WO2020112627A1 - Combinations of parp inhibitors and mapk activators to treat cancer - Google Patents

Abstract

This application describes compounds, compositions, and combinations thereof that can be used to treat cancer, such as cancers with and without BRCA, BRAF and/or RAS mutations.

Description

COMBINATIONS OF PARP INHIBITORS AND MAPK ACTIVATORS TO TREAT

CANCER

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62/772,445, filed November 28, 2018, which is hereby incorporated by reference in its entirety. This application is also related to U.S. Provisional Application No. 62/541,911, filed August 7, 2017, and U.S. Provisional Application No. 62/608,265, filed December 20, 2017, each of which is hereby incorporated by reference in its entirety. This application is also related to U.S. Provisional Application No. 62/291,931, filed February 5, 2016, U.S. Provisional Application No. 62/344,612, filed June 2, 2016, and U.S. Provisional Application No. 62/424,792, filed November 21, 2016, and International Application No. PCT/US2017/01653, filed February 3, 2017, each of which is hereby incorporated by reference in its entirety.

[0003] FIELD

[0004] The disclosure generally refers to a combination of compounds to treat cancer.

[0005] BACKGROUND

[0006] Resistant tumors continue to be a problem. Thus, there is a need to increase the

effectiveness of compounds to treat drug resistant tumors. The embodiments in tumors described herein fill these needs as well as others.

[0007] SUMMARY

[0008] In some embodiments, methods of treating a metastatic or non-metastatic tumor are provided. In some embodiments, the tumor is a solid tumor. In some embodiments, the method comprises administering to the subject a PARP inhibitor and a MAPK activator, wherein the tumor is a solid tumor. In some embodiments, the tumor has a genotype of BRCAl/2 WT,

BRAF WT, and a mutated RAS.

[0009] In some embodiments, a pharmaceutical composition comprising a PARP inhibitor and a MAPK activator is provided. In some embodiments, a pharmaceutical composition for treating a solid tumor that does not have a BRAF mutation (e.g. V600E or V600K) and/or a BRCA mutation, the composition comprising a PARP inhibitor and a MAPK activator is provided. In some embodiments, the solid tumor has a mutant RAS.

[0010] In some embodiments, uses of a PARP inhibitor and a MAPK activator for treating a solid tumor in a subject, wherein the tumor does not have a BRAF mutation (e.g. V600E or V600K) and/or a BRCA mutation are provided. In some embodiments, the tumor contains a mutant RAS at, for example, G12.

[0011] In some embodiments, the subject that has a solid tumor the tumor is breast cancer, lung cancer, colon cancer, brain cancer, pancreatic cancer, skin cancer, thyroid cancer, stomach cancer, kidney cancer, liver cancer, ovarian cancer, uterine cancer, melanoma, prostate cancer, and the like or the tumor has metastasized from these primary sites to a secondary site.

[0012] BRIEF DESCRIPTION OF FIGURES

[0013] FIG. 1, Panels A, B, and C, illustrate the effects of a combination of a PARP inhibitor and a MAPK activator.

[0014] FIG. 2, Panels A, B, and C, illustrate the effects of a combination of a PARP inhibitor and a MAPK activator.

[0015] FIG. 3, Panels A, B, and C, illustrate the effects of a combination of a PARP inhibitor and a MAPK activator.

[0016] FIG. 4, Panels A, B, and C, illustrate the effects of a combination of a PARP inhibitor and a MAPK activator.

[0017] FIG. 5ig, Panels A, B, and C, illustrate the effects of a combination of a PARP inhibitor and a MAPK activator.

[0017] DETAILED DESCRIPTION

[0018] This application describes combinations of compounds and methods of using the same.

The compounds and combinations can also be prepared as pharmaceutical compositions that can be administered in a unit dosage form or in different dosage forms.

[0019] RAF265 refers to a compound of Formula I, or a pharmaceutically acceptable salt

thereof:

[0020] AD80 refers to a compound of Formula II, or a pharmaceutically acceptable salt thereof:

II.

[0021] GDC0879 refers to a compound of Formula III, or a pharmaceutically acceptable salt thereof:

III.

[0022] Dabrafenib refers to a compound of Formula IV, or a pharmaceutically acceptable salt thereof:

[0023] Reference is made throughout the present specification BRAF inhibitors. Examples include, but are not limited to, RAF265, AD80, GDC0879, or dabrafenib, and pharmaceutically acceptable salts thereof. Other BRAF, CRAF, or pan-RAF inhibitors can also be substituted, such as vemurafenib, encorafenib, lifirafenib, sorafenib,

AZ628, ZM336372, NVPBHG712, LY3009120, TAK632, MLN2480, or XP102.

Thus, for the avoidance of doubt, where RAF265, AD80, GDC0879, dabrafenib, vemurafenib, sorafenib, encorafenib, lifirafenib, AZ628, ZM336372, NVPBHG712, LY3009120, TAK632, MLN2480, or XP102 is referenced, it is disclosed that BRAF inhibitors can be used generally or other specific types of BRAF inhibitors can also be used. This reference also shall be construed to include pharmaceutically acceptable salts of the compounds described herein. In some embodiments a MAPK activator is a BRAF inhibitor. In some embodiments, the compounds are BRAF V600E or V600K inhibitors.

[0024] As used herein, a MAPK activator refers to a compound or therapeutic that activate

MAPK (MAP kinase) pathway. In some embodiments, a MAPK activator is a panRAF inhibitor, a BRAF V600(E/K) inhibitor, a multi-kinase inhibitor, such as, but not limited to, MEK inhibitors that can also inhibit against BRAF and/or CRAF.

[0025] As used herein, a PARP inhibitor is a compound that inhibit PARP (poly ADP ribose polymerase). Examples of PARP inhibitors include, but are not limited to, Olaparib, Rucaparib, Veliparib, Talazoparib, AG-14361, INO-1001, A-966492, Niraparib, PJ34 HC1, AZD2461, E7449, Pamiparib (BGB-290), or any combination thereof. [0026] In some embodiments, a combination of a PARP inhibitor and a MAPK inhibitor is administered to treat a tumor in a subject. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is wt BRCA1. In some embodiments, the tumor is wt BRCA2. In some embodiments, the tumor is wt BRCA1 and wt BRCA2. In some embodiments, the tumor is wt BRAF. In some embodiments, the tumor is mutant BRAF. In some embodiments, the tumor is wt RAS. In some embodiments, the tumor is mutant RAS. In some embodiments, the tumor is mutant RAS G12. In some embodiments, the tumor is wt BRCA1 and/or wt BRCA2, wt BRAF and mutant RAS ( e.g . RAS G12 mutant). In some embodiments, the tumor has a RAS G12C, G12D, G12V, or G13D mutation. In some embodiments, the tumor is free of RAS G12C, G12D, G12V, or G13D mutations.

[0027] In some embodiments, the PARP inhibitor and the MAPK activator are combined

(simultaneously or sequentially) with additional cancer treating therapeutics, such as but not limited to DNA damaging agents. Examples of such DNA damaging agents include, but are not limited to, agents that cause double strand breaks (DSBs), single strand breaks, antimetabolites, DNA crosslinkers, topoisomerase inhibitors, polymerase inhibitors, or alkylating agents. In some embodiments, the DNA damaging agent is a nucleoside analog. In some embodiments, the nucleoside analog is cytosine arabinoside, fludarabine, cladribine, or gemcitabine. In some embodiments, the DNA damaging agent is gemcitabine, cytosine arabinoside, fludarabine, cladribine, 5-FU, cytarabine, methotrexate, pyrimethamine, bleomycin, oxaliplatin, cisplatin, carboplatin, etoposide, doxorubicin, vinorelbine, mitoxantrone, podophyllotoxin, aphidicolin, fotemustine, carmustine, S-23906, S39, SN-38, topotecan, camptothecin, rebeccamycin, and the like. These agents can be combined with PARP inhibitor and/or MAPK activator, or a pharmaceutically acceptable salt thereof, either singularly or in combinations.

[0028] In some embodiments, the MAPK activator is a MEK inhibitor.

[0029] In some embodiments, the compositions or methods are combined with an additional therapeutic. In some embodiments, the additional therapeutic is a microtubule stabilizer. A non-limiting example of a microtubule stabilizer is a taxane. In some embodiments, the taxane is, but not limited to, paclitaxel, docetaxel, cabazitaxel and the like. In some embodiments, taxane is a protein-bound taxane. For example, paclitaxel can be protein- bound paclitaxel, which can also be referred to as a nanoparticle albumin-bound paclitaxel or nab-paclitaxel. One non- limiting example of a protein bound paclitaxel is Abraxane^®. In some embodiment, other taxanes are bound to a protein.

[0030] The compounds, compositions, and combinations thereof can be used in any of the

methods described herein, including, but not limited to, treating cancer or a tumor in a subject, such as melanoma, pancreatic cancer, lung cancer ( e.g . NSCLC or SCLC), colon cancer, ovarian cancer, prostate cancer, or breast cancer. In some embodiments the tumor is a breast cancer, lung cancer, colon, cancer, brain cancer, pancreatic cancer, skin cancer, thyroid cancer, stomach cancer, kidney cancer, liver cancer, ovarian cancer, uterine cancer, melanoma, prostate cancer, and the like.

[0031] In some embodiments, compositions, such as pharmaceutical compositions or fixed

dosage forms or fixed dose combination of the different inhibitors are provided. A fixed dosage form or combination is one where the amount or ratio of the active ingredients is fixed to one another in the dosage form. As used herein the combination can also include a“fixed dose combination” (FDC). These fixed dose combinations can be in the form of pill, capsule, tablet, pill in pill, capsule in capsule, bilayer tablet or other formulation method with physical separation between. As described herein, the different inhibitors can be administered in combination to lead to a“combined administration.” Combined administration shall refer to the active ingredients that are present in the fixed dose fomr or combination are being released from such composition in a coordinated fashion, either sequentially, or more or less simultaneously. For example, in one embodiment the PARP inhibitor release may start somewhat earlier than the MAPK activator release, or vice versa, but the release of the other active ingredient may start shortly thereafter, thus leading to an overlapping release profile of both compounds from the fixed dose form or combination. In some embodiments, the release of both active ingredients may take place sequentially, i.e. first PARP inhibitor may be released and once finalized, MAPK activator may be released subsequently, or vice versa, as further described herein. The compositions can also comprise a MEK inhibitor, EGFR inhibitor or an additional therapeutic ( e.g . taxanes) as described herein. In some embodiments, the compositions can be free of a MEK inhibitor, EGFR inhibitor, or an additional therapeutic. The combination of the PARP inhibitor and the MAPK activator, or pharmaceutically acceptable salts thereof, and uses of the combination provided herein demonstrate surprising and unexpected ability to treat cancers and other unexpected results as described herein. In some embodiments, the combinations retard tumor progression. In some embodiments, the combinations reduce tumor size. In some embodiments, the combinations re-sensitize tumors that have become resistant to MAPK activators and/or PARP inhibitors. In some embodiments, the combinations sensitize tumors that are resistant to MAPK activators and/or PARP inhibitors. A tumor that is re- sensitized refers to a tumor that has become resistant or is expected to become resistant to a primary treatment, such as those described herein, including the PARP inhibitors and the MAPK activators. A tumor that is sensitized refers to a tumor that was resistant to a treatment and is now able to be treated with the treatment. For example, tumors that do not respond to PARP inhibitor are sensitized to PARP inhibitors when the tumor is treated with a combination of a PARP inhibitor and a MAPK activator. In some embodiments, the sensitization is provided by pre-treating tumors with the DNA damaging agent.

[0032] The combinations can also be administered in conjunction with an EGFR inhibitor. The combinations can also be administered without an EGFR inhibitor. Examples of EGFR inhibitors include, but are not limited to, cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib and erlotinib. The combinations can also be administered in conjunction with or without a taxane. Non- limiting examples of taxanes are described herein. The combinations described herein can be combined into the same formulation or unit dosage form or administered separately but can still be considered being combined because they are being administered to a patient with the intent to treat the cancer with each of the therapeutics.

[0033] In some embodiments, the combination is used in maintenance therapy and/or secondary therapy. Maintenance therapy, or secondary therapy, refers to treating a patient with a secondary therapy who had cancer and has already been treated with a primary treatment and the tumor responded to the primary treatment. Maintenance therapy can be used to either slow the tumor’s ability to grow, if not completely eliminated, or inhibit the tumor from recurring if the tumor is completely eliminated. Often maintenance therapy is used where the tumor is stable, or the patient has had a complete response ( e.g . is considered in remission). However, maintenance therapy can also be used when the subject has had a partial response or simply a response to the primary therapy. The combination can also include an EGFR inhibitor, or a taxane as described herein.

[0034] In some embodiments, methods are provided for treating cancer metastasis, the method comprising administering to the subject a PARP inhibitor and a MAPK activator, such as, but not limited to, a BRAF, CRAF, or pan-RAF inhibitor (e.g. RAF265, AD80,

GDC0879, dabrafenib, vemurafenib, encorafenib, sorafenib, lifirafenib, AZ628,

ZM336372, NVPBHG712, FY3009120, TAK632, MFN2480, and/or XP102). In some embodiments, the MAPK activator is a MEK inhibitor. The combination can also include an EGFR inhibitor, or a taxane, non- limiting examples of which are provided herein. In some embodiments, the metastatic cancer is metastatic melanoma, pancreatic cancer, lung cancer, colon cancer, ovarian cancer, prostate cancer, or breast cancer.

[0035] Cancers (tumors) often become resistant to treatments due to selection pressures from the treatments themselves. Thus, a treatment such as a PARP inhibitor can initially work, but then stop working after a period of time due to developing resistance. This resistance can be overcome or lessened by administering the combinations provided herein.

Accordingly, in some embodiments, methods of treating a resistant cancer are provided.

In some embodiments, the method comprising administering to a subject with a treatment resistant cancer a PARP inhibitor and a MAPK activator. Examples of which are described herein. In some embodiments, the cancer is resistant to any one of the PARP inhibitors or any one of the MAPK activators described herein, including, but not limited to, RAF265, AD80, GDC0879, dabrafenib, vemurafenib, sorafenib, encorafenib, lifirafenib, AZ628, ZM336372, NVPBHG712, FY3009120, TAK632, MFN2480, and/or XP102. In some

embodiments, the method comprises administering the therapeutics with a MEK inhibitor, an EGFR inhibitor, and/or a taxane, or any combination thereof, non- limiting examples of which are provided herein. [0036] Pharmaceutical Compositions/ Formulations

[0037] Pharmaceutical compositions can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. The formulations may contain a buffer and/or a preservative. The compounds and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including via inhalation, topically, nasally, orally, parenterally (e.g., intravenously, intraperitoneally, intravesically or intrathecally) or rectally in a vehicle comprising one or more

pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice.

[0038] Pharmaceutical compositions can include effective amounts of one or more compound(s) described herein together with, for example, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or other carriers. Such

compositions may include diluents of various buffer content (e.g., TRIS or other amines, carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially in the physiological pH range), N-glycylglycine, sodium or potassium phosphate (dibasic, tribasic), etc. or TRIS-HCl or acetate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., surfactants such as Pluronics, Tween 20, Tween 80

(Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol, parabens, etc.) and bulking substances (e.g., sugars such as sucrose, lactose, mannitol, polymers such as polyvinylpyrrolidones or dextran, etc.); and/or incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. or into liposomes. Hyaluronic acid may also be used. Such compositions can be employed to influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of a compound described herein. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference.

The compositions can, for example, be prepared in liquid form, or can be in dried powder, such as lyophilized form. Particular methods of administering such compositions are described infra. [0039] Where a buffer is to be included in the formulations described herein, the buffer can be selected from sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)-aminomethane, or mixtures thereof. The buffer can also be glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate or mixtures thereof.

[0040] Where a pharmaceutically acceptable preservative is to be included in a formulation of one of the compounds described herein, the preservative can be selected from phenol, m- cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof.

[0041] The preservative is present in a concentration from about 0.1 mg/ml to about 50 mg/ml, in a concentration from about 0.1 mg/ml to about 25 mg/ml, or in a concentration from about 0.1 mg/ml to about 10 mg/ml.

[0042] The use of a preservative in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

[0043] The formulation may further comprise a chelating agent where the chelating agent may be selected from salts of ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof.

[0044] The chelating agent can be present in a concentration from 0.1 mg/ml to 5 mg/ml, from 0.1 mg/ml to 2 mg/ml or from 2 mg/ml to 5 mg/ml.

[0045] The use of a chelating agent in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

[0046] The formulation of the compounds described herein may further comprise a stabilizer selected from high molecular weight polymers and low molecular compounds where such stabilizers include, but are not limited to, polyethylene glycol ( e.g . PEG 3350), polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g. sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, and threonine or any mixture thereof. The stabilizer can also be L-histidine, imidazole or arginine.

[0047] The high molecular weight polymer can be present in a concentration from 0.1 mg/ml to 50 mg/ml, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10 mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30 mg/ml to 50 mg/ml.

[0048] The low molecular weight compound can be present in a concentration from 0.1 mg/ml to 50 mg/ml, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10 mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30 mg/ml to 50 mg/ml.

[0049] The use of a stabilizer in pharmaceutical compositions is well-known to the skilled

person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

[0050] The formulation of the compounds described herein may further include a surfactant. In some embodiments, the surfactant may be selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters,

polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g. Tween- 20, or Tween- 80), monoglycerides or ethoxylated derivatives thereof,

diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids, glycerophospho lipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium, docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N,N-dimethyl-3- ammonio-l-propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids ( e.g . l-acyl-sn-glycero-3- phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine,

dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N,N-dimethylammonio- 1-propanesulfo nates, 3-cholamido- 1-propyldimethylammonio- 1-propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases) (e.g. cetyl-trimethylammonium bromide, cetylpyridinium chloride), non-ionic surfactants,

polyethyleneoxide/polypropyleneoxide block copolymers (Pluronics/Tetronics, Triton X- 100, Dodecyl b-D-glucopyranoside) or polymeric surfactants (Tween-40, Tween- 80, Brij-35), fusidic acid derivatives— (e.g. sodium tauro-dihydrofusidate etc.), long-chain fatty acids and salts thereof C6-C12 (e.g. oleic acid and caprylic acid), acylcarnitines and derivatives, N_a -acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N_a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N_a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof.

[0051] The use of a surfactant in pharmaceutical compositions is well-known to the skilled

person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

[0052] Pharmaceutically acceptable sweeteners can be part of the formulation of the compounds described herein. Pharmaceutically acceptable sweeteners include at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4,r,6'-trichloro-4,r,6'-trideoxygalactosucrose), saccharin, sodium or calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey.

[0053] Intense sweeteners are conveniently employed in low concentrations. For example, in the case of sodium saccharin, the concentration may range from 0.04% to 0.1% (w/v) based on the total volume of the final formulation or is about 0.06% in the low-dosage formulations and about 0.08% in the high-dosage ones. The bulk sweetener can effectively be used in larger quantities ranging from about 10% to about 35%, or from about 10% to 15% (w/v).

[0054] The formulations of the compounds described herein may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in

Remington: The Science and Practice of Pharmacy, 19th edition, 1995, where such conventional techniques of the pharmaceutical industry involve dissolving and mixing the ingredients as appropriate to give the desired end product.

[0055] The phrase“pharmaceutically acceptable” or“therapeutically acceptable” refers to

molecular entities and compositions that are physiologically tolerable and preferably do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. As used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a State government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia (e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985)) for use in animals, and more particularly in humans.

[0056] Administration of the compounds described herein may be carried out using any method known in the art. For example, administration may be transdermal, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intracerebroventricular, intrathecal, intranasal, aerosol, by suppositories, or oral administration. A pharmaceutical composition of the compounds described herein can be for administration for injection, or for oral, pulmonary, nasal, transdermal, ocular administration.

[0057] For oral administration, the pharmaceutical composition of the compounds described herein can be formulated in unit dosage forms such as capsules or tablets. The tablets or capsules may be prepared by conventional means with pharmaceutically acceptable excipients, including binding agents, for example, pregelatinised maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose; fillers, for example, lactose, microcrystalline cellulose, or calcium hydrogen phosphate; lubricants, for example, magnesium stearate, talc, or silica; disintegrants, for example, potato starch or sodium starch glycolate; or wetting agents, for example, sodium lauryl sulphate. Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl- p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound. In some embodiments, the unit dosage form can be formulated as a combination product that comprises both a PARP inhibitor and a MAPK activator. In some embodiments, the unit dosage form refers to one composition that comprises a PARP inhibitor and a second composition that comprises a MAPK activator.

[0058] For parenteral administration, the compounds described herein are administered by either intravenous, subcutaneous, or intramuscular injection, in compositions with

pharmaceutically acceptable vehicles or carriers. The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, for example, suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0059] For administration by injection, the compound(s) can be used in solution in a sterile

aqueous vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic. The pharmaceutical compositions of the compounds described herein may be formulated with a pharmaceutically acceptable carrier to provide sterile solutions or suspensions for injectable administration. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspensions in liquid prior to injection or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, or the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations ( e.g ., liposomes) may be utilized. Suitable

pharmaceutical carriers are described in“Remington's pharmaceutical Sciences” by E. W. Martin. The injection formulation can comprise a combination of the compounds described herein. The injection formulation can also be prepared by combining separate formulations into one. The formulations can also be administered sequentially or simultaneously or nearly simultaneously.

[0060] The compounds can also be formulated in rectal compositions, for example, suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides.

[0061] Furthermore, the compounds can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0062] The compositions can, if desired, be presented in a pack or dispenser device that can contain one or more-unit dosage forms containing the active ingredient. The pack can, for example comprise metal or plastic foil, for example, a blister pack. The pack or dispenser device can be accompanied by instructions for administration.

[0063] The compounds described herein also include derivatives referred to as prodrugs, which can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.

[0064] Dosages

[0065] The compounds described herein may be administered to a patient at therapeutically

effective doses to prevent, treat, or control one or more diseases described herein, such as but not limited to, the cancers described herein. Pharmaceutical compositions comprising one or more of compounds described herein may be administered to a patient in an amount sufficient to elicit an effective therapeutic response in the patient. An amount adequate to accomplish this is defined as“therapeutically effective dose.” The dose can be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the area to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound or vector in a particular subject.

[0066] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The LD50 and the ED50 can be determined for the components alone or the combination. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio,

LD50/ED50. In some embodiments, combinations that exhibit large therapeutic indices are used. While compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize potential damage to normal cells and, thereby, reduce side effects.

The side effects can be avoided, in some embodiments, by using a combination of a PARP inhibitor and a MAPK activator as described herein. The side effects can be avoided or reduced by using lower doses of one or more of the therapeutics.

[0067] The data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. In some embodiments, the dosage of such compounds lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration. For any compound described herein, 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 that achieves a half- maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography (HPLC). In general, the dose equivalent of a modulator is from about 1 ng/kg to 10 mg/kg for a typical subject.

[0068] The amount and frequency of administration of the compounds described herein and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. In general, it is contemplated that an effective amount would be from 0.001 mg/kg to 10 mg/kg body weight, and in particular from 0.01 mg/kg to 1 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unit dosage form. [0069] In some embodiments, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 500 mg, or from about 0.01 mg to about 250 mg, according to the particular application. In some embodiments, the amount of a BRAF, CRAF, or pan-RAF inhibitor, or a pharmaceutically acceptable salt thereof,

administered to the subject is less than, about, or is, 960 mg, 720 mg, 480 mg, 240 mg, 150 mg, 100 mg, 50 mg, or 25 mg twice daily. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.

Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.

[0070] In some embodiments, one or more compounds described herein are administered with another compound. The administration may be sequentially or concurrently. The combination may be in the same dosage form or administered as separate doses. In some embodiments, the combination is administered with one or more DNA damaging agents. In some embodiments, the DNA damaging agent is gemcitabine, 5-FU, cytarabine, methotrexate, pyrimethamine, bleomycin, oxaliplatin, cisplatin, carboplatin, etoposide, doxorubicin, vinorelbine, mitoxantrone, podophyllotoxin, aphidicolin, fotemustine, carmustine, S-23906, S39, SN-38, topotecan, camptothecin, rebeccamycin, and the like.

In some embodiments, the DNA damaging agent is administered before the BRAF, CRAF, or pan-RAF inhibitor. In some embodiments, the DNA damaging agent is administered at least, or about 10, 20, 30, 40, 50, 60, 120, 180, 240, 300, or 360 minutes before the PARP inhibitor and/or the MAPK activator. In some embodiments, the DNA damaging agent is administered at least, or about, 1, 2, 3, 4, or 5 days before the PARP inhibitor and/or the MAPK activator. In some embodiments, the DNA damaging agent is administered to the subject prior to PARP inhibitor and/or the MAPK activator is administered to the subject. In some embodiments, the DNA damaging agent is administered at least, or about 10, 20, 30, 40, 50, 60, 120, 180, 240, 300, or 360 minutes before the PARP inhibitor and/or the MAPK activator. In some embodiments, the DNA damaging agent is administered at least, or about, 1, 2, 3, 4, or 5 days before the PARP inhibitor and/or the MAPK activator.

[0071] In some embodiments, the amount of the MAPK activator inhibitor can be from about 1 mg to about 100 mg, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 25 mg to about 100 mg, from about 50 mg to about 100 mg, or from about 75 mg to about 100 mg. In some embodiments, the amount of a MAPK activator can be from about 1 mg to about 80 mg, from about 1 mg to about 60 mg, from about 1 mg to about 40 mg, from about 1 mg to about 20 mg, or from about 1 mg to about 10 mg. In some embodiments, the amount of a MAPK activator can be from about 5 mg to about 80 mg. In some embodiments, the amount of a MAPK activator is from about 5 mg to about 240 mg.

[0072] In some embodiments, the DNA damaging agent is administered in dose of, about, or less than 1250 mg/m², 1000 mg/m², 800 mg/m², 600 mg/m², 400 mg/m², 200 mg/m², 100 mg/m², or 50 mg/m², 25 mg/m², 10 mg/m², or 5 mg/m² or any range in between. In some embodiments, the dose of the DNA damaging agent is considered a sublethal dose for the patient or subject.

[0073] The compounds described herein can also be administered with anti-nausea agents, which can also be referred to as anti-emetics. Examples of such agents include, but are not limited to, dolasetron, granisetron, ondansetron, tropisetron, palonosetron, mirtazapine, aprepitant, casopitant, and the like.

[0074] Medical Use

[0075] The compositions described herein may be useful for treating cancer. Examples of such cancers include, but are not limited to, those described herein. In some embodiments, the tumor is negative for a BRAF mutation. In some embodiments, the tumor is wild-type

BRAF. In some embodiments, the tumor has a mutation in BRAF. In some

embodiments, the tumor has a BRAF V600E mutation. In some embodiments, the tumor is free of a BRAF V600E mutation. In some embodiments, the tumor has a BRAF V600K mutation. In some embodiments, the tumor is free of a BRAF V600K mutation. In some embodiments, the tumor has a RAS (e.g. KRAS, NRAS, and/or HRAS) mutation. In some embodiments, the RAS mutation is G12C, G12D, G12V, or G13D. In some embodiments, the tumor is free of a RAS mutation. In some embodiments, the tumor is wild-type RAS. For the avoidance of doubt, the term“RAS” can refer to KRAS, NRAS, and/or HRAS. In some embodiments, the RAS is KRAS. In some embodiments, the RAS is NRAS. In some embodiments, the RAS is HRAS. In some embodiments, the tumor is wt BRCA1 and/or wt BRCA2.

[0076] In some embodiments, the tumor is analyzed for mutations prior to administering a

combination. In some embodiments, the tumor is analyzed for a BRAF V600E mutation. In some embodiments, the tumor is analyzed for a BRAF V600K mutation. In some embodiments, the tumor is analyzed for a RAS G12C mutation. In some embodiments, the tumor is analyzed for a RAS G12D mutation. In some embodiments, the tumor is analyzed for a RAS G12S mutation. In some embodiments, the tumor is analyzed for a RAS G12V mutation. In some embodiments, the tumor is analyzed for a RAS G13D mutation. In some embodiments, the patient is only treated with a combination if no mutation in BRAF is found. In some embodiments, the patient is only treated with a combination if a mutation in BRAF is found. In some embodiments, the patient is only treated with a combination if no mutation in RAS is found. In some embodiments, the patient is only treated with a combination if a mutation in RAS is found. In some embodiments, the patient is only treated with a combination if no mutation in BRCA1 and/or BRCA2 is found. In some embodiments, the patient is only treated if the patient is wt BRAF, wt BRCA1 and/or wt BRCA2, and mutant RAS.

[0077] In some embodiments, methods of treating cancer are provided. In some embodiments, the cancer is as described herein. In some embodiments, the cancer is metastatic cancer that originated as one of the cancers described herein. Accordingly, as described herein, methods of treating metastatic cancer are provided.

[0078] In some embodiments, the methods described herein comprise administering a

combination as described herein. In some embodiments, the PARP inhibitor is administered to the subject simultaneously with MAPK activator or sequentially (before or after) the MAPK activator. In some embodiments, the method comprises initially administering the PARP inhibitor or the MAPK activator and then before the either therapeutic is completely administered administering the other therapeutic. Such administration can be referred to as overlapping the therapeutics. In some embodiments, the combination is also administered with a MEK inhibitor or an EGFR inhibitor as described herein. The compounds can be administered in any order, these are simply examples only and are not intended to be limiting. In some embodiments, the subject is administered a DNA damaging agent as described herein prior to being treated with the with the PARP inhibitor and/or the MAPK activator. Accordingly, in some

embodiments, the subject is pre-treated with a DNA damaging agent.

[0079] In some embodiments, the methods described herein comprise detecting a BRAF,

BRCA1, BRCA2, and/or RAS mutation in the subject’s tumor and treating the subject with a combination in the subject that does not have a BRAF and/or BRCA mutation.

The methods of treatment and order of administration of the different active ingredients can be performed according to any method described herein. This can be done, for example, to ensure that the patient will benefit from the treatment. However, there is no requirement that they specifically be tested for such mutation. In some embodiments, the mutation that is not detected is BRAF V600E or V600K. In some embodiments, a subject with a RAS mutation is treated with combinations described herein. In some embodiments, the subject that is treated has a tumor that is wild-type BRAF and mutated RAS. In some embodiments, the mutant RAS comprises a mutation as described herein. In some embodiments, the subject that is treated has a tumor with a mutated BRAF and a mutated RAS. In some embodiments, the mutations of each are those that are described herein. In some embodiments, the subject that is treated has a tumor with a mutated BRAF and a wild-type RAS. The mutations can be any mutation, such as those described herein. The mutations present in the tumor can be detected by any method, such as PCR, RT-PCR, genomic sequencing, RNA sequencing, northern blot, southern blot, western blot, or any other molecular technique that can be used to detect mutations in BRAF and/or RAS. The specific method of detecting mutations in BRAF and/or RAS is not critical. The mutation can be detected in any tumor sample. The tumor sample can be obtained through, for example, a biopsy. A blood sample may also be used to identify the mutation status of the tumor. The sample and the technique for detecting the presence or absence of a mutation is not critical to the methods described herein. The tumor may also be BRCA wild type.

[0080] In some embodiments, methods of treating a drug resistant tumor are provided. In some embodiments, the methods comprise administering a PARP inhibitor and/or the MAPK activator. In some embodiments, the drug resistant tumor is resistant to treatment consisting of a PARP inhibitor and/or the MAPK activator. In some embodiments, the drug resistant tumor is a metastatic tumor. In some embodiments, the metastatic tumor is a metastatic melanoma, metastatic pancreatic tumor, metastatic lung tumor, metastatic colon tumor, metastatic ovarian tumor, metastatic prostate tumor, metastatic lung tumor, or metastatic breast tumor. In some embodiments, the drug resistant tumor is a melanoma, pancreatic tumor, lung tumor, colon tumor, ovarian tumor, prostate tumor, lung tumor, or breast tumor, or other type of cancer described herein.

[0081] In some embodiments, the drug resistant tumor is characterized as wild-type BRAF. In some embodiments, the drug resistant tumor is characterized as mutant BRAF. In some embodiments, the mutant BRAF is BRAF V600E or V600K.

[0082] In some embodiments, the drug resistant tumor is characterized as wild-type RAS. In some embodiments, the drug resistant tumor is characterized as mutant RAS. In some embodiments, the method of treating a drug resistant tumor further comprises detecting the presence or absence of a BRAF V600E or V600K mutation in a tumor sample derived from the subject prior to the administering step. In some embodiments, the methods comprise detecting the presence or absence of a RAS mutation in a tumor sample derived from the subject prior to the administering step.

[0083] As described herein, in some embodiments, the combinations described herein can be administered by any suitable route, including, but not limited to, via inhalation, topically, nasally, orally, parenterally (e.g., intravenously, intraperitoneally, intravesically or intrathecally) or rectally in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard practice.

[0084] Embodiments provided herein also provided for kits. In some embodiments, the kits comprise a pharmaceutical composition comprising a PARP inhibitor and/or the MAPK activator, or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition comprising a DNA damaging agent. In some embodiments, one

pharmaceutical composition comprises both. In some embodiments, they are separate pharmaceutical compositions. In some embodiments, the kits comprise a first pharmaceutically acceptable container comprising the PARP inhibitor and a second pharmaceutically acceptable container comprising the MAPK activator. In some embodiments, the containers are sterile and pyrogen free. In some embodiments, the kits comprise prescribing information. In some embodiments, the prescribing information comprises instructions for administering the PARP inhibitor and/or the MAPK activator to a subject with a tumor characterized as provided for herein.

[0085] Embodiments provided herein also provide for containers comprising a pharmaceutical composition comprising a PARP inhibitor and/or the MAPK activator and prescribing information, wherein the prescribing information comprises instructions for

administering the PARP inhibitor and/or the MAPK activator to a subject with a tumor characterized as described herein. In some embodiments, the tumor is a tumor as described herein, such as a solid tumor. In some embodiments, the container comprises a capsule, tablet, or other oral dosage form comprising the PARP inhibitor and/or the MAPK activator. In some embodiments, the instructions further provide for

administering to the subject an EGFR inhibitor or a MEK inhibitor or a taxane such as, but not limited to, those described herein.

[0086] Definitions

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the compositions and compounds described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only not intended to be limiting. Other features and advantages of the compositions and compounds described herein will be apparent from the following detailed description and claims.

[0088] As used herein, the phrase“pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0089] By“pharmaceutical formulation” it is further meant that the carrier, solvent, excipients and salt must be compatible with the active ingredient of the formulation (e.g. a compound described herein). It is understood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and“pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application.

[0090] As used herein,“pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic. The present disclosure includes pharmaceutically acceptable salts of any compound(s) described herein.

[0091] Pharmaceutically acceptable salts can be synthesized from the parent compound 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 in an organic solvent, or in a mixture of the two; generally, non- aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, and the like. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p.

1445 (1990).

[0092] Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals

(e.g., solubility, bio availability, manufacturing, etc.) the compounds described herein can be delivered in prodrug form and can be administered in this form for the treatment of disease.“Prodrugs” are intended to include any covalently bonded carriers that release an active parent drug of described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds described herein wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds described herein.

[0093] As used herein,“treating” or“treatment” includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.“Treating” or“treatment” of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease- state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease- state, i.e., causing regression of the disease state.

[0094] As used herein,“mammal” or“subject” refers to human and non-human patients. In some embodiments, the subject is a subject in need thereof. The term“subject” and “patient” can be used interchangeably. As used herein, a patient that is“in need thereof’ is a subject that has been identified as needing the treatment or suspected of needing the treatment. For example, a subject that has been diagnosed with cancer can be considered a subject in need thereof.

[0095] As used herein, the term“therapeutically effective amount” refers to a compound, or a combination of compounds, described herein present in or on a recipient in an amount sufficient to elicit biological activity, e.g. pain relief. In some embodiments, the combination of compounds is a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased decrease in pain, or some other beneficial effect of the combination compared with the individual components.

[0096] All percentages and ratios used herein, unless otherwise indicated, are by weight.

[0097] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions described herein also consist essentially of, or consist of, the recited components, and that the processes described herein also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the process remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0098] As used throughout this disclosure, the singular forms“a,”“an,” and“the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a composition” includes a plurality of such compositions, as well as a single composition, and a reference to“a therapeutic agent” is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth. Thus, for example, a reference to“a host cell” includes a plurality of such host cells, and a reference to“an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.

[0099] The compounds described herein can be prepared according to known methods.

[0100] Examples

[0101] The following examples are illustrative, but not limiting, of the methods and

compositions described herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in therapy and that are obvious to those skilled in the art are within the spirit and scope of the compounds and methods described herein.

[0102] EXAMPLE 1: PARP INHIBITORS AND MAPK ACTIVATORS INHIBIT TUMOR GROWTH

[0103] MDAMB231 were grown to determine the effect of a combination of PARP inhibitors and MAPK activators on colony formation. Colony formation assays of MDAMB231 breast cancer cells following treatments with differential doses of rucaparib +/- differential doses of RAF265. Rucaparib, which is a PARP inhibitor, doses (uM): 100,

50, 25, 13, 6, 3. RAF265 doses (uM): 100, 50, 25, 13, 6, 3. Combination doses (rucaparib

(uM)+RAF265 (uM)): 30+15, 15+8, 8+4, 4+2, 2+1, 1+0.5. B) Colony formation assays of T47D breast cancer cells following treatments with differential doses of rucaparib +/- differential doses of RAF265. Rucaparib doses (uM): 50, 25, 13, 6, 3, 1.5. RAF265 doses

(uM): 25, 13, 6, 3, 1.5, 0.75. Combination doses (rucaparib (uM)+RAF265 (uM)): 20+2,

10+1, 5+0.5, 2.5+0.25, 1.25+0.13, 0.6+0.07. C) Colony formation assays of SW620 colorectal cancer cells following treatments with differential doses of rucaparib +/- differential doses of RAF265. Rucaparib doses (uM): 100, 50, 25, 13, 6, 3. RAF265 doses (uM): 25, 13, 6, 3, 1.5, 0.75. Combination doses (rucaparib (uM)+RAF265 (uM)):

20+2, 10+1, 5+0.5, 2.5+0.3, 1.3+0.15, 0.6+0.07. The results demonstrated the ability of the combination to reduce colony formation in a synergistic manner in a tumor type that is BRCA wt, BRAF wt, Ras wt or mutant. The results are illustrated in FIG. 1. These results were surprising and unexpected and allow new treatments for cancers with such a mutation profile to be treated that otherwise had few options for treatment.

[0104] EXAMPLE 2. PARP INHIBITORS AND MAPK ACTIVATORS INHIBIT TUMOR

GROWTH. Similar to Example 1, colony formation assays were performed utilizing a different combination of a PARP inhibitor and a MAPK activator. A) Colony formation assays of HCT116 colorectal cancer cells following treatments with differential doses of niraparib +/- differential doses of RAF265. Niraparib doses (uM): 100, 50, 25, 13, 6, 3. RAF265 doses (uM): 25, 13, 6, 3, 1.5, 0.75. Combination doses (niraparib

(uM)+RAF265 (uM)): 20+5, 10+2.5, 5+1.25, 2.5+0.6, 1.25+0.3, 0.6+0.15. B) Colony formation assays of Panel pancreatic cancer cells following treatments with differential doses of niraparib +/- differential doses of RAF265. Niraparib doses (uM): 5, 2.5, 1.25, 0.6, 0.3, 0.15. RAF265 doses (uM): 50, 25, 13, 6, 3, 1.5. Combination doses (niraparib (nM)+RAF265 (uM)): 500+2, 250+1, 125+0.5, 63+0.3, 31+0.15, 16+0.07. C) Colony formation assays of A549 lung cancer cells following treatments with differential doses of niraparib +/- differential doses of RAF265. Niraparib doses (uM): 100, 50, 25, 13, 6,

3. RAF265 doses (uM): 20, 10, 5, 2.5, 1.25, 0.6. Combination doses (niraparib

(uM)+RAF265 (uM)): 20+2, 10+1, 5+0.5, 2.5+0.3, 1.25+0.15, 0.6+0.07. The results demonstrated the ability of the combination to reduce colony formation in a synergistic manner in a tumor type that is BRCA wt, BRAF wt and mutant Ras. The results are illustrated in FIG. 2. These results were surprising and unexpected and allow new treatments for cancers with such a mutation profile to be treated that otherwise had few options for treatment.

[0105] EXAMPLE 3. PARP INHIBITORS AND MAPK ACTIVATORS INHIBIT TUMOR

GROWTH. Similar to Examples 1 and 2, colony formation assays were performed utilizing a different combination of a PARP inhibitor and a MAPK activator. A) Colony formation assays of SK-Mel2 melanoma cells following treatments with differential doses of olaparib +/- differential doses of RAF265. Olaparib doses (uM): 100, 50, 25,

13, 6, 3. RAF265 doses (uM): 5, 2.5, 1.25, 0.6, 0.3, 0.15. Combination doses (olaparib (uM)+RAF265 (uM)): 30+2, 15+1, 7.5+0.5, 3.75+0.25, 1.88+0.13, 0.94+0.07. B)

Colony formation assays of MiaPaCa2 pancreatic cancer cells following treatments with differential doses of olaparib +/- differential doses of RAF265. Olaparib doses (uM):

100, 50, 25, 13, 6, 3. RAF265 doses (uM): 100, 50, 25, 13, 6, 3. Combination doses

(olaparib (uM)+RAF265 (uM)): 10+1, 5+0.5, 2.5+0.25, 1.25+0.13, 0.6+0.06, 0.3+0.03. C) Colony formation assays of 501mel melanoma cells following treatments with differential doses of olaparib +/- differential doses of RAF265. Olaparib doses (uM):

200, 100, 50, 25, 13, 6. RAF265 doses (uM): 100, 50, 25, 13, 6, 3. Combination doses (olaparib (uM)+RAF265 (uM)): 30+5, 15+2.5, 8+1.25, 4+0.6, 2+0.3, 1+0.15. The results demonstrated the ability of the combination to reduce colony formation in a synergistic manner in a tumor type that is BRCA wt, BRAF wt or mutant, and mutant Ras. The results are illustrated in FIG. 3. These results were surprising and unexpected and allow new treatments for cancers with such a mutation profile to be treated that otherwise had few options for treatment.

[0106] EXAMPLE 4. PARP INHIBITORS AND MAPK ACTIVATORS INHIBIT TUMOR

GROWTH. Similar to Examples 1, 2, and 3, colony formation assays were performed utilizing a different combination of a PARP inhibitor and a MAPK activator. A) Colony formation assays of DLD1 colorectal cancer cells following treatments with differential doses of nirparib +/- differential doses of dabrafenib. Niraparib doses (uM): 100, 50, 25, 13, 6, 3. Dabrafenib doses (uM): 100, 50, 25, 13, 6, 3. Combination doses (niraparib (uM)+dabrafenib (uM)): 5+10, 2.5+5, 1.25+2.5, 0.6+1.25, 0.3+0.6, 0.15+0.3. B) Colony formation assays of BxPC3Ml pancreatic cancer cells following treatments with differential doses of rucaparib +/- differential doses of lifirafenib. Rucaparib doses (uM): 100, 50, 25, 13, 6, 3. Lifirafenib doses (uM): 25, 13, 6, 3, 1.5, 0.75. Combination doses (rucaparib (uM)+lifirafenib (uM)): 20+5, 10+2.5, 5+1.25, 2.5+0.6, 1.25+0.3, 0.6+0.15.

C) Colony formation assays of BxPC3Ml pancreatic cancer cells following treatments with differential doses of talazoparib +/- differential doses of RAF265. Talazoparib doses (uM): 10, 5, 2.5, 1.25, 0.6, 0.3. RAF265 doses (uM): 10, 5, 2.5, 1.25, 0.6, 0.3. Combination doses (talazoparib (uM)+RAF265 (uM)): 2+1, 1+0.5, 0.5+0.25, 0.25+0.13, 0.13+0.06, 0.06+0.03. The results demonstrated the ability of the combination to reduce colony formation in a synergistic manner in a tumor type that is BRCA wt, BRAF wt,

Ras G12 or G13 mutant. The results are illustrated in FIG. 4. These results were surprising and unexpected and allow new treatments for cancers with such a mutation profile to be treated that otherwise had few options for treatment.

[0107] EXAMPLE 5. PARP INHIBITORS AND MAPK ACTIVATORS INHIBIT TUMOR GROWTH. Similar to Examples 1, 2, 3, and 4, colony formation assays were performed utilizing a different combination of a PARP inhibitor and a MAPK activator. A) Colony formation assays of 501mel melanoma cells following treatments with differential doses of olaparib +/- differential doses of AD80. Olaparib doses (uM): 200, 100, 50, 25, 13, 6. AD80 doses (uM): 2, 1, 0.5, 0.25, 0.13, 0.06. Combination doses (olaparib (uM)+AD80 (nM)): 2+500, 1+250, 0.5+125, 0.25+63, 0.13+32, 0.06+16. B) Colony formation assays of HT29 colorectal cancer cells following treatments with differential doses of rucaparib +/- differential doses of AD80. Rucaparib doses (uM): 100, 50, 25, 13, 6, 3. AD80 doses (uM): 2, 1, 0.5, 0.25, 0.13, 0.06. Combination doses (rucaparib (uM)+AD80 (nM)): 2+500, 1+250, 0.5+125, 0.25+63, 0.13+32, 0.06+16. C) Colony formation assays of Panel pancreatic cancer cells following treatments with differential doses of talazoparib +/- differential doses of AD80. Talazoparib doses (nM): 1000, 500, 250, 125, 63, 32. AD80 doses (nM): 1000, 500, 250, 125, 63, 32. Combination doses (talazoparib

(nM)+AD80 (nM)): 500+500, 250+250, 125+125, 63+63, 32+32, 16+16. The results demonstrated the ability of the combination to reduce colony formation in a synergistic manner in a tumor type that is BRCA wt, BRAF wt or mutant, Ras wt or mutant. The results are illustrated in FIG. 5. These results were surprising and unexpected and allow new treatments for cancers with such a mutation profile to be treated that otherwise had few options for treatment.

[0108] While the embodiments described herein have been described with reference to

examples, those skilled in the art recognize that various modifications may be made without departing from the spirit and scope thereof.

[0109] All of the above U.S. patents, U.S. patent application publications, U.S. patent

applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety.

Claims

What is claimed is:

1. A method of treating a solid metastatic or non- metastatic tumor in a subject comprising administering to the subject a PARP inhibitor and a MAPK activator.

2. The method of claim 1, wherein the tumor has a genotype of BRCAl/2 WT, BRAF WT, a mutated RAS, or any combination thereof.

3. The method of claim 2, wherein the RAS mutation is RAS G12 mutation.

4. The method of any one of claims 1-3, wherein the PARP inhibitor is rucaparib, olaparib, veliparib, talazoparib, AG-14361, INO-1001, A-966492, niraparib, PJ34 HC1, AZD2461, E7449, pamiparib (BGB-290), or any combination thereof.

5. The method of any one of claims 1-4, wherein the MAPK activator is a panRAF inhibitor, a BRAF V600E inhibitor, a multi-kinase inhibitor, such as, but not limited to, MEK inhibitors that can also inhibit against BRAF and/or CRAF.

6. The method of claim 5, wherein the MAPK activator is a BRAF inhibitor that is specific for a DFG-out (inactive) conformation of a BRAF inhibitor, a CRAF inhibitor, and a pan-RAF inhibitor, or a pharmaceutically acceptable salt thereof.

7. The method of claim 5, wherein the MAPK activator is RAF265, AD80, GDC0879, dabrafenib, vemurafenib, encorafenib, lifirafenib, sorafenib, AZ628, ZM336372, NVPBHG712, LY3009120, TAK632, MLN2480, or XP102, or a pharmaceutically acceptable salt thereof, or any combination thereof.

8. The method of any one of the preceding claims, wherein the tumor is breast cancer, lung cancer, colon, cancer, brain cancer, pancreatic cancer, skin cancer, thyroid cancer, stomach cancer, kidney cancer, liver cancer, ovarian cancer, uterine cancer, melanoma, prostate cancer, and the like.

9. The method of claim 1, wherein the PARP inhibitor is rucaparib and the MAPK activator is RAF265 and/or dabrafenib.

10. The method of any of the preceding claims, the method further comprising administering a DNA damaging agent to the subject.

11. The method of claim 10, wherein the DNA damaging agent is an agent that cause double strand breaks (DSBs), single strand breaks, an antimetabolite, a DNA crosslinker, a topoisomerases inhibitor, a polymerase inhibitor, nucleoside analog, or an alkylating agent.

12. The method of claim 10, wherein the DNA damaging agent is gemcitabine, 5-FU, cytarabine, methotrexate, pyrimethamine, bleomycin, oxaliplatin, cisplatin, carboplatin, etoposide, doxorubicin, vinorelbin, mitoxantrone, podophyllotoxin, aphidicolin, fotemustine, carmustine, S- 23906, S39, SN-38, topotecan, camptothecin, rebeccamycin, or any pharmaceutically acceptable salt thereof.

13. The method of claim 10, wherein the DNA damaging agent is gemcitabine, methotrexate, camptothecin, and/or pyrimethamine, or a pharmaceutically acceptable salt thereof.

14. The method of claim 1, wherein the PARP inhibitor and the MAPK activator are administered sequentially, simultaneously, or in an overlapping manner.

15. The method of claim 1, wherein the PARP inhibitor is administered to the subject prior to the MAPK activator being administered to the subject.

16. The method of claim 1, wherein the PARP inhibitor is administered to the subject after the MAPK activator being administered to the subject.

17. The method of claim 1, wherein the subject is administered a dose of the PARP inhibitor, or a pharmaceutically acceptable salt thereof, that is about or less than 960 mg, 720 mg, 480 mg, 240 mg, 150 mg, 100 mg, 50 mg, or 25 mg twice daily.

18. The method of claim 5, wherein the MEK inhibitor is trametinib.

19. The method of any one of claims 1-20, further comprising administering an EGFR inhibitor.

20. The method of claim 30, wherein the EGFR inhibitor is cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib or erlotinib.

21. The method of claim any one of the preceding claims, wherein the tumor size is reduced in the subject.

22. The method of claim 23, wherein the tumor size is reduced about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%.

23. The method of claim 1, wherein the tumor does not increase in size after the administration step.

24. A method of treating a subject with a solid tumor without a BRAF V600E or V600K mutation and/or without a BRCA mutation, the method comprising administering to the subject a PARP inhibitor and a MAPK activator.

25. The method of claim 26, wherein the tumor has a mutant RAS gene.

26. A method of treating a metastatic solid tumor without a BRAF V600E or V600K mutation and/or without a BRCA mutation in a subject, the method comprising administering to the subject a PARP inhibitor and a MAPK activator.

27. The method of claim 28, wherein the tumor has a mutant RAS gene.

28. A pharmaceutical composition comprising a PARP inhibitor and a MAPK activator.

29. The pharmaceutical composition of claim 28, wherein the PARP inhibitor is Rucaparib, Olaparib, Veliparib, Talazoparib, AG-14361, INO-1001, A-966492, Niraparib, PJ34 HC1,

AZD2461, E7449, Pamiparib (BGB-290), or any combination thereof.

30. The pharmaceutical composition of claims 28 or 29, wherein the MAPK activator is RAF265, AD80, GDC0879, dabrafenib, vemurafenib, encorafenib, lifirafenib, sorafenib, AZ628, ZM336372, NVPBHG712, LY3009120, TAK632, MLN2480, or XP102, or a pharmaceutically acceptable salt thereof, or any combination thereof.

31. The pharmaceutical composition of any one of claims 28-30, wherein the PARP inhibitor is rucaparib and the MAPK activator is RAF265 and/or dabrafenib.

32. A pharmaceutical composition for treating a solid tumor that does not have a BRAF mutation, such asV600E or V600K, and/or a BRCA mutation, the composition comprising a PARP inhibitor and a MAPK activator.

33. The pharmaceutical composition of claim 32, wherein the solid tumor has a mutant RAS.

34. The pharmaceutical composition of claims 32 or 33, wherein the PARP inhibitor is

Rucaparib, Olaparib, Veliparib, Talazoparib, AG-14361, INO-1001, A-966492, Niraparib, PJ34 HC1, AZD2461, E7449, Pamiparib (BGB-290), or any combination thereof.

35. The pharmaceutical composition of claims 32 or 34, wherein the MAPK activator is RAF265, AD80, GDC0879, dabrafenib, vemurafenib, encorafenib, lifirafenib, sorafenib, AZ628, ZM336372, NVPBHG712, LY3009120, TAK632, MLN2480, or XP102, or a pharmaceutically acceptable salt thereof, or any combination thereof.

36. The pharmaceutical composition of any one of claims 32-35, wherein the PARP inhibitor is rucaparib and the MAPK activator is RAF265 and/or dabrafenib.

37. A fixed unit dosage form comprising a PARP inhibitor and a MAPK activator.

38. The fixed unit dosage form of claim 37, wherein the PARP inhibitor is Rucaparib, Olaparib, Veliparib, Talazoparib, AG-14361, INO-1001, A-966492, Niraparib, PJ34 HC1, AZD2461, E7449,

Pamiparib (BGB-290), or any combination thereof.

39. The fixed unit dosage form of claims 37 or 38, wherein the MAPK activator is RAF265, AD80, GDC0879, dabrafenib, vemurafenib, encorafenib, lifirafenib, sorafenib, AZ628, ZM336372, NVPBHG712, LY3009120, TAK632, MLN2480, or XP102, or a pharmaceutically acceptable salt thereof, or any combination thereof.

40. The fixed unit dosage form of any one of claims 37-39, wherein the PARP inhibitor is rucaparib and the MAPK activator is RAF265 and/or dabrafenib.

41. Use of a PARP inhibitor and a MAPK activator for treating a solid tumor in a subject, wherein the tumor does not have a BRAF mutation, such as V600E or V600K, and/or a BRCA mutation.

42. The use of claim 41, wherein the solid tumor is tumor is breast cancer, lung cancer, colon, cancer, brain cancer, pancreatic cancer, skin cancer, thyroid cancer, stomach cancer, kidney cancer, liver cancer, ovarian cancer, uterine cancer, melanoma, prostate cancer, and the like.