Combinations for use in treating cancer

Abstract

The present disclosure relates to a method of treating cancer, comprising co-administering to a patient in need thereof mirdametinib (Compound A), or a pharmaceutically acceptable salt thereof, and 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea (Compound B), or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 379,617, filed October 14, 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates to a method of treating cancer comprising co-administering Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Also disclosed is a pharmaceutical composition of Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, for use in such cancer treatment. The present disclosure further relates to the use of a combination of Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for cancer treatment. [Background technology]

[0003] Certain cancers harbor mutations in the mitogen-activated protein kinase (MAPK) signaling pathway, leading to hyperactivity and proliferation of mutated cells. Although the FDA has approved kinase inhibitors that target specific mutations, recurrences still occur. Therefore, there is a continuing need for regimens to treat cancer. Summary of the Invention

[0004] Disclosed herein are methods for treating a patient with a solid tumor, comprising co-administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of Compound A is about 1 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt thereof, is about 2 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of Compound A is a total amount of up to 10 mg per day, and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt thereof, is about 5 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is administered in two equal doses.

[0005] In certain embodiments, Compound B is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt form is hydroxypropylmethylcellulose acetate succinate.

[0006] In other embodiments, Compound A, or a pharmaceutical salt form thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in the same or different dosage forms.

[0007] In still other embodiments, Compound A is administered in free base form.

[0008] In some embodiments, Compound B or a pharmaceutically acceptable salt thereof is administered once daily.

[0009] In other embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered prior to, simultaneously with, or after administration of Compound B, or a pharmaceutically acceptable salt thereof.

[0010] In certain embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or Compound B, or a pharmaceutically acceptable salt thereof, is administered orally.

[0011] In yet other embodiments, the solid tumor is selected from the group consisting of malignant peripheral nerve sheath tumor, biliary tract cancer, breast cancer, cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, colorectal cancer, thyroid cancer, hepatocellular carcinoma, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, ovarian cancer, melanoma, lung cancer, and peritoneal serous carcinoma. In some embodiments, the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer. In certain embodiments, the patient has non-small cell lung cancer. In some embodiments, the patient has NSCLC that is BRAF class II / III / fusion mutated or KRAS mutant NSCLC.

[0012] In certain embodiments, the patient has melanoma. In some embodiments, the patient has melanoma that is NRAS mutant cutaneous melanoma.

[0013] In some embodiments, the patient has endometrial cancer, in other embodiments, the patient has ovarian cancer, and in yet other embodiments, the patient has low-grade serous ovarian cancer.

[0014] In some embodiments, the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2.

[0015] In certain embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28-day dosing cycle comprising administering Compound A, or a pharmaceutically acceptable salt thereof, twice daily and administering Compound B, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, the 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles.

[0016] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and / or Compound B, or a pharmaceutically acceptable salt thereof, are administered in the form of a tablet and / or capsule.

[0017] definition To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0018] Generally, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless otherwise defined, 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 disclosure belongs.

[0019] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The term "a" (or "an"), as well as the terms "one or more" and "at least one," may be used interchangeably herein. In certain embodiments, the term "a" or "an" means "single." In other embodiments, the term "a" or "an" includes "two or more" or "plural."

[0020] Furthermore, as used herein, "and / or" should be interpreted as a specific disclosure of each of the two specified features or components, regardless of the presence or absence of the other. Thus, when used in phrases such as "A and / or B" herein, the term "and / or" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, when used in phrases such as "A, B, and / or C," the term "and / or" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0021] The term "Compound A" refers to the single enantiomer N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (mirdametinib).

[0022] The term "Compound B" refers to a compound having the following structure: [ka] This compound is also known as 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea.

[0023] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as, for example, a human subject.

[0024] As used herein, the terms "treat," "treated," and "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Accordingly, those in need of treatment include those already diagnosed with or suspected of having a disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; a decrease in the extent of the condition, disorder, or disease; a stabilized (i.e., non-worsening) state of the condition, disorder, or disease; a delay in the onset or slowing of the progression of the condition, disorder, or disease; an improvement or remission (partial or complete) of the condition, disorder, or disease state; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or an enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival if not receiving treatment. The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to that amount of a compound that is sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or clinician.

[0025] In certain embodiments, a subject is "treated" successfully for cancer (e.g., lung cancer or ovarian cancer) according to the methods of the present invention if the patient shows one or more of the following: a reduction in the number of cancer cells or the complete absence thereof; alleviation of one or more symptoms associated with the particular cancer; a reduction in morbidity and mortality; an improvement in quality of life; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), an increase in stable disease (SD), a decrease in progressive disease (PD), an increase in time to progression (TTP), or any combination thereof. In some embodiments, nationally or internationally recognized standards for treatment outcome in a given cancer can be used to determine whether a combination of effective amounts of compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof meets any of these specific endpoints (e.g., CR, PFS, PR).

[0026] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation, being suitable for use in contact with the tissues or organs of humans and animals, without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and being commensurate with a reasonable benefit / risk ratio. Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).Excipients can include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and hydrating agents. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0027] The term "pharmaceutical composition" as used herein refers to a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and can be manufactured or sold as part of a therapeutic regimen for the treatment of a mammalian disease, subject to the approval of a government regulatory agency. Pharmaceutical compositions can be formulated, for example, for oral administration in a unit dosage form (e.g., tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate embolic agents and in a solvent system suitable for intravenous use); for intrathecal injection, for intraventricular injection, for intraparenchymal injection, or in any other pharmaceutically acceptable formulation.

[0028] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of Compound A or Compound B. These salts can be prepared in situ during the manufacturing process of an administration vehicle or dosage form, or by separately reacting a purified compound of the present invention in its free base form with a suitable organic or inorganic acid and then isolating the salt formed during purification. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.)

[0029] Pharmaceutically acceptable salts of the subject compounds include, for example, the conventional non-toxic salts or quaternary ammonium salts of the compounds derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like.

[0030] In certain embodiments, compounds of the present invention may contain one or more acidic functional groups and thus can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the manufacturing process of an administration vehicle or dosage form, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, e.g., Berge et al., supra.)

[0031] The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some embodiments, the term "about" or "approximately" refers to an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% relative to a reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0032] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any suitable route, such as those described herein.

[0033] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound, or pharmaceutical composition thereof, that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease.

[0034] The terms "co-administration," "co-administering," or "co-administered" refer to the administration of a combination of therapeutic agents, such as, for example, Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof. The combination can be administered as two separate entities, such as, for example, separate capsules or tablets, or as a single combined entity, such as, for example, the same capsule or tablet. One therapeutic agent (e.g., Compound A, or a pharmaceutically acceptable salt thereof) can be administered prior to, simultaneously with, or after the other therapeutic agent (e.g., Compound B, or a pharmaceutically acceptable salt thereof) is administered to the subject.

[0035] Whenever an embodiment is described herein as "comprising," it is understood that analogous embodiments described as "consisting of" and / or "consisting essentially of" are also provided.

[0036] The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0037] Disclosed herein is a method of treating a patient having a solid tumor, comprising co-administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the present disclosure provides a method of treating a patient having a solid tumor, comprising co-administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 1 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg to about 8 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is less than 10 mg, less than 9 mg, less than 8 mg, less than 7 mg, or less than 6 mg per day.

[0040] In some embodiments, a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is administered in two equal doses. In this embodiment, a single dose of Compound A or a pharmaceutically acceptable salt thereof is about 0.5 mg to about 5 mg. In some embodiments, a single dose of Compound A or a pharmaceutically acceptable salt thereof is about 1 mg to about 4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, or about 5 mg.

[0041] In some embodiments, Compound A is administered in free base form. In some embodiments, the therapeutically effective amount of Compound A (as the free base) is about 1 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A (as the free base) is about 2 mg to about 8 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A (as the free base) is less than 10 mg, less than 9 mg, less than 8 mg, less than 7 mg, or less than 6 mg per day.

[0042] In some embodiments, a therapeutically effective amount of Compound A (as the free base) is administered in two equal doses. In this embodiment, a single dose of Compound A (as the free base) is about 0.5 mg to about 5 mg. In some embodiments, a single dose of Compound A (as the free base) is about 1 mg to about 4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, or about 5 mg.

[0043] In some embodiments, the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 2 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 2 mg to about 45 mg, 2 mg to about 40 mg, about 5 mg to about 45 mg, or about 5 mg to about 40 mg. In some embodiments, the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt thereof, is about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg.

[0044] In some embodiments, Compound B or a pharmaceutically acceptable salt thereof is administered once daily.

[0045] In some embodiments, Compound B is administered in free base form. In some embodiments, Compound B is in a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is a hydrochloride salt form. In some embodiments, the pharmaceutically acceptable salt form is hydroxypropylmethylcellulose acetate succinate ("HPMCAS").

[0046] In some embodiments, the therapeutically effective amount of Compound B is about 2 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of Compound B is about 2 mg to about 45 mg, 2 mg to about 40 mg, about 5 mg to about 45 mg, or about 5 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound B is about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 25 mg, about 26 mg, about 27 ...8 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 8 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg.

[0047] In some embodiments, Compound B is administered once daily.

[0048] In some embodiments, a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is administered in two separate doses of about 2 mg to about 4 mg (a total daily dose of 4 mg to about 8 mg), and a therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg to about 40 mg administered once per day.

[0049] In some embodiments, a therapeutically effective amount of Compound A (as the free base) is administered in two separate doses of about 2 mg to about 4 mg (total daily dose of 4 mg to about 8 mg), and a therapeutically effective amount of Compound B is about 5 mg to about 40 mg administered once daily.

[0050] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and / or Compound B, or a pharmaceutically acceptable salt thereof, are administered orally.

[0051] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in the same dosage form or different dosage forms. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in different dosage forms. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered before, simultaneously with, or after administration of Compound B, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered before, simultaneously with, or after administration of Compound B, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in the same dosage form. In some embodiments, the dosage form comprising Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, is a capsule.

[0053] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt thereof are administered to treat a patient with a solid tumor. In some embodiments, the solid tumor is selected from the group consisting of malignant peripheral nerve sheath tumor, biliary tract cancer, breast cancer, cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, colorectal cancer, thyroid cancer, hepatocellular carcinoma, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, ovarian cancer, melanoma, lung cancer, and peritoneal serous carcinoma. In some embodiments, the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer. In certain embodiments, the patient has non-small cell lung cancer. In some embodiments, the patient has non-small cell lung cancer (NSCLC) that is BRAF class II / III / fusion mutated NSCLC or KRAS mutant NSCLC.

[0054] In certain embodiments, the patient has melanoma. In some embodiments, the patient has melanoma that is NRAS mutant cutaneous melanoma.

[0055] In some embodiments, the patient has endometrial cancer, in other embodiments, the patient has ovarian cancer, and in yet other embodiments, the patient has low-grade serous ovarian cancer.

[0056] In some embodiments, the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2.

[0057] In certain embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28-day dosing cycle comprising administering Compound A, or a pharmaceutically acceptable salt thereof, twice daily and administering Compound B, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, the 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles.

[0058] All publications (including patents and patent applications) cited herein are hereby incorporated by reference. [Example]

[0059] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of this application.

[0060] A Phase 1 / 2a, open-label, multicenter, dose-escalation and expansion study of Compound A in combination with Compound B will be conducted in adult patients with histologically confirmed, advanced (American Joint Committee on Cancer (AJCC) Stage III or IV) metastatic or unresectable solid tumors that are refractory to or have progressed on or after at least one line of appropriate prior systemic anti-cancer therapy, including chemotherapy, immunotherapy, or an appropriate targeted therapy, or for which no treatment is available or who have not tolerated prior standard therapy.

[0061] The study will be conducted in two sequential parts: Part 1, dose escalation (Phase 1), and Part 2, dose expansion (Phase 2a).

[0062] Participants will receive oral administration of Compound A (free base) and Compound B on a daily, continuous schedule. Compound A (free base) will be administered twice daily (BID) and Compound B will be administered once daily (QD). Each treatment cycle will last 28 days.

[0063] Part 1 (Phase 1 Dose Escalation): Part 1 of the study will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and preliminary evidence of antitumor activity. Part 1 will also identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of Compound A (free base) in combination with Compound B.

[0064] Part 1 Eligible Population: Part 1 includes participants with advanced metastatic or unresectable solid tumors harboring oncogenic mutations or other MAPK pathway abnormalities. MAP pathway mutations and abnormalities include tumors harboring known mutational status and oncogenic mutations in the BRAF gene (including BRAF class I or V600 mutations, kinase-activating BRAF class II or non-V600 mutations, kinase-impairing class III or non-V600 mutations, or BRAF fusions), ARAF, and RAF1 / CRAF. Additionally, participants with tumors harboring mutations in NRAS, KRAS, or HRAS, NF1, MAP2K1, MAP2K2, and MAPK1 are also eligible for Part 1. Participants with colorectal cancer (CRC) or pancreatic KRAS-mutated tumors will be limited to no more than one-third of participants enrolled in each Part 1 cohort to increase participant diversity.

[0065] Tumor mutation status will be determined by Clinical Laboratory Improvement Act (CLIA)-certified next-generation sequencing (NGS) assay of archival tumor samples or fresh tumor biopsies. This information may be available from prior reports obtained any time before study treatment initiation or from local laboratory assays performed during screening.

[0066] Dose Escalation Plan for Part 1: The planned dose levels for Compound A (free base) and Compound B for Part 1 are shown below: Cohort 1: 2 mg BID Compound A (free base) + 5 mg QD Compound B Cohort 2: 2 mg BID Compound A (free base) + 10 mg QD Compound B Cohort 3: 2 mg BID Compound A (free base) + 20 mg QD Compound B Cohort 4: 2 mg BID Compound A (free base) + 30 mg QD Compound B Cohort 5: 3 mg BID Compound A (free base) + 30 mg QD Compound B Cohort 6: 4 mg BID Compound A (free base) + 30 mg QD Compound B

[0067] If the planned highest dose level (Cohort 6) is approved by the Cohort Management Committee (CMC) based on Bayesian Optimal Interval (BOIN) estimates of toxicity rates and review of all available data from the study, the sponsor may continue dose escalation in consultation with the CMC. The highest doses of Compound A (as free base) and Compound B in Part 1 dose escalation will not exceed 8 mg BID and 40 mg QD, respectively.

[0068] If the planned dose levels are not tolerated based on Bayesian optimal interval (BOIN) estimates of toxicity rates derived from observed dose-limiting toxicity (DLT) rates and / or review of all available data from the study, an alternative dose search may be performed to identify the optimal dose ratio for the drug combination. Alternative dose-finding schemes may consider increasing the dose of compound A (as free base) while decreasing the dose of compound B.

[0069] After dose escalation is complete, the MTD is calculated using isotonicity regression. Specifically, the MTD is selected as the dose with an isotonicity estimate of toxicity rate ≤ 0.359 that is closest to the target toxicity rate.

[0070] An intolerable dose is defined as a study treatment dose that exceeds the target DLT rate.

[0071] Dose escalation will be discontinued when an intolerable dose is reached or the highest planned dose level of Compound A (as free base) or Compound B (8 mg BID or 40 mg QD, respectively) is tolerated.

[0072] Selection of RP2D for Part 1: Based on evaluation of all available study data from Part 1, recommend the doses and dosing schedules to be used as the RP2D for Compound A (free base) and Compound B in Part 2.

[0073] Part 2 (Phase 2a Dose Expansion): Part 2 will begin after the RP2D of the combination of Compound A (free base) and Compound B has been identified in Part 1. Part 2 may begin in parallel with the conduction and analysis of the Part 1 PDx expansion cohort, or may begin afterward.

[0074] Part 2 will examine the safety, tolerability, efficacy, PK, and PDx of Compound A (as the free base) in combination with Compound B.

[0075] Part 2 will follow a parallel design and include one or more dose expansion cohorts, with each participant treated with a combination of Compound A (free base) and Compound B at the RP2D.

[0076] Participants experiencing a treatment-emergent adverse event (TEAE) requiring a change in treatment will be managed according to the applicable guidelines of this protocol.

[0077] Part 2 Eligible Population: The Part 2 eligible population includes participants with advanced metastatic or unresectable solid tumors harboring oncogenic mutations unique to each expansion cohort. Tumor mutation status should be determined by CLIA-compliant NGS assay of archival tumor samples or fresh tumor biopsies. This information may be available from historical reports obtained any time before study treatment initiation or from local laboratory assays performed during screening.

[0078] At the sponsor's discretion, one or more of the following cohorts may be initiated in parallel or sequentially: 1. Expansion Cohort A (n=20 evaluable participants): Participants with cutaneous melanoma harboring an NRAS mutation. a. At least 15 of the 20 participants (75%) in Cohort A must have an NRAS Q61x mutation (i.e., Q61R, Q61K, or Q61L). 2. Expansion Cohort B (n=30 evaluable participants): Participants with KRAS-mutated NSCLC a. At least 15 (50%) of the 30 evaluable participants in Cohort B must have the KRAS G12V mutation. 3. Expansion Cohort C (n=30 evaluable participants): Participants with NSCLC or cutaneous melanoma harboring BRAF class II or class III mutations or BRAF fusions. Cohort C1: Approximately 15 evaluable participants with NSCLC harboring BRAF class II or class III mutations or BRAF fusions. b. Cohort C2: Approximately 15 evaluable participants with cutaneous melanoma harboring BRAF class II or class III mutations or BRAF fusions.

Claims

1. 1. A method of treating a patient having a solid tumor, comprising co-administering to the patient a therapeutically effective amount of mirdametinib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the therapeutically effective amount of mirdametinib or a pharmaceutically acceptable salt thereof is from about 1 mg to about 10 mg per day.

3. 3. The method of claim 1 or 2, wherein the therapeutically effective amount of 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof is from about 2 mg to about 50 mg per day.

4. 3. The method of claim 1 or 2, wherein the therapeutically effective amount of mirdametinib is a total amount of up to 10 mg per day and the therapeutically effective amount of 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or a pharmaceutically acceptable salt thereof, is from about 5 mg to about 40 mg per day.

5. 5. The method of claim 4, wherein the therapeutically effective amount of mirdametinib is administered in two equal doses.

6. 6. The method of any one of claims 1 to 5, wherein 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea is in the form of a pharmaceutically acceptable salt.

7. 7. The method of claim 6, wherein the pharmaceutically acceptable salt form is hydroxypropyl methylcellulose acetate succinate.

8. The method according to any one of claims 1 to 7, wherein mirdametinib or a pharmaceutically acceptable salt thereof and 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof are administered in the same or different dosage forms.

9. 9. The method of claim 8, wherein mirdametinib is administered in free base form.

10. The method according to any one of claims 1 to 9, wherein 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof is administered once a day.

11. The method of claim 10, wherein mirdametinib or a pharmaceutically acceptable salt thereof is administered before, simultaneously with, or after administration of 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 1 to 11, wherein mirdametinib or a pharmaceutically acceptable salt thereof and 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof are orally administered.

13. 13. The method of any one of claims 1 to 12, wherein the solid tumor is selected from the group consisting of malignant peripheral nerve sheath tumor, biliary tract cancer, breast cancer, cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, colorectal cancer, thyroid cancer, hepatocellular carcinoma, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, ovarian cancer, melanoma, lung cancer, and peritoneal serous carcinoma.

14. 14. The method of claim 13, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

15. 15. The method of claim 14, wherein the patient has non-small cell lung cancer.

16. 16. The method of claim 15, wherein the patient has non-small cell lung cancer (NSCLC) that is a BRAF class II / III / fusion mutated NSCLC or a KRAS mutant NSCLC.

17. 14. The method of claim 13, wherein the patient has melanoma.

18. 18. The method of claim 17, wherein the patient has a melanoma that is an NRAS mutant cutaneous melanoma.

19. 14. The method of claim 13, wherein the patient has endometrial cancer.

20. 14. The method of claim 13, wherein the patient has ovarian cancer.

21. 14. The method of claim 13, wherein the patient has low-grade serous ovarian cancer.

22. 22. The method of any one of claims 1 to 21, wherein the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2.

23. A 28-day dosing cycle comprising twice-daily administration of mirdametinib or a pharmaceutically acceptable salt thereof and once-daily administration of 1-((1S,1aS,6bS)-5-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1 to 22, wherein mirdametinib or a pharmaceutically acceptable salt thereof and 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof are administered in a dose-dependent manner.

24. 24. The method of claim 23, wherein the 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles.

25. The method according to any one of claims 1 to 24, wherein mirdametinib, or a pharmaceutically acceptable salt thereof, and / or 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or a pharmaceutically acceptable salt thereof, is administered in the form of a tablet and / or a capsule.

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