Therapeutic composition, combination, and method of use

Abstract

To provide methods useful for treating abnormal cell growth, such as cancer, in a subject, such as a human.SOLUTION: Provided is a method comprising the step of administering a FAK inhibitor (e.g., VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766).SELECTED DRAWING: None

Description

Background

[0001] Convincing evidence suggests that focal adhesion kinase (FAK), also known as PTK2, a non-receptor tyrosine kinase in the cytoplasm, plays an essential role in the cell-matrix signaling pathway (Clark and Brugge 1995, Science 268:233-239), and that abnormal activation of PTK2 is associated with an increased potential for tumor metastasis (Owens et al., 1995, Cancer Research 55:2752-2755). FAK was initially identified as a 125 kDa protein highly tyrosine-phosphorylated in cells transformed by v-Src. FAK is encoded by the PTK2 gene in humans. Subsequently, FAK was found to be a tyrosine kinase localized in focal adhesions. Focal adhesions are the contact points between cultured cells and the underlying substrate and are sites of strong tyrosine phosphorylation. FAK is phosphorylated and thus activated in response to the binding of the extracellular matrix (ECM) to integrins. In recent years, studies have shown that an increase in FAK mRNA levels is associated with the invasive transformation of tumors, and that attenuation of FAK expression (by use of antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al., 1996, Cell Growth and Diff. 7:413-418). In addition to being expressed in most tissue types, FAK is found at elevated levels in most human cancers, for example in highly invasive metastases, including cancers of the thyroid, prostate, cervix, colon, rectum, oral epithelium, ovary, and breast. Therefore, compounds, combinations of compounds, compositions, and methods for inhibiting FAK in a subject are desired.

[0002] Components of the RAS / RAF / MEK / ERK signaling pathway also represent opportunities for the treatment of abnormal cell growth, such as cancer.

[0003] International Publication No. 2015 / 120289 discloses a method for treating a subject having cancer, comprising the step of administering a therapeutically effective dose of a FAK inhibitor (e.g., VS-6063) in combination with a MEK inhibitor (e.g., GDC-0623, cobimetinib, trametinib, pimacertib, AZD6244) to the subject, thereby treating the subject.

[0004] International Publication No. 2014 / 059095 and Br J Cancer. May 2019;120(10):975-981 concern the use of combinations of specific FAK inhibitors and specific MEK inhibitors (trametinib) in the treatment of cancer. Summary

[0005] The combination of a FAK inhibitor (e.g., VS-6063) and a RAF / MEK dual inhibitor (e.g., CH5126766) can enhance the generation and efficacy of tumor-specific cytotoxic lymphocytes, providing a promising method for more effectively treating the diseases or disorders described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer as described herein)). VS-6063 or a pharmaceutically acceptable salt thereof (FAK inhibitor) can be used in combination with CH5126766 or a pharmaceutically acceptable salt thereof (RAF / MEK dual inhibitor) to treat the diseases or disorders described herein, e.g., abnormal cell growth (e.g., cancer as described herein).

[0006] Therefore, certain combinations (e.g., combinations described herein (e.g., FAK inhibitors in combination with RAF / MEK dual inhibitors)) are provided herein that can be used to treat abnormal cell growth in a subject (e.g., human), such as cancer (e.g., cancer with RAS mutations).

[0007] A method for treating a subject having cancer is described herein, comprising the step of administering a therapeutically effective dose of VS-6063 or a pharmaceutically acceptable salt thereof (FAK inhibitor) in combination with CH5126766 or a pharmaceutically acceptable salt thereof (RAF / MEK dual inhibitor), wherein the cancer is a cancer having a RAS mutation. In some embodiments, the RAS mutation is a KRAS mutation or an NRAS mutation.

[0008] A method for treating a subject with cancer is described herein, comprising the step of administering to the subject a therapeutically effective dose of VS-6063 or a pharmaceutically acceptable salt thereof in combination with a RAF / MEK biinhibitor, wherein the RAF / MEK biinhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is caused by a mutation in RAS, BRAF, or NF-1. In some embodiments, the cancer is a cancer having an RAS mutation. In other embodiments, the cancer has a KRAS mutation or an NRAS mutation.

[0009] This specification describes the use of VS-6063 or a pharmaceutically acceptable salt thereof in combination with a RAF / MEK bipolar inhibitor for treating cancer, wherein the RAF / MEK bipolar inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is caused by mutations in RAS, BRAF, or NF-1. In some embodiments, the cancer has an RAS mutation. In other embodiments, the cancer has a KRAS mutation or an NRAS mutation.

[0010] A method for treating a subject having cancer is described herein, comprising the step of administering a therapeutically effective dose of CH5126766 or a pharmaceutically acceptable salt thereof in combination with a FAK inhibitor, wherein the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is caused by a mutation in RAS, BRAF, or NF-1. In some embodiments, the cancer has an RAS mutation. In other embodiments, the cancer has a KRAS mutation or an NRAS mutation.

[0011] This specification describes the use of CH5126766 or a pharmaceutically acceptable salt thereof in combination with a FAK inhibitor for treating cancer, wherein the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is caused by mutations in RAS, BRAF, or NF-1. In some embodiments, the cancer has an RAS mutation. In other embodiments, the cancer has a KRAS mutation or an NRAS mutation.

[0012] A method for treating a subject with cancer is described herein, comprising the step of administering a therapeutically effective dose of a RAF / MEK dual inhibitor in combination with a FAK inhibitor, wherein the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof, and the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof.

[0013] This specification describes the use of a RAF / MEK dual inhibitor in combination with a FAK inhibitor for the treatment of cancer, wherein the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof, and the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, cancer is caused by mutations in RAS, BRAF, or NF-1.

[0015] In some embodiments, the cancer is selected from ovarian cancer, lung cancer, colon cancer, and pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is low-grade serous ovarian cancer. In some embodiments, the cancer is lung cancer. In other embodiments, the cancer is colon cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is selected from low-grade serous ovarian cancer, lung cancer, colon cancer, and pancreatic cancer.

[0016] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered twice weekly. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered twice daily. In other embodiments, the FAK inhibitor (e.g., VS-6063) is administered once daily. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) and the FAK inhibitor (e.g., VS-6063) are administered for at least three weeks. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) and the FAK inhibitor (e.g., VS-6063) are administered independently in cycles of three weeks of administration followed by one week of rest. In some embodiments, both the RAF / MEK dual inhibitor (e.g., CH5126766) and the FAK inhibitor (e.g., VS-6063) are administered simultaneously in cycles of three weeks of administration followed by one week of rest.

[0017] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 0.5 mg to approximately 10 mg. In further embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 4 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of 3.2 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 100 mg to approximately 400 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 100 mg to approximately 500 mg. In further embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 200 mg to approximately 500 mg. In other embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 200 mg to approximately 600 mg. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 0.5 mg to approximately 10 mg, and the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 100 mg to approximately 400 mg. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 4 mg twice weekly, and the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 200 mg twice daily. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of 3.2 mg twice weekly, and the FAK inhibitor (e.g., VS-6063) is administered in doses of 200 mg twice daily. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of approximately 4 mg twice weekly, and the FAK inhibitor (e.g., VS-6063) is administered at a dose of approximately 400 mg twice daily. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 3.2 mg twice weekly, and the FAK inhibitor (e.g., VS-6063) is administered at a dose of 400 mg twice daily. Detailed Description of the Invention

[0018] A method for treating abnormal cell growth, such as cancer, comprising the step of administering a FAK inhibitor and a RAF / MEK dual inhibitor, wherein the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof, is described in particular herein.

[0019] Treatment and administration methods The methods described herein relate to treating a subject (e.g., a human subject) suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer as described herein)) with a FAK inhibitor in combination with a RAF / MEK bilayer inhibitor, where the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK bilayer inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. In this specification, “administered in combination” means that two (or more) different treatments are delivered to the subject while the subject is suffering from the disorder, for example, that two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder is cured or eliminated or the treatment is terminated for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second treatment is initiated, thus resulting in an overlap in administration. This may be referred to herein as “simultaneous” or “parallel delivery.” In other embodiments, the delivery of one treatment is completed before the delivery of the other treatment begins. In some embodiments of any case, the combined administration makes the treatments more effective. For example, the second treatment is more effective than what would be seen if it were administered in the absence of the first treatment, e.g., an equivalent effect is seen with a lesser second treatment, or the second treatment alleviates symptoms to a greater extent, or a similar situation is seen with respect to the first treatment. In some embodiments, the delivery results in symptom relief, or other parameters related to the impairment being greater than what might be observed with the other treatment delivered in the absence of the first treatment. The effects of the two treatments are somewhat additive, fully additive, or greater than additive. The delivery may be such that the effect of the first treatment being delivered is still detectable when the second treatment is delivered.

[0020] In some embodiments, the method includes administering a FAK inhibitor (e.g., VS-6063) before administering a RAF / MEK bilayer (e.g., CH5126766). In some embodiments, the method includes administering a FAK inhibitor (e.g., VS-6063) after administering a RAF / MEK bilayer (e.g., CH5126766). In some embodiments, the method includes administering a FAK inhibitor (e.g., VS-6063) in parallel with the administration of a RAF / MEK bilayer (e.g., CH5126766). In some embodiments, the FAK inhibitor is VS-6063 (PF-04554878, defactinib) or a pharmaceutically acceptable salt thereof. In some embodiments, the RAF / MEK bilayer is CH5126766 or a pharmaceutically acceptable salt thereof.

[0021] Tumor microenvironment The compound combinations described herein also relate to methods for modulating or regulating the tumor microenvironment in subjects (e.g., subjects having cancer as described herein). In this specification, “tumor microenvironment” refers to the cellular environment in which a tumor resides, including perivascular tissue, immune cells, fibroblasts, myeloid-derived inflammatory cells, lymphocytes, signaling molecules, and the extracellular matrix (ECM). Tumors and their surrounding microenvironment are closely related and constantly interacting. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis, and inducing peripheral immune tolerance, while immune cells in the microenvironment can influence the growth and evolution of cancer cells.

[0022] In this specification, the term “immunosuppressive cells” refers to cells that contribute to or promote an immunosuppressive tumor microenvironment. The presence of a population of immunosuppressive cells in the tumor microenvironment, also referred to herein as “tumor-associated immunosuppressive cells,” increases the tumor’s resistance to the immune response, resulting in tumor protection, tumor evasion, and / or tumor metastasis. Unless counteracted in some way, tumor-associated immunosuppressive cells can reduce the effectiveness of immune-mediated anticancer treatments. Numerous tumor-associated immunosuppressive cells exist, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells.

[0023] In some embodiments, the compound combinations described herein enhance the efficacy of tumor-specific cytotoxic lymphocytes or antitumor cytotoxic T cells. In some embodiments, the FAK inhibitors described herein (e.g., VS-6063) target immunosuppressive cells in the tumor microenvironment. In some embodiments, the FAK inhibitors described herein (e.g., VS-6063) act as tumor-stromal regulation of dense fibrous stroma and / or as a barrier against T cell infiltration via FAK-regulated pro-inflammatory and / or pro-fibrotic cytokine secretion. In some embodiments, BRAF inhibition activates stromal cells (e.g., cancer-activated fibroblasts, cell adhesion molecules) that lead to FAK-dependent cancer survival signaling (e.g., in melanoma).

[0024] Abnormal cell growth The methods described herein concern the treatment of abnormal cell growth in subjects (e.g., human subjects). In this specification, abnormal cell growth means cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition) unless otherwise indicated. This includes abnormal cell growth of the following: (1) tumor cells (tumors) that proliferate, for example, by expressing mutant tyrosine kinases or overexpressing receptor tyrosine kinases; (2) benign and malignant cells of other proliferative disorders that result in abnormal tyrosine kinase activation; (3) any tumors that proliferate, for example, by receptor tyrosine kinases; (4) any tumors that proliferate, for example, by abnormal serine / threonine kinase activation; and (5) benign and malignant cells of other proliferative disorders that result in abnormal serine / threonine kinase activation. Abnormal cell growth can refer to cell growth in epithelial cells (e.g., carcinomas, adenocarcinomas); mesenchymal cells (e.g., sarcomas (e.g., leiomyosarcomas, Ewing's sarcomas)); hematopoietic cells (e.g., lymphomas, leukemias, myelodysplasia (e.g., precancerous)); or other cells (e.g., mesotheliomas and other tumors of unknown origin).

[0025] In some embodiments, the method is effective in treating non - blood malignancies. In some embodiments, the method is effective in treating pancreatic cancer, non - small cell lung cancer (NSCLC), small cell lung cancer (SCLC), mesothelioma, breast cancer, and ovarian cancer. In certain embodiments, the breast cancer is triple - negative breast cancer (e.g., breast cancer that does not express genes related to estrogen receptor, progesterone receptor, and Her2 / neu). In certain embodiments, the lung cancer is non - small cell lung cancer (NSCLC), e.g., KRAS - mutant NSCLC. In certain embodiments, the ovarian cancer is advanced ovarian cancer (e.g., advanced ovarian cancer or metastatic ovarian cancer). In certain embodiments, the ovarian cancer is low - grade serous ovarian cancer. In certain embodiments, the low - grade serous ovarian cancer is KRAS - mutant low - grade serous ovarian cancer. In certain embodiments, the method is effective in treating mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma). In some embodiments, the cancer is pancreatic cancer.

[0026] Neoplastic disease Abnormal cell growth can refer to neoplastic disease. "Neoplastic disease" is a disease or disorder characterized by cells having the ability of autonomous growth or replication, e.g., an abnormal state characterized by proliferative cell growth. An abnormal mass of tissue, or "neoplasm", resulting from abnormal cell growth or division can be benign, pre - cancerous (intra - epithelial carcinoma) or malignant (cancer).

[0027] Exemplary neoplastic diseases include carcinomas, sarcomas, metastatic diseases (e.g., tumors arising from prostate, colon, lung, breast, and liver origin), hematopoietic neoplastic diseases, e.g., leukemia, metastatic tumors. Treatment with the compound can be in an amount effective for the remission of at least one symptom of the neoplastic disease, e.g., suppression of cell proliferation, reduction of tumor mass, etc.

[0028] Cancer In some embodiments, the methods of the present invention may be useful for the treatment of cancers including, for example, solid tumors, soft tissue tumors, and their metastases. In some embodiments, the methods of the present invention may be useful for the treatment of cancers in which the MEK-ERK pathway is activated. The disclosed methods may also be useful for treating non-solid cancers. Exemplary solid tumors include malignant tumors of various organ systems (e.g., sarcomas, adenocarcinomas, and carcinomas), such as those of the lung, breast, lymphatic system, gastrointestinal tract (e.g., colon), and urogenital system (e.g., renal tumors, urothelial tumors, or testicular tumors), pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma), non-small cell lung cancer, pancreas (e.g., metastatic pancreatic adenocarcinoma), and small intestine cancer.

[0029] Cancers may also include uterine cancer (e.g., endometrial cancer, uterine tumors, cervical cancer, etc.), biliary cancer, and biliary tract cancer (e.g., cholangiocarcinoma, bile duct cancer, gallbladder cancer, etc.).

[0030] The cancer can be a primary tumor, i.e., located at the anatomical site where tumor growth begins. The cancer can also be metastatic, i.e., appear at at least one second anatomical site other than the anatomical site where tumor growth begins. The cancer can also be a recurrent cancer, i.e., a cancer that recurs after a period during which the cancer was undetectable after treatment. The recurrent cancer can be anatomically located at the same location as the original tumor, e.g., anatomically near the original tumor, or in the same region as the original tumor, e.g., in a lymph node near the original tumor, or at a distance from the original tumor, e.g., in a region anatomically distant from the original tumor.

[0031] Cancer may also have RAS mutations, meaning that the cancer is caused by a mutation in the RAS gene (HRAS, NRAS, or KRAS). Cancer may also have KRAS mutations, meaning that the cancer is caused by a mutation in the KRAS gene. Cancer may also have NRAS mutations, meaning that the cancer is caused by a mutation in the NRAS gene. In some embodiments, the cancer is ovarian cancer caused by a mutation in the RAS gene (e.g., the KRAS gene). In some embodiments, the cancer is low-grade ovarian cancer or mucinous ovarian cancer, both caused by a mutation in the RAS gene (e.g., the KRAS gene). In some embodiments, the cancer is lung cancer caused by a mutation in the RAS gene (e.g., the KRAS gene). In some embodiments, the cancer is colon cancer caused by a mutation in the RAS gene (e.g., the KRAS gene or NRAS gene). In some embodiments, the cancer is pancreatic cancer caused by a mutation in the RAS gene (e.g., the KRAS gene).

[0032] Other cancers that may be mentioned include, for example, epithelial carcinoma, breast, lung, pancreatic, colorectal (e.g., metastatic colorectal, e.g., KRAS mutation metastatic), prostate, head and neck, melanoma, acute myeloid leukemia, and glioblastoma. Exemplary breast cancers include triple-negative breast cancer, basal-like breast cancer, low-claudin breast cancer, and treatment-resistant invasive, inflammatory, metaplastic, and advanced Her-2-positive or ER-positive cancers.

[0033] Other examples of mutated genes in cancer include EGFR, FGFR, ALK, ROS1, PI3K, NF-1, BRAF, HRAS, KRAS, and NRAS. The cancer is preferably a KRAS mutation and / or NRAS mutation cancer, more preferably a KRAS mutation or NRAS mutation colon cancer, or a KRAS mutation solid tumor (preferably ovarian cancer, lung cancer (especially non-small cell lung cancer), colon cancer, and pancreatic cancer).

[0034] Other cancers include those of the brain, abdomen, esophagus, gastrointestinal tract, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovary, retinoblastoma, Wilms' tumor, multiple myeloma, skin, lymphoma, hematological and myelomatous cancers (e.g., advanced hematological malignancies, leukemia, e.g., acute myeloid leukemia (e.g., primary or secondary), acute lymphoblastic leukemia, acute lymphoblastic leukemia, T-cell leukemia, hematological malignancies, advanced myeloproliferative disorders, myelodysplastic syndromes, relapsed or refractory multiple myeloma, advanced myeloproliferative disorders), retina, bladder, cervix, kidney, endometrium, meningioma, lymphoma, skin, uterus, lung, non-small cell lung, nasopharyngeal carcinoma, neuroblastoma, solid tumors, hematological malignancies, squamous cell carcinoma, testis, thyroid, mesothelioma, and brain. These include vulvar, sarcoma, intestinal, oral, endocrine, salivary, spermatogenic seminoma, sporadic medullary thyroid carcinoma, nonproliferative testicular cell carcinoma, malignant mast cell-associated cancer, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0035] Examples of cancers include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-associated lymphoma, AIDS-associated malignancies, anal cancer, astrocytoma, cholangiocarcinoma, extrahepatic and bladder cancer; bone cancer, osteosarcoma / malignant fibrous histiocytoma, brainstem glioma, brain tumor, brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual tract and hypothalamic glioma; breast cancer; bronchial adenoma / carcinoid, carcinoid tumor, carcinoid tumor, gastrointestinal; carcinoma, adrenocortical; carcinoma, islet cell; carcinoma of unknown primary origin; central nervous system lymphoma, primary Cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, cervical cancer; chronic lymphocytic leukemia; chronic myeloid leukemia; chronic myeloproliferative disorders; clear cell sarcoma of the tendon sheath; colon cancer; colorectal cancer; cutaneous T-cell lymphoma; endometrial cancer; ependymoma, epithelial carcinoma, ovarian cancer; esophageal cancer; esophageal cancer, Ewing family tumors; extracranial germ cell tumors, extragonadal germ cell tumors; extrahepatic bile duct cancer; eye cancer, retinoblastoma; gallbladder cancer; stomach cancer; gastric cancer; gastrointestinal carcinoid tumors; germ cell tumors, extracranial; germ cell tumors, extragonadal; germ cell tumors, ovarian; gestational trophoblastic neoplasm; glioma, glioma, visual tract and hypothalamus; hairy cell white Blood cancer; head and neck cancer; hepatocellular (liver) cancer; Hodgkin lymphoma; Hodgkin lymphoma; Hodgkin lymphoma during pregnancy; hypopharyngeal cancer; hypothalamic and optic tract glioma; islet cell carcinoma (pancreatic endocrine); Kaposi's sarcoma; kidney cancer; pharyngeal cancer; pharyngeal cancer; leukemia, acute lymphoblastic; leukemia, acute lymphoblastic; leukemia, acute bone marrow; leukemia, acute bone marrow; leukemia, chronic lymphocytic; leukemia, chronic myeloid; leukemia, hair cell; lip and oral cancer; liver cancer; lung cancer, non-small cell; lung cancer, small cell; lymphoblastic leukemia, chronic lymphocytic leukemia; lymphoma, AIDS-related; lymphoma, central nervous system Primary lymphoma; cutaneous T-cell lymphoma; Hodgkin's lymphoma; Hodgkin's lymphoma; Hodgkin's lymphoma during pregnancy; non-Hodgkin's lymphoma; non-Hodgkin's lymphoma during pregnancy; primary central nervous system lymphoma; macroglobulinemia, Waldenström; male breast cancer; malignant mesothelioma, adult; malignant mesothelioma; malignant thymoma; medulloblastoma, Merkel cell carcinoma; malignant mesothelioma; metastatic squamous cell carcinoma of unknown primary origin; multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytic neoplasm; mycosis fungoides; myelodysplastic syndrome; chronic myeloid leukemia; myeloleukemia, multiple myeloma;Myeloproliferative disorders, chronic; nasal and paranasal sinus cancer; nasopharyngeal cancer; neuroblastoma; non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy; non-small cell lung cancer; oral cancer; oral and lip cancer; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; ovarian cancer; ovarian epithelial carcinoma; ovarian germ cell tumors; low-grade ovarian tumors; pancreatic cancer; pancreatic cancer; islet cell pancreatic cancer; paranasal and nasal sinus cancer; parathyroid cancer; Penile cancer; pheochromocytoma; pineal and supratentorial primitive neuroectodermal tumors; pituitary tumors; plasma cell neoplasms / multiple myeloma; pleuroblastoma; pregnancy and breast cancer; pregnancy and Hodgkin lymphoma; pregnancy and non-Hodgkin lymphoma; primary central nervous system lymphoma; primary liver cancer; primary liver cancer; prostate cancer; rectal cancer; renal cell carcinoma (kidney cancer); renal cell carcinoma; transitional cell carcinoma of the renal pelvis and ureter; retinoblastoma; rhabdomyoblastoma Sarcoma; salivary gland cancer; salivary gland cancer; sarcoma, Ewing family tumor; sarcoma, Kaposi's sarcoma; sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; sarcoma, rhabdomyosarcoma; sarcoma, soft tissue; sarcoma, soft tissue; Sézary syndrome; skin cancer; skin cancer; skin cancer (melanoma); skin cancer, Merkel cells; small cell lung cancer; small intestine cancer; soft tissue sarcoma; soft tissue sarcoma; squamous epithelial cervical cancer of unknown primary origin, metastatic; gastric cancer; gastric cancer; te Examples include primitive neuroectodermal tumors; T-cell lymphoma, cutaneous; testicular cancer; thymoma; malignant thymoma; thyroid cancer; thyroid cancer; transitional cell carcinoma of the renal pelvis and ureter; gestational trophoblastic neoplasm; cancer of unknown primary site; transitional cell carcinoma of the ureter and renal pelvis; urethral cancer; uterine sarcoma; vaginal cancer; optic tract and hypothalamic glioma; vulvar cancer; Waldenström macroglobulinemia; and Wilms' tumor. Metastases of the above-mentioned cancers can also be treated according to the methods described herein.

[0036] In some embodiments, the tumor is a tumor of hematopoietic and lymphoid tissue, or a tumor that affects the blood, bone marrow, lymph, and lymphatic system. Examples of hematological malignancies include acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute monocytic leukemia, other leukemias, Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0037] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is refractory (e.g., resistant) to standard treatment.

[0038] The methods described herein can alleviate, relieve, or completely eliminate the disorder and / or symptoms associated with the disorder, preventing further deterioration, slowing the rate of progression, or minimizing the rate of recurrence of the disorder if it was initially eliminated (i.e., avoiding relapse). Preferred doses and treatment regimens may vary depending on the specific compound and / or pharmaceutical composition used, as well as the mode of delivery of the compound and / or pharmaceutical composition. In some embodiments, the methods statistically significantly increase the mean survival, statistically significantly increase the mean progression-free survival, and / or statistically significantly decrease the rate of relapse in subjects treated with the combinations described herein.

[0039] In some embodiments, cancers include lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS-mutated NSCLC; metastatic cancer), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer (e.g., unresectable low-grade ovarian cancer, advanced or metastatic ovarian cancer), rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., breast cancer that does not express genes related to estrogen receptor, progesterone receptor, and Her2 / neu)), and uterine cancer. , carcinoma of the fallopian tube, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, cancer of the prostate, chronic or acute leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney (e.g., Wilms' tumor, rhabdoid tumor; nephroma (e.g., mesodermal nephroma)) or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), or one or more of the aforementioned cancers. In some embodiments, the cancer is ovarian cancer, pancreatic cancer, non-small cell lung cancer, or head and neck cancer. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (e.g., the subject has a locally recurrent disease, e.g., cancer).

[0040] The method of the present invention intends to administer a therapeutically effective amount of a single or multiple dose of a FAK inhibitor in combination with a RAF / MEK dual inhibitor, where the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. The combination, for example, the combination described herein, e.g., a FAK inhibitor (e.g., VS-6063) in combination with a RAF / MEK dual inhibitor (e.g., CH5126766), can be administered at regular intervals depending on the nature, severity, and degree of the condition in question. In some embodiments, the combination described herein, e.g., a FAK inhibitor in combination with a RAF / MEK dual inhibitor, is administered as a single dose, where the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. In some embodiments, the combinations described herein, for example, an FAK inhibitor combined with a RAF / MEK biinhibitor, are administered in multiple doses, where the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK biinhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutically effective dose of the combinations described herein, for example, an FAK inhibitor (e.g., VS-6063) combined with a RAF / MEK biinhibitor (e.g., CH5126766), may be administered orally at regular intervals (e.g., every 1, 2, 3, 4, 5, or 6 days, or every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses at intervals of 1, 2, 3, 4, 5, 6, 7, 8, 9 months or longer). In some embodiments, a therapeutically effective dose of any combination described herein, for example, a FAK inhibitor (e.g., VS-6063) combined with a RAF / MEK bilayer (e.g., CH5126766) which may be administered orally regularly (e.g., twice a week), may be administered orally regularly (e.g., twice a day).In some embodiments, a therapeutically effective dose of any combination described herein, for example, a FAK inhibitor (e.g., VS-6063) combined with a RAF / MEK bilayer (e.g., CH5126766) that can be administered orally regularly (e.g., twice a week), may be administered orally once daily. In some embodiments, a therapeutically effective dose of any combination described herein, for example, a FAK inhibitor (e.g., VS-6063) combined with a RAF / MEK bilayer (e.g., CH5126766) that can be administered orally regularly (e.g., three times a week), may be administered orally twice daily. VS-6063 and CH5126766 may each be in the form of a pharmaceutically acceptable salt.

[0041] In some embodiments, the combinations described herein, for example, an FAK inhibitor (VS-6063) combined with a RAF / MEK dual inhibitor (e.g., CH5126766) administered orally at predetermined intervals (e.g., twice a week), are administered orally regularly (e.g., twice daily) for three weeks, followed by a one-week rest period (or an interval in which neither the FAK inhibitor (e.g., VS-6063) nor the RAF / MEK dual inhibitor (e.g., CH5126766) is administered), and then repeated periodically (e.g., three weeks administration, one week rest, three weeks administration, one week rest, etc.). In some embodiments, CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are each administered for at least three weeks. In some embodiments, CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are each administered for at least four weeks. In some embodiments, CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are administered for at least 5 weeks each. In some embodiments, CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are administered in cycles of 4 weeks of administration followed by at least 1 week of rest. In other embodiments, CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are administered in cycles of 5 or 6 weeks of administration followed by 1 or 2 weeks of rest.

[0042] The timing of the one-week rest period for VS-6063 or its pharmaceutically acceptable salt and the timing of the one-week rest period for CH5126766 or its pharmaceutically acceptable salt may be simultaneous or different. In a preferred embodiment, the timing of the one-week rest period for VS-6063 or its pharmaceutically acceptable salt and the timing of the one-week rest period for CH5126766 or its pharmaceutically acceptable salt are simultaneous.

[0043] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered orally once weekly. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered orally twice weekly. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered orally three times weekly. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered orally four times weekly. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered orally five times weekly. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered orally once daily. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered orally twice daily. CH5126766 may also be in the form of a pharmaceutically acceptable salt.

[0044] In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered orally twice daily. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered orally once daily. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 100 mg to approximately 400 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 100 mg to approximately 500 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 200 mg to approximately 500 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 200 mg to approximately 600 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 200 mg. In some embodiments, the FAK inhibitor (e.g., VS-6063) is administered in doses of approximately 400 mg. It should be understood that a FAK inhibitor (e.g., VS-6063) may be administered at a certain dose during any of the regular time periods described herein. For example, a FAK inhibitor (e.g., VS-6063) may be administered at a dose of approximately 200 mg twice daily. A FAK inhibitor (VS-6063) may be administered at a dose of approximately 400 mg twice daily.

[0045] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 0.5 mg to approximately 10 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 0.5 mg to approximately 7 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 0.5 mg to approximately 5 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 1 mg to approximately 10 mg. In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of approximately 4 mg. In other embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered in doses of 3.2 mg. It should be understood that the RAF / MEK dual inhibitor (e.g., CH5126766) may be administered in any of the regular time frames described herein. For example, a RAF / MEK dual inhibitor (e.g., CH5126766) may be administered at a dose of approximately 0.5 mg to approximately 10 mg twice weekly. A RAF / MEK dual inhibitor (e.g., CH5126766) may be administered at a dose of approximately 4 mg twice weekly. A RAF / MEK dual inhibitor (e.g., CH5126766) may be administered at a dose of 3.2 mg twice weekly. CH5126766 may also be in the form of a pharmaceutically acceptable salt.

[0046] As described herein, FAK inhibitors (e.g., VS-6063) may be administered in combination with RAF / MEK dual inhibitors (e.g., CH5126766). For example, CH5126766 or a pharmaceutically acceptable salt thereof may be administered in doses of approximately 0.5 mg to approximately 10 mg, and VS-6063 or a pharmaceutically acceptable salt thereof may be administered in doses of approximately 100 mg to approximately 400 mg. CH5126766 or a pharmaceutically acceptable salt thereof may be administered in doses of approximately 3 mg to approximately 5 mg, and VS-6063 or a pharmaceutically acceptable salt thereof may be administered in doses of approximately 100 mg to approximately 400 mg. CH5126766 or a pharmaceutically acceptable salt thereof may be administered twice weekly in doses of approximately 3 mg to approximately 5 mg, and VS-6063 or a pharmaceutically acceptable salt thereof may be administered twice daily in doses of approximately 100 mg to approximately 400 mg. CH5126766 or a pharmaceutically acceptable salt thereof may be administered at a dose of approximately 4.0 mg twice weekly, and VS-6063 or a pharmaceutically acceptable salt thereof may be administered at a dose of approximately 200 mg twice daily. CH5126766 or a pharmaceutically acceptable salt thereof may be administered at a dose of approximately 3.2 mg twice weekly, and VS-6063 or a pharmaceutically acceptable salt thereof may be administered at a dose of approximately 200 mg twice daily. CH5126766 or a pharmaceutically acceptable salt thereof may be administered at a dose of approximately 3.2 mg twice weekly, and VS-6063 or a pharmaceutically acceptable salt thereof may be administered at a dose of approximately 400 mg twice daily.

[0047] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered according to the following steps. (a) Administer RAF / MEK dual inhibitors twice a week for 3 weeks. (b) For the following week, discontinue administration of the compound or salt. (c) Then, steps (a) and (b) are repeated at least once.

[0048] In some embodiments, the RAF / MEK dual inhibitor (e.g., CH5126766) is administered by the following method (R1) or (R2). (R1) (A1) (A1a) A RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 4 mg twice a week for 3 weeks. (A1b) For the following week, administration of the RAF / MEK dual inhibitor (e.g., CH5126766) is suspended (i.e., a 3-week administration / 1-week rest cycle, totaling 4 weeks), (A1c) Steps (A1a) and (A1b) are then repeated at least once. (R2) (A2) First, (A2a) A RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 4 mg twice a week for 3 weeks. (A2b) For the following week, administration of the RAF / MEK dual inhibitor (e.g., CH5126766) is discontinued. (A2c) Then, steps (A2a) and (A2b) are repeated at least once. (B2) After that, (B2a) A RAF / MEK dual inhibitor (e.g., CH5126766) is administered at a dose of 3.2 mg twice a week for 3 weeks. (B2b) For the following week, administration of the RAF / MEK dual inhibitor (e.g., CH5126766) is discontinued. (B2c) Steps (B2a) and (B2b) are then repeated at least once.

[0049] In some embodiments, (i) a four-week cycle consisting of steps (a) and (b), and (ii) a four-week cycle consisting of steps (A1a) and (A1b) are repeated, for example, 2 times (8 weeks) to 90 times (approximately 6 years and 11 months), more specifically, 8 times (32 weeks) to 18 times (72 weeks). The number of repeated cycles may be predetermined, but may be changed based on the judgment of a physician or veterinarian, for example, depending on the condition of the subject. Furthermore, administration may be discontinued in the middle of a cycle, for example, based on the judgment of a physician or veterinarian, depending on the condition of the subject.

[0050] In some embodiments, the 4-week cycle consisting of steps (A2a) and (A2b) is repeated, for example, 2 times (8 weeks) to 45 times (approximately 3 years and 5 months), more specifically, 8 times (32 weeks) to 18 times (72 weeks). The number of repeated cycles may be predetermined, but may be changed based on the judgment of a physician or veterinarian, for example, depending on the condition of the subject. Furthermore, administration may be discontinued in the middle of a cycle, for example, based on the judgment of a physician or veterinarian, depending on the condition of the subject.

[0051] In some embodiments, the 4-week cycle consisting of steps (B2a) and (B2b) is repeated, for example, 2 times (8 weeks) to 45 times (approximately 3 years and 5 months), more specifically, 8 times (32 weeks) to 18 times (72 weeks). The number of repeated cycles may be predetermined, but may be changed based on the judgment of a physician or veterinarian, for example, depending on the condition of the subject. Furthermore, administration may be discontinued in the middle of a cycle, for example, based on the judgment of a physician or veterinarian, depending on the condition of the subject.

[0052] In some embodiments, the single dose of the RAF / MEK dual inhibitor (e.g., CH5126766) is preferably 3.2 mg or 4 mg. More preferably 4 mg, and can be reduced to 3.2 mg. The single dose of the FAK inhibitor (e.g., VS-6063) is preferably 200 mg or 400 mg. More preferably 200 mg, and can be increased to 400 mg.

[0053] The duration for which a RAF / MEK dual inhibitor (e.g., CH5126766) is used in combination with a FAK inhibitor (e.g., VS-6063) may be determined based on the judgment of a physician or veterinarian, for example, depending on the patient's condition. Furthermore, depending on the patient's condition, administration of either or both of the RAF / MEK dual inhibitor (e.g., CH5126766) and / or the FAK inhibitor (e.g., VS-6063) may be discontinued based on the judgment of a physician or veterinarian.

[0054] compound The methods described herein particularly include the step of administering to a subject with cancer a FAK inhibitor in combination with a RAF / MEK dual inhibitor, wherein the FAK inhibitor is VS-6063 or a pharmaceutically acceptable salt thereof, and the RAF / MEK dual inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof.

[0055] VS-6063 Examples of FAK inhibitors include VS-6063 or its pharmaceutically acceptable salts (e.g., VS-6063 hydrochloride). VS-6063 and related compounds are also disclosed, for example, in U.S. Patent No. 7,928,109 (the contents of which are incorporated herein by reference). VS-6063 is also known as defactinib and PF-04554878, and has the following structure: [ka] It has.

[0056] In some embodiments, VS-6063 may form a pharmaceutically acceptable salt (e.g., VS-6063 hydrochloride). In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof may be present in the composition in amounts of 5, 10, 11, 12, 12.5, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60% w / w or more. In some embodiments, VS-6063 or a pharmaceutically acceptable salt thereof may be present in the composition in amounts of about 5 to about 60% w / w, about 5 to about 50% w / w, about 10 to about 50% w / w, or about 10 to about 40% w / w.

[0057] CH5126766 CH5126766 is a RAF / MEK dual inhibitor and is also known as RO5126766. Methods using CH5126766 or a pharmaceutically acceptable salt thereof are included herein. CH5126766 (free base) is given by the following formula: [ka] It is represented by [this].

[0058] The CH5126766 or a pharmaceutically acceptable salt thereof used in the present invention is preferably a potassium salt of CH5126766. A potassium salt of CH5126766 is preferably, for example, of the following formula: [ka] It is a salt represented by [this symbol].

[0059] For example, CH5126766 and its pharmaceutically acceptable salts are disclosed in International Publication No. 2007 / 091736 and International Publication No. 2009 / 014100, and can be prepared according to the methods described in these publications.

[0060] Cancer combination therapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) are administered together with additional therapies (e.g., cancer treatment). In one embodiment, a mixture of one or more compounds or pharmaceutical compositions may be administered together with the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof). In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) may be administered together with the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) for the treatment of various diseases, including cancer.

[0061] In various embodiments, a combination therapy comprising the compounds or pharmaceutical compositions described herein may mean (1) a pharmaceutical composition comprising one or more compounds in combination with the combination described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof), and (2) a simultaneous administration of one or more compounds or pharmaceutical compositions described herein and the combination described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof), wherein the compounds or pharmaceutical compositions described herein are not formulated in the same composition. In some embodiments, the combination described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) is administered together with additional treatment (e.g., additional cancer treatment). In some embodiments, the additional treatment (e.g., additional cancer treatment) may be administered simultaneously (e.g., at the same time) or sequentially with the same or separate compositions. Sequential administration refers to administering one treatment before administering the additional treatment (e.g., compound or therapy) (e.g., immediately before, less than 5 minutes, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 hours or more; 4, 5, 6, 7, 8, 9 days or more; 1, 2, 3, 4, 5, 6, 7, 8 weeks or more prior). The order of administration of the first and second compounds or therapies can also be reversed. In some embodiments, FAK inhibitors (e.g., VS-6063) and RAF / MEK dual inhibitors (e.g., CH5126766) are administered at different regular time intervals. For example, RAF / MEK dual inhibitors (e.g., CH5126766) are administered twice a week, once a week, or every three or four days, while FAK inhibitors (e.g., VS-6063) may be administered once or twice a day.

[0062] The methods of the present invention may be used or administered in combination with one or more additional therapies (e.g., cancer treatments, e.g., surgical procedures, additional drugs or therapeutic agents) for the treatment of the disorders / diseases mentioned herein. The additional therapies (e.g., cancer treatments, e.g., drugs or therapeutic agents described herein) may be administered in the same formulation or in separate formulations. When administered in separate formulations, the compounds of the present invention may be administered sequentially or concurrently with the other drugs.

[0063] In addition to being able to be administered in combination with one or more additional therapies (e.g., cancer treatments, surgical procedures, additional drugs or therapeutic agents), the method of the present invention can be administered simultaneously or sequentially (as a combined preparation) to obtain the desired effect. This is particularly desirable when the therapeutic profiles of each compound are different, resulting in improved therapeutic outcomes due to the combined effect of the two drugs.

[0064] Exemplary cancer treatments include, for example, chemotherapy, targeted therapies such as antibody therapy, immunotherapy, and hormone therapy. Examples of each of these treatments are provided below.

[0065] chemotherapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) are administered in conjunction with chemotherapy. Chemotherapy is the treatment of cancer using drugs that can destroy cancer cells. "Chemotherapy" typically refers to cytotoxic drugs that affect rapidly dividing cells in general, in contrast to targeted therapy. Chemotherapy drugs interfere with cell division by various possible means, such as DNA replication or the segregation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some specificity can arise because normal cells can generally repair DNA damage, whereas many cancer cells cannot.

[0066] Examples of chemotherapeutic agents used in cancer chemotherapy include, for example, anti-antimetabolites (e.g., folic acid, purines, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle toxins, cytotoxic agents, topoisomerase inhibitors, etc.). Exemplary drugs include acralubicin, actinomycin, alitretinoin, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrin, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carbocon, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin. Cladribine, Clofarabine, Chrysanthanspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolsin, Docetaxel, Doxorubicin, Efaproxial, Erethcromol, Elsamitrusine, Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide, Furoxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel (for intracerebral implantation)(implant), hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, ilofluben, ixabepyrone, larotaxel, leucovorin, doxorubicin liposome, daunorubicin liposome, ronidamin, lomustine, rucanton, mannosulfan, masopropyl, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitogluzone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omasetaxin, ortataxel, oxaliplatin, paclitaxel, pegasparagauze, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, predni Examples include mustine, procarbazine, larcitrexed, ranimustine, rubitecan, sapacitabine, semustine, citimazine seradenovec, strataplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, thiazophrine, thioguanine, tipifarnib, topotecan, trabectedin, triadicone, triethylenemelamine, triplatin, tretinoin, treosulfan, trophosphamide, uramustine, barrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunin, vinorelbine, vorinostat, zolubicin, and other cell division inhibitors or cytotoxic agents described herein.

[0067] Because some drugs function better when combined than when administered alone, two or more drugs are often administered simultaneously or sequentially. In many cases, two or more chemotherapeutic agents are used as combination chemotherapy. In some embodiments, chemotherapeutic agents (including combination chemotherapy) can be used in combination with the combinations described herein (e.g., a FAK inhibitor combined with a RAF / MEK dual inhibitor).

[0068] Targeted therapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) are administered in conjunction with targeted therapy. Targeted therapy consists of the use of drugs specific to unregulated proteins in cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzyme domains of mutated, overexpressed, or otherwise important proteins in cancer cells. Well-known examples include tyrosine kinase inhibitors such as axitinib, bosutinib, cedilanib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, restaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, as well as cyclin-dependent kinase inhibitors such as albocidib and cericyclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to proteins on the surface of cancer cells. Examples include trastuzumab (HERCEPTIN®), an anti-HER2 / neu antibody typically used in breast cancer, and rituximab and tocitumomab, anti-CD20 antibodies typically used in various B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin difutitox. Targeted therapies may also include small peptides as “auto-induction devices” that can bind to cell surface receptors or the extracellular matrix surrounding the affected tumor. Radionuclides (e.g., RGD) that bind to these peptides, if they decay in the vicinity of the cells, ultimately kill the cancer cells. An example of such a therapy is BEXXAR®.

[0069] immunotherapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) are administered in conjunction with immunotherapy. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight tumors. Modern methods for generating an immune response against tumors include the use of IL-2 and intravesical BCG immunotherapy for bladder cancer, as well as the use of interferon and other cytokines to induce an immune response in subjects with renal cell carcinoma, melanoma, multiple myeloma, chronic myeloid leukemia, and hairy cell leukemia.

[0070] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy because the donor's immune cells can often attack the tumor in a graft-versus-tumor effect. In some embodiments, immunotherapeutic agents can be used in combination with the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof).

[0071] In some embodiments, the immunotherapy agent is a compound (e.g., ligand, antibody) that inhibits the immune checkpoint blockade pathway. Cancer immunotherapy refers to the use of the immune system to treat cancer. The three main groups of immunotherapies used to treat cancer are cell-based therapies, antibody-based therapies, and cytokine therapies. All groups utilize the expression of slightly different structures (e.g., molecular structures, antigens, proteins, molecules, carbohydrates) on the surface of cancer cells that can be detected by the immune system. Examples of cancer immunotherapies (i.e., antitumor immunotherapy or antitumor immunotherapy agents) include immune checkpoint antibodies (e.g., PD-1 antibody, PD-L1 antibody, PD-L2 antibody, CTLA-4 antibody, TIM3 antibody, LAG3 antibody, TIGIT antibody) and cancer vaccines (i.e., antitumor vaccines).

[0072] In some embodiments, the immunotherapy agent is an anti-CTLA-4 antibody (e.g., ipilimumab, tremelimumab), anti-TIM3, anti-LAG3, or anti-TIGIT. In some embodiments, the immunotherapy agent is an anti-PD-1 ligand (e.g., PD-L1 (e.g., B7-H1 or CD274) or PD-L2 (e.g., B7-DC or CD273)). In some embodiments, the immunotherapy agent is an anti-PD-1 antibody (e.g., anti-PD-1 or anti-PD-L1) (e.g., nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538), CT-011, AMP-224, pembrolizumab, pizilizumab, or MK-3475). In some embodiments, the immunotherapy agent is an anti-PD-L1 antibody (e.g., BMS936559 (i.e., MDX-1105), MEDI4736, MSB0010718C (avelumab), or MPDL-3280A). In some embodiments, the immunotherapy agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy. In some embodiments, the immunotherapy agent is a costimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40). In some embodiments, the method further includes the step of administering an additional chemotherapeutic agent or radiotherapy. In some embodiments, the method further includes the step of administering a cytotoxic agent. In some embodiments, the cytotoxic agent is gemcitabine or paclitaxel (e.g., nab-paclitaxel). In some embodiments, the immunotherapy agent is a costimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0073] Anti-inflammatory drugs In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) may be administered together with an anti-inflammatory agent. Examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), and enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, iso). Examples include xicam, fenamic acid derivatives (fenamic acid-based) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxib-based) (celecoxib), and sulfonanilide drugs (nimeslide). Steroids (e.g., hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone).

[0074] Pain relievers In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) can be administered together with an analgesic. Analgesics include opiates (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetamol, and nonsteroidal anti-inflammatory drugs (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprozin) Examples include phenamic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (fenamic acid derivatives) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxib derivatives) (celecoxib), and sulfonanilide drugs (nimeslide).

[0075] Antiemetic In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) may be administered together with an antiemetic. Antiemetics include 5-HT3 receptor antagonists (drasetron (Anzemet), granisetron (Kytril, Sankuso), ondansetron (Zofran), tropisetron (Naboban), palonosetron (Aloxi), mirtazapine (Remeron)), dopamine antagonists (domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide (Regran), arizaprid, prochlorperazine (Compadin)), and dopamine antagonists (domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide (Regran), arizaprid, prochlorperazine (Compadin)). Examples include stemzine, bukkastem, stemethyl, phenothyl, NK1 receptor antagonists (aprepitant (Emend)), antihistamines (cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Gravol, Dramamine), meclozine (Bonin, Antibart), promethazine (Pentazin, Fenelgan, Promacot), hydroxyzine), benzodiazapines (lorazepam, midazolam), anticholinergics (hyostine), and steroids (dexamethasone).

[0076] Hormone therapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof) are administered in conjunction with hormone therapy. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast cancer and prostate cancer. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, the administration of hormone agonists such as progestogens may be therapeutically beneficial. In some embodiments, hormone therapy agents can be used in combination with the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof in combination with CH5126766 or a pharmaceutically acceptable salt thereof).

[0077] Radiation therapy In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof combined with CH5126766 or a pharmaceutically acceptable salt thereof) can be used in combination with directed energy or particle or radioisotope therapy, such as radiotherapy or radiation oncology, for the treatment of proliferative disorders, such as cancer, such as cancers associated with cancer stem cells. The methods of the present invention may be administered to a subject simultaneously or sequentially with directed energy or particle or radioisotope therapy. For example, the methods of the present invention may be administered before, during, or after directed energy or particle or radioisotope therapy, or in combination thereof. Directed energy or particle therapy may include whole-body irradiation, local irradiation, or point irradiation. Directed energy or particles may originate from accelerators, synchrotrons, nuclear reactions, vacuum tubes, lasers, or radioisotopes. Therapies may include external beam radiation therapy, remote therapy, close-range radiation therapy, sealed-source radiation therapy, whole-body radioisotope therapy, or unsealed-source radiation therapy. Therapies may include the ingestion or proximity of radioisotopes, such as radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, or carbon. External beam radiation may include directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio waves, millimeter waves, microwaves, infrared, visible, ultraviolet, X-rays, or gamma-ray photons). The radiation may be directed at any part of the object requiring treatment.

[0078] Surgical treatment In some embodiments, the combinations described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof combined with CH5126766 or a pharmaceutically acceptable salt thereof) can be used in combination with surgical procedures, e.g., surgical exploration, intervention, biopsy, for the treatment of proliferative disorders, e.g., cancer, e.g., cancer associated with cancer stem cells. The methods of the present invention may be administered to a subject simultaneously or sequentially with a surgical procedure. For example, the methods of the present invention may be administered before (preoperative), during or after (postoperative) a surgical procedure, or in combination thereof. A FAK inhibitor (e.g., VS-6063) may be administered before (preoperative) a surgical procedure, and a RAF / MEK dual inhibitor (e.g., CH5126766) may be administered during or after (postoperative) a surgical procedure. Alternatively, a RAF / MEK dual inhibitor (e.g., CH5126766) may be administered before the surgical procedure (preoperatively), and a FAK inhibitor (e.g., VS-6063) may be administered during or after the surgical procedure (postoperatively). The surgical procedure may be a biopsy in which one or more cells are collected for further analysis. The biopsy may be performed using, for example, a scalpel, needle, catheter, endoscope, spatula, or scissors. The biopsy may be an excisional biopsy, incisional biopsy, core biopsy, or needle biopsy, for example, a needle aspiration biopsy. The surgical procedure may involve the removal of localized tissue suspected of being cancerous or identified as cancerous. For example, surgery may involve the removal of a cancerous lesion, lump, polyp, or mole. Surgery may involve the removal of a larger volume of tissue, for example, breast, bone, skin, fat, or muscle. The surgery may involve the removal of an organ or segment, such as the lungs, throat, tongue, bladder, cervix, ovaries, testes, lymph nodes, liver, pancreas, brain, eyes, kidneys, gallbladder, stomach, colon, rectum, or part or all of the intestines. In one embodiment, the cancer is breast cancer, such as triple-negative breast cancer, and the surgical procedure is a mastectomy or partial mastectomy.

[0079] First-line therapy In some embodiments, the present invention describes a method for treating a human subject having cancer, wherein the subject has failed to receive first-line treatment (e.g., first-line therapy for cancer) (e.g., has relapsed, was insensitive, or received little or no benefit). The present invention also provides a method for treating a human subject having cancer, wherein the method of the present invention is administered together with an additional agent. In some embodiments, the additional agent is a first-line therapy for cancer.

[0080] First-line therapy is typically the first treatment given for a disease (e.g., cancer as described herein). First-line therapy is often a set of standard treatments, such as surgical intervention followed by chemotherapy and radiation. When used alone, first-line therapy is generally considered the best treatment. If first-line therapy does not cure the disease or causes severe side effects, other treatments may be added or used instead. First-line therapy is also referred to as induction therapy, primary therapy, and primary treatment.

[0081] For example, first-line therapies for Hodgkin lymphoma include Adcetris (brentuximab vedotin), Adriamycin PFS (doxorubicin hydrochloride), Adriamycin RDF (doxorubicin hydrochloride), Ambochorin (chlorambucil), Ambochorin (chlorambucil), Blenoxan (bleomycin), Bleomycin, Brentuximab vedotin, Chlorambucil, Clafen (cyclophosphamide), Cyclophosphamide, Cytoxa Possible examples include cin (cyclophosphamide), dacarbazine, doxorubicin hydrochloride, DTIC Dome (dacarbazine), Leukeran (chlorambucil), lymphorizin (chlorambucil), lomustine, Matsuran (procarbazine hydrochloride), Neosal (cyclophosphamide), procarbazine hydrochloride, Verban (vinblastine sulfate), Versal (vinblastine sulfate), vinblastine sulfate, Vincasal PFS (vincristine sulfate), and vincristine sulfate.

[0082] In some embodiments, first-line therapy, for example, for Hodgkin lymphoma, involves the administration of a therapeutic agent, for example, a combination of therapeutic agents described herein. For example, a combination may include doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine sulfate, and dacarbazine (i.e., ABVD). Another example is a combination of doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine sulfate, and etoposide (i.e., ABVE). In some embodiments, a combination includes doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine sulfate, etoposide, prednisone, and cyclophosphamide (i.e., ABVE-PC). In some embodiments, a combination includes vincristine sulfate, doxorubicin hydrochloride (Adriamycin), methotrexate, and prednisone (i.e., VAMP).

[0083] Approved treatments and combinations for various types of cancer can be found on the National Cancer Institute's (NIN) cancer website, http: / / www.cancer.gov / cancertopics / druginfo / drug-page-index.

[0084] Second-line therapy In some embodiments, the present invention describes a method for treating a human subject with cancer, wherein the subject has failed to respond to second-line treatment or subsequent treatments (e.g., second-line therapy for cancer or third-line therapy for cancer) (e.g., has relapsed, was insensitive, or received little or no benefit). The present invention also provides a method for treating a human subject with cancer, wherein the method of the present invention is administered in conjunction with an additional agent. In some embodiments, the additional agent is a first-line or second-line therapy for cancer. Second-line therapy generally refers to treatment given when initial treatment (e.g., first-line therapy) does not produce the desired outcome, e.g., is ineffective, ineffective, or becomes ineffective. Second-line therapy is typically considered or given when a subject does not respond to or develops resistance to initial treatment (e.g., first-line therapy). For example, second-line therapy is typically considered or given to a subject with relapsed or refractory disease.

[0085] Dosage and Administration The combinations of the present invention may be administered orally, parenterally, topically, rectally, or via an implanted reservoir, preferably by oral or injectable administration. In some cases, the pH of the composition (e.g., a pharmaceutical composition) may be adjusted using pharmaceutically acceptable acids, bases, or buffers to enhance the stability or efficacy of the composition.

[0086] In some embodiments, the subject is administered orally in the form of a composition (e.g., a pharmaceutical composition). In some embodiments, the composition (e.g., a pharmaceutical composition) is administered orally in any orally acceptable dosage form, including liqui-gel, tablets or capsules, syrups, emulsions, and aqueous suspensions. The liqui-gel may optionally contain gelatin, plasticizers, and / or opacifiers to achieve a suitable viscosity, and the liqui-gel may be coated with an enteric coating approved for use, such as shellac. When used as an oral dosage form, additional thickeners, such as gum, e.g., xanthan gum, starch, e.g., corn starch, or gluten, may be added to achieve the desired viscosity of the composition (e.g., a pharmaceutical composition). Certain sweeteners and / or flavorings and / or colorings may be added, if desired.

[0087] In some embodiments, the subject is administered in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions. The composition (e.g., pharmaceutical composition) may also be a unit dosage form suitable for a single dose of a precise amount. The pharmaceutical composition may contain a pharmaceutically acceptable carrier in addition to the compounds described herein (e.g., FAK inhibitors (e.g., VS-6063), RAF / MEK dual inhibitors (e.g., CH5126766)), and may optionally further contain one or more pharmaceutically acceptable excipients, such as excipients, lubricants (coatings), binders, disintegrants, stabilizers, flavorings, bases, dispersants, diluents, surfactants, emulsifiers, etc. In addition, tablets may contain other medical or pharmaceutical agents, carriers, and / or adjuvants.

[0088] Examples of excipients include starches (such as starch, potato starch, and corn starch), lactose, crystalline cellulose, and calcium hydrogen phosphate.

[0089] Examples of lubricants (coating agents) include ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin.

[0090] Examples of binders include polyvinylpyrrolidone and macrogol, as well as the same compounds mentioned with respect to excipients.

[0091] Examples of disintegrants include chemically modified starches and celluloses such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinylpyrrolidone, as well as the same compounds mentioned with respect to excipients.

[0092] Examples of stabilizers include para-hydroxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0093] Examples of flavoring agents include commonly used sweeteners, acidulants, and flavorings.

[0094] Examples of bases include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; lanolinic acid; petrolatum; paraffin; bentonite; glycerin; and glycol oil.

[0095] Examples of dispersants include cellulose derivatives (such as gum arabic, tragacanth, and methylcellulose), polyester stearate, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbate, and sorbitan fatty acid esters.

[0096] Examples of solvents and diluents in liquid formulations include phenol, chlorocresol, purified water, and distilled water.

[0097] Examples of surfactants and emulsifiers include polysorbate 80, polyoxyl stearate 40, and lauromacrogol.

[0098] The preferred content of RAF / MEK inhibitors (e.g., CH5126766) or FAK (e.g., VS-6063) inhibitors contained in the formulation may vary depending on the dosage form, but is generally 0.01% to 100% by weight relative to the total weight of the formulation.

[0099] The content of the RAF / MEK inhibitor (e.g., CH5126766) in the formulation can be appropriately set according to the prescribed dose. A preferred content is, for example, 0.01 mg to 10 mg, and in the case of capsules, it may be, for example, 0.1 mg to 4 mg. A more preferred content is, for example, 0.8 mg.

[0100] Examples of pharmaceutical compositions include compressed tablets (e.g., direct compressed tablets) containing, for example, an FAK inhibitor (e.g., VS-6063) or a RAF / MEK dual inhibitor (e.g., CH5126766).

[0101] Tablets containing an active ingredient or therapeutic ingredient (for example, compounds described herein (e.g., FAK inhibitors (e.g., VS-6063) and RAF / MEK bi-inhibitors (e.g., CH5126766))) are also provided. In addition to the active ingredient or therapeutic ingredient, the tablets may contain several inert materials such as carriers. Pharmaceutically acceptable carriers may be sterile liquids, such as water, and oils, such as oils of petroleum, vegetable, or synthetic origin, such as peanut oil and sesame oil. Saline solution and aqueous dextrose may also be used as liquid carriers. Thus, oral dosage forms for use according to the present invention can be formulated in the conventional manner using one or more pharmaceutically acceptable carriers, including additives and auxiliaries that facilitate the processing of the active ingredient into a pharmaceutically usable preparation.

[0102] Additives can impart good powder flow and compressibility properties to materials being compressed. Examples of additives are listed, for example, in *Handbook of Pharmaceutical Excipients (5th Edition), edited by Raymond C. Rowe, Paul J. Sheskey, and Sian C. Owen; published by Pharmaceutical Press*.

[0103] With regard to oral administration, the active ingredients, such as the compounds described herein (e.g., FAK inhibitors (e.g., VS-6063), RAF / MEK dual inhibitors (e.g., CH5126766)), can be readily formulated by combining them with pharmaceutically acceptable carriers known in the art. Such carriers enable the active ingredients of the present invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in water or a non-aqueous medium, etc., for oral administration by the subject. Pharmacological preparations for oral use can be made using solid additives. The resulting mixtures can optionally be ground, and the granular mixtures can be processed after appropriate addition of suitable adjuvants to obtain, for example, tablets. Suitable additives such as diluents, binders or disintegrants are optionally desirable. Furthermore, the FAK inhibitors (e.g., VS-6063) and RAF / MEK dual inhibitors (e.g., CH5126766) can be formulated separately according to the methods described above.

[0104] Dosage may be modified depending on the dosage form used and the route of administration utilized. The appropriate formulation, route of administration, and dosage may be selected by the individual physician in consideration of the patient's condition (see, for example, Fingl et al., 1975, “The Pharmacological Basis of Therapeutics”). Lower or higher doses than those described above may be required. Specific doses and treatment regimens for any particular subject may depend on a variety of factors, including the specific compound used, age, weight, overall health, sex, diet, administration time, excretion rate, drug combination, severity and course of symptoms, condition or symptoms, the subject's tendency toward the disease, condition or symptoms, and the judgment of the physician performing the treatment. One course of treatment may consist of one or more separate administrations of the compounds described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and / or CH5126766 or a pharmaceutically acceptable salt thereof).

[0105] Oral dosage forms may be provided as packaging or dispenser devices, such as FDA-approved kits, which may contain one or more unit dosage forms containing the active ingredient, if desired. Packaging may include, for example, metal or plastic foil, such as blister packs. Packaging or dispenser devices may be accompanied by instructions for administration. Packaging or dispensers may also be accompanied by notices relating to the form of container prescribed by government agencies that regulate the manufacture, use or sale of medicinal products, which reflect the agency's approval of the form of composition or administration to humans or animals. Such notices may, for example, relate to labeling approved by the U.S. Food and Drug Administration for prescription drugs, or to approved product inserts.

[0106] The administration regimen used in this invention enables long-term administration of a RAF / MEK dual inhibitor (e.g., CH5126766) in combination with a FAK inhibitor (e.g., VS-6063) while minimizing side effects and maintaining drug efficacy. In addition, the administration regimen and combination enable the treatment or prevention of cytoproliferative disorders, particularly cancer, while minimizing the burden on the patient.

[0107] definition In this specification, the articles “a” and “an” refer to one or more (e.g., at least one) grammatical objects of the article.

[0108] In this specification, “about” and “approximately” refer to the acceptable degree of error in the measured quantity, taking into account the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10 percent, and more typically within 5 percent.

[0109] In this specification, the amount of a compound effective in treating a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer as described herein)), i.e., “effective amount” or “effective course,” means the amount of the compound that, when administered to a subject once or multiple times, is more effective in treating the subject or in curing, reducing, alleviating, or improving a subject having a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer as described herein)) than would be expected in the absence of such treatment (e.g., placebo treatment).

[0110] In this specification, the term “pharmaceutically acceptable” means a compound or carrier (e.g., an excipient) that can be administered to a subject together with the compounds described herein (e.g., VS-6063 or its pharmaceutically acceptable salts and / or CH5126766 or its pharmaceutically acceptable salts) and is nontoxic when administered in a dose sufficient to deliver a therapeutic dose of the compound without destroying its pharmacological activity.

[0111] In this specification, the term “pharmaceutically acceptable salt” refers to a derivative of a compound described herein (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and / or CH5126766 or a pharmaceutically acceptable salt thereof), where the compound is modified by converting an existing acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include mineral or organic salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and so on. Examples of pharmaceutically acceptable salts in this disclosure include conventional non-toxic salts of the compounds described herein, formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts in this disclosure can be synthesized by conventional chemical methods from compounds described herein containing a basic or acidic moiety (e.g., VS-6063 or a pharmaceutically acceptable salt thereof and / or CH5126766 or a pharmaceutically acceptable salt thereof). Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of water and an organic solvent. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17. thFound in ed, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977) (each of which is incorporated herein by reference in its entirety). Examples of pharmaceutically acceptable salts also include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; sulfonates such as methanesulfonate, benzenesulfonate, and toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt.

[0112] In this specification, the term “oral dosage form” refers to a composition or medium used to administer a drug, such as a therapeutic agent, such as a compound described herein, to a subject. Typically, an oral dosage form is administered by mouth, but “oral dosage form” is intended to encompass any substance administered to a subject and absorbed through the membranes of the digestive tract, such as the mouth, esophagus, stomach, small intestine, large intestine, and colon, such as mucous membranes. For example, “oral dosage form” includes a solution administered to the stomach via a feeding tube.

[0113] In this specification, the terms “to treat” or “treatment” mean the application or administration of a compound alone or in combination with additional agents to a subject having, for example, a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e

[0114] The phrases “combined with” or “in combination with,” and the terms “simultaneous administration,” “to administer simultaneously,” or “to provide simultaneously,” as used herein in the context of the administration of the compounds or therapies described herein, mean that two (or more) different compounds or therapies are delivered to a subject while the subject is suffering from a disease or disorder (e.g., cancer), for example, that two (or more) different compounds or therapies are delivered to the subject after the subject has been diagnosed with a disease or disorder (e.g., a disease or disorder described herein, e.g., cancer) and before the disease or disorder is cured or eliminated or the treatment is terminated for any other reason. The combination can produce a synergistic result, i.e., a result greater than an additive result, for example, at least 20, 50, 70, or 100% greater than the additive case.

[0115] In this specification, the phrase “synergistic effect” refers to an effect (e.g., therapeutic effect) greater than the additive effect of two or more compounds or compositions. An example of a synergistic effect is the administration of a certain amount of FAK inhibitor (e.g., VS-6063) used in combination with a certain amount of RAF / MEK bilayer (e.g., CH5126766) that results in a therapeutic effect greater than the additive therapeutic effect of each inhibitor used alone.

[0116] In this specification, “one course of treatment” includes one or more separate administrations of the therapeutic agent. One course of treatment may include one or more cycles of the therapeutic agent.

[0117] In this specification, "cycle" refers to a period of time during which a drug is administered to a patient, in the context of a single cycle of drug administration. Preferably, one cycle is equal to four weeks.

[0118] Many ranges, for example, ranges relating to the amount of drug administered per day, are provided herein. In some embodiments, the range includes both endpoints. In other embodiments, the range excludes one or both endpoints. For example, the lower endpoint may be excluded from the range. Thus, in such embodiments, the range of 100–400 mg / day excluding the lower endpoint would include amounts greater than 100 mg / day and less than or equal to 400 mg / day.

[0119] In this specification, the term “subject” is intended to include humans and non-human animals. In some embodiments, the subject is human. Exemplary human subjects include human subjects having or suffering from any of the diseases or disorders described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer as described herein)). The term “non-human animal” in this invention includes all vertebrates, e.g., non-mammals (e.g., chickens, amphibians, reptiles), as well as mammals, e.g., non-human primates, domesticated animals and / or animals useful for agriculture, e.g., sheep, dogs, cats, cattle, pigs, etc.

[0120] The phrase "twice a week" means that the RAF / MEK dual inhibitor (e.g., CH5126766) is administered twice within a one-week period. The administration may be given twice on the same day, or once on different days (which may be consecutive days), but preferably on different days. More preferably, the administration may be given, for example, on days 1 and 4 or 2 and 5 of the period, so that the RAF / MEK dual inhibitor (e.g., CH5126766) is administered at as uniform an interval as possible, i.e., an interval of 3-4 days. The one-week period may begin, for example, on Monday, or for example, on Tuesday. If the two administrations are given on different days, each administration may be given at any time, but preferably at the same time of day (e.g., after breakfast). [Examples]

[0121] The following representative examples are intended to aid in illustrating the present invention and are not intended to limit the scope of the invention, nor should they be interpreted as such.

[0122] In Examples 1 and 2 below, and in Tables 1 to 4 below, "CH5126766" refers to the potassium salt of CH5126766, and "VS-6063" refers to the hydrochloride salt of VS-6063.

[0123] Example 1. Phase I trial of the combination of VS-6063 (FAK inhibitor) and CH5126766 (RAF / MEK dual inhibitor) in patients with advanced solid tumors [NCT03875820] method: This study explored dose escalation, mandatory biopsy, and expansion cohorts. CH5126766 was administered twice weekly, and VS-6063 was administered twice daily (BD). Each cycle consisted of administering both drugs on a 3-week on / 1-week rest basis (1 cycle = 4 weeks). Three dose levels were explored in the dose escalation cohort. Dose level 1 included a schedule of 3.2 mg CH5126766 + 200 mg BD of VS-6063, dose level 2A included a schedule of 4 mg CH5126766 + 200 mg BD of VS-6063, and dose level 2B included a schedule of 3.2 mg CH5126766 + 400 mg BD of VS-6063. The maximum dose was determined such that, among six patients at the same dose level, one or fewer patients experienced a protocol-specified drug-related toxicity (DLT). The safety and toxicity profiles of CH5126766 and VS-6063 were evaluated. The causal relationship and graded severity of each adverse event were determined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Disease response was examined every two cycles according to RECIST criteria version 1.1. Serum tumor markers were also examined in eligible patients. Data related to progression-free survival were also collected.

[0124] Findings: The most common adverse events during dose escalation were rash, as well as non-dose-limiting nausea and hyperbilirubinemia. DLTs were not observed in either cohort 1 or 2A. A grade 2 rash DLT requiring interruption or dose reduction in the first cycle was observed in cohort 2B (corresponding to dose level 2B), and therefore cohort 2A (corresponding to dose level 2A) was designated as the recommended phase 2 dose (R2PD). KRAS-mutated ovarian cancer (3 cases of low-grade serous and 1 case of mucinous adenocarcinoma) and KRAS-mutated lung cancer with evaluable response showed partial responses. Two cases of NRAS-mutated colorectal cancer were treated and showed stable disease with a reduction of over 50% in CEA levels. Pancreatic cancer with KRAS mutations showed a minor response (-19%, -14%, and -11% in cycles 2, 4, and 6, respectively), with a reduction of over 50% in CA19-9 levels.

[0125] Representative results regarding disease response, serum tumor markers, and treatment duration obtained to date are shown in Example 2.

[0126] Conclusion: In patients with ovarian cancer and other tumors bearing KRAS and / or NRAS mutations, the combination of CH5126766 and VS-6063 demonstrates tolerability and high activity.

[0127] Example 2. Combination of CH5126766 and VS-6063 in a patient with advanced solid tumors. In Tables 1-4 below, "CH" represents the potassium salt of CH5126766, and "VS" represents the hydrochloride of VS-6063. The potassium salt of CH5126766 was administered twice weekly, and VS-6063 hydrochloride was administered twice daily (BID). Each cycle consisted of administering both drugs on a 3-week / 1-week rest basis (1 cycle = 4 weeks). "PR" represents partial response, "SD" represents stable disease, and "N / A" represents no data.

[0128] Table 1

[0129] Table 2

[0130] Table 3

[0131] Table 4

Claims

1. A pharmaceutical product for treating cancer in a subject, comprising CH5126766 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein CH5126766 or a pharmaceutically acceptable salt thereof is used in combination with VS-6063 or a pharmaceutically acceptable salt thereof, and the cancer is an advanced solid tumor.

2. The pharmaceutical product according to claim 1, wherein the cancer is selected from the group consisting of ovarian cancer, lung cancer, colon cancer, and pancreatic cancer.

3. The pharmaceutical product according to claim 1 or 2, wherein the cancer is ovarian cancer.

4. The pharmaceutical product according to claim 3, wherein the ovarian cancer is low-grade serous ovarian cancer.

5. The pharmaceutical product according to claim 1 or 2, wherein the cancer is lung cancer.

6. The pharmaceutical product according to claim 5, wherein the lung cancer is non-small cell lung cancer.

7. The pharmaceutical product according to claim 1 or 2, wherein the cancer is colon cancer.

8. The pharmaceutical product according to claim 1 or 2, wherein the cancer is pancreatic cancer.

9. The pharmaceutical product according to claim 8, wherein the pancreatic cancer is pancreatic adenocarcinoma.

10. A pharmaceutical product according to any one of claims 1 to 9, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered twice a week.

11. The pharmaceutical product according to any one of claims 1 to 10, wherein VS-6063 or a pharmaceutically acceptable salt thereof is administered twice daily.

12. The pharmaceutical product according to any one of claims 1 to 10, wherein VS-6063 or a pharmaceutically acceptable salt thereof is used to be administered once daily.

13. The pharmaceutical product according to any one of claims 1 to 12, wherein CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are administered for at least three weeks.

14. The pharmaceutical product according to any one of claims 1 to 13, wherein CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are used to be administered independently in a cycle of administration for three weeks followed by a one-week rest period.

15. The pharmaceutical product according to any one of claims 1 to 13, wherein CH5126766 or a pharmaceutically acceptable salt thereof and VS-6063 or a pharmaceutically acceptable salt thereof are administered simultaneously in a cycle of administration for three weeks followed by a one-week rest period.

16. A pharmaceutical product according to any one of claims 1 to 15, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.5 mg to about 10 mg.

17. The pharmaceutical product according to any one of claims 1 to 16, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered in a dose of about 4 mg.

18. A pharmaceutical product according to any one of claims 1 to 16, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered in a dose of 3.2 mg.

19. The pharmaceutical product according to any one of claims 1 to 18, wherein VS-6063 or a pharmaceutically acceptable salt thereof is used to be administered in a dose of about 100 mg to about 400 mg.

20. The pharmaceutical product according to any one of claims 1 to 18, wherein VS-6063 or a pharmaceutically acceptable salt thereof is administered in a dose of about 100 mg to about 500 mg.

21. The pharmaceutical product according to any one of claims 1 to 18, wherein VS-6063 or a pharmaceutically acceptable salt thereof is used to be administered in a dose of about 200 mg to about 500 mg.

22. The pharmaceutical product according to any one of claims 1 to 18, wherein VS-6063 or a pharmaceutically acceptable salt thereof is used to be administered in a dose of about 200 mg to about 600 mg.

23. A pharmaceutical product according to any one of claims 1 to 18, wherein VS-6063 or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 200 mg.

24. The pharmaceutical product according to any one of claims 1 to 18, wherein VS-6063 or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 400 mg.

25. A pharmaceutical product according to any one of claims 1 to 15, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.5 mg to about 10 mg, and VS-6063 or a pharmaceutically acceptable salt thereof is administered in a dose of about 100 mg to about 400 mg.

26. The pharmaceutical product according to any one of claims 1 to 15, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered twice a week at a dose of approximately 4 mg, and VS-6063 or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of approximately 200 mg.

27. The pharmaceutical product according to any one of claims 1 to 15, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered twice weekly at a dose of 3.2 mg, and VS-6063 or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of 200 mg.

28. The pharmaceutical product according to any one of claims 1 to 15, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered twice a week at a dose of approximately 4 mg, and VS-6063 or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of approximately 400 mg.

29. The pharmaceutical product according to any one of claims 1 to 15, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered at a dose of 3.2 mg twice weekly, and VS-6063 or a pharmaceutically acceptable salt thereof is administered at a dose of 400 mg twice daily.

30. A pharmaceutical product according to any one of claims 1 to 29, wherein CH5126766 or a pharmaceutically acceptable salt thereof is used for oral administration.

31. A pharmaceutical product according to any one of claims 1 to 30, wherein VS-6063 or a pharmaceutically acceptable salt thereof is used for oral administration.

32. A pharmaceutical product according to any one of claims 1 to 31, comprising a potassium salt of CH5126766 as a pharmaceutically acceptable salt of CH5126766.

33. A pharmaceutical product according to any one of claims 1 to 32, wherein the cancer has a mutation in the RAS.

34. A pharmaceutical product according to any one of claims 1 to 33, wherein the cancer has a mutation in HRAS, KRAS, or NRAS.

35. A pharmaceutical product according to any one of claims 1 to 34, wherein the cancer has a mutation in KRAS.

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