WO2016025621A1 - Méthodes de traitement à l'aide d'un inhibiteur d'erk - Google Patents

Méthodes de traitement à l'aide d'un inhibiteur d'erk Download PDF

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WO2016025621A1
WO2016025621A1 PCT/US2015/044890 US2015044890W WO2016025621A1 WO 2016025621 A1 WO2016025621 A1 WO 2016025621A1 US 2015044890 W US2015044890 W US 2015044890W WO 2016025621 A1 WO2016025621 A1 WO 2016025621A1
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cancer
compound
mutated
melanoma
braf
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PCT/US2015/044890
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Gordon L. BRAY
Ellen H. Filvaroff
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Celgene Avilomics Research, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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 present invention provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with one or both of ER 1 and ERK2.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • the processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells.
  • the ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras.
  • Activation of Ras leads to the recruitment and activation of Raf, a serine- threonine kinase.
  • Raf Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates one or both of ERK1 and ERK2.
  • MEK1/2 When activated, one or both of ERKl and ERK2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation.
  • the ERK MAPK pathway is one of the most important for cell proliferation, and human tumor data suggest that the ERK/MAPK pathway is frequently activated in many tumors.
  • Ras genes which are upstream of one or both of ER l and ERK2, are mutated in several cancers including, but not limited to, colorectal, melanoma, lung, breast and pancreatic tumors.
  • BRAF a serine- threonine kinase of the Raf family
  • Tumor types with the most frequent mutation in BRAF include melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers.
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERKl and ERK2.
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERKl and ERK2 comprising administering to a patient in need thereof a pharmaceutically acceptable composition comprising N-(2-((2-((2-methoxy-5-methylpyridin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-5-methylphenyl)acry 1:
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2 comprising administering to a patient in need thereof a pharmaceutically acceptable composition comprising a phosphate salt of Compound 1, depicted below:
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of a proliferative disorder, wherein the method comprises administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer, wherein the method comprises administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.
  • the cancer is a locally advanced cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is recurring. In some embodiments, the cancer is refractory.
  • the cancer is a RAF inhibitor-resistant cancer.
  • the RAF inhibitor-resistant cancer is a BRAF inhibitor-resistant cancer.
  • the cancer is a MEK inhibitor-resistant cancer. [0014] In certain embodiments, the cancer is a MAPK pathway-mediated cancer.
  • the cancer is a BRAF -mutated cancer.
  • the BRAF-mutated cancer is a BRAF V600 -mutated cancer, such as BRAF
  • the cancer is a RAS-mutated cancer.
  • the RAS-mutated involves codons 12, 13, or 61.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the RAS-mutated cancer is an NRAS-mutated cancer, including, but not limited to, NRAS Q61R , NRAS Q61K , NRAS Q61L , or NRAS Q61H .
  • the RAS-mutated cancer is an HRAS-mutated cancer, including, but not limited to, HRAS G12V , HRAS Q61R , and HRAS G12S .
  • the cancer is selected from multiple myeloma, breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach (gastric), skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung, bone, colon, thyroid, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma (including uveal melanoma) sarcoma, bladder carcinoma, liver carcinoma (e.g., hepatocellular carcinoma (HCC)) and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pha
  • the cancer is selected from carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • a sarcoma is a soft tissue sarcoma.
  • a lymphoma is non-Hodgkin's lymphoma.
  • a lymphoma is large cell immunoblastic lymphoma.
  • the cancer is selected from adenocarcinoma; adenoma; adrenocortical cancer; bladder cancer; bone cancer; brain cancer; breast cancer; cancer of the buccal cavity; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine carcinoma; epidermoid carcinoma; esophageal cancer; eye cancer; follicular carcinoma; gallbladder cancer; prostate, AML, multiple myeloma (MM), gastrointestinal cancer, such as, for example, gastrointestinal stromal tumor; cancer of the genitourinary tract; glioblastoma; hairy cell carcinoma; various types of head and neck cancer; hepatic carcinoma; hepatocellular cancer; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; cancer of the large intestine; laryngeal cancer; liver cancer; lung cancer, such as, for example, adenocarcinoma of the lung, anaplastic carcinoma of the lung, pa
  • the cancer is selected from melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), multiple myeloma (MM), and leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia.
  • a leukemia is acute lymphoblastic leukemia.
  • the cancer is selected from melanoma, colorectal cancer, lung cancer, or pancreatic.
  • the cancer is melanoma.
  • the melanoma is uveal melanoma.
  • the melanoma is a melanoma of the skin.
  • the melanoma is locally advanced.
  • the melanoma is metastatic.
  • the melanoma is recurring.
  • the melanoma is BRAF v600 -mutated melanoma.
  • the melanoma is a RAS-mutated melanoma.
  • the melanoma is NRAS- mutated melanoma.
  • the melanoma is wild type for KRAS, NRAS or BRAF.
  • the melanoma is a BRAF inhibitor-resistant (e.g., Vemurfenib- resistant, dabrafenib-resistant, encorafenib-resistant, etc.) melanoma.
  • the cancer is a VemR (i.e., Vemurfenib-resistant) BRAF-mutated melanoma.
  • the melanoma is relapsed.
  • the melanoma is refractory.
  • the cancer is colorectal cancer. In certain embodiments, the colorectal cancer is locally advanced. In certain embodiments, the colorectal cancer is metastatic. In certain embodiments, the colorectal cancer is a BRAF-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a BRAF v600 -mutated colorectal cancer. In certain embodiments, the colorectal cancer is a RAS-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a KRAS-mutated colorectal cancer. In some embodiments, the colorectal cancer is relapsed. In some embodiments, the colorectal cancer is refractory.
  • the cancer is pancreatic cancer.
  • the pancreatic cancer is locally advanced.
  • the pancreatic cancer is metastatic.
  • the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).
  • the pancreatic cancer is a RAS-mutated pancreatic cancer.
  • the pancreatic cancer is a KRAS-mutated pancreatic cancer.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the pancreatic cancer is relapsed.
  • the pancreatic cancer is refractory.
  • the cancer is a papillary thyroid cancer.
  • the papillary thyroid cancer is locally advanced.
  • the papillary thyroid cancer is metastatic.
  • the papillary thyroid cancer is recurring.
  • the papillary thyroid cancer is BRAF-mutated papillary thyroid cancer.
  • the papillary thyroid cancer is BRAF v600 -mutated papillary thyroid cancer.
  • the papillary thyroid cancer is relapsed.
  • the papillary thyroid cancer is refractory.
  • the papillary thyroid cancer may include undifferentiated or dedifferentiated histology.
  • the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the lung cancer is locally advanced.
  • the lung cancer is metastatic.
  • the lung cancer is a RAS-mutated lung cancer.
  • the lung cancer is KRAS-mutated lung cancer.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the lung cancer is relapsed.
  • the lung cancer is refractory.
  • the cancer is a leukemia.
  • a leukemia is a chronic leukemia.
  • a leukemia is chronic myeloid leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia (AML).
  • a leukemia is acute monocytic leukemia (AMoL, or AML-M5).
  • a leukemia is acute lymphoblastic leukemia (ALL).
  • a leukemia is acute T cell leukemia.
  • a leukemia is myelomonoblastic leukemia.
  • a leukemia is human B cell precursor leukemia. In certain embodiments, a leukemia has a Flt3 mutation or rearrangement. In some embodiments, the leukemia is relapsed. In some embodiments, the leukemia is refractory.
  • the cancer is a CNS cancer, for instance CNS tumors.
  • a CNS tumor is a glioblastoma or glioblastoma multiforme (GBM).
  • the present invention relates to a method of treating stomach (gastric) and esophageal tumors and cancers.
  • the cancer is multiple myeloma (MM).
  • the multiple myeloma is locally advanced.
  • the multiple myeloma is metastatic.
  • the multiple myeloma is a RAS-mutated multiple myeloma.
  • the multiple myeloma is KRAS-mutated multiple myeloma.
  • the RAS-mutated multiple myeloma is a KRAS-mutated multiple myeloma, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the multiple myeloma is relapsed.
  • the multiple myeloma is refractory.
  • the cancer is hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the HCC is locally advanced.
  • the HCC is metastatic.
  • the cancer is a RAS-mutated HCC.
  • the cancer is KRAS-mutated HCC.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the hepatocellular carcinoma is relapsed.
  • the hepatocellular carcinoma is refractory.
  • provided methods comprise orally administering to a patient compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, provided methods comprise orally administering to a patient compositions comprising the phosphate salt of Compound 1. In some embodiments, such compositions are capsule formulations.
  • provided methods comprise administering a composition which comprises Compound 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • provided methods comprise administering a composition which comprises the phosphate salt of Compound 1, and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • the present invention also provides dosing regimens and protocols for the administration of Compound 1, or a pharmaceutically acceptable salt thereof, to patients in need thereof. In certain embodiments, the present invention also provides dosing regimens and protocols for the administration of the phosphate salt of Compound 1 to patients in need thereof.
  • Figure 1 depicts an XRPD pattern of Form A of the phosphate salt of Compound 1.
  • Figure 2 depicts an XRPD pattern of Form B of the phosphate salt of Compound 1.
  • Figure 3 depicts an XRPD pattern of Form C of the phosphate salt of Compound 1.
  • Figure 4 depicts an XRPD pattern of Form D of the phosphate salt of Compound 1.
  • Figure 5 depicts graphically the regression of LOX IMVI (melanoma) tumor xenografts when treated with the phosphate salt of Compound 1. Reductions in tumor volume averaging 93% to 95%> (compared with vehicle controls) were observed on Day 20 at doses of 60.5 mg/kg and 121 mg/kg, respectively, administered for seven consecutive days beginning on day 13 after tumor cell implantation.
  • Figure 6 depicts graphically the in vivo inhibition of HCT-116 (KRAS G13D mutant CRC) xenografts by Compound 1.
  • Tumor growth inhibition with Compound 1 varied from 57% (compared to vehicle control) at 12.5 mg/kg BID to 77% inhibition at doses of 100 mg/kg QD. Animals were treated for 21 consecutive days.
  • Figure 7A depicts in vitro assays of Compound 1 against Panc-1 (a.k.a PANC-1) pancreatic cancer cells.
  • Figure 7B depicts in vitro assays of Compound 1 against MIA PaCa-2 (a.k.a. Mia PaCa, a.k.a. MiaPaCa) pancreatic cancer cells.
  • Figure 7C depicts in vitro assays of Compound 1 against HS294T melanoma.
  • Figure 8 depicts the phase overall study design.
  • Figure 9A depicts a first in vitro assay of Compound 1 against HCT-116 colorectal cancer cells. As shown in Figure 9A, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1321.30 nM.
  • Figure 9B depicts a second in vitro assay of Compound 1 against HCT-116 colorectal cancer cells. As shown in Figure 9B, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1169.50 nM
  • Figure 10 depicts an in vitro assay of Compound 1 against KRAS-mutant q61H NCI- H460 lung cancer cells. As shown in Figure 10, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 6839.12 nM.
  • Figure 11 depicts an in vitro assay of Compound 1 against KRAS-unknown NCI- H522 lung cancer cells. As shown in Figure 11, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 2338.84 nM.
  • Figure 12 depicts an in vitro assay of Compound 1 against p.G469A NCI-H1755 lung cancer cells. As shown in Figure 12, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 722.77 nM.
  • Figure 13 depicts an in vitro assay of Compound 1 against KRAS-mutant p.G12V NCI-H727 lung cancer cells. As shown in Figure 13, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 762.08 nM.
  • Figure 14 depicts an in vitro assay of Compound 1 against KRASunknown NCI- H522 lung cancer cells. As shown in Figure 14, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 3006.08 nM.
  • Figure 15A depicts a second in vitro assay of Compound 1 against Mia PaCa-2 pancreatic cancer cells. As shown in Figure 15 A, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1238.80 nM.
  • Figure 15B depicts a third in vitro assay of Compound 1 against Mia PaCa-2 pancreatic cancer cells. As shown in Figure 15B, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1534.62 nM
  • Figure 16 depicts a second in vitro assay of Compound 1 against HS294T melanoma cells. As shown in Figure 16, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1202.26 nM.
  • Figure 17A depicts a growth inhibition assay of Compound 1 against NRAS and BRAF mutant vemurafenib-resistant melanoma cell lines. As shown in Figure 17A, Compound 1 inhibits growth of both NRAS and BRAF mutant vemurafenib-resistant melanoma cell lines with an average GI50 of 290 nM.
  • Figure 17B depicts an in vitro assay of Compound 1 against NRAS and BRAF mutant vemurafenib-resistant melanoma cell lines.
  • Compound 1 induced cell death in all NRAS and BRAF mutant vemurafenib-resistant melanoma cell lines except in line 4 (in which the effect was cytostatic) at 10 ⁇ .
  • a "disease or disorder associated with one or both of ERKl and ERK2" means any disease or other deleterious condition in which one or both of ERKl and ERK2, or a mutant thereof, is known or suspected to play a role.
  • ERK1 and ERK2 are downstream targets within the MAPK pathway.
  • a disease or disorder associated with one or both of ER 1 and ERK2 includes those in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role, including one or both of ERKl and ERK2 as well as other nodes in the MAPK pathway upstream from ERK (such as Ras, Raf and Mek) .
  • another embodiment of the present invention relates to preventing, treating, stabilizing or lessening the severity or progression of one or more diseases in which one or both of ERKl and ERK2, or a mutant thereof, is known or suspected to play a role.
  • the present invention relates to a method of treating or lessening the severity of a proliferative disorder, wherein said method comprises administering to a patient in need thereof Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.
  • the term "irreversible” or “irreversible inhibitor” refers to an inhibitor (i.e. a compound) that is able to be covalently bonded to a target protein kinase in a substantially non-reversible manner. That is, whereas a reversible inhibitor is able to bind to (but is generally unable to form a covalent bond to) the target protein kinase, and therefore can become dissociated from the target protein kinase, an irreversible inhibitor will remain substantially bound to the target protein kinase once covalent bond formation has occurred. Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the time with which the inhibitor is in contact with the enzyme.
  • Such methods include, but are not limited to, enzyme kinetic analysis of the inhibition profile of the compound with the protein kinase target, the use of mass spectrometry of the protein drug target modified in the presence of the inhibitor compound, discontinuous exposure, also known as "washout," experiments, and the use of labeling, such as radiolabeled inhibitor, to show covalent modification of the enzyme, as well as other methods known to one of skill in the art.
  • a "therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
  • a "therapeutically effective amount" is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating one or more symptoms of a disease or disorder associated with one or both of ERKl and ERK2.
  • subject means a mammal and includes human and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.).
  • domestic animals e.g., horses, dogs, cats, etc.
  • treat refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disease or disorder, or one or more symptoms of the disease or disorder.
  • treatment refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disease or disorder, or one or more symptoms of the disease or disorder, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • the term “treating” includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • treating includes preventing relapse or recurrence of a disease or disorder.
  • unit dosage form refers to a physically discrete unit of inventive formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2 comprising administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1, depicted below:
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERK1 and ERK2 comprising administering to a patient in need thereof a pharmaceutically acceptable composition comprising a phosphate salt of Compound 1, depicted below:
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2 comprising administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable composition is an oral dosage form.
  • the pharmaceutically acceptable composition is formulated as a capsule.
  • Compound 1 and compositions described herein are generally useful for the inhibition of protein kinase activity of one or more enzymes.
  • Examples of kinases that are inhibited by Compound 1 and compositions described herein and against which the methods described herein are useful include one or both of ER 1 and ERK2, or a mutant thereof.
  • the classical Mitogen-Activated Protein Kinase (MAPK) Pathway is a three-tiered, kinase cascade (RAF-MEK-ERK) with a central role in regulating proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals.
  • MAPK Mitogen-Activated Protein Kinase
  • RAF-MEK-ERK three-tiered, kinase cascade
  • Aberrant activation of the MAPK pathway is a frequent event in human cancer and pathway activity in treatment naive tumors is often the result of activating mutations involving either the RAS family of proto- oncogenes or the B isoform of RAF (BRAF).
  • BRAF B isoform of RAF
  • RAS receptor tyrosine kinases
  • pancreatic ductal adenocarcinomas PDACs
  • PDACs pancreatic ductal adenocarcinomas
  • NRAS Neuronal adenocarcinomas
  • Somatic point mutations involving the serine -threonine kinase BRAF typically involve exons 11 (the P-loop) and 15 (the activation segment) of the kinase domain and more than 90% involve a single amino acid substitution (V600E or K) (Brose et al, 2002 Cancer Res. 2002 Dec 1; 62(23):6997-7000; Davies, H. et al. 2002 Nature June 27, 417(6892):949-54 ; Pratilas, C. et al. Curr. Top. Micrbiol. Immunol. 2012, 355:83-98; De Luca et al., 2012 Expert Opin. Ther. Targets.
  • MAPK pathway activation in BRAF mutated tumors occurs independently of RTK signaling or RAS and does not require the formation of RAF dimers (Poulikakos, P. I. et al. Sci. Signal. 2011 Mar 29, 4(166):pel6).).
  • Activating mutations in BRAF have been identified in 8% of human cancers, and are most commonly found in hairy cell leukemias (in virtually all cases), metastatic melanomas (50-60%), papillary thyroid carcinomas (approximately 45%) and colorectal cancers (5-8%) (Pratilas, C. 2012; Xing 2005 doer Relat. Cancer. 2005 Jun;12(2):245-62; Samuel J. N. Engl. J. Med. 2014 Jan 16, 370(3):286-8).
  • the downstream substrates for oncogenic BRAF are MEK1 and MEK2, which are activated through phosphorylation.
  • MEK1 and MEK2 are tyrosine and serine/threonine dual-specificity kinases that are very substrate specific and have no known targets other than ERK proteins.
  • ERK extracellular signal-regulated kinase 1 and ERK 2 function as the major MAPK effector of the RAS and BRAF oncoproteins.
  • Activated ERK phosphorylates a multitude of downstream targets including RSK (p90 ribosomal S6 kinase).
  • RSK in turn, phosphorylates several cytoplasmic targets and transcriptional regulators.
  • ERK nuclear substrates include the Ternary Complex Factor (TCF) transcription factors, which play a major role in inducing IEG (Immediate Early Gene) expression.
  • TCF Ternary Complex Factor
  • the IEG products such as c-Fos and c-Myc in turn, activate late response genes that promote cell survival, proliferation and motility. (Mendoza, M.C. et al. Trends Biochem. Sci. 2011 Trends Biochem Sci. Jun 36(6):320-8. doi).
  • mutant BRAF small molecule inhibitors of mutant BRAF and MEK
  • MAPK pathway inhibition As a viable therapeutic approach.
  • the inhibitors of mutant BRAF, vemurafenib (Roche/Genentech, So. San Francisco, CA) and dabrafenib (Glaxo Smith-Klein, city, state) have been approved by the U.S. FDA, European Medicines Agency and Australian TGA for the treatment of locally-advanced or metastatic melanoma in patients with BRAF V60 ° mutations, based on compelling improvements in response rates, progression-free and overall survival compared with dacarbazine chemotherapy (McArthur, G.A. et al.
  • Results associated with MEK inhibitor therapy were not as compelling as those observed among patients treated with BRAF inhibitor therapy, owing at least in part, to the higher therapeutic index of vemurafenib or dabrafenib (which affects BRAF in a mutant-specific manner) compared with MEK inhibitors (McArthur, G.A. et al. Lancet Oncology, 2014; Hauschild, A. et al. Lancet, 2012 Jul 28, 380(9839):358-65; and Lancet Oncol. 2012 Nov 13(11): 1087-95). Additionally, Flaherty et al. (Flaherty K et al. N. Engl. J. Med. 2012 Jul 12 367(2): 107-14).
  • SCH772984 was able to effectively reduce pERK and pRSK expression and inhibit proliferation in a BRAF V60 ° mutant melanoma cell line (A101D) that was rendered dually resistant to BRAF and MEK inhibition. (Cancer Discov; AACR, 2013 3(7); 742-50).
  • Compound 1 is a potent inhibitor of the kinase activities of ERK1 and ERK2 with IC 50 in the 10-20 nM range. Compound 1 irreversibly inhibits ERK 1 and 2 through formation of a covalent adduct with critical cysteine residues (amino acid 183 in ERK1 and 166 in ERK2) in the vicinity of the ATP binding pocket. In an analysis of 258 kinases, Compound 1 was shown to exhibit good overall kinase selectivity profile.
  • Compound 1 has demonstrated potent in vitro anti-proliferative activity against a large number of cancer cell lines of various tissue origins. Bioinformatic analyses indicate that tumors with activating mutations of BRAF are enriched within the set of sensitive cell lines to Compound 1: of the 27 BRAF -mutant cancer cell lines tested, 25 (93%) demonstrated sensitivity to Compound 1 inhibition (GI 50 ⁇ 1 ⁇ ). In the same cancer cell panel screening, 28 of 37 (76%) KRAS-mutant cancer cell lines were sensitive to Compound 1. Compound 1 exhibits inhibitory activity against A375 melanoma cells that have acquired in vitro resistance to BRAF and MEK inhibition.
  • ERK inhibitors may provide effective therapy in tumors resistant to inhibitors of BRAF or MEK. Rationale for Treating Select Tumor Types
  • PDAC Pancreatic Ductal Adenocarcinoma
  • a model for PDAC oncogenesis in which mutational activation of KRAS followed by loss of CDK 2A, TP53 and SMAD4 tumor suppressor genes defines the key genetic steps in the progression from normal epithelium through the various stages of pancreatic intraductal neoplasia to invasive PDAC (Hezel AF, Kimmelman AC, Stanger BZ et al., Genes & Development 2006; 20: 1218-49; Yeh JJ, Der C, Expert Opin Ther Targets 2007; 11(5):673- 94..).
  • the frequent and early mutation of KRAS in this progression has been particularly well- defined.
  • CRC Metastatic Colorectal Cancer
  • KRAS Activating mutations in KRAS account for approximately 40% of CRC; these involve almost exclusively codons 12 and 13 (Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A., Pathology - Research and Practice 2009; 205:858-62).
  • PDAC mutations in KRAS are an early event in the genetic progression from early foci of intestinal crypt dysplasia to invasive CRC.
  • Gene sequencing studies of 11 colorectal tumors revealed that KRAS was the most frequently mutated oncogene and second only to TP53 mutations for all mutated genes (Baines AT, Xu D, Der CJ., Future Med Chem 2011; 3(14): 1787-1808).
  • tumor cell lines with acquired resistance to BRAF and/or MEK inhibition demonstrate retained sensitivity to ERK inhibition (Morris EJ, Jha S, Restaino CR et al., Cancer Discovery 2013;3:742-50; Hatzivassiliou G, Liu B, O'Brien C et al, Mol Cancer Ther 2012; 11 : 1143-54).
  • Compound 1, and pharmaceutically acceptable salts thereof described herein is an inhibitor of one or both of ERK1 and ERK2.
  • ERK is one of the key components in the RAS-RAF-MEK-ERK MAPK pathway and that ERK1 and ERK2 are downstream nodes within the MAPK pathway.
  • an ERK inhibitor can treat disease or disorders in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role, including one or both of ERK1 and ERK2 as well as other nodes in the MAPK pathway upstream from ERK (such as Ras, Raf and Mek).
  • ERK is a downstream target
  • ERK inhibitors are believed to be able to overcome, in some instances, drug resistance induced by inhibitors of targets upstream of ERK within the MAPK pathway.
  • RAF or MEK utilized in the treatment of K-RAS and B-RAF mutant tumors have resulted in such drug resistance.
  • drug resistance has been associated with other tumors driven by hyperactivation of the MAPK pathway (such as NF1 mutant tumors).
  • Kinase selectivity was achieved through silencing the selective Cys in a combination of the interactions between the covalent inhibitors of the invention and unique amino acids in the ATP binding pocket. Targeting the selective Cys provides for prolonged pharmacodynamics in silencing ERK activity, as well as potential lower doses in cancer treatment, compared to reversible inhibitors.
  • Compound 1, and pharmaceutically acceptable salts thereof are inhibitors of one or both of ERK1 and ERK2 protein kinases, and EPvKl and ERK2 are downstream targets within the MAPK pathway.
  • such compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role.
  • Such disease, condition, or disorder may be referred to herein as associated with the MAPK pathway or alternatively as associated with one or both of ERKl and ERK2.
  • Such diseases, conditions, or disorders may also be refererd to herein as an "ERKl- or ERK2 -mediated disease, condition, or disorder.”
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of the MAPK pathway (at any level in Ras-Raf-Mek-ERK), including one or both of ERKl and ERK2 protein kinases, is implicated in said disease, condition, or disorder wherein said method comprises administering to a patient in need thereof Compound 1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for overcoming drug resistance to Raf or Mek inhibitors, comprising the step of administering to a patient an inhibitor compound of one or both of ERKl and ERK2 such as Compound 1, or a pharmaceutically acceptable salt thereof.
  • the mechanism of drug resistance is through mutation of a target protein or reactivation of the MAPK pathway.
  • the term “resistance” may refer to changes in a wild-type nucleic acid sequence coding a target protein, and/or to the amino acid sequence of the target protein and/or to the amino acid sequence of another protein, which changes, decreases or abolishes the inhibitory effect of the inhibitor on the target protein.
  • the term “resistance” may also refer to overexpression or silencing of a protein differing from a target protein that can reactivate the MAPK pathway or other survival pathways.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERK1 and ERK2, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.
  • treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • General diseases, disorders, or conditions treated by Compound 1, and pharmaceutically acceptable salts thereof include cancer, an autoimmune disorder, a neurodegenerative or neurological disorder, liver disease, a cardiac disorder, schizophrenia, or a bone-related disorder.
  • the present invention relates to a method of treating or lessening the severity of a disease, condition, or disorder selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone -related diseases, wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of treating a cancer.
  • the present invention provides a method for treating cancer in a patient comprising the step of administering to said patient a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.
  • the cancer is recurring.
  • the cancer is refractory.
  • the cancer is metastatic.
  • the cancer is locally advanced.
  • the cancer is a RAF inhibitor-resistant cancer.
  • the RAF inhibitor-resistant cancer is a BRAF inhibitor-resistant cancer.
  • the cancer is a MEK inhibitor-resistant cancer.
  • the cancer is a MAPK-mediated cancer.
  • the cancer is a BRAF -mutated cancer.
  • the BRAF-mutated cancer is a BRAF V600 -mutated cancer, such as BRAF V600E and
  • the cancer is a RAS-mutated cancer.
  • the RAS-mutated involves codons 12, 13, or 61.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the RAS-mutated cancer is an NRAS-mutated cancer, including, but not limited to, NRAS Q61R , NRAS Q61K , NRAS Q61L , or NRAS Q61H .
  • the RAS-mutated cancer is an HRAS-mutated cancer, including, but not limited to, HRAS G12V , HRAS Q61R , and HRAS G12S .
  • the cancer is selected from multiple myeloma, breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach (gastric), skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung, bone, colon, thyroid, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma (including uveal melanoma) sarcoma, bladder carcinoma, liver carcinoma (e.g., hepatocellular carcinoma (HCC)) and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, phary
  • the cancer is selected from carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • a sarcoma is a soft tissue sarcoma.
  • a lymphoma is non-hodgkins lymphoma.
  • a lymphoma is large cell immunoblastic lymphoma.
  • the cancer is selected from adenocarcinoma; adenoma; adrenocortical cancer; bladder cancer; bone cancer; brain cancer; breast cancer; cancer of the buccal cavity; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine carcinoma; epidermoid carcinoma; esophageal cancer; eye cancer; follicular carcinoma; gallbladder cancer; prostate, AML, multiple myeloma (MM), gastrointestinal cancer, such as, for example, gastrointestinal stromal tumor; cancer of the genitourinary tract; glioblastoma; hairy cell carcinoma; various types of head and neck cancer; hepatic carcinoma; hepatocellular cancer; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; cancer of the large intestine; laryngeal cancer; liver cancer; lung cancer, such as, for example, adenocarcinoma of the lung, anaplastic carcinoma of the lung, pa
  • the cancer is selected from melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), multiple myeloma (MM), and leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia.
  • a leukemia is acute lymphoblastic leukemia.
  • the cancer is selected from melanoma, colorectal cancer, lung cancer, or pancreatic cancer.
  • the cancer is melanoma.
  • the melanoma is uveal melanoma.
  • the melanoma is a melanoma of the skin.
  • the melanoma is locally advanced.
  • the melanoma is metastatic.
  • the melanoma is recurring.
  • the melanoma is refractory.
  • the melanoma is BRAF v60 °- mutated melanoma.
  • the melanoma is a RAS-mutated melanoma.
  • the melanoma is NRAS-mutated melanoma. In certain embodiments, the melanoma is wild type for KRAS, NRAS or BRAF. In certain embodiments, the melanoma is a BRAF inhibitor-resistant (e.g., Vemurfenib-resistant, dabrafenib-resistant, encorafenib-resistant, etc.) melanoma. In certain embodiments, the cancer is a Vem (i.e., Vemurfenib-resistant) BRAF -mutated melanoma.
  • the cancer is colorectal cancer. In certain embodiments, the colorectal cancer is locally advanced. In certain embodiments, the colorectal cancer is metastatic. In certain embodiments, the colorectal cancer is recurring. In certain embodiments, the colorectal cancer is refractory. In certain embodiments, the colorectal cancer is a BRAF- mutated colorectal cancer. In certain embodiments, the colorectal cancer is a BRAF v600 -mutated colorectal cancer. In certain embodiments, the colorectal cancer is a RAS-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a KRAS-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a NRAS-mutated colorectal cancer.
  • the cancer is pancreatic cancer.
  • the pancreatic cancer is locally advanced.
  • the pancreatic cancer is metastatic.
  • the pancreatic cancer is locally recurring.
  • the pancreatic cancer is refractory.
  • the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).
  • the pancreatic cancer is a RAS-mutated pancreatic cancer.
  • the pancreatic cancer is a KRAS- mutated pancreatic cancer.
  • the pancreatic cancer is KRAS-mutated pancreatic cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the cancer is a papillary thyroid cancer.
  • the papillary thyroid cancer is locally advanced.
  • the papillary thyroid cancer is metastatic.
  • the papillary thyroid cancer is refractory.
  • the papillary thyroid cancer is recurring.
  • the papillary thyroid cancer is BRAF-mutated papillary thyroid cancer.
  • the papillary thyroid cancer is BRAF v600 -mutated papillary thyroid cancer.
  • the papillary thyroid cancer includes undifferentiated or dedifferentiated histology.
  • the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the lung cancer is locally advanced.
  • the lung cancer is metastatic.
  • the lung cancer is recurring.
  • the lung cancer is refractory.
  • the lung cancer is a RAS-mutated lung cancer.
  • the lung cancer is KRAS-mutated lung cancer.
  • the lung cancer is a KRAS-mutated lung cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the cancer is a leukemia.
  • a leukemia is a chronic leukemia.
  • a leukemia is chronic myeloid leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia (AML).
  • a leukemia is acute monocytic leukemia (AMoL, or AML-M5).
  • a leukemia is acute lymphoblastic leukemia (ALL).
  • a leukemia is acute T cell leukemia.
  • a leukemia is myelomonoblastic leukemia.
  • a leukemia is human B cell precursor leukemia.
  • a leukemia has a Flt3 mutation or rearrangement.
  • the cancer is a CNS cancer, for instance CNS tumors.
  • a CNS tumor is a glioblastoma or glioblastoma multiforme (GBM).
  • the present invention relates to a method of treating stomach (gastric) and esophageal tumors and cancers.
  • the cancer is multiple myeloma (MM).
  • the multiple myeloma is locally advanced.
  • the multiple myeloma is metastatic.
  • the multiple myeloma is locally recurring.
  • the multiple myeloma is refractory.
  • the multiple myeloma is a RAS-mutated multiple myeloma.
  • the multiple myeloma is KRAS-mutated multiple myeloma.
  • the RAS-mutated multiple myeloma is a KRAS-mutated multiple myeloma, including, but not limited to, KRAS ,
  • KRAS G13C/D KRAS Q61L/H/R .
  • the cancer is hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the HCC is locally advanced.
  • the HCC is metastatic.
  • the HCC is locally recurring.
  • the HCC is refractory.
  • the cancer is a RAS-mutated HCC.
  • the cancer is KRAS-mutated HCC.
  • the RAS-mutated cancer is a KRAS- mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • leukemia e.g., AML
  • liver e.g., AML
  • lung melanoma
  • ovarian e.g., pancreatic, prostate, or thyroid.
  • the cancer is selected from breast, colorectal, endometrial, liver, lung, melanoma, ovarian, pancreatic, or thyroid.
  • the cancer is selected from colorectal, lung, melanoma, or pancreatic.
  • the cancer is selected from colorectal, melanoma, or pancreatic.
  • the cancer is a RAF inhibitor resistant cancer, for example the cancer is a BRAF inhibitor resistant cancer. In certain embodiments, the cancer is a MEK inhibitor resistant cancer.
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or conditions associated with one or both of ER 1 and ERK2, wherein the method comprises administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof. It is understood that in instances where the methods described herein refer to administering Compound 1, such methods are equally applicable to methods of administering a salt form of Compound 1, e.g., a phosphate salt of Compound 1. Accordingly, methods provided herein are to be understood to encompass either the administration of Compound 1 or a pharmaceutically acceptable salt thereof.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 1% to about 60% of Compound 1, or a pharmaceutically acceptable salt thereof, based upon total weight of the formulation.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising the phosphate salt of Compound 1.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 2% to about 18% or about 4% to about 12% or about 5% to about 10% or about 6% to about 9% or about 7% to about 8% of the phosphate salt of Compound 1 based upon total weight of the composition.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%), about 14% or about 15% of the phosphate salt of Compound 1, based on total weight of the composition.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 20% to about 60% or about 25%o to about 55% or about 30% to about 50% or about 40% to about 50% or about 45% to 46% of the phosphate salt of Compound 1 based upon total weight of the formulation.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 25%, about 30%, about 35%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55%) of the phosphate salt of Compound 1, based on total weight of the composition.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 6%, about 7%, about 8%), about 9%, about 10%, about 11%, about 12%, or about 13% of the phosphate salt of Compound 1 based upon total weight of given composition or formulation.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 43%, about 44%, about 45%, about 46%), about 47%, or about 48% of the phosphate salt of Compound 1 based upon total weight of given composition or formulation.
  • provided methods comprise administering a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, one, two, three, or four times a day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily ("QD").
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.
  • twice daily administration refers to a compound or composition that is administered "BID".
  • a "BID" dose is a particular dose (e.g., a 150 mg dose) that is administered twice a day (i.e., two doses of 150 mg administered at two different times in one day).
  • twice daily administration refers to a compound or composition that is administered in two different doses, wherein the first administered dose differs from the second administered dose.
  • a 180 mg dose administered twice daily can be administered as two separate doses, one 150 mg dose and one 30 mg dose, wherein each dose is administered at a different time in one day.
  • a 180 mg dose administered twice daily can be administered 90 mg BID (i.e., three 30 mg doses administered at different times in one day).
  • a total daily dose of 180 mg of Compound 1, or a pharmaceutically acceptable salt thereof can be administered as a 150 mg dose administered at a given timepoint (for example, in the morning) and a 30 mg dose administered at a later timepoint (for example, in the evening).
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered three times a day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered "TID", or three equivalent doses administered at three different times in one day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered in three different doses, wherein at least one of the administered doses differs from another administered dose.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered four times a day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered "QID" , or four equivalent doses administered at four different times in one day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered in four different doses, wherein at least one of the administered doses differs from another administered dose.
  • provided methods comprise administering a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, once a day ("QD"). In some embodiments, provided methods comprise administering a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered once or twice daily for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered once daily for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered once or twice daily for an amount of time during a period of 28 days ("a 28-day cycle"). In some embodiments, a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily for at least one 28-day cycle. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily for 21 consecutive days of at least one 28-day cycle.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered once or twice daily for at least two, at least three, at least four, at least five or at least six 28-day cycles. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily for at least seven, at least eight, at least nine, at least ten, at least eleven or at least twelve 28-day cycles. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice daily for at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen or at least twenty 28-day cycles. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a patient for the duration of the patient's life.
  • two adjacent 28-day cycles may be separated by a rest period. Such a rest period may be one, two, three, four, five, six, seven or more days during which the patient is not administered a unit dose of Compound 1, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, two adjacent 28-day cycles are continuous.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered once or twice daily for at least two, at least three, at least four, at least five consecutive days every seven days.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered once daily for at least five consecutive days every seven days.
  • Comound 1, or a pharmaceutically acceptable salt thereof is administered every other day.
  • Comound 1, or a pharmaceutically acceptable salt thereof is administered every third day.
  • a tablet or capsule is typically a unit dosage form.
  • the unit dosage forms described herein refer to an amount of the active pharmaceutical ingredient, i.e., free base form Compound 1.
  • a pharmaceutical composition comprises a salt form of Compound 1, for example a phosphate salt form
  • the amount of the salt form present in the composition is an amount that is equivalent to a unit dose of the free base Compound 1.
  • a pharmaceutical composition comprising the phosphate salt of Compound 1 would contain 6.07 mg of the phosphate salt form necessary to deliver an equivalent 5 mg unit dose of the free base Compound 1.
  • a unit dosage form contains 5 mg Compound 1.
  • a unit dosage form contains 30 mg Compound 1.
  • a unit dosage form contains 150 mg Compound 1.
  • the present invention provides a method for treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERK1 and ERK2 in a patient in need thereof, comprising the step of administering to said patient one or more unit doses of a provided formulation.
  • the present invention provides a method for treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERK1 and ERK2 in a patient in need thereof comprising the step of administering to said patient one or more unit doses of the present invention wherein said unit dose provides about 5 mg to about 1000 mg of Compound 1.
  • a formulation of the present invention provides about 1 mg, 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650
  • the present invention provides a method for treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERKl and ERK2 in a patient in need thereof, comprising the step of administering to said patient one or more unit doses of the present invention wherein a unit dose provides about 5 mg, 30 mg, or 150 mg of Compound 1.
  • a unit dose formulation of the present invention provides about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of Compound 1.
  • the present invention provides a method for treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERKl and ERK2 in a patient in need thereof, comprising the step of administering to said patient one or more unit doses comprising the phosphate salt of Compound 1, wherein the phosphate salt of Compound 1 is in an amount equivalent to any of the above unit dosage amounts of Compound 1.
  • provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 1 mg to about 10 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 2 mg to about 8 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 4 mg to about 6 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 5 mg.
  • provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 20 mg to about 40 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 25 mg to about 35 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 28 mg to about 32 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 30 mg.
  • provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 100 mg to about 200 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 125 mg to about 175 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 140 mg to about 160 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a composition comprising a unit dose of Compound 1, wherein the unit dose is about 150 mg.
  • a unit dose of Compound 1 is administered once a day (QD). In some embodiments, a unit dose of Compound 1 is administered twice a day . In some embodiments, a unit dose of Compound 1 is administered BID.
  • the unit dose of Compound 1 is about 25 mg to 750 mg, or about 25 mg to about 625 mg, or about 25 mg to about 500 mg, or about 25 mg to about 375 mg, or about 25 mg to about 250 mg, or about 25 mg to about 125 mg, or about 25 mg to about 75 mg, or about 75 mg to about 750 mg, or about 75 mg to about 625 mg, or about 75 mg to about 500 mg, or about 75 mg to about 375 mg, or about 75 mg to about 250 mg, or about 75 mg to about 125 mg, or about 125 mg to about 750 mg, or about 125 mg to about 625 mg, or about 125 mg to about 500 mg, or about 125 mg to about 375 mg, or about 125 mg to about 250 mg, or about 250 mg to about 750 mg, or about 250 mg to about 625 mg, or about 250 mg to about 500 mg, or about 250 mg to about 375 mg, or about 375 mg to about 750 mg, or about 250 mg to about 625 mg, or about 250 mg to about 500 mg, or
  • the unit dose of Compound 1 is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285
  • Compound 1 is administered once a day. In certain embodiments, Compound 1 is administered once a day in the morning. In certain embodiments, Compound 1 is administered once a day at night. In certain embodiments, Compound 1 is administered once a day under fasted conditions. In certain embodiments, Compound 1 is administered once a day in the morning under fasted conditions.
  • Compound 1 is administered two, three or four times a day. In some embodiments, Compound 1 is administered two, three or four times a day, wherein each dose is identical. In some embodiments, Compound 1 is administered two, three or four times a day, wherein at least one dose is different from another dose. In some such embodiments, each dose may be independently selected from those doses or dose ranges in the two preceeding paragraphs.
  • provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising one or more unit doses of Compound 1.
  • a unit dose is about 5mg, about 30 mg, or about 150 mg and is present in the form of the phosphate salt of Compound 1.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer, the method comprising administering to a patient in need thereof a solid oral dosage form comprising a unit dose of Compound 1, wherein the unit dose is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, wherein the therapeutically effective amount is a total daily dose selected from about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, wherein the therapeutically effective amount is a total daily dose is about 100 mg to about 3000 mg, or about 500 mg to about 3000 mg, or about 100 mg to about 2500 mg, or about 500 mg to about 2500 mg, or about 100 mg to about 2200 mg, or about 500 mg to about 2200 mg, or about 600 mg to about 2200 mg, or about 700 mg to about 2200 mg, or about 800 to about 2200 mg, or about 800 to about 2100 mg, or about 800 to about 2000 mg.
  • the daily dose is about 800 mg to about 2000 mg.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, wherein the therapeutically effective amount is a total daily dose is about 10 mg to about 500 mg, or about 10 mg to about 450 mg, or about 10 mg to about 425 mg, or about 10 mg to about 400 mg, or about 10 mg to about 375 mg, or about 10 mg to about 350 mg, or about 10 mg to about 325 mg, or about 10 mg to about 300 mg, or about 10 mg to about 275 mg, or about 10 to about 250 mg, or about 10 to about 225 mg, or about 10 mg to about 200 mg, or about 10 mg to about 190 mg, or about 10 mg to about 180 mg, or about 10 mg to about 170 mg, or about 10 mg to about 160 mg, or about 10 mg to about 150 mg, or about 10 mg to about 140 mg, or about 10 mg to about 130 mg, or about 10 mg to about 120 mg
  • a total daily dose of Compound 1 is administered as a single dose.
  • a total daily dose of Compound 1 is administered as two, three or four doses in one day, wherein each dose is identical.
  • a total daily dose of Compound 1 is administered as two, three or four doses in one day, wherein at least one dose is different from another dose.
  • the doses are independently selected from about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280
  • a total daily dose of Compound 1 is administered once daily (QD), wherein the dose is selected from about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 180 mg, about 330 mg, about 480 mg, or about 640 mg.
  • a total daily dose of Compound 1 is administered once daily (QD), wherein the dose is selected from about 20 mg, about 40 mg, about 80 mg, or about 160 mg.
  • a total daily dose of Compound 1 is administered once daily (QD), wherein the therapeutically effective amount is a total daily dose selected from about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 2
  • a total daily dose of Compound 1 is administered once daily (QD), wherein the dose is selected from about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 35 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg,
  • a pharmaceutically acceptable composition comprising Compound 1 is administered twice daily. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered "BID". In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered in two different doses, wherein the first administered dose differs from the second administered dose.
  • a pharmaceutically acceptable composition comprising Compound 1 is administered three times a day. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered "TID". In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered in three different doses, wherein at least one of the administered doses differs from another administered dose. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered four times a day. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered "QID". In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered in four different doses, wherein at least one of the administered doses differs from another administered dose.
  • a total daily dose of Compound 1 is administered to a patient once a day under fasted conditions.
  • the total daily dose is any of those contemplated above and herein.
  • a total daily dose of 100 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 200 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 300 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 400 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 500 mg of Compound 1 is administered to a patient once a day, under fasted conditions.
  • a total daily dose of 600 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 700 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 800 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 900 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 1000 mg of Compound 1 is administered to a patient once a day, under fasted conditions.
  • a total daily dose of 1100 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 1200 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 1300 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 1400 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 1500 mg of Compound 1 is administered to a patient once a day, under fasted conditions.
  • a total daily dose of 1600 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 1700 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 1800 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 1900 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of 2000 mg of Compound 1 is administered to a patient once a day, under fasted conditions. In some embodiments, a total daily dose of greater than 2000 mg of Compound 1 is administered to a patient once a day, under fasted conditions.
  • a therapeutically effective amount of Compound 1 is administered over a period of 28 consecutive days ("a 28-day cycle").
  • a therapeutically effective amount of Compound 1 is administered over a period of 28 consecutive days ("a 28-day cycle"), wherein dosing occurs daily for 21 consecutive days out of a 28 day cycle. In some such embodiments, dosing occurs once daily. In some such embodimemts, dosing occurs once daily under fasting conditions.
  • a therapeutically effective amount of Compound 1 is administered for two, three, four, five or six 28-day cycles. In some embodiments, a therapeutically effective amount of Compound 1 is administered for seven, eight, nine, ten, eleven, twelve or more 28-day cycles. In some embodiments, a pharmaceutically acceptable composition comprising Compound 1 is administered for at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen or at least twenty 28-day cycles. In some embodiments, a therapeutically effective amount of Compound 1 is administered to a patient for the duration of the patient's life. Formulations Comprising Compound 1 or a Pharmaceutically Acceptable Salt Thereof
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable composition is an oral dosage form.
  • the pharmaceutically acceptable composition is formulated as a capsule.
  • the pharmaceutically acceptable composition is a blended powder.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising the phosphate salt of Compound 1.
  • the present invention provides a composition comprising a pharmaceutically acceptable salt form of Compound 1 selected from the group consisting of phosphate salt forms, HCl salt forms, HBr salt forms, bis-phosphate salt forms, sulfate salt forms, bis-sulfate salt forms, tosylate salt forms, mesylate salt forms, besylate salt forms, maleate salt forms, and oxalate salt forms.
  • the present invention provides a composition comprising a pharmaceutically acceptable salt form of Compound 1 selected from the group consisting of phosphate salt forms.
  • provided formulations may comprise one or more solubilizers.
  • Solubilizers include, by way of example and without limitation, cyclodextrins such as alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-beta- cyclodextrin, hydroxymethyl cyclodextrin, hydroxyethyl cyclodextrin, and hydroxybutyl cyclodextrin, carboxymethyl cyclodextrin, carboxyethyl cyclodextrin, carboxypropyl cyclodextrin, carboxybutyl cyclodextrin, methylcarboxymethyl cyclodextrin; amino cyclodextrin, sulfobutyl-ether-P-cyclodextrin sodium salt ("SBECD", also referred to herein as betadex sulfobutyl ether
  • provided compositions comprise from about 1% to about 50% solubilizer, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 1% to about 45%, or about 1% to about 40%>, or about 1% to about 35%o, or about 1% to about 30%, or about 1% to about 25%, or about 1% to about 20% solubilizer based on the total weight of the composition.
  • provided compositions comprise about 1% to about 10% solubilizer, based on the total weight of composition. In certain embodiments, provided compositions comprise about 1% to about 9%, or about 1% to about 8%, or about 1% to about 7%), or about 1% to about 6%, or about 1% to about 5%, or about 2% to about 4% solubilizer based on the total weight of the composition.
  • provided compositions comprise a solubilizer in an amount of about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%), about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%), about 3.8%, about 3.9%, or about 4.0%.
  • provided compositions comprise a solubilizer in an amount of about 3.33%.
  • provided compositions comprise about 10% to about 30% solubilizer, based on the total weight of composition. In certain embodiments, provided compositions comprise about 10% to about 25%, or about 15% to about 25%, or about 17% to about 23%, or about 18% to about 22%, or about 19% to about 21% solubilizer based on the total weight of the composition.
  • provided compositions comprise a solubilizer in an amount of about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%. In certain embodiments, provided compositions comprise a solubilizer in an amount of about 20%.
  • compositions comprise sulfobutyl-ether- - cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 45%, or about 1% to about 40%), or about 1% to about 35%, or about 1% to about 30%>, or about 1% to about 25%, or about 1% to about 20% solubilizer based on the total weight of the composition.
  • provided compositions comprise sulfobutyl-ether- - cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 10%. In some embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 9%, or about 1% to about 8%, or about 1% to about 7%), or about 1% to about 6%, or about 1% to about 5%, or about 2% to about 4%. In certain embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 3.33%.
  • provided compositions comprise sulfobutyl-ether- - cyclodextrin sodium salt as a solubilizer in an amount of about 10% to about 30%. In some embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt in an amount of about 10% to about 25%, or about 15% to about 25%, or about 17% to about 23%, or about 18% to about 22%, or about 19% to about 21%. In certain embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 20%. ii. Surfactants/Wetting Agents
  • Surfactants/wetting agents are well known in the art and typically facilitate drug release and absorption by enhancing the solubility of poorly- soluble drugs.
  • Representative surfactants/wetting agents include, but are not limited to, poloxamers, polyoxyethylene ethers (e.g., polyethylene glycol), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates such as polysorbate 80, cetyl alcohol, glycerol fatty acid esters (e.g., triacetin, glycerol monostearate, and the like), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium, Vitamin E TPGS, copovidone, polyvinyl alcohol (
  • compositions comprise from about 0.1% to about 10%), or from about 0.1 %> to about 9%>, or from about 0.1 %> to about 8%>, or from about 0.1 %> to about 7%), or from about 0.1 %> to about 6%>, or from about 0.1 %> to about 5%>, or from about 0.1 %> to about 4%, or from about 0.1% to about 3%, or from about 0.1% to about 2% surfactant/wetting agent, or from about 0.1% to about 1%, or from about 0.1% to about 0.5%, or from about 0.2% to about 0.4% surfactant/wetting agent based upon total weight of the formulation.
  • provided compositions comprise from about 0.1 %> to about 10%), or from about 0.2%> to about 8%>, or from about 0.5%> to about 5%>, or from about 1%> to about 5%, or from about 1% to about 4%, or from about 1% to about 3%, or from about 1.5% to about 2.5% surfactant/wetting agent based upon total weight of the formulation.
  • a provide composition comprises about 2%> surfactant/wetting agent.
  • provided compositions comprise about 0.1 %>, about 0.2%>, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%), about 2.6%), about 2.7%>, about 2.8%>, about 2.9%> or about 3.0% surfactant/wetting agent.
  • a provide composition comprises about 0.33% surfactant/wetting agent.
  • a surfactant/wetting agent is a surfactant/wetting agent such as sodium lauryl sulfate (SLS).
  • SLS sodium lauryl sulfate
  • a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.1% to about 10%, or from about 0.1% to about 9%), or from about 0.1 %> to about 8%>, or from about 0.1 %> to about 7%>, or from about 0.1 %> to about 6%), or from about 0.1 %> to about 5%>, or from about 0.1 %> to about 4%>, or from about 0.1 %> to about 3%.
  • a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 2%.
  • a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.1%, about 0.2%>, about 0.3%>, about 0.4%>, about 0.5%>, about 0.6%>, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0%.
  • a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.33%.
  • provided formulations may comprise one or more dispersing agents.
  • Dispersing agents are substances added to a formulation to prevent settling, clumping, or gelling.
  • compound 2 in certain formulations has a tendency to gel in the presence of moisture. It has been found that the use of certain dispersing agents can minimize such gelling.
  • Dispersing agents include, by way of example and without limitation, salts such as sodium carbonate, sodium bicarbonate, sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, potassium chloride, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, and sodium chloride, sugars such as mannitol, fructose, sucrose, xylitol maleic acid, sorbitol, and dextrose, and acids such as D,L-malic acid, and the like, and combinations thereof.
  • salts such as sodium carbonate, sodium bicarbonate, sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, potassium chloride, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, and sodium chloride
  • sugars such as mannitol, fructose, sucrose, xylitol maleic acid, sorbitol, and dextrose
  • acids such as D,L-malic acid
  • provided compositions comprise from about 0.1 % to about 20%) dispersing agent, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1 % to about 15%, or about 0.1 % to about 10%>, or about 0.1%) to about 8%, or about 0.1 % to about 7%, or about 0.1 % to about 6%, or about 0.1% to about 5%), or about 0.1% to about 4%, or about 0.1% to about 3%, or about 0.1% to about 2%, or about 0.1% to about 1%, or about 0.2% to about 0.8%, or about 0.2% to about 0.6%, or about 0.3%) to about 0.5%) dispersing agent.
  • compositions comprise from about 0.5% to about 10%), or about 0.5% to about 5%, or about 1% to about 5%, or about 1% to about 4%, or about 1%) to about 3.5%), or about 1.5% to about 3.5%, or about 2% to about 3% dispersing agent.
  • compositions comprise about 0.1%, about 0.2%>, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%), about 2.6%), about 2.7%, about 2.8%, about 2.9%> or about 3.0% dispersing agent.
  • provided compositions comprise about 0.4%> dispersing agent. In certain embodiments, provided compositions comprise about 0.5%> dispersing agent. In certain embodiments, provided compositions comprise about 0.42%> dispersing agent.
  • provided compositions comprise about 2.0% dispersing agent. In certain embodiments, provided compositions comprise about 3.0%> dispersing agent In certain embodiments, provided compositions comprise about 2.5% dispersing agent.
  • a dispersing is a bicarbonate salt, such as sodium bicarbonate.
  • provided compositions comprise sodium bicarbonate as a dispersing agent in an amount of about 0.1% to about 15%, or about 0.1% to about 10%, or about 0.1% to about 8%), or about 0.1%> to about 7%, or about 0.1%> to about 6%, or about 0.1%> to about 5%, or about O.P/o to about 4%, or about 0.1 % to about 3%.
  • compositions comprise sodium bicarbonate as a dispersing agent in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0%.
  • provided compositions comprise about 0.4%> sodium bicarbonate. In certain embodiments, provided compositions comprise about 0.5%> sodium bicarbonate. In certain embodiments, provided compositions comprise about 0.42% sodium bicarbonate.
  • provided compositions comprise about 2.0%> sodium bicarbonate. In certain embodiments, provided compositions comprise about 3.0%> sodium bicarbonate. In certain embodiments, provided compositions comprise about 2.5% sodium bicarbonate. iv. Fillers
  • compositions for use in the present invention may comprise one or more fillers. Fillers are used in the formulation of solid oral dosage forms to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix.
  • Suitable fillers are known in the art.
  • suitable fillers include but are not limited to starch, PVP (polyvinyl pyrrolidone), celluloses such as low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose (e.g., Avicel®), silicified microcrystalline cellulose (Prosolv 50), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose (e.g., sodium carboxymethyl cellulose) and ethylcellulose, pregelatinized starch, alginates, gelatin, polyethylene oxide, acacia, dextrin, sucrose, lactose (e.g., lactose monohydrate), mannitol, magnesium aluminum silicate, and polymethacrylates.
  • PVP polyvinyl pyrrolidone
  • HPC hydroxypropyl cellulose
  • microcrystalline cellulose e.g., Avicel®
  • silicified microcrystalline cellulose Prosolv 50
  • Fillers include agents selected from the group consisting of silicic acid, microcrystalline cellulose (e.g., Avicel®), starch, pregelatinized starch, sugars such as lactose, sucrose, glucose, dextrose, fructose, maltose, a suitable inorganic calcium salts such as dibasic calcium phosphate and calcium sulfate, polyols such as sorbitol, mannitol, lactitol, malitol and xylitol, or a combination thereof.
  • silicic acid e.g., Avicel®
  • starch pregelatinized starch
  • sugars such as lactose, sucrose, glucose, dextrose, fructose, maltose
  • a suitable inorganic calcium salts such as dibasic calcium phosphate and calcium sulfate
  • polyols such as sorbitol, mannitol, lactitol, malitol and xylit
  • a filler is selected from the group consisting of microcrystalline cellulose, starch, pregelatinized starch, dextrose, sucrose, dibasic calcium phosphate, calcium sulfate, mannitol, or a combination thereof.
  • provided compositions comprise from about 10% to about 90%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 85% filler, based upon total weight of the formulation.
  • provided compositions comprise from about 10%> to about 50%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10%> to about 40%> filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 30%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 25% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 20% to about 25% filler, based upon total weight of the formulation.
  • provided compositions comprise about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29% or about 30% filler.
  • provided compositions comprise from about 40% to about 90%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 50% to about 90% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 60% to about 90%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 70% to about 90% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 75% to about 85%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 78% to about 82% filler, based upon total weight of the formulation.
  • provided compositions comprise about 70%, about 71%, about 73%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90% filler.
  • the filler is microcrystalline cellulose.
  • provided compositions comprise from about 10% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 85% microcrystalline cellulose, based upon total weight of the formulation.
  • provided compositions comprise from about 10% to about 50% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 40% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 30% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 25% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 20% to about 25% microcrystalline cellulose, based upon total weight of the formulation.
  • provided compositions comprise about 14%, about 15%, about 16%>, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%), about 28%, about 29% or about 30% microcrystalline cellulose.
  • provided compositions comprise from about 40% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 50% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 60% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 70% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 75% to about 85% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 78% to about 82% microcrystalline cellulose, based upon total weight of the formulation.
  • provided compositions comprise about 70%, about 71%, about 73%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%), about 87%, about 88%, about 89%, or about 90% microcrystalline cellulose.
  • Disintegrants comprise about 70%, about 71%, about 73%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%), about 87%, about 88%, about 89%, or about 90% microcrystalline cellulose.
  • compositions for use in the present invention may further comprise one or more disintegrants.
  • Incorporation of suitable disintegrant(s) into provided compositions may facilitate breakdown of provided compositions.
  • inclusion of disintegrants may be particularly desired in provided compositions that contain active compound(s).
  • Suitable disintegrants include, but are not limited to, clays, agar, calcium carbonate, sodium carbonate, sodium bicarbonate, cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), starch, sodium carboxymethyl starch (sodium starch glycolate), calcium carboxymethyl cellulose, pregelatinized starch, microcrystalline cellulose, cross-linked polyvinylpyrrolidone (e.g., crospovidone), potato or tapioca starch, alginic acid, certain silicates, microcrystalline starch, water insoluble starch, magnesium aluminum silicate (Veegum) or a combination thereof.
  • a suitable disintegrants is selected from cross-linked polyvinylpyrrolidone, starch, pregelatinized starch, sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, clay, or a combination thereof.
  • provided formulations comprise from about 1% to about 30% disintegrant, based upon total weight of the formulation. In some embodiments, provided formulations comprise from about 1% to about 25%, about 1% to about 20% disintegrant, about 1%) to about 15%) disintegrant, about 1% to about 10%> disintegrant, about 2% to about 8% disintegrant, about 3% to about 7% disintegrant, or about 4% to about 6% disintegrant. In some embodiments, provided formulations comprise about 1%, about 2%, about 3%, about 4%, about 5%), about 6%), about 7%, about 8%, about 9%, or about 10% disintegrant, based upon total weight of the formulation. In certain embodiments, provided formulations comprise about 5% disintegrant, based upon total weight of the formulation.
  • a disintegrant in a provided composition is a cross-linked polymer such as cross-linked polyvinylpyrrolidone.
  • a disintegrant is cross-linked polyvinylpyrrolidone.
  • a disintegrant is cross-linked polyvinylpyrrolidone in an amount of about 1% to about 25%, about 1% to about 20% disintegrant, about 1% to about 15% disintegrant, about 1% to about 10% disintegrant, about 2% to about 8%) disintegrant, about 3% to about 7% disintegrant, or about 4% to about 6%.
  • provided formulations comprise about 1%, about 2%, about 3%, about 4%, about 5%), about 6%), about 7%, about 8%, about 9%, or about 10% cross-linked polyvinylpyrrolidone, based upon total weight of the formulation.
  • compositions of the present invention may further comprise one or more glidants.
  • a glidant is a substance that is added to a powder to improve its flowability.
  • Such compounds include, without limitation, colloidal silica (also referred to as colloidal silicon dioxide), fumed silica, talc, starch, DL-leucine, metallic stearates such as sodium stearate, calcium stearate, zinc stearate and magnesium stearate, sodium lauryl sulfate, and the like, and combinations thereof.
  • provided compositions comprise from about 0.1% to about 3% glidant, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1% to about 2.5%, or about 0.1 % to about 2.0%, or about 0.1% to about 1.5%, or about 0.5% to about 1.5%, or about 0.8% to about 1.2% glidant. In certain embodiments, provided compositions comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%), or about 2% glidant.
  • a glidant is colloidal silica.
  • provided compositions comprise from about 0.1 % to about 2.5%, or about 0.1 % to about 2.0%>, or about 0.1%) to about 1.5%, or about 0.5%> to about 1.5% colloidal silica, based on the total weight of the composition.
  • provided compositions comprise from about 0.5%> to about 1.5% colloidal silica.
  • provided compositions comprise 1.0% colloidal silica. vii. Lubricants
  • compositions of the present invention may further comprise one or more lubricants.
  • Lubricants are agents added in small quantities to formulations to improve certain processing characteristics. For example, lubricants prevent the formulation mixture from sticking to the compression machinery and enhance product flow by reducing interparticulate friction.
  • Such compounds include, by way of example and without limitation, sodium oleate, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, polyethylene glycol, talc, boric acid, mineral oil, stearic acid, sodium benzoate, sodium acetate, sodium chloride, DL- leucine, glyceryl behenate, magnesium lauryl sulfate, sodium lauryl sulfate, hydrogenated vegetable oil, glyceryl distearate, sodium stearyl fumarate, sodium oleate, fatty acids (e.g., palmitic and stearic acids) and other materials known to one of ordinary skill in the art.
  • fatty acids e.g., palmitic and stearic acids
  • provided compositions comprise from about 0.1 % to about 3% lubricant, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1 % to about 2.5%, or about 0.1 % to about 2.0%>, or about 0.1%) to about 1.5%, or about 0.5% to about 1.5%, or about 0.8% to about 1.2% lubricant.
  • compositions comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%), or about 2%> lubricant.
  • a lubricant is magnesium stearate.
  • provided compositions comprise from about 0.1% to about 2.5% magnesium stearate.
  • provided compositions comprise from about 0.1 %> to about 2.0% magnesium stearate.
  • provided compositions comprise from about 0.5%> to about 1.5% magnesium stearate.
  • provided compositions comprise about 1% magnesium stearate.
  • the present invention provides a method of treating a cancer, the method comprising administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1 or a pharmaceutically acceptable salt thereof.
  • provided methods comprise administering to a patient in need thereof a phosphate salt of Compound 1.
  • the present invention provides a pharmaceutically acceptable salt of Compound 1.
  • the present invention provides a phosphate salt of Com ound 1, depicted below:
  • a phosphate salt of Compound 1 can exist in a variety of physical forms.
  • a phosphate salt of Compound 1 can be in solution, suspension, or in solid form.
  • a phosphate salt of Compound 1 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof.
  • a phosphate salt of Compound 1 is anhydrous.
  • a phosphate salt of Compound 1 is a hydrate.
  • a phosphate salt of Compound 1 is a solvate. In some embodiments, a phosphate salt of Compound 1 is a dehydrate. In some embodiments, a phosphate salt of Compound 1 is a desolvate. Exemplary solid forms are described in more detail below.
  • the present invention provides a phosphate salt of Compound 1 substantially free of impurities.
  • substantially free of impurities means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess phosphoric acid, excess compound 1, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, a phosphate salt of Compound 1.
  • extraneous matter may include excess phosphoric acid, excess compound 1, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, a phosphate salt of Compound 1.
  • at least about 95% by weight of a phosphate salt of Compound 1 is present.
  • at least about 99% by weight of a phosphate salt of Compound 1 is present.
  • a phosphate salt of Compound 1 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a phosphate salt of Compound 1 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • a phosphate salt of Compound 1 contains no more than about 1.0% are percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • a phosphate salt of Compound 1 is also meant to include all tautomeric forms of a phosphate salt of Compound 1. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • a phosphate salt of Compound 1 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • a phosphate salt of Compound 1 is a crystalline solid.
  • a phosphate salt of Compound 1 is a crystalline solid substantially free of amorphous a phosphate salt of Compound 1.
  • the term "substantially free of amorphous a phosphate salt of Compound 1" means that the compound contains no significant amount of amorphous a phosphate salt of Compound 1.
  • at least about 95% by weight of crystalline a phosphate salt of Compound 1 is present.
  • at least about 99% by weight of crystalline a phosphate salt of Compound 1 is present.
  • a phosphate salt of Compound 1 can exist in at least four distinct polymorphic forms.
  • the present invention provides a polymorphic form of a phosphate salt of Compound 1 referred to herein as Form A.
  • the present invention provides a polymorphic form of a phosphate salt of Compound 1 referred to herein as Form B.
  • the present invention provides a polymorphic form of a phosphate salt of Compound 1 referred to herein as Form C.
  • the present invention provides a polymorphic form of a phosphate salt of Compound 1 referred to herein as Form D.
  • a phosphate salt of Compound 1 is amorphous. In some embodiments, a phosphate salt of Compound 1 is amorphous, and is substantially free of crystalline phosphate salt of Compound 1.
  • Polymorphs of a phosphate salt of Compound 1 include Forms A-D, described further below. Accordingly, it has been found that a phosphate salt of Compound 1 can exist in at least four distinct polymorphic forms.
  • the present invention provides a polymorphic form of a phosphate salt of Compound 1 referred to herein as Form A.
  • the present invention provides a polymorphic form of a phosphate salt of Compound 1 referred to herein as Form B.
  • the present invention provides a polymorphic form of a phosphate salt of Compound 1 referred to herein as Form C.
  • the present invention provides a polymorphic form of a phosphate salt of Compound 1 referred to herein as Form D.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising a phosphate salt of Compound 1 of Form A.
  • a phosphate salt of Compound 1 is of Form A and has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 1 below.
  • the position 2d? is within ⁇ 0.2.
  • Form A is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1, and 20.8. In some embodiments, Form A is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1, and 20.8. In some embodiments, Form A is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1, and 20.8.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 1.
  • a phosphate salt of Compound 1 is of Form B and has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 2 below.
  • the position 2d? is within ⁇ 0.2.
  • Form B is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0. In some embodiments, Form B is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0. In some embodiments, Form B is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 2.
  • a phosphate salt of Compound 1 is of Form C and has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 3 below.
  • the position 2d? is within ⁇ 0.2.
  • Form C is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5. In some embodiments, Form C is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5. In some embodiments, Form C is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 3.
  • a phosphate salt of Compound 1 is of Form D and has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 4 below.
  • the position 2d? is within ⁇ 0.2.
  • Form D is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.1, 10.4, and 25.1. In some embodiments, Form D is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.1, 10.4, and 25.1. In some embodiments, Form D is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 9.1, 10.4, and 25.1.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 4.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 1% to about 60% of a phosphate salt of Compound 1, based upon total weight of given composition or formulation (wt %).
  • a provided composition, or formulation thereof comprises from about 1 wt% to about 50 wt% of a phosphate salt of Compound 1.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 1 wt% to about 20 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 2 wt% to about 18 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 4 wt% to about 12 wt% of a phosphate salt of Compound 1.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 5 wt% to about 10 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 6 wt% to about 9 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 7 wt% to about 8 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising about 7.59 wt% of a phosphate salt of Compound 1.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 20 wt% to about 60 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 25 wt% to about 55 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 30 wt% to about 50 wt% of a phosphate salt of Compound 1.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 35 wt% to about 50 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 40 wt% to about 50 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 41 wt% to about 49 wt% of a phosphate salt of Compound 1.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 42 wt% to about 48 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 43 wt% to about 47 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 44 wt% to about 46 wt% of a phosphate salt of Compound 1.
  • provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 45 wt% to about 46 wt% of a phosphate salt of Compound 1. In some embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising about 45.53 wt% of a phosphate salt of Compound 1.
  • provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1, wherein Compound 1 is in the form of a phosphate salt of any one of Forms A, B, C, or D, and wherein the unit dose is any of those described above and herein.
  • provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1, wherein Compound 1 is in the form of a phosphate salt of Form A, and wherein the unit dose is any of those described above and herein.
  • provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1, wherein Compound 1 is in the form of a phosphate salt of Form A, and wherein the unit dose is about 5 mg. In certain embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1, wherein Compound 1 is in the form of a phosphate salt of Form A, and wherein the unit dose is about 30 mg. In certain embodiments, provided methods comprise administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1, wherein Compound 1 is in the form of a phosphate salt of Form A, and wherein the unit dose is about 150 mg.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer described herein, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof. In certain embodiments, such methods comprise administering to a patient in need thereof a phosphate salt of Compound 1 of Form A. [00236] In some embodiments, the present invention provides a method of treating, stabilizing or lessening the severity or progression of a BRAF-mutated cancer, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof.
  • such methods comprise administering to a patient in need thereof a phosphate salt of Compound 1 of Form A.
  • the BRAF-mutated cancer is a BRAF V600 -mutated cancer, such as BRAF V600E , BRAF V600K , BRAF V600R , and BRAF V600D .
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a RAS-mutated cancer, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof.
  • such methods comprise administering to a patient in need thereof a phosphate salt of Compound 1 of Form A.
  • the RAS-mutation involves codons 12, 13, or 61.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the RAS-mutated cancer is an NRAS-mutated cancer, including, but not limited to, NRAS Q61R , NRAS Q61K , NRAS Q61L , or NRAS ⁇ 61H .
  • the RAS-mutated cancer is an HRAS-mutated cancer, including, but not limited to, HRAS G12V , HRAS Q61R , and HRAS G12S .
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a melanoma, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof.
  • such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a colorectal cancer, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof. In certain embodiments, such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a pancreatic cancer, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof. In certain embodiments, such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a thyroid cancer, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof.
  • such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a lung cancer, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof.
  • such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a leukemia, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof.
  • such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a CNS cancer, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof. In certain embodiments, such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a multiple myeloma, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof. In certain embodiments, such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of an HCC, wherein said method comprises administering to a patient in need thereof the phosphate salt of Compound 1, or a pharmaceutically acceptable composition thereof.
  • such methods comprise administering to a patient in need thereof a the phosphate salt of Compound 1 of Form A.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising the phosphate salt of Compound 1, wherein the amount of phosphate salt is sufficient to deliver about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 180 mg, about 330 mg, about 480 mg, or about 640 mg of the free base of Compound 1.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients selected from one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants, lubricants, or combinations thereof.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients selected from betadex sulfobutylether sodium, sodium lauryl sulfate, sodium bicarbonate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate, wherein the amount of each component is based upon the total weight of the composition.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer, for example, a BRAF-mutated cancer, a RAF-mutated cancer, a melanoma, a colorectal cancer, a lung cancer, a leukemia, or a pancreatic cancer, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising: (a) about 1% to about 60% phosphate salt of Compound 1; (b) about 1% to about 50% solubilizer; (c) about 0.1 % to about 10%> surfactant/wetting agent; (d) about 0.1%) to about 20%) dispersing agent; (e) about 10%> to about 90%> filler; (f) about 1% to about 30%o disintegrant; (g) about 0.1 % to about 3% glidant; and (h) about 0.1% to about 3% lubricant; wherein the amount of each component is based upon the total weight of the
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of a cancer, for example, a RAS-mutated cancer, a RAF- mutated cancer, a melanoma, a colorectal cancer, a lung cancer, or a pancreatic cancer, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising: (a) about 1% to about 60% phosphate salt of Compound 1; (b) about 1% to about 50%) betadex sulfobutylether sodium; (c) about 0.1% to about 10% sodium lauryl sulfate; (d) about 0.1% to about 20% sodium bicarbonate; (e) about 10% to about 90% microcrystalline cellulose; (f) about 1% to about 30% crospovidone; (g) about 0.1% to about 3% colloidal silicon dioxide; and (h) about 0.1% to about 3% magnesium stearate; wherein the amount of each component is based upon the total weight
  • the pharmaceutical composition is selected from those in Table 5:
  • provided formulations are prepared by dry blending Compound 1, or a pharmaceutically acceptable salt thereof, and excipients. Exemplary such methods are described below and in the Examples section.
  • a provided formulation is prepared by a process comprising: (a) blending a surfactant/wetting agent, a dispersing agent, a solubilizer, and a disintegrant to form a first blended powder;
  • a provided formulation is prepared by a process comprising:
  • capsules are filled with the final blended powder.
  • the above procedure is used to prepare a capsule containing Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 1 wt% to about 20 wt%, or from about 2 wt% to about 18 wt%, or from about 4 wt% to about 12 wt%, or from about 5 wt% to about 10 wt%, or from about 6 wt% to about 9 wt%, or from about 7 wt% to about 8 wt%.
  • the above procedure is used to prepare a capsule containing the phosphate salt of Compound 1 in an amount of about 7.59 wt%.
  • the phosphate salt of Compound 1 is of Form A.
  • a provided formulation is prepared by a process comprising:
  • a provided formulation is prepared by a process comprising:
  • capsules are filled with the final blended powder.
  • a provided formulation is prepared by a process comprising:
  • a provided formulation is prepared by a process comprising:
  • the above procedure is used to prepare a capsule containing Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 20 wt% to about 60 wt%, or from about 25 wt% to about 55 wt%, or from about 30 wt% to about 50 wt%, or from about 35 wt% to about 50 wt%, or from about 40 wt% to about 50 wt%, or from about 41 wt% to about 49 wt%, or from about 42 wt% to 48 wt%, or from about 43 wt% to 47 wt%, or from about 44 wt% to about 46 wt%, or from about 45 wt% to about 46 wt%.
  • the above procedure is used to prepare a capsule containing the phosphate salt of Compound 1 in an amount of about 45.53 wt%.
  • the phosphate salt of Compound 1 is of Form A.
  • Compound 1 is prepared according to the following general procedure.
  • Step 2 can be carried out by adding Intermediate 1 to a suitable coupling partner in the presence of Na 2 C0 3 , a degassed solvent (e.g., tert-amyl alcohol), a suitable palladium catalyst (e.g., tris-dibenzylamino dipalladium) and a suitable phosphine ligand (e.g., Dave Phos) under conditions suitable to effect coupling.
  • a degassed solvent e.g., tert-amyl alcohol
  • a suitable palladium catalyst e.g., tris-dibenzylamino dipalladium
  • a suitable phosphine ligand e.g., Dave Phos
  • Compound 1 showed activity in various assays described at Examples 415-418 and in Table A (see Compound 1-90 therein) of the '230 publication. Data disclosed therein for Compound 1 is reproduced below in Table 6.
  • Table 6 summarizes the activity of Compound 1 in each of the following assays: ERK1 Omnia WT ATP KM IC 5 o (nM) - measuring the degree of inhibition of wildtype (“WT”) ER 1 activity
  • ERK1/ERK2 PRSK HCT116 EC 50 (nM) - measuring the degree of inhibition of the kinase activity of ERK1 and ERK2 to phosphorylate a substrate, p90RSK, in HCT116 cells (colorectal carcinoma cell line)
  • Form A of the phosphate salt of Compound 1 was prepared as follows.
  • Procedure A Compound 1 was dissolved in 15X tetrahydrofuran. One molar equivalent of 2 molar phosphoric acid in acetonitrile was charged. The batch was slurried at 20 °C for 1 to 2 hours. The solvent was removed under reduced pressure. The resulting solids were slurried in acetone for about 16 hours at 20 °C, filtered and dried.
  • Procedure B Compound 1 was dissolved in THF. Equal molar equivalent of 1.08 M phosphoric acid in acetonitrile was charged. The sample was shaken at ambient temperature at 200 PvPM for 1 hour. The solvent was removed under nitrogen purge. The resulting solids were slurried in acetone with a stirring bar at ambient temperature overnight, then filtered and dried in vacuum oven at 30 °C overnight.
  • Procedure C Compound 1 was dissolved in THF (20X vol) at 20 °C. Seeds of Compound 2 Form A (5% wt) were charged. A I M solution of phosphoric acid (1 mol eq.) in ethanol was charged. The batch was left under vigorous agitation for two hours. Solvent exchange to isopropyl acetate was carried out with a constant volume distillation under reduced pressure, with temperature not exceeding 40 °C. The batch was cooled to 20 °C. The solvent was removed under nitrogen purge. The batch was filtered, washed two times with isopropyl acetate and dried in a vacuum oven at ⁇ 40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure D Compound 1 was dissolved in 9X vol THF/ H 2 0 (95:5 vol). A solution of H 3 PO 4 (1.2 mol eq.) in ethanol was charged to a second flask, seeds of Form A (5%) were charged and vigorous agitation was started. The solution of Compound 1 was charged to the H 3 PO 4 solution (reverse addition) over one hour. The slurry was aged for one hour. Solvent exchange to ethanol was started (constant volume vacuum distillation with continuous addition of ethanol, final THF NMT 0.5%). The batch was cooled to 20 °C, filtered and dried in a vacuum oven at -40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure E Compound 1 was dissolved in 10X vol THF/H 2 0 (95:5 vol). Isopropyl alcohol (5X vol) was charged. Constant volume distillation, with continuous addition of isopropyl alcohol was started at atmospheric pressure. Solvent exchange was carried out until THF content was below 5%. Compound 1 recrystallized during the solvent exchange. The batch was cooled to 30 °C. A 1M solution of H 3 PO 4 in IPA was charged over 2 hours. Seeds of Form A (1%) were then charged. The batch was stirred vigorously overnight. The batch was filtered and dried in a vacuum oven at ⁇ 40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure F Compound 1 was dissolved in 9X vol THF/H 2 0 (95:5 vol). After polish filtration, distillation to reduce volume from 9X to 5X was performed, followed by addition of 8X ethyl acetate to bring the total volume to 13X. Solvent exchange to ethyl acetate, with constant volume distillation was carried out (final THF NMT 2%). The temperature was then reduced to 30 °C. Seeds of the phosphate salt of Compound 1 (1% wt) were charged. A solution of H 3 PO 4 (1.2 eq.) in ethanol (5X) was then dosed in over 2 hours. The temperature was reduced to 20 °C, the batch was aged for 12 hours under vigorous stirring, then filtered, washed two times with ethyl acetate and dried in a vacuum oven at ⁇ 40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure G Compound 1 was charged to a reactor, then ethanol (4X vol) and ethyl acetate (6X), were charged. The batch was agitated at 30 °C. A solution of H 3 PO 4 (1.2 mol eq.) in ethanol (2X vol) was charged over 2 hours. Seeds of Form A (1%) were charged. The batch was filtered, washed two times with ethyl acetate, dried overnight at -40 °C, under vacuum with nitrogen bleed.
  • the position 2d? is within ⁇ 0.2.
  • Figure 1 depicts an XRPD pattern of Form A of the phosphate salt of compound 1.
  • This experiment describes the identification of certain tumor cell lines that are sensitive to treatment with Compound 1, or a pharmaceutically acceptable salt thereof.
  • Cells were grown in RPMI1640, 10%FBS, 2 mM L-alanyl-L-Glutamine, lmM Na Pyruvate or a special medium in a humidified atmosphere of 5% C0 2 at 37 °C. Cells were seeded into 384-well plates and incubated in a humidified atmosphere of 5% C0 2 at 37 °C. Compounds were serially diluted 3.16-fold and assayed over ten concentrations at a final assay concentration of 0.1% DMSO from the highest test concentrations specified in the sample information chapter. Compounds were added 24 hours post cell seeding. At the same time, a time zero untreated cell plate was generated.
  • GI 50 is the concentration needed to reduce the observed growth by half. This is the concentration that inhibits the growth midway between untreated cells and the number of cells seeded in the well (Time zero value).
  • the tables below provide data on the sensitivity of the indicated tumor cell line to Compound 1. Proliferation of the tumor cell lines provided below is inhibited by Compound 1.
  • GI 50 data for NRAS mutant and HRAS mutant cell lines shown below in Table 8 and Table 9, respectively.
  • TGI tumor growth inhibition
  • Compound 1 elicited dose and schedule dependent tumor growth inhibition in the HCT1 16 xenograft model (57% to 93% TGI), with a minimum efficacious dose (70%> TGI) of 50 mg/kg/day, correlating to an area under the plasma concentration-time curve (AUC) of 1470 ng-hr/mL on the final day of dosing (See Figure 6) Occupancy of ER (i.e., the proportion of ER protein bound to Compound 1), measured in tumor lysates collected on the last day of dosing with Compound 1 was comparable to tumor growth inhibition, and is summarized in Table 13.
  • TGI Tumor Growth Inhibition
  • ERK Occupancy ERK Occupancy
  • AUC area under the concentration-time curve
  • BID twice daily
  • ND not determined
  • QD once daily
  • a Doses of Compound 1 refer to the free base.
  • Occupancy Assay A A standard curve of recombinant ER 1 (Millipore 14-439, lot 2052233) was prepared by first incubating human rER l with an excess of a probe compound that covalently binds to ERK, final concentration 0.6 ⁇ in lysis buffer. The rERKl standard was then diluted to concentrations of 0.34, 1.02, 3.06, 9.18, 27.54, 82.62, 250 ngs/60 ⁇ , and 60 was added to the sample plate. The following protocol was used for Erk occupancy in tumor homogenates.
  • the MSD assay was accomplished by first thawing the plate containing the rER l standard curve samples and tumor lysates at 4 °C on a plate shaker. An MSD ER plate for detection of total ERK 1/2 (MesoScale Discovery, Cat# K15107A-3) was blocked with 3% BSA in TBST as per kit instructions. Blocking reagent was removed and the plate was washed 3 times with MSD washing buffer (IX TBST). All samples were mixed with an equal volume of MSD lysis buffer (containing 2X protease and phosphatase inhibitors) spiked with 0.5% SDS to a final SDS concentration of 0.25%. Equal volumes of the clicked samples were then added to two separate MSD wells, one for detection of biotin probe (for determination of free ERK) and one for detection of total ERK for normalization.
  • MSD lysis buffer containing 2X protease and phosphatase inhibitors
  • the plate was incubated for 2 hours at room temperature under constant shaking, washed 3 times with MSD washing buffer, tapped dry, then incubated with 25 ⁇ of either ERK SULFO-TAG detection antibody (for total ERK detection, diluted 1 :50 in 1% BSA in TBST) or SULFO-TAG streptavidin detection protein (MesoScale Discovery Cat#R32AD-l;for free ERK detection, diluted 1 :500 in 1%BSA in TBST). Following incubation under constant shaking for 1 hour at room temperature, the plate was washed 3 more times with MSD washing buffer, tapped to dry, and 150 ⁇ , of IX MSD read buffer added (per kit instructions).
  • Tumor growth inhibition (calculated in the same manner as in Example 4) following administration of Compound 1 in the A375 xenograft model at 100 mg/kg QD and 50 mg/kg BID was 84% and 87%, respectively (Table 14).
  • Occupancy i.e., the proportion of phosphorylated ERK protein bound to Compound 1 in tumor lysates 2 to 8 hours after the last dose was 48% to 54% in the 50 mg/kg BID treatment group and 82% to 86% in the 100 mg/kg QD treatment group (Table 14).
  • Plasma exposure of Compound 1 in the 50 mg/kg BID group was 9280 ng-hr/mL (Table 14).
  • a Doses of Compound 1 refer to the free base.
  • Occupancy Assay B For determination of pERK occupancy and total ERK levels, a tERK pERK kit from Mesoscale Discovery was used (MSD K15107D-3, RockviUe, MD). The kit contains a capture plate containing a tERK spot, a pERK spot and 2 BSA spots. Parallel plates were blocked with 3% bovine serum albumin (BSA) for 1 hour at room temperature. The blocking buffer was discarded and 30 ⁇ , of lysate was added to each plate. The pERK covalent probe compound at 10 mM stock was diluted to 2 ⁇ in lysis buffer. To each well 3.3 ⁇ probe compound was added so that the final concentration per well was 0.2 ⁇ .
  • BSA bovine serum albumin
  • ERK occupancy in tumors was determined by measuring total ERK and free ERK (ERK not bonded with Compound 1) using a commercially available kit for detection of ERKl/2, and occupied ERKl/2 using a covalent probe compound.
  • the ERK occupancy levels obtained with the dosing regimens evaluated are presented in Table 15. Plasma concentrations of Compound 1 following the final dose in each group were determined by LC/MS/MS and plasma exposures are summarized in Table 15.
  • TGI Tumor Growth Inhibition
  • ERK Occupancy ERK Occupancy
  • TGI tumor growth inhibition
  • a Doses of Compound 1 refer to the free base.
  • mice dosed on last day of study for exposure assessment regardless of dose regimen. e Tumors in this group spontaneously regressed, which possibly inflated the TGI.
  • Compound 1 inhibited tumor growth in an A375 xenograft mouse model, with a minimum efficacious dose of 50 mg/kg/day, corresponding to an AUCO-8 hr of 4350 ng-hr/mL and target occupancy of 59%. Comparable tumor growth inhibition was observed in mice dosed daily at 25 mg/kg or every other day at 50 mg/kg (53% for both groups), and similarly between mice that were dosed daily at 50 mg/kg and those dosed at 100 mg/kg every other day (68% and 69%), respectively). These data suggest that reduced dose frequency could inhibit tumor growth as effectively as daily administration.
  • A375 cells were cultured in IMDM media in the presence of 10% FBS and were made resistant to a Raf inhibitor by continuous culture in the presence of increasing concentrations of Vemurafenib. These cells are referred to as A375-R.
  • HCT-116 cells KRAS mutant
  • HCT116R trametinib
  • Inhibition of proliferation was assayed by measuring the difference in cell growth after 72 h between cells treated with Compund 1 and cells treated with DMSO (control).
  • Cells were plated in 96-well plates in full media (10% FBS in DMEM for A375 and A375-R, or 10% FBS in RPMI for HCT-116 or HCT-116R) at 3000 cells per well.
  • Compound 1 was serially diluted in 3-fold dilutions in DMSO, and added to the cells 6 hours after plating at a final concentration of 0.1% DMSO, 5% FBS.
  • GI 50 is defined as the 50% inhibition of the cell growth from day 0 to 72 h after treatment relative to DMSO treated control.
  • Results of GI 50 for Compound 1 in parental A375, BRAF inhibitor resistant A375 cells, HCT-116 parental, and Mek-inhibitor resistant HCT-116 is shown in Table 16 below. As shown in Tables 16 and 17, A375R and HCT116R cells are more sensitive to Compound 1 than a BRAF inhibitor (BRAFi) or a MEK inihibitor (MEKi), respectively.
  • BRAFi BRAF inhibitor
  • MEKi MEK inihibitor
  • A-375 BRAF mutant melanoma line
  • A-375R Vemurafenib-resistant A-375.
  • ERKi ERK inhibitor
  • HCT-l 16 KRAS colon cancer.
  • HCT-116R trametinib-resistant HCT-l 16.
  • ERKi ERK inhibitor
  • This Example describes experiments relating to the effect of Compound 1 (free base) on a Panel (a.k.a. PANC-1) pancreatic cancer cell line, a MIA PaCa-2 pancreatic cancer cell line, an HS294T melanoma cell line, an HCT-1 16 colorectal cancer cell line, a KRAS-mutant q61H NCI-H460 lung cancer cell line, a KRAS-unknown NCI-H522 lung cancer cell line, a p. G469A NCI-1755 lung cancer cell line, a KRAS-mutant p. G12V NCI-H727 lung cancer cell line, and a KRAS-mutant NCI-H522 lung cancer cell line.
  • cells were plated at a density of 3000 cells/well in 90 of growth media on 96 well clear bottom black-well plates (Corning Cat# 3904) and incubated overnight under standard cell culture growth conditions at 37 °C 5% C0 2 .
  • the outer most rows and columns of wells were filled with culture media, without cells, to avoid evaporation effects on subsequent readouts.
  • Results are depicted graphically in Figures 7 and 9-16. A curve crossing below the X-axis indicates that cell number has dropped below the starting point (i.e., the cells are dying).
  • Figure 9 depicts (a) a first in vitro assay of Compound 1 against HCT-116 colorectal cancer cells; and (b) a second in vitro assay of Compound 1 against HCT-116 colorectal cancer cells.
  • Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1321.30 nM.
  • Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1169.50 nM.
  • Figure 10 depicts an in vitro assay of Compound 1 against KRAS-mutant q61H NCI- H460 lung cancer cells. As shown in Figure 10, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 6839.12 nM.
  • Figure 11 depicts an in vitro assay of Compound 1 against KRAS-unknown NCI- H522 lung cancer cells. As shown in Figure 11, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 2338.84 nM.
  • Figure 12 depicts an in vitro assay of Compound 1 against p.G469A NCI-H1755 lung cancer cells. As shown in Figure 12, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 722.77 nM.
  • Figure 13 depicts an in vitro assay of Compound 1 against KRAS-mutant p.G12V NCI-H727 lung cancer cells. As shown in Figure 13, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 762.08 nM.
  • Figure 14 depicts an in vitro assay of Compound 1 against KRASunknown NCI-H522 lung cancer cells. As shown in Figure 14, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 3006.08 nM.
  • Figure 15 depicts (a) a second in vitro assay of Compound 1 against Mia PaCa-2 pancreatic cancer cells; and (b) a third in vitro assay of Compound 1 against Mia PaCa-2 pancreatic cancer cells.
  • Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1238.80 nM.
  • Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1534.62 nM
  • Figure 16 depicts a second in vitro assay of Compound 1 against HS294T melanoma cells. As shown in Figure 16, Compound 1 induces cell death (cytotoxic) effect (noted by the curve crossing the X-axis) at 1202.26 nM.
  • the primary objectives of the study are to assess the safety, tolerability, and PK of the phosphate salt of Compound 1 when administered orally to subjects with locally-advanced or metastatic relapsed or refractory, BRAF-(e.g., BRAF V600 ) or RAS- mutated solid tumors and to define its maximally tolerated dose (MTD).
  • BRAF-(e.g., BRAF V600 ) or RAS- mutated solid tumors and to define its maximally tolerated dose (MTD).
  • Secondary Objective The secondary objective of the study is to conduct a preliminary assessment of the anti-tumor activity of the phosphate salt of Compound 1.
  • Exploratory Objectives The exploratory objectives of the study are (1) explore the relationship between the Compound 1 exposure (AUC) and response (safety and efficacy); (2) explore the influence of intrinsic and extrinsic factors that may influence Compound 1 exposures (e.g., age, gender, body weight, tumor type, measures of end-organ function, associated inter- individual and residual variability in Compound 1 recipients, etc.) (3) evaluate Compound 1 binding to ERK in peripheral blood mononuclear cells (PBMCs) and tumor biopsies, as well as inhibition of ERK signaling in tumor biopsies obtained prior to and during treatment with Compound 1 (4) characterize the principal metabolites of Compound 1 in plasma; and (5) explore changes to the levels of 4 -hydroxycholesterol (a marker of CYP3A activity) in plasma samples obtained prior to and during treatment with Compound 1.
  • AUC Compound 1 exposure
  • response safety and efficacy
  • intrinsic and extrinsic factors that may influence Compound 1 exposures (e.g., age, gender
  • the primary endpoints of this study are (1) safety as defined by the type, incidence and severity of adverse events, dose limiting toxicities, the MTD of Compound 1, and changes from baseline in selected laboratory analytes, vital signs and ECG findings; and (2) PK endpoints: C max , AUC, T max , 1 1 / 2 , CL/F, Vz/F and accumulation index of Compound 1.
  • the secondary endpoints of this study are anti-tumor activity as measured by response rate, duration of response, disease control rate, progression-free survival and overall survival.
  • Exploratory endpoints are (1) PK endpoints as assessed by non-mixed effect modeling (NMEM) compartment analysis; (2) clinically relevant intrinsic/extrinsic covariates of Compound 1 exposure from population PK analysis; (3) mechanism-based modeling of Compound 1 exposure and response relationships; (4) relationship between Compound 1 exposure (as measured by AUC) and binding to ERK in PBMCs and tumor biopsies obtained during vs. pre-treatment; (5) relationship between Compound 1 binding to ERK and inhibition of ERK signaling in tumor biopsies during vs.
  • NMEM non-mixed effect modeling
  • This study is an open-label, multicenter, Phase la study in subjects with locally- advanced or metastatic, RAS or BRAF (e.g., BRAF V60 °) -mutated solid tumors who are intolerant of, resistant to or have relapsed after at least one line of therapy and for whom no standard therapy exists.
  • the study will be conducted in two parts: Dose Escalation (Part 1) and Cohort Expansion (Part 2). For both parts, each 28-day cycle will consist of 21 consecutive days of Compound 1 treatment followed by a 7 day rest period. Subjects may continue Compound 1 until progression of their underlying malignancy, the occurrence of intolerable toxicity or physician/subject decision to discontinue Compound 1. Subjects who discontinue study treatment for reasons other than progression will be requested to continue follow-up on study until progression, initiation of new anti-cancer therapy, or withdrawal of consent for further study participation.
  • RAS or BRAF e.g., BRAF V60 °
  • Part 1 Cohorts of subjects with either BRAF (e.g., BRAF V600 )-mutated cancers (e.g. melanomas, colorectal cancer (CRC), papillary thyroid carcinomas) or RAS-mutated cancers (e.g. pancreatic ductal adenocarcinomas (PDAC), CRC, melanomas, non-small cell lung cancer (NSCLC)), or relapsed or refractory tumors will receive increasing doses of Compound 1 in order to assess its safety and tolerability, the MTD and PK profile.
  • BRAF e.g., BRAF V600
  • CRC colorectal cancer
  • RAS-mutated cancers e.g. pancreatic ductal adenocarcinomas (PDAC), CRC, melanomas, non-small cell lung cancer (NSCLC)
  • PDAC pancreatic ductal adenocarcinomas
  • NSCLC non-small cell lung cancer
  • the initial cohort will receive 20 mg
  • Cycle 1 Days 1-28 will constitute the dose-limiting toxicity (DLT) assessment period for purposes of non-tolerated dose (NTD) and MTD determination.
  • DLT dose-limiting toxicity
  • NTD non-tolerated dose
  • MTD mobility-tolerated dose
  • a modified accelerated titration design will be used to establish initial toxicity.
  • cohorts of one or more subjects each will be given Compound 1 at doses that will increase in 100% increments per cohort until the first occurrence of a Grade >2, study drug-related toxicity in Cycle 1.
  • the accelerated phase will end and all subsequent cohorts (including the cohorts in question) will be expanded to 6-9 sequentially enrolled subjects.
  • a dose escalation schedule with dose increments not to exceed 50% will concurrently be initiated in order to establish the NTD and MTD.
  • Smaller dose increments and/or additional subjects within a dose cohort as well as modified dosing schedules may be evaluated, if necessary, based on toxicity, PK/PD or findings on tumor biopsies.
  • Dose escalation decisions will be made at the discretion of the Study Review Committee (SRC), composed of representatives of the Sponsor (i.e. the medical monitor, drug safety physician and study manager) as well as the principal investigators from each of the participating institutions at which one or more study subjects was enrolled. See Figure 8.
  • SRC Study Review Committee
  • a dose will be considered intolerable if >33%> of evaluable subjects in a dose cohort experience DLT during Cycle 1.
  • the putative MTD will be defined as the last dose below the NTD, at which ⁇ 33%> of evaluable subjects experienced DLT during Cycle 1. Investigation of an intermediate dose between the NTD and the putative MTD may be required to determine the MTD with greater precision, as may alternate regimens if emerging PK results suggest they may be appropriate. A dose intermediate between the NTD and putative MTD may still be explored following initiation of Part 2 (see below).
  • Part 1 subjects will be evaluable for DLT if a.) they received the prescribed dose of Compound 1 on at least 80% of treatment days in Cycle 1 (i.e. 17 of 21 days), and have sufficient data for safety evaluation by the SRC, or b.) experienced a DLT.
  • Non-DLT evaluable subjects within a given dose cohort will be replaced. Approximately 40 subjects in 10 dose cohorts are anticipated in Part 1 for initial assessment of safety, NTD/MTD, and PK (intensive blood sampling).
  • Intrasubject dose escalation will not be allowed during the DLT assessment period; however, in Cycle 2 and beyond, subjects without evidence of disease progression who are tolerating their assigned dose of Compound 1 may (at the investigator's discretion) escalate to the highest dose level shown to be adequately tolerated by at least one cohort of subjects in this study (i.e. ⁇ 33% of evaluable subjects having experienced a DLT at that dose level).
  • Part 2 In Part 2, subjects will receive Compound 1 at or below the MTD until progression of disease, intolerable toxicity or physician/subject decision to discontinue Compound 1. Approximately 42-60 subjects belonging to one of three tumor- specific cohorts will be evaluated for additional assessments of safety, PK (intensive sampling) and antitumor activity:
  • Recurrent/progressed NRAS G12, G13 or Q61
  • BRAF V600 -mutant e.g., V600E or V600K
  • tumor specific expansion cohorts may be modified (or additional cohorts may be added) that would allow an assessment of Compound 1 in other tumor types of interest.
  • Subjects in Part 2 will be required to undergo tumor biopsies in order to obtain tumor tissue for PD biomarkers at Screening (up to 28 days before Cycle 1, Day 1 of Compound 1) and during Cycle 1 (days 16 through 21). Enrollment into each tumor specific cohort will follow a two-stage design: if at least one objective response or 3 subjects with stable disease lasting >16 weeks (i.e., through the 2 nd on-treatment, tumor assessment time point) is observed from among the first 14 efficacy-evaluable patients enrolled, the remainder of the cohort (the 2 nd stage) will be completed in order to insure the availability of data from approximately 20 evaluable subjects.
  • accrual to the 2 nd stage may be suspended until it can be determined with certainty that at least one of the aforementioned criteria for enrollment of the 2 nd stage have been met. In the absence of either of the aforementioned criteria, enrollment into a given cohort will cease after 14 subjects. Decisions to expand or curtail enrollment into each tumor-specific cohort will be made in consultation with the Safety Review Committee.
  • the study design includes: (1) a screening period from day -28 to day -1; (2) a treatment and evaluation period, during which time Compound 1 is administered on Days 1-21 of 28-day cycles until tumor progression, unacceptable toxicity or subject/physician decision to discontinue Compound 1 (Part 1 : Dose-escalation; Part 2: Cohort expansion) ; and (3) an end of treatment and follow up period comprising end of treatment procedures and safety follow-up for 28 days after last dose of Compound 1 or until disease progression (in subjects who discontinue Compound 1 for reasons other than progression).
  • Study Design Rationale This is a Phase la, multicenter, open-label study of orally administered Compound 1.
  • Compound 1 has a strong biological rationale for the treatment of subjects with locally-advanced or metastatic, relapsed or refractory cancers in which MAPK pathway dysregulation is pathogenetic. The safety, tolerability, PK/PD and preliminary efficacy of Compound 1 will be evaluated in this study. As noted, the study will be conducted in two parts: dose escalation (Part 1) and cohort expansion (Part 2). In both parts, eligibility will be confined to those subject whose tumors harbor specific activating mutations RAS or BRAF (e.g., BRAF V60 °).
  • RAS or BRAF e.g., BRAF V60 °
  • Missense mutations involving codons 12, 13 and 61 are responsible for the vast majority of RAS-driven tumors.
  • glutamine and lysine substitutions at codon 600 of BRAF (V600E or V600K) comprise the vast majority of all BRAF mutations.
  • Other substitutions at codon 600 of BRAF e.g., V600R,V600D
  • non-V600 activating mutations of BRAF e.g., L597R S or Q, K601E
  • Tumors with non-V600 activating mutations in BRAF may be responsive to MEK inhibitor therapy and therefore, subjects whose tumors harbor these mutations may enroll in Part 1 of the study for determination of NTD/MTD.
  • Part 2 will enroll approximately 42-60 subjects with pre-specified tumor types characterized by mutations in the classical MAPK pathway that are regarded as important to their continued growth and proliferation. Part 2 will further assess the safety and tolerability profile of Compound 1 at the dose and schedule established in Part 1 and provide a preliminary assessment of anti-tumor activity.
  • Part II Disease-specific inclusion criteria - Part II only: As paired tumor samples are required in Part 2 (at Screening and in Cycle 1), subjects with access to tumor tissue capable of being biopsied using non-significant risk biopsy procedures (including, but not limited to, liver, skin/subcutaneous or superficial lymph node biopsy) will be considered for study participation.
  • non-significant risk biopsy procedures including, but not limited to, liver, skin/subcutaneous or superficial lymph node biopsy
  • tumors of the following types that are resistant to or have progressed after at least one line of therapy (or where the subject is intolerant of therapy, as defined above) and for which no standard therapy exists:
  • Melanomas recurrent/progressed, locally advanced, unresectable or metastatic NRAS-mutant (G12, G13, or Q61) melanoma; locally advanced, unresectable or metastatic, BRAF V600 -mutant melanoma (e.g., V600E, V600K, etc.) progressed on BRAF inhibitor (e.g., vemurafenib, dabrafenib), MEK inhibitor (eg, trametinib, cobimetinib [formerly GDC-0973] or selumetinib) or combination BRAF/MEK inhibitor therapy.
  • BRAF inhibitor e.g., vemurafenib, dabrafenib
  • MEK inhibitor eg, trametinib, cobimetinib [formerly GDC-0973] or selumetinib
  • Subjects with a history of anti- CTLA 4 (ipilimumab; Yervoy ® ) or other immune checkpoint blockade inhibitors (e.g., pembrolizumab; nivolumab) as their last therapy prior to enrolling in this trial are eligible as long as they have radiographic evidence of disease progression as defined by Immune -Related Response Criteria.
  • ipilimumab Yervoy ®
  • other immune checkpoint blockade inhibitors e.g., pembrolizumab; nivolumab
  • Colorectal cancer recurrent/progressed, locally advanced, unresectable or metastatic BRAF- (e.g., BRAF V600 ) or RAS- (e.g., KRAS- (G12, G13 or Q61)) mutant CRC recurrent or progressed after at least one fluoropyrimidine-based regimen.
  • BRAF V600 e.g., BRAF V600
  • RAS- e.g., KRAS- (G12, G13 or Q61) mutant CRC recurrent or progressed after at least one fluoropyrimidine-based regimen.
  • Pancreatic ductal adenocarcinoma recurrent/progressed, locally advanced, unresectable or metastatic PDAC recurrent or progressed after at least one gemcitabine- or fluropyrimidine -based regimen.
  • Serum AST/SGOT and ALT/SGPT ⁇ 3.0 x Upper Limit of Normal (ULN) or ⁇ 5.0 x ULN if liver metastases are present
  • Compound 1 will be supplied as capsules in three strengths, 5, 30 and 150-mg for oral administration.
  • the 5, 30, and 150-mg Compound 1 capsules are equivalent to 6.07, 36.42, and 182.10 mg Compound 1 phosphate salt respectively.
  • the 5, 30, and 150 mg strength dose are encapsulated in size 4 reddish brown, size 4 reddish brown /white opaque, and size 0 reddish brown capsule shells, respectively (See Table 5, supra).
  • the capsules contain the following excipients: betadex sulfobutyl ether sodium, sodium lauryl sulfate, sodium bicarbonate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate.
  • Compound 1 will be administered once daily in the morning on an empty stomach (i.e. 1 hour before breakfast) with at least 200 mL of water after an overnight fast lasting at least 6 hours in both Parts 1 and 2. Subjects will administer Compound 1 on Days 1 through 21 of each 28 day treatment cycle. On study days that require PK assessments, Compound 1 will be administered in the clinic in the fasted state after any predose assessments are completed. On all other days, subjects will self-administered their assigned doses at home. Subjects may continue study treatment for as long as they continue to derive clinical benefit or until the occurrence of documented disease progression, intolerable toxicity or subject/investigator decision to discontinue study treatment for other reasons.
  • subjects will be assigned sequentially to each successive dose cohort using an interactive voice response scheme (IVRS). Progression from one dose level to the next higher dose level will follow satisfactory review of relevant safety and available PK/PD data from lower dose cohorts (see below). There will be a minimum of 28 days after the first dose has been administered to the last subject enrolled to a given cohort between dose escalations. Within each dose cohort, enrollment will be staggered so that there is a minimum of 24 hours between the Cycle 1, Day 1 dose for each subject, in order to evaluate acute toxicity. In Part 2, subjects will be treated at or below the MTD within cohorts defined by specified tumor types.
  • IVRS interactive voice response scheme
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • DLTs Dose-limiting toxicities
  • cohorts Upon completion of the accelerated phase (i.e. single subject cohorts), cohorts will consist of 6-9 subjects.
  • the algorithm for dose escalation is as follows:
  • Subjects should continue to adhere to the protocol-specified schedule of study visits/assessments during periods of Compound 1 interruption. Repeat PK/PD evaluations may be conducted following continuation/resumption of Compound 1 treatment at a lower dose. [00372] Subjects who require interruption of dosing for more than 28 days beyond Cycle 1 for treatment related toxicity will permanently discontinue Compound 1 treatment. On rare occasion, such subjects may derive benefit from resumption of Compound 1 treatment. Investigators should notify the sponsor's medical monitor for any permanent discontinuation of study treatment as a result of TEAEs.
  • a total of 7 subjects have been treated with the phosphate salt of Compound 1 at doses varying from 20 to 160 mg/day administered on 21 consecutive days, followed by a 7 day treatment-free interval each 28 day cycle.
  • Cohort #1 was a single subject cohort, treated with 20mg/day for pancreatic cancer (tumor not tested for RAS mutation, per protocol); duration of Rx: 2 cycles (off study for progressive disease after cycle 2).
  • Cohort #2 was a single subject cohort, treated with 40 mg/day for adenocarcinoma of the jejunum (KRAS G12C mutation); duration of Rx: 2 cycles (off study for progressive disease after cycle 2).
  • Cohort #3 was a single subject cohort, treated with 80 mg/day for high grade neuroendocrine tumor (KRAS G12 mutation); duration of Rx: 1 cycle (off study for progressive disease after cycle 1).
  • Cohort #4 represents the first four-subject cohort.
  • Cohert #4 Subject 1 was treated with 160 mg/day for NSCLC (KRAS G12C mutation); duration of Rx: 2.5 cycles (continuing on study at 50% dose, 80 mg/day - response to date: stable disease).
  • Cohort #4, Subject 2 was treated with 160 mg/day for NSCLC (KRAS G12C mutation); duration of Rx: 0.75 cycles (continuing on study; no response assessment to date).
  • Cohort #4 Subject 3 was treated with 160 mg/day for endometrial cancer (KRAS G12D mutation); duration of Rx: 0.75 cycles (continuing on study; no response assessment to date).
  • Cohort #4, Subject 4 was treated with 160 mg/day for CRC (KRAS G12V mutation); duration of Rx: 0.5 cycles (continuing on study; no response assessment to date).

Abstract

La présente invention concerne des méthodes de traitement, de stabilisation ou de réduction de la gravité ou de la progression d'une maladie ou d'un trouble associé à l'ERK1 et/ou à l'ERK2.
PCT/US2015/044890 2014-08-13 2015-08-12 Méthodes de traitement à l'aide d'un inhibiteur d'erk WO2016025621A1 (fr)

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