WO2023209611A1 - Méthodes de traitement du cancer avec un inhibiteur du b-raf, en particulier le lifirafenib - Google Patents

Méthodes de traitement du cancer avec un inhibiteur du b-raf, en particulier le lifirafenib Download PDF

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WO2023209611A1
WO2023209611A1 PCT/IB2023/054325 IB2023054325W WO2023209611A1 WO 2023209611 A1 WO2023209611 A1 WO 2023209611A1 IB 2023054325 W IB2023054325 W IB 2023054325W WO 2023209611 A1 WO2023209611 A1 WO 2023209611A1
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braf
nras
compound
cancer
fusion
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PCT/IB2023/054325
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English (en)
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Lusong LUO
Zhiyu TANG
Tian YU
Katie Wood
Gilbert Wong
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Beigene Switzerland Gmbh
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the method relates to the use of a B-Raf inhibitor, particularly 5- ((( 1 R, 1 aS,6bR)- 1 -(6-(trifluoromethy 1)- 1 H-benzo(d)imidazol-2-yl)- 1 a,6b-dihydro- 1 H- cyclopropa(b)benzofuran-5-yl)oxy)-3,4-dihydro-l ,8-naphthyridin-2(lH)-one or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, for treating cancer.
  • a B-Raf inhibitor particularly 5- ((( 1 R, 1 aS,6bR)- 1 -(6-(trifluoromethy 1)- 1 H-benzo(d)imidazol-2-yl)- 1 a,6b-dihydro- 1 H- cyclo
  • cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death and is characterized by the proliferation of malignant cells which have the potential for unlimited growth, local expansion and systemic metastasis.
  • Deregulation of normal processes include abnormalities in signal transduction pathways and response to factors which differ from those found in normal cells.
  • Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the y-phosphate of the ATP-Mg2+ complex to said amino acid side chain. These enzymes control the majority of the signaling processes inside cells, thereby governing cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins.
  • Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division.
  • Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex intermeshed pathways where each kinase is
  • RECTIFIED SHEET (RULE 91 ) ISA/EP regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems. Due to their physiological relevance, variety and ubiquitousness, protein kinases have become one of the most important and widely studied family of enzymes in biochemical and medical research.
  • the protein kinase family of enzymes is typically classified into two main subfamilies: Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the amino acid residue they phosphorylate.
  • the protein serine/threonine kinases includes cyclic AMP- and cyclic GMP-dependent protein kinases, calcium and phospholipid dependent protein kinase, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins.
  • Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases.
  • tyrosine kinases phosphorylate tyrosine residues.
  • Tyrosine kinases play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet derived growth factor receptor and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much work is also in progress to identify modulators of tyrosine kinases as well.
  • RTKs Receptor tyrosine kinases
  • Ras-Raf-MEK-ERK kinase pathway Downstream of the several RTKs lie several signaling pathways, among them is the Ras-Raf-MEK-ERK kinase pathway. It is currently understood that activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases. These kinases then phosphorylate and activate the intracellular protein
  • RECTIFIED SHEET (RULE 91 ) ISA/EP kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and 2.
  • This signaling pathway also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, mediates cellular responses to growth signals. The ultimate function of this is to link receptor activity at the cell membrane with modification of cytoplasmic or nuclear targets that govern cell proliferation, differentiation, and survival.
  • MAPK mitogen-activated protein kinase
  • Ras mutations or Raf mutations has frequently been found in human cancers, and represents a major factor determining abnormal growth control. In human malignances, Ras mutations are common, having been identified in about 30% of cancers.
  • the Ras family of GTPase proteins proteins which convert guanosine triphosphate to guanosine diphosphate
  • the Raf family is composed of three related kinases (A-, B- and C-Raf) that act as downstream effectors of Ras.
  • Ras-medicated Raf activation in turn triggers activation of MEK1 and MEK2 (MAP / ERK kinases 1 and 2) which in turn phosphorylate ERK1 and ERK2 (extracellular signal-regulated kinases 1 and 2) on th tyrosine- 185 and threonine- 183.
  • Activated ERK 1 and ERK2 translocate and accumulate in the nucleus, where they can phosphorylate a variety of substrates, including transcription factors that control cellular growth and survival.
  • the kinase components of the signaling cascade are merging as potentially important targets for the modulation of disease progression in cancer and other proliferative diseases.
  • MEK1 and MEK2 are members of a larger family of dual- specificity kinases (MEK1 -7) that phosphorylate threonine and tyrosine residues of various MAP kmases.
  • MEK1 and MEK2 are encoded by distinct genes, but they share high homology (80%) both within the C- terminal catalytic kinase domains and the most of the /V -terminal regulatory region.
  • Oncogenesis forms of MEK1 and MEK2 have not been found in human cancers, but constitutive activation of MEK has been shown to result in cellular transformation. In addition to Raf, MEK can also be activated by other oncogene as well. So far, the only known substrates of MEK1 and MEK2 are ERK1 and ERK2. This unusual substrate specificity in addition to the unique ability
  • RECTIFIED SHEET (RULE 91 ) ISA/EP to phosphorylate both tyrosine and threonine residues places MEK1 and MEK2 at a critical point in the signal transduction cascade which allows it to integrate many extracellular signals into the MAPK pathway.
  • an inhibitor of a protein of the MAPK kinase pathway should be of value both as an anti-proliferative, pro-apoptotic and anti- invasive agent for use in the containment and/or treatment of proliferative or invasive disease.
  • MEK a protein of the MAPK kinase pathway
  • a compound having MEK inhibitory activity effectively induces inhibition of ERK1/2 activity and suppression of cell proliferation (The Journal of Biological Chemistry, vol. 276, No. 4 pp. 2686-2692, 2001), and the compound is expected to show effects on diseases caused by undesirable cell proliferation, such as tumor genesis and/or cancer.
  • RECTIFIED SHEET (RULE 91 ) ISA/EP 108(6) 467-470, Davies (2002) supra, and Garnett et al., Cancer Cell (2004) supra) and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system), colorectal cancer, including large intestinal colon carcinoma (Yuen et al Cancer Res. (2002) 62(22) 6451 -6455, Davies (2002) supra and Zebisch et al., Cell. Mol. Life Sci. (2006), gastric cancer (Lee et al Oncogene (2003) 22(44) 6942- 6945), carcinoma of the head and neck including squamous cell carcinoma of the head and neck (Cohen et al J.
  • leukemias include leukemias (Garnett et al., Cancer Cell (2004) supra, particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al Leukemia (2005) 19(2) 310-312), acute myelogenous leukemia (AML) (Lee et al Leukemia (2004) 18(1) 170- 172, and Christiansen et al Leukemia (2005) 19(12) 2232-2240), myelodysplasia syndromes (Christiansen et al Leukemia (2005) supra) and chronic myelogenous leukemia (Mizuchi et al Biochem.
  • leukemias Garnett et al., Cancer Cell (2004) supra, particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al Leukemia (2005) 19(2) 310-312
  • AML acute myelogenous leukemia
  • myelodysplasia syndromes Christian
  • a method of treating a cancer in a subject in need thereof comprising administering to said subject Compound A having the name of 5-(((lR,laS,6bR)-l-(6- (trifluoromethyl)-lH-benzo(d)imidazol-2-yl)-la,6b-dihydro-lH-cyclopropa(b)benzofuran-5- yl)oxy)-3,4-dihydro-l,8-naphthyridin-2(lH)-one, or the structure of formula (I):
  • Also provided herein is a method for treating a cancer in a subject in need thereof, comprising administering to said subject the combination of an inhibitor of BRAF and an inhibitor of MEK, wherein the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, and their combination thereof, wherein the inhibitor of MEK is not Compound B.
  • the method comprises administering a lead-in dose of Compound A in a lead-in dosing period and administering a maintenance dose of Compound A in a maintenance dosing regimen, wherein the lead-in dose of Compound A during the lead-in dosing period is lower than the maintenance dose of Compound A administered during the maintenance dosing regimen.
  • the method comprises administering Compound A in an intermittent dosing regimen; the intermittent dosing regimen comprises at least one treatment cycle; each treatment cycle comprises at least one break day; and Compound A is not administered on the break day.
  • the method of treating begins with administering Compound A with a lead-in dosing period or an intermittent dosing regimen.
  • the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer, and non-small cell lung cancer.
  • the cancer is melanoma.
  • the melanoma is cutaneous melanoma.
  • the melanoma is metastatic melanoma.
  • cancer is ovarian cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, RAF, BRAF, CRAF, ARAF, and their combination thereof; preferably RAS, NRAS, KRAS, RAF, BRAF, and their combination thereof; more preferably NRAS, KRAS, BRAF, and their combination thereof.
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; more preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and their combination thereof.
  • the cancer is characterized by other MAPK pathway genomic aberration.
  • the other MAPK pathway genomic aberration is RASA1 splice isoform.
  • the other MAPK pathway genomic aberration is RASA1 chr5: 86,587,807.
  • the treating begins with a lead-in dosing period; the lead-in dosing period comprises 2 to 48 days; and the dose of Compound A in the lead-in dosing period is lower than the dose of Compound A administered after the lead-in dosing period.
  • the method comprises administering a lead-in dose of Compound A in a lead-in dosing period; or the method comprises administering a lead-in dose of Compound A in a lead-in dosing period and administering a maintenance dose of Compound A in a maintenance dosing regimen; and the lead-in dose of Compound A during the lead-in dosing period is lower than the maintenance dose of Compound A administered during the maintenance dosing regimen.
  • the lead-in dosing period further comprises 1 to 14 break day(s);
  • Compound A is not administered in the break day(s); and the break days are consecutive days or non-consecutive days.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the lead-in dose of Compound A is administered in the first 5 days of each cycle; and Compound A is not administered in the last 2 days of each cycle. In one embodiment, the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of each cycle; and Compound A is not administered in the last 2 days of each cycle.
  • Compound A is administered at about 5 mg per day or about 10 mg per day during the lead-in dosing period. In one embodiment, Compound A is administered once per day during the lead-in dosing period.
  • the treating comprises an intermittent dosing regimen; the intermittent dosing regimen comprises 2 to 28 days; the intermittent dosing regimen further comprises 1 to 14 break days; Compound A is not administered in the break day(s); the break day(s) are consecutive days or non-consecutive days.
  • the intermittent dosing regimen comprises 1 to 4 cycles, wherein every cycle consists of 7 days; Compound A is administered in the first 5 days of each cycle; and Compound A is not administered in the last 2 days of each cycle.
  • Compound A is administered at about 15 mg per day or about 20 mg per day during the intermittent dosing regimen. In one embodiment, Compound A is administered once per day during the intermittent dosing regimen.
  • Compound A is administered at about 10 mg QD during the lead-in dosing period. In one embodiment, Compound A is administered at about 15 mg QD or about 20 mg QD during the intermittent dosing regimen. In one embodiment, Compound A is administered at about 15 mg QD or about 20 mg QD during the maintenance dosing regimen. [0034] In one embodiment, Compound A is administered one to three times a day. In one embodiment, Compound A is administered once a day. In one embodiment, Compound A is administered at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg per day.
  • Compound A is administered at about 15 mg per day or about 20 mg per day after the lead-in dosing period or the intermittent dosing regimen. In one embodiment, Compound A is administered once per day.
  • the method as described herein provides a plasma Compound A AUC24h between about 16,686 ng*h/ml and about 25,030 ng*h/ml in the subject. In one embodiment, the method as described herein provides a plasma Compound A AUC24h between about 22,052 ng*h/ml and about 33,078 ng*h/ml in the subject. In one embodiment, the method as described herein provides a plasma Compound A AUC2411 between about 38,358 ng*h/ml and about 57,536 ng*h/ml in the subject. In one embodiment, the method as described herein provides a plasma Compound A AUC2411 between about 41,534 ng*h/ml and about 62,302 ng*h/ml in the subject.
  • the subject achieves a stable disease, a partial response, or a complete response. In one embodiment, the subject does not experience a progressive disease.
  • Fig. 1 describes the best change (%) from baseline in sum of diameters per RECIST 1.1 (efficacy in total 37 evaluable patients).
  • Fig. 2 describes the study schema of dose-escalation and dose-finding component to establish the MTD and/or RP2D and to evaluate the PK of Compound A in combination with Compound B.
  • Fig. 3 describes the best change (%) from baseline in sum of diameters per RECIST 1.1 LGSOC patients.
  • Fig. 4 describes the mean plasma concentrations over time by doselevel and cycle presented graphically on a logarithmic scale.
  • Fig. 5 describes the Dose Escalation/Dose Finding Study Design/Schema.
  • Lead-in periods of 7 or 21 days are considered based on emergent data; DLT period adjusted as appropriate to include lead-in days.
  • BID twice a day
  • MTD maximum tolerated dose
  • PK pharmacokinetic(s)
  • QD once a day
  • RP2D recommended phase 2 dose.
  • Compound A refers to the compound having the name of 5- ((( 1 R, 1 aS,6bR)- 1 -(6-(trifluoromethy 1)- 1 H-benzo(d)imidazol-2-yl)- 1 a,6b-dihydro- 1 H- cyclopropa(b)benzofuran-5-yl)oxy)-3,4-dihydro-l,8-naphthyridin-2(lH)-one, or the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.
  • Compound A is disclosed and claimed, along with pharmaceutically acceptable salts thereof, and also as solvates thereof, as being useful as an inhibitor of BRAF activity, particularly in treatment of cancer, in WO2013097224, the entire disclosure of which is incorporated herein by reference.
  • Compound A is compound 2.2b in WO2013097224.
  • Compound A can be prepared as described in WO2013097224.
  • the international nonproprietary name of Compound A is lifirafenib.
  • Compound A is a hydrate.
  • “Compound A” as used herein refers to Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.
  • Compound B refers to the compound having the name of N-((R)- 2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, or the structure of formula (II): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.
  • Compound B is disclosed and claimed, along with pharmaceutically acceptable salts thereof, and also as solvates thereof, as being useful as an inhibitor of MEK activity, particularly in treatment of cancer, in W02002/06213, the entire disclosure of which is incorporated herein by reference.
  • Compound B is compound 49A in W02002/06213.
  • Compound B can be prepared as described in W02002/06213.
  • the international nonproprietary name of Compound B is mirdametinib.
  • “Compound B” as used herein refers to Compound B or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.
  • a MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase enzymes MEK1 or MEK2. They can be used to affect the MAPKZERK pathway.
  • MEK inhibitors include, but are not limited to, N-[3-[3-cyclopropyl-5-(2-fluoro-4- iodoanilino)-6,8-dimethyl-2,4,7-tnoxopyrido[4,3-d]pyrimidin-l-yl]phenyl]acetamide (GSK1120212), 6-(4-bromo-2-fluoro anilino)-7-fluoro-N-(2-hydroxyethoxy)-3- methylbenzimidazole-5-carboxamide (MEK162), N-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6- methoxyphenyl]-l-(2,3-dihydroxypropyl)cyclopropan
  • a BRAF inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase enzymes BRAF. They can be used to affect the MAPK/ERK pathway.
  • BRAF inhibitors include, but are not limited to, dabrafenib, vemurafenib, encorafenib, lifirafemb, LY3009120, PLX8394, LXH254, MLN2480, Raf709, TAK632, and PLX7904.
  • the term “combination” refers to more than one therapeutically active agents, such as Compound A and an inhibitor of MEK, used in coordinated fashion but does not
  • RECTIFIED SHEET (RULE 91 ) ISA/EP necessary mean that the more than one therapeutical active agents are in the same composition nor administered at the exact same time.
  • more than one therapeutically active agents can have separate dosing regimens, such as, one therapeutically active agent can be administered once a day while the other therapeutically active agent can be administered multiple times a day, or the different therapeutic agents can be dosed on different days.
  • the inhibitor of MEK is not Compound B.
  • neoplasm refers to an abnormal growth of cells or tissue and is understood to include benign, i.e., non-cancerous growths, and malignant, i.e., cancerous growths.
  • neoplastic means of or related to a neoplasm.
  • the term “agent” is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. Accordingly, the term “anti-neoplastic agent” is understood to mean a substance producing an anti-neoplastic effect in a tissue, system, animal, mammal, human, or other subject. It is also to be understood that an “agent” may be a single compound or a combination or composition of two or more compounds.
  • treating means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • prevention is not an absolute term. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing
  • RECTIFIED SHEET (RULE 91 ) ISA/EP cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • the term “effective amount” means that amount of a drug or pharmaceutical agent that elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • Compound A and/or any one of the MEK inhibitors disclosed herein may contain one or more chiral atoms, or may otherwise be capable of existing as enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of Compound A and inhibitors of MEK.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, compounds of formula (I) or (II) or a salt thereof and a solvent. Also, it is understood that compounds A and B may be presented, separately or both, as solvates. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethylsulforide, ethanol and acetic acid. In one embodiment, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. In another embodiment, the solvent used is water (i.e., a hydrate).
  • Compound A and any one of inhibitors of MEK as disclosed herein may have the ability to crystallize in more than one form, a characteristic, which is known polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of Compound A and inhibitors of MEK.
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in
  • Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • the terms “about” and “approximately,” when used in connection with a numeric value or range of values which is provided to characterize a particular solid form e.g., a specific temperature or temperature range, such as, for example, that describes a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the solid form.
  • Techniques for characterizing crystal forms and amorphous solids include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), singlecrystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.
  • TGA thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • XRPD X-ray powder diffractometry
  • IR infrared
  • Raman spectroscopy solid-state and solution nuclear magnetic resonance (NMR) spectroscopy
  • optical microscopy hot stage optical microscopy
  • SEM scanning electron microscopy
  • PSA
  • the terms “about” and “approximately,” when used in this context, indicate that the numeric value or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or
  • the value of an XRPD peak position may vary by up to ⁇ 0.2° 29 (or ⁇ 0.2 degrees 29) while still describing the particular XRPD peak.
  • the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base.
  • Suitable pharmaceutically acceptable base addition salts of the compounds provided herein include, but are not limited to those well-known in the art, see for example, Remington 's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy:, 19 th eds., Mack Publishing, Easton PA (1995).
  • stereoisomer or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • the compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
  • stereomerically pure forms of such compounds are encompassed by the embodiments disclosed herein.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein.
  • isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions
  • the compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
  • the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of the E and Z isomers.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other.
  • concentrations of the isomeric forms depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution
  • pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • the compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N).
  • an “isotopologue” is an isotopically enriched compound.
  • the term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.
  • “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • the term “isotopic composition” refers to the amount of each isotope present for a given atom.
  • Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be
  • isotopologues of the compounds for example, the isotopologues are deuterium, carbon- 13, or nitrogen- 15 enriched compounds.
  • Treating means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • “treating” means an alleviation, in whole or in part, of a disorder, disease or condition, or a slowing, or halting of further progression or worsening of those symptoms.
  • Preventing means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
  • the term “effective amount” in connection with a compound means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.
  • subject includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig, in one embodiment a mammal, in another embodiment a human.
  • compositions which include a Compound A, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Compound A is as described above.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical composition including admixing a Compound A with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Such elements of the pharmaceutical compositions utilized may be presented in separate pharmaceutical combinations or formulated together in one pharmaceutical composition. Accordingly, the invention further provides a pharmaceutically acceptable carriers, diluents, or excipients.
  • ISA/EP provides a pharmaceutical composition containing Compound A and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Compound A described above may be utilized in any of the compositions described above.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose depends on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
  • Compounds A and B may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It is appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that the Compounds A and B may be compounded together in a pharmaceutical composition.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.
  • Compound A may be employed in combination in accordance with the disclosure by administration simultaneously in a unitary pharmaceutical composition including both compounds.
  • the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.
  • kits or kit of parts as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A according to the disclosure.
  • the kit can contain Compound A in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
  • kit of parts comprising components: Compound A in association with a pharmaceutically acceptable excipients, diluents, or carrier.
  • the kit can also be provided with instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that are provided to a doctor, for example by a drug product label, or they can be of the kind that are provided by a doctor, such as instructions to a patient.
  • the term “lead-in dose(s)” as used herein is understood to mean one or more doses of Compound A having a dosage lower than the maintenance dose administered to the subject to, for example, lower the increase of the plasma or blood concentration level of the drug.
  • the “lead-in dose” can increase the plasma or blood concentration of the drug to a therapeutically effective level.
  • the “lead-in dose” can increase the plasma or blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug.
  • the “lead-in dose” can be administered once per day, or more than once per day (e.g., up to 4 times per day).
  • the “lead-in dose” is administered once a day.
  • the lead-in dose is an amount from about 40% to about 95% of the maintenance dose; suitably from about 55% to about 95%; suitably from about 65% to about 85%; suitably about 40%; suitably about 50%; suitably about 60%; suitably about 70%; suitably about 75%;
  • the lead-in dose of Compound A (based on weight of unsalted/unsolvated amount) administered as part of the combination is an amount selected from about 3 mg to about 60 mg; suitably, the amount is selected from about 5 mg to about 40 mg; suitably, the amount is selected from about 5 mg to about 30 mg; suitably, the amount is selected from about 5 mg to about 20 mg; suitably, the amount is selected from about 5 mg to about 15 mg; suitably, the amount is selected from about 5 mg to about 10 mg.
  • the amount of Compound A administered as part of the combination can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg; preferably about 5 mg, about 10 mg, or about 15 mg; more preferably about 10 mg.
  • the term “maintenance dose” as used herein is understood to mean a dose that is serially administered (for example; at least twice), and which is intended to either slowly raise plasma or blood concentration levels of the compound to a therapeutically effective level, or to maintain such a therapeutically effective level.
  • the maintenance dose is generally administered with a daily dose higher than the total daily dose of the lead-in dose.
  • the maintenance dose of Compound A (based on weight of unsalted/unsolvated amount) administered as part of the combination is an amount selected from about 3 mg to about 60 mg; suitably, the amount is selected from about 5 mg to about 40 mg; suitably, the amount is selected from about 10 mg to about 30 mg; suitably, the amount is selected from about 15 mg to about 20 mg.
  • the amount of Compound A administered as part of the combination can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg; preferably about 10 mg, about 15 mg, about 20 mg, or about 25 mg; more preferably about 15 mg, or about 20 mg.
  • maintenance dosing regimen as used herein is understood to mean a time period, wherein the maintenance dose is administered per day.
  • break day as used herein is understood to mean the time period when Compound A is not administered.
  • the break days comprise 1 to 14 days; suitably from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 5 days; suitably for 4 days; suitably for 3 days; suitably for 2 days; suitably for 1 day.
  • the break days are consecutive days or non-consecutive days.
  • lead-in dosing period is understood to mean the time period when the lead-in dose(s) may be administered. In one embodiment, the lead-in dosing
  • ISA/EP period comprises 1 to 48 days.
  • the lead-in dosing period further comprises 0-14 break day(s), preferably 0-7 break day(s), preferably break day(s),0-4 break day(s), preferably 0-2 break day(s), wherein Compound A is not administered in the break day(s).
  • the lead-in dose is administered for from 1 to 48 days; suitably from 1 to 28 days; suitably from 1 to 21 days; suitably from 1 to 14 days; suitably from 1 to 7 days; suitably from 1 to 5 days; suitably from 2 to 5 days; suitably for 5 days; suitably for 4 days; suitably for 3 day; suitably for 2 day; suitably for 1 day, followed by a maintenance dose.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the lead-in dose of Compound A is administered in the first 5 days of the 7-day cycle; and Compound A is not administered in the last 2 days of the 7-day cycle.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the lead-in dose of Compound A is administered in the first 5 days of the 7-day cycle; and Compound A is not administered in the last 2 days of the 7-day cycle.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of the 12-day cycle; and Compound A is not administered in the last 2 days of the 12-day cycle.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of the 7-day cycle; and Compound A is not administered in the last 2 days of the 10-day cycle.
  • the lead-in dosing period comprises 1 cycle. In one embodiment, the lead-in dosing period comprises 2 cycles. In one embodiment, the lead-in dosing period comprises 3 cycles. In one embodiment, the lead-in dosing period comprises 4 cycles.
  • the term “intermittent dosing regimen” as used herein is understood to mean a time period comprising break day(s).
  • the intermittent dosing regimen comprises 2 to 28 days.
  • the intermittent dosing regimen further comprises 1-14 break day(s); suitably 1 to 7 break days; suitably 1 to 5 break days; suitably 1 to 3 break days; suitably 5 break days; suitably 4 break days; suitably 3 break days; suitably 2 break day; suitably 1 break day, wherein Compound A is not administered in the break day(s).
  • the maintenance dose is administered in the intermittent dosing regimen.
  • the intermittent dosing regimen comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the maintenance dose of Compound A is administered in the first 5 days of the 7-day cycle; and
  • the intermittent dosing regimen comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the maintenance dose of Compound A is administered in the first 5 days of the 7-day cycle; and Compound A is not administered in the last 2 days of the 7-day cycle.
  • the intermittent dosing regimen comprises 1 cycle. In one embodiment, the intermittent dosing regimen comprises 2 cycles. In one embodiment, the intermittent dosing regimen comprises 3 cycles. In one embodiment, the intermittent dosing regimen comprises 4 cycles.
  • the amount of Compound A (based on weight of unsalted/unsolvated amount) administered as a part of the combination is an amount selected from about 3 mg to about 60 mg; suitably, the amount is selected from about 5 mg to about 60 mg; suitably, the amount is selected from about 5 mg to about 40 mg; suitably, the amount is selected from about 10 mg to about 40 mg; suitably, the amount is selected from about 15 mg to about 40 mg; suitably, the amount is selected from about 15 mg to about 30 mg; suitably, the amount is about 20 mg.
  • the amount of Compound A administered as a part of the combination can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg; preferably about 5 mg, about 10 mg, about 15 mg, or about 20 mg, more preferably about 10 mg, about 15 mg, or about 20 mg.
  • the selected amount of Compound A is administered from 1 to 4 times a day.
  • the selected amount of Compound A is administered twice a day.
  • the selected amount of Compound A is administered once a day.
  • the treatment of a cancer may be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see Thereasse P., et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer E.A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). European J. Cancer; 2009; (45) 228-247). Overall responses for all possible combinations of tumor responses in target and nontarget lesions with or without the appearance of new lesions are as follows:
  • CR complete response
  • PR partial response
  • SD stable disease
  • PD progressive disease.
  • complete response is the disappearance of all target lesions
  • partial response PR
  • partial response is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter
  • progressive disease is at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions
  • stable disease (SD) is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.
  • complete response is the disappearance of all non-target lesions and normalization of tumor marker level
  • incomplete response/stable disease is the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits
  • progressive disease is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
  • the baseline MRI scan is defined as the assessment performed at the end of the post-surgery rest period, prior to initiating or re-initiating compound treatment.
  • the baseline MRI is used as the reference for assessing complete response (CR) and partial response (PR).
  • the smallest SPD sum of the products of perpendicular diameters obtained either at baseline or at subsequent assessments are designated the nadir assessment and utilized as the reference for determining progression.
  • subjects receive either no glucocorticoids or are on a stable dose of glucocorticoids.
  • a stable dose is defined as the same daily dose for the 5 consecutive days preceding the MRI scan. If the prescribed glucocorticoid dose is changed in the 5 days before the baseline scan, a new baseline scan is required with glucocorticoid use meeting the criteria described above. The following definitions are used.
  • Measurable lesions are contrast-enhancing lesions that can be measured bi-dimensionally. A measurement is made of the maximal enhancing tumor diameter (also known as the longest diameter, LD). The greatest perpendicular diameter is measured on the same image. The cross hairs of bi-dimensional measurements should cross and the product of these diameters are calculated.
  • Minimal Diameter T1 -weighted image in which the sections are 5 mm with 1 mm skip.
  • the minimal LD of a measurable lesion is set as 5 mm by 5 mm. Larger diameters may be required for inclusion and/or designation as target lesions. After baseline, target lesions that become smaller than the minimum requirement for measurement or become no longer amenable to bi-dimensional measurement are recorded at the default value of 5 mm for each diameter below 5 mm. Lesions that disappear are recorded as 0 mm by 0 mm.
  • Multi centric Lesions Lesions that are considered multicentric (as opposed to continuous) are lesions where there is normal intervening brain tissue between the two (or more) lesions. For multicentric lesions that are discrete foci of enhancement, the approach is to separately measure each enhancing lesion that meets the inclusion criteria. If there is no normal brain tissue between two (or more) lesions, they are considered the same lesion.
  • Nonmeasurable Lesions All lesions that do not meet the criteria for measurable disease as defined above are considered non-measurable lesions, as well as all non-enhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include foci of enhancement that are less than the specified smallest diameter (i.e., less than 5 mm by 5 mm), non-enhancing
  • ISA/EP lesions e.g., as seen on T1 -weighted post-contrast, T2-weighted, or fluid-attenuated inversion recovery (FLAIR) images
  • FLAIR fluid-attenuated inversion recovery
  • Hemorrhagic lesions often have intrinsic T1 -weighted hyperintensity that could be misinterpreted as enhancing tumor, and for this reason, the pre-contrast T1 -weighted image may be examined to exclude baseline or interval sub-acute hemorrhage.
  • Target lesions Up to 5 measurable lesions can be selected as target lesions with each measuring at least 10 mm by 5 mm, representative of the subject’s disease;
  • Non-target lesions All other lesions, including all nonmeasurable lesions (including mass effects and T2/FLAIR findings) and any measurable lesion not selected as a target lesion.
  • target lesions are to be measured as described in the definition for measurable lesions and the SPD of all target lesions is to be determined. The presence of all other lesions is to be documented.
  • the baseline classification of lesions as target and non-target lesions are maintained and lesions are documented and described in a consistent fashion over time e.g., recorded in the same order on source documents and eCRFs). All measurable and nonmeasurable lesions must be assessed using the same technique as at baseline (e.g., subjects should be imaged on the same MRI scanner or at least with the same magnet strength) for the duration of the study to reduce difficulties in interpreting changes.
  • target lesions are measured and the SPD calculated.
  • Non-target lesions are assessed qualitatively and new lesions, if any, are documented separately.
  • a time point response is determined for target lesions, non-target lesions, and new lesion. Tumor progression can be established even if only a subset of lesions is assessed. However, unless progression is observed, objective status (stable disease, PR or CR) can only be determined when all lesions are assessed.
  • Compound A having the name of 5-(((lR,laS,6bR)-l-(6-
  • kits comprising a combination provided herein and means for monitoring patient response to administration of said combination provided herein.
  • the patient has colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer, and non-small cell lung cancer.
  • the patient response measured is inhibition of disease progression, inhibition of tumor growth, reduction of primary and/or secondary tumor(s), relief of tumor-related symptoms, improvement in quality of life, delayed appearance of primary and/or secondary tumors, slowed development of primary and/or secondary tumors, decreased occurrence of primary and/or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth or regression of tumor.
  • kits comprising a combination provided herein and means for measuring the amount of inhibition of B-RAF or MEK in a patient.
  • kits comprise means for measuring inhibition of B-RAF or MEK in circulating plasma, blood, or tumor cells and/or skin biopsies or tumor biopsies/aspirates of a patient.
  • kits comprising a combination provided herein and means for measuring the amount of inhibition of B-RAF or MEK before, during
  • the patient has colorectal cancer, pancreatic cancer, melanoma, ovarian cancer, or non-small cell lung cancer.
  • kits provided herein comprise an amount of a combination provided herein effective for treating or preventing colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer, and non-small cell lung cancer.
  • the kits provided herein comprise an amount of a combination provided herein effective for treating or preventing colorectal cancer, pancreatic cancer, melanoma, ovarian cancer, or non-small cell lung cancer.
  • kits provided herein further comprise instructions for use, such as for administering a combination provided herein and/or monitoring patient response to administration of the combination.
  • a method of treating a cancer in a subject in need thereof comprising administering to said subject the combination disclosed herein.
  • the treating begins with a lead-in dosing period; the lead-in dosing period comprises 2 to 48 days; and the dose of Compound A in the lead-in dosing period is lower than the dose of Compound A administered after the lead-in dosing period.
  • the method comprises administering a lead-in dose of Compound A in a lead-in dosing period; or the method comprises administering a lead-in dose of Compound A in a lead-in dosing period and administering a maintenance dose of Compound A in a maintenance dosing regimen; and the lead-in dose of Compound A during the lead-in dosing period is lower than the maintenance dose of Compound A administered during the maintenance dosing regimen.
  • the lead-in dosing period further comprises 1 to 14 break day(s);
  • Compound A is not administered in the break day(s); and the break days are consecutive days or non-consecutive days.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 7 days; the lead-in dose of Compound A is administered in the first 5 days of each cycle; and Compound A is not administered in the last 2 days of each cycle.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of the 12-day cycle; and Compound A is not administered in the last 2 days of the 12-day cycle.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A is administered in the first 10 days of the 7-day cycle; and Compound A is not administered in the last 2 days of the 10-day cycle.
  • Compound A in the lead-in dosing period, is administered about 5 or about 10 mg per day; preferably about 10 mg per day.
  • Compound A in the lead-in dosing period, is administered once per day.
  • the treating begins with an intermittent dosing regimen; the intermittent dosing regimen comprises 2 to 28 days; the intermittent dosing regimen further comprises 1 to 14 break days;
  • Compound A is not administered in the break day(s); the break day(s) are consecutive days or non-consecutive days.
  • the intermittent dosing regimen comprises 1 to 4 cycles, wherein every cycle consists of 7 days; Compound A is administered in the first 5 days of each cycle; and Compound A is not administered in the last 2 days of each cycle.
  • Compound A in the intermittent dosing regimen, is administered about 15 or about 20 mg per day.
  • Compound A is administered once per day.
  • Compound A is administered with a lead-in dosing period, or an intermittent dosing regimen at the beginning.
  • Compound A is administered about 15 or about 20 mg per day after the lead-m dosing period, or an intermittent dosing regimen.
  • Compound A is administered once per day.
  • the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer, and non-small cell lung cancer.
  • the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, RAF, BRAF, CRAF, ARAF, and their combination thereof; preferably RAS, NRAS, KRAS, RAF, BRAF, and their combination thereof; more preferably NRAS, KRAS, BRAF, and their combination thereof.
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; more preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and their combination thereof.
  • the cancer is characterized by other MAPK pathway genomic aberration.
  • the other MAPK pathway genomic aberration is RAS Al splice isoform.
  • the other MAPK pathway genomic aberration is RASA1 chr5: 86,587,807.
  • the cancer is characterized by a mutation in a gene selected from the group consisting of ARAF, BRAF, RAFI, KRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, and their combination thereof.
  • the cancer is characterized by a mutation selected from the group consisting of BRAF N20T, BRAF A33T, BRAF S36A, BRAF V47_G393del, BRAF V47_G327del, BRAF V47_D380del, BRAF V47_M438del, BRAF N49I, BRAF M53I, BRAF L64I, BRAF G69S, BRAF A81_D380del, BRAF A81_M438del, BRAF G104E, BRAF T119S, BRAF P141L, BRAF S151A, BRAF P162S, BRAF V169 G327del, BRAF V169 D380del, BRAF R188T, BRAF Q201H, BRAF G203_G393del, BRAF K205Q, BRAF V226L, BRAF E228V, BRAF R239Q, BRAF T241P, BRAF T241M, BRAF L245F, BRAF A2
  • RECTIFIED SHEET (RULE 91 ) ISA/EP V600K, BRAF V600R, BRAF V600Q, BRAF V600dup, BRAF V600delinsYM, BRAF V600M, BRAF V600L, BRAF V600D, BRAF V600_K601delinsE, BRAF V600E, BRAF V600A, BRAF V600G, BRAF K601del, BRAF K601Q, BRAF K601E, BRAF K601_W604del, BRAF K601T, BRAF K601I, BRAF K601_S602delinsNT, BRAF K601N, BRAF S602T, BRAF S602Y, BRAF S602F, BRAF R603*, BRAF W604del, BRAF W604R, BRAF W604G, BRAF S605A, BRAF S605F, BRAF S605E, BRAF S605G, BRAF S605N,
  • the cancer is characterized by a mutation selected from the group consisting of KIAA1549-BRAF fusion, BCAS1-BRAF fusion, CCDC6-BRAF fusion, CDC42BPB-BRAF fusion, FAM131B-BRAF fusion, FXR1-BRAF fusion, GIT2-BRAF fusion, KLHL7-BRAF fusion, RNF130-BRAF fusion, TMEM106B-BRAF fusion, MKRN1-BRAF fusion, AGAP3-BRAF fusion, AGK-BRAF fusion, AKAP9-BRAF fusion, ARMCI 0-BRAF fusion, CUL1-BRAF fusion, GTF2I-BRAF fusion, PAPS SI -BRAF fusion, PCBP2-BRAF fusion, PPFIBP2-BRAF fusion, SND1-BRAF fusion, TRIM24-BRAF fusion, ZKSCAN1-BRAF fusion, SEPT3-BRAF fusion, and
  • the cancer is characterized by a mutation selected from the group consisting of NRAS G12A, NR AS G12C, NRAS G12D, NR AS G12N, NRAS G12P, NRAS G12R, NRAS G12S, NRAS G12V, NRAS G12Y, NRAS G13A, NRAS G13C, NRAS G13D, NRAS G13E, NRAS G13N, NRAS G13R, NRAS G13S, NRAS G13V, NRAS A18T, NRAS I24N, NRAS P34L, NRAS Y40*, NRAS Q43*, NRAS T50I, NRAS T58I, NRAS A59G, NRAS A59D, NRAS A59T, NRAS G60E, NRAS G60R, NRAS Q61E, NRAS Q61H, NRAS Q61H, NRAS Q61K
  • the cancer harbors the mutations as described herein. In some embodiments, the subject with the cancer harbors the mutations as described herein.
  • the cancer is melanoma. In one embodiment, the melanoma is cutaneous melanoma. In one embodiment, the melanoma is metastatic melanoma. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is non-small cell lung cancer.
  • each of Compound A is administered one to three times a day. In one embodiment, Compound A is administered once a day.
  • said administration of the combination results in an AUC24h of Compound A between about 16,686 ng*h/ml and about 25,030 ng*h/ml.
  • said administration of the combination results in an AUC2411 of Compound A between about 22,052 ng*h/ml and about 33,078 ng*h/ml.
  • said administration of the combination results in an AUC2411 of Compound A between about 38,358 ng*h/ml and about 57,536 ng*h/ml.
  • said administration of the combination results in an AUC2411 of Compound A between about 41,534 ng*h/ml and about 62,302 ng*h/ml.
  • the AUC2411 is measured in the subject’s plasma. In some embodiments, the AUC2411 is measured in the subject’s blood. In some embodiments, the AUC2411 is measured in the subject’s plasma or blood on Day 29. In some embodiments, the AUC2411 is measured in the subject’s plasma or blood on Day 29 with maintenance dose.
  • the subject achieves a stable disease, a partial response, or a complete response. In one embodiment, the subject achieves a partial response or a complete response. In one embodiment, the subject achieves a complete response. In one embodiment, the subject does not experience a progressive disease. In one embodiment, the subject achieves a stable disease. In one embodiment, the subject achieves a partial response. In one embodiment, the subject achieves a stable disease, a partial response, or a complete response for 1 week, 2 weeks, 3 weeks, or 4 weeks.
  • the subject achieves a stable disease, a partial response, or a complete response for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months. In one embodiment, the subject achieves a stable disease, a partial response, or a complete response for 1 year, 2 years, 3 years or 4 years.
  • RECTIFIED SHEET (RULE 91 ) ISA/EP
  • a method of treating a cancer in a subject in need thereof comprising administering to said subject the combination of an inhibitor of BRAF and an inhibitor of MEK, wherein the cancer is characterized by a mutation selected from the group consisting of RAS, NRAS, KRAS, and their combination thereof; preferably NRAS, and KRAS, and their combination thereof; more preferably KRAS.
  • the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, ovarian cancer and non- small cell lung cancer.
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof; more preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and their combination thereof.
  • the dosage form and administration route should be selected depending on the compatibility of the combined Compound A and an inhibitor of MEK.
  • the administration of Compound A and an inhibitor of MEK is understood to include the administration of Compound A and an inhibitor of MEK concomitantly or sequentially, or alternatively as a fixed dose combination of the at least two active components.
  • COMPOUND A USED AS A SINGLE AGENT AND OTHER COMBINATIONS [00142] Provided here is a method of treating a cancer in a subject in need thereof, comprising administering to the subject Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.
  • the method comprises administering a lead-in dose of Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer,
  • RECTIFIED SHEET (RULE 91 ) ISA/EP isotopologue, solvate, or prodrug thereof in a lead-in dosing period and administering a maintenance dose of Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof in a maintenance dosing regimen, wherein the lead-in dose of Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof during the lead-in dosing period is lower than the maintenance dose of Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof administered during the maintenance dosing regimen.
  • the method comprises administering Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof in an intermittent dosing regimen; the intermittent dosing regimen comprises at least one treatment cycle; each treatment cycle comprises at least one break day; and
  • the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, and thyroid tumor.
  • the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, RAF, BRAF, CRAF, ARAF, and their combination thereof.
  • the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, RAF, BRAF, and their combination thereof.
  • the cancer is characterized by a mutation in a gene selected from the group consisting of NRAS, KRAS, BRAF, and their combination thereof.
  • the cancer is characterized by:
  • RECTIFIED SHEET (RULE 91 ) ISA/EP (i) a mutation in a gene selected from the group consisting of ARAF, BRAF, RAFI, KRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, and their combination thereof;
  • RECTIFIED SHEET (RULE 91 ) ISA/EP fusion, RNF130-BRAF fusion, TMEM106B-BRAF fusion, MKRNl-BRAF fusion, AGAP3-BRAF fusion, AGK-BRAF fusion, AKAP9-BRAF fusion, ARMCI 0-BRAF fusion, CUL1-BRAF fusion, GTF2I-BRAF fusion, PAPSS1-BRAF fusion, PCBP2-BRAF fusion, PPFIBP2-BRAF fusion, SND1-BRAF fusion, TRIM24-BRAF fusion, ZKSCAN1- BRAF fusion, SEPT3-BRAF fusion, and their combination thereof; or
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof.
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof.
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and their combination thereof.
  • the cancer is characterized by other MAPK pathway genomic aberration.
  • the other MAPK pathway genomic aberration is RASA1 splice isoform.
  • the other MAPK pathway genomic aberration is RASA1 chr5: 86,587,807.
  • the cancer is melanoma.
  • the melanoma is cutaneous melanoma.
  • the melanoma is metastatic melanoma.
  • the cancer is ovarian cancer.
  • the cancer is non-small cell lung cancer.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered one to three times a day.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered once a day.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg per day.
  • the lead-in dosing period is 2 to 48 days.
  • 1 to 14 days of the lead-in period are break days, wherein: Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is not administered on the break days; and the break days are consecutive days or non-consecutive days.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein each cycle is 7 days; Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered on the first 5 days of each cycle of the lead-in dosing period; and Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is not administered on the last 2 days of each cycle of the lead- in dosing period.
  • the lead-in dosing period comprises 1 to 4 cycles, wherein every cycle consists of 12 days; the lead-in dose of Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug
  • RECTIFIED SHEET (RULE 91 ) ISA/EP thereof is administered on the first 10 days of each cycle of the lead-in dosing period; and Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is not administered on the last 2 days of each cycle of the lead-in dosing period.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered at about 5 mg per day or about 10 mg per day during the lead-in dosing period.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered at about 10 mg per day during the lead-in dosing period.
  • the intermittent dosing regimen is 2 to 28 days, wherein:
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is not administered on the break days; and the break days are consecutive days or non-consecutive days.
  • the intermittent dosing regimen comprises 1 to 4 cycles, wherein each cycle is 7 days; Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered on the first 5 days of each cycle of the intermittent dosing regimen; and Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is not administered on the last 2 days of each cycle of the intermittent dosing regimen.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered at about 15 mg per day or about 20 mg per day during the intermittent dosing regimen.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered once per day during the intermittent dosing regimen.
  • the treating begins with administering Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof with a lead-in dosing period or an intermittent dosing regimen.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered at about 15 mg or about 20 mg per day after the lead-in dosing period or the intermittent dosing regimen.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered at about 15 mg QD or about 20 mg QD during the intermittent dosing regimen.
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered at about 15 mg QD or about 20 mg QD during the maintenance dosing regimen.
  • each of Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered once per day.
  • the method provides a plasma Compound A AUC2411 between about 16,686 ng*h/ml and about 25,030 ng*h/ml in the subject.
  • the method provides a plasma Compound A AUC2411 between about 22,052 ng*h/ml and about 33,078 ng*h/ml in the subject.
  • the method provides a plasma Compound A AUC2411 between about 38,358 ng*h/ml and about 57,536 ng*h/ml in the subject.
  • the method provides a plasma Compound A AUC2411 between about 41,534 ng*h/ml and about 62,302 ng*h/ml in the subject.
  • the AUC2411 is measured in the subject’s plasma. In some embodiments, the AUC2411 is measured in the subject’s blood. In some embodiments, the AUC2411 is measured in the subject’s plasma or blood on Day 29. In some embodiments, the AUC2411 is measured in the subject’s plasma or blood on Day 29 with maintenance dose.
  • the subject achieves a stable disease, a partial response, or a complete response.
  • the subject achieves a partial response or a complete response.
  • the subject achieves a complete response.
  • the subject does not experience a progressive disease.
  • the subject achieves a stable disease.
  • the subject achieves a partial response.
  • the subject achieves a stable disease, a partial response, or a complete response for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, the subject achieves a stable disease, a partial response, or a complete response for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months. In one embodiment, the subject achieves a stable disease, a partial response, or a complete response for 1 year, 2 years, 3 years, or 4 years.
  • [00191] Provided herein is a method of treating a cancer in a subject in need thereof, comprising administering to said subject the combination of Compound A and an inhibitor of MEK, wherein the inhibitor of MEK is not Compound B, or Selumetinib (AZD6244).
  • the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, and their combination thereof.
  • the cancer is characterized by a mutation in a gene selected from the group consisting of NRAS, KRAS, and their combination thereof.
  • the cancer is characterized by a mutation in KRAS.
  • the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, and thyroid tumor.
  • the cancer is selected from the group consisting of melanoma, ovarian cancer, and non-small cell lung cancer.
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS
  • RECTIFIED SHEET (RULE 91 ) ISA/EP G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof.
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof.
  • the cancer is characterized by a mutation selected from the group consisting of NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and their combination thereof.
  • the cancer is characterized by:
  • a mutation in a gene selected from the group consisting of ARAF, BRAF, RAFI, KRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, and their combination thereof;
  • BRAF Q609E BRAF Q609L, BRAF Q609H, BRAF E61 ID, BRAF L613F, BRAF G615R, BRAF L618F, BRAF W619R, BRAF S637*, BRAF V639I, BRAF E648Q, BRAF Y656D, BRAF R671Q, BRAF P676S, BRAF L678I, BRAF V681I, BRAF E695K, BRAF K698R, BRAF L71 IF, BRAF A712T, BRAF R719S, BRAF H725Y, BRAF A728V, BRAF P731T, BRAF P731S, BRAF P731L, BRAF A762E, BRAF A762V, and their combination thereof;
  • Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof is administered at about 10 mg QD during the lead-in dosing period.
  • Compound A can be prepared as described in WO2013097224. In one embodiment, Compound A may be prepared according to the methods below:
  • Step A (lS,laS,6bR)-ethyl 5-((7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4-yl)oxy)- la,6b-dihydro- 1 H-cyclopropa(b)benzo
  • Step B (!S,laS,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4-yl)oxy)-la,6b- dihydro- 1 H-cyclopropa(b)benzofuran- 1 -carboxylic acid
  • Step C 5-(((lR, 1 aS,6bR)- 1 -(6-(trifluoromethyl)- lH-benzo(d)imidazol-2-yl)- 1 a,6b-dihydro-lH-cyclopropa(b)benzofuran-5-yl)oxy)-3,4-dihydro-l,8-naphthyridin-2(lH)-one [00210] The mixture of the product of Step B (50 mg, 0.15 mmol), 4- (trifluoromethyl)benzene-l,2-diamine (26 mg, 0.15 mmol), DIPEA (0.1 mL) and HATU (84 mg, 0.22 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic phase
  • Compound B can be prepared as described in W02002/06213. In one embodiment, Compound B may be prepared according to the methods below:
  • Step A To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (2.25 g, 5.10 mmol) in dry tetrahydrofuran under nitrogen atmosphere, at -15 °C was added diphenylphosphimc chloride (1.26 mL, 6.63 mole) drop wise.
  • Step B N-((R)-2,2-Dimethyl-(l,3)dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide (0.210 g, 0.40 mmol) was suspended in 10:1 methanol/H O and pTsOH’ELO (0.008 g, 0.04 mmol) was added. The mixture was stirred at ambient temperature for 18 hrs, during which all solids dissolved to give a colorless, clear solution. The solution was diluted with EtOAc. The organic solution was washed with sodium bicarbonate (2x), brine (lx) and dried over Na2SO4.
  • Study Compound A was a Phase la/lb, open-label, multiple-dose, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and preliminary antitumor activities of the RAF dimer inhibitor Compound A in patients with solid tumors. This was a 2- stage study, consisting of a Phase 1 a dose-escalation and dose-finding component to establish the MTD and recommended phase 2 dose (RP2D), followed by a Phase lb dose-expansion component, to investigate efficacy in selected tumor types and further evaluate safety and tolerability of Compound A.
  • Phase 1 a dose-escalation and dose-finding component to establish the MTD and recommended phase 2 dose (RP2D)
  • Phase lb dose-expansion component to investigate efficacy in selected tumor types and further evaluate safety and tolerability of Compound A.
  • the MTD of Compound A was determined as 40 mg once a day, and 30 mg once a day was chosen as the RP2D for the associated Phase lb study (indication-specific expansion cohorts).
  • TEAE 87 (90.6%) patients experienced at least 1 TEAE assessed as related to Compound A by the investigator.
  • the most commonly occurring TEAEs assessed as related to Compound A treatment were fatigue (38.5%), dysphonia (26.0%), palmar- plantar erythrodysaesthesia syndrome (20.8%), decreased appetite (21.9%), thrombocytopenia and rash (19.8%, each), diarrhea (18.8%), dermatitis acneiform (17.7%), nausea (16.7%), hypertension (12.5%), and glossodyma and vomiting (10.4%, each).
  • Treatment-emergent serious adverse events 20 patients (20.8%) had at least 1 treatment-related treatment- emergent serious adverse event. These were thrombocytopenia and pyrexia in 3 patients (3.1%), febrile neutropenia and hypothyroidism in 2 patients (2.1%), and fatigue, pneumonia, alanine aminotransferase increased, liver function test abnormal, stomatitis, hyperbilirubinaemia, hyponatraemia, syncope, drug reaction with eosinophilia and systemic symptoms, and hypertension in 1 patient each (1.0%).
  • RECTIFIED SHEET (RULE 91 ) ISA/EP preferred term were hypertension, fatigue, thrombocytopenia, and hyponatremia, these AEs were manageable. No cutaneous squamous cell carcinoma was found with Compound A in this study. [00231] Antitumor activity was not only observed in patients with B-RAF mutated solid tumors including melanoma, thyroid cancer, papillary thyroid cancer, and ovarian cancer, with a highest objective response rate (ORR) of 57.1% in patients with B-RAF V600 mutated melanoma, but also in patients with K-RAS mutated NSCLC and endometrial cancer.
  • ORR objective response rate
  • Stage 1 and Stage 2 were conducted. Twenty-two solid tumor patients and 20 advanced melanoma patients were enrolled. Based on the acquired data of Compound A from Stage 1 study, 20 mg once a day was recommended in the dose expansion stage. In Stage 2 dose expansion, 20 patients with advanced melanoma harboring B-RAF mutation were treated and Compound A was tolerated at 20 mg once aday. Clinical and durable benefit was seen in several patients at Compound A monotherapy once a day dosing levels from 10 mg to 30 mg. However, the percentage of patients experiencing platelet decreased events at 20 mg was rising and, as noted by the Safety Monitoring Committee(SMC), had the potential to cause a risk/benefit ratio imbalance in these trial patients.
  • SMC Safety Monitoring Committee
  • Study Compound A was completed and reported without the results on ClinicalTrials.gov with an identifier of NCT03641586 and a title of “The Study of Compound A in Chinese Subjects With Local Advanced or Metastatic Malignant Solid Tumor,” the entire disclosure of which is incorporated herein by reference.
  • Study Compound A was a 3-stage study consisting of a dose-escalation and dosefinding stage (Stage 1) to explore the MTD and to determine the RP2D, followed by a dose expansion stage (Stage 2) to explore the antitumor activity of Compound A by assessing the
  • RECTIFIED SHEET (RULE 91 ) ISA/EP ORR of melanomausing Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
  • the third stage (Stage 3) was an evaluation of the effect of food on single and multiple oral doses of Compound A. Stage 3 of the study was not carried out.
  • Stage 1 and Stage 2 were conducted. Twenty-two solid tumor patients and 20 advanced melanoma patients were enrolled. Based on the acquired data of Compound A from Stage 1 of the Compound A study, 20 mg once a day was recommended in the dose expansion stage. In Stage 2 dose expansion, 20 patients with advanced melanoma harboring B-RAF mutation were treated and Compound A was tolerated at 20 mg once aday. Clinical and durable benefit was seen in several patients at Compound A monotherapy once a day dosing levels from 10 mg to 30 mg.
  • Phase 1 trial PK analysis was conducted by using plasma concentrationsfrom 35 patients who received doses of 15 mg twice daily, 5, 10, 20, 30, 40, 50, or 60 mg oncedaily (Phase 1 A), and 96 patients who received doses of 30 mg once daily (Phase IB).
  • the PK Analysis Set for both Phase 1 A and Phase IB was defined as patients who had receivedat least the first dose of Compound A and provided PK samples per protocol following first dosing on Day 1.
  • PK parameters were calculated by noncompartmental analysis methods and are presented in Table 2. Mean plasma concentrations over time by doselevel and cycle are presented graphically in Fig. 4 on a logarithmic scale.
  • the accumulation ratios (Phase 1A) of Cmax, AUCo-9, and AUCo-24 for (Cycle 2 Dayl)/(Cycle 1 Day 1) were similar for 10 mg to 50 mg dose levels, with average accumulation by dose level ranging from 3.3- to 6.1 -fold for Cmax, and from 3.6- to 7.6-fold for AUC0-9 and AUCo-24.
  • the terminal half-life was able to be measured for only three patients and ranged from 15 to 59 hours; however, because samples were not collected beyond 72 hours after dosing, the estimation of terminal half-life should be interpreted with caution.
  • Study Compound A+Compound B was an open-label, multicenter, dose-escalation and expansion Phase lb study investigating the safety, pharmacokinetics, and preliminary antitumor activity of the RAF dimer inhibitor Compound A in combination with MEK inhibitor Compound B in patients with advanced or refractory solid tumors.
  • intermittent dosing was QD dosing for 5 days followed by a 2-day break.
  • Protocol Title A Phase lb, Open-Label, Dose-escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activities of a RAF Dimer Inhibitor Compound A in Combination with a MEK inhibitor Compound B in Patients with Advanced or Refractory Solid Tumors
  • Level 1 15 mg Compound A + 2 mg Compound B given QD (continuous dosing regimen); enrolled 6 patients with 5 completed and 1 ongoing.
  • Level 2 20 mg Compound A + 2 mg Compound B given QD (continuous dosing regimen); enrolled 8 patients with 2 completed, 2 discontinued, and 4 ongoing.
  • Level 3 a 20 mg Compound A + 3 mg Compound B given QD for 5 days followed by a 2-day break (intermittent dosing regimen); enrolled 6 patients with 1 discontinued and 5 ongoing.
  • Level 4a 20 mg Compound A + 4 mg Compound B given QD for 5 days followed by a 2-day break (intermittent dosing regimen); enrolled 6 patients with 4 discontinued and 2 ongoing.
  • the RP2D were determined based on safety, tolerability, PK, preliminary efficacy, and other available data.
  • PK parameters including but not limited to single dose: AUC, Cmax, and Tmax; steady state: AUClast,ss, Cmax,ss, and Tmax,ss.
  • Efficacy parameters including:
  • ORR defined as the proportion of patients who had confirmed CR or PR assessed by investigator using RECIST 1.1.
  • Disease control rate defined as the proportion of patients with best overall response of confirmed CR, PR, or stable disease.
  • Duration of response defined as the time from the first determination of an objective response per RECIST 1.1, until the first documentation of progression or death, whichever occurs first.
  • Clinical benefit rate defined as the proportion of patients with best overall response of confirmed CR or PR or stable disease lasting 24 weeks.
  • PFS defined as the time from first dose of study treatment to the first documented disease progression or death due to any cause, whichever occurs first.
  • RECTIFIED SHEET (RULE 91 ) ISA/EP [003081
  • mitogen activated protein kinase (MAPK) signaling including phosphorylated extracellular signal-regulated kinase (phospho- ERK), v-RAF murine sarcoma viral oncogene homolog B (B-RAF), KRAS proto- oncogene, GTPase (K-RAS), NRAS proto-oncogene, GTPase (N-RAS), A-Raf proto-oncogene serine/threonine kinase (A-RAF), neurofibromin 1 (NF1) mutation, B-RAF or Raf-1 protooncogene serine/threonine kinase (C-RAF) amplification and other aberrations in, or affecting, the MAPK pathway.
  • MAPK mitogen activated protein kinase
  • phospho- ERK phosphorylated extracellular signal-regulated kinase
  • B-RAF
  • ORR as described in Part A. Also, duration of response, disease control rate, clinical benefit rate, and PFS were evaluated.
  • PK parameters for Compound B and the active metabolite PD-0315209 including but not limited to: AUC, Cmax, and Tmax.
  • PK parameters for Compound A including but not limited to: AUC, Cmax, and Tmax.
  • RECTIFIED SHEET (RULE 91 ) ISA/EP serine/threonine kinase 1 (AKT1), MET proto-oncogene, receptor tyrosine kinase (MET), KIT proto-oncogene, receptor tyrosine kinase (KIT), and insulin like growth factor 1 receptor (IGF1R)).
  • AKT1 serine/threonine kinase 1
  • MET MET proto-oncogene
  • MET receptor tyrosine kinase
  • KIT KIT proto-oncogene
  • IGF1R insulin like growth factor 1 receptor
  • Part A consisted of a dose-escalation and dose-finding component to establish the MTD and/or RP2D and to evaluate the PK of Compound B (and its active metabolite PD- 0315209) in combination with Compound A (see Fig. 2 Study Schema).
  • Part B consisted of a component to further evaluate the PK, safety, and tolerability of the combination of Compound B and Compound A and to assess the preliminary antitumor activity of the combination in patients in each of the 3 groups with selected tumor types.
  • Levels 1 and 2 were dosed continuously; levels 3a and 4a were dosed on an intermittent schedule: QD doses for 5 days followed by a 2-day break. Other cohorts were dosed on the following intermittent schedule: QD doses for 5 days followed by a 2- day break/4-week cycles. Lead-in periods of 7 or 21 days may be considered based on emergent based on emergent data; DLT period was adjusted as appropriate to include lead-in days. Abbreviations: BID, twice a day; QD, once a day; RP2D, recommended phase 2 dose.
  • Baseline tumor tissue was mandatory for mutation and biomarker analysis, either from archived tumor tissue or fresh tumor biopsies. With the patient’s consent, a follow-up biopsy may be taken for the analysis of PD biomarkers, ideally from the same tumor lesion if it was readily accessible.
  • paired fresh tumor biopsies were mandatory and were collected within the 8 weeks before the first dose of study treatment and again at a time post-dose to assess PD biomarkers.
  • blood samples were collected from all patients for mutation profiling by next generation sequencing. Additional biomarker analysis from the blood might also be conducted by other assay types.
  • Level 3b and 3c Two dose escalation arms, Levels 3b and 3c, were planned to be opened in parallel. Subsequent dose levels were based on emergent data. Lead-in periods of 7 or 21 days may also be considered whereby the DLT period would adjust as appropriate to include the lead-in days. [00323] Level 3c and subsequent levels implemented BID dosing for Compound B.
  • Part A was a multicenter, open-label, multiple-dose, dose-escalation study in patients with tumors harboring B-RAF or K-RAS/N-RAS mutations or MAPK pathway or other genomic aberrations that may potentially respond to a RAF dimer inhibitor or a MEK inhibitor (including
  • RECTIFIED SHEET (RULE 91 ) ISA/EP BRAF, ARAF, RAFI, KRAS, NRAS, HR AS, NF1, MAP2K1, MAP2K2, MAPK1, EGER, GNA11, GNAQ, PIK3CA, PIK3CB, PTEN, AKT1, MET, KIT, or IGF1R).
  • the study recruited no more than 50% of patients with CRC or pancreatic cancer with confirmed K-RAS mutations.
  • Investigators were encouraged to enroll patients with non-small cell adenocarcinoma of the lung (NSCLC-adenoca) harboring any variants of KRAS, NRAS, or BRAF mutations or cutaneous melanoma harboring any variants of KRAS or NRAS mutations.
  • NSCLC-adenoca non-small cell adenocarcinoma of the lung
  • BRAF mutations or cutaneous melanoma harboring any variants of KRAS or NRAS mutations.
  • the clinical data from patients with NSCLC-adenoca or cutaneous melanoma harboring the required mutation status facilitated the sponsor’s selection of the population(s) of likely responders in the Part B dose expansion cohorts.
  • the SMC evaluated safety data after patients have completed at least 1 cycle of treatment and decide upon subsequent dose levels.
  • Dose escalation proceeded if no DLT was observed during the DLT period in a minimum of 3 DLT evaluable patients. If a DLT occurred within the DLT observation period at a given dose level, enrollment for that dose level may be expanded per the modified 3+3 design rules and as follows:
  • Dose escalation may proceed if the DLT rate was ⁇ 1/3
  • the MTD was defined as the highest dose level at which ⁇ 1/3 of the patients experience a DLT.
  • More than 3 patients may be enrolled for a given dose level in the absence of a DLT. In such cases, the dose escalation decision was made based on the above 3+3 rules.
  • the recommended Phase 2 dose and dosing regimen used in Part B were determined by the SMC and the sponsor based on the available data on safety, PK, preliminary antitumor activity, and other pertinent data.
  • the SMC may decide to evaluate an intermediate, not predefined, previously evaluated or not previously evaluated dose or a less frequent dosing regimen that does not exceed the MTD level if evaluation of toxicity at such a dose or schedule was desired.
  • a minimum of 6 patients were enrolled in Part A at the dosing level and regimen determined by the SMC to be utilized in Part B.
  • An initial lead-in dose (14 days with alternative options of 7 and 21 days) given prior to the target dose for one or both agents, may be proposed to facilitate subsequent dose
  • RECTIFIED SHEET (RULE 91 ) ISA/EP escalation when evaluating the MTD of a dosing regimen and in consideration of a RP2D.
  • the lead-in dose was at least one dose level lower than the target dose.
  • the decision to evaluate a regimen that includes a lead-in dose were made by the sponsor in consultation with members of the SMC.
  • Part B was comprised of 3 indication expansion cohorts:
  • Group 1 Non-small cell lung cancer with confinned K-RAS mutations, approximately 15 patients
  • Group 2 Endometrial cancer with confirmed K-RAS mutations, approximately 15 patients
  • Group 3 Tumor types of interest based on clinical data observed in Part A, approximately 15 patients
  • Tumor response were assessed by investigators based on RECIST 1.1.
  • tumor response was also assessed by investigators based on RECIST 1.1 and Gynecological Cancer Intergroup (GCIG CA-125) criteria.
  • GCIG CA-125 Gynecological Cancer Intergroup
  • the first priority was to enroll patients into Part A (dose ranging component of the study).
  • Screening evaluations were performed within 28 days prior to the first administration of study treatment. Patients who agreed to participate signed the informed consent form (ICF) prior to undergoing any screening procedure. Screening evaluations may be repeated as needed within the Screening Period; the investigator was to assess patient eligibility according to the latest screening assessment results. If a patient was rescreened, a new ICF were required.
  • ICF informed consent form
  • a baseline tumor tissue was mandatory for mutation and biomarker analysis, either from archived tumor tissue or fresh tumor biopsies. With patient consent, a follow-up biopsy may be taken for the analysis of PD biomarkers, ideally from the same tumor lesion if it was readily accessible.
  • paired fresh tumor biopsies were mandatory and were collected within the 8 weeks before the first dose of study treatment and again at a time postdose to assess PD biomarkers (NOTE: fresh biopsies taken within 8 weeks of the first dose of study treatment but prior to signing the ICF were allowed if this was part of standard-of-care).
  • NOTE fresh biopsies taken within 8 weeks of the first dose of study treatment but prior to signing the ICF were allowed if this was part of standard-of-care.
  • the End of Treatment Visit was conducted within 7 days after the Investigator determines that the study treatments were no longer used. If routine laboratory tests (e.g., hematology, serum chemistry) were completed within 7 days before the End of Treatment Visit, these tests need not be repeated. Tumor assessment was not required at the End of Treatment Visit provided that fewer than 6 weeks have passed since the last assessment.
  • the DLT window included all lead-in treatment days as well as 28 days at the target dose of the combination. For the patients who have completed the DLT window, they should have received 80% of the intended dose over each of the lead in and target dose periods of the DLT window or have experienced a DLT.
  • Grade 3 febrile neutropenia defined as absolute neutrophil count [ANC] ⁇ 1000/mm 3 with a single temperature of > 38.3°C (101°F) or a sustained temperature of 38°C (100.4°F) for > 1 hour
  • Grade 2 or greater ocular toxicities such as blurred vision, decreased vision, glaucoma, retinal detachment, or retinal vascular disorder
  • Patients who experienced a DLT during the DLT assessment window and patients who had clinically significant Grade 2 toxicities that were considered related to Compound A and/or Compound B after the DLT assessment window may temporarily or permanently suspend taking study treatment.
  • patients In Part A of the study, patients must have a known mutation status and a histologically or cytologically confirmed advanced tumor including NSCLC, CRC, ovarian cancer, endometrial cancer, thyroid cancer, melanoma, pancreatic cancer, and any tumor harboring an oncogenic B-RAF or K-RAS/N-RAS mutation, or MAPK pathway or other genomic aberrations that may potentially respond to a RAF dimer inhibitor or a MEK inhibitor (as described in inclusion criterion below) for which no effective standard therapy was available or acceptable to the patient.
  • Group 1 Non-small cell lung cancer with confirmed K-RAS mutation
  • Group 2 Endometrial cancer with confirmed K-RAS mutation
  • Group 3 Tumor types of interest based on clinical data observed in Part A
  • Patients must have archival tumor tissue or agree to a tumor biopsy at baseline for mutation and biomarkers analysis.
  • Acceptable tumor mutations by local (for initial enrollment) or central (for confirmation) testing include: BRAF, ARAF, RAFI, KRAS, NRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, EGFR, GNA11, GNAQ, PIK3CA, PIK3CB, PTEN, AKT1, MET, KIT, IGF1R.
  • Serum total bilirubin 1.5 x ULN (total bilirubin must be ⁇ 3 * ULN for patients with Gilbert’s syndrome)
  • AST Aspartate aminotransferase
  • ALT alanine aminotransferase
  • Non-childbearing potential i.e., physiologically incapable of becoming pregnant
  • [00413] is postmenopausal (total cessation of menses for 1 year).
  • Childbearing potential has a negative serum pregnancy test within 7 days of the first dosing of study treatment, was not breast feeding, and uses protocol-approved contraception before study entry and throughout the study until 7 months after the last study treatment administration.
  • LVEF left ventricular ejection fraction
  • HIV human immunodeficiency virus
  • liver disease Any clinically significant active or known history of liver disease including but not limited to cirrhosis.
  • hepatitis serology and viral load were tested at screening. Patients who were hepatitis B surface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody positive at screening must not be enrolled until further definite testing with hepatitis B virus (HBV) DNA titers was ⁇ 500 lU/mL or hepatitis C virus (HCV) RNA polymerase chain reaction test was negative.
  • HBV hepatitis B surface antigen
  • HCV hepatitis C virus
  • [00437] Has an increased serum calcium (> 1 x ULN) or serum phosphorus (> 1 * ULN) level.
  • Compound A drug product was supplied as 5-mg units.
  • Compound B was supplied as 1-mg units and 2-mg units.
  • Level 1 Compound B at 2 mg QD and Compound A at 15 mg QD
  • Level 2 Compound B at 2 mg QD and Compound A at 20 mg QD
  • Level 3 a Compound B at 3 mg and Compound A at 20 mg given QD for 5 days followed by a 2-day break (intermittent dosing regimen)
  • Level 4a Compound B at 4 mg and Compound A at 20 mg given QD for 5 days followed by a 2-day break (intermittent dosing regimen)
  • RECTIFIED SHEET (RULE 91 ) ISA/EP [004611 Level 4a with Compound A 20 mg + Compound B 4 mg intermittent dosing (both agents given QD for 5 days followed by a 2-day break every week) was determined to not be a tolerable dose regimen based on observed 2 events of Grade 4 thrombocytopenia with associated bleeding. To mitigate the risk of thrombocytopenia, cohorts may include a lead-in dosing period for Compound A with or without Compound B.
  • Level 3b included a lead-in dose of Compound B 3 mg + Compound A 10 mg given QD for 5 days followed by a 2-day break (intermittent dosing regimen) for 14 days, followed by Compound B 3 mg + Compound A 20 mg given QD for 5 days followed by a 2-day break (intermittent dosing regimen) for each 28-day cycle.
  • Level 3 c included a lead-in dose of Compound B 2 mg BID + Compound A 10 mg QD given for 5 days followed by a 2-day break (intermittent dosing regimen) for 14 days, followed by Compound B 2 mg BID + Compound A 15 mg QD given for 5 days followed by a 2-day break (intermittent dosing regimen) for each 28-day cycle.
  • Compound B BID dosing was evaluated as it provided more consistent study drug exposure as observed in prior clinical studies.
  • Compound B has been administered as a monotherapy at doses ranging from 1 mg QD to 30 mg BID utilizing several different dosing regimens.
  • the most frequently reported adverse events have been rash, nausea, vomiting, diarrhea, and fatigue, with most events being mild-to-moderate in severity.
  • the dose levels in subsequent cohorts may be modified by the sponsor in consultation with the SMC based on the evaluation of all available study data. Additional dose levels or dosing regimens (with or without the lead-in, along with lower, intermediate, or higher doses, and/or BID dosing, either intermittently or continuously, for Compound A and/or Compound B)
  • RECTIFIED SHEET (RULE 91 ) ISA/EP may be considered. Any modification of dose levels or dosing regimens were reviewed and approved by the SMC and the sponsor.
  • the sponsor made a recommendation on the selection of the Compound A /Compound B dose and schedule based on available safety, tolerability, efficacy, PK, and other clinical data from Part A.
  • Study treatment may not occur until all treatment-related AEs have returned to baseline or Grade 1 severity except for alopecia or AEs that, in the opinion of the investigator, were not considered a safety risk for the patient. If a treatment delay was due to worsening of hematologic or biochemical parameters, the frequency of relevant blood tests should be increased as clinically indicated.
  • Dose Delay, Modification, and Permanent Discontinuation of Study Treatment Every effort was made to administer study treatment as described in the proposed dose levels for Part A and for Part B, upon declaration of the RP2D for expansion cohorts [00479] However, in the event of significant toxicity, dosing may be interrupted and / or dose (s) modified. After any interruption lasting less than 21 days, study treatment may be resumed at the same dose or at a reduced dose depending on the toxicity, grade, prior events and number of dose reductions.
  • a patient must discontinue treatment with Compound A and Compound B if, after treatment was resumed at a lower dose, the toxicity recurs with the same or worse severity.
  • Patients requiring more than 2 dose reductions of either or both study drugs discontinued study treatment except when, in the judgment of the treating investigator, a patient was benefitting from treatment. For these patients, treatment may be continued after consultation with and approval by the sponsor.
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • ANC absolute neutrophil count
  • AST aspartate aminotransferase
  • CMV cytomegalovirus
  • DILI drug- induced liver injury
  • EBV Epstein-Barr virus
  • ECG electrocardiogram
  • Hgb hemoglobin
  • LVEF left ventricular ejection fraction
  • QTc corrected QT
  • RPED retinal pigment epithelial detachment
  • RVO retinal vein occlusion.
  • thrombocytopenia For Grades 3 and 4 thrombocytopenia, additional evaluations may be done as clinically indicated. This may include anti-platelet antibody testing (prior to platelet transfusion or other empiric treatment such as glucocorticoids or IVIG, or other, if possible); a peripheral blood smear; thrombopoietin level testing; platelet- derived growth factor level and other (von Willebrand factor, fibrin) testing; and a bone marrow biopsy These tests may be carried out locally or centrally as available and as per institutional practice and procedures.
  • Part A if a patient progressed on Compound A /Compound B without other safety concerns, the patient may be treated with a higher dose of Compound A /Compound B after consultation with the medical monitor.
  • the higher dose must be determined to be well tolerated by previous SMC recommendation.
  • Any medical condition that the investigator or sponsor determines may jeopardize the patient’s safety, if he or she were to continue the study treatment (i.e., RVO)
  • Screening evaluations were performed within 28 days prior to the first administration of study treatment. Patients who agree to participate signed the ICF prior to undergoing any screening procedure. Screening evaluations may be repeated as needed within the Screening Period; the investigator was to assess patient eligibility according to the latest screening assessment results.
  • Results of standard of care tests or examinations performed prior to obtaining informed consent and 28 days prior to the first dose of the study treatment(s) may be used for the purposes of screening rather than repeating the standard of care tests, unless otherwise indicated.
  • Rescreening under limited conditions may be allowed after consultation with medical monitor. Rescreening was allowed only once.
  • Demographic data included age or year of birth, sex, and self-reported race/ethnicity.
  • Medical history includes any history of clinically significant disease, surgery, or cancer history; reproductive status (i.e., of childbearing potential or no childbearing potential);
  • RECTIFIED SHEET (RULE 91 ) ISA/EP history of alcohol consumption (i.e., presence or absence); and all medications (i.e., prescription drugs, over-the- counter drugs, herbal or homeopathic remedies, nutritional supplements) used by the patient within 28 days before the first dose of study treatment.
  • Cancer history included cancer diagnosis, prior surgery, prior radiotherapy; prior drug therapy including start and stop dates, best response, and reason for discontinuation.
  • Radiographic studies performed prior to study entry may be collected for review by the investigator.
  • study site personnel After a patient was screened and the investigator determines the patient was eligible for enrollment, study site personnel completed a Treatment Authorization Packet and send it to the medical monitor or designee to approve the enrollment. Study site personnel should ensure that a medical monitor approval has been received before dosing the patient with the study treatment.
  • Vital signs included measurements of temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic) after the patient has been sitting for at least 5 minutes. Vital signs should be taken within 60 minutes pre-dose and within 60 minutes post-dose at each specified visit.
  • a centralized ECG laboratory may be used in this study in selected study sites. Calibrated ECG machines were provided to these sites and ECG collected from the sites were reviewed centrally. In other sites, local ECG machines were used.
  • ECG assessment should be performed after vital signs were collected and prior to blood draws.
  • LVEF left ventricular ejection fraction
  • Adverse events were graded and recorded throughout the study. Characterization of toxicities included severity, duration, and time to onset.
  • Results of standard-of-care tests or examinations performed prior to obtaining informed consent 28 days prior to the first administration of study treatment may be used for the purposes of screening rather than repeating the standard of care tests. Radiological assessment of tumor response was performed approximately every 8 ( ⁇ 1) weeks after Cycle 1 Day 1 in the first year and approximately every 12 ( ⁇ 1) weeks thereafter.
  • Tumor assessments must include CT scans (with oral/IV contrast, unless contraindicated) or MRI, with preference for CT, of the chest, abdomen, and pelvis. All measurable and evaluable lesions were assessed and documented at the Screening Visit and reassessed at each subsequent tumor evaluation. The same radiographic procedure used to assess disease sites at screening was required to be used throughout the study (i.e., the same contrast protocol for CT/MRI scans).
  • Imaging of the brain was required during screening.
  • contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed.
  • PET positron emission tomography
  • CT/MRI acquisition must be consistent with the standards for a full contrast diagnostic CT/MRI scan.
  • CT scans of the neck or extremities should also be performed if clinically indicated and followed throughout the study, if there was evidence of metastatic disease in these regions at screening.
  • other methods of assessment of target lesion and nontarget lesions per RECIST 1.1 may be used.
  • Tumor response were assessed by the investigators using RECIST 1.1. The same evaluator should perform assessments, if possible, to ensure internal consistency across visits. [00556] After the first documentation of response (CR or PR), confirmation of tumor response should occur at 4 weeks or later ( V 4 weeks) after the first response or at the next scheduled assessment time point.
  • PK assay plasma samples were assayed for Compound A (and possibly its major metabolites), Compound B, and Compound B’s metabolite concentrations with use of a validated chromatography assay.
  • Patient eligibility was determined based on a tumor mutation identified by central laboratory testing or by a local assay result obtained in the tumor tissue sample collected at any time prior to screening.
  • Baseline tumor tissue sample was mandatory for mutation and biomarker analysis, either from archived tumor tissue or fresh tumor biopsies.
  • a follow-up biopsy may be taken (ideally from the same tumor lesion if it was readily accessible) at Cycle 3 and when the patient stops treatment due to disease progression.
  • For Group 2 in Part B paired fresh tumor biopsies to assess PD biomarkers were mandatory; the first biopsy was collected during the 8 weeks before the first dose and again at a time post-dose to assess PD biomarkers.
  • blood samples were collected from all patients for mutation profiling by next generation sequencing. Additional biomarker analysis from the blood might also be conducted by other assay types, such as RNA- Seq.
  • Tumor tissue was of good quality based on total and viable tumor content. Fine needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples were not acceptable.
  • Fresh biopsies were limited to readily accessible tumor lesions (i.e., skin; peripheral lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed using CT guidance). If performed, a tissue cylinder should be obtained that has a proper size for histological examination and biomarker analysis (i.e., pERK; genomic profiling).
  • tumor lesions i.e., skin; peripheral lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed using CT guidance.
  • a tissue cylinder should be obtained that has a proper size for histological examination and biomarker analysis (i.e., pERK; genomic profiling).
  • Safety Analysis Set included all patients who received at least 1 dose of study treatment (either Compound A or Compound B).
  • Efficacy Evaluable Analysis Set included all dosed patients who have evaluable disease at baseline, and at least 1 evaluable postbaseline tumor response assessment.
  • DLT Evaluable Analysis Set included patients who received at least 80% of the assigned dose of Compound A and Compound B during the dose-escalation phase (Part A) or who experienced a DLT during the dose-escalation phase (Part A).
  • PK Analysis Set included all dosed patients for whom valid Compound A or Compound B PK parameters can be estimated.
  • PD Analysis Set includes all patients with valid PD sampling after treatment with Compound A/Compound B.
  • time-to-event endpoints including PFS and duration of response were analyzed by Kaplan-Meier methods.
  • the survival functions of the time-to-event endpoints were summarized for the 25th percentile, median, and 75th percentile and their 95% Cis.
  • the rates of [00594] PFS and duration of response at Month 3 and every subsequent 3 months as appropriate and their 95% Cis were derived based on Kaplan-Meier estimates.
  • graphs of Kaplan- Meier estimates of survival functions were presented.
  • Safety endpoints (other than DLTs) were summarized using the Safety Analysis Set. All summaries of safety were by dose level for Part A and by group for Part B.
  • Treatment exposure were summarized descriptively for each of the 2 study treatments. Measures of extent of exposure included the number of treatment cycles received, duration of exposure, dose intensity, relative dose intensity and cumulative dose received. The number of patients with dose delay and reason for dose discontinuation were summarized as well, as appropriate.
  • Adverse events were coded using MedDRA, and AE data were summarized by system organ class and preferred term. The frequency and percentage of patients by reported
  • RECTIFIED SHEET (RULE 91 ) ISA/EP system organ class /preferred term were summarized, with the number of AEs counted as well. Adverse events were also summarized by worst AE severity /grade and AE relationship to each study treatment. In addition, the number of SAEs and TEAEs that lead to discontinuation of study treatment was also summarized.
  • a by-subject AE data listing including verbatim term, MedDRA system organ class and preferred term, severity, outcome and relationship to study treatment, were provided. Separate listings were generated for serious AEs and AEs leading to discontinuation of study treatment.
  • Clinical laboratory e.g., hematology, serum chemistry
  • Abnormal laboratory values were flagged and identified as those outside (above or below) the normal range.
  • Reference (normal) ranges for laboratory parameters were included in the clinical study report for this protocol.
  • Descriptive summary statistics e.g., n, mean, standard deviation, median, minimum, maximum for continuous variables; n (%) for categorical variables
  • Laboratory values were summarized by visit and by worst postbaseline visit.
  • LVEF left ventricular ejection fraction
  • PK variables e.g., AUC, Cmax, and Tmax
  • AUC, Cmax, and Tmax a metabolite calculated for Compound B, its active metabolite Compound B’s metabolite, and Compound A as appropriate using noncompartmental methods. Summary statistics were provided. Additional PK parameters, including those of the potential metabolite(s) of Compound A, may also be calculated if available.
  • the plasma concentration data and PK parameters were tabulated and summarized for each cycle at which pharmacokinetics were to be measured in Part A and Part B. Descriptive statistics included means, medians, minimums, maximums, standard deviation, coefficient of variation (CV), geometric mean, and geometric CV as appropriate. Mean plasma concentrations was also plotted against time for each dose level. Additional PK analyses may be conducted as appropriate.
  • Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. Results of such analyses may be reported separately from the clinical study report.
  • Part A Approximately 30 to 60 patients for the dose-escalation phase until MTD and/or RP2D determination
  • Part B Approximately 45 patients for expansion in 3 selected groups (15 patients per group). Each group were evaluated separately and can be closed due to lack of clinical efficacy based on statistical evaluation or insufficient patient recruitment. If promising preliminary efficacy results have been observed in 1 of the groups after treating all planned patients (i.e., higher ORR or longer PFS), more numbers of patients could be added to the group to further assess the efficacy of the combination before moving into Phase 2/3 clinical development or regulatory discussions.
  • a TEAE was defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of study drug and 30 days after the last dose of study drug or initiation of new anticancer therapy, whichever occurs first.
  • Treatment-emergent AEs Grade 3 assessed as related to Compound A by SOC and PT were presented overall.
  • No patients in Cohort 3b Compound A 20 mg + Compound B 3 mg with
  • the inventors surprising and unexpectedly discovered that the inclusion of the lead-in dose regimen reduced the severity and occurrence of the side effects, and thus, achieved tolerable toxicity.
  • the inventors further surprising and unexpectedly discover that the inclusion of the intermittent dosing regimen reduced the severity and occurrence of the side effects as well, and thus, achieved tolerable toxicity.
  • Table 5 provides details with respect to the objective response data and disease control data.
  • BOR Best Overall Response
  • CR Complete Response
  • PR Partial Response
  • SD Stable Disease
  • PD Progressive Disease
  • NE/NA Not Evaluable/Not Assessed
  • CI Confidence Interval
  • CBR Clinical Benefit Rate
  • DOR Duration of Response
  • Fig. 1 describes the best change (%) from baseline in sum of diameters per
  • Fig. 1 showed the following:
  • Fig. 3 describes the best change (%) from baseline in sum of diameters per RECIST 1.1 LGSOC patients.
  • BID twice a day
  • DLT dose-limiting toxicity
  • L lifirafenib
  • M mirdametinib
  • MTD maximum tolerated dose
  • PK pharmacokinetic(s)
  • QD once a day
  • RP2D recommended phase 2 dose.
  • DL 4b M 2 mg BID + L 10 mg QD
  • DL 4c M 3 mg BID + L 10 mg QD
  • DLTs occurring in more than 1 patient included thrombocytopenia and febrile neutropenia (2 patients each); no DLTs occurred after the lead-in approach.
  • the combination showed antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC), and endometrial cancer.
  • LGSOC low-grade serous ovarian cancer
  • NSCLC non-small cell lung cancer
  • endometrial cancer endometrial cancer

Abstract

L'invention concerne une méthode de traitement d'un cancer chez un sujet en ayant besoin, comprenant l'administration audit sujet d'environ 5 mg, d'environ 10 mg, d'environ 15 mg, d'environ 20 mg, d'environ 25 mg, d'environ 30 mg, d'environ 35 mg, ou d'environ 40 mg de composé A ayant la structure de formule (I) : ou un sel, un tautomère, un stéréoisomère, un énantiomère, un isotopologue, un solvate ou un promédicament pharmaceutiquement acceptable de celui-ci avec une période de dosage initiale ou un régime posologique intermittent.
PCT/IB2023/054325 2022-04-26 2023-04-26 Méthodes de traitement du cancer avec un inhibiteur du b-raf, en particulier le lifirafenib WO2023209611A1 (fr)

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