Methods for treating mesonephric cancers using RAF / MEK inhibitor-FAK inhibitor combination therapy

Abstract

The present disclosure provides methods for treating mesonephric cancers in a subject in need thereof comprising administering a RAF / MEK inhibitor in combination with a FAK inhibitor.

Description

Atty. Dkt. No.: 115872-3447METHODS FOR TREATING MESONEPHRIC CANCERS USING RAF / MEK INHIBITOR-FAK INHIBITOR COMBINATION THERAPY CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 762,561, filed February 24, 2025, which are incorporated herein by reference in their entireties.TECHNICAL FIELD

[0002] The present technology relates to methods for treating mesonephric cancers in a subject in need thereof comprising administering a RAF / MEK inhibitor in combination with a FAK inhibitor.GOVERNMENT SUPPORT

[0003] This invention was made with government support under CA008748 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0004] The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or constitute prior art to the present technology.

[0005] Gynecologic mesonephric cancer is a rare cancer that commonly metastasizes and has no standard treatment options. It is now understood that gynecologic mesonephric cancer is best characterized as a group of diseases, mesonephric carcinoma and mesonephric-like carcinoma, unified by similar histologic appearance and nearly ubiquitous association with a MAP Kinase alteration, most commonly KRAS [1], Mesonephric carcinomas are most frequently found involving the uterine cervix. They are not associated with human papillomavirus (HPV) infection and instead arise from mesonephric (Wolffian) duct remnants within the cervical wall [2-4], Mesonephric-like carcinomas arise in the uterine corpus, ovary, para-adnexal soft tissue, or vagina. Unlike cervical mesonephric carcinomas, mesonephric-like carcinomas do not have identifiable Wolffian remnant origins, however they are histologically and molecularly similar to mesonephric cervical cancer [5-8],-1- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447

[0006] Mesonephric / Mesonephric-like cancer (MC) is best grouped as one unique disease given the common histologic and molecular characteristics seen regardless of site of origin, and the ways in which these differ from the more common histology’s of cancer arising from the cervix, uterus, ovary or vagina. MC does not express the estrogen or progesterone receptor by immunohistochemistry, is mismatch repair (MMR) retained, and is not known to be associated with BRCA mutations, making patients poor candidates for pembrolizumab, endocrine agents or PARP inhibitors. Sixty percent of MC present at an advanced (II-IV) stage and the majority develop recurrent disease [9], MC is most commonly treated with surgery and then with palliative chemotherapy or radiation therapy at time of recurrence. In a review of recurrent MC cases by Montagut and colleagues the median time to recurrence following initial diagnosis and treatment was 2.1 years, with 50% of patients dead from their disease within a year of first recurrence

[0010] , Unfortunately, there are currently no clinical trials open within the United States offering novel treatment for MC (www.clinicaltrials.gov).

[0007] Accordingly, there is an urgent need for better treatment options for patients with recurrent MC.SUMMARY OF THE PRESENT TECHNOLOGY

[0008] In one aspect, the present disclosure provides a method for treating mesonephric cancer in a patient in need thereof comprising administering to the patient an effective amount of a RAF / MEK inhibitor and an effective amount of a FAK inhibitor. Examples of suitable RAF / MEK inhibitors include, but are not limited to, avutometinib, binimetinib, dabrafenib, trametinib, cobimetinib, ulixertinib, selumetinib, pimasertib, mirdametinib, refametinib, PD-0325901, TAK733, MEK162, WX-554, RO4987655, GDC-0973, AZD8330, GDC-0623 (RG 7421), CH5126766 (RO5126766), HL-085, SHR7390, TQ-B3234, CS-3006, and FCN-159. In some embodiments, the FAK inhibitor is an ATP-competitive FAK inhibitor or a specific FAK inhibitor. Examples of suitable FAK inhibitors include, but are not limited to, TAE226, PF-573228, VS-4718, IN10018, defactinib, GSK2256098, conteltinib, VS-6062, VS-6063, APG-2449, C4, Yll, Y15, orR2.Additionally or alternatively, in some embodiments of the methods disclosed herein, the mesonephric cancer is mesonephric carcinoma or mesonephric-like carcinoma. In certain-2- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447embodiments, the mesonephric cancer occurs in a tissue or an organ selected from among uterine cervix, ovary, vagina, uterine corpus, or endometrium.

[0009] Additionally or alternatively, in certain embodiments of the methods disclosed herein, the mesonephric cancer comprises a KRAS mutation (e.g., KRAS G12V, KRAS G12A, KRAS G12D, KRAS Q61H, KRAS Q61R, and KRAS G12S).

[0010] In any and all embodiments of the methods disclosed herein, the RAF / MEK inhibitor is sequentially, simultaneously, or separately administered with the FAK inhibitor. In some embodiments, the RAF / MEK inhibitor or the FAK inhibitor is administered orally, intravenously, intramuscularly, intraperitoneally, or subcutaneously.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows the experimental scheme of the phase 2 clinical trial on avutometinib (VS-6766) and defactinib (VS-6063) combination therapy.

[0012] FIG. 2 shows baseline characteristics for Stage I MC patients.

[0013] FIG. 3 shows interim results for alterations in target lesions in Stage I MC patients treated with avutometinib and defactinib.

[0014] FIG. 4 shows a summary of molecular and clinical features in Stage I MC patients treated with avutometinib and defactinib.

[0015] FIG. 5 shows interim results for adverse laboratory events related to treatment in Stage I MC patients.

[0016] FIG. 6 shows interim results for adverse treatment-related events in Stage I MC patients treated with avutometinib and defactinib.DETAILED DESCRIPTION

[0017] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the present methods are described below in various levels of detail in order to provide a substantial understanding of the present technology.

[0018] In practicing the present methods, many conventional techniques in molecular biology, protein biochemistry, cell biology, immunology, microbiology and recombinant DNA are used. See, e.g., Sambrook and Russell eds. (2001) Molecular Cloning: A Laboratory Manual, 3rd edition; the series Ausubel etal. eds. (2007) Current Protocols in -3- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447Molecular Biology, the series Methods in Enzymology (Academic Press, Inc., N. Y.);MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach,' Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual,' Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition; Gait ed. (1984) Oligonucleotide Synthesis,' U.S. Patent No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization,' Anderson (1999) Nucleic Acid Hybridization,' Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); and Herzenberg et al. eds (1996) Weir ’s Handbook of Experimental Immunology. Methods to detect and measure levels of polypeptide gene expression products (i.e., gene translation level) are well-known in the art and include the use of polypeptide detection methods such as antibody detection and quantification techniques. (See also, Strachan & Read, Human Molecular Genetics, Second Edition. (John Wiley and Sons, Inc., NY, 1999)).Definitions

[0019] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs. As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. For example, reference to “a cell” includes a combination of two or more cells, and the like. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, analytical chemistry and nucleic acid chemistry and hybridization described below are those well-known and commonly employed in the art.

[0020] As used herein, the term “about” in reference to a number is generally taken to include numbers that fall within a range of 1%, 5%, or 10% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value).-4- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447

[0021] As used herein, the “administration” of an agent or drug to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including but not limited to, orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), rectally, intrathecally, intratumorally or topically. Administration includes self-administration and the administration by another.

[0022] As used herein, the term “biological sample” means sample material derived from living cells. Biological samples may include tissues, cells, protein or membrane extracts of cells, and biological fluids (e.g., ascites fluid or cerebrospinal fluid (CSF)) isolated from a subject, as well as tissues, cells and fluids present within a subject. Biological samples of the present technology include, but are not limited to, samples taken from breast tissue, renal tissue, the uterine cervix, the endometrium, the head or neck, the gallbladder, parotid tissue, the prostate, the brain, the pituitary gland, kidney tissue, muscle, the esophagus, the stomach, the small intestine, the colon, the liver, the spleen, the pancreas, thyroid tissue, heart tissue, lung tissue, the bladder, adipose tissue, lymph node tissue, the uterus, ovarian tissue, adrenal tissue, testis tissue, the tonsils, thymus, blood, hair, buccal, skin, serum, plasma, CSF, semen, prostate fluid, seminal fluid, urine, feces, sweat, saliva, sputum, mucus, bone marrow, lymph, and tears. Biological samples can also be obtained from biopsies of internal organs or from cancers. Biological samples can be obtained from subjects for diagnosis or research or can be obtained from non-diseased individuals, as controls or for basic research. Samples may be obtained by standard methods including, e.g., venous puncture and surgical biopsy. In certain embodiments, the biological sample is a tissue sample obtained by needle biopsy.

[0023] As used herein, a "control" is an alternative sample used in an experiment for comparison purpose. A control can be "positive" or "negative." For example, where the purpose of the experiment is to determine a correlation of the efficacy of a therapeutic agent for the treatment for a particular type of disease, a positive control (a compound or composition known to exhibit the desired therapeutic effect) and a negative control (a subject or a sample that does not receive the therapy or receives a placebo) are typically employed.

[0024] As used herein, the term “effective amount” refers to a quantity sufficient to achieve a desired therapeutic and / or prophylactic effect, e.g, an amount which results in the prevention of, or a decrease in a disease or condition described herein or one or more signs or -5- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447symptoms associated with a disease or condition described herein. In the context of therapeutic or prophylactic applications, the amount of a composition administered to the subject will vary depending on the composition, the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds. In the methods described herein, the therapeutic compositions may be administered to a subject having one or more signs or symptoms of a disease or condition described herein. As used herein, a "therapeutically effective amount" of a composition refers to composition levels in which the physiological effects of a disease or condition are ameliorated or eliminated. A therapeutically effective amount can be given in one or more administrations.

[0025] As used herein, “expression” includes one or more of the following: transcription of the gene into precursor mRNA; splicing and other processing of the precursor mRNA to produce mature mRNA; mRNA stability; translation of the mature mRNA into protein (including codon usage and tRNA availability); and glycosylation and / or other modifications of the translation product, if required for proper expression and function.

[0026] As used herein, “FAK” encodes a cytoplasmic protein tyrosine kinase which is found concentrated in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents. The encoded protein is a member of the FAK subfamily of protein tyrosine kinases but lacks significant sequence similarity to kinases from other subfamilies. Activation of this gene may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to certain neural peptides or to cell interactions with the extracellular matrix.

[0027] The term “FAK inhibitor” refers to a compound that is capable of interacting with, and inhibiting the enzymatic activity of FAK. As used herein, inhibiting FAK enzymatic activity means reducing the ability of FAK to phosphorylate a substrate peptide or protein. In some embodiments, the FAK inhibitor reduces FAK enzymatic activity by at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In various embodiments, the concentration of FAK inhibitor required to reduce FAK enzymatic activity is less than about 1 pM, less than about 500 nM, less than about 100 nM, or less than -6- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447about 50 nM. In some embodiments, the FAK inhibitor is selective, e.g., the FAK inhibitor reduces the ability of FAK to phosphorylate a substrate peptide or protein at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect, e.g., reduction of the enzymatic activity of a different kinase.

[0028] As used herein, the term “gene” means a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression.

[0029] As used herein, the terms “individual”, “patient”, or “subject” can be an individual organism, a vertebrate, a mammal, or a human. In some embodiments, the individual, patient or subject is a human.

[0030] As used herein, the term “pharmaceutically-acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal compounds, isotonic and absorption delaying compounds, and the like, compatible with pharmaceutical administration. Pharmaceutically-acceptable carriers and their formulations are known to one skilled in the art and are described, for example, in Remington's Pharmaceutical Sciences (20thedition, ed. A. Gennaro, 2000, Lippincott, Williams & Wilkins, Philadelphia, Pa.).

[0031] As used herein, the term “polynucleotide” or “nucleic acid” means any RNA or DNA, which may be unmodified or modified RNA or DNA. Polynucleotides include, without limitation, single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, RNA that is mixture of single-and double-stranded regions, and hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and doublestranded regions. In addition, polynucleotide refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons.

[0032] As used herein, the terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to mean a polymer comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres. Polypeptide-7- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.

[0033] As used herein, “prevention” or “preventing” of a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0034] As used herein, the term “separate” therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes.

[0035] As used herein, the term “sequential” therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case.

[0036] As used herein, the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time.

[0037] As used herein, the term “therapeutic agent” is intended to mean a compound that, when present in an effective amount, produces a desired therapeutic effect on a subject in need thereof.

[0038] “Treating” or “treatment” as used herein covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, z.e., arresting its development; (ii) relieving a disease or disorder, z.e., causing -8- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447regression of the disorder; (iii) slowing progression of the disorder; and / or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. In some embodiments, treatment means that the symptoms associated with the disease are, e.g., alleviated, reduced, cured, or placed in a state of remission.

[0039] It is also to be appreciated that the various modes of treatment or prevention of disorders as described herein are intended to mean “substantial,” which includes total but also less than total treatment, and wherein some biologically or medically relevant result is achieved. The treatment may be a continuous prolonged treatment for a chronic disease or a single, or few time administrations for the treatment of an acute condition.Mesonephric Cancers

[0040] Mesonephric adenocarcinoma (MNAC) is an extremely rare and highly malignant tumor in the female reproductive system. It is considered to originate from the embryonal remnants of mesonephric ducts (also known as Wolffian ducts). During embryonic development, the females have 2 sets of paired primitive reproductive ducts: the para-mesonephric (Mullerian) and the mesonephric (Wolffian) ducts. In the embryologic females, Mullerian ducts become the female reproductive ducts, while the mesonephric ducts degenerate. However, vestiges of mesonephric ducts may persist along the female genital tract in the form of epithelial inclusions which are called mesonephric remnants. The embryological remnants are found pre-dominantly in the para-ovarian region (epoophoron and paroophoron) and deep in the cervical stroma in the lateral walls. Therefore, MNACs in the female genital tract occur most commonly in the cervix and vagina, and less frequently in the upper female genital tract. MNACs was rarely reported to arise in the uterine corpus, but was never reported in the ovary. It was reported that adenocarcinomas of endometrium and ovary shared morphologic, immuonphenotypic, and molecular features with MNAC, but were lack of association with mesonepheric remnants or hyperplasia. Hence, mesonephric-like adenocarcinomas (MLAs) are recently defined as tumors exhibiting the classic morphologic features of mesonephric carcinoma, but occurring outside of the cervix and without convincing mesonephric remnants.FAK Inhibitors

[0041] Focal adhesion kinase (FAK), also known as PTK2, is a non-receptor tyrosine kinase encoded by the PTK2 gene. It plays a critical role in signal transduction mediated by -9- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447both growth factor receptors and integrins. FAK inhibitors can be ATP-competitive FAK inhibitors or specific FAK inhibitors. Specific FAK inhibitors bind to distinct kinase domain sites and do not directly compete with ATP binding are being developed in recent years. Examples of FAK inhibitors, include but are not limited to, TAE226, PF-573228, VS-4718, IN10018, defactinib, GSK2256098, conteltinib, VS-6062, VS-6063, APG-2449, C4, Yll, Y15, orR2.RAF / MEK Inhibitors

[0042] BRAF and KRAS are two key oncogenes in the RAS / RAF / MEK / MAPK signaling pathway. RAF / MEK inhibitors can be selective or non-selective small molecules. Examples of RAF / MEK inhibitors include, but are not limited to, avutometinib, binimetinib, dabrafenib, trametinib, cobimetinib, ulixertinib, selumetinib, pimasertib, mirdametinib, refametinib, PD-0325901, TAK733, MEK162, WX-554, RO4987655, GDC-0973, AZD8330, GDC-0623 (RG 7421), CH5126766 (RO5126766), HL-085, SHR7390, TQ-B3234, CS-3006, and FCN-159.Formulations Including RAF / MEK Inhibitors and / or FAK Inhibitors of the Present Technology

[0043] The pharmaceutical compositions of the present technology can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.Formulations may optionally contain solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, pH modifiers, isotonic agents, thickening or emulsifying agents, stabilizers and preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. In certain embodiments, the compositions disclosed herein are formulated for administration to a mammal, such as a human.

[0044] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing -10- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, cyclodextrins, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0045] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Compositions formulated for parenteral administration may be injected by bolus injection or by timed push, or may be administered by continuous infusion.

[0046] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to-11- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0047] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents such as phosphates or carbonates.

[0048] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0049] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting-12- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.Methods of the Present Technology

[0050] In one aspect, the present disclosure provides a method for treating mesonephric cancer in a patient in need thereof comprising administering to the patient an effective amount of a RAF / MEK inhibitor and an effective amount of a FAK inhibitor. Examples of suitable RAF / MEK inhibitors include, but are not limited to, avutometinib, binimetinib, dabrafenib, trametinib, cobimetinib, ulixertinib, selumetinib, pimasertib, mirdametinib, refametinib, PD-0325901, TAK733, MEK162, WX-554, RO4987655, GDC-0973, AZD8330, GDC-0623 (RG 7421), CH5126766 (RO5126766), HL-085, SHR7390, TQ-B3234, CS-3006, and FCN-159. In some embodiments, the FAK inhibitor is an ATP-competitive FAK inhibitor or a specific FAK inhibitor. Examples of suitable FAK inhibitors include, but are not limited to, TAE226, PF-573228, VS-4718, IN10018, defactinib, GSK2256098, conteltinib, VS-6062, VS-6063, APG-2449, C4, Yll, Y15, orR2.Additionally or alternatively, in some embodiments of the methods disclosed herein, the mesonephric cancer is mesonephric carcinoma or mesonephric-like carcinoma. In certain embodiments, the mesonephric cancer occurs in a tissue or an organ selected from among uterine cervix, ovary, vagina, uterine corpus, or endometrium.

[0051] Additionally or alternatively, in certain embodiments of the methods disclosed herein, the mesonephric cancer comprises a KRAS mutation (e.g., KRAS G12V, KRAS G12A, KRAS G12D, KRAS Q61H, KRAS Q61R, and KRAS G12S).

[0052] Additionally or alternatively, in some embodiments of the combination therapy methods disclosed herein, the time to response and / or duration of response is improved relative to that observed with monotherapy with a RAF / MEK inhibitor or FAK inhibitor.

[0053] Additionally or alternatively, in some embodiments of the methods disclosed herein, the RAF / MEK inhibitor and the FAK inhibitor are administered sequentially, simultaneously, or separately. The RAF / MEK inhibitor and the FAK inhibitor may be-13- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447administered orally, parenterally, by inhalation spray, intranasally, buccally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intravenously, or subcutaneously. Formulations including the RAF / MEK inhibitor and FAK inhibitor disclosed herein may be designed to be short-acting, fast-releasing, or long-acting. In other embodiments, compounds can be administered in a local rather than systemic means, such as administration (e.g., by injection) at a tumor site.

[0054] Additionally or alternatively, in some embodiments of the methods disclosed herein, the RAF / MEK inhibitor can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a FAK inhibitor to a patient with a mesonephric cancer.

[0055] In some embodiments, the RAF / MEK inhibitor and FAK inhibitor are administered to a patient, for example, a mammal, such as a human, in a sequence and within a time interval such that the inhibitor that is administered first acts together with the inhibitor that is administered second to provide greater benefit than if each inhibitor were administered alone. For example, the RAF / MEK inhibitor and the FAK inhibitor can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, the RAF / MEK inhibitor and the FAK inhibitor are administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect of the combination of the at least two inhibitors. In one embodiment, the RAF / MEK inhibitor and the FAK inhibitor exert their effects at times which overlap. In some embodiments, the RAF / MEK inhibitor and the FAK inhibitor are each administered as separate dosage forms, in any appropriate form and by any suitable route. In other embodiments, the RAF / MEK inhibitor and the FAK inhibitor are administered simultaneously in a single dosage form.-14- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447

[0056] It will be appreciated that the frequency with which any of these therapeutic agents can be administered can be once or more than once over a period of about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 20 days, about 28 days, about a week, about 2 weeks, about 3 weeks, about 4 weeks, about a month, about every 2 months, about every 3 months, about every 4 months, about every 5 months, about every 6 months, about every 7 months, about every 8 months, about every 9 months, about every 10 months, about every 11 months, about every year, about every 2 years, about every 3 years, about every 4 years, or about every 5 years.

[0057] For example, the RAF / MEK inhibitor and the FAK inhibitor may be administered daily, weekly, biweekly, or monthly for a particular period of time. The RAF / MEK inhibitor and the FAK inhibitor may be dosed daily over a 14 day time period, or twice daily over a seven day time period. The RAF / MEK inhibitor and the FAK inhibitor may be administered daily for 7 days.

[0058] Alternatively, a RAF / MEK inhibitor or FAK inhibitor may be administered daily, weekly, biweekly, or monthly for a particular period of time followed by a particular period of non-treatment. In some embodiments, a RAF / MEK inhibitor or FAK inhibitor can be administered daily for 14 days followed by seven days of non-treatment, and repeated for two more cycles of daily administration for 14 days followed by seven days of non-treatment. In some embodiments, a RAF / MEK inhibitor or FAK inhibitor can be administered twice daily for seven days followed by 14 days of non-treatment, which may be repeated for one or two more cycles of twice daily administration for seven days followed by 14 days of non-treatment.

[0059] In some embodiments, a RAF / MEK inhibitor or FAK inhibitor is administered daily over a period of 14 days. In another embodiment, a RAF / MEK inhibitor or FAK inhibitor is administered daily over a period of 12 days, or 11 days, or 10 days, or nine days, or eight days. In another embodiment, a RAF / MEK inhibitor or FAK inhibitor is administered daily over a period of seven days. In another embodiment, a RAF / MEK inhibitor or FAK inhibitor is administered daily over a period of six days, or five days, or four days, or three days.-15- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447

[0060] In some embodiments, individual doses of a RAF / MEK inhibitor or FAK inhibitor are administered within a time interval such that the two inhibitors can work together (e.g., within 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 5 days, 6 days, 1 week, or 2 weeks). In some embodiments, the treatment period during which the therapeutic agents are administered is then followed by a non-treatment period of a particular time duration, during which the therapeutic agents are not administered to the patient. This non-treatment period can then be followed by a series of subsequent treatment and non-treatment periods of the same or different frequencies for the same or different lengths of time. In some embodiments, the treatment and non-treatment periods are alternated. It will be understood that the period of treatment in cycling therapy may continue until the patient has achieved a complete response or a partial response, at which point the treatment may be stopped. Alternatively, the period of treatment in cycling therapy may continue until the patient has achieved a complete response or a partial response, at which point the period of treatment may continue for a particular number of cycles. In some embodiments, the length of the period of treatment may be a particular number of cycles, regardless of patient response. In some other embodiments, the length of the period of treatment may continue until the patient relapses.

[0061] In some embodiments, the RAF / MEK inhibitor and FAK inhibitor are cyclically administered to a patient. Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second agent and / or third agent (e.g., a second and / or third prophylactic or therapeutic agent) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the efficacy of the treatment.

[0062] In some embodiments, the RAF / MEK inhibitor is administered for a particular length of time prior to administration of the FAK inhibitor. For example, in a 21 -day cycle, RAF / MEK inhibitor may be administered on days 1 to 5, days 1 to 7, days 1 to 10, or days 1 to 14, and the FAK inhibitor may be administered on days 6 to 21, days 8 to 21, days 11 to 21, or days 15 to 21. In other embodiments, the FAK inhibitor is administered for a particular length of time prior to administration of the RAF / MEK inhibitor. For example, in a 21 -day cycle, the FAK inhibitor may be administered on days 1 to 5, days 1 to 7, days 1 to-16- 4931-7791-1839.1Atty. Dkt. No.: 115872-344710, or days 1 to 14, and the RAF / MEK inhibitor may be administered on days 6 to 21, days 8 to 21, days 11 to 21, or days 15 to 21.

[0063] In one embodiment, the administration is on a 21 -day dose schedule in which a once daily dose of the RAF / MEK inhibitor is administered beginning on day eight for seven days, followed by seven days of non-treatment, in combination with twice-daily administration of the FAK inhibitor for seven days followed by 14 days of non-treatment (e.g., RAF / MEK inhibitor is administered on days 8-14 and the FAK inhibitor is administered on days 1-7 of the 21 -day schedule). In another embodiment, the administration is on a 21-day dose schedule in which a once daily dose of FAK inhibitor is administered beginning on day eight for seven days, followed by seven days of non-treatment, in combination with twice-daily administration of RAF / MEK inhibitor for seven days followed by 14 days of non-treatment (e.g., the FAK inhibitor is administered on days 8-14 and RAF / MEK inhibitor is administered on days 1-7 of the 21 -day schedule).

[0064] In some embodiments, a RAF / MEK inhibitor in combination with a FAK inhibitor are each administered at a dose and schedule typically used for that agent during monotherapy. In other embodiments, a RAF / MEK inhibitor and a FAK inhibitor are administered concomitantly, one or both of the agents can advantageously be administered at a lower dose than typically administered when the agent is used during monotherapy, such that the dose falls below the threshold that an adverse side effect is elicited.

[0065] The therapeutically effective amounts or suitable dosages of the RAF / MEK inhibitor, and the FAK inhibitor in combination depends upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual patient. In certain embodiments, the suitable dose level is one that achieves a therapeutic response as measured by tumor regression or other standard measures of disease progression, progression free survival, or overall survival. In other embodiments, the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.

[0066] Suitable daily dosages of RAF / MEK inhibitors can generally range, in single or divided or multiple doses, from about 10% to about 120% of the maximum tolerated dose as a single agent. In certain embodiments, the suitable dosages of RAF / MEK inhibitors are-17- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447from about 20% to about 100% of the maximum tolerated dose as a single agent. In other embodiments, the suitable dosages of RAF / MEK inhibitors are from about 25% to about 90% of the maximum tolerated dose as a single agent. In some embodiments, the suitable dosages of RAF / MEK inhibitors are from about 30% to about 80% of the maximum tolerated dose as a single agent. In other embodiments, the suitable dosages of RAF / MEK inhibitors are from about 40% to about 75% of the maximum tolerated dose as a single agent. In some embodiments, the suitable dosages of RAF / MEK inhibitors are from about 45% to about 60% of the maximum tolerated dose as a single agent. In other embodiments, suitable dosages of RAF / MEK inhibitors are about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, or about 120% of the maximum tolerated dose as a single agent.

[0067] Suitable daily dosages of FAK inhibitors can generally range, in single or divided or multiple doses, from about 10% to about 120% of the maximum tolerated dose as a single agent. In certain embodiments, the suitable dosages of FAK inhibitors are from about 20% to about 100% of the maximum tolerated dose as a single agent. In other embodiments, the suitable dosages of FAK inhibitors are from about 25% to about 90% of the maximum tolerated dose as a single agent. In some embodiments, the suitable dosages of FAK inhibitors are from about 30% to about 80% of the maximum tolerated dose as a single agent. In other embodiments, the suitable dosages of FAK inhibitors are from about 40% to about 75% of the maximum tolerated dose as a single agent. In some embodiments, the suitable dosages of FAK inhibitors are from about 45% to about 60% of the maximum tolerated dose as a single agent. In other embodiments, suitable dosages of FAK inhibitors are about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, or about 120% of the maximum tolerated dose as a single agent.

[0068] Dosage, toxicity and therapeutic efficacy of any therapeutic agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and-18- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indices are advantageous. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[0069] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds may be within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 ( / .< ., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to determine useful doses in humans accurately. Levels in plasma may be measured, for example, by high performance liquid chromatography.

[0070] Typically, an effective amount of a RAF / MEK inhibitor or a FAK inhibitor, sufficient for achieving a therapeutic or prophylactic effect, may range from about 0.000001 mg per kilogram body weight per day to about 10,000 mg per kilogram body weight per day. Suitably, the dosage ranges are from about 0.0001 mg per kilogram body weight per day to about 100 mg per kilogram body weight per day. For example dosages can be 1 mg / kg body weight or 10 mg / kg body weight every day, every two days or every three days or within the range of 1-10 mg / kg every week, every two weeks or every three weeks. In one embodiment, a single dosage of a RAF / MEK inhibitor or a FAK inhibitor ranges from 0.001-10,000 micrograms per kg body weight. In one embodiment, RAF / MEK inhibitor or FAK inhibitor concentrations in a carrier range from 0.2 to 2000 micrograms per delivered milliliter. An exemplary treatment regime entails administration once per day or once a week. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, or until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.-19- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447

[0071] In some embodiments, a therapeutically effective amount of a RAF / MEK inhibitor or a FAK inhibitor may be defined as a concentration of the RAF / MEK inhibitor or FAK inhibitor at the target tissue of 10'12to 10'6molar, e.g., approximately 10'7molar. This concentration may be delivered by systemic doses of 0.001 to 100 mg / kg or equivalent dose by body surface area. The schedule of doses would be optimized to maintain the therapeutic concentration at the target tissue, such as by single daily or weekly administration, but also including continuous administration (e.g., parenteral infusion or transdermal application).

[0072] The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compositions described herein can include a single treatment or a series of treatments.

[0073] The mammal treated in accordance with the present methods can be any mammal, including, for example, farm animals, such as sheep, pigs, cows, and horses; pet animals, such as dogs and cats; laboratory animals, such as rats, mice and rabbits. In some embodiments, the mammal is a human.Kits of the Present Technology

[0074] The present disclosure provides kits for treating mesonephric cancers comprising a RAF / MEK inhibitor, FAK inhibitor, and instructions for treating mesonephric cancers. When simultaneous administration is contemplated, the kit may comprise a RAF / MEK inhibitor, and FAK inhibitor that has been formulated into a single pharmaceutical composition such as a tablet, or as separate pharmaceutical compositions. When the RAF / MEK inhibitors, and FAK inhibitors disclosed herein are not administered simultaneously, the kit may comprise a RAF / MEK inhibitor, and FAK inhibitor that has been formulated as separate pharmaceutical compositions either in a single package, or in separate packages.

[0075] The kits may further comprise pharmaceutically acceptable excipients, diluents, or carriers that are compatible with one or more kit components described herein. Optionally, the above described components of the kits of the present technology are packed in suitable containers and labeled for the treatment of mesonephric cancers. In some embodiments, the -20- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447mesonephric cancer comprises a KRAS mutation (e.g., KRAS G12V, KRAS G12A, KRAS G12D, KRAS Q61H, KRAS Q61R, KRAS G12S). The kits may optionally include instructions customarily included in commercial packages of therapeutic products, that contain information about, for example, the indications, usage, dosage, manufacture, administration, contraindications and / or warnings concerning the use of such therapeutic products.EXAMPLES

[0076] The present technology is further illustrated by the following Examples, which should not be construed as limiting in any way.Example 1: A Phase II Study of Avutometinib and Defactinib in Advanced or Recurrent Gynecologic Mesonephric Cancer

[0077] Objective: Mesonephric carcinoma arises from cervix, while mesonephric-like carcinoma originates in other organs including endometrium, vagina or ovary. These cancers are jointly referred to as gynecologic mesonephric cancer (GMC) and are unified by similar histologic appearance, propensity for lung metastases, and nearly ubiquitous association with RAS / MAPK pathway alterations (-96%), most commonly KRAS. Avutometinib in combination with defactinib showed considerable activity in patients with low grade serous ovarian cancer (LGSOC), with highest response rates seen in those patients with a KRAS mutation (44% response rate).

[0078] Methods'. We designed a phase II single-institution, study of avutometinib (RAF / MEK clamp; taken PO twice weekly) in combination with defactinib (FAK inhibitor; taken PO twice daily), both 3 weeks on / 1 week off, for women with RECIST 1.1 measurable advanced or recurrent GMC (NCT05787561). See FIG. 1.

[0079] Inclusion Criteria:i. Female patients > 18 years of ageii. Histologic confirmation of Mesonephric or Mesonephric-like cancer (MC). Patients with mixed histology are eligible if the disease at time of recurrence is deemed by the treating physician to be driven by the MC component.iii. Measurable disease according to RECIST 1.1-21- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447iv. Patients must have persistent or recurrent disease

[0080] Exclusion Criteria:i. Systemic anti-cancer therapy (other than endocrine therapy) within 4 weeks, 1 cycle, or 5 half-lives (whichever is shortest) of the first dose of study intervention; Endocrine therapy within 1 week of the first dose of study intervention.ii. Major surgery within 4 weeks , minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study intervention.iii. Prior treatment with a MEK or RAF or FAK inhibitor iv. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or drainage PEG tube

[0081] Utilizing Simon 2-stage design, 13 patients were enrolled, with > 1 confirmed response needed for advancement to second stage and accrual of additional 7 patients. If > 3 confirmed responses out of 20 patients are seen, then this will be considered a positive study. Molecular results via CLIA approved NGS sequencing platform were collected.

[0082] Results'. 13 patients were enrolled, with GMC originating from the cervix (N=5), endometrium (N=3), or ovary (N=5). Median age of participants was 66 (53-85). Patients had a median of 3 prior lines of therapy (0-7) and 77% (N=10) received prior radiation. See FIG. 2.

[0083] All 13 patients experienced tumor reduction in response to treatment with avutometinib in combination with defactinib. As of the data-cutoff, there have been 2 confirmed partial responses (PRs) and 2 unconfirmed PRs (FIG. 3). Eight patients discontinued due to progression (7 radiographic, 1 clinical) and 5 patients remain on treatment. Molecular results are available for 11 / 13 patients with 10 / 11 displaying a RAS / MAPK pathway alteration, most commonly KRAS G12V (N=6, 55%) (FIG. 4). Grade 3 adverse events related to treatment occurred in 3 patients (rash[l], diarrheafl], fatigue / edemaf l ]); Grade 3 laboratory toxicity related to treatment occurred in 3 patients (elevated :CPK[2], bilirubin[l], alkaline phosphatasefl]). See FIGs. 5-6. No patients have-22- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447discontinued treatment due to toxicity. No Grade 4 or 5 related adverse events or laboratory toxicity were noted.EQUIVALENTS

[0084] The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the present technology. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0085] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0086] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.-23- 4931-7791-1839.1Atty. Dkt. No.: 115872-3447

[0087] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.REFERENCES1. da Silva, E.M., et al., Mesonephric and mesonephric-like carcinomas of the female genital tract: molecular characterization including cases with mixed histology and matched metastases. Mod Pathol, 2021. 34(8): p. 1570-1587.2. Ferry, J. A. and R.E. Scully, Mesonephric remnants, hyperplasia, and neoplasia in the uterine cervix. A study of 49 cases. Am J Surg Pathol, 1990. 14(12): p. 1100-11.3. Clement, P.B., et al., Malignant mesonephric neoplasms of the uterine cervix. A report of eight cases, including four with a malignant spindle cell component. Am J Surg Pathol, 1995. 19(10): p. 1158-71.4. Mirkovic, J., et al., Targeted genomic profding reveals recurrent KRAS mutations and gain of chromosome Iq in mesonephric carcinomas of the female genital tract. Mod Pathol, 2015. 28(11): p. 1504-14.5. McFarland, M., C.M. Quick, and W.G. McCluggage, Hormone receptor-negative, thyroid transcription factor 1 -positive uterine and ovarian adenocarcinomas: report of a series of mesonephric-like adenocarcinomas. Histopathology, 2016. 68(7): p. 1013-20.6. Kenny, S.L., et al., Mesonephric adenocarcinomas of the uterine cervix and corpus: HPV-negative neoplasms that are commonly PAX8, CA125, andHMGA2 positive and that may be immunoreactive with TTF1 and hepatocyte nuclear factor 1-beta. Am J Surg Pathol, 2012. 36(6): p. 799-807.7. Na, K. and H.S. Kim, Clinicopathologic and Molecular Characteristics of Mesonephric Adenocarcinoma Arising From the Uterine Body. Am J Surg Pathol, 2019. 43(1): p. 12-25.8. Wu, H., et al., Mesonephric adenocarcinoma of the uterine corpus. Int J Clin Exp Pathol, 2014. 7(10): p. 7012-9.-24- 4931-7791-1839.1Atty. Dkt. No.: 115872-34479. Pors, J., et al., Clinicopathologic Characteristics of Mesonephric Adenocarcinomas and Mesonephric-like Adenocarcinomas in the Gynecologic Tract: A Multi-institutional Study. Am J Surg Pathol, 2021. 45(4): p. 498-506.10. Montagut, C., et al., Activity of chemotherapy with carboplatin plus paclitaxel in a recurrent mesonephric adenocarcinoma of the uterine corpus. Gynecol Oncol, 2003. 90(2): p. 458-61.11. Cheng, D.T., et al., Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) : A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. J Mol Diagn, 2015. 17(3): p. 251-64.4931-7791-1839.1

Claims

Atty. Dkt. No.: 115872-3447WHAT IS CLAIMED IS1. A method for treating mesonephric cancer in a patient in need thereof comprising administering to the patient an effective amount of a RAF / MEK inhibitor and an effective amount of a FAK inhibitor.

2. The method of claim 1, wherein the RAF / MEK inhibitor is selected from the group consisting of avutometinib, binimetinib, dabrafenib, trametinib, cobimetinib, ulixertinib, selumetinib, pimasertib, mirdametinib, refametinib, PD-0325901, TAK733, MEK162, WX-554, RO4987655, GDC-0973, AZD8330, GDC-0623 (RG7421), CH5126766 (RO5126766), HL-085, SHR7390, TQ-B3234, CS-3006, andFCN-159.

3. The method of claim 1 or 2, wherein the FAK inhibitor is TAE226, PF-573228, VS-4718, IN10018, defactinib, GSK2256098, conteltinib, VS-6062, VS-6063, APG-2449, C4, Yll, Y15, orR2.

4. The method of any one of claims 1-3, wherein the FAK inhibitor is an ATP-competitive FAK inhibitor or a specific FAK inhibitor.

5. The method of any one of claims 1-4, wherein the mesonephric cancer is mesonephric carcinoma or mesonephric-like carcinoma.

6. The method of claim 5, wherein the mesonephric cancer occurs in a tissue or an organ selected from among uterine cervix, ovary, vagina, uterine corpus, or endometrium.

7. The method of any one of claims 1-5, wherein the mesonephric cancer comprises a KRAS mutation.

8. The method of claim 8, wherein the KRAS mutation is selected from the group consisting of KRAS G12V, KRAS G12A, KRAS G12D, KRAS Q61H, KRAS Q61R, and KRAS G12S.

9. The method of any one of claims 1-8, wherein the RAF / MEK inhibitor is sequentially, simultaneously, or separately administered with the FAK inhibitor.

10. The method of any one of claims 1-9, wherein the RAF / MEK inhibitor or the FAK inhibitor is administered orally, intravenously, intramuscularly, intraperitoneally, or subcutaneously.-26- 4931-7791-1839.1

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