BR112017028519B1 - USE OF DEFACTINIB IN THE PREPARATION OF A MEDICATION FOR THE TREATMENT OF CANCER - Google Patents

Abstract

THERAPEUTIC COMPOSITIONS, COMBINATIONS AND METHODS OF USE. This invention relates to methods comprising administering a FAK inhibitor and an immunotherapeutic agent such as anti-PD-1 or anti-PD-L1; which are useful in treating abnormal cell growth, such as cancer, in mammals, especially humans.

Description

RELATED REQUESTS

[001] The present application claims priority under 35 U.S.C. §119 (e) to the American provisional patent application, US.S.N. 62/186,197, filed June 29, 2015, which is incorporated herein by reference in its entirety.

FIELD OF INVENTION

[002] This invention relates to methods of treating a disease or disorder described herein (e.g., abnormal cell growth (e.g., cancer)), comprising administering to an individual (e.g., a human subject) a FAK inhibitor and an immunotherapeutic agent.

BASICS OF THE INVENTION

[003] Compelling evidence suggests that focal adhesion kinase (FAK), namely PTK2, a cytoplasmic non-receptor tyrosine kinase, plays an essential role in cellular matrix signal transduction pathways (Clark and Brugge 1995, Science 268: 233-239) and its aberrant activation is associated with an increased metastatic potential of tumors (Owens et al., 1995, Cancer Research 55: 2752-2755). FAK was originally identified as a 125 kDa protein highly tyrosine phosphorylated in v-Src-transformed cells. FAK is encoded by the PTK2 gene in humans. FAK was later found to be a tyrosine kinase that localizes to focal adhesions, which are points of contact between cultured cells and their underlying substrate and sites of intense tyrosine phosphorylation. FAK is phosphorylated and therefore activated in response to extracellular matrix (ECM) binding to integrins. Recently, studies have demonstrated that an increase in FAK mRNA levels accompanied invasive transformation of tumors and attenuation of FAK expression (through the use of antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al., 1996, Cell Growth and Diff 7:413418). In addition to being expressed in most tissue types, FAK is found at high levels in most human cancers, for example in highly invasive metastases. For example, U.S. Patent No. 8,247,411 relates to a broad class of novel pyrimidine derivatives that are kinase inhibitors, and more specifically, FAK inhibitors. Compounds like these may be useful in treating abnormal cell growth.

[004] Cancers can be recognized by the immune system and regulate and even eliminate tumors. Immune checkpoints refer to a multitude of inhibitory pathways that help maintain self-tolerance and modulate the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. Tumors co-opt certain immune checkpoint pathways as a mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. The development of checkpoint-blocking antibodies, e.g., inhibitory receptors, that target or are directed against, e.g., cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), may facilitate treatment of a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)). CTLA-4 and PD-1 can function as negative regulators and have nonredundant roles in modulating immune responses. They are expressed on tumor-specific T cells and can lead to compromised activation and suppressed effector functions, e.g., prophylaxis, cytokine secretion, and tumor cell lysis. CTLA-4 can attenuate early activation of naïve and memory T cells. PD-1 is involved in modulating the activity of T cells in, e.g., peripheral tissues through interaction with its ligands, i.e., PD-L1 and PD-L2. Immune checkpoint pathway blockers (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4) may enhance antitumor immunity and provide opportunities to treat a disease or disorder, described herein (e.g. e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)), e.g., providing more effective treatment for individuals suffering from cancer.

[005] Although durable responses to single-agent immune checkpoint inhibitors have been reported, additional approaches are needed to extend this therapeutic benefit to a greater proportion of cancer patients. Consequently, substantial efforts are underway to identify agents that can enhance T cell-mediated tumor cell killing and potentiate the effects of checkpoint inhibitors. Focal Adhesion Kinase (FAK) and the closely related PYK2 family member are potentially valuable targets in this regard due to the role of these enzymes in regulating key cell populations in the tumor microenvironment. FAK inhibitors can increase cytotoxic T cells (CD8+ expressing cytotoxic T cells) in tumors and decrease immune cell populations that suppress the host's antitumor immune response (T-regs, M2 tumor-associated macrophages, myeloid-derived suppressor cells ). FAK inhibitors can enhance the PD-1/PD-L1 immune checkpoint pathway and can enhance the antitumor efficacy of several antitumor immunotherapies. A combination of a cancer therapy (e.g., a FAK inhibitor) with a cancer immunotherapy (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4) can increase generation and efficacy of tumor-specific cytotoxic lymphocytes and provide a promising approach to more effectively treat a disease or disorder, described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)). The compounds described herein, e.g., FAK inhibitors, can be used in combination with an immunotherapy described herein, to prevent and treat a disease or disorder, described herein, e.g., abnormal cell growth (e.g., a cancer, described herein). ).

SUMMARY OF THE INVENTION

[006] In one aspect, described herein is a method for treating a human subject suffering from a disease or disorder, described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)), comprising administering a FAK inhibitor in combination with an immunotherapeutic procedure or agent (e.g., wherein the immunotherapeutic agent is a compound that inhibits the immune checkpoint blockade pathway).

[007] In some embodiments, the cancer is a solid tumor, soft tissue tumor, metastasis or non-solid cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a malignancy (e.g., sarcomas, adenocarcinomas, and carcinomas) of an organ (e.g., lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial or testicular tumors), pharynx, prostate and ovary). In some embodiments, the cancer is a mesothelioma; neurofibromatosis; for example, neurofibromatosis type 2, neurofibromatosis type 1; kidney cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; ovary; breast cancer; a tumor in the nervous system; schwannoma; meningioma; schwannomatosis; acoustic neuroma; adenoid cystic carcinoma; ependymoma; or ependymal tumors. In some embodiments, the cancer is mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), breast cancer (e.g., triple negative breast cancer), ovarian cancer (e.g., ovarian cancer advanced), lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC)), or a non-hematolotic malignancy. In some embodiments, the cancer is melanoma (e.g., metastasis from locally mutated malignant or advanced cutaneous melanoma with N-Ras), colorectal cancer (e.g., metastatic colorectal cancer), leukemia (e.g., acute myeloid leukemia), adenocarcinoma (e.g., e.g., pancreatic adenocarcinoma), or a solid tumor (e.g., locally advanced solid tumor, metastatic solid tumor, hepatocellular carcinoma).

[008] In some embodiments, the FAK inhibitor is administered orally.

[009] In some embodiments, the FAK inhibitor is VS-4718, VS-5095, VS-6062, VS-6063, BI 853520 or GSK2256098.

[0010] In some embodiments, the FAK inhibitor is VS-4718. In some embodiments, the FAK inhibitor is VS-6063.

[0011] In some embodiments, the FAK inhibitor is administered at least once per day. In some embodiments, the FAK inhibitor is administered once daily. In some embodiments, the FAK inhibitor is administered twice daily.

[0012] In some embodiments, the FAK inhibitor is administered at about 100 mg to about 2000 mg.

[0013] In some embodiments, the FAK inhibitor is VS-6063 and the FAK inhibitor is administered at about 200 mg to about 600 mg twice daily. In some embodiments, VS-6063 is administered before or after (e.g., immediately before or immediately after) consumption of food.

[0014] In some embodiments, the FAK inhibitor is VS-4718 and the FAK inhibitor is administered at about 300 mg to about 500 mg once per day. In some embodiments, the FAK inhibitor is VS-4718 and the FAK inhibitor is administered at about 200 mg to about 400 mg twice daily.

[0015] In some embodiments, the immunotherapeutic agent is administered parenterally.

[0016] In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (e.g., ipilimumab, tremelimumab). In some embodiments, the immunotherapeutic agent is an anti-PD-1 ligand (e.g., PD-LI (e.g., B7-HI or CD274) or PD-L2 (e.g., B7-DC or CD273)). In some embodiments, the immunotherapeutic 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; In some embodiments, the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559 (i.e., MDX-1105), MEDI4736; MSB0010718C (avelumab), or MPDL-3280A). In some embodiments, the immunotherapeutic agent is a checkpoint blocking antibody (e.g., IMP321, MGA271). In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (e.g., ipilimumab, tremelimumab, anti-TIM3, anti-LAG3, anti-TIGIT). In some embodiments, the immunotherapeutic agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy. In some embodiments, the immunotherapeutic agent is a costimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40). In some embodiments, the method further comprises administering an additional chemotherapeutic agent or radiation therapy. In some embodiments, the method further comprises administering a cytotoxic agent. In some embodiments, the cytotoxic agent is gemcitabine or paclitaxel (e.g., nab-paclitaxel). In some embodiments, the immunotherapeutic agent is a costimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0017] In some embodiments, the method further comprises administering an additional chemotherapeutic agent or radiation therapy. In some embodiments, the additional therapeutic agent is selected from: alkylating agents, antimetabolites, antibiotics, hormonal therapy agents, plant-derived antitumor substances, cytotoxic topoisomerase inhibitory agents, immunological agents, biological response modifiers, other anticancer agents, other antiangiogenic compounds, platinum-coordinated compounds, tyrosine kinase inhibitors, antibodies and interferons.

[0018] In some embodiments, the FAK inhibitor is administered before the immunotherapeutic agent is administered. In some embodiments, the FAK inhibitor is administered after administration of the immunotherapeutic agent. In some embodiments, the FAK inhibitor is administered simultaneously with the immunotherapeutic agent.

[0019] In some embodiments, the individual has been previously treated with a chemotherapeutic agent or radiation therapy. In some embodiments, the individual has failed (e.g., relapsed from, insensitive to, received no or little benefit) conventional or standard cancer treatment (e.g., surgery, first-line cancer therapy). In some embodiments, the individual has failed (e.g., relapsed from, insensitive to, received no or little benefit) first-line treatment (e.g., first-line therapy for cancer).

[0020] In some embodiments, the individual is identified to have high PD-L1 or PD-L2, for example, high PD-L1 or PD-L2 in tumor cells. In some embodiments, the individual is identified to have low PD-L1 or PD-L2, e.g., low PD-L1 or PD-L2 on tumor cells. In some embodiments, the individual is identified to express genes induced by interferon gamma (IFN-γ).

DETAILED DESCRIPTION OF THE INVENTION

[0021] Described herein are methods for treating abnormal cell growth, for example, cancer, for example, a cancer described herein, the method comprising administering a FAK inhibitor and a cancer immunotherapy. Applicants have discovered that treating an individual suffering from abnormal cell growth, e.g., cancer, with a FAK inhibitor in combination with a cancer immunotherapy, more effectively prevents and treats abnormal cell growth, e.g., cancer. , than with any of the isolated agents.

Treatment and administration methods.

[0022] The methods described herein relate to treating a human subject suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)) with a FAK inhibitor in combination with a cancer immunotherapy. Administered "in combination", as used herein, means that two (or more) different treatments are delivered to the individual during the course of the individual's affliction with the disorder, e.g., the two or more treatments are delivered after the individual has been diagnosed. with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, delivery of one treatment is still occurring when delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to here as "simultaneous" or "simultaneous delivery." In other embodiments, delivery of one treatment ends before delivery of the other treatment begins. In some modalities of both cases, treatment is more effective due to combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment. , or the analogous situation is seen with the first treatment. In some embodiments, the distribution is such that the reduction of a symptom or other parameter related to the disorder is greater than what would be observed with one treatment distributed in the absence of the other. The effect of the two treatments may be partially additive, fully additive, or greater than additive. The distribution may be such that an effect of the first distribution treatment is still detectable when the second is distributed.

[0023] In some embodiments, the method comprises administering a FAK inhibitor prior to administering a cancer immunotherapy. In some embodiments, the method comprises administering a FAK inhibitor following administration of a cancer immunotherapy. In some embodiments, the method comprises administering a FAK inhibitor simultaneously with administering a cancer immunotherapy. In some embodiments, the FAK inhibitor is VS-4718 (PND-1186), VS-6063 (PF-04554878; defactinib), VS-6062 (PF-562271), VS-5095, GSK2256098, or BI 853520.

Abnormal cell growth

[0024] The methods described herein are directed to treating or preventing abnormal cell growth in an individual (e.g., a human individual). Abnormal cell growth, as used herein and unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate, for example, expressing a mutated tyrosine kinase or overexpressing a receptor tyrosine kinase; (2) benign and malignant cells from other proliferative diseases, for example, in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate, for example, by receptor tyrosine kinases; (4) any tumors that proliferate, for example, by aberrant serine/threonine kinase activation; and (5) benign and malignant cells from other proliferative diseases, for example, in which aberrant serine/threonine kinase activation occurs. Abnormal cell growth may refer to cell growth in epithelium (e.g., carcinomas, adenocarcinomas); mesenchymal (e.g. sarcomas (e.g. leiomyosarcoma, Ewing sarcoma)); hematopoietic (e.g. lymphomas, leukemias, myelodysplasias (e.g. pre-malignant)); or other cells (e.g. melanoma, mesothelioma and other tumors of unknown origin).

[0025] In some embodiments, the method is effective in treating non-hematological malignancies. In some embodiments, the method is effective in treating pancreas, non-small cell lung carcinoma (NSCLC), small cell lung carcinoma (SCLC), mesothelioma, melanoma, breast and ovarian cancer. In one embodiment, the breast cancer is a triple negative breast cancer (e.g., breast cancer that does not express the genes for the estrogen receptor, progesterone receptor, and Her2/neu). In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC. In one embodiment, the ovarian cancer is advanced ovarian cancer (e.g., advanced ovarian cancer or metastatic ovarian cancer). In one embodiment, the method is effective in treating mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma).

Neoplastic disorders

[0026] Abnormal cell growth may refer to a neoplastic disorder. A "neoplastic disorder" is a disease or disorder characterized by cells that possess the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. An abnormal mass of tissue as a result of abnormal cell growth or division, or a "neoplasm," may be benign, premalignant (carcinoma in situ), or malignant (cancer).

[0027] Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from prostate, colon, lung, breast and liver origin), hematopoietic neoplastic disorders, e.g., leukemias, metastatic tumors. Treatment with the compound may be in an amount effective to improve at least one symptom of the neoplastic disorder, e.g., reduced cell proliferation, reduced tumor mass, etc.

Cancer

[0028] The inventive methods of the present invention may be useful in the prevention and treatment of cancer, including, for example, solid tumors, soft tissue tumors and their metastases. The disclosed methods are also useful in the treatment of non-solid cancers. Exemplary solid tumors include, but are not limited to, malignant tumors (e.g., sarcomas, adenocarcinomas, and carcinomas) of various organ systems, such as lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., , renal, urothelial or testicular tumors), pharynx, prostate and ovary. Exemplary adenocarcinomas include, but are not limited to, colorectal cancer, renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma), non-small cell lung carcinoma, pancreatic cancer (e.g., metastatic pancreatic adenocarcinoma), and bowel cancer. slender.

[0029] Cancer may include mesothelioma; neurofibromatosis; for example, neurofibromatosis type 2, neurofibromatosis type 1; kidney cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; ovary; breast cancer; a tumor in the nervous system; schwannoma; meningioma; schwannomatosis; acoustic neuroma; adenoid cystic carcinoma; ependymoma; or ependymal tumors. In some embodiments, the cancer exhibits decreased expression and/or mutation of merlin, and/or deletion and/or hypermethylation of the NF-2 gene promoter. In one embodiment, the cancer is mesothelioma that exhibits decreased expression and/or mutation of merlin and/or deletion and/or hypermethylation of the NF-2 gene promoter.

[0030] In some embodiments, the cancer is kidney cancer.

[0031] Cancer may include cancers characterized as comprising cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells. Cancer may include cancers that have been characterized as enriched in cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells (e.g., a tumor enriched in cells that have undergone an epithelial-to-mesenchymal transition or a metastatic tumor).

[0032] The cancer may be a primary tumor, that is, located at the anatomical site of the beginning of tumor growth. Cancer may also be metastatic, that is, appearing in at least a second anatomical location in addition to the anatomical site of initiation of tumor growth. Cancer can be a recurrent cancer, that is, cancer that returns after treatment and after a period of time, in which the cancer was undetectable. Recurrent cancer may be anatomically localized to the original tumor, for example, anatomically close to the original tumor; regionally to the original tumor, for example, in a lymph node located close to the original tumor; or distantly from the original tumor, for example, anatomically in a region remote from the original tumor.

[0033] Cancer may also include, for example, but is not limited to epithelial, breast, lung, pancreatic, colorectal (e.g., metastatic colorectal, e.g., metastatic K Ras mutated), prostate, head and neck, melanoma (e.g. metastatic or locally advanced N Ras mutated malignant cutaneous melanoma), acute myeloid leukemia and glioblastoma. Exemplary breast cancers include, but are not limited to, triple-negative breast cancer, basal-like breast cancer, claudin-low breast cancer, invasive, inflammatory, metaplastic, and advanced Her-2-positive or ER-positive therapy-resistant cancer. .

[0034] Other types of cancers include, but are not limited to, brain, abdomen, esophagus, gastrointestinal, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovary, retinoblastoma, Wilm's tumor, multiple myeloma, skin, lymphoma, blood cancers and bone marrow (e.g., advanced hematologic malignancies, leukemia, e.g., acute myeloid leukemia (e.g., primary or secondary), acute lymphoblastic leukemia, acute lymphocytic leukemia, T-cell leukemia, hematologic malignancies, advanced myeloproliferative disorders, myelodysplastic syndrome , recurrent or refractory multiple myeloma, advanced myeloproliferative disorders), retinal, bladder, cervical, kidney, endometrial, meningioma, lymphoma, skin, uterus, lung, non-small cell lung, nasopharyngeal carcinoma, neuroblastoma, solid tumor, hematologic malignancy, carcinoma squamous cell, testicular, thyroid, mesothelioma, cerebral vulva, sarcoma, intestinal, oral, endocrine, salivary, spermatocytic seminoma, sporadic medullary thyroid carcinoma, non-proliferated testicular cells, malignant mastoid cell-related cancers, non-Hodgkin's lymphoma and diffuse large B-cell lymphoma.

[0035] Exemplary cancers include: acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, childhood; Acute myeloid leukemia, adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-related lymphoma; AIDS-related malignancies; Anal Cancer; Astrocytoma, Infantile Cerebellar; Astrocytoma, Infant Brain; Bile duct cancer, Extrahepatic; Bladder cancer; Bladder cancer, childhood; Bone cancer, osteosarcoma/malignant fibrous histiocytoma; Brainstem glioma, childhood; Brain tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain tumor, Cerebellar astrocytoma, Childhood; Brain tumor, Cerebral astrocytoma/Malignant glioma, Childhood; Brain Tumor,Ependymoma, Childhood; Brain tumor, Medulloblastoma, Childhood; Brain tumor, Primary supratentorial neuroectodermal tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain tumor, childhood (other); Breast cancer; Breast cancer and pregnancy; Breast cancer, childhood; Breast Cancer, Male; Bronchial adenomas/carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, islet cell; Carcinoma of Unknown Primary Site; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical cancer; childhood cancers; Chronic lymphocytic leukemia; Chronic myeloid leukemia; Chronic myeloproliferative disorders; Clear cell sarcoma of tendon sheaths; Colon cancer; Colorectal Cancer, Childhood; Cutaneous T-cell lymphoma; Endometrial cancer; Ependymoma, Childhood; Epithelial Cancer, Ovary; Esophageal cancer; Esophageal cancer, childhood; Ewing Family of Tumors; Extracranial germ cell tumor, Childhood; Extragonadal germ cell tumor; Extrahepatic bile duct cancer; Eye cancer, intraocular melanoma; Eye cancer, Retinoblastoma; Gallbladder cancer; Gastric cancer (Stomach); Gastric (stomach) cancer, childhood; Gastrointestinal Carcinoid Tumor; Germ cell tumor, extracranial, childhood; Germ cell tumor, Extragonadal; Germ cell tumor, ovary; Gestational trophoblastic tumor; Glioma, childhood brain stem; Glioma, Infantile Visual Pathway and Hypothalamic; Hairy cell leukemia; Head and neck cancer; Hepatocellular (liver) cancer, Adult (primary); Hepatocellular cancer (liver), childhood (primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's lymphoma during pregnancy; Hypopharyngeal cancer; Visual and Hypothalamic pathway glioma, Childhood; Intraocular Melanoma; Islet cell carcinoma (endocrine pancreas); Kaposi's sarcoma; Kidney cancer; Laryngeal cancer; Laryngeal cancer, childhood; Leukemia, acute lymphoblastic, adult; Leukemia, acute lymphoblastic, childhood; Leukemia, acute myeloid, adult; Leukemia, acute myeloid, childhood; Leukemia, chronic lymphocytic; Leukemia, chronic myelogenous; Leukemia, hairy cells; Lip and oral cavity cancer; Liver cancer, adult (primary); Liver cancer, childhood (primary); Lung cancer, non-small cell; Lung cancer, small cell; Acute lymphoblastic leukemia, adult; Acute lymphoblastic leukemia, childhood; Lymphocytic leukemia, chronic; Lymphoma, related to AIDS; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T Cell; Lymphoma, Hodgkin, Adult; Lymphoma, Hodgkin, Childhood; Lymphoma, Hodgkin during pregnancy; Lymphoma, non-Hodgkin, Adult; Lymphoma, Non-Hodgkin, Childhood; Lymphoma, non-Hodgkin during pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male breast cancer; Malignant mesothelioma, adult; Malignant mesothelioma, childhood; Malignant thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel cell carcinoma; Mesothelioma, malignant; Metastatic squamous neck cancer with occult primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple myeloma/Plasma cell neoplasm; Mycosis Fungoides; Myelodysplastic syndromes; Chronic myeloid leukemia; Acute myeloid leukemia, Childhood; Myeloma, Multiple; Myeloproliferative disorders, chronic; Nasal cavity and Paranasal sinus cancer; Nasopharyngeal cancer; Nasopharyngeal cancer, childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin Lymphoma, Childhood; Non-Hodgkin's lymphoma during pregnancy; Non-small cell lung cancer; Oral cancer, childhood; Oral cavity and lip cancer; Oropharyngeal cancer; Osteosarcoma/malignant fibrous histiocytoma of bones; Ovarian cancer, childhood; Epithelial Ovarian Cancer; Ovarian germ cell tumor; Tumor of low malignant potential of the ovary; Pancreatic cancer; Pancreatic cancer, childhood; Pancreatic cancer, islet cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid cancer; Penile cancer; Pheochromocytoma; Primitive Pineal and Supratentorial Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma cell neoplasm/multiple myeloma; Pleuropulmonary Blastoma; Pregnancy and breast cancer; lymphoma in pregnancy and Hodgkin's lymphoma; lymphoma in pregnancy and non-Hodgkin lymphoma; Primary Central Nervous System Lymphoma; Primary liver cancer, adult; Primary liver cancer, childhood; Prostate cancer; Rectal cancer; Renal cell (kidney) cancer; Renal cell cancer, childhood; Renal Pelvis and Ureter, Transient Cellular Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary gland cancer; Salivary gland cancer, childhood; Sarcoma, Ewing Family of Tumors; Sarcoma, Kaposi; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, soft tissue, adult; Sarcoma, soft tissue, childhood; Sezary syndrome; Skin cancer; Skin cancer, childhood; Skin cancer (melanoma); Skin carcinoma, Merkel cell; Small cell lung cancer; Small intestine cancer; Soft tissue sarcoma, adult; Soft tissue sarcoma, childhood; Squamous neck cancer with occult, metastatic primary; Stomach (gastric) cancer; Stomach (gastric) cancer, childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T-cell lymphoma, cutaneous; Testicular cancer; Thymoma, Childhood; Thymoma, malignant; Thyroid cancer; Thyroid cancer, childhood; Transient Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic tumor, gestational; Cancer of Unknown Primary Site, Childhood; Uncommon childhood cancers; Ureter and Renal Pelvis, Transient Cellular Cancer; Urethral cancer; Uterine sarcoma; Vaginal cancer; Visual and Hypothalamic Pathway Glioma, Childhood; Vulvar Cancer; Waldenstrom's macroglobulinemia; and Wilms Tumor. Metastases from the above-mentioned cancers can also be treated and/or prevented according to the methods described here.

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

[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) after standard therapy.

[0038] The methods described herein can reduce, improve, or completely eliminate the disorder and/or its associated symptoms, to prevent it from worsening, to decrease the rate of progression, or to minimize the rate of recurrence of the disorder once it has been initially eliminated (i.e. is, to avoid a relapse). A suitable dose and therapeutic regimen may vary depending on the specific compounds, combinations and/or pharmaceutical compositions used and the mode of delivery of the compounds, combinations and/or pharmaceutical compositions. In some embodiments, the method increases the average length of survival, increases the average progression-free survival time and/or reduces the recurrence rate, of individuals treated with the combinations described herein in a statistically significant manner.

[0039] In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC, metastatic cancer), bone cancer, pancreatic cancer, skin cancer , head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer (e.g., advanced or metastatic ovarian cancer, low-grade unresectable ovarian cancer), rectal cancer, cancer of the anal region, stomach cancer , colon cancer, breast cancer (e.g., triple-negative breast cancer, e.g., breast cancer that does not express the genes for the estrogen receptor, progesterone receptor, and Her2/neu)), uterine cancer, carcinoma of the fallopian tubes, endometrial carcinoma, cervical carcinoma, 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 , adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney cancer (e.g., Wilms tumor, Rhabdoid tumor ; nephroma (e.g., mesoblastic nephroma)) or ureter, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma) or a combination of one or more of the above cancers. In some embodiments, the cancer is ovarian cancer, pancreatic cancer, non-small cell lung cancer, head and neck cancer. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (e.g., the individual has a locally recurrent disease, e.g., cancer).

[0040] The inventive methods of the present invention contemplate single and multiple administrations of a therapeutically effective amount of a FAK inhibitor in combination with immunotherapy. Combinations, for example, a combination as described herein, for example, a FAK inhibitor in combination with an immunotherapy, may be administered at regular intervals depending on the nature, severity and extent of the individual's condition. In some embodiments, a combination, as described herein, for example, a FAK inhibitor in combination with an immunotherapy, is administered in a single dose. In some embodiments, a combination, as described herein, for example, a FAK inhibitor in combination with an immunotherapy, is administered in multiple doses. In some embodiments, a therapeutically effective amount of a combination as described herein, e.g., a FAK inhibitor in combination with an immunotherapy, may be administered orally and periodically at regular intervals (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times every 1, 2, 3, 4, 5 or 6 days, or every 1, 2, 3, 4, 5, 6, 7, 8 or 9 weeks or every 1 2, 3, 4, 5, 6, 7, 8, 9 months or more).

[0041] In some embodiments, a combination, as described herein, for example, a FAK inhibitor in combination with an immunotherapy, is administered at a predetermined interval (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times every 1, 2, 3, 4, 5 or 6 days, or every 1, 2, 3, 4, 5, 6, 7, 8 or 9 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9 months or more).

Compounds

[0042] The methods described herein comprise administering a FAK inhibitor and an immunotherapy to an individual with abnormal cell growth. Exemplary compounds that inhibit FAK include, but are not limited to, the following:

FAK inhibitors

[0043] Potent FAK protein tyrosine kinase inhibitors can be adapted for therapeutic use as antiproliferative (e.g., anticancer), antitumor (e.g., effective against solid tumors), antiangiogenesis (e.g., stopping or preventing proliferation) agents. of blood vessels) in mammals, particularly in humans. The compounds described herein, e.g., FAK inhibitors, may be useful in preventing and treating a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein) ). The compounds described herein, e.g., FAK inhibitors, may be useful in the prevention and treatment of non-hematologic malignancies, a variety of human hyperproliferative disorders, such as malignant and benign tumors of the liver, kidney, bladder, breast, gastric, ovary, collaterals, prostate, pancreatic, lung, vulva, thyroid, liver carcinomas, sarcomas, glioblastomas, head and neck, and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) and benign prostatic hyperplasia (e.g., BPH), and in the prevention and treatment of disorders such as mesothelioma. In some embodiments, the compounds described herein, e.g., FAK inhibitors, inhibit protein tyrosine kinase 2 (PYK2).

[0044] In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts, are present in a composition in the amount of 5, 10, 11, 12, 12.5, 13, 14, 15, 20, 25, 30, 35 , 40, 45, 50, 55, 60% w/w or greater. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are present in a composition in the amount of about 5% to 60%, 5% to 50%, 10% to 50%, 10% to 40% w/w. .

[0045] The following examples of FAK inhibitors include, but should not be construed as limited to:

Compounds VS-4718 and VS-5095

[0046] Examples of FAK inhibitors include, but are not limited to, VS-4718, VS-5095, and related compounds, or a pharmaceutically acceptable salt thereof. Compounds VS-4718, VS-5095 and related compounds are described in documents PCT/US2010/045359 and US20110046121, the contents of which are incorporated in their entirety. A compound of Formula (Ia) is also referred to as VS-4718. A compound of Formula (Ib) is also referred to as VS-5095. In some embodiments, the FAK inhibitor is a compound of Formula (Ia) or (Ib):

GSK2256098

[0047] Examples of FAK inhibitors also include, but are not limited to, GSK2256098 and related compounds, or a pharmaceutically acceptable salt thereof. GSK2256098 and related compounds are described in US20100113475, US20100317663, US20110269774, US20110207743, US20140155410 and US20140107131, the contents of which are incorporated herein in their entirety. In some embodiments, the FAK inhibitor is a compound of Formula (I-c1), (I-c2), (I-c3), (I-c4) or (I-c5):

Compound VS-6063 and VS-6062

[0048] Examples of FAK inhibitors also include, but are not limited to, VS-6063, VS-6062 and related compounds, or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride, VS-6062 hydrochloride) . VS-6063, VS-6062, and related compounds are also disclosed in, for example, U.S. Pat. US No. 7,928,109, EP1578732, PCT/IB2004/202744, PCT/IB2003/005883, PCT/IB2005/001201 and PCT/IB2006/003349, the contents of which are incorporated herein by reference. VS-6063 is also known as a compound of Formula (Id), defactinib and PF-04554878. VS-6062 is also known as a compound of Formula (Id) and PF-00562271. In some embodiments, the FAK inhibitor is a compound of Formula (Id) or (Ie):

Other FAK inhibitors

[0049] Examples of FAK inhibitors also include, but are not limited to, a compound of Formula (If), Formula (Ig) and related compounds, or a pharmaceutically acceptable salt thereof. A compound of Formula (If) and related compounds are described in U.S. Pat. No. 8,569,298, the contents of which are incorporated herein in their entirety. In some embodiments, the FAK inhibitor is 2-[[2[(1,3-dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-5-fluoro-N-methoxy- benzamide, or a compound of formula (If):

[0050] In some embodiments, the FAK inhibitor is BI 853520.

Immunotherapy

[0051] The methods described herein comprise administering a FAK inhibitor and an immunotherapy to an individual with abnormal cell growth. Exemplary immunotherapies include, but are not limited to, the following.

[0052] In some embodiments, the immunotherapeutic agent is a compound (e.g., a ligand, an antibody) that inhibits the immune checkpoint blockade pathway. Cancer immunotherapy refers to using the immune system to treat cancer. Three main groups of immunotherapy used to treat cancer include cell-based, antibody-based, and cytokine therapies. All groups explore displaying cancer cells of subtly different structures (e.g., molecular structure, antigens, proteins, molecules, carbohydrates) on their surface that can be detected by the immune system. Cancer immunotherapy (i.e., antitumor immunotherapy or antitumor immunotherapeutics) includes, but is not limited to, immune checkpoint antibodies (e.g., PD-1 antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA antibodies, 4, TIM3 antibodies, LAG3 antibodies, TIGIT antibodies); and cancer vaccines (i.e., antitumor vaccines).

[0053] Cell-based therapies (e.g., cancer vaccines) generally involve removing immune cells from an individual suffering from cancer, either from the blood or from a tumor. Tumor-specific immune cells will be activated, grown and returned to an individual suffering from cancer, where the immune cells provide an immune response against the cancer. Cell types that can be used in this way are, for example, natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, dendritic cells, CAR-T therapies (i.e., chimeric antigen receptor T cells that are T created to target specific antigens), TIL therapy (i.e., administration of tumor-infiltrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines. An exemplary cell-based therapy is Provenge. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0054] Interleukin-2 and interferon-alpha are examples of cytokines, proteins that regulate and coordinate the behavior of the immune system.

[0055] Antibody therapies are antibody proteins produced by the immune system and which bind to a target antigen on the surface of a cell. Antibodies are typically encoded by an immunoglobulin gene or genes, or fragments thereof. In normal physiology, antibodies are used by the immune system to fight pathogens. Each antibody is specific to one or a few proteins, and those that bind to cancer antigens are used, for example, to treat cancer. Antibodies are able to specifically bind an antigen or epitope. (Fundamental Immunology, 3rd Edition, W.e., Paul, ed., Raven Press, NY (1993). Specific binding occurs to the corresponding antigen or epitope, even in the presence of a heterogeneous population of proteins and other biological products. Specific binding of an antibody indicates that it binds to its target antigen or epitope with an affinity that is substantially greater than binding to irrelevant antigens. The relative difference in affinity is generally at least 25% greater, more often at least 50% greater. , most often at least 100% greater.The relative difference can be at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or at least 1000 times, for example.

[0056] Exemplary types of antibodies include, without limitation, human, humanized, chimeric, monoclonal, polyclonal, single-chain, antibody fragments and diabodies. Once bound to a cancer antigen, antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor from interacting with its ligand or deliver a chemotherapy or radiation payload, which can lead to cell death. Exemplary antibodies for the treatment of cancer include, but are not limited to, Alemtuzumab, Bevacizumab, Bretuximab vedotin, Cetuximab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Ipilimumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, Nivolumab, Pembrolizumab, Avelumab, be and pidilizumab.

Checkpoint blocking antibodies

[0057] The methods described herein comprise, in some embodiments, treating a human subject suffering from a disease or disorder, described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent ). In some embodiments, the immunotherapeutic agent is a compound (e.g., an inhibitor or antibody) that inhibits the immune checkpoint blockade pathway. Immune checkpoint proteins, under normal physiological conditions, maintain self-tolerance (e.g., prevent autoimmunity) and protect tissues from damage when the immune system is responding to, e.g., pathogenic infection. Immune checkpoint proteins can be deregulated by tumors as an important immune resistance mechanism. (Pardoll, Nature Rev. Cancer, 2012, 12, 252-264). Agonists of costimulatory receptors or antagonists of inhibitory signals (e.g., immune checkpoint proteins) provide an amplification of antigen-specific T cell responses. Antibodies that block immune checkpoints do not target tumor cells directly, but typically target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

[0058] Exemplary checkpoint blocking antibodies include, but are not limited to, anti-CTLA-4, anti-PD-1, anti-LAG3 (i.e., antibodies against lymphocyte activation gene 3) and anti-TIM3 (i.e. antibodies against T cell membrane protein 3). Examples of anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. Examples of anti-PD-1 ligands include, but are not limited to, PD-L1 (i.e., B7-H1 and CD274) and PD-L2 (i.e., B7-DC and CD273). Exemplary anti-PD-1 antibodies include, but are not limited to, nivolumab (i.e., MDX-1106, BMS-936558, or ONO-4538)), CT-011, AMP-224, pembrolizumab (trade name Keytruda), and MK -3475. Examples of PD-L1-specific antibodies include, but are not limited to, BMS936559 (i.e., MDX-1105), MEDI4736, and MPDL-3280A. Exemplary checkpoint blocking antibodies also include, but are not limited to, IMP321 and MGA271.

[0059] Regulatory T cells (e.g., CD4+, CD25+ or T-reg) are also involved in policing the distinction between foreign (eg, foreign) antigens and may represent an important mechanism in suppressing the immune response in many types of cancer . T-reg cells can emerge from the thymus (i.e., "natural T-reg") or can differentiate from mature T cells under circumstances of peripheral tolerance induction (i.e., "induced T-reg"). Strategies that minimize the action of T-reg cells, therefore, should facilitate the immunological response to tumors. (Sutmuller, van Duivernvoorde et al., 2001).

[0060] In some embodiments, compounds (compounds described herein, e.g., a FAK inhibitor) and compositions (e.g., compositions comprising a compound, described herein, e.g., a FAK inhibitor) are used with an immunotherapy of cancer (e.g., a checkpoint blocking antibody) to treat an individual (e.g., a human subject), e.g., suffering from a disease or disorder, described herein (e.g., abnormal cell growth, e.g., cancer (e.g. a cancer, described here)).

[0061] The inventive methods of the present invention contemplate single and multiple administrations of a therapeutically effective amount of a compound, as described herein. The compounds, for example a compound as described herein, may be administered at regular intervals depending on the nature, severity and extent of the individual's condition. In some embodiments, a compound described herein is administered in a single dose. In some embodiments, a compound described herein is administered in multiple doses.

Costimulatory antibodies

[0062] The methods described herein comprise, in some embodiments, treating a human subject suffering from a disease or disorder, described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent ). In some embodiments, the immunotherapeutic agent is an inhibitor or costimulatory antibody. In some embodiments, the methods described herein comprise anti-4-1BB, anti-OX40, anti-GITR, anti-CD27 and anti-CD40 depletion or activation, and variants thereof.

Additional Therapeutic Agents/Combined Therapy

[0063] The methods of the present invention can be administered in combination with an additional agent (e.g., therapeutic agent). The additional agent may include, but is not limited to, an antitumor or anticancer agent, for example, an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, of the cell cycle, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones and anti-androgens.

[0064] In some embodiments, the methods and compositions described herein (e.g., a FAK inhibitor in combination with an immunotherapy) are administered in conjunction with an additional therapy (e.g., cancer treatment). In one embodiment, a mixture of one or more compounds or pharmaceutical compositions can be administered with the combination described herein, for example, a FAK inhibitor in combination with an immunotherapy, to an individual in need thereof. In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) may be administered with the combination described herein, e.g., a FAK inhibitor in combination with an immunotherapy, for the treatment or prevention of various diseases, including , for example, cancer, diabetes, neurodegenerative diseases, cardiovascular diseases, blood clotting, inflammation, flushing, obesity, aging, stress, etc. In various embodiments, combination therapies comprising a compound or pharmaceutical composition described herein may refer to (1) pharmaceutical compositions comprising one or more compounds in combination with the combination described herein, e.g., an inhibitor of FAK in combination with an immunotherapy; and (2) co-administration of one or more compounds or pharmaceutical compositions described herein with the combination described herein, e.g., a FAK inhibitor in combination with an immunotherapy, wherein the compound or pharmaceutical composition described herein does not was formulated in the same compositions. In some embodiments, the combinations described herein (e.g., a FAK inhibitor in combination with an immunotherapy) are administered with an additional treatment (e.g., an additional cancer treatment). In some embodiments, the additional treatment (e.g., an additional cancer treatment) may be administered simultaneously (e.g., at the same time), in the same or separate compositions, or sequentially. Sequential administration refers to administering a treatment before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours, 4, 5, 6, 7, 8, 9 or more days before) administering an additional treatment (e.g., a compound or therapy). The order of administration of the first and second compound or therapy can also be reversed.

[0065] The methods of the invention can be used or administered in combination with one or more additional therapies (e.g., cancer treatment, e.g., surgery, additional drug(s) or therapeutic agents) for the treatment of disorders/diseases mentioned. Additional therapies (e.g., cancer treatment, e.g., drug(s) or therapeutic agents described herein) may be administered in the same formulation or in separate formulations. If administered in separate formulations, the compounds of the invention can be administered sequentially or simultaneously with the other drug(s).

[0066] In addition to being administered in combination with one or more additional therapies (e.g., cancer treatment, e.g., surgery, additional drug(s) or therapeutic agents), the methods of the invention can be administered simultaneously (as a combined preparation) or sequentially to achieve the desired effect. This is especially desirable when the therapeutic profile of each compound is different, so that the combined effect of the two drugs provides an improved therapeutic result.

[0067] Examples of cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, immunotherapy and hormonal therapy. Examples of each of these treatments are provided below.

Chemotherapy

[0068] In some embodiments, the methods of the invention are administered with chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" generally refers to cytotoxic drugs that affect rapidly dividing cells, generally in contrast to targeted therapy. Chemotherapy drugs interfere with cell division in several possible ways, for example, by duplicating DNA or separating newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally do not. they can.

[0069] The methods of the invention can be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons and/or biological response modifiers. In this regard, the following is a non-limiting list of examples of additional agents, e.g., additional therapeutic agents, that can be used with the methods of the invention. • Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280 , apaziquone, brostalicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinated alkylating compounds include, but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satrplatin; • Antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocphosphate, enocitabine , S-1, gemcitabine, fludarabine, 5-azacytidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethinylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, Nelarabine, nolatrexed, ocphosphate, premetrexed disodium, pentostatin, pelitrexol, raltitrexed , triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or, for example, one of the preferred antimetabolites disclosed in European patent application No. 239362, such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N - methylamino]-2-thenoyl)-L-glutamic; • Antibiotics include, but are not limited to: aclarubicin, actinomycin D, amrubicin, anamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebecamycin, estelamer, streptozocin , valrubicin or zinostatin; • Hormone therapy agents, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, antiestrogens, such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara ), or antiestrogenics, such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3'- (trifluoromethyl)propionanilide) and their combinations ; • Plant-derived antitumor substances include, for example, those selected from mitotic inhibitors, e.g., vinblastine, docetaxel (Taxotere), and paclitaxel; • Cytotoxic topoisomerase inhibitory agents include one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diphlomotecan, irinotecan HCl (Camptosar), edothecarin, epirubicin (Ellence), etoposide , exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan, and combinations thereof; • Immunologicals include, but are not limited to, interferons and various other immune-boosting agents. Interferons include, but are not limited to, interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, or interferon gamma-n1. Other agents include, but are not limited to, filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, and Provenge; • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses such as the survival, growth, or differentiation of tissue cells to direct them to have antitumor activity. Such agents include, but are not limited to, crestin, lentinan, sizofiran, picibanil or ubenimex; • Other anticancer agents include, but are not limited to, alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, Bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, 1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase , pentostatin, tazarotna, TLK-286, Velcade, Tarceva or Tretinoin; • Other antiangiogenic compounds include, but are not limited to, acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtite, combretastatin A-4, endostatin, halofuginone, rebimastat, removerb, Revlimide, squalamine, ukranine, and Vitaxin; • Platinum-coordinated compounds include, but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin; • Camptothecin derivatives include, but are not limited to, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edothecarin, and topotecan; • Tyrosine kinase inhibitors include, but are not limited to, Iressa or SU5416; • Antibodies include, but are not limited to Herceptin, Erbitux, Avastin or Rituximab; and • Interferons include, but are not limited to, interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a, or interferon gamma-n1.

[0070] Because some drugs work better than alone, two or more drugs are often administered at the same time or sequentially. Often, two or more chemotherapy agents are used as combination chemotherapy. In some embodiments, chemotherapy agents (including combination chemotherapy) may be used in combination with the methods described herein.

Targeted therapy

[0071] In some embodiments, the methods of the invention are administered with a targeted therapy. Direct therapy involves the use of specific agents targeting dysregulated proteins in cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzyme domains in mutated, overexpressed or otherwise critical proteins within the cancer cell. Prominent examples are tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy, in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells. Examples include, but are not limited to, the anti-HER2/neu antibody, trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody, rituximab and tositumomab, typically used in a variety of B cell malignancies. Other exemplary antibodies include, but are not limited to, Ctuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab and Gemtuzumab. Examples of fusion proteins include, but are not limited to, Aflibercept and Denileukin diftitox. Direct therapy may also involve small peptides such as "targeting devices" that can bind to cell surface receptors or the affected extracellular matrix around the tumor. The radionuclides that are linked to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide degrades in the vicinity of the cell. An example of this therapy includes BEXXAR®. In some embodiments, targeted therapy can be used in combination with the methods of the invention.

Anti-inflammatory agents

[0072] The methods of the invention can be administered with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory agents (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), Enolic acid derivatives (Oxicam) (Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam), Fenamic acid derivatives ( Fenamates) (Mefenamic acid, Chlorfenamic acid, Flufenamic acid, Tolfenamic acid), selective COX-2 inhibitors (Coxibs) (Celecoxib), sulfonanilides (Nimesulide, Steroids (e.g., hydrocortisone (Cortisol), cortisone acetate, prednisone,). prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone).

Analgesic agents

[0073] The methods of the invention can be administered with analgesic agents. Analgesics include, but are not limited to, opiates (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetal and nonsteroidal anti-inflammatory agents (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), Enolic acid derivatives (Oxicam) (Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam), Fenamic acid derivatives (Fenamates) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (Coxibs) (Celecoxib) , sulfonanilides (Nimesulide).

Antiemetic agents

[0074] The methods of the invention can be administered with an antiemetic agent. Antiemetic agents include, but are not limited to, 5-HT3 receptor antagonists (Dolasetron (Anzemet), Granisetron (Kytril, Sancuso), Ondansetron (Zofran), Tropisetron (Navoban), Palonosetron (Aloxi), Mirtazapine (Remeron)) , Dopamine antagonists (Domperidone, Olanzapine, Droperidol, Haloperidol, Chlorpromazine, Promethazine, Prochlorperazine, Metoclopramide (Reglan), Alizapride, Prochlorperazine (Compazine, Estemzine, Bucastem, Stemethyl, Phenotil), NK1 receptor antagonist (Aprepitant (Emend), Anti -histamines (Cyclizine, Diphenhydramine (Benadryl), Dimenhydrinate (Gravol, Dramamine), Meclozine (Bonina, Antivert), Promethazine (Pentazine, Phenergan, Promacot), Hydroxyzine), benzodiazapines (Lorazepam, Midazolam), Anticholinergics (hyoscine), steroids ( Dexamethasone).

Radiation therapy

[0075] The methods of the invention may be used in combination with directed energy or particle or radioisotope treatments, e.g., radiation therapies, e.g., radiation oncology, for the treatment of proliferative diseases, e.g., cancer, e.g. , cancer associated with cancer stem cells. The methods of the invention can be administered to a subject simultaneously or sequentially along with energy or directed particle, or radioisotope treatments. For example, the methods of the invention can be administered before, during or after directed energy or particle, or radioisotope treatment, or a combination thereof. Directed energy or particle therapy may include total body irradiation, local body irradiation, or spot irradiation. The directed energy or particle may originate from an accelerator, synchrotron, nuclear reaction, vacuum tube, laser, or a radioisotope. Therapy may include external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, systemic radioisotope therapy, or unsealed source radiation therapy. Therapy may comprise ingesting or placing in proximity to a radioisotope, e.g., radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon. External beam radiation may include exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio waves, millimeter wave, microwave, infrared, visible, ultraviolet , X-ray or gamma-ray photons). Radiation can be directed to any part of the individual that requires treatment.

Surgery

[0076] The methods of the invention can be used in combination with surgery, for example, surgical exploration, intervention, biopsy, for the treatment of proliferative disease, for example, cancer, for example, cancer associated with cancer stem cells. The methods of the invention can be administered to a subject simultaneously or sequentially in conjunction with surgery. For example, the methods of the invention can be administered before (pre-operative), during or after (post-operative) surgery, or a combination thereof. The surgery may be a biopsy during which one or more cells are collected for further analysis. The biopsy can be performed, for example, with a scalpel, a needle, a catheter, an endoscope, a spatula or scissors. The biopsy may be an excisional biopsy, an incisional biopsy, a core biopsy or a needle biopsy, for example a needle aspiration biopsy. Surgery may involve removing localized tissue suspected of being or identified as cancerous. For example, the procedure may involve removing a cancerous lesion, nodule, polyp, or wart. The procedure may involve removing large amounts of tissue, such as breast, bone, skin, fat, or muscle. The procedure may involve removing part or all of an organ or node, for example, lung, throat, tongue, bladder, cervix, ovary, testicle, lymph nodes, liver, pancreas, brain, eye, kidney, gallbladder bile, stomach, colon, rectum or intestine. In one embodiment, the cancer is breast cancer, for example, triple negative breast cancer, and the surgery is a mastectomy or lumpectomy.

First-line therapy

[0077] The present invention describes a method of treating a human subject with cancer, wherein the subject has failed (e.g., relapsed from, insensitive to, received no or little benefit) first-line treatment (e.g., first-line therapy line for cancer). The present invention also describes a method of treating a human subject with cancer, wherein the methods of the invention are administered with an additional agent. In some embodiments, the additional agent is a first-line therapy for cancer.

[0078] First-line therapy is typically the first treatment given for a disease (e.g., cancer, as described herein). It is often part of a standard set of treatments, such as surgery followed by chemotherapy and radiation. When used alone, first-line therapy is generally accepted as the best treatment. If it does not cure the disease or causes serious side effects, other treatment(s) may be added or used instead. First-line therapy is also called induction therapy, primary therapy, and primary treatment.

[0079] For example, first-line therapy, for example, for Hodgkin's lymphoma may include: Adcetris (Vedotina Brentuximab), Adriamycin PFS (Doxorubicin Hydrochloride), Adriamycin RDF (Doxorubicin Hydrochloride), Amboclorin (Chlorambucil), Ambochlorin (Chlorambucil),Blenoxan (Bleomycin), Bleomycin, Brentuximab Vedotin, Chlorambucil, Clafen (Cyclophosphamide),Cyclophosphamide, Cytoxan (Cyclophosphamide), Dacarbazine, Doxorubicin Hydrochloride, DTIC-Dome (Dacarbazine), Leukeran (Chlorambucil), Lympholizine ( Chlorambucil) .

[0080] In some embodiments, first-line therapy, for example, for Hodgkin's lymphoma comprises the administration of a combination of therapeutic agents, for example, therapeutic agents, as described herein. For example, the combination may include Doxorubicin Hydrochloride (Adriamycin), Bleomycin, Vinblastine Sulfate, and Dacarbazine (i.e., ABVD). As another example, the combination may include Doxorubicin Hydrochloride (Adriamycin), Bleomycin, Vinblastine Sulfate, and Etoposide (i.e., ABVE). In some embodiments, the combination comprises Doxorubicin Hydrochloride (Adriamycin), Bleomycin, Vinblastine Sulfate, Etoposide, Prednisone and Cyclophosphamide (i.e., ABVE-PC). In some embodiments, the combination comprises Vincristine Sulfate, Doxorubicin Hydrochloride (Adriamycin), Methotrexate and Prednisone (i.e., VAMP).

[0081] Approved therapeutic agents and combinations for different types of cancer can be found on the National Cancer Institute at the National Institutes of Health Cancer website at http://www.cancer.gov/cancertopics/druginfo/drug-page-index Therapy second line

[0082] The present invention describes a method of treating a human subject with cancer, in which the subject has failed (e.g., relapsed from a second-line treatment that was insensitive to, did not receive, or benefited little from) (e.g., second-line therapy line for cancer). The present invention also describes a method of treating a human subject with cancer, wherein the methods of the invention are administered with an additional agent. In some embodiments, the additional agent is a first- or second-line therapy for cancer. Second-line therapy generally refers to treatment that is given when initial treatment (e.g., first-line therapy) does not achieve a desired result, e.g., does not work, is not effective; stops working. Second-line therapy is typically considered or administered when an individual does not respond to or develops resistance to initial treatment (e.g., first-line therapy). For example, second-line therapy is typically considered or administered to an individual with recurrent or refractory disease.

Administration and dosage

[0083] The methods of this invention comprise the administration of compounds described herein (for example, a composition comprising a compound described herein). The compounds described herein can be administered orally, parenterally, topically, rectally or via an implanted reservoir, preferably by oral administration or administration by injection. In some cases, the compound is administered as a composition comprising a compound described herein. In some embodiments, the pH of the composition (e.g., pharmaceutical composition) can be adjusted with pharmaceutically acceptable acids, bases, or buffers to increase the stability or effectiveness of the composition.

[0084] In some embodiments, a composition is administered to the individual comprising a compound, as described herein, for example, a FAK inhibitor (e.g., a FAK inhibitor, as described herein) orally.

[0085] In some embodiments, a composition is administered to the individual comprising an immunotherapy (an immunotherapy, as described herein), parenterally (e.g., intravenously).

Oral administration

[0086] The methods described herein comprise administering a composition to an individual (e.g., pharmaceutical composition) comprising a FAK inhibitor and a composition comprising an immunotherapeutic agent. In some embodiments, the composition is administered to the individual comprising a FAK inhibitor orally. In some embodiments, the composition (e.g., pharmaceutical composition) is administered orally in any orally acceptable dosage form including, but not limited to, tablets or capsules, liquid gels, syrups, emulsions, and aqueous suspensions. Liquid gels may include gelatins, plasticizers and/or opacifiers as necessary to obtain a suitable consistency and may be coated with enteric coatings that are approved for use, e.g., shellac. Additional thickening agents, e.g., gums, e.g., xanthine gum, starches, e.g., corn starch or gluten, may be added to obtain a desired consistency of the composition (e.g., pharmaceutical composition) when used as a dosage. oral. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. In some embodiments, the subject is administered the composition comprising a FAK inhibitor orally.

[0087] In some embodiments, the composition is administered to the individual (e.g., pharmaceutical composition) in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained-release formulations, solution and suspension. The composition (e.g., pharmaceutical composition) may be in unit dosage forms suitable for single administration of precise dosages. Pharmaceutical compositions may comprise, in addition to a compound as described herein (e.g., a FAK inhibitor (e.g., VS-6063 or a pharmaceutically acceptable salt thereof); a pharmaceutically acceptable carrier and may optionally further comprise one or more pharmaceutically acceptable excipients, such as, for example, stabilizers, diluents, binders and lubricants. Additionally, the tablet may include other medicinal or pharmaceutical agents, carriers and/or adjuvants. directly), for example, comprising a FAK inhibitor (e.g., VS-6063 or a pharmaceutically acceptable salt thereof).

[0088] Tablets comprising the active or therapeutic ingredient (e.g., compound as described herein) are also provided (e.g., a FAK inhibitor (e.g., VS-6063 or a pharmaceutically acceptable salt thereof). In addition to the active ingredients or therapeutic, tablets may contain a number of inert materials, such as carriers. Pharmaceutically acceptable carriers may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, sesame oil and the like. Saline solutions and aqueous dextrose may also be used as liquid carriers. Oral dosage forms for use in accordance with the present invention may thus be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries. , which facilitate the processing of active ingredients into preparations that can be used pharmaceutically.

[0089] Excipients can impart good powder flow and compression characteristics to the material being compacted. Examples of excipients are described, for example, in the Handbook of Pharmaceutical Excipients (5th edition), Edited by Raymond C Rowe, Paul J. Sheskey and Sian C. Owen; Publisher: Pharmaceutical Press.

[0090] For oral administration, the active ingredients, e.g., the compound as described herein (e.g., a FAK inhibitor (e.g., VS-6063 or a pharmaceutically acceptable salt thereof), can be readily formulated by combining of the active ingredients with pharmaceutically acceptable carriers well known in the art. Such carriers allow the active ingredients of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, pastes, powders or granules, suspensions or solutions in water or non-water media. aqueous preparations, and the like, for oral ingestion by an individual. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture and processing the mixture into granules, after adding suitable auxiliaries, if desired. , to obtain, for example, tablets. Suitable excipients such as diluents, binders or disintegrants may be desirable.

[0091] The dosage may vary according to the dosage form used and the route of administration used. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, for example, Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics"). Lower or higher doses than those mentioned above may be required. The specific dosage and treatment regimens for any particular individual will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms and the judgment of the physician. A course of therapy may comprise one or more separate administrations of a compound as described herein (e.g., a FAK inhibitor, an immunotherapy). A course of therapy may comprise one or more cycles of a compound as described herein (e.g., a FAK inhibitor, an immunotherapy).

[0092] In some embodiments, a cycle, as used herein, in the context of a drug administration cycle, refers to a period of time for which a drug is administered to a patient. For example, if a drug is administered during a 21-day cycle, periodic administration, e.g., daily or twice a day, is administered for 21 days. A medication may be administered for more than one cycle. Rest periods can be interposed between cycles. A rest cycle can be 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 1, 2, 3, 4, 5, 6, 7 days or 1, 2, 3, 4 or more weeks in length.

[0093] The oral dosage forms may, if desired, be presented in a packaging device or dispenser, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The packaging may, for example, include metal or plastic foil, such as a blister pack. The packaging device or dispenser may be accompanied by administration instructions. The packaging or dispenser may also be accompanied by a notice associated with the container in accordance with a form prescribed by a governmental agency that regulates the manufacture, use or sale of pharmaceutical products, which notation reflects the agency's approval of the form of the compositions or human or veterinary administration. This notification, for example, may be from US Food and Drug Administration-approved labeling for prescription drugs or from an approved product registration.

Parenteral formulations

[0094] The methods described herein comprise administering to an individual a composition (e.g., pharmaceutical composition) comprising a FAK inhibitor and a composition comprising an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is administered parenterally (e.g., intravenously). In some embodiments, an immunotherapy described herein is formulated with a pharmaceutical excipient suitable for parenteral administration. Exemplary forms of parenteral administration include intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion.

[0095] Forms in which an immunotherapy (e.g., an immunotherapy, described herein) can be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution and similar pharmaceutical carriers.

[0096] Aqueous solutions in saline can also be used for injection. Exemplary excipients include ethanol, glycerol, propylene glycol, liquid polyethylene glycol, cyclodextrin derivatives and vegetable oils.

[0097] Sterile injectable solutions can be prepared by incorporating an immunotherapy (e.g., an immunotherapy, described herein) in the required amount in the appropriate solvent with one or more excipients, followed by filtered sterilization. Dispersions can be prepared by incorporating a sterile halofuginone or a pharmaceutically acceptable salt thereof into a sterile vehicle. An injectable formulation can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. Injectable compositions may contain from about 0.1 to about 5% w/w of a compound as described herein.

[0098] This description is not limited in its application to the details of the compositions, for example, combinations of compounds, or the specific order of preparation or administration of the compounds. The compounds, e.g., combinations of compounds, described herein, may suitably be prepared using other techniques and/or administered in various ways. Furthermore, the phraseology and terminology used herein are for descriptive purposes and should not be considered limiting.

Definitions

[0099] As used herein, the articles "a" and "an" refer to one or more than one (e.g., at least one) of the grammatical object of the article.

[00100] "About" and "approximately" generally mean an acceptable degree of error for the quantity measured with the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

[00101] As used herein, an amount of a compound effective to treat a disease or disorder, described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)), "effective amount " or "effective course" refers to an amount of the compound that is effective, after single or multiple dose administration or administration to an individual, in treating an individual or in curing, alleviating, alleviating or ameliorating an individual with a disease or disorder, described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)) beyond that expected in the absence of such treatment (e.g., placebo treatment).

[00102] The term "pharmaceutically acceptable", as used herein, refers to a compound or carrier (e.g., excipient) that can be administered to an individual, together with a compound, described herein, and that does not destroy its pharmacological activity and is non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[00103] The term "pharmaceutically acceptable salts", as used herein, refers to derivatives of a compound, described herein, in which the compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines; alkaline or organic salts of acid residues, such as carboxylic acids; It's similar. Pharmaceutically acceptable salts of the disclosure include, but are not limited to, conventional non-toxic salts of a compound described herein formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the disclosure can be synthesized from a compound described herein that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th 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.

[00104] The term "oral dosage form", as used herein, refers to a composition or medium used to administer an agent, e.g., a therapeutic agent, e.g., a compound, as described herein, to an individual . Typically, an oral dosage form is administered through the mouth, however, "oral dosage form" is intended to cover any substance that is administered to an individual and is absorbed through a membrane, e.g., a mucous membrane. of the gastrointestinal tract, including, for example, the mouth, esophagus, stomach, small intestine, large intestine and colon. For example, "oral dosage form" covers a solution that is administered through a feeding tube into the stomach.

[00105] The term "treat" or "treatment", as used herein, refers to the application or administration of a compound, alone or in combination with an additional agent, to an individual, for example, an individual who has a disease or disorder, described herein (e.g., an abnormal cell growth, e.g., cancer (e.g., a cancer, described herein) or suffers from a disease or disorder, described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein), a symptom of a disease or disorder, described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)), or a predisposition to a disease or disorder, described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)), for the purpose of curing, healing, alleviating, alleviating, altering, remedying, improving, progressing or affect the disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancer, as described herein)).

[00106] As used herein, "administered in combination", "co-administration", "co-administer" means that two or more agents are administered to an individual at the same time or within an interval, such that there is a overlapping of an effect of each agent on the individual. Preferably, the administrations of the agents are spaced sufficiently closely together so that a combinatorial effect is achieved. The interval can be a range of minutes, hours, days, or weeks. Generally, the agents are simultaneously bioavailable, e.g., detectable, in the individual. The first, second and third agents can be administered in any order, or as one or more preparations that include two more of the agents. In a preferred embodiment, at least one administration of one of the agents, e.g., the first agent, is made within minutes, one, two, three or four hours, or even within one or two days of the other agent, e.g. second agent or third agent. In some cases, combinations can obtain synergistic results, that is, greater than additive results, for example, at least 20, 50, 70 or 100% greater than additives.

[00107] The course of therapy, as referred to herein, comprises one or more separate administrations of a therapeutic agent. A course of therapy may comprise one or more cycles of a therapeutic agent.

[00108] A cycle, as used herein in the context of a drug administration cycle, refers to a period of time for which a drug is administered to a patient. For example, if a drug is administered during a 21-day cycle, periodic administration, e.g., daily or twice a day, is administered for 21 days. A medication may be administered for more than one cycle. In some embodiments, a first and second or subsequent cycle are the same in terms of either or both duration and periodic administration. In embodiments, a first and second or subsequent cycle differ in terms of one or both phases and periodic administration. Rest periods can be interposed between cycles. A rest cycle can be 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 1, 2, 3, 4, 5, 6, 7 days or 1, 2, 3, 4 or more weeks in length.

[00109] Numerous ranges, for example, ranges for the amount of a drug administered per day, are provided here. In some embodiments, the strip includes both ends. In other embodiments, the strip excludes one or both ends. By way of example, the track may exclude the bottom end. Thus, in such an embodiment, a range of 250 to 400 mg/day, excluding the lower end, would cover an amount greater than 250 which is less than or equal to 400 mg/day.

[00110] As used herein, the term "individual" is intended to include human and non-human animals. In some embodiments, the individual is human. Examples of human subjects include a human subject with a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)) or is suffering from a disease or disorder, described herein. (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer, described herein)). The term "non-human animals" of the invention includes all vertebrates, e.g. non-mammals (such as chickens, amphibians, reptiles) and mammals such as non-human primates, useful domestic and/or agricultural animals, e.g. sheep, dog, cat, cow, pig, etc.

BRIEF DESCRIPTION OF THE DRAWINGS

[00111] FIG. 1 shows an exemplary effect of FAK Inhibitors compared to other Tyrosine Kinase Inhibitors on T cell proliferation.

[00112] FIG. 2 shows an exemplary effect of the FAK Inhibitor VS-4718 alone and in combination with anti-PD-1 on the survival of a colorectal cancer model.

[00113] FIG. 3 shows an exemplary effect of immune checkpoint pathway blockers and correlation with immune response biomarkers.

[00114] FIG. 4 shows an increase in the antitumor efficacy of costimulatory antibodies by FAK inhibitors.

[00115] FIG. 5 shows an exemplary exemplary effect of FAK inhibitors on CD8 + T cells.

[00116] FIG. 6 shows the exemplary effect of FAK inhibitors on markers of T cell exhaustion.

EXAMPLES

[00117] The disclosure is further described in the following examples, which do not limit the scope of the claims.

Example 1. FAK/PYK2 Inhibition Improves the Efficacy of Immune Checkpoint Inhibition

[00118] The small molecule FAK/PYK2 inhibitor VS-6063 is shown to inhibit monocyte-derived macrophages, decrease IL-6 and IL-8 production from macrophages in vitro, and reduce tumor-associated macrophages in tumor models. xenograft. Furthermore, in contrast to other protein kinase inhibitors, such as the SRC inhibitor dasatinib and the MEK inhibitor trametinib, which potentially impair CD8+ cytotoxic T cell proliferation, VS-4718 and VS-6063 stimulate T cell proliferation. cytotoxic CD8+ (FIG. 1). Primary human CD8+ T cells isolated from healthy donor PBMCs were incubated in the presence of anti-CD3/anti-CD28 coated beads with increasing concentrations of VS-4718 or VS-6063 for 72 hours and assayed for BrdU incorporation as a measure. of new DNA synthesis. Both FAK inhibitors dose-dependently increased CD8+ T cell proliferation.

[00119] Based on the inhibition of tumor-associated macrophages and the increase in CD8+ T cells, the potentiation of FAK/PYK2 inhibitors on the antitumor efficacy of an anti-PD-1 monoclonal antibody in syngeneic mouse tumor models was investigated. Mice harboring established syngeneic MC38 colorectal tumors were treated with VS-4718 for 5 days before combined treatment with anti-PD1 antibody along with continued VS-4718 administration. The combination of VS-4718 with anti-PD1 prolonged median overall survival to 42 days compared to median overall survival of 21, 25, and 28 days with vehicle control, anti-PD-1 agent, and single-agent VS-4718, respectively. (FIG. 2). Furthermore, at day 56, 30% of mice treated with the VS-4718/anti-PD-1 combination were still surviving compared to no surviving mice in the vehicle, single-agent VS-4718, and single-agent anti-PD-1 groups. .

[00120] FAK kinase inhibitor or FAK genetic ablation induced complete tumor regression in a squamous cell carcinoma model through an immunological mechanism, suggested by an increase in CD8+ and CD4+ T cells and a decrease in T-regs .

[00121] The general pattern of immune cell changes in response to FAK inhibitors has emerged across syngeneic models of skin, pancreatic, lung and breast cancers. Increased cytotoxic T cells were observed in the tumor (e.g., the CD8+ T cell population). A decrease in immune cell populations that suppress the antitumor immune response (e.g., T-regs, M2 tumor-associated macrophages, MDSCs) was also observed. A pattern of increased PDL1 tumor cells and an increase in PD-1 and cytotoxic T cells was also observed. Data suggest synergy between FAK inhibitors and immune checkpoint antibodies (anti-PD-1 anti-CTLA-4) in several tumor models.

Example 2. Efficacy of FAK Inhibitors with Anti-PD-1 and Correlation with Biomarkers

[00122] Mice with syngeneic MC38 tumors were randomized when tumors reached 50-100mm3 and treated with either vehicle, VS-4718 (75 mg/kg, BID, p.o. until the end of the experiment), anti-PD1 (clone RMP1 -14, 10 mg/kg ip on days 1, 4, 8, 11) or VS-4718 + anti-PD1. The average tumor volume over the elapsed days is shown in FIG. 3A. The combination of VS-4718 and anti-PD1 improved antitumor efficacy in syngeneic MC38 colorectal pigment mice.

[00123] MC38 syngeneic tumors were randomized when tumors reached 50-100mm3 and then treated with any vehicle, VS-4718 (50 mg/kg, BID), anti-PD1 (clone RMP1-14, 5 mg/kg on days 1, 4, 8, 11) or VS-4718 + anti-PD1 for 12 days, at which time tumors were processed live for flow cytometry (Fig. 3B-D). The combination of VS-4718 and anti-PD1 in MC38 tumors reduced T-regs and increased CD8+ T cells.

[00124] Syngeneic MC38 tumors were randomized when tumors reached 50-100mm3 and then treated with any vehicle, VS-4718 (75 mg/kg, BID, p.o.), anti-4-1BB (clone LOB12.3, 10 mg/kg i.p. on days 1, 4, 8, 11) or VS-4718 + anti-4-1BB. Mean tumor volume is plotted over time in FIG. 4. The combination of VS-4718 and anti-4-1BB improves antitumor efficacy in mice bearing syngeneic MC38 collagen colorectal tumor.

[00125] CD8+ T cells were isolated from fresh, healthy human PBMCs by negative immunomagnetic bead separation. Purified CD8+ T cells were plated on CD3-coated plates in the presence or absence of VS-4718, VS-6063, or GSK2256098 for 72 hours. Assay wells were pulsed with BrdU during the last 3-4 hours of culture and subjected to a BrdU incorporation assay for the determination of actively proliferating cells. The data shown in FIG. 5 are shown as fold exchange versus DMSO control wells.

[00126] CD8+ T cells isolated from healthy fresh human PBMCs by negative immunomagnetic bead separation were plated on anti-CD3 coated plates in the presence of VS-4718 (FIG. 6A) or VS-6063 (FIG. 6B) for 72 hours and then harvested and labeled with anti-LAG3 or anti-PD-1 for flow cytometry analysis.

[00127] FAK inhibitors alter the tumor's immune balance to enhance the effectiveness of various immuno-oncology agents. The combination of FAK inhibitors substantially improves the antitumor efficacy of anti-PD-1 or anti-4-1BB relative to each immuno-oncology antibody alone. FAK inhibitor + anti-PD-1 combination decreases T-regs and increases CD8+ T cells in MC38 tumors. FAK inhibitors increase CD8+ T cell proliferation, decrease markers of CD8+ T cell exhaustion, and increase T cell-mediated tumor cell killing in vitro.

Claims (17)

1. Use of defactitinib CHARACTERIZED to be in the manufacture of a medicinal product for the treatment of cancer selected from the group consisting of: lung cancer, breast cancer, lymphoid cancer, cancer of the gastrointestinal or genitourinary tract, mesothelioma, neurofibromatosis, kidney cancer, cancer of liver, thyroid cancer, ovarian cancer, schwannoma, meningioma, schwannomatosis, acoustic neuroma, adenoid cystic carcinoma, ependymoma, melanoma, colorectal cancer, pancreatic cancer, and leukemia, in combination with an immunotherapeutic agent selected from the group consisting of a anti-PD-1 ligand, an anti-PD-1 antibody and an anti-PD-L1 antibody. 2. Use, according to claim 1, CHARACTERIZED by the fact that defactitinib is administered orally. 3. Use, according to claim 1, CHARACTERIZED by the fact that the immunotherapeutic agent is administered parenterally. 4. Use, according to claim 3, CHARACTERIZED by the fact that the immunotherapeutic agent is: a) an anti-PD-1 ligand selected from PD-L1 and PD-L2; or b) an anti-PD-1 antibody selected from nivolumab, CT-011; AMP-224; pembrolizumab; pidilizumab and MK-3475; or c) an anti-PD-L1 antibody selected from BMS936559, MEDI4736, MSB0010718C (avelumab) or MPDL-3280A. 5. Use, according to claim 4, CHARACTERIZED by the fact that the anti-PD-1 ligand is B7-HI or CD274. 6. Use, according to claim 4, CHARACTERIZED by the fact that the PD-L2 ligand is B7-DC or CD273. 7. Use, according to claim 4, CHARACTERIZED by the fact that the anti-PD-1 antibody is nivolumab or pembrolizumab. 8. Use, according to claim 4, CHARACTERIZED by the fact that the anti-PD-1 antibody is avelumab. 9. Use, according to claim 1, CHARACTERIZED by further comprising: a) an additional chemotherapeutic agent or radiation therapy; or b) a cytotoxic agent. 10. Use, according to claim 9, CHARACTERIZED by the fact that the additional therapeutic agent is selected from: alkylating agents, anti-metabolites, antibiotics, hormonal therapy agents, antitumor substances derived from plants, cytotoxic topoisomerase inhibitory agents, immunological agents, biological response modifiers, other anticancer agents, other anti-angiogenic compounds, platinum-coordinated compounds, tyrosine kinase inhibitors, antibodies and interferons. 11. Use, according to claim 6, CHARACTERIZED by the fact that the cytotoxic agent is gemcitabine or paclitaxel. 12. Use, according to claim 11, CHARACTERIZED by the fact that paclitaxel is nab-paclitaxel. 13. Use, according to claim 1, CHARACTERIZED by the fact that the individual has been previously treated with a chemotherapeutic agent or radiation therapy. 14. Use, according to claim 1, CHARACTERIZED by the fact that the individual: a) failed conventional or standard cancer treatment; or b) failed first-line treatment as first-line therapy for cancer. 15. Use, according to claim 14, CHARACTERIZED by the fact that the individual has relapsed from, is insensitive to, and has received no or little benefit from, conventional or standard cancer treatment. 16. Use, according to claim 14, CHARACTERIZED by the fact that the standard or conventional cancer treatment is surgery or first-line therapy for cancer. 17. Use, according to claim 1, CHARACTERIZED by the fact that the individual is: a) identified to have high PD-L1 or PD-L2 in tumor cells; or b) identified to have low PD-L1 or PD-L2 on tumor cells; or c) identified to express genes (IFN-γ) induced by gamma interferon.