapsed or refractory chronic lymphocytic leukemia (CLL).
  • the cancer is relapsed or refractory small lymphocytic lymphoma (SLL). In some embodiments, the cancer is relapsed or refractory non-CLL/SLL lymphoma. In some embodiments, the cancer is relapsed or refractory high risk CLL or high risk SLL.
  • SLL small lymphocytic lymphoma
  • a method of treating a relapsed or refractory hematologic cancer in an individual in need thereof which comprises administering a combination of an HDAC inhibitor and an immune checkpoint inhibitor.
  • the individual has relapsed or has developed a refractory hematologic cancer to an existing therapy.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HCl.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations thereof.
  • PD-Ll also known as B7-H1, CD274
  • PD-1 Programmed Death 1
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of ⁇ 3. In some embodiments, the relapsed or refractory hematologic cancer is leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • the relapsed or refractory hematologic cancer is a relapsed or refractory B-cell malignancy.
  • the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell proly
  • CLL chronic lympho
  • the relapsed or refractory hematologic cancer is relapsed or refractory CLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory SLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory DLBCL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory mantle cell lymphoma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory FL.
  • the relapsed or refractory hematologic cancer is relapsed or refractory Waldenstrom's macroglobulinemia. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory multiple myeloma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Burkitt's lymphoma.
  • the hematologic cancer is a metastasized hematologic cancer.
  • the metastasized hematologic cancer is leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.
  • the metastasized hematologic cancer is a T-cell malignancy.
  • the T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal K/T-cell lymphomas, or treatment-related T- cell lymphomas.
  • PTCL-NOS peripheral T-cell lymphoma not otherwise specified
  • anaplastic large cell lymphoma angioimmunoblastic lymphoma
  • ATLL adult T-cell leukemia/lymphoma
  • blastic K-cell lymphoma enteropathy-type T-cell lymphoma
  • the metastasized hematologic cancer is a B-cell proliferative disorder.
  • the metastasized hematologic cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
  • the metastasized hematologic cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • FL
  • DLBCL is further divided into subtypes: activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL.
  • ABC-DLBCL is characterized by a CD79B mutation.
  • ABC-DLBCL is characterized by a CD79A mutation.
  • the ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof.
  • the cancer is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia.
  • the metastasized hematologic cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the metastasized hematologic cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the metastasized hematologic cancer is follicular lymphoma (FL). In some embodiments, the metastasized hematologic cancer is multiple myeloma. In some embodiments, the
  • metastasized hematologic cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the metastasized hematologic cancer is small lymphocytic lymphoma (SLL). In some embodiments, the metastasized hematologic cancer is non-CLL/SLL lymphoma. In some embodiments, the metastasized hematologic cancer is high risk CLL or high risk SLL.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • the metastasized hematologic cancer is non-CLL/SLL lymphoma. In some embodiments, the metastasized hematologic cancer is high risk CLL or high risk SLL.
  • described herein is a method of treating a metastasized hematologic cancer in an individual in need thereof which comprises administering a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the abexinostat or a salt thereof is abexinostat HC1. In some embodiments, the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations thereof.
  • PD-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of TIM3. In some embodiments,
  • the metastasized hematologic cancer is leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the metastasized hematologic cancer is a metastasized B- cell malignancy.
  • the metastasized B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non- CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, medias
  • CLL
  • the metastasized hematologic cancer is metastasized CLL. In some embodiments, the metastasized hematologic cancer is metastasized SLL. In some embodiments, the metastasized hematologic cancer is metastasized DLBCL. In some embodiments, the metastasized hematologic cancer is metastasized mantle cell lymphoma. In some embodiments, the metastasized hematologic cancer is metastasized FL. In some embodiments, the metastasized hematologic cancer is metastasized Waldenstrom's macroglobulinemia. In some embodiments, the metastasized hematologic cancer is metastasized multiple myeloma. In some embodiments, the metastasized hematologic cancer is metastasized Burkitt's lymphoma.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of cancer.
  • the additional therapeutic agent is an anticancer agent for the treatment of a solid tumor.
  • the additional therapeutic agent is an anticancer agent for the treatment of a hematologic cancer.
  • the additional anticancer agent is an anticancer agent for the treatment of a B-cell malignancy, such as CLL, SLL, DLBCL, mantle cell lymphoma, or Waldenstrom's macroglobulinemia.
  • the additional anticancer agent is an anticancer agent for the treatment of a solid tumor such as bladder, breast, colon, pancreatic, lung, prostate, ovarian, proximal or distal bile duct cancer, or melanoma.
  • anticancer agent include chemotherapeutic agents, biologic agents, radiation therapy, thermal therapy, or surgery.
  • the HDAC inhibitor is abexinostat or salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCN1, or any combinations thereof.
  • PD-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • the additional therapeutic agent is a BTK inhibitor, such as ibrutinib.
  • a BTK inhibitor such as ibrutinib.
  • an HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor can be administered in combination with a BTK inhibitor (e.g., ibrutinib) for the treatment of cancer (e.g., a solid tumor or a hematological
  • a HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor such as for example irinotecan, cisplatin, carboplatin, methotrexate, etoposide, bleomycin, vinblastine, actinomycin (dactinomycin), cyclophosphamide, ifosfamide, gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-Allylamino-17-Deme
  • an anticancer agent such as for example irinotecan,
  • a HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor are administered in combination with an anticancer agent such as for example inhibitors of mitogen-activated protein kinase signaling, e.g., U0126,
  • a HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor such as for example adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin;
  • aclarubicin acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;
  • ambomycin ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;
  • bicalutamide bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil;
  • cirolemycin cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate;
  • etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; benzrabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride;
  • metoprine meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an anticancer agent such as for example 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox;
  • an anticancer agent such as for example 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox;
  • amifostine aminolevulinic acid
  • amrubicin amsacrine
  • anagrelide anastrozole
  • antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
  • azatyrosine baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;
  • benzochlorins benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;
  • calcipotriol calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine;
  • carboxamide-amino-triazole carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;
  • combretastatin analogue conagenin; crambescidin 816; crisnatol; cryptophycin 8;
  • cryptophycin A derivatives curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;
  • didemnin B didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;
  • leuprolide+estrogen+progesterone leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;
  • lurtotecan lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;
  • mifepristone miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N- acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neri
  • nitrullyn 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;
  • oligonucleotides include signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;
  • spiromustine splenopentin
  • spongistatin 1 squalamine
  • stem cell inhibitor stem-cell division inhibitors
  • stipiamide stem-cell division inhibitors
  • stromelysin inhibitors sulfinosine
  • superactive vasoactive intestinal peptide antagonist suradista; suramin; swainsonine; synthetic glycosaminoglycans;
  • tallimustine tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;
  • thrombopoietin mimetic thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine;
  • triciribine trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;
  • tyrphostins UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an anticancer agent such as for example alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g.,
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, lomusitne, etc.
  • triazenes decarbazine, etc.
  • antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an anticancer agent such as for example vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha, IL-2, IL-21).
  • an anticancer agent such as for example vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha, IL-2, IL-21).
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an anticancer agent such as for example nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • alkyl sulfonates e.
  • antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine,
  • Cytarabine purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an anticancer agent such as for example
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
  • estrogens e.g., diethlystilbestrol, ethinyl estradiol
  • antiestrogen e.g., tamoxifen
  • androgens e.g., testosterone propionate, fluoxymesterone
  • antiandrogen e.g., flutamide
  • gonadotropin releasing hormone analog e.g., leuprolide
  • platinum coordination complexes e.g., cisplatin, carboblatin
  • anthracenedione e.g., mitoxantrone
  • substituted urea e.g., hydroxyurea
  • methyl hydrazine derivative e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an anticancer agent such as for example thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150), factor Vila inhibitors, ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048.
  • an anticancer agent such as for example thrombolytic agents (e.g., alteplase anistreplase, streptokinas
  • dexamethasone high-dose cytarabine, (Ara C), cisplatin), ESHAP (etoposide (VP- 16), methyl-prednisolone, and high-dose cytarabine (Ara-C), cisplatin), CDE (cyclophosphamide, doxorubicin and etoposide), Velcade® (bortezomib) plus Doxil® (liposomal doxorubicin), Revlimid® (lenalidomide) plus dexamethasone, and bortezomib plus dexamethasone.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an anticancer agent such as for example a cancer vaccine.
  • a cancer vaccine is a peptide-based vaccine, a nucleic acid based vaccine, a cell-based vaccine, a virus-based or viral fragment based vaccine, an antibody or antibody fragment based vaccine, or an antigen presenting cell (APC) based vaccine (e.g. dendritic cell based vaccine).
  • APC antigen presenting cell
  • Exemplary cancer vaccines include Gardasil®, Cervarix®, sipuleucel-T (Provenge®), NeuVaxTM, HER-2 ICD peptide-based vaccine, HER-2/neu peptide vaccine, AdHER2/neu dendritic cell vaccine, HER-2 pulsed DC1 vaccine, Ad-sig-hMUC- l/ecdCD40L fusion protein vaccine, MVX-ONCO-1, hTERT/survivin/CMV multipeptide vaccine, E39, J65, PlOs-PADRE, rV-CEA-Tricom, GVAX®, Lucanix®, HER2 VRP, AVX901, ONT-10, ISA101, ADXS11-001, VGX-3100, INO-9012, GSK1437173A, BPX- 501, AGS-003, IDC-G305, HyperAcute®-Renal (HAR) immunotherapy, Prevenarl3, MAGER-3.A1, NA17.A2, DCVax
  • NCT02193503, Maxivax SA ITL-007-ATCR-MBC
  • NCT01741038, Immunovative Therapies, Limited CDR0000644921 (NCT00923143, Abramson cancer center of the University of Pennsylvania), SuMo-Sec-01 (NCT00108875, Julius Maximilians Universitaet Hospital), or MCC-15651 (NCT01176474, Medarex, Inc, BMS).
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional anticancer agent or therapy for the treatment of cancer.
  • the additional therapy for the treatment of cancer is selected from among administration of a chemotherapeutic agent, a biologic agent, radiation therapy, bone marrow transplant or surgery.
  • the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof
  • a HDAC inhibitor is administered in combination with one or more immune checkpoint inhibitors. In some embodiments, a HDAC inhibitor is administered in combination with at least two immune checkpoint inhibitors.
  • the immune checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a breast cancer.
  • therapeutic agents for the treatment of breast cancer include, but are not limited to, ado-trastuzumab emtansine (Kadcyla), anastrozole (Arimidex), capecitabine (Xeloda), cyclophosphamide (Clafen, Cytoxan, Neosar), docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin PFS, Adriamycin RDF), epirubicin hydrochloride (Ellence), everolimus, exemestane (Aromasin), fluorouracil (Efudex, Fluoroplex), fulvestrant
  • the additional therapeutic agent is a BTK inhibitor (e.g., ibrutinib).
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are administered in combination with ado-trastuzumab emtansine (Kadcyla), anastrozole (Arimidex), capecitabine (Xeloda), cyclophosphamide (Clafen, Cytoxan, Neosar), docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin PFS, Adriamycin RDF), epirubicin hydrochloride (Ellence), everolimus, exemestane (Aromasin), fluorouracil (Efudex, Fluoroplex), fulvestrant (Faslodex), gemcitabine hydrochloride (Gemzar), goserelin acetate (Zoladex), ixabepilone (Ixempra), lapatinib ditosylate (Tykerb), let
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered sequentially,
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a colon cancer.
  • exemplary therapeutic agents for the treatment of colon cancer include, but are not limited to, capecitabine (e.g. Xeloda), cetuximab (e.g. Erbitux), bevacizumab (e.g. Avastin), fluorouracil (e.g. Adrucil, Efudex, Fluoroplex), irinotecan hydrochloride (e.g. Camptosar), leucovorin calcium (e.g. Wellcovorin), oxaliplatin (e.g. Eloxatin), panitumumab (e.g.
  • Vectibix Vectibix
  • regorafenib e.g. Stivarga
  • ziv-aflibercept e.g. Zaltrap
  • CAPOX capecitabine and oxaliplatin
  • FOLFIRI leucovorin calcium, fluorouracil, and irinotecan hydrochloride
  • FOLFIRI-BE V ACIZUM AB FOLFIRI-CETUXIMAB
  • FOLFOX leucovorin calcium, fluorouracil, and oxaliplatin
  • XELOX capecitabine and oxaliplatin
  • the additional therapeutic agent is a BTK inhibitor (e.g., ibrutinib).
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered in combination with capecitabine (e.g. Xeloda), cetuximab (e.g. Erbitux), bevacizumab (e.g. Avastin), fluorouracil (e.g. Adrucil, Efudex, Fluoroplex), irinotecan hydrochloride (e.g. Camptosar), leucovorin calcium (e.g. Wellcovorin), oxaliplatin (e.g. Eloxatin), panitumumab (e.g. Vectibix), regorafenib (e.g.
  • capecitabine e.g. Xeloda
  • cetuximab e.g. Erbitux
  • bevacizumab e.g. Avastin
  • fluorouracil e.g. Adrucil, Efudex, Fluoroplex
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a bladder cancer.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a bladder cancer.
  • exemplary therapeutic agents for the treatment of bladder cancer include, but are not limited to, doxorubicin hydrochloride (Adriamycin PFS/RDF), cisplatin, mitomycin, fluorouracil, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, docetaxel, thiotepa (Thioplex, Tepadina), immunotherapeutic agents (e.g. Bacille Calmette-Guerin, interferon alfa-2b), and radiation therapeutic agents.
  • the additional therapeutic agent is a BTK inhibitor (e.g., ibrutinib).
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are administered in combination with doxorubicin hydrochloride (Adriamycin PFS/RDF), cisplatin, mitomycin, fluorouracil, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, docetaxel, thiotepa (Thioplex, Tepadina), immunotherapeutic agents (e.g. Bacille Calmette-Guerin, interferon alfa-2b), and radiation therapeutic agents.
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a bladder cancer.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a colon cancer.
  • exemplary therapeutic agents for the treatment of colon cancer include, but are not limited to, fluorouracil (Adrucil), bevacizumab (Avastin), irinotecan hydrochloride
  • the additional therapeutic agent is a BTK inhibitor (e.g., ibrutinib).
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered in combination with fluorouracil (Adrucil), bevacizumab
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a colon cancer.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a lung cancer.
  • exemplary therapeutic agents for the treatment of lung cancer include, but are not limited to, Adriamycin IV, Rheumatrex, Mustargen, methotrexate (Abitrexate), Abraxane, afatinib dimaleate (Gilotrif), pemetrexed disodium (Alimta), bevacixumab, carboplatin, cisplatin, crizotinib, erlotinib hydrochloride, Etopophos (etoposide phosphate), Folex, Folex PFS, gefitinib (Iressa), gemcitabine hydrochloride (Gemzar), topotecan hydrochloride (Hycamtin), Methotrexate LPF, Mexate, Mexate-AQ, paclitaxel, Paraplat, Paraplatin, Platinol, Platinol, Platinol,
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are administered in combination with Adriamycin IV, Rheumatrex, Mustargen, methotrexate (Abitrexate), Abraxane, afatinib dimaleate (Gilotrif), pemetrexed disodium (Alimta), bevacixumab, carboplatin, cisplatin, crizotinib, erlotinib hydrochloride, Etopophos (etoposide phosphate), Folex, Folex PFS, gefitinib (Iressa), gemcitabine hydrochloride (Gemzar), topotecan hydrochloride (Hycamtin), Methotrexate LPF, Mexate, Mexate-AQ, paclitaxel, Paraplat, Paraplatin, Platinol, Platinol-AQ, Tarceva, Taxol, Xalkori, Toposar, VePesi
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a lung cancer.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of an ovarian cancer.
  • Exemplary therapeutic agents for the treatment of ovarian cancer include, but are not limited to, doxorubicin hydrochloride (Adriamycin PFS/RDF), carboplatin, cyclophosphamide (Clafen), cisplatin, Cytoxan, Dox-SL, DOXIL, doxorubicin hydrochloride liposome (Evacet), gemcitabine hydrochloride (Gemzar), topotecan hydrochloride
  • the additional therapeutic agent is a BTK inhibitor (e.g., ibrutinib).
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are administered in combination with doxorubicin hydrochloride (Adriamycin PFS/RDF), carboplatin, cyclophosphamide (Clafen), cisplatin, Cytoxan, Dox-SL, DOXIL, doxorubicin hydrochloride liposome (Evacet), gemcitabine hydrochloride (Gemzar), topotecan hydrochloride (Hycamtin), Neosar, Paclitaxel, Paraplat, Paraplatin, Platinol, Platinol-AQ, Taxol and BEP.
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of an ovarian cancer.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a pancreatic cancer.
  • additional therapeutic agent for the treatment of pancreatic cancer include, but are not limited to, Adriamycin PFS IV, Adrucil, Efudex, erlotinib hydrochloride, Fluoroplex, fluorouracil, gemcitabine hydrochloride (Gemzar), mitomycin C, Tarceva, Oxaliplatin paclitaxel-protein bound IV, and capecitabine.
  • the additional therapeutic agent is a BTK inhibitor (e.g., ibrutinib).
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered in combination with Adriamycin PFS IV, Adrucil, Efudex, erlotinib hydrochloride, Fluoroplex, fluorouracil, gemcitabine hydrochloride (Gemzar), mitomycin C, Tarceva, Oxaliplatin paclitaxel-protein bound IV, and capecitabine.
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a pancreatic cancer.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a prostate cancer.
  • additional therapeutic agents for the treatment of prostate cancer include, but are not limited to, abiraterone acetate, cabazitaxel, degarelix, docetaxel, enzalutamide, leuprolide acetate, prednisone, denosumab, sipuleucel-T, abraxane and gemzar, and radium 223 dichloride.
  • the additional therapeutic agent is a BTK inhibitor (e.g., ibrutinib).
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered in combination with abiraterone acetate, cabazitaxel, degarelix, docetaxel, enzalutamide, leuprolide acetate, prednisone, denosumab, sipuleucel-T, abraxane and gemzar, and radium 223 dichloride.
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a prostate cancer.
  • a HDAC inhibitor, and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a proximal or distal bile duct cancer.
  • additional therapeutic agent for the treatment of proximal or distal bile duct cancer include, but are not limited to, cisplatin, gemcitabine, fluorouracil, and doxorubicin.
  • the additional therapeutic agent is a BTK inhibitor (e.g., ibrutinib).
  • abexinostat or a salt thereof, and an immune checkpoint inhibitor are administered in combination with cisplatin, gemcitabine, fluorouracil, and doxorubicin.
  • abexinostat or a salt thereof and an immune checkpoint inhibitor are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a proximal or distal bile duct cancer.
  • Pathogenic infections can contribute to about 15-20% of human cancers.
  • pathogens e.g. virus
  • pathogens can encode proteins that can modulate host cellular signaling pathways that control proliferation, differentiation, cell death, genomic integrity, and/or the immune system.
  • a pathogen inserts its viral genes into a host cell to enhance already existing oncogenic genes in the genome.
  • a pathogen exerts chronic nonspecific inflammations in the host which leads to development of cancer.
  • a method of treating an infection in an individual in need thereof which comprises administering a combination of a HDAC inhibitor (e.g., abexinostat or a salt thereof) and an immune checkpoint inhibitor.
  • a HDAC inhibitor e.g., abexinostat or a salt thereof
  • the infection is a chronic infection.
  • the infections include, but are not limited to, infections caused by a virus, bacterium, parasite, protozoan, or fungus.
  • the pathogen is a cancer-associated pathogen.
  • the cancer-associated pathogen is any pathogen that can either directly or indirectly cause or induce cancer, or pathogens that are opportunistic.
  • the cancer -associated pathogen is a cancer-inducing pathogen.
  • "indirectly" refers to the byproduct of a pathogen, such as, for example, an inflammation caused by the pathogen, or such as toxins produced by the pathogen that can lead to cancer.
  • the infection is caused by a virus.
  • the virus is a DNA virus or an RNA virus.
  • the DNA virus is a single- stranded (ss) DNA virus, a double-stranded (ds) DNA virus, or a DNA virus that contains both ss and ds DNA regions.
  • an RNA virus is a single-stranded (ss) RNA virus or a double-stranded (ds) RNA virus.
  • a ssRNA virus is further classified into a positive-sense RNA virus or a negative-sense RNA virus.
  • Exemplary dsDNA viruses include families from: Myoviridae, Podoviridae,
  • Siphoviridae Alloherpesviridae, Herpesviridae, Malacoherpesviridae, Lipothrixviridae, Rudiviridae, Adenoviridae, Ampullaviridae, Ascoviridae, Asfaviridae, Baculoviridae, Bicaudaviridae, Clavaviridae, Corticoviridae, Fuselloviridae, Globuloviridae, Guttaviridae, Hytrosaviridae, Iridoviridae, Marseilleviridae, Mimiviridae, Nimaviridae, Pandoraviridae, Papillomaviridae, Phycodnaviridae, Plasmaviridae, Polydnaviruses, Polyomaviridae, Poxviridae, Sphaerolipoviridae, and Tectiviridae.
  • Exemplary ssDNA viruses include families from: Anelloviridae,
  • An exemplary DNA virus that contains both ss and ds DNA regions is from the group of pleolipoviruses.
  • the pleolipoviruses include Haloarcula hispanica pleomorphic virus 1, Halogeometricum pleomorphic virus 1, Halorubrum pleomorphic virus 1, Halorubrum pleomorphic virus 2, Halorubrum pleomorphic virus 3, and Halorubrum pleomorphic virus 6.
  • Exemplary dsRNA viruses include families from: Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae, Hypoviridae, Megavirnaviridae, Partitiviridae,
  • Exemplary positive-sense ssRNA viruses include families from:
  • Alphaflexiviridae Alphatetraviridae, Alvernaviridae, Arteriviridae, Astroviridae,
  • Closteroviridae Coronaviridae, Dicistroviridae, Flavivindae, Gammaflexiviridae, Iflaviridae, Leviviridae, Luteoviridae, Marnaviridae, Mesoniviridae, Narnaviridae, Nodaviridae, Permutotetraviridae, Picornaviridae, Potyviridae, Roniviridae, Secoviridae, Togaviridae, Tombusviridae, Tymoviridae, and Virgaviridae.
  • Exemplary negative-sense ssRNA viruses include families from: Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Nyamiviridae, Arenaviridae, Bunyaviridae, Ophioviridae, and Orthomyxoviridae.
  • Exemplary viruses include, but are not limited to: Abelson leukemia virus,
  • Abelson murine leukemia virus Abelson's virus, Acute laryngotracheobronchitis virus, Sydney River virus, Adeno associated virus group, Adenovirus, African horse sickness virus, African swine fever virus, AIDS virus, Aleutian mink disease parvovirus,
  • alphaherpesvirus 2 bovine coronavirus, bovine ephemeral fever virus, bovine
  • bovine leukemia virus bovine leukosis virus
  • bovine mammillitis virus bovine papillomavirus
  • bovine papular stomatitis virus bovine parvovirus
  • bovine syncytial virus bovine type C oncovirus
  • bovine viral diarrhea virus Buggy Creek virus, bullet shaped virus group
  • Bunyamwera virus supergroup Bunyavirus, Burkitt's lymphoma virus, Bwamba Fever, CA virus, Calicivirus, California encephalitis virus, camelpox virus, canarypox virus, canid herpesvirus, canine coronavirus, canine distemper virus, canine herpesvirus, canine minute virus, canine parvovirus, Cano Delgadito virus, caprine arthritis virus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus, Cardiovirus, caviid herpesvirus 1, Cercopithecid herpesvirus 1, cercopithecine her
  • Cytomegalovims cytomegalovims group, cytoplasmic polyhedrosis vims, deer
  • papillomavirus deltaretrovims, dengue vims, Densovims, Dependovims, Dhori vims, diploma vims, Drosophila C vims, duck hepatitis B vims, duck hepatitis vims 1, duck hepatitis vims 2, duovims, Duvenhage vims, Deformed wing vims DWV, eastern equine encephalitis vims, eastern equine encephalomyelitis vims, EB vims, Ebola vims, Ebola-like vims, echo vims, echovims, echovims 10, echovims 28, echovims 9, ectromelia vims, EEE vims, EIA vims, EIA vims, encephalitis vims, encephalomyocarditis group vims, encephalomyocarditis vims, Enterovims, enzyme
  • hepatoencephalomyelitis reovims 3 Hepatovims, heron hepatitis B vims, herpes B vims, herpes simplex vims, herpes simplex vims 1, herpes simplex vims 2, herpesvims, herpesvims 7, Herpesvims ateles, Herpesvims hominis, Herpesvims infection, Herpesvirus saimiri, Herpesvirus suis, Herpesvirus varicellae, Highlands J virus, Hirame rhabdovirus, hog cholera virus, human adenovirus 2, human alphaherpesvirus 1, human alphaherpesvirus 2, human alphaherpesvirus 3, human B lymphotropic virus, human betaherpesvirus 5, human coronavirus, human cytomegalovirus group, human foamy virus, human gammaherpesvirus 4, human gammaherpesvirus 6, human hepatitis
  • simian T cell lymphotrophic virus simian virus, simian virus 40, Simplexvirus, Sin Nombre virus, Sindbis virus, smallpox virus, South American hemorrhagic fever viruses, sparrowpox virus, Spumavirus, squirrel fibroma virus, squirrel monkey retrovirus, SSV 1 virus group, STLV (simian T lymphotropic virus) type I, STLV (simian T lymphotropic virus) type II, STLV (simian T lymphotropic virus) type III, stomatitis papulosa virus, submaxillary virus, suid alphaherpesvirus 1, suid herpesvirus 2, Suipoxvirus, swamp fever virus, swinepox virus, Swiss mouse leukemia virus, TAC virus, Tacaribe complex virus, Tacaribe virus, Tanapox virus, Taterapox virus, Tench reovirus, Theiler's
  • encephalomyelitis virus Theiler's virus, Thogoto virus, Thottapalayam virus, Tick borne encephalitis virus, Tioman virus, Togavirus, Torovirus, tumor virus, Tupaia virus, turkey rhinotracheitis virus, turkeypox virus, type C retroviruses, type D oncovirus, type D retrovirus group, ulcerative disease rhabdovirus, Una virus, Uukuniemi virus group, vaccinia virus, vacuolating virus, varicella zoster virus, Varicellovirus, Varicola virus, variola major virus, variola virus, Vasin Gishu disease virus, VEE virus, Venezuelan equine encephalitis virus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagic fever virus, vesicular stomatitis virus, Vesiculovirus, Vilyuisk virus, viper retrovirus, viral haemorrhagic septicemia virus, Visna Ma
  • a virus is a cancer-associated virus.
  • cancer-associated viruses include, but are not limited to, human T-cell leukemia virus (HTLV-1), hepatitis C virus (HCV), hepatitis B virus (HBV), human papillomavirus (HPV), Epstein- Barr Virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV)/Human Herpes Virus 8 (HHV8), human immunodeficiency virus (HIV), and influenza.
  • HTLV-1 human T-cell leukemia virus
  • HCV hepatitis C virus
  • HBV hepatitis B virus
  • HPV human papillomavirus
  • HPV Epstein- Barr Virus
  • KSHV Kaposi's sarcoma-associated herpesvirus
  • HHV8 Human Herpes Virus 8
  • HAV human immunodeficiency virus
  • a cancer-associated pathogen is a bacterium, a fungus, a parasite, or a protozoan.
  • bacteria include: Helicobacter pyloris, Borelia burgdorferi, Legionella pneumophilia, Mycobacteria spp. (e.g., M. tuberculosis, M. avium, M.
  • Streptococcus Streptococcus
  • Streptococcus agalactiae Group B Streptococcus
  • Streptococcus viridans group
  • Streptococcus faecalis Streptococcus bovis
  • Streptococcus anaerobic spp.
  • Streptococcus pneumoniae pathogenic Campylobacter sp., Enterococcus sp., Haemophilus influenzae, Bacillus anthracis, Corynebacterium diphtheriae, Coryne bacterium sp.,
  • Erysipelothrix rhusiopathiae Clostridium perjringens, Clostridium tetani, Chlamydia trachomatis, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides sp., Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidum, Treponema per pneumonia, Leptospira, and Actinomyces israelii.
  • fungi examples include: Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Chlamydia trachomatis, Candida albicans.
  • Other infectious organisms i.e., protists
  • Plasmodium falciparum and Toxoplasma gondii examples include: Plasmodium falciparum and Toxoplasma gondii.
  • Examples of parasites include Schistosoma haematobium (squamous cell carcinoma of the bladder), Schistosoma japonicum, and liver flukes, Opisthorchis viverrini and
  • An example of protozoan includes Plasmodium (also known as malaria parasite).
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an additional therapeutic agent for the treatment of a pathogenic infection.
  • the additional therapeutic agent is a therapeutic agent for the treatment of a viral infection, a bacterial infection, a fungus infection, a parasitic infection, or a protozoan infection.
  • the therapeutic agent for treatment of a viral infection is an antiviral agent.
  • the therapeutic agent for treatment of a bacterial infection is an antibacterial agent.
  • the therapeutic agent for treatment of a fungus infection is an antifungal agent.
  • the therapeutic agent for treatment of a parasitic infection is an antiparasitic agent.
  • the therapeutic agent for treatment of a protozoan infection is an antiprotozoal agent.
  • the pathogen is a cancer-associated pathogen.
  • a HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of a viral infection.
  • antiviral agents include, but are not limited to, immunostimulants such as interferon (e.g., alpha interferons, beta interferons, gamma interferons, pegylated alpha interferons, pegylated beta interferons, pegylated gamma interferons and mixtures of any two or more thereof), granulocyte macrophage colony - stimulating factor, echinacin, isoprinosine, adjuvants, biodegradable microspheres (e.g., polylactic galactide) and liposomes (into which the compound is incorporated), and thymus factors; immunosuppressants such as cyclosporin, azatioprin, methotrexate,
  • immunostimulants such as interferon (
  • nucleoside and nucleotide antiviral agents such as abacavir, acyclovir (ACV), adefovir, zidovudine (ZDV), ribavirin, lamivudine, adefovir and entecavir, tenofovir, emtricitabine, telbuvidine, clevudine, valtorcitabine, cidofovir, and derivatives thereof; protease inhibitors such as saquinavir, riton
  • a viral infection is caused by a hepatitis virus, such as a hepatitis C virus, or a hepatitis B virus; human immunodeficiency virus (HIV), or an influenza virus such as influenza A virus, or influenza B virus.
  • a HDAC inhibitor e.g., abexinostat or a salt thereof
  • an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of a viral infection caused by such as for example, a hepatitis virus, HIV, or an influenza virus.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of a hepatitis infection, such as an infection caused by hepatitis C virus (HCV) or hepatitis B virus (HBV).
  • HCV hepatitis C virus
  • HBV hepatitis B virus
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of HIV infection.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of influenza virus infection.
  • antiviral agents for the treatment of HCV infection include, but are not limited to, interferon or interferon derivatives such as Interferon alfa-2a, Interferon alfa-2b, Peginterferon alfa-2a, Peginterferon alfa-2b, recombinant interferon alfa-2a, Sumiferon (a purified blend of natural alpha interferons), ALFERON ® (a mixture of natural alpha interferons), consensus alpha interferon, pegylated interferon lambda; nucleoside analogs such as ribavirin or its derivatives, D-ribavirin, L-ribavirin, or taribavirin; nucleoside and nucleotide NS5B polymerase inhibitors such as sofosbuvir; NS5A inhibitors such as daclatasvir, ledipasvir, ABT-267, ACH-3102, GS-5816, GS-5885, ID
  • dasatinib and AZM-475271 for the inhibition of SRC
  • imatinib for the inhibition of BCR
  • dasatinib for the inhibition of EPHA2
  • AZD-1152 for the inhibition of AURKB
  • Other examples of known kinase inhibitors include, but are not limited to, sorafenib (for the inhibition of BRAF); BMS-599626 (for the inhibition of ERBB4); PD-0332991 and flavopiridol (for the inhibition of CDK4).
  • antiviral agents for the treatment of HBV infection include, but are not limited to, interferons or interferon derivatives such as interferon alfa-2b and peginterferon alfa-2a; nucleoside analogues such as lamivudine (Epivir-HBV), adfovir dipivoxil (Hepsera), entecavir (Baraclude), telbivudine (Tyzeka/Sebivo), tenofovir (Viread), L-FMAU
  • interferons or interferon derivatives such as interferon alfa-2b and peginterferon alfa-2a
  • nucleoside analogues such as lamivudine (Epivir-HBV), adfovir dipivoxil (Hepsera), entecavir (Baraclude), telbivudine (Tyzeka/Sebivo), tenofovir (Viread),
  • Non-nucleoside antivirals such as BAM 205 (NOV-205), Myrcludex B, HAP compound Bay 41-4109, REP 9 AC, nitazoxanide (Alinia), dd-RNAi compound, ARC-520, NVR-1221 and IHVR-25; non-interferon immune enhancers such as thymosin alpha- 1 (zadaxin), interleukin-7 (CYT107), DV-601, HBV core antigen vaccine, GS-9620 and GI13000; post-exposure and/or post-liver transplant treatment such as hyperHEP S/D, Nabi-HB and Hepa Gam B; and alternative natural agents such as milk thistle.
  • non-nucleoside antivirals such as BAM 205 (NOV-205), Myrcludex B, HAP compound Bay 41-4109, REP 9 AC, nitazoxanide (Alinia), dd-RNAi compound, ARC-520, NVR-1221 and IHVR-25
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of HIV infection.
  • antiviral agents for the treatment of HIV infection include, but are not limited to, multi-class combination drugs such as atripla (efavirenz + tenofovir + emtricitabine);
  • complera eviplera, rilpivirine + tenofovir + emtricitabine
  • strisent elvitegravir + cobicistat+ tenofovir + emtricitabine
  • 572-Trii dolutegravir + abacavir + lamivudine or
  • nucleoside/nucleotide reverse transcriptase inhibitors include combivir (zidovudine + lamivudine, AZT + 3TC); emtriva (emtricitabine, FTC); epivir (lamivudine, 3TC); epzicom (Livexa, abacavir + lamivudine, ABC+3TC); retrovir
  • N RTIs non-nucleoside reverse transcriptase inhibitors
  • Ad5 gag/pol/nef HVTN 502/Merck 023
  • Ad5 gag/pol/nef HVTB 503
  • DNA-Ad5 gag/pol/nef/nev HVTN505
  • combination therapy to elicit an immune response such as pegylated interferon alfa, hydroxyurea, mycophenolate mofetil (MP A) and its ester derivative mycophenolate mofetil (MMF); ribavirin, IL-2, IL-12, polymer polyethyleneimine (PEI), or a combination thereof
  • HIV-related opportunistic infection treatments such as Co-trimoxazole
  • alternative life-style combination therapy such as acupuncture and exercise.
  • antiviral agents for the treatment of influenza virus infection include, but are not limited to, antiviral drugs such as neuraminidase inhibitors (e.g. oseltamivir, peramivir and zanamivir) and admantanes (e.g.
  • amantadine and rimantadine seasonal flu vaccines (antigens representing three (trivalent) or four (quadrivalent) influenza virus strains) such as Flumist Quadrivalent (Medlmmune, Gaithersburg, Maryland), Fluarix Quadrivalent (Glaxo Smith Kline, Research Triangle Park, North Carolina), Fluzone Quadrivalent (Sanofi Pasteur, Swiftwater, Pennsylvania), Flulaval Quadrivalent, (ID Biomedical Corporation of Quebec/GlaxoSmith Kline, Research Triangle Park, North Carolina), Flucelvax (Novartis Vaccines and Diagnostics, Cambridge, Massachusetts), and FluBlok (Protein Sciences, Meriden, Connecticut); and combination drugs for the treatment of influenza including one or more immunomodulators such as immune suppressors or enhancers and anti-inflammatory agents.
  • immunomodulators such as immune suppressors or enhancers and anti-inflammatory agents.
  • the anti-inflammatory agent can be non-steroidal, steroidal, or a combination thereof.
  • non-steroidal anti-inflammatory agents include, but are not limited to, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam; salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofen
  • steroidal antiinflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyl- triamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone,
  • corticosteroids such as hydrocortisone, hydroxyl- triamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone,
  • desoxycorticosterone acetate dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenolone acetonide, medrys
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of a human
  • HPV infection papillomavirus
  • antiviral agents for the treatment of HPV infection include, but are not limited to, podofilox or imiquimod.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of an Epstein-Bar virus (EBV) infection.
  • EBV Epstein-Bar virus
  • antiviral agents for the treatment of EBV infection include, but are not limited to, acyclovir, ganciclovir, and foscarnet.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of a human T-cell leukemia virus (HTLV-1) infection.
  • antiviral agents for the treatment of HTLV-1 include, but are not limited to, mogamulizumab, interferon alpha, zidovudine, valproic acid, arsenic trioxide, and chemotherapeutic agents such as CHOP, R-CHOP, and the like.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiviral agent for the treatment of Kaposi's sarcoma- associated herpesvirus (KSHV)/human herpes virus 8 (HHV8) infection.
  • KSHV Kaposi's sarcoma- associated herpesvirus
  • HHV8 human herpes virus 8
  • antiviral agents for the treatment of KSHV/HHV8 include, but are not limited to, ganciclovir, valganciclovir, cidofovir, and foscarnet.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antibacterial agent for the treatment of a bacterial infection.
  • antibacterial agents include, but are not limited to, aminoglycosides such as amikacin, arbekacin, bekanamycin, dibekacin, framycetin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, ribostamycin, rhodostreptomycin, spectinomycin, hygromycin B, paromomycin sulfate, sisomicin, isepamicin, verdamicin, astromicin, streptomycin, tobramycin, and apramycin; ansamycins such as geldanamycin, herbimycin, rifaximin or streptomycin; carbapenem (beta-lactam) such as Imipenem, meropenem, ertapenem,
  • Cephalonium Cefaloridine(cephaloradine), Cefalotin (cephalothin; Keflin), Cefapirin (cephapirin; Cefadryl), Cefatrizine, Cefazaflur, Cefazedone, Cefazolin (cephazolin; Ancef, Kefzol), Cefradine (cephradine; Velosef), Cefroxadine, Ceftezole Cefaclor (Ceclor, Distaclor, Keflor, Raniclor), Cefonicid (Monocid), Cefprozil (cefproxil; Cefzil), Cefuroxime (Zefu, Zinnat, Zinacef, Ceftin, Biofuroksym, Xorimax), Cefoperazone (Cefobid),Ceftazidime (Meezat,Fortum, Fortaz), Ceftobiprole, Ceftaroline; glycopeptide antibiotics such as
  • troleandomycin or tylosin
  • ketolides such as telithromycin, cethromycin, solithromycin, spiramycin, ansamycin, oleandomycin, or carbomycin
  • monobactam such as aztreonam
  • nitrofurans such as furazolidone, furylfuramide, nitrofurantoin, nitrofurazone, nifuratel, nifurquinazol, nifurtoinol, nifuroxazide or ranbezolid
  • oxazolidinones such as linezolid, posizolid, torezolid, radezolid, cycloserine, rivaroxaban or oxazolidinone and derivatives of
  • penicillins such as all natural penicillins (e.g.
  • adipyl-6-APA amoxicillin, ampicillin, butyiyl-6-APA, decanoyl-6-APA, heptanoyl-6-APA, hexanoyl-6-APA, nonanoyl-6-APA, octanoyl-6-APA, penicillin F, penicillin G, penicillin V, penicillin mX, penicillin X, 2- thiopheynlacetyl-6-APA, or valeiyl-6-APA, azlocillin, flucloxacillin, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate; polypeptides such as bacitracin, colistin or polymyxin B; quinolones such as cinoxacin, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid, roso
  • tetracycline such as naturally occurring tetracycline, chlortetracycline, oxytetracycline, demeclocycline, doxycycline, lymecycline, meclocycline, methacycline, minocycline or rolitetracycline; anti-mycobacteria agents such as clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampin (rifampicin), rifabutin, rifapentine or streptomycin.
  • anti-mycobacteria agents such as clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampin (rifampicin), rifabutin, rifapentine or strepto
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antifungal agent for the treatment of a fungal infection.
  • antifungal agents include, but are not limited to, polyene antifungals such as amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin or rimocidin; imidazoles such as bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole or tioconazole; triazoles such as albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole or voriconazole; thiazoles such as abafungal agents
  • allylamines such as amorolfin, butenafine, naftifine or terbinafine
  • echinocandins include anidulafungin, caspofungin or micafungin
  • antifungal macrolides such as polyene
  • antimycotics e.g., amphotericin B, nystatin benzoic acid); ciclopirox; flucytosine;
  • griseofulvin haloprogin; polygodial; tolnaftate; undecylenic acid; or crystal violet; and natural alternatives such as oregano, allicin, citronella oil, coconut oil, iodine, lemon myrtle, neem seed oil, olife leaf, orange oil, palmarosa oil, patchouli, selenium, tea tree oil, zinc, horopito, turnip, chives, radish and garlic.
  • oregano allicin, citronella oil, coconut oil, iodine, lemon myrtle, neem seed oil, olife leaf, orange oil, palmarosa oil, patchouli, selenium, tea tree oil, zinc, horopito, turnip, chives, radish and garlic.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiparasitic agent for the treatment of a parasitic infection.
  • antiparasitic agents include, but are not limited to, antimony-containing compounds, such as meglumine antimoniate and sodium stibogluconate, amphotericin B, ketoconazole, itraconazole, fluconazole, miltefosine, paromomycin, and pentamidine.
  • a HDAC inhibitor and an immune checkpoint inhibitor are administered in combination with an antiprotozoal agent for the treatment of a protozoan infection.
  • antiprotozoal agents include, but are not limited to, Acetarsol,
  • Azanidazole Chloroquine, Metronidazole, Nifuratel, Nimorazole, Omidazole, Propenidazole, Secnidazole, Sineflngin, Tenonitrozole, Temidazole, Tinidazole, and pharmaceutically acceptable salts or esters thereof.
  • the biomarker profile indicates the expression of a biomarker, the expression level of a biomarker, mutations in a biomarker, or the presence of a biomarker.
  • the biomarker profile is compared to a control biomarker profile.
  • the therapeutic regimen is a combination of a HDAC inhibitor and an immune check point inhibitor.
  • the biomarker profile is analyzed prior, during, and/or post administration of a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the HDAC inhibitor is abexinostat HC1.
  • the HDAC inhibitor is abexinostat tosylate.
  • a biomarker is any cytogenetic, cell surface molecular or protein or RNA expression marker. In some embodiments, a biomarker includes
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • A2aR B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, and VTCN1.
  • the expression level of a biomarker selected from Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIRl, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, and VTCN1 is compared to a control.
  • a biomarker selected from Programmed Death-Ligand 1 (PD-L
  • phosphatidylserine OX- 40, SLAM, TIGHT, VISTA, and VTCN1 is decreased by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 75-fold, 100-fold, 200-fold, 500-fold, 1000-fold, or less compared to the control.
  • the expression level of a biomarker selected from Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7- DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIRl, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, and VTCN1 is increased by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold,
  • the control is the expression level of Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIRl, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, and VTCN1 in an individual who does not have a cancer, or the expression level of an individual prior to treatment with a combination of a
  • an elevated expression level of a biomarker selected from:
  • P-L1 Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 PD-L2
  • B7-DC PD-L2
  • A2aR B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, and VTCN1 is associated with a poor prognosis.
  • an elevated expression level of a biomarker selected from: Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2, LAG3, and TEVI3 is associated with a poor prognosis.
  • an elevated expression level of a biomarker selected from: Programmed Death-Ligand 1 (PD- Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2, LAG3, and TIM3 is associated with decreased survival, tumor size increase, tumor aggressiveness, recurrence, metastasis, and/or decreased tumor-infiltrating lymphocytes.
  • a biomarker is selected from biomarkers that are expressed by or correlate with a solid tumor, such as for example bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma.
  • biomarkers for bladder cancer include BTA Stat, BTA Track, MP 22, Bladder Chek, immunocyt, UroVysion, cytokeratins 8, 18 and 19, telomerase TRAP, hTert and hTR, BLCA-4, survivn, hyaluronic acid/hyaluronidase, DD23 monoclonal antibody, fibronectin and HCG.
  • biomarkers for colon cancer include CEA, CA 19-9, CYFRA 21-1, ferritin, osteopontin, p53, seprase and EGFR.
  • biomarkers for lung cancer include ERCC-1, NSE, ProGRP, SCC, beta-tubulin, RRM1, EGFR, VEGF, CYFRA-21-1, CEA, CRP, LDH, CA125, CgA, NCAM and TPA.
  • biomarkers for ovarian cancer include CA125, Her-2/neu, Akt-2, inhibin, HLA-G, TATI, CAS A, TPA, CEA, LP A, PAI-1, IL-6, kallikreins 5, 6, 7, 8, 9,10, 11, 13, 14, 15, ⁇ ⁇ ⁇ , prostasin, osteopontin, HE4, mitogen-activated protein kinase, IGFBP-2, RSF-1 and NAC-1.
  • biomarkers for pancreatic cancer include CA19-9, CEA, TIMP-1, CA50, CA242, MUC1, MUC5AC, Claudin 18 and annexin A8.
  • biomarkers for prostate cancer include PSA, human kallikrein 2, IGF-1, IGFBP-3, PC A3, AMACR, GSTPi, CDKN1B, Ki-67, PTEN, and PSCA.
  • biomarkers for proximal or distal bile duct carcinoma include CA125, CA19-9, CEA, CgA, MUC1, MUC5AC, PML, p53, DPC4, Ki67, matrix metalloproteinases, alpha- fetoprotein, N-cadherin, VEGF-C, claudins, thrombospondin-1, cytokeratins and CYFRA 21- 1.
  • biomarkers for breast cancer include HER-1, -2, -3, -4; EGFR; HER-2/neu; Foxp3 + ; ATAD2; DERL1; ESR1; CC D1; MYC; E2F1; EK2A; CRYAB; HSPB2; FOXM1; D MT3B; and MAT1A.
  • the expression level of a biomarker associated with a solid tumor e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma
  • a control e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma
  • the expression level of a biomarker associated with a solid tumor is increased by 0.5- fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6- fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50- fold, 75-fold, 100-fold, 200-fold, 500-fold, 1000-fold, or more compared to the control.
  • a biomarker associated with a solid tumor e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma
  • the expression level of a biomarker associated with a solid tumor is decreased by 0.5-fold, 1- fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5- fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 75- fold, 100-fold, 200-fold, 500-fold, 1000-fold, or less compared to the control.
  • a biomarker associated with a solid tumor e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma
  • control is the expression level of a biomarker associated with a solid tumor (e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma) in an individual who does not have a cancer, or the expression level of an individual prior to treatment with a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • a solid tumor e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma
  • the expression level of a biomarker associated with a solid tumor e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma
  • a biomarker associated with a solid tumor e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma
  • a combination therapy that comprises a HDAC inhibitor and an immune checkpoint inhibitor.
  • the expression level of a biomarker associated with a solid tumor e.g. bladder cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and proximal or distal bile duct carcinoma
  • a therapeutic regimen selection or optimization that comprises a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • a biomarker is selected from biomarkers that are expressed by or correlate with a hematologic cancer, such as for example CLL, DLBCL, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.
  • biomarkers for CLL include del(17pl3.1), del(l lq22.3), del(l lq23), unmutated IgVH together with ZAP- 70+ and/or CD38+, trisomy 12, del(13ql4), complex karyotype, TP53, NOTCH1, SF3B1, BIRC3, LPL, and CLLU1.
  • biomarkers for DLBCL include BCL6, GCET1, MUM1, CD10, FOXP1, miR-21, miR-23A, miR-27A, miR-19A, miR-195, miR- LET7G, miR-127, miR-222, miR-221, t(14: 18), trisomy 3, del(8p23.1), del(8p23.1-21.2), del(8p), t(6; 14)(p25;q32), TP53, TP21, BCL2, BCL6, MYC, Ki-67, and CD43.
  • biomarkers for mantle cell lymphoma include t(l I; 14)(ql3;q32), MFC, CDKN2A, TNFRSF10B, CCDN1, Ki-67, and SOX11.
  • biomarker for Waldenstrom's macroglobulinemia include CD 19, CD20, CD22, CD38, CD79a, CD5, CD138, monoclonal surface Ig, MYD88, CXCR4, TP53, AIM, IgH, del(6q), and trisomy 18.
  • the biomarker profile of a hematologic cancer is the presence or absence of a biomarker, such as a cytogenetic mutation.
  • the biomarker profile of a hematologic cancer is the expression level of a biomarker.
  • the expression level of a biomarker associated with a hematologic cancer e.g. CLL, DLBCL, mantle cell lymphoma, or Waldenstrom's macroglobulinemia
  • the expression level of a biomarker associated with a hematologic cancer e.g.
  • CLL, DLBCL, mantle cell lymphoma, or Waldenstrom's macroglobulinemia is increased by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5- fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9- fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 75-fold, 100-fold, 200-fold, 500-fold, 1000- fold, or more compared to the control.
  • the expression level of a biomarker associated with a hematologic cancer e.g.
  • CLL, DLBCL, mantle cell lymphoma, or Waldenstrom's macroglobulinemia is decreased by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5- fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8- fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 75-fold, 100-fold, 200-fold, 500-fold, 1000-fold, or less compared to the control.
  • the control is the expression level of a biomarker associated with a hematologic cancer (e.g.
  • CLL CLL, DLBCL, mantle cell lymphoma, or Waldenstrom's macroglobulinemia
  • a biomarker associated with a hematologic cancer e.g. CLL, DLBCL, mantle cell lymphoma, or
  • Waldenstrom's macroglobulinemia is used for patient selection, stratification, or monitoring for development of resistance for a combination therapy that comprises a HDAC inhibitor and an immune checkpoint inhibitor.
  • a biomarker associated with a hematologic cancer e.g. CLL, DLBCL, mantle cell lymphoma, or
  • Waldenstrom's macroglobulinemia is used for a therapeutic regimen selection or
  • optimization that comprises a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • a biomarker is tumor-infiltrating lymphocytes (TILs).
  • TILs tumor-infiltrating lymphocytes
  • the expression level of immune checkpoint proteins (e.g. PD-1) by tumor-infiltrating lymphocytes is compared with the expression level of control tumor- infiltrating lymphocytes.
  • the expression level of immune checkpoint proteins e.g.
  • PD-1) by tumor-infiltrating lymphocytes is increased by 0.5-fold, 1-fold, 1.5- fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7- fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 75-fold, 100-fold, 200-fold, 500-fold, 1000-fold, or more compared to the control.
  • the expression level of immune checkpoint proteins e.g.
  • PD-1) by tumor- infiltrating lymphocytes is decreased by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 75-fold, 100-fold, 200-fold, 500-fold, 1000-fold, or less compared to the control.
  • the control is obtained from an individual who does not have a cancer or from an individual prior to treatment with a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • an elevated expression level of an immune checkpoint protein e.g. PD-1 by tumor-infiltrating lymphocytes is associated with impaired effector function such as cytokine production and cytotoxic efficacy against tumor cells, and/or poor prognosis.
  • an immune checkpoint protein e.g. PD-1
  • a biomarker is absolute lymphocyte count (ALC).
  • ALC absolute lymphocyte count
  • the ALC level is greater than 100, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 cells ⁇ L, or higher.
  • the ALC level is less than 100, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 cells ⁇ L, or lower.
  • ALC levels higher than about 1000 cells/ is associated with improved overall survival.
  • the biomarker includes a mutation or modification in BTK.
  • the modification is a mutation at amino acid position 481 in BTK.
  • the mutation is C481 S in BTK.
  • the therapeutic regimen of a HDAC inhibitor and an immune checkpoint inhibitor is modified based on the presence or absence of C481 S mutation in BTK. Diagnostic Methods
  • Circulating levels of biomarkers in a blood sample obtained from a candidate subject are measured, for example, by ELISA, radioimmunoassay (RIA), electrochemiluminescence (ECL), Western blot, multiplexing technologies, or other similar methods.
  • Cell surface expression of biomarkers are measured, for example, by flow cytometry, immunohistochemistry, Western Blot, immunoprecipitation, magnetic bead selection, and quantification of cells expressing either of these cell surface markers.
  • Biomarker RNA expression levels could be measured by RT-PCR, Qt-PCR, microarray, Northern blot, or other similar technologies.
  • determining the expression or presence of the biomarker of interest at the protein and/or nucleotide level is accomplished using any detection method known to those of skill in the art.
  • detecting expression or “detecting the level of is intended determining the expression level or presence of a biomarker protein or gene in the biological sample.
  • detecting expression encompasses instances where a biomarker is determined not to be expressed, not to be detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed.
  • the one or more subpopulation of lymphocytes are isolated, detected or measured. In certain embodiments, the one or more subpopulations of lymphocytes are isolated, detected or measured using immunophenotyping techniques. In other embodiments, the one or more subpopulations of lymphocytes are isolated, detected or measured using fluorescence activated cell sorting (FACS) techniques.
  • FACS fluorescence activated cell sorting
  • the determining step requires determining the expression or presence of a biomarker. In certain aspects, the methods described herein, the determining step requires determining the expression or presence of a combination of biomarkers.
  • the expression or presence of these various biomarkers and any clinically useful prognostic markers in a biological sample are detected at the protein or nucleic acid level, using, for example, immunohistochemistry techniques or nucleic acid- based techniques such as in situ hybridization and RT-PCR.
  • the expression or presence of one or more biomarkers is carried out by a means for nucleic acid amplification, a means for nucleic acid sequencing, a means utilizing a nucleic acid microarray (DNA and RNA), or a means for in situ hybridization using specifically labeled probes.
  • the determining the expression or presence of one or more biomarkers is carried out through gel electrophoresis. In one embodiment, the determination is carried out through transfer to a membrane and hybridization with a specific probe.
  • the determining the expression or presence of one or more biomarkers carried out by a diagnostic imaging technique.
  • the determining the expression or presence of one or more biomarkers carried out by a detectable solid substrate is paramagnetic nanoparticles functionalized with antibodies.
  • kits for detecting or measuring residual lymphoma following a course of treatment in order to guide continuing or discontinuing treatment or changing from one therapeutic regimen to another comprising determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes in a subject wherein the course of treatment is treatment with a HDAC inhibitor and an immune checkpoint inhibitor.
  • Methods for detecting expression of the biomarkers described herein, within the test and control biological samples comprise any methods that determine the quantity or the presence of these markers either at the nucleic acid or protein level. Such methods are well known in the art and include but are not limited to western blots, northern blots, ELISA, immunoprecipitation, immunofluorescence, flow cytometry, immunohistochemistry, nucleic acid hybridization techniques, nucleic acid reverse transcription methods, and nucleic acid amplification methods.
  • expression of a biomarker is detected on a protein level using, for example, antibodies that are directed against specific biomarker proteins. These antibodies are used in various methods such as Western blot, ELISA, multiplexing technologies, immunoprecipitation, or immunohistochemistry techniques.
  • detection of biomarkers is accomplished by ELISA. In some embodiments,
  • detection of biomarkers is accomplished by electrochemiluminescence (ECL).
  • ECL electrochemiluminescence
  • any means for specifically identifying and quantifying a biomarker for example, biomarker, a biomarker of cell survival or proliferation, a biomarker of apoptosis, or the like, in the biological sample of a candidate subject is contemplated.
  • expression level of a biomarker protein of interest in a biological sample is detected by means of a binding protein capable of interacting specifically with that biomarker protein or a biologically active variant thereof.
  • labeled antibodies, binding portions thereof, or other binding partners are used.
  • label when used herein refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody so as to generate a "labeled" antibody.
  • the label is detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, catalyzes chemical alteration of a substrate compound or composition that is detectable.
  • the antibodies for detection of a biomarker protein are either monoclonal or polyclonal in origin, or are synthetically or recombinantly produced.
  • the amount of complexed protein for example, the amount of biomarker protein associated with the binding protein, for example, an antibody that specifically binds to the biomarker protein, is determined using standard protein detection methodologies known to those of skill in the art.
  • a detailed review of immunological assay design, theory and protocols are found in numerous texts in the art (see, for example, Ausubel et al., eds. (1995) Current Protocols in Molecular Biology) (Greene Publishing and Wiley-Interscience, NY)); Coligan et al., eds. (1994) Current Protocols in Immunology (John Wiley & Sons, Inc., New York, N.Y.).
  • the choice of marker used to label the antibodies will vary depending upon the application. However, the choice of the marker is readily determinable to one skilled in the art. These labeled antibodies are used in immunoassays as well as in histological applications to detect the presence of any biomarker or protein of interest.
  • the labeled antibodies are either polyclonal or monoclonal. Further, the antibodies for use in detecting a protein of interest are labeled with a radioactive atom, an enzyme, a chromophoric or fluorescent moiety, or a colorimetric tag as described elsewhere herein.
  • the choice of tagging label also will depend on the detection limitations desired.
  • Enzyme assays typically allow detection of a colored product formed by interaction of the enzyme-tagged complex with an enzyme substrate.
  • Radionuclides that serve as detectable labels include, for example, 1-131, 1-123, 1-125, Y-90, Re-188, Re-186, At-211, Cu-67, Bi-212, and Pd-109.
  • enzymes that serve as detectable labels include, but are not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and glucose-6-phosphate dehydrogenase.
  • Chromophoric moieties include, but are not limited to, fluorescein and rhodamine.
  • the antibodies are conjugated to these labels by methods known in the art.
  • enzymes and chromophoric molecules are conjugated to the antibodies by means of coupling agents, such as dialdehydes, carbodiimides, dimaleimides, and the like.
  • conjugation occurs through a ligand-receptor pair.
  • suitable ligand-receptor pairs are biotin- avidin or biotin-streptavidin, and antibody-antigen.
  • expression or presence of one or more biomarkers or other proteins of interest within a biological sample is determined by radioimmunoassays or enzyme-linked immunoassays (ELISAs), competitive binding enzyme-linked immunoassays, dot blot (see, for example, Promega Protocols and Applications Guide, Promega Corporation (1991), Western blot (see, for example, Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Vol. 3, Chapter 18 (Cold Spring Harbor Laboratory Press, Plainview, N. Y.), chromatography such as high performance liquid chromatography (HPLC), or other assays known in the art.
  • the detection assays involve steps such as, but not limited to, immunoblotting, immunodiffusion, Immunoelectrophoresis, or immunoprecipitation.
  • the methods of the invention are useful for identifying and treating cancer, including those listed above, that are refractory to (i.e., resistant to, or have become resistant to) first-line oncotherapeutic treatments.
  • the expression or presence of one or more of the biomarkers described herein are also determined at the nucleic acid level.
  • Nucleic acid-based techniques for assessing expression are well known in the art and include, for example, determining the level of biomarker mRNA in a biological sample. Many expression detection methods use isolated RNA. Any RNA isolation technique that does not select against the isolation of mRNA is utilized for the purification of RNA (see, e.g., Ausubel et al., ed. (1987-1999) Current Protocols in Molecular Biology (John Wiley & Sons, New York). Additionally, large numbers of tissue samples are readily processed using techniques well known to those of skill in the art, such as, for example, the single-step RNA isolation process disclosed in U.S. Pat. No. 4,843,155.
  • nucleic acid probe refers to any molecule that is capable of selectively binding to a specifically intended target nucleic acid molecule, for example, a nucleotide transcript. Probes are synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are discussed above or that are known in the art. Examples of molecules that are utilized as probes include, but are not limited to, RNA and DNA.
  • isolated mRNA are used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses and probe arrays.
  • One method for the detection of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that hybridize to the mRNA encoded by the gene being detected.
  • the nucleic acid probe comprises of, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to an mRNA or genomic DNA encoding a biomarker, biomarker described herein above.
  • Hybridization of an mRNA with the probe indicates that the biomarker or other target protein of interest is being expressed.
  • the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose.
  • the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in a gene chip array.
  • a skilled artisan readily adapts known mRNA detection methods for use in detecting the level of mRNA encoding the biomarkers or other proteins of interest.
  • An alternative method for determining the level of an mRNA of interest in a sample involves the process of nucleic acid amplification, e.g., by RT-PCR (see, for example, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88: 189 193), self-sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci.
  • biomarker expression is assessed by quantitative fluorogenic RT- PCR (i.e., the TaqManO System).
  • RNA of interest Expression levels of an RNA of interest are monitored using a membrane blot (such as used in hybridization analysis such as Northern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See U.S. Pat. Nos. 5,770,722, 5,874,219, 5,744,305, 5,677,195 and 5,445,934, which are incorporated herein by reference.
  • the detection of expression also comprises using nucleic acid probes in solution.
  • microarrays are used to determine expression or presence of one or more biomarkers.
  • Microarrays are particularly well suited for this purpose because of the reproducibility between different experiments.
  • DNA microarrays provide one method for the simultaneous measurement of the expression levels of large numbers of genes. Each array consists of a reproducible pattern of capture probes attached to a solid support. Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning Hybridization intensities for each probe on the array are determined and converted to a quantitative value representing relative gene expression levels. See, U.S. Pat. Nos.
  • High-density oligonucleotide arrays are particularly useful for determining the gene expression profile for a large number of RNA's in a sample.
  • an array is fabricated on a surface of virtually any shape or even a multiplicity of surfaces.
  • an array is a planar array surface.
  • arrays include peptides or nucleic acids on beads, gels, polymeric surfaces, fibers such as fiber optics, glass or any other appropriate substrate, see U.S. Pat. Nos.
  • arrays are packaged in such a manner as to allow for diagnostics or other manipulation of an all-inclusive device.
  • a sample for use in a method described herein is from any tissue or fluid from a patient.
  • Samples include, but are not limited, to whole blood, dissociated bone marrow, bone marrow aspirate, pleural fluid, peritoneal fluid, central spinal fluid, abdominal fluid, pancreatic fluid, cerebrospinal fluid, ascites, pericardial fluid, urine, saliva, bronchial lavage, sweat, tears, ear flow, sputum, hydrocele fluid, semen, vaginal flow, milk, amniotic fluid, and secretions of respiratory, intestinal or genitourinary tract.
  • a sample is a blood serum sample.
  • a sample is from a fluid or tissue that is part of, or associated with, the lymphatic system or circulatory system.
  • a sample is a blood sample that is a venous, arterial, peripheral, tissue, cord blood sample.
  • a sample is a blood cell sample containing one or more peripheral blood mononuclear cells (PBMCs).
  • PBMCs peripheral blood mononuclear cells
  • the sample contains one or more circulating tumor cells (CTCs).
  • CTCs circulating tumor cells
  • DTC disseminated tumor cells
  • samples are obtained from a patient by any suitable means of obtaining the sample using well-known and routine clinical methods.
  • Procedures for obtaining fluid samples from an individual are well known. For example, procedures for drawing and processing whole blood and lymph are well-known and can be employed to obtain a sample for use in the methods provided.
  • an anti-coagulation agent e.g., EDTA, or citrate and heparin or CPD (citrate, phosphate, dextrose) or comparable substances
  • the blood sample is collected in a collection tube that contains an amount of EDTA to prevent coagulation of the blood sample.
  • procedures for collecting various body samples are well known in the art.
  • procedures for collecting a breast tissue sample are well known, and can be obtained by for example, fine needle aspiration biopsy, core needle biopsy, or excisional biopsy.
  • Fixative and staining solutions can be applied to the cells or tissues for preserving the specimen and for facilitating examination.
  • a sample is a cell sample, such as a cell of the hematologic malignant cell line, or the solid tumor cell line.
  • a hematologic malignant cell line include cells obtained from, for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell
  • CLL chronic lymphocytic
  • a solid tumor cell line include cells obtained from, for example, bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, or melanoma.
  • a sample is a hematologic malignant cell or population of hematologic malignant cells.
  • the cell lines include, A20, J558, BALM-1, BALM-2, BALM-3, EL4, Jurkat, THPl, OCI-Lyl, OCI-Ly2, OCI-Ly3, OCI-Ly4, OCI-Ly6, OCI-Ly7, OCI-LylO, OCI-Lyl8, OCI-Lyl9, U2932, DB, HBL-1, RIVA, SUDHL2, or TMD8.
  • the cell lines are sensitive to a treatment of a combination with a HDAC and an immune checkpoint inhibitor.
  • the cell lines are sensitive to a treatment of a combination with a HDAC inhibitor, an immune checkpoint inhibitor, and an additional anticancer agent.
  • a sample is a solid tumor cell or population of solid tumor cells.
  • the cell lines include, 293-T, 4T1, 721, 9L, A2780, ALC, B 16, B35, BCP- 1, BEAS-2B, BHK-21, BR 293, BxPC3, C3H-10T1/2, COR-L23, COS-7, CT26, DH82, DU145, DuCaP, EMT6/AR1, EMT6/AR10.0, H1299, H69, HeLa, Hepalclc7, High Five cells, HT-29, MCF-7, MDA-MB-231, MDA-MB-468, MG63, MDCK II, MRC5, RIN-5F, or T84.
  • the cell lines are sensitive to a treatment of a combination with a HDAC inhibitor and an immune checkpoint inhibitor. In some instances, the cell lines are sensitive to a treatment of a combination with a HDAC inhibitor, an immune checkpoint inhibitor, and an additional anticancer agent.
  • the collection of a sample from the individual is performed at regular intervals, such as, for example, one day, two days, three days, four days, five days, six days, one week, two weeks, weeks, four weeks, one month, two months, three months, four months, five months, six months, one year, daily, weekly, bimonthly, quarterly, biyearly or yearly.
  • the collection of a sample is performed at a predetermined time or at regular intervals relative to the treatment of a combination of a HDAC and an immune checkpoint inhibitor.
  • a sample is collected from a patient at a predetermined time or at regular intervals prior to, during, or following treatment or between successive treatments with a combination of a HDAC inhibitor and an immune checkpoint inhibitor.
  • a sample is collected from a patient at a predetermined time or at regular intervals prior to, during, or following treatment or between successive treatments with a combination of a HDAC inhibitor, an immune checkpoint inhibitor, and an additional anticancer agent.
  • a sample is also collected from a patient at a
  • a HDAC inhibitor predetermined time or at regular intervals prior to, during, or following treatment or between successive treatments of one or more of a HDAC inhibitor, an immune checkpoint inhibitor, and/or an additional anticancer agent.
  • compositions that comprise (a) a HDAC inhibitor and an immune checkpoint inhibitor, and (b) a pharmaceutically-acceptable excipient.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the abexinostat or a salt thereof is abexinostat HC1.
  • the abexinostat or a salt thereof is abexinostat tosylate.
  • the immune checkpoint inhibitor is an inhibitor of
  • PD-Ll Programmed Death-Ligand 1
  • PD-1 Programmed Death 1
  • CTLA-4 B7H1, B7H4, OX- 40
  • CD137 CD40, 2B4
  • IDOl IDOl
  • ID02 IDOl
  • VISTA IDOl
  • CD27 CD28
  • PD-L2 B7-DC, CD273
  • LAG3, CD80 CD86, PDL2, B7H3, HVEM, BTLA, KIR, GAL9, TIM3, A2aR, MARCO (macrophage receptor with collagenous structure), PS (phosphatidylserine), ICOS (inducible T cell costimulator), HAVCR2, CD276, VTCN1, CD70, CD 160, or any combinations thereof.
  • the immune checkpoint inhibitor is an inhibitor of PD-Ll . In some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In some embodiments, the immune checkpoint inhibitor is an inhibitor of LAG3. In some embodiments, the immune checkpoint inhibitor is an inhibitor of TIM3.
  • abexinostat or a salt thereof is amorphous or crystalline. In some embodiments, abexinostat or a salt thereof is milled or a nano-particle. In some embodiments, the pharmaceutical composition is a combined dosage form.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995);
  • a pharmaceutical combination refers to a mixture of abexinostat or a salt thereof, an immune checkpoint inhibitor, and/or an additional therapeutic agent with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • therapeutically effective amounts of the compounds disclosed herein are administered having a disease, disorder, or condition to be treated.
  • the mammal is a human.
  • the therapeutically effective amounts of the compounds may vary depending on the compounds, severity of the disease, the age and relative health of the subject, and other factors.
  • the term "combination” as used herein, means a product that results from the mixing or combining of abexinostat or a salt thereof and an immune checkpoint inhibitor (and any additional therapeutic agents) and includes both fixed and non-fixed combinations.
  • the term "fixed combination” means that abexinostat or a salt thereof and the immune checkpoint inhibitor are both administered in a single entity or dosage form.
  • the term “non-fixed combination” means that abexinostat or a salt thereof and the immune checkpoint inhibitor are administered as separate entities or dosage forms either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • the pharmaceutical combination and/or composition described herein also include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
  • bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • the pharmaceutical combination and/or compositions also include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium
  • the pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • compositions including a compound described herein are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • Antifoaming agents reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing.
  • Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.
  • Antioxidants include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required.
  • BHT butylated hydroxytoluene
  • antioxidants enhance chemical stability where required.
  • compositions provided herein also include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • formulations described herein benefit from antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • polysorbate 20 (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
  • Binders impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel ® ), hydroxypropylmethylcellulose, hydroxy ethylcellulose, hydroxypropylcellulose (e.g.,
  • Klucel ® ethylcellulose (e.g., Ethocel ® ), and microcrystalline cellulose (e.g., Avicel ® );
  • a “carrier” or “carrier materials” include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with compounds disclosed herein, such as, compounds of abexinostat, and the release profile properties of the desired dosage form.
  • exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.
  • “Pharmaceutically compatible carrier materials” include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid,
  • phosphotidylcholine sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,
  • Disposing agents include materials that control the diffusion and homogeneity of a drug through liquid media or a granulation method or blend method. In some embodiments, these agents also facilitate the effectiveness of a coating or eroding matrix.
  • Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween ® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone ® ), and the carbohydrate-based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
  • HPMCAS hydroxypropylmethylcellulose acetate stearate
  • PVA polyvinyl alcohol
  • pyrrolidone/vinyl acetate copolymer S630
  • 4-(l, l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde also known as tyloxapol
  • poloxamers e.g., Pluronics F68 ® , F88 ® , and F108 ® , which are block copolymers of ethylene oxide and propylene oxide
  • poloxamines e.g., Tetronic 908 , also known as Poloxamine 908 , which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)
  • polyvinylpyrrolidone K12 polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium
  • Dispersing agents particularly useful in liposomal dispersions and self-emulsifying dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl my ri state.
  • Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present compositions.
  • diluent refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution. In certain embodiments, diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling.
  • Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel ® ; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;
  • compressible sugar such as Di- Pac ® (Amstar)
  • mannitol hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar
  • disintegrate includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.
  • disintegration agents or disintegrants facilitate the breakup or disintegration of a substance.
  • disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® P100, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxy
  • carboxymethylcellulose or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked
  • alginate such as alginic acid or a salt of alginic acid such as sodium alginate
  • a clay such as Veegum ® HV (magnesium aluminum silicate)
  • a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth
  • sodium starch glycolate bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.
  • Drug absorption typically refers to the process of movement of drug from site of administration of a drug across a barrier into a blood vessel or the site of action, e.g., a drug moving from the gastrointestinal tract into the portal vein or lymphatic system.
  • enteric coating is a substance that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon.
  • the enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a higher pH, typically a pH of 6 to 7, and thus dissolves sufficiently in the small intestine or colon to release the active agent therein.
  • Erosion facilitators include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.
  • Filling agents include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • “Flavoring agents” and/or “sweeteners” useful in the formulations described herein include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet ® ), maltol, mannitol, maple,
  • Lubricants and “glidants” are compounds that prevent, reduce or inhibit adhesion or friction of materials.
  • exemplary lubricants include, e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex ® ), higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a methoxypolyethylene glycol such as CarbowaxTM, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lau
  • a "measurable serum concentration” or “measurable plasma concentration” describes the blood serum or blood plasma concentration, typically measured in mg, ⁇ g, or ng of therapeutic agent per mL, dL, or L of blood serum, absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng/ml or ⁇ g/ml.
  • “Pharmacodynamics” refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action. [00316] “Pharmacokinetics” refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.
  • Plasticizers are compounds used to soften the microencapsulation material or film coatings to make them less brittle.
  • Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin.
  • plasticizers can also function as dispersing agents or wetting agents.
  • Solubilizers include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS,
  • dimethylacetamide N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like.
  • Stabilizers include compounds such as any antioxidation agents, buffers, acids, preservatives and the like.
  • Step state is when the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant plasma drug exposure.
  • Suspending agents include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxy ethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics,
  • “Surfactants” include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
  • Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g.,
  • polyoxyethylene (60) hydrogenated castor oil and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
  • surfactants are included to enhance physical stability or for other purposes.
  • Viscosity enhancing agents include, e.g., methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.
  • Weight agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.
  • dosage forms which comprise a HDAC inhibitor and an immune checkpoint inhibitor.
  • the HDAC inhibitor is abexinostat or a salt thereof.
  • the dosage form is a combined dosage form.
  • the dosage form is a solid oral dosage form.
  • the dosage form is a tablet, pill, or capsule.
  • the dosage form is a controlled release dosage form, delayed release dosage form, extended release dosage form, pulsatile release dosage form, multiparticulate dosage form, or mixed immediate release and controlled release formulation.
  • the dosage form comprises a controlled release coating.
  • the dosage forms comprises a first controlled release coating which controls the release of abexinostat or a salt thereof, and a second controlled release coating which controls the release of the immune checkpoint inhibitor.
  • the combination provides a synergistic or additive therapeutic effect compared to administration of abexinostat or a salt thereof, or the second anticancer agent alone.
  • the pharmaceutical combination described herein may be formulated for administration via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, or intramuscular
  • buccal e.g., intranasal
  • the terms “subject”, “individual” and “patient” are used interchangeably and mean an animal, preferably a mammal, including a human or non- human. None of the terms require the supervision (continuous or otherwise) of a medical professional.
  • the pharmaceutical combination described herein are formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • compositions for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, 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, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings for this purpose, in some embodiments, concentrated sugar solutions are used, which, in particular embodiments, optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are added. All formulations for oral administration should be in dosages suitable for such administration.
  • the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder,
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, in some embodiments, pharmaceutical formulations described herein are administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
  • solid dosage forms e.g., tablets, effervescent tablets, and capsules
  • solid dosage forms are prepared by mixing particles of abexinostat or a salt thereof, with one or more pharmaceutical excipients to form a bulk blend composition.
  • these bulk blend compositions as homogeneous, it is meant that the particles of abexinostat or a salt thereof are dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
  • the individual unit dosages also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.
  • Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986).
  • Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.
  • the pharmaceutical solid dosage forms described herein can include a compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a film coating is provided around the formulation of abexinostat or a salt thereof.
  • some or all of the particles of abexinostat are not microencapsulated and are uncoated.
  • Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch,
  • hydroxypropylmethylcellulose hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.
  • Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC),
  • hydroxypropylmethycellulose phthalate hydroxypropylmethylcellulose acetate stearate (HPMCAS)
  • sucrose xylitol
  • lactitol mannitol
  • sorbitol sodium chloride
  • polyethylene glycol polyethylene glycol
  • Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form.
  • Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product,
  • methylcrystalline cellulose e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® PI 00, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium
  • carboxymethylcellulose (Ac-Di-Sol ® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum ® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation- exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.
  • a cross-linked starch such as sodium starch glycolate
  • Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step.
  • Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel ® ), hydroxypropylmethylcellulose (e.g.
  • binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl
  • palmitostearate palmitostearate
  • glyceryl benzoate magnesium or sodium lauryl sulfate, and the like.
  • Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including i l l dextrates and maltodextnn), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
  • non water-soluble diluent represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm 3 , e.g. Avicel, powdered cellulose), and talc.
  • Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 ® ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.
  • quaternary ammonium compounds e.g., Polyquat 10 ®
  • sodium oleate sodium lauryl sulfate
  • magnesium stearate sodium docusate
  • triacetin vitamin E TPGS and the like.
  • Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
  • Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
  • polyvinylpyrrolidone K17 polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30
  • polyethylene glycol e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl
  • Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
  • BHT butylated hydroxytoluene
  • sodium ascorbate sodium ascorbate
  • tocopherol sodium ascorbate
  • additives used in the solid dosage forms described herein there is considerable overlap between additives used in the solid dosage forms described herein.
  • the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein.
  • the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
  • one or more layers of the pharmaceutical formulation are plasticized.
  • a plasticizer is generally a high boiling point solid or liquid.
  • Plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition.
  • Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
  • Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above.
  • compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents.
  • the compressed tablets will include a film surrounding the final compressed tablet.
  • the film coating can provide a delayed release of abexinostat or a salt thereof or the second agent, from the formulation.
  • the film coating aids in patient compliance (e.g., Opadry ® coatings or sugar coating). Film coatings including Opadry ® typically range from about 1% to about 3% of the tablet weight.
  • the compressed tablets include one or more excipients.
  • a capsule is prepared, for example, by placing the bulk blend of the formulation of abexinostat or the second agent, described above, inside of a capsule.
  • the formulations non-aqueous suspensions and solutions
  • the formulations are placed in a soft gelatin capsule.
  • the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.
  • the formulation is placed in a sprinkle capsule, wherein the capsule can be swallowed whole or the capsule can be opened and the contents sprinkled on food prior to eating.
  • the therapeutic dose is split into multiple (e.g., two, three, or four) capsules.
  • the entire dose of the formulation is delivered in a capsule form.
  • the particles of abexinostat or a salt thereof, and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.
  • dosage forms include microencapsulated formulations.
  • one or more other compatible materials are present in the microencapsulation material.
  • Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
  • Materials useful for the microencapsulation described herein include materials compatible with abexinostat or a salt thereof, which sufficiently isolate the compound of any of abexinostat, from other non-compatible excipients.
  • Materials compatible with compounds of any of abexinostat are those that delay the release of the compounds of any of abexinostat, in vivo.
  • Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel ® or Nisso HPC, low- substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat ® , Metolose SR, Methocel ® -E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel ® -A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and
  • Ethylcelluloses Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel ® , Aqualon ® -EC, Surelease ® , Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol ® , carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon ® -CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR ® , monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit ® EPO, Eudragit ® L30D-55, Eudragit ® FS 30D Eudragit ® L100-55, Eudragit ® L100, Eudragit ® S100, Eudragit ® RD100, Eudragit
  • plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material.
  • microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF).
  • the microencapsulation material is Klucel.
  • the microencapsulation material is methocel.
  • microencapsulated compounds of any of abexinostat or a salt thereof are formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath.
  • roller compaction extrusion/spheronization, coacervation, or nanoparticle coating are used.
  • the particles of compounds of any of abexinostat or a salt thereof are microencapsulated prior to being formulated into one of the above forms.
  • some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington 's Pharmaceutical Sciences, 20th Edition (2000).
  • the solid dosage formulations of the compounds of any of abexinostat or a salt thereof are plasticized (coated) with one or more layers.
  • a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition.
  • Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
  • a powder including the formulations with a compound of any of abexinostat or a salt thereof, described herein is formulated to include one or more pharmaceutical excipients and flavors.
  • such a powder is prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units.
  • Effervescent powders are also prepared in accordance with the present disclosure.
  • Effervescent salts have been used to disperse medicines in water for oral administration.
  • Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • the acids and the base react to liberate carbon dioxide gas, thereby causing "effervescence.”
  • effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.
  • the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a
  • the enteric coated dosage form is a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated.
  • the enteric coated oral dosage form is a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
  • delayed release refers to the delivery so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations.
  • the method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract.
  • the polymers described herein are anionic carboxylic polymers.
  • the polymers and compatible mixtures thereof, and some of their properties include, but are not limited to:
  • Shellac also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7;
  • Acrylic polymers The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers.
  • the Eudragit series E, L, S, RL, RS and E are available as solubilized in organic solvent, aqueous dispersion, or dry powders.
  • the Eudragit series RL, E, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting.
  • the Eudragit series E dissolve in the stomach.
  • the Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine;
  • Cellulose Derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution.
  • Cellulose acetate phthalate (CAP) dissolves in pH >6.
  • Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles ⁇ 1 ⁇ .
  • Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides.
  • Suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)).
  • Eastman methylcellulose
  • HPMCS hydroxypropylmethylcellulose acetate succinate
  • AQOAT Shin Etsu
  • HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable.
  • the performance can vary based on the degree and type of substitution.
  • suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
  • AS-LG LF
  • MF AS-MG
  • HF AS-HG
  • PVAP Poly Vinyl Acetate Phthalate
  • PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids.
  • the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art.
  • Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate.
  • anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
  • a plasticizer especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
  • Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.
  • colorants e.g., carnuba wax or PEG are added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
  • lubricants e.g., carnuba wax or PEG
  • abexinostat are delivered using a pulsatile dosage form.
  • a pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites.
  • Many other types of controlled release systems known to those of ordinary skill in the art and are suitable for use with the formulations described herein.
  • Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and polycaprolactone; porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp.
  • compositions that include particles of abexinostat or a salt thereof, described herein and at least one dispersing agent or suspending agent for oral administration to a subject.
  • the formulations are a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
  • Liquid formulation dosage forms for oral administration can be aqueous
  • the liquid dosage forms include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent.
  • the aqueous dispersions can further include a crystalline inhibitor.
  • the aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours.
  • the homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.
  • a starch e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ®
  • a cellulose such as a wood product
  • methylcrystalline cellulose e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® PI 00, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium
  • carboxymethylcellulose (Ac-Di-Sol ® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum ® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation- exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like.
  • a cross-linked starch such as sodium starch glycolate
  • the dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween ® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone ® ), and the carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC- L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g.
  • HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone ® , e.g., S-630), 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68 , F88 , and F108 , which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908 ® , also known as Poloxamine 908 ® , which is a
  • polyvinylpyrrolidone PVP
  • hydroxypropylcellulose and hydroxypropyl cellulose ethers e.g., FIPC, FIPC-SL, and FIPC-L
  • hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat ® USP 2910 (Shin-Etsu)
  • carboxymethylcellulose sodium methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl- cellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate;
  • polyvinyl alcohol PVA
  • 4-(l, l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde PVA
  • poloxamers e.g., Pluronics F68 ® , F88 ® , and F108 ® , which are block copolymers of ethylene oxide and propylene oxide
  • poloxamines e.g., Tetronic 908 ® , also known as Poloxamine 908 ® ).
  • wetting agents suitable for the aqueous suspensions and dispersions described herein include, but are not limited to, cetyl alcohol, glycerol monostearate, poly oxy ethylene sorbitan fatty acid esters (e.g., the commercially available Tweens ® such as e.g., Tween 20 ® and Tween 80 ® (ICI Specialty Chemicals)), and
  • polyethylene glycols e.g., Carbowaxs 3350 ® and 1450 ® , and Carbopol 934 ® (Union
  • oleic acid glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and the like.
  • Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.
  • Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.
  • Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methyl cellulose, xanthan gum,
  • the concentration of the viscosity enhancing agent will depend upon the agent selected and the viscosity desired.
  • sweetening agents suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,
  • acacia syrup acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butters
  • the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 1.0% the volume of the aqueous dispersion.
  • the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.005%) to about 0.5% the volume of the aqueous dispersion.
  • the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.01%> to about 1.0% the volume of the aqueous dispersion.
  • the liquid formulations can also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
  • emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • the pharmaceutical formulations described herein can be self-emulsifying drug delivery systems (SEDDS).
  • SEDDS self-emulsifying drug delivery systems
  • Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets.
  • emulsions are created by vigorous mechanical dispersion.
  • SEDDS as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation.
  • An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase can be added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient.
  • the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients.
  • SEDDS provide improvements in the bioavailability of hydrophobic active ingredients.
  • Methods of producing self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is specifically incorporated by reference.
  • Intranasal formulations are known in the art and are described in, for example, U.S. Pat. Nos. 4,476,1 16, 5,116,817 and 6,391,452, each of which is specifically incorporated by reference.
  • Formulations that include abexinostat which are prepared according to these and other techniques well-known in the art are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995).
  • formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions,
  • Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. In some embodiments, minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents are also present.
  • the nasal dosage form should be isotonic with nasal secretions.
  • the pharmaceutical compositions are in a form as an aerosol, a mist or a powder.
  • Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit is determined by providing a valve to deliver a metered amount.
  • capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch.
  • buccal formulations are administered using a variety of formulations known in the art.
  • formulations include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739, 136, each of which is specifically incorporated by reference.
  • the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa.
  • the buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery is provided essentially throughout.
  • Buccal drug delivery avoids the
  • the bioerodible (hydrolysable) polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa.
  • polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as "carbomers” (Carbopol , which can be obtained from B.F. Goodrich, is one such polymer).
  • other components are also incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like.
  • the compositions are in the form of tablets, lozenges, or gels formulated in a conventional manner.
  • transdermal formulations described herein are administered using a variety of devices which have been described in the art.
  • such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of which is specifically incorporated by reference in its entirety.
  • the transdermal dosage forms described herein incorporate certain pharmaceutically acceptable excipients which are conventional in the art.
  • the transdermal formulations described herein include at least three components: (1) a formulation of a compound of abexinostat or a salt thereof; (2) a penetration enhancer; and (3) an aqueous adjuvant.
  • transdermal formulations can include additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like.
  • the transdermal formulation can further include a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin.
  • the transdermal formulations described herein can maintain a saturated or supersaturated state to promote diffusion into the skin.
  • formulations suitable for transdermal administration of compounds described herein employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • transdermal delivery of the compounds described herein can be accomplished by means of iontophoretic patches and the like.
  • transdermal patches can provide controlled delivery of abexinostat or a salt thereof. The rate of absorption can be slowed by using rate- controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • An absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • formulations include a combination of a HDAC inhibitor and an immune checkpoint inhibitor, suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol,
  • formulations suitable for subcutaneous injection also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • compounds described herein are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.
  • parenteral injections involve bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some
  • the pharmaceutical composition described herein is in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contains formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, in some embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension also contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions provided herein can also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer),
  • poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran are examples of poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • the compounds described herein are administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the compounds described herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • kits and articles of manufacture are also described herein.
  • Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • the articles of manufacture provided herein contain packaging materials.
  • packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected
  • the container(s) include abexinostat or a salt thereof, optionally in a composition or in combination with an immune checkpoint inhibitor as disclosed herein.
  • kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application.
  • the label also indicates directions for use of the contents, such as in the methods described herein.
  • the pharmaceutical combinations and/or compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
  • the pack for example, contains metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is also
  • pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Example 1 Combination Therapy of Abexinostat and an anti-PDl antibody in a Pan02 Syngeneic Mouse Model
  • mice were inoculated subcutaneously with syngeneic tumor cells from Pan02 (murine model of pancreatic cancer). Treatment began when mean tumor size reached approximately 63-88 mm 3 . Treatments were one of the following (10 mice per group): (1) vehicle 1, administered orally once a day for 5 weeks and vehicle 2, administered intraperitoneally, twice a day, 5 days on, 2 days off, for 5 weeks; (2) abexinostat (12.5), administered intraperitoneally twice a day, 5 days on, 2 days off; (3) anti-PDl antibody (RMP1-14, rat monoclonal antibody to PD-1), lOC ⁇ g/animal administered intraperitoneally twice every week for 5 weeks; or (4) abexinostat (12.5 mg/kg), administered intraperitoneally twice a day, 5 days on, 2 days off and anti-PDl antibody, lOC ⁇ g/animal administered intraperitoneally twice every week for 5 weeks. (Fig. 1).
  • Tumor volume was measured periodically until 45 days post-innoculation of Pan02 cells.
  • the combination of abexinostat and anti-PD-1 antibody was found to have a combination benefit in reducing tumor volume compared to anti-PD-1 antibody alone or to abexinostat alone (Fig. 1).

Abstract

L'invention concerne des procédés pour le traitement d'un cancer, lesquels procédés consistent à administrer à un sujet qui en a besoin une combinaison comprenant de l'abexinostat ou un sel de celui-ci et un inhibiteur de point de contrôle immunitaire.
PCT/US2016/053479 2015-09-25 2016-09-23 Traitement à l'aide d'inhibiteurs d'hdac et d'immunothérapie WO2017053823A1 (fr)

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CN108576205A (zh) * 2018-03-22 2018-09-28 湖北省农业科学院农产品加工与核农技术研究所 一种草莓联合干燥的处理方法
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CN115317493A (zh) * 2022-06-22 2022-11-11 中山大学 一种硼酸类小分子化合物在制备增强免疫检查点抑制剂疗效及治疗白血病药物中的应用
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