Co-administration of mirdametinib and lifirafenib for use in the treatment of cancer - Patent Application 20100222999

Abstract

The present disclosure relates to a method of treating cancer comprising co-administering mirdametinib, or a pharmaceutically acceptable salt form thereof, and lifirafenib, or a pharmaceutically acceptable salt form thereof, to a patient in need thereof. Also disclosed are pharmaceutical compositions of mirdametinib, or a pharmaceutically acceptable salt form thereof, and lifirafenib, or a pharmaceutically acceptable salt form thereof, for use in such cancer treatment, and the use of these compounds for the manufacture of a medicament for the treatment of cancer.

Description

[Technical Field]

[0001] The present disclosure relates to a method for treating cancer, comprising co-administering mirdametinib or a pharmaceutically acceptable salt form thereof and lifirafenib or a pharmaceutically acceptable salt form thereof to a patient in need thereof. Also disclosed are pharmaceutical compositions of mirdametinib or a pharmaceutically acceptable salt form thereof and lifirafenib or a pharmaceutically acceptable salt form thereof for use in such cancer treatment. The present disclosure further relates to the use of a combination of mirdametinib or a pharmaceutically acceptable salt form thereof and lifirafenib or a pharmaceutically acceptable salt form thereof for the manufacture of a medicament for cancer treatment. [Background technology]

[0002] N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide ("Compound A," "mirdametinib," "PD-0325901")) is a small molecule drug designed to inhibit mitogen-activated protein kinase 1 ("MEK1") and mitogen-activated protein kinase 2 ("MEK2"). MEK1 and MEK2 are proteins that play key roles in the mitogen-activated protein kinase ("MAPK") signaling pathway. The MAPK pathway is essential for cell survival and proliferation, and inappropriate activation of this pathway has been shown to help enable tumor growth. Mirdametinib is a highly specific, non-ATP-competitive inhibitor of MEK1 and MEK2. Through this mechanism of action, mirdametinib significantly inhibits the phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby impairing tumor cell growth in culture and in vivo. In addition, increased MEK / ERK activity induced by inflammatory cytokines has been shown to contribute to the inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

[0003] 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyldin-2(1H)-one (“Compound B,” “lifirafenib,” “BGB-283”)” is a novel, first-in-class, investigational RAF dimer inhibitor that exhibits potent and reversible inhibition of wild-type A-RAF, B-RAF, C-RAF, and B-RAFV600E, as well as EGFR and K-RAS, enabling efficacy across a broad range of tumor types driven by mutations in the MAPK pathway (e.g., tumors with K-RAS driver mutations).

[0004] Therapeutic agents targeting the oncogenic B-RAF have been developed within the past decade. Clinical trials demonstrated unprecedented clinical responses superior to the then-standard treatment, dacarbazine (Chapman 2011), leading to the US FDA approval of four drugs and two combination regimens targeting the MAPK pathway (Chapman 2011; Hauschild 2012; Larkin 2014; Long 2015). Importantly, early attempts focused on B-RAF inhibitor monotherapy. However, resistance rapidly developed in most patients, with progression-free survival (PFS) of less than 6 months with these agents (Chapman 2011; Hauschild 2012). Insights from translational research have highlighted MAPK reactivation as a major resistance mechanism (Rizos 2014; Kwong 2015), leading to therapeutic strategies that simultaneously target B-RAF and MEK. This has resulted in a nearly doubling of PFS (Larkin 2014; Long 2015). However, although long-term disease control has been achieved in some patients, resistance continues to develop in the majority of patients (Flaherty 2012a; Flaherty 2012b; reviewed by Reddy 2016). Therefore, the combination of a second-generation B-RAF inhibitor with a MEK inhibitor is highly desirable as a novel combination. [Brief explanation of the drawings]

[0005] [Figure 1] 1 shows the mean tumor volume over time in Balb / c nude mice implanted with Calu-6 tumors and treated with various concentrations of Compound A and Compound B maleate.

[0006] [Figure 2] 1 shows the body weight over time of mice implanted with Calu-6 tumors and treated with various concentrations of Compound A and Compound B maleate.

[0007] [Figure 3] 1 shows the percentage change in final volume relative to baseline for each individual Calu-6 tumor in Balb / c nude mice implanted with Calu-6 tumors and treated with various concentrations of Compound A and Compound B maleate.

[0008] [Figure 4] Best change (%) from baseline in tumor size (defined by the sum of the longest diameters of target lesions) in patients with advanced or refractory solid tumors harboring mutations in MAPK genes is shown. Summary of the Invention

[0009] The present disclosure features compositions and methods useful for treating various cancers, comprising co-administration of mirdametinib, or a pharmaceutically acceptable salt form thereof, and lifirafenib, or a pharmaceutically acceptable salt form thereof. In some embodiments, the present disclosure provides a method of 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 form thereof, and a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof. In some embodiments, the present disclosure provides the use of a combination of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, for the manufacture of a medicament for treating a patient with a solid tumor.

[0010] In some embodiments, the therapeutically effective amount of Compound A is from about 1 mg to about 5 mg per day. In some embodiments, the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is from about 5 mg to about 40 mg per day.

[0011] In some embodiments, the therapeutically effective amount of Compound A is about 1 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 15 mg per day.

[0012] In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day.

[0013] In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day.

[0014] In some embodiments, the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 10 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day.

[0015] In some embodiments, the therapeutically effective amount of Compound A is about 5 mg per day, and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 10 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 5 mg per day, and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 1 mg per day, and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 2 mg per day, and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 2 mg per day, and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day.In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 5 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 10 mg per day.

[0016] In some embodiments, Compound B is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt form of Compound B is a maleate salt. In some embodiments, the maleate salt is a sesqui-maleate salt.

[0017] In some embodiments, the therapeutically effective amount of Compound A is about 1 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 5 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 1 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 7 mg per day.

[0018] In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 10 mg to about 30 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 13 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 27 mg per day.

[0019] In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 15 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 34 mg per day.

[0020] In some embodiments, the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 20 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 27 mg per day.

[0021] In some embodiments, the therapeutically effective amount of Compound A is about 5 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 25 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 5 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 34 mg per day.

[0022] In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 1 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day.In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 13 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 7 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 13 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 7 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 13 mg per day.

[0023] In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in the same or different dosage forms. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in the same dosage form. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered orally.

[0024] In some embodiments, the dosage form is a capsule.

[0025] In some embodiments, Compound A is administered once per day. In some embodiments, Compound B or a pharmaceutically acceptable salt form thereof is administered once per day.

[0026] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: a. Compound A or a pharmaceutically acceptable salt form thereof; b. Compound B or a pharmaceutically acceptable salt form thereof; c. fillers, d. disintegrants, and e. Lubricants.

[0027] In some embodiments, the pharmaceutically acceptable salt of Compound B is a maleate salt of Compound B.

[0028] In some embodiments, the pharmaceutical composition comprises about 0.8 mg to about 1.2 mg of Compound A. In some embodiments, the pharmaceutical composition comprises about 1.5 mg to about 2.5 mg of Compound A.

[0029] In some embodiments, the pharmaceutical composition comprises about 6 mg to about 8 mg of Compound B as the maleate salt. In some embodiments, the pharmaceutical composition comprises about 20 mg to about 35 mg of Compound B as the maleate salt.

[0030] In some embodiments, the filler in the pharmaceutical composition is present at about 80 wt / wt% to about 90 wt / wt%. In some embodiments, the filler in the pharmaceutical composition is present at about 72.5 wt / wt% to about 85 wt / wt%. In some embodiments, the filler in the pharmaceutical composition is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, dicalcium phosphate, and combinations thereof. In some embodiments, the filler comprises microcrystalline cellulose. In some embodiments, the filler in the pharmaceutical composition comprises silicified microcrystalline cellulose.

[0031] In some embodiments, the disintegrant in the pharmaceutical composition is present at about 3.5 wt / wt% to about 4.5 wt / wt%. In some embodiments, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, and combinations thereof. In some embodiments, the disintegrant in the pharmaceutical composition comprises croscarmellose sodium.

[0032] In some embodiments, the lubricant in the pharmaceutical composition is present at about 1.5 wt / wt% to about 5.0 wt / wt%. In some embodiments, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, glyceryl dibehenate, talc, and combinations thereof. In some embodiments, the lubricant in the pharmaceutical composition comprises sodium stearyl fumarate. In some embodiments, the lubricant in the pharmaceutical composition comprises magnesium stearate.

[0033] In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is a tablet or a capsule. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is a capsule.

[0034] In some embodiments, the capsule comprises about 1 mg of Compound A and about 7 mg of the maleate salt of Compound B, wherein each component of the capsule is as follows: a. about 0.8 wt / wt% to about 1.2 wt / wt% of Compound A; b. about 6 wt / wt% to about 8 wt / wt% of a maleate salt of Compound B; c. about 80 wt / wt% to about 90 wt / wt% silicified microcrystalline cellulose; d. about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium; e. about 1.5 wt / wt% to about 5.0 wt / wt% sodium stearyl fumarate, and f. A gelatin capsule encapsulating components a to e.

[0035] In some embodiments, the capsule contains about 2 mg of Compound A and about 27 mg of the maleate salt of Compound B, where each component of the capsule is as follows: a. about 0.8 wt / wt% to about 1.3 wt / wt% of Compound A; b. about 12.3 wt / wt% to about 15.0 wt / wt% of a maleate salt of Compound B; c. about 72.5 wt / wt% to about 85 wt / wt% silicified microcrystalline cellulose; d. about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium; e. about 1.5 wt / wt% to about 5.0 wt / wt% sodium stearyl fumarate, and f. A gelatin capsule encapsulating components a to e.

[0036] In some embodiments, Compound A or a pharmaceutically acceptable salt form thereof and Compound B or a pharmaceutically acceptable salt form thereof are administered to treat a patient with cancer. In some embodiments, the cancer is 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, lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, colorectal cancer ("CRC"), thyroid cancer, hepatocellular carcinoma, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, ovarian cancer, melanoma, and peritoneal serous carcinoma. In some embodiments, the patient has non-small cell lung cancer. In some embodiments, the patient has endometrial cancer. In some embodiments, the patient has ovarian cancer. In some embodiments, the patient has low-grade serous ovarian cancer. In some embodiments, the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2. In some embodiments, the patient has a confirmed mutation in RASA1 and / or RAF1.

[0037] In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising (a) a 21 day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, followed by (b) a 7 day period during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising (a) a 21 day period during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, followed by (b) a 7 day period during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each period comprising: (i) a 5-day period during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (ii) two days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) a 7-day period during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising: (i) a 5-day period during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (ii) two days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle that includes (a) three 7-day periods, each period including (i) 4 days during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) 3 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 4 days during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) 3 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

[0038] In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day administration cycle comprising (a) 21 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day administration cycle comprising (a) 21 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising (i) 5 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 2 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; and (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising (i) 5 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 2 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each period comprising (i) 4 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 3 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 4 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 3 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0039] In some embodiments, the 28-day dosing cycle is repeated for a total of up to 24 consecutive 28-day dosing cycles.

[0040] In some embodiments, only Compound B or a pharmaceutically acceptable salt form thereof is administered during the lead-in period prior to the first 28-day administration cycle described above. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as or less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above.

[0041] In some embodiments, one or both of Compound A or a pharmaceutically acceptable salt form thereof and Compound B or a pharmaceutically acceptable salt form thereof are administered during the lead-in period prior to the first cycle of the 28-day administration cycle described above at a dose that is less than the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt form thereof and Compound B or a pharmaceutically acceptable salt form thereof administered during the first cycle of the 28-day administration cycle described above. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above.

[0042] In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg to about 5 mg per day. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg per day. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 2 mg per day. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 3 mg per day.

[0043] In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 25 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 20 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 15 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 10 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 15 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 20 mg per day.

[0044] In some embodiments, Compound B administered during the lead-in period is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a maleate (which may be a sesqui-maleate). In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 5 mg to about 40 mg per day. In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 5 mg to about 30 mg per day. In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 5 mg to about 25 mg per day. In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 7 mg per day. In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 13 mg per day. In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg per day. In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 27 mg per day.

[0045] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and / or Compound B or a pharmaceutically acceptable salt thereof are administered daily during the lead-in period. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and / or Compound B or a pharmaceutically acceptable salt thereof are administered once daily during the lead-in period. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt form thereof are administered orally during the lead-in period.

[0046] 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 or different dosage forms during the lead-in period. 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 during the lead-in period. In some embodiments, the dosage form is a capsule.

[0047] 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 during the lead-in period. In some embodiments, Compound A is administered before, simultaneously with, or after administration of Compound B, or a pharmaceutically acceptable salt thereof, during the lead-in period. In some embodiments, the dosage form of Compound A, or a pharmaceutically acceptable salt thereof, is a capsule. In some embodiments, the dosage form of Compound B, or a pharmaceutically acceptable salt thereof, is a capsule.

[0048] In some embodiments, the lead-in period begins 21 days before the first 28-day administration cycle. In some embodiments, the lead-in period begins 14 days before the first 28-day administration cycle. In some embodiments, the lead-in period begins 10 days before the first 28-day administration cycle. In some embodiments, the lead-in period begins 7 days before the first 28-day administration cycle.

[0049] In some embodiments, described herein are methods of treating a patient having a solid tumor, comprising administering 2 mg of Compound A as the free base and 15 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0050] In some embodiments, described herein are methods of treating a patient having a solid tumor, comprising administering 2 mg of Compound A as the free base and 20 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0051] In some embodiments, described herein are methods of treating a patient having a solid tumor, the methods comprising a 7-day cycle comprising: (a) administering 3 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by (b) 2 consecutive days without administration of Compound A or Compound B.

[0052] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 3 mg of Compound A free base and 10 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 14 consecutive days, followed by (b) (i) administering 3 mg of Compound A free base and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days.

[0053] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 2 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 1 mg of Compound A free base twice daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle that includes administering neither Compound A nor Compound B for 2 consecutive days.

[0054] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 1 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle that includes administering neither Compound A nor Compound B for 2 consecutive days.

[0055] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 2 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle that includes administering neither Compound A nor Compound B for 2 consecutive days.

[0056] In some embodiments, described herein are methods of treating a patient having a solid tumor, the methods comprising a 7-day cycle comprising: (a) administering 4 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by (b) 2 consecutive days without administration of Compound A or Compound B.

[0057] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) a 7-day treatment cycle comprising administering 3 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of either Compound A or Compound B.

[0058] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 4 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle that includes administering neither Compound A nor Compound B for 2 consecutive days.

[0059] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) (i) administering 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days.

[0060] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 4 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 4 mg of Compound A free base once daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle that includes administering neither Compound A nor Compound B for 2 consecutive days.

[0061] In some embodiments, described herein are methods of treating a patient having a solid tumor, comprising administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0062] In some embodiments, described herein are methods of treating a patient with a solid tumor, comprising administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0063] In some embodiments, described herein are methods of treating a patient having a solid tumor, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0064] In some embodiments, described herein are methods of treating a patient having a solid tumor, comprising administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily.

[0065] In some embodiments, described herein are methods of treating a patient having a solid tumor, comprising administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily.

[0066] In some embodiments, described herein are methods of treating a patient having a solid tumor, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily. definition

[0067] To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0068] 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.

[0069] 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 terms "a" (or "an"), as well as "one or more" and "at least one," can 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 "plurality."

[0070] Furthermore, as used herein, "and / or" shall be construed as specifically disclosing the two specified features or components, with or without the other. Thus, the term "and / or," when used in phrases such as "A and / or B," is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or," when used in phrases such as "A, B, and / or C," is intended to encompass each of the following aspects: 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).

[0071] The terms "Compound A," "mirdametinib," and "PD-0325901" refer to the single enantiomer N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide. The structure of Compound A is as follows: [ka]

[0072] The terms "Compound B," "lifirafenib," and "BGB-283" refer to the single enantiomer 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopenta[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one. The structure of Compound B is as follows: [ka]

[0073] 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, e.g., with reference to a mammalian subject (e.g., a human subject).

[0074] As used herein, the terms "treat," "treated," and "treating" refer to both therapeutic treatment and prophylactic or preventative measures aimed at preventing or slowing down (alleviating) an undesirable physiological condition, disorder, or disease, or achieving a beneficial or desired clinical outcome. Accordingly, those in need of treatment also include those already diagnosed with or suspected of having a disorder. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; a decrease in the severity 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 in the state of the condition, disorder, or disease, or remission (whether partial or total), whether detectable or undetectable; 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 sufficient, when administered, to prevent the occurrence of, or alleviate to some extent, one or more symptoms of, the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound 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.

[0075] In certain embodiments, if the subject shows one or more of the following: reduction or complete absence of cancer cell count; alleviation of one or more symptoms associated with specific cancer; reduction in morbidity and mortality; improvement in quality of life; increase in 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), stable disease (SD), decrease in progression (PD), increase in time to progression (TTP), or any combination thereof, the subject is "treated" with cancer (for example, lung cancer or ovarian cancer) according to the method of the present invention.In some embodiments, the nationally or internationally accepted standard of therapeutic outcome for a given cancer can be used to determine whether the combination of effective doses of mirdametinib and lifirafenib meets any of these specific endpoints (for example, CR, PFS, PR).

[0076] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle (e.g., liquid or solid filler, diluent, excipient, solvent, or encapsulating material). In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and 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, according to a reasonable benefit / risk ratio. Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins:Philadelphia,PA, 2005;Handbook of Pharmaceutical Excipients,5 thEdition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3 rd 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 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, flow agents (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration. 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.

[0077] As used herein, the term "pharmaceutical composition" refers to a composition comprising the compound described herein, formulated with a pharmaceutically acceptable excipient, and can be manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for treating disease in mammals.The pharmaceutical composition can be formulated, for example, for oral administration in unit dosage form (e.g., as a tablet, capsule, caplet, gel cap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution that does not contain particulate matter and in a solvent system suitable for intravenous use); for intrathecal injection; for intraventricular injection; for intraparenchymal injection; or any other pharmaceutically acceptable formulation.

[0078] 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 invention in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed during subsequent 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, lauryl sulfonate, and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.)

[0079] Pharmaceutically acceptable salts of the subject compounds include, for example, conventional non-toxic salts or quaternary ammonium salts derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.) and organic acids (e.g., 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, etc.).

[0080] In certain embodiments, the compounds of the present invention may contain one or more acidic functional groups and, therefore, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In such cases, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic base addition salts of the compounds of the present invention. Such salts can be prepared in situ during the manufacturing process of the administration vehicle or dosage form, or by separately reacting the purified compound in its free acid form with a suitable base (e.g., hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, aluminum, and the like. 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.)

[0081] The term "about" or "approximately" refers to within an acceptable range of error for a particular value, in the judgment of 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" refers to 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 up to 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of a reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0082] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation containing a compound as described herein) to a subject or system. Administration to an animal subject (e.g., a human) can be by any suitable route (e.g., a route described herein).

[0083] 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.

[0084] The terms "co-administration," "co-administering," or "co-administered" refer to the administration of a combination of therapeutic agents (e.g., a combination of mirdametinib and lifirafenib). The combination may be administered as two separate entities (e.g., separate capsules or tablets) or as a single combined entity (e.g., the same capsule or tablet). One therapeutic agent (e.g., Compound A or a pharmaceutically acceptable salt form thereof) may be administered before, simultaneously with, or after the other therapeutic agent (e.g., Compound B or a pharmaceutically acceptable salt form thereof) is administered to a subject.

[0085] Whenever an embodiment is described herein using the term "comprising," it should be understood that otherwise similar embodiments described using the terms "consisting of" and / or "consisting essentially of" are also provided.

[0086] The details of one or more embodiments are set forth in the description that follows. Other features, objects, and advantages will be apparent from the description and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0087] The present inventors have developed a method for treating certain cancers by co-administration of mirdametinib and lifirafenib, and also disclose dosage forms comprising these compounds for co-administration, and the use of these compounds for the manufacture of a medicament for the treatment of certain cancers.

[0088] In some embodiments, the 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 form thereof, and a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof.

[0089] In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt form thereof is about 1 mg to about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt form thereof is about 1 mg to about 12 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt form 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 form thereof is 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, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg.

[0090] In some embodiments, Compound A is in the form of a free base.

[0091] In some embodiments, 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 B or a pharmaceutically acceptable salt thereof is about 5 mg to about 35 mg, about 5 mg to about 30 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, or about 5 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 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, or about 10 mg to about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, or about 15 mg to about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, or about 20 mg to about 25 mg per day. In some embodiments, the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 25 mg to about 40 mg, about 25 mg to about 35 mg, or about 25 mg to about 30 mg per day. In some embodiments, the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 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 19 mg, about 20 mg, about 21 mg, about 22 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, or about 40 mg per day.

[0092] In some embodiments, the therapeutically effective amount of Compound A is about 1 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 15 mg per day.

[0093] In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day.

[0094] In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day.

[0095] In some embodiments, the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 10 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day.

[0096] In some embodiments, the therapeutically effective amount of Compound A is about 5 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 10 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 5 mg per day and the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 40 mg per day.

[0097] In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 1 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day.In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day.

[0098] In some embodiments, Compound B is in a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is a maleate salt. In some embodiments, the maleate salt is a sesqui-maleate salt.

[0099] In some embodiments, the therapeutically effective amount of the maleate form of Compound B is about 5 mg to about 35 mg per day. In some embodiments, the therapeutically effective amount of the maleate form of Compound B is about 5 mg to about 30 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, or about 5 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of the maleate form of Compound B is about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, or about 10 mg to about 15 mg per day. In some embodiments, the therapeutically effective amount of the maleate form of Compound B is about 15 mg to about 30 mg, about 15 mg to about 25 mg, or about 15 mg to about 20 mg per day. In some embodiments, the therapeutically effective amount of the maleate form of Compound B is about 20 mg to about 30 mg or about 20 mg to about 25 mg per day. In some embodiments, the therapeutically effective amount of the maleate form of Compound B is about 25 mg to about 30 mg per day. In some embodiments, the therapeutically effective amount of the maleate form of Compound B is 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 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, or about 35 mg.

[0100] In some embodiments, the therapeutically effective amount of Compound A is about 1 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 5 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 1 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 7 mg per day.

[0101] In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 10 mg to about 30 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 13 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 27 mg per day.

[0102] In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 15 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 34 mg per day.

[0103] In some embodiments, the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 20 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 27 mg per day.

[0104] In some embodiments, the therapeutically effective amount of Compound A is about 5 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 25 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount of Compound A is about 5 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 34 mg per day.

[0105] In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 1 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day.In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 13 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 7 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 13 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 7 mg per day. In some embodiments, the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 13 mg per day.

[0106] In some embodiments, Compound A or a pharmaceutically acceptable salt form thereof is administered once per day. In some embodiments, Compound B or a pharmaceutically acceptable salt form thereof is administered once per day.

[0107] In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in the same or different dosage forms. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in different dosage forms. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, is administered before, simultaneously with, or after administration of Compound B, or a pharmaceutically acceptable salt form thereof.

[0108] In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in the same dosage form. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered orally. In some embodiments, the dosage form comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is a capsule.

[0109] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: a. Compound A or a pharmaceutically acceptable salt form thereof; b. Compound B or a pharmaceutically acceptable salt form thereof; c. fillers, d. disintegrants, and e. Lubricants.

[0110] In some embodiments, the pharmaceutical composition comprises about 0.8 mg to about 1.2 mg of Compound A. In some embodiments, the pharmaceutical composition comprises about 1.5 mg to about 2.5 mg of Compound A. In some embodiments, the pharmaceutical composition comprises about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg of Compound A.

[0111] In some embodiments, the pharmaceutical composition comprises about 20 mg to about 35 mg of Compound B maleate. In some embodiments, the pharmaceutical composition comprises about 22 mg to about 34 mg of Compound B maleate. In some embodiments, the pharmaceutical composition comprises about 23 mg to about 29 mg of Compound B maleate. In some embodiments, the pharmaceutical composition comprises about 25 mg to about 28 mg of Compound B maleate. In some embodiments, the pharmaceutical composition comprises 20 mg, about 21 mg, about 22 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, or about 35 mg of Compound B maleate.

[0112] In some embodiments, the pharmaceutical composition comprises a filler. In some embodiments, the pharmaceutical composition comprises about 70 wt / wt% to about 90 wt / wt% of the filler. In some embodiments, the pharmaceutical composition comprises about 72.5 wt / wt% to about 85 wt / wt% of the filler. In some embodiments, the pharmaceutical composition comprises about 80 wt / wt% to about 90 wt / wt% of the filler. In some embodiments, the pharmaceutical composition comprises about 70 wt / wt%, about 72.5 wt / wt%, about 75 wt / wt%, about 80 wt / wt%, about 85 wt / wt%, or about 90 wt / wt% of the filler.

[0113] In some embodiments, the filler is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, dicalcium phosphate, and combinations thereof. In some embodiments, the filler comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 70 wt / wt% to about 90 wt / wt% silicified microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 72.5 wt / wt% to about 85 wt / wt% silicified microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 80 wt / wt% to about 90 wt / wt% silicified microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 70 wt / wt%, about 72.5 wt / wt%, about 75 wt / wt%, about 80 wt / wt%, about 85 wt / wt%, or about 90 wt / wt% silicified microcrystalline cellulose.

[0114] In some embodiments, the pharmaceutical composition comprises about 3.5 wt / wt% to about 4.5 wt / wt% of disintegrant, hi some embodiments, the pharmaceutical composition comprises about 3.5 wt / wt%, about 4.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, or about 4.5 wt / wt% of disintegrant.

[0115] In some embodiments, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, and combinations thereof. In some embodiments, the disintegrant comprises croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.5 wt / wt%, about 4.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, or about 4.5 wt / wt% croscarmellose sodium.

[0116] In some embodiments, the pharmaceutical composition comprises about 1.5 wt / wt% to about 5 wt / wt% of a lubricant, hi some embodiments, the pharmaceutical composition comprises about 1.5 wt / wt%, about 2 wt / wt%, about 2.5 wt / wt%, about 3 wt / wt%, about 3.5 wt / wt%, about 4 wt / wt%, about 4.5 wt / wt%, or about 5 wt / wt% of a lubricant.

[0117] In some embodiments, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, glyceryl dibehenate, talc, and combinations thereof. In some embodiments, the lubricant comprises sodium stearyl fumarate or magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.5 wt / wt%, about 2 wt / wt%, about 2.5 wt / wt%, about 3 wt / wt%, about 3.5 wt / wt%, about 4 wt / wt%, about 4.5 wt / wt%, or about 5 wt / wt% sodium stearyl fumarate. In some embodiments, the pharmaceutical composition comprises about 1.5 wt / wt%, about 2 wt / wt%, about 2.5 wt / wt%, about 3 wt / wt%, about 3.5 wt / wt%, about 4 wt / wt%, about 4.5 wt / wt%, or about 5 wt / wt% magnesium stearate.

[0118] In some embodiments, the pharmaceutical composition is administered orally. In some embodiments, the pharmaceutical composition is a tablet or capsule. In some embodiments, the pharmaceutical composition is a capsule.

[0119] In some embodiments, the capsule comprises about 1 mg of Compound A and about 7 mg of the maleate salt of Compound B, wherein each component of the capsule is as follows: a. about 0.8 wt / wt% to about 1.2 wt / wt% of Compound A; b. about 6 wt / wt% to about 8 wt / wt% of a maleate salt of Compound B; c. about 80 wt / wt% to about 90 wt / wt% silicified microcrystalline cellulose; d. about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium; e. about 1.5 wt / wt% to about 5.0 wt / wt% sodium stearyl fumarate, and f. A gelatin capsule encapsulating components a to e.

[0120] In some embodiments, the capsule contains about 2 mg of Compound A and about 27 mg of the maleate salt of Compound B, where each component of the capsule is as follows: a. about 0.8 wt / wt% to about 1.3 wt / wt% of Compound A; b. about 12.3 wt / wt% to about 15.0 wt / wt% of a maleate salt of Compound B; c. about 72.5 wt / wt% to about 85 wt / wt% silicified microcrystalline cellulose; d. about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium; e. about 1.5 wt / wt% to about 5.0 wt / wt% sodium stearyl fumarate, and f. A gelatin capsule encapsulating components a to e.

[0121] In some embodiments, Compound A or a pharmaceutically acceptable salt form thereof and Compound B or a pharmaceutically acceptable salt form 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, lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and peritoneal serous carcinoma. In some embodiments, the patient has non-small cell lung cancer. In some embodiments, the patient has endometrial cancer. In some embodiments, the patient has ovarian cancer. In some embodiments, the patient has low-grade serous ovarian cancer. In some embodiments, the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2. In some embodiments, the patient has a confirmed mutation in RASA1 and / or RAF1.

[0122] In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising (a) a 21 day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, followed by (b) a 7 day period during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising (a) a 21 day period during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, followed by (b) a 7 day period during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each period comprising: (i) a 5-day period during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (ii) two days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) a 7-day period during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising: (i) a 5-day period during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (ii) two days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle that includes (a) three 7-day periods, each period including (i) 4 days during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) 3 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. In some embodiments, Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 4 days during which both Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) 3 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt form thereof, nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

[0123] In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day administration cycle comprising (a) 21 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day administration cycle comprising (a) 21 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising (i) 5 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 2 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; and (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising (i) 5 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 2 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each period comprising (i) 4 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 3 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered. In some embodiments, the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered in a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 4 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 3 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0124] In some embodiments, the 28-day dosing cycle is repeated for a total of up to 24 consecutive 28-day dosing cycles.

[0125] In some embodiments, only Compound B or a pharmaceutically acceptable salt form thereof is administered during the lead-in period prior to the first 28-day administration cycle described above. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as or less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above.

[0126] In some embodiments, one or both of Compound A or a pharmaceutically acceptable salt form thereof and Compound B or a pharmaceutically acceptable salt form thereof are administered during the lead-in period prior to the first cycle of the 28-day administration cycle described above at a dose that is less than the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt form thereof and Compound B or a pharmaceutically acceptable salt form thereof administered during the first cycle of the 28-day administration cycle described above. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first cycle of the 28-day administration cycle described above.

[0127] In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg to about 5 mg per day. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg per day. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 2 mg per day. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 3 mg per day.

[0128] In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 25 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 20 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 15 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 10 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 15 mg per day. In some embodiments, the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 20 mg per day.

[0129] In some embodiments, Compound B administered during the lead-in period is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a maleate (which may be a sesqui-maleate). In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 5 mg to about 40 mg per day. In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 5 mg to about 30 mg per day. In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 5 mg to about 25 mg per day. In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 7 mg per day. In some embodiments, the amount of Compound B administered during the lead-in period as a maleate (which may be a sesqui-maleate) is about 13 mg per day. In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg per day. In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 27 mg per day.

[0130] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and / or Compound B or a pharmaceutically acceptable salt thereof are administered daily during the lead-in period. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and / or Compound B or a pharmaceutically acceptable salt thereof are administered once daily during the lead-in period. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt form thereof are administered orally during the lead-in period.

[0131] 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 or different dosage forms during the lead-in period. 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 during the lead-in period. In some embodiments, the dosage form is a capsule.

[0132] 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 during the lead-in period. In some embodiments, Compound A is administered before, simultaneously with, or after administration of Compound B, or a pharmaceutically acceptable salt thereof, during the lead-in period. In some embodiments, the dosage form of Compound A, or a pharmaceutically acceptable salt thereof, is a capsule. In some embodiments, the dosage form of Compound B, or a pharmaceutically acceptable salt thereof, is a capsule.

[0133] In some embodiments, the lead-in period begins 21 days before the first 28-day administration cycle. In some embodiments, the lead-in period begins 14 days before the first 28-day administration cycle. In some embodiments, the lead-in period begins 10 days before the first 28-day administration cycle. In some embodiments, the lead-in period begins 7 days before the first 28-day administration cycle.

[0134] In some embodiments, methods of treating patients with solid tumors are described herein, comprising administering 2 mg of Compound A as the free base and 15 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg.

[0135] In some embodiments, methods of treating a patient with a solid tumor are described herein, comprising administering 2 mg of Compound A as the free base and 20 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg.

[0136] In some embodiments, described herein are methods of treating patients with solid tumors, comprising a 7-day cycle comprising: (a) administering 3 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by (b) 2 consecutive days without administering Compound A or Compound B. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg.

[0137] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 3 mg of Compound A free base and 10 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 3 mg of Compound A free base and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg. In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the treatment period is about 27 mg.

[0138] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 2 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 1 mg of Compound A free base twice daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg. In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the treatment period is about 20 mg.

[0139] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 1 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg. In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the treatment period is about 27 mg.

[0140] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 2 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. In some embodiments, the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) administered during the lead-in period is about 20 mg. In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) administered during the treatment period is about 27 mg.

[0141] In some embodiments, methods of treating patients with solid tumors are described herein, comprising a 7-day cycle comprising: (a) administering 4 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by (b) 2 consecutive days without administering Compound A or Compound B. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg.

[0142] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) A method is provided herein, comprising: (i) administering 3 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg. In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the treatment period is about 27 mg.

[0143] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 4 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. In some embodiments, the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) administered during the lead-in period is about 20 mg. In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) administered during the treatment period is about 27 mg.

[0144] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) A method is provided herein, comprising: (i) administering 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. In some embodiments, the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) administered during the lead-in period is about 13 mg. In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) administered during the treatment period is about 20 mg.

[0145] In some embodiments, there is provided a method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 4 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) Methods are described herein that include (i) administering 4 mg of Compound A free base once daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. In some embodiments, Compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. In some embodiments, the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) administered during the lead-in period is about 13 mg. In some embodiments, the amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) administered during the treatment period is about 20 mg.

[0146] In some embodiments, methods of treating patients with solid tumors are described herein, comprising administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, Compound B is in a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg.

[0147] In some embodiments, methods of treating patients with solid tumors are described herein, comprising administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, Compound B is in a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg.

[0148] In some embodiments, methods of treating patients with solid tumors are described herein, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, Compound B is in a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg.

[0149] In some embodiments, methods of treating patients with solid tumors are described herein, comprising administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily. In some embodiments, Compound B is in a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, each dose of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg.

[0150] In some embodiments, methods of treating patients with solid tumors are described herein, comprising administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily. In some embodiments, Compound B is in a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, each dose of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg.

[0151] In some embodiments, methods of treating patients with solid tumors are described herein, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily. In some embodiments, Compound B is in a pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt form is the maleate salt (which may be the sesqui-maleate salt). In some embodiments, each dose of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg. [Example]

[0152] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications and changes therein will be suggested to those skilled in the art, and that such modifications and changes are included within the spirit and scope of this application.

[0153] Example 1: Combination Effect of Compound A and Compound B in KRAS-mutated NSCLC Cell Lines Cell viability studies for the combined treatment of Compound A (mirdametinib) and Compound B (lifirafenib maleate) were conducted in human non-small cell lung cancer and colon cancer cell lines (A549, NCI-H2122, NCI-H23, Sk-Lu-1, Calu-1, NCI-H1299, NCI-H358) harboring K-RAS mutations.

[0154] The mutant cell lines used were grown according to standard cell culture techniques with various concentrations of mirdametinib and lifirafenib (0-10 μM) diluted in dimethyl sulfoxide (54686.500, biomol.). Cell lines were cultured in RPMI 1640 medium (22400-089, GIBCO®), McCoy's 5a (16600-082, GIBCO®), or DMEM (11965-092, GIBCO®), each containing 10% fetal bovine serum (SH30084.03, Hyclone™) and 1% penicillin-streptomycin (15140-148, Invitrogen).

[0155] Briefly, for each experiment, approximately 3,000 cells were seeded into each well of a 96-well plate and the plate was incubated overnight. Various levels of mirdametinib and lifirafenib were added to each well, and the cells were incubated for 3 days. Cell viability was quantified using the CellTiter-Glo® Luminescent Cell Viability Assay (G7570, Promega™) with a BMG LABTECH PERAstar FS plate reader according to the manufacturer's instructions.

[0156] result Compound A (mirdametinib) and Compound B (lifirafenib maleate) synergistically inhibited the growth of multiple K-RAS-mutated non-small cell lung cancer and colorectal cancer cell lines. In seven of the eight cell lines evaluated, the combination of mirdametinib and lifirafenib maleate demonstrated synergistic cell killing activity compared to either compound alone. [Table 1]

[0157] No shift: Combining Compound B maleate and Compound A resulted in less than a 2-fold EC 50 A shift was detected.

[0158] Example 2: Efficacy study of Compound A and Compound B in a Calu-6 K-RAS mutant human lung adenocarcinoma xenograft model in Balb / c nude mice 1. Purpose of the test The efficacy of Compound B maleate and Compound A, alone or in combination, on the growth of subcutaneous Calu-6 tumors harboring K-RAS gene mutations in BALB / c nude mice will be determined.

[0159] 2. Study Design The experimental design of the efficacy study is shown in Table 2. [Table 2]

[0160] 3.Material 3.1 Animals and housing conditions Six to eight week old female Balb / c nude mice with an average body weight of approximately 18 g were housed under standard laboratory conditions and given free access to sterile food and water.

[0161] 3.2 Cells Calu-6 cell line was cultured in Minimum Essential Medium (ThermoFisher, #11095080) containing phosphate-buffered saline (Gibco®, #C20012500BT), non-essential amino acids (ThermoFisher, #11140-050), fetal bovine serum (ExCell™ Bio, #FND500), Matrigel® (Corning, #354234), and penicillin / streptomycin (ThermoFisher, #15140122)).

[0162] 3.4 Formulation Method The required amount of methylcellulose was slowly added to purified water (approximately 60%-80% of the total volume) with stirring until a visually clear solution was obtained. Purified water was then added to reach the final volume, and the mixture was stirred until a visually homogeneous solution was obtained. The solution was autoclaved. Tween®-80 was then added to a final concentration of 1% (v / v), and the solution was stored at 4°C.

[0163] The formulations of the dosing solutions for Groups 1-5 are shown in Table 3 below. Both compounds were formulated as homogenous suspensions, prepared once a week, and stored in the dark at 4°C. The required amount of test article was added with stirring to a volume slightly less than the calculated volume of vehicle solution. Vehicle solution was added to reach the final volume, and the mixture was stirred for at least 10 minutes until a visually homogenous suspension was obtained. The homogenous dosing solution for each group was divided for each dosing day. On the day of dosing, before each administration, the tube containing the divided dosing solution was vortexed or inverted until a homogenous suspension was obtained. [Table 3]

[0164] 4. Experimental methods and procedures: 4.1 Cell culture Calu-6 tumor cells were cultured in MEM medium (supplemented with 10% FBS, 1% NEAA, and 1x penicillin / streptomycin) at 37°C in a 5% CO atmosphere. Tumor cells were routinely subcultured twice a week according to ATCC instructions.

[0165] 4.2 Mycoplasma testing and short tandem repeat (STR) analysis STR and mycoplasma testing were performed to ensure the authenticity and quality of the tumor cells, and the results showed that the Calu-6 cells used in this study were STR correct and mycoplasma negative.

[0166] 4.3 Tumor cell inoculation and mouse grouping Calu-6 tumor cells (5 x 10 in 0.1 ml of 50% Matrigel in MEM) were injected into the right flank of each mouse. 6 Matrigel® cells were subcutaneously inoculated into the animals. The tubes and syringes containing the suspended cells were kept on ice to avoid solidification of the Matrigel®. Cell injections were performed in a two-fold excess amount. When the average tumor volume reached the size shown in Table 2, the animals were randomly assigned to the groups shown in Table 2 and the first administration was performed.

[0167] 4.4 Administration Test article and vehicle solutions were administered by oral gavage ("po") twice daily (BID, with at least 8 hours between each dose). Dosing solutions were prepared as completely homogenous suspensions once weekly prior to each dose, as described in Table 3. Dose volumes were determined based on the results of the previous mouse weight measurements. Throughout the study, animals received one of the treatments according to the parameters described in Table 2.

[0168] 4.5 Tumor Measurement and Sampling Tumor volume and mouse weight were measured three times a week after tumors became palpable and before randomization and group allocation. Thereafter, tumor volume and mouse weight were measured in two dimensions using calipers twice a week until termination. Tumor volume was calculated in mm using the following formula: 3 Expressed in units: V = 0.5L x W 2 (L and W are the long and short diameters of the tumor, respectively.) The TGI value on day X for the drug A treatment group was calculated as follows: TGI (%) = {1 - [mTV (drug on day X) - mTV (drug on day 0)] / [mTV (vehicle on day X) - mTV (vehicle on day 0)]} x 100 (mTV means mean tumor volume)

[0169] 4.6 Statistical analysis Two-way ANOVA was performed to compare tumor volumes between different treatment groups, and P<0.05 was considered statistically significant.

[0170] 5. Summary of Results Treatment with all tested doses of Compound B maleate and Compound A (alone or in combination) resulted in significant inhibition of Calu-6 tumor growth compared to vehicle control (Figures 1 and 3). Adding increasing doses of Compound A to a fixed dose of Compound B maleate resulted in dose-dependent enhancement of tumor growth inhibition. This result is consistent with in vitro data demonstrating synergistic cell killing effects of the two compounds in K-RAS mutant cancer cell lines. In this experiment, maximal tumor growth inhibition was observed at doses of 1.25 mg / kg Compound B maleate and 5 mg / kg Compound A.

[0171] Figure 2 shows that the weights of the mice remained relatively stable over time, with only minor differences between groups, suggesting that the combination of Compound A and Compound B maleate was well tolerated.

[0172] Example 3: Synergistic effect between Compound A and Compound B We applied the BIGL method with a Highest Single Agent (HSA) null model to evaluate the synergistic effect of combining a BRAF inhibitor (BGB-283, lifirafenib) with a MEK inhibitor (PD-0325901, mirdametinib) in multiple KRAS mutant cell lines. The HSA model does not attempt to model interaction effects; the predicted effect of the combination is the minimum of both monotherapy curves.

[0173] Data were collected from three plates with the same layout, including negative and positive controls, eight doses of each single agent, and 8 x 8 = 64 dose combinations. Raw signals were normalized by controls before pooling for analysis. Both raw and normalized data are shown in the data plots.

[0174] The presence or absence of synergistic or antagonistic effects was assessed by statistical tests. Two types of tests were performed. Overall test (meanR): evaluates how the predicted response surface differs from the observed response surface. If the null hypothesis is rejected, this test suggests that at least some dose combinations may exhibit synergistic or antagonistic behavior. Dose combination study (maxR): Evaluate the presence or absence of synergistic or antagonistic effects for each dose combination and provide a point-by-point classification as such.

[0175] All of the above test statistics have well-specified null distributions under a set of assumptions (i.e., normality of the Z-scores). If this assumption is not met, the distributions of these statistics can be estimated using bootstrap. We obtained results based on both normal and bootstrap errors.

[0176] Details of the statistical analysis can be found in Van der Borght, K., et al., Sci Rep 7:17935 (2017) and in the methodology vignette. [Table 4]

[0177] Example 4: Antiproliferative effects of compound B in combination with different MEK inhibitors in K / N-RAS mutant NSCLC and CRC cells The antiproliferative activity of compounds in a panel of RAS-mutated NSCLC and CRC cell lines was quantified using the CellTiter-Glo Luminescent Cell Viability Assay (Promega). See Yuan et al., Molecular Oncology 14 (2020) 1833-1849 (the entire disclosure of which is incorporated herein by reference). The number of cells seeded per well of a 96-well plate was optimized for each cell line to ensure logarithmic growth over the 3-day treatment period. Cells were incubated for 16 hours and then treated in duplicate with a 10-point dilution series. After 3 days of compound exposure, an equal volume of CellTiter-Glo reagent as cell culture medium was added to each well. The mixture was mixed on an orbital shaker for 2 minutes to lyse the cells, followed by incubation at room temperature for 10 minutes to allow the luminescent signal to develop and stabilize. The luminescent signal was measured using a PHERAstar FS reader (BMG Labtech).

[0178] Excess over Highest Single Agent (EOHSA) is a standard criterion for assessing the effect of drug combinations on cell growth inhibition. EOHSA was used to analyze the excess inhibitory effect produced by drug combinations relative to the greater effect produced by the two single agents at corresponding concentrations. For analytical purposes, the logarithms of the difference between each raw measurement / positive and negative control were assumed to follow normal distributions with different means but the same variance. EOHSA for each dose combination was calculated by fitting a model using maximum likelihood and applying the fitted model to the EOHSA formula.

[0179] Tables 5-7 show the inhibition rates observed in multiple cell lines for the combination of Compound B with various MEK inhibitors. p values ​​( *) was calculated using the testing procedure described by Perone et al., J Am Stat Assoc. 99:1002-14. This calculation was applied to control for a false discovery excess of 5% for the hypothesis that at least one of the dose combinations tested has a synergistic effect per EOHSA. Tables 5-7 show the synergistic effect ( ** ) indicates the percentage of dose combinations studied with a 2-fold EC50 shift detected after combining Compound B with a MEK inhibitor was defined as no shift. [Table 5-6] [Table 7]

[0180] Example 5: Human Clinical Trials Part 1 of the lifirafenib and mirdametinib phase 1b dose-escalation trial has included 26 patients with advanced, metastatic, or unresectable solid tumors to date. Patients were treated in four sequential dose cohorts. The first two dose cohorts (DL1 and DL2) evaluated lifirafenib and mirdametinib administered once daily on a continuous dosing schedule. Cohort DL1 included a combination of 15 mg lifirafenib and 2 mg mirdametinib in six subjects, and cohort DL2 evaluated a combination of 20 mg lifirafenib and 2 mg mirdametinib in eight subjects. The latter two dose cohorts (DL3a and DL4a) evaluated lifirafenib and mirdametinib in an intermittent dosing schedule (once daily for 5 days, followed by 2 days off weekly). The DL3a cohort included a combination of 20 mg lifirafenib and 3 mg mirdametinib in six subjects, and the DL4a cohort evaluated a combination of 20 mg lifirafenib and 4 mg mirdametinib in six subjects. All dose cohorts consisted of a 28-day treatment cycle. Initial results in patients with advanced solid tumors (e.g., ovarian cancer, CRC, NSCLC, and endometrial cancer) are shown in Figure 4.

[0181] Following completion of dose cohort 4a, Part 1 (Phase 1b dose escalation) will continue with two parallel dose arms (arms b and c). In both arms, lifirafenib and mirdametinib will be evaluated in consecutive dose escalation cohorts on an intermittent dosing schedule (five days on treatment, followed by two days off treatment each week). Each treatment cycle will last 28 days. The lifirafenib dose will be fixed across all dose escalation cohorts in both arms. In arm b, lifirafenib will be administered once daily as a lead-in dose of 15 mg for the first 2 weeks (14 days), followed by a target dose of 20 mg for the 28-day treatment period. In arm c, lifirafenib will be administered once daily as a lead-in dose of 10 mg for the first 2 weeks (14 days), followed by a target dose of 15 mg for the 28-day treatment period. The starting dose cohort in arm b (DL3b) will evaluate lifirafenib at 15 mg and 20 mg once daily (lead-in and target doses, respectively) in combination with mirdametinib at 3 mg once daily. The starting dose cohort in arm c (DL3c) will evaluate lifirafenib at 10 mg and 15 mg once daily (lead-in and target doses, respectively) in combination with mirdametinib at 2 mg twice daily. Subsequent dose escalation cohorts will include 1-2 mg escalation once daily (arm b) and 1-2 mg escalation twice daily (arm b), if tolerated.

[0182] A standalone Phase 1b / 2a dose-finding study will be conducted to evaluate lifirafenib and mirdametinib in patients with advanced, metastatic, or unresectable solid tumors. Part 1 of the study (Phase 1b dose escalation) will include two parallel dose-escalation arms (Arms a and b). Both arms will evaluate lifirafenib and mirdametinib in three consecutive dose-escalation cohorts. Both drugs will be administered on a continuous dosing schedule, with each treatment cycle lasting 28 days. The lifirafenib dose will be fixed across the dose-escalation cohorts in both arms. In Arm a, lifirafenib will be administered at a dose of 5 mg once daily, and in Arm b, lifirafenib will be administered at a dose of 5 mg twice daily. The starting dose cohort in Arm a (DL1a) will evaluate the combination of lifirafenib 5 mg once daily and mirdametinib 2 mg twice daily. The starting dose cohort for group b (DL1b) evaluates the combination of lifirafenib 5 mg twice daily and mirdametinib 2 mg twice daily. Dose escalation can proceed in two additional sequential cohorts (DL2a to DL3a for group b and DL2b to DL3b for group b). This means that after the starting dose cohort (DL1a and DL1b), two subsequent dose escalation cohorts for each group evaluate the same lifirafenib dose (5 mg once daily for group b and 5 mg twice daily for group b) in combination with mirdametinib doses increased by 2 mg at each escalation step in both groups (4 mg twice daily for DL2a and DL2b, and 6 mg twice daily for DL3a and DL3b). Example 4: Capsule formulation [Table 8]

[0183] Other Aspects All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that a term in this application is found to have a different definition in a document incorporated herein by reference, the definition set forth herein shall control for that term.

[0184] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications. Also, it will be understood that this application is intended to cover any variations, uses, or adaptations of the present disclosure that may be applied to the essential features set forth above, which generally follow principles and come within known or customary practice in the art to which this invention pertains, including departures from the present disclosure that come within the scope of the claims.

[0185] In addition to the various embodiments described herein, the present disclosure includes the following embodiments, numbered E1 through E369. This list of embodiments is provided as an exemplary list, and the present application is not limited to these embodiments.

[0186] E1. A method of treating a patient having a solid tumor, comprising co-administering to said patient a therapeutically effective amount of Compound A (mirdametinib) or a pharmaceutically acceptable salt form thereof and a therapeutically effective amount of Compound B (lifirafenib) or a pharmaceutically acceptable salt form thereof.

[0187] E2. The method according to E1, wherein said therapeutically effective amount of compound A is about 1 mg to about 5 mg per day.

[0188] E3. The method of E1, wherein said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is from about 5 mg to about 40 mg per day.

[0189] E4. The method of E1, wherein said therapeutically effective amount of Compound A is about 1 mg per day and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 5 mg to about 15 mg per day.

[0190] E5. The method of E1, wherein said therapeutically effective amount of Compound A is about 2 mg per day and said therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 40 mg per day.

[0191] E6. The method of E1, wherein said therapeutically effective amount of Compound A is about 2 mg per day and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 35 mg per day.

[0192] E7. The method of E1, wherein said therapeutically effective amount of Compound A is about 3 mg per day and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 5 mg to about 40 mg per day.

[0193] E8. The method of E1, wherein said therapeutically effective amount of Compound A is about 3 mg per day and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 35 mg per day.

[0194] E9. The method of E1, wherein said therapeutically effective amount of Compound A is about 4 mg per day and said therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 10 mg to about 40 mg per day.

[0195] E10. The method of E1, wherein said therapeutically effective amount of Compound A is about 4 mg per day and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 35 mg per day.

[0196] E11. The method of E1, wherein said therapeutically effective amount of Compound A is about 5 mg per day and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 10 mg to about 40 mg per day.

[0197] E12. The method of E1, wherein said therapeutically effective amount of Compound A is about 5 mg per day and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 40 mg per day.

[0198] E13. The method of any one of E1-E12, wherein compound B is in the form of a pharmaceutically acceptable salt.

[0199] E14. The method of E13, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0200] E15. The method of E14, wherein said therapeutically effective amount of Compound A is about 1 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 5 mg to about 10 mg per day.

[0201] E16. The method of E14, wherein said therapeutically effective amount of Compound A is about 1 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 7 mg per day.

[0202] E17. The method of E14, wherein said therapeutically effective amount of Compound A is about 2 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 10 mg to about 30 mg per day.

[0203] E18. The method of E14, wherein said therapeutically effective amount of Compound A is about 2 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 13 mg per day.

[0204] E19. The method of E14, wherein said therapeutically effective amount of Compound A is about 2 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg per day.

[0205] E20. The method of E14, wherein said therapeutically effective amount of Compound A is about 3 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 15 mg to about 40 mg per day.

[0206] E21. The method of E14, wherein said therapeutically effective amount of Compound A is about 3 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg per day.

[0207] E22. The method of E14, wherein said therapeutically effective amount of Compound A is about 3 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 34 mg per day.

[0208] E23. The method of E14, wherein said therapeutically effective amount of Compound A is about 4 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg to about 40 mg per day.

[0209] E24. The method of E14, wherein said therapeutically effective amount of Compound A is about 4 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg per day.

[0210] E25. The method of E14, wherein said therapeutically effective amount of Compound A is about 5 mg per day and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 25 mg to about 40 mg per day.

[0211] E26. The method of E14, wherein said therapeutically effective amount of Compound A is about 5 mg per day and said therapeutically effective amount of Compound B as the maleate salt is about 34 mg per day.

[0212] E27. The method of any one of E1-E26, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in the same or different dosage forms.

[0213] E28. The method of E27, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in the same dosage form.

[0214] E29. The method of claim 328, wherein the dosage form is a capsule.

[0215] E30. The method of any one of E1-E29, wherein Compound A is administered once per day.

[0216] E31. The method of any one of E1-E30, wherein Compound B or a pharmaceutically acceptable salt form thereof is administered once per day.

[0217] E32. The method of E27, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in different dosage forms.

[0218] E33. The method of E32, wherein Compound A is administered before, simultaneously with, or after said administration of Compound B or a pharmaceutically acceptable salt form thereof.

[0219] E34. The method of E27 or E28, wherein said dosage form of Compound A is a capsule.

[0220] E35. The method of any one of E27 to E34, wherein said dosage form of Compound B or a pharmaceutically acceptable salt thereof is a capsule.

[0221] E36. The method of any one of E1-E35, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered orally.

[0222] E37. The method of any one of E1 to E36, 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, lung adenocarcinoma, squamous non-small cell lung carcinoma, non-squamous non-small cell lung carcinoma, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and peritoneal serous carcinoma.

[0223] E38. The method of E37, wherein said patient has non-small cell lung cancer.

[0224] E39. The method of E37, wherein said patient has endometrial cancer.

[0225] E40. The method of E37, wherein said patient has ovarian cancer.

[0226] E41. The method of E40, wherein said patient has low-grade serous ovarian cancer.

[0227] E42. The method of any one of E1-E41, wherein said patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2.

[0228] E43. The method of any one of E1-E42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

[0229] E44. The method of any one of E1-E42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

[0230] E45. The method of any one of E1-E42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising: (i) a 5-day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (ii) two days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) a 7-day period during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

[0231] E46. The method of any one of E1-E42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising: (i) a 5-day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (ii) two days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) a 7-day period during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

[0232] E47. The method of any one of E1-E42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) 4 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (ii) 3 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

[0233] E48. The method of any one of E1-E42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) 4 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered; and (ii) 3 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

[0234] E49. The method of any one of E43-E48, wherein said 28-day administration cycle is repeated for a maximum of 24 consecutive 28-day administration cycles.

[0235] E50. The method of any one of E43-E49, wherein only Compound B or a pharmaceutically acceptable salt form thereof is administered during a lead-in period prior to the first 28 day administration cycle.

[0236] E51. The method of E50, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is the same as or less than said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said initial 28 day administration cycle.

[0237] E52. The method of E51, wherein said lead-in period begins 21 days prior to said initial 28-day administration cycle.

[0238] E53. The method of E52, wherein said lead-in period begins 14 days prior to said initial 28-day administration cycle.

[0239] E54. The method of E52, wherein said lead-in period begins 10 days prior to said initial 28-day administration cycle.

[0240] E55. The method of E52, wherein said lead-in period begins 7 days prior to said initial 28-day administration cycle.

[0241] E56. The method according to any one of E50 to E55, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 25 mg per day.

[0242] E57. The method according to any one of E50 to E55, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 20 mg per day.

[0243] E58. The method according to any one of E50 to E55, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 15 mg per day.

[0244] E59. The method according to any one of E50 to E55, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 25 mg per day.

[0245] E60. The method according to any one of E50 to E55, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 10 mg per day.

[0246] E61. The method according to any one of E50 to E55, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 15 mg per day.

[0247] E62. The method according to any one of E50 to E55, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 20 mg per day.

[0248] E63. The method according to any one of E50 to E55, wherein compound B administered during said lead-in period is in the form of a pharmaceutically acceptable salt.

[0249] E64. The method of E63, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0250] E65. The method according to E64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 40 mg per day.

[0251] E66. The method according to E64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 30 mg per day.

[0252] E67. The method according to E64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 25 mg per day.

[0253] E68. The method according to E64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 7 mg per day.

[0254] E69. The method of E64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 13 mg per day.

[0255] E70. The method of E64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 20 mg per day.

[0256] E71. The method of E64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 27 mg per day.

[0257] E72. The method of any one of E50 to E71, wherein Compound B or a pharmaceutically acceptable salt thereof is administered daily during said lead-in period.

[0258] E73. The method of any one of E50 to E72, wherein compound B or a pharmaceutically acceptable salt thereof is administered once daily during said lead-in period.

[0259] E74. The method of any one of E43-E49, wherein one or both of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered during a lead-in period prior to an initial 28 day administration cycle at a dose that is less than the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, administered during said initial 28 day cycle.

[0260] E75. The method of E74, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle.

[0261] E76. The method of E74, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle.

[0262] E77. The method according to any one of E74 to E76, wherein said amount of compound A or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 1 mg to about 5 mg per day.

[0263] E78. The method of any one of E74 to E76, wherein said amount of Compound A or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 1 mg per day.

[0264] E79. The method of any one of E74 to E76, wherein said amount of Compound A or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 2 mg per day.

[0265] E80. The method of any one of E74 to E76, wherein said amount of Compound A or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 3 mg per day.

[0266] E81. The method of any one of E74 to E80, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first 28 day administration cycle.

[0267] E82. The method of any one of E74 to E80, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the initial 28 day administration cycle.

[0268] E83. The method according to any one of E74 to E80, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 25 mg per day.

[0269] E84. The method according to any one of E74 to E80, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 20 mg per day.

[0270] E85. The method according to any one of E74 to E80, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 15 mg per day.

[0271] E86. The method according to any one of E74 to E80, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 5 mg per day.

[0272] E87. The method according to any one of E74 to E80, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 10 mg per day.

[0273] E88. The method according to any one of E74 to E80, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 15 mg per day.

[0274] E89. The method according to any one of E74 to E80, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 20 mg per day.

[0275] E90. The method of any one of E74 to E89, wherein Compound B administered during said lead-in period is in the form of a pharmaceutically acceptable salt.

[0276] E91. The method of E90, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0277] E92. The method of E91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 40 mg per day.

[0278] E93. The method of E91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 30 mg per day.

[0279] E94. The method of E91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 25 mg per day.

[0280] E95. The method of E91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 7 mg per day.

[0281] E96. The method of E91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 13 mg per day.

[0282] E97. The method of E91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 20 mg per day.

[0283] E98. The method of E91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 27 mg per day.

[0284] E99. The method of any one of E74-E98, wherein said lead-in period begins 21 days prior to said initial 28-day administration cycle.

[0285] E100. The method of any one of E74-E98, wherein said lead-in period begins 14 days prior to said initial 28-day administration cycle.

[0286] E101. The method of any one of E74-E98, wherein said lead-in period begins 10 days prior to said initial 28-day administration cycle.

[0287] E102. The method of any one of E74-E98, wherein said lead-in period begins 7 days prior to said initial 28-day administration cycle.

[0288] E103. The method according to any one of E74 to E102, wherein said compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are each administered daily during said lead-in period.

[0289] E104. The method according to any one of E74 to E102, wherein said compound A or a pharmaceutically acceptable salt thereof and said compound B or a pharmaceutically acceptable salt thereof are each administered once daily during said lead-in period.

[0290] E105. The method of any one of E74 to 104, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in the same or different dosage forms during said lead-in period.

[0291] E106. The method according to E105, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in the same dosage form during said lead-in period.

[0292] E107. The method of E106, wherein said dosage form is a capsule.

[0293] E108. The method according to E105, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in different dosage forms during said lead-in period.

[0294] E109. The method according to E108, wherein compound A is administered during said lead-in period before, simultaneously with, or after said administration of compound B or a pharmaceutically acceptable salt form thereof.

[0295] E110. The method according to E108 or E109, wherein said dosage form of Compound A or a pharmaceutically acceptable salt thereof is a capsule.

[0296] E111. The method according to E108 or E109, wherein said dosage form of Compound B or a pharmaceutically acceptable salt thereof is a capsule.

[0297] E112. The method of any one of E74 to E111, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered orally during said lead-in period.

[0298] E113. The method of any one of E1-E112, wherein said patient has a confirmed mutation in RASA1 and / or RAF1.

[0299] E114. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 1 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day.

[0300] E115. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day.

[0301] E116. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day.

[0302] E117. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day.

[0303] E118. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day.

[0304] E119. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day.

[0305] E120. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day.

[0306] E121. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day.

[0307] E122. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day.

[0308] E123. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day.

[0309] E124. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day.

[0310] E125. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day.

[0311] E126. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day.

[0312] E127. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day.

[0313] E128. The method of E1, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day.

[0314] E129. The method according to any one of E114 to E128, wherein compound B is in the form of a pharmaceutically acceptable salt.

[0315] E130. The method according to E129, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0316] E131. The method of E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 1 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg per day.

[0317] E132. The method according to E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg per day.

[0318] E133. The method according to E130, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and said therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg per day.

[0319] E134. The method according to E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg per day.

[0320] E135. The method according to E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg per day.

[0321] E136. The method according to E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg per day.

[0322] E137. The method according to E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg per day.

[0323] E138. The method according to E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 27 mg per day.

[0324] E139. The method according to E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg per day.

[0325] E140. The method according to E130, wherein said therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and said therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 7 mg per day.

[0326] E141. The method of E130, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 13 mg per day.

[0327] E142. The method of E130, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 7 mg per day.

[0328] E143. The method of E130, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 13 mg per day.

[0329] E144. The method of E130, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 7 mg per day.

[0330] E145. The method of E130, wherein said therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 13 mg per day.

[0331] E146. The method of any one of E114 to E145, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in the same or different dosage forms.

[0332] E147. The method according to E146, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in the same dosage form.

[0333] E148. The method of claim 147, wherein the dosage form is a capsule.

[0334] E149. The method of any one of E114 to E148, wherein compound A or a pharmaceutically acceptable salt thereof is administered once per day.

[0335] E150. The method of any one of E114 to E149, wherein Compound B or a pharmaceutically acceptable salt form thereof is administered once per day.

[0336] E151. The method of E146, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in different dosage forms.

[0337] E152. The method according to E151, wherein Compound A is administered before, simultaneously with, or after said administration of Compound B or a pharmaceutically acceptable salt form thereof.

[0338] E153. The method according to E151 or E152, wherein said dosage form of Compound A or a pharmaceutically acceptable salt thereof is a capsule.

[0339] E154. The method according to E151 or E152, wherein said dosage form of Compound B or a pharmaceutically acceptable salt thereof is a capsule.

[0340] E155. The method of any one of E114 to E154, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered orally.

[0341] E156. The method according to any one of E114 to E155, 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, lung adenocarcinoma, squamous non-small cell lung carcinoma, non-squamous non-small cell lung carcinoma, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and serous carcinoma of the peritoneum.

[0342] E157. The method of E156, wherein said patient has non-small cell lung cancer.

[0343] E158. The method of E156, wherein said patient has endometrial cancer.

[0344] E159. The method of E156, wherein said patient has ovarian cancer.

[0345] E160. The method of E156, wherein said patient has low-grade serous ovarian cancer.

[0346] E161. The method of any one of E114 to E160, wherein the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2.

[0347] E162. The method of any one of E114 to E161, wherein the patient has a confirmed mutation in RASA1 and / or RAF1.

[0348] E163. The method of any one of E114-162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28-day administration cycle comprising: (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt thereof, is administered.

[0349] E164. The method of any one of E114 to E162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28 day administration cycle comprising: (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt thereof, are administered, followed by (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt thereof, is administered.

[0350] E165. The method of any one of E114 to E162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising: (i) a 5-day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (ii) two days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered; and (b) a 7-day period during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered.

[0351] E166. The method of any one of E114 to E162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising: (i) a 5-day period during which both Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (ii) two days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered, followed by (b) seven days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered.

[0352] E167. The method of any one of E114 to E162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising: (i) 4 days during which both Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (ii) 3 days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered; and (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered.

[0353] E168. The method of any one of claims E114 to E162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising: (i) 4 days during which both Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (ii) 3 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt thereof, is administered, followed by (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered.

[0354] E169. The method of any one of E163-E168, wherein said 28-day administration cycle is repeated for a maximum of a total of 24 consecutive 28-day administration cycles.

[0355] E170. The method of any one of E163-E168, wherein only Compound B or a pharmaceutically acceptable salt form thereof is administered during a lead-in period prior to the first 28 day administration cycle.

[0356] E171. The method of E170, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as or less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle.

[0357] E172. The method of E171, wherein said lead-in period begins 21 days prior to said initial 28-day administration cycle.

[0358] E173. The method of E171, wherein said lead-in period begins 14 days prior to said initial 28-day administration cycle.

[0359] E174. The method of E171, wherein said lead-in period begins 10 days prior to said initial 28-day administration cycle.

[0360] E175. The method of E171, wherein said lead-in period begins 7 days prior to said initial 28-day administration cycle.

[0361] E176. The method according to any one of E163 to E168, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 25 mg per day.

[0362] E177. The method according to any one of E163 to E168, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 20 mg per day.

[0363] E178. The method according to any one of E163 to E168, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 15 mg per day.

[0364] E179. The method according to any one of E163 to E168, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 5 mg per day.

[0365] E180. The method according to any one of E163 to E168, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 10 mg per day.

[0366] E181. The method according to any one of E163 to E168, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 15 mg per day.

[0367] E182. The method according to any one of E163 to E168, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 20 mg per day.

[0368] E183. The method according to any one of E163 to E168, wherein compound B administered during said lead-in period is in the form of a pharmaceutically acceptable salt.

[0369] E184. The method according to E183, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0370] E185. The method according to E184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 40 mg per day.

[0371] E186. The method according to E184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 30 mg per day.

[0372] E187. The method according to E184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 25 mg per day.

[0373] E188. The method according to E184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 7 mg per day.

[0374] E189. The method according to E184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 13 mg per day.

[0375] E190. The method according to E184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 20 mg per day.

[0376] E191. The method according to E184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 27 mg per day.

[0377] E192. The method of any one of E170 to E191, wherein Compound B or a pharmaceutically acceptable salt thereof is administered daily during said lead-in period.

[0378] E193. The method according to any one of E170 to E192, wherein compound B or a pharmaceutically acceptable salt thereof is administered once daily during said lead-in period.

[0379] E194. The method of any one of E163 to E168, wherein one or both of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered during a lead-in period prior to an initial 28 day administration cycle at a dose that is less than the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, administered during said initial 28 day cycle.

[0380] E195. The method of E194, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle.

[0381] E196. The method of E194, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle.

[0382] E197. The method according to any one of E194 to E196, wherein said amount of compound A or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 1 mg to about 5 mg per day.

[0383] E198. The method according to any one of E194 to E196, wherein said amount of Compound A or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 1 mg per day.

[0384] E199. The method according to any one of E194 to E196, wherein said amount of Compound A or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 2 mg per day.

[0385] E200. The method of any one of E194 to E196, wherein said amount of Compound A or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 3 mg per day.

[0386] E201. The method of any one of E194 to E200, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first 28 day administration cycle.

[0387] E202. The method according to any one of E194 to E200, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first 28 day administration cycle.

[0388] E203. The method according to any one of E194 to E202, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 25 mg per day.

[0389] E204. The method according to any one of E194 to E202, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 20 mg per day.

[0390] E205. The method according to any one of E194 to E202, wherein said amount of compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is from about 5 mg to about 15 mg per day.

[0391] E206. The method according to any one of E194 to E202, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 5 mg per day.

[0392] E207. The method according to any one of E194 to E202, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 10 mg per day.

[0393] E208. The method according to any one of E194 to E202, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 15 mg per day.

[0394] E209. The method according to any one of E194 to E202, wherein said amount of Compound B or a pharmaceutically acceptable salt thereof administered during said lead-in period is about 20 mg per day.

[0395] E210. The method according to any one of E194 to E209, wherein compound B administered during said lead-in period is in the form of a pharmaceutically acceptable salt.

[0396] E211. The method of E210, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0397] E212. The method according to E211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 40 mg per day.

[0398] E213. The method of E211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 30 mg per day.

[0399] E214. The method according to E211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is from about 5 mg to about 25 mg per day.

[0400] E215. The method of E211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 7 mg per day.

[0401] E216. The method of E211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 13 mg per day.

[0402] E217. The method of E211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 20 mg per day.

[0403] E218. The method of E211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 27 mg per day.

[0404] E219. The method of any one of E194-E218, wherein said lead-in period begins 21 days prior to said first 28-day administration cycle.

[0405] E220. The method of any one of E194 to E218, wherein said lead-in period begins 14 days prior to said first 28-day administration cycle.

[0406] E221. The method of any one of E194-E218, wherein said lead-in period begins 10 days prior to said first 28-day administration cycle.

[0407] E222. The method of any one of E194 to E218, wherein said lead-in period begins 7 days prior to said first 28-day administration cycle.

[0408] E223. The method according to any one of E194 to E222, wherein said compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are each administered daily during said lead-in period.

[0409] E224. The method according to any one of E194 to E222, wherein said compound A or a pharmaceutically acceptable salt thereof and said compound B or a pharmaceutically acceptable salt thereof are each administered once daily during said lead-in period.

[0410] E225. The method according to any one of E194 to 222, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in the same or different dosage forms during said lead-in period.

[0411] E226. The method according to E225, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in the same dosage form during said lead-in period.

[0412] E227. The method of E226, wherein said dosage form is a capsule.

[0413] E228. The method of E225, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in different dosage forms during said lead-in period.

[0414] E229. The method according to E228, wherein compound A is administered during said lead-in period before, simultaneously with, or after said administration of compound B or a pharmaceutically acceptable salt form thereof.

[0415] E230. The method according to E228 or E229, wherein said dosage form of Compound A or a pharmaceutically acceptable salt thereof is a capsule.

[0416] E231. The method according to E228 or E229, wherein said dosage form of Compound B or a pharmaceutically acceptable salt thereof is a capsule.

[0417] E232. The method according to any one of E194 to E231, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are orally administered during said lead-in period.

[0418] E233. The method of any one of E1-E232, wherein compound A is provided in the form of a pharmaceutically acceptable salt.

[0419] E234. The method of any one of E1-E232, wherein Compound A is provided in the form of a free base.

[0420] E235. A method of treating a patient with a solid tumor, comprising administering 2 mg of Compound A as the free base and 15 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0421] E236. The method of E235, wherein compound B is administered as a pharmaceutically acceptable salt form.

[0422] E237. The method according to E236, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0423] E238. The method according to E237, wherein the amount of Compound B as maleate (which may be sesqui-maleate) is about 20 mg.

[0424] E239. A method of treating a patient with a solid tumor, comprising administering 2 mg of Compound A as the free base and 20 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0425] E240. The method of E239, wherein Compound B is administered as a pharmaceutically acceptable salt form.

[0426] E241. The method according to E240, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0427] E242. The method according to E241, wherein the amount of Compound B as maleate (which may be sesqui-maleate) is about 27 mg.

[0428] E243. A method of treating a patient having a solid tumor, comprising: (a) administering 3 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by (b) 2 consecutive days without administration of Compound A or Compound B for a 7-day cycle.

[0429] E244. The method according to E243, wherein compound B is administered as a pharmaceutically acceptable salt form.

[0430] E245. The method according to E244, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0431] E246. The method according to E245, wherein the amount of Compound B as maleate (which may be sesqui-maleate) is about 27 mg.

[0432] E247. A method of treating a patient with a solid tumor, comprising: (a) a lead-in period comprising the administration of 3 mg of Compound A free base and 10 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 14 consecutive days, followed by (b) (i) administering 3 mg of Compound A free base and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days.

[0433] E248. The method according to E247, wherein compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

[0434] E249. The method according to E248, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0435] E250. The method according to E249, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 13 mg.

[0436] E251. The method according to E250, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said treatment period is about 27 mg.

[0437] E252. A method of treating a patient with a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 2 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) (i) administering 1 mg of Compound A free base twice daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days.

[0438] E253. The method according to E252, wherein Compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

[0439] E254. The method according to E253, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0440] E255. The method according to E254, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 13 mg.

[0441] E256. The method according to E255, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said treatment period is about 20 mg.

[0442] E257. A method of treating a patient having a solid tumor, comprising: (a) administering 4 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by (b) 2 consecutive days without administration of Compound A or Compound B for a 7-day cycle.

[0443] E258. The method of E257, wherein compound B is administered as a pharmaceutically acceptable salt form.

[0444] E259. The method of E258, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0445] E260. The method according to E259, wherein the amount of Compound B as maleate (which may be sesqui-maleate) is about 27 mg.

[0446] E261. A method of treating a patient with a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) administering 1 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days.

[0447] E262. The method of E261, wherein Compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

[0448] E263. The method according to E262, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0449] E264. The method according to E263, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 20 mg.

[0450] E265. The method according to E264, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said treatment period is about 27 mg.

[0451] E266. A method of treating a patient with a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) a 7-day treatment cycle comprising administering 2 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B.

[0452] E267. The method according to E266, wherein compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

[0453] E268. The method according to E267, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0454] E269. The method according to E268, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 20 mg.

[0455] E270. The method according to E269, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said treatment period is about 27 mg.

[0456] E271. A method of treating a patient with a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) a 7-day treatment cycle comprising administering 3 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B.

[0457] E272. The method of E271, wherein Compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

[0458] E273. The method according to E272, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0459] E274. The method according to E273, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 20 mg.

[0460] E275. The method according to E274, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said treatment period is about 27 mg.

[0461] E276. A method of treating a patient with a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) administering 4 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days.

[0462] E277. The method of E276, wherein compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

[0463] E278. The method according to E277, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0464] E279. The method according to E278, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 20 mg.

[0465] E280. The method according to E279, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said treatment period is about 27 mg.

[0466] E281. A method of treating a patient with a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of either Compound A or Compound B.

[0467] E282. The method according to E281, wherein Compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

[0468] E283. The method according to E282, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0469] E284. The method according to E283, wherein the amount of Compound B as maleate (which may be sesqui-maleate) administered during said lead-in period is about 13 mg.

[0470] E285. The method according to E284, wherein the amount of Compound B as maleate (which may be sesqui-maleate) administered during said treatment period is about 20 mg.

[0471] E286. A method of treating a patient with a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 4 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) (i) administering 4 mg of Compound A free base once daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days.

[0472] E287. The method according to E286, wherein compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

[0473] E288. The method according to E287, wherein said pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt).

[0474] E289. The method according to E288, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said lead-in period is about 13 mg.

[0475] E290. The method according to E289, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during said treatment period is about 20 mg.

[0476] E291. A method of treating a patient having a solid tumor, comprising administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0477] E292. A method of treating a patient having a solid tumor, comprising administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0478] E293. A method of treating a patient having a solid tumor, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

[0479] E294. A method of treating a patient having a solid tumor, comprising administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily.

[0480] E295. A method of treating a patient having a solid tumor, comprising administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily.

[0481] E296. A method of treating a patient with a solid tumor, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, twice daily.

[0482] E297. The method according to any one of E292 to E296, wherein compound B is in the form of a pharmaceutically acceptable salt.

[0483] E298. The method of E297, wherein said pharmaceutically acceptable salt form is a maleate salt which may be a sesqui-maleate salt.

[0484] E299. The method of E297, wherein each dose of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 7 mg.

[0485] E300. The method according to any one of E235 to E299, wherein compound A and compound B or a pharmaceutically acceptable salt form thereof are administered in the same or different dosage forms during said lead-in period and / or said treatment period.

[0486] E301. The method of E301, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in the same dosage form during said lead-in period and / or said treatment period.

[0487] E302. The method of E302, wherein said dosage form is a capsule.

[0488] E303. The method according to any one of E235 to E300, wherein compound A and compound B or a pharmaceutically acceptable salt form thereof are administered in different dosage forms during said lead-in period and / or said treatment period.

[0489] E304. The method according to E303, wherein Compound A is administered before, simultaneously with, or after said administration of Compound B or a pharmaceutically acceptable salt form thereof.

[0490] E305. The method according to E303 or E304, wherein said dosage form of Compound A is a capsule.

[0491] E306. The method according to any one of E303 to E305, wherein said dosage form of Compound B or a pharmaceutically acceptable salt thereof is a capsule.

[0492] E307. The method according to any one of E235 to E306, wherein Compound A and Compound B or a pharmaceutically acceptable salt form thereof are administered orally.

[0493] E308. The method according to any one of E235 to E307, 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, lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and serous carcinoma of the peritoneum.

[0494] E309. The method of E308, wherein said patient has non-small cell lung cancer.

[0495] E310. The method of E308, wherein said patient has endometrial cancer.

[0496] E311. The method of E308, wherein said patient has ovarian cancer.

[0497] E312. The method of E311, wherein said patient has low-grade serous ovarian cancer.

[0498] E313. The method of any one of E235 to E312, wherein the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2.

[0499] E314. The method of any one of E235 to E313, wherein said patient has a confirmed mutation in RASA1 and / or RAF1.

[0500] E315. Pharmaceutical composition, a. Compound A, b. Compound B or a pharmaceutically acceptable salt form thereof; c. fillers, d. disintegrants, and e. The pharmaceutical composition, comprising a lubricant.

[0501] E316. The pharmaceutical composition of E315, wherein Compound A is present in an amount of about 0.8 mg to about 1.2 mg.

[0502] E317. The pharmaceutical composition of E315, wherein Compound A is present in an amount of about 1.5 mg to about 2.5 mg.

[0503] E318. The pharmaceutical composition according to any one of E315 to E317, wherein said pharmaceutically acceptable salt of Compound B is a maleate salt (which may be a sesqui-maleate salt) of Compound B and is present in about 6 mg to about 8 mg.

[0504] E319. The pharmaceutical composition according to any one of E315 to E317, wherein said pharmaceutically acceptable salt of Compound B is a maleate salt (which may be a sesqui-maleate salt) of Compound B and is present in about 20 mg to about 35 mg.

[0505] E320. The pharmaceutical composition of any one of E315 to E319, wherein said filler is present at about 80 wt / wt% to about 90 wt / wt%.

[0506] E321. The pharmaceutical composition of any one of E315 to E319, wherein said filler is present at about 72.5 wt / wt% to about 85 wt / wt%.

[0507] E322. The pharmaceutical composition according to any one of E315 to E321, wherein said disintegrant is present at about 3.5 wt / wt% to about 4.5 wt / wt%.

[0508] E323. The pharmaceutical composition according to any one of E315 to E322, wherein said lubricant is present at about 1.5 wt / wt% to about 5.0 wt / wt%.

[0509] E324. The pharmaceutical composition according to any one of E315 to E323, wherein said filler is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, dicalcium phosphate, and combinations thereof.

[0510] E325. The pharmaceutical composition according to E324, wherein said filler comprises microcrystalline cellulose.

[0511] E326. The pharmaceutical composition according to E325, wherein said microcrystalline cellulose is silicified microcrystalline cellulose.

[0512] E327. The pharmaceutical composition according to any one of E315 to E326, wherein said disintegrant is selected from the group consisting of croscarmellose, sodium starch glycolate, crospovidone, alginic acid, and combinations thereof.

[0513] E328. The pharmaceutical composition according to E327, wherein said disintegrant comprises croscarmellose sodium.

[0514] E329. The pharmaceutical composition according to any one of E315 to E328, wherein said lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, glyceryl dibehenate, talc, or combinations thereof.

[0515] E330. The pharmaceutical composition according to E329, wherein said lubricant comprises sodium stearyl fumarate.

[0516] E331. The pharmaceutical composition according to E329, wherein said lubricant comprises magnesium stearate.

[0517] E332. The pharmaceutical composition according to any one of E315 to E331, wherein said pharmaceutically acceptable salt of Compound B is a maleate salt of Compound B (which may be a sesqui-maleate salt).

[0518] E333. The pharmaceutical composition according to any one of E315 to E332, wherein said pharmaceutical composition is a tablet or a capsule.

[0519] E334. The pharmaceutical composition according to E333, wherein said pharmaceutical composition is a capsule.

[0520] E335. The pharmaceutical composition according to E334, wherein the capsule contains about 1.0 mg of Compound A and about 7 mg of maleate (which may be sesqui-maleate) of Compound B, and each component of the capsule is as follows: a. about 0.8 wt / wt% to about 1.2 wt / wt% of Compound A; b. about 6 wt / wt% to about 8 wt / wt% of a maleate salt (which may be a sesqui-maleate salt) of Compound B; c. about 80 wt / wt% to about 90 wt / wt% silicified microcrystalline cellulose; d. about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium; e. about 1.5 wt / wt% to about 5.0 wt / wt% sodium stearyl fumarate; and f. A gelatin capsule encapsulating components a to e.

[0521] E336. The pharmaceutical composition according to E334, wherein the capsule contains about 2.0 mg of compound A and about 27 mg of maleate (which may be sesqui-maleate) of compound B, and each component of the capsule is as follows: a. about 0.8 wt / wt% to about 1.3 wt / wt% of Compound A; b. about 12.3 wt / wt% to about 15.0 wt / wt% of a maleate salt (which can be a sesqui-maleate salt) of Compound B; c. about 72.5 wt / wt% to about 85 wt / wt% silicified microcrystalline cellulose; d. about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium; e. about 1.5 wt / wt% to about 5.0 wt / wt% sodium stearyl fumarate; and f. A gelatin capsule encapsulating components a to e.

[0522] E337. A method of treating a patient with a solid tumor, comprising administering to said patient in need thereof a pharmaceutical composition according to any one of E315 to E336.

[0523] E338. The method of E337, wherein said solid tumor is selected from the group consisting of malignant peripheral nerve sheath tumor, biliary tract cancer, breast cancer, cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, lung adenocarcinoma, squamous non-small cell lung carcinoma, non-squamous non-small cell lung carcinoma, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and peritoneal serous carcinoma.

[0524] E339. The method of E338, wherein said patient has non-small cell lung cancer.

[0525] E340. The method of E338, wherein said patient has endometrial cancer.

[0526] E341. The method of E338, wherein said patient has ovarian cancer.

[0527] E342. The method of E341, wherein said patient has low-grade serous ovarian cancer.

[0528] E343. The method of any one of E338 to E342, wherein said patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2.

[0529] E344. The method according to any one of E338 to E343, wherein the pharmaceutical composition according to any one of E315 to E335 is administered in a 28-day administration cycle comprising (a) 21 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (b) 7 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0530] E345. The method according to any one of E338 to E343, wherein the pharmaceutical composition according to any one of E315 to E335 is administered in a 28-day administration cycle comprising (a) 21 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0531] E346. The method of any one of E338 to E343, wherein the pharmaceutical composition of any one of E315 to E335 is administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising (i) 5 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 2 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; and (b) 7 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0532] E347. The method of any one of E338 to E344, wherein the pharmaceutical composition of any one of E315 to E335 is administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising (i) 5 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 2 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0533] E348. The method of any one of E338 to E343, wherein the pharmaceutical composition of any one of E315 to E335 is administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising (i) 4 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 3 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; and (b) 7 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0534] E349. The method of any one of E338 to E343, wherein the pharmaceutical composition of any one of E315 to E335 is administered in a 28-day administration cycle comprising: (a) three 7-day periods each comprising (i) 4 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) 3 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0535] E350. The method of any one of E334-E349, wherein said 28-day administration cycle is repeated for a maximum of 24 consecutive 28-day administration cycles.

[0536] E351. The method according to any one of E338 to E343, wherein the pharmaceutical composition according to any one of E315 to E335 is administered in a 7-day administration cycle comprising (a) 5 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 2 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

[0537] E352. The method of any one of E338 to E351, wherein said patient has a confirmed mutation in RASA1 and / or RAF1.

[0538] E353. Use of a combination of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, for the manufacture of a medicament for treating a patient with a solid tumor.

[0539] E354. The use according to E353, wherein Compound A and Compound B or a pharmaceutically acceptable salt form thereof are in the same or different dosage forms.

[0540] E355. The use according to E354, wherein Compound A and Compound B or a pharmaceutically acceptable salt form thereof are in the same dosage form.

[0541] E356. Use of E355, wherein said dosage form is a pharmaceutical composition according to any one of E315 to E350.

[0542] E357. The use according to E354, wherein Compound A and Compound B or a pharmaceutically acceptable salt form thereof are administered in different dosage forms.

[0543] E358. The use according to E357, wherein compound A is administered before, simultaneously with, or after said administration of compound B or a pharmaceutically acceptable salt form thereof.

[0544] E359. The use according to E357 or E358, wherein said dosage form of compound A is a capsule.

[0545] E360. The use according to any one of E357 to E359, wherein said dosage form of Compound B or a pharmaceutically acceptable salt thereof is a capsule.

[0546] E361. The use according to any one of E357 to E359, wherein the pharmaceutically acceptable salt of Compound B is a maleate salt of Compound B.

[0547] E362. The use according to any one of E357 to E360, wherein Compound A and Compound B or a pharmaceutically acceptable salt form thereof are administered orally.

[0548] E363. The use according to any one of E353 to E360, 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, lung adenocarcinoma, squamous non-small cell lung carcinoma, non-squamous non-small cell lung carcinoma, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and serous carcinoma of the peritoneum.

[0549] E364. The use of E363, wherein said patient has non-small cell lung cancer.

[0550] E365. The use of E363, wherein said patient has endometrial cancer.

[0551] E366. The use according to E363, wherein said patient has ovarian cancer.

[0552] E367. The use according to E366, wherein said patient has low-grade serous ovarian cancer.

[0553] E368. The use of any one of E353 to E367, wherein said patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2.

[0554] E369. The use of any one of E353 to E367, wherein said patient has a confirmed mutation in RASA1 and / or RAF1. List of References Chapman PB, Hauschild A, Robert C, et al.Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med.2011;364(26):2507-16. Hauschild A,Grob JJ,Demidov LV,et al.Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre,open-label,phase 3 randomised controlled trial.Lancet.2012;380(9839):358-65. Kwong,Lawrence N.,et al.“Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma.” The Journal of clinical investigation 125.4(2015):1459-1470. Larkin,James,et al.“Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.” New England Journal of Medicine 371.20(2014):1867-1876. Long,Georgina V.,et al.“Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre,double-blind,phase 3 randomised controlled trial.” The Lancet 386.9992(2015):444-451. Flaherty,Keith T.,et al.“Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.” New England Journal of Medicine 367.18(2012):1694-1703 Flaherty KT,Robert C,Hersey P,et al.Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med.2012;367(2):107-14. Reddy,Sangeetha M.,Alexandre Reuben,and Jennifer A.Wargo. “Influences of BRAF inhibitors on the immune microenvironment and the rationale for combined molecular and immune targeted therapy.” Current oncology reports 18.7(2016):42 Rizos,Helen,et al.“BRAF inhibitor resistance mechanisms in metastatic melanoma:spectrum and clinical impact.” Clinical cancer research 20.7(2014):1965-1977 The present invention provides, for example, the following items. (Item 1) A method of treating a patient having a solid tumor, comprising co-administering to said patient a therapeutically effective amount of Compound A (mirdametinib) or a pharmaceutically acceptable salt form thereof and a therapeutically effective amount of Compound B (lifirafenib) or a pharmaceutically acceptable salt form thereof. (Item 2) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound A is about 1 mg to about 5 mg per day. (Item 3) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 5 mg to about 40 mg per day. (Item 4) 2. The method according to item 1, wherein the therapeutically effective amount of compound A is about 1 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 5 mg to about 15 mg per day. (Item 5) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound A is about 2 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 5 mg to about 40 mg per day. (Item 6) 2. The method according to item 1, wherein the therapeutically effective amount of compound A is about 2 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 35 mg per day. (Item 7) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound A is about 3 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 5 mg to about 40 mg per day. (Item 8) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound A is about 3 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 35 mg per day. (Item 9) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound A is about 4 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 10 mg to about 40 mg per day. (Item 10) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound A is about 4 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 35 mg per day. (Item 11) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound A is about 5 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 10 mg to about 40 mg per day. (Item 12) Item 1. The method according to item 1, wherein the therapeutically effective amount of compound A is about 5 mg per day, and the therapeutically effective amount of compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 40 mg per day. (Item 13) 13. The method according to any one of items 1 to 12, wherein compound B is in the form of a pharmaceutically acceptable salt. (Item 14) 14. The method of claim 13, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 15) Item 15. The method of item 14, wherein the therapeutically effective amount of compound A is about 1 mg per day and the therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 5 mg to about 10 mg per day. (Item 16) 15. The method of item 14, wherein the therapeutically effective amount of compound A is about 1 mg per day and the therapeutically effective amount of compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg per day. (Item 17) Item 15. The method of item 14, wherein the therapeutically effective amount of compound A is about 2 mg per day and the therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 10 mg to about 30 mg per day. (Item 18) 15. The method of item 14, wherein the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 13 mg per day. (Item 19) 15. The method of item 14, wherein the therapeutically effective amount of Compound A is about 2 mg per day and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. (Item 20) Item 15. The method according to item 14, wherein the therapeutically effective amount of compound A is about 3 mg per day, and the therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 15 mg to about 40 mg per day. (Item 21) 15. The method of item 14, wherein the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. (Item 22) 15. The method of item 14, wherein the therapeutically effective amount of Compound A is about 3 mg per day and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 34 mg per day. (Item 23) Item 15. The method according to item 14, wherein the therapeutically effective amount of compound A is about 4 mg per day and the therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg to about 40 mg per day. (Item 24) 15. The method of item 14, wherein the therapeutically effective amount of Compound A is about 4 mg per day and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. (Item 25) Item 15. The method according to item 14, wherein the therapeutically effective amount of compound A is about 5 mg per day and the therapeutically effective amount of compound B as the maleate salt (which may be a sesqui-maleate salt) is about 25 mg to about 40 mg per day. (Item 26) 15. The method of item 14, wherein the therapeutically effective amount of Compound A is about 5 mg per day and the therapeutically effective amount of Compound B as the maleate salt is about 34 mg per day. (Item 27) 27. The method according to any one of items 1 to 26, wherein compound A and compound B or a pharmaceutically acceptable salt form thereof are administered in the same or different dosage forms. (Item 28) 28. The method of item 27, wherein compound A and compound B or a pharmaceutically acceptable salt form thereof are administered in the same dosage form. (Item 29) 29. The method of claim 28, wherein the dosage form is a capsule. (Item 30) 30. The method according to any one of items 1 to 29, wherein compound A is administered once per day. (Item 31) 31. The method of any one of items 1 to 30, wherein compound B or a pharmaceutically acceptable salt form thereof is administered once daily. (Item 32) 28. The method of item 27, wherein Compound A and Compound B or a pharmaceutically acceptable salt form thereof are administered in different dosage forms. (Item 33) 33. The method of item 32, wherein compound A is administered before, simultaneously with, or after said administration of compound B or a pharmaceutically acceptable salt form thereof. (Item 34) 29. The method according to item 27 or item 28, wherein the dosage form of compound A is a capsule. (Item 35) 35. The method according to any one of items 27 to 34, wherein said dosage form of compound B or a pharmaceutically acceptable salt thereof is a capsule. (Item 36) 36. The method according to any one of items 1 to 35, wherein compound A and compound B or a pharmaceutically acceptable salt form thereof are administered orally. (Item 37) 37. The method according to any one of items 1 to 36, 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, lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and peritoneal serous carcinoma. (Item 38) 38. The method of claim 37, wherein the patient has non-small cell lung cancer. (Item 39) 38. The method of claim 37, wherein the patient has endometrial cancer. (Item 40) 38. The method of claim 37, wherein the patient has ovarian cancer. (Item 41) 41. The method of claim 40, wherein the patient has low-grade serous ovarian cancer. (Item 42) 42. The method of any one of items 1 to 41, wherein the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2. (Item 43) 43. The method of any one of items 1 to 42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. (Item 44) 43. The method of any one of items 1 to 42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, followed by (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. (Item 45) 43. The method of any one of items 1 to 42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising (i) a 5 day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) two days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) a 7 day period during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. (Item 46) 43. The method of any one of items 1 to 42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) a 5 day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) two days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) a 7 day period during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. (Item 47) 43. The method of any one of items 1 to 42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) 4 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) 3 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. (Item 48) 43. The method of any one of items 1 to 42, wherein Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) 4 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) 3 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. (Item 49) 49. The method of any one of items 43 to 48, wherein the 28-day administration cycle is repeated for a total of up to 24 consecutive 28-day administration cycles. (Item 50) 50. The method of any one of items 43 to 49, wherein only Compound B or a pharmaceutically acceptable salt form thereof is administered during a lead-in period prior to the first 28 day administration cycle. (Item 51) 51. The method of item 50, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as or less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle. (Item 52) 52. The method of claim 51, wherein the lead-in period begins 21 days prior to the initial 28-day administration cycle. (Item 53) 53. The method of claim 52, wherein the lead-in period begins 14 days prior to the initial 28-day administration cycle. (Item 54) 53. The method of claim 52, wherein the lead-in period begins 10 days prior to the initial 28-day administration cycle. (Item 55) 53. The method of claim 52, wherein the lead-in period begins 7 days prior to the initial 28-day administration cycle. (Item 56) 56. The method according to any one of items 50 to 55, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 25 mg per day. (Item 57) 56. The method according to any one of items 50 to 55, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 20 mg per day. (Item 58) 56. The method according to any one of items 50 to 55, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 15 mg per day. (Item 59) 56. The method according to any one of items 50 to 55, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg per day. (Item 60) 56. The method according to any one of items 50 to 55, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 10 mg per day. (Item 61) 56. The method according to any one of items 50 to 55, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 15 mg per day. (Item 62) 56. The method according to any one of items 50 to 55, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 20 mg per day. (Item 63) 56. The method according to any one of items 50 to 55, wherein compound B administered during the lead-in period is in the form of a pharmaceutically acceptable salt. (Item 64) 64. The method of claim 63, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 65) Item 65. The method according to item 64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 40 mg per day. (Item 66) Item 65. The method according to item 64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 30 mg per day. (Item 67) Item 65. The method of item 64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 25 mg per day. (Item 68) Item 65. The method of item 64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 7 mg per day. (Item 69) Item 65. The method of item 64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg per day. (Item 70) Item 65. The method of item 64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg per day. (Item 71) Item 65. The method of item 64, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 27 mg per day. (Item 72) 72. The method according to any one of items 50 to 71, wherein compound B or a pharmaceutically acceptable salt thereof is administered daily during said lead-in period. (Item 73) 73. The method according to any one of items 50 to 72, wherein compound B or a pharmaceutically acceptable salt thereof is administered once daily during said lead-in period. (Item 74) 50. The method of any one of items 43 to 49, wherein one or both of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered during a lead-in period prior to an initial 28 day administration cycle at a dose that is less than the therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, administered during said initial 28 day cycle. (Item 75) 75. The method of item 74, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the first 28-day administration cycle. (Item 76) 75. The method of item 74, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle. (Item 77) 77. The method according to any one of items 74 to 76, wherein the amount of compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg to about 5 mg per day. (Item 78) 77. The method of any one of items 74 to 76, wherein the amount of compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg per day. (Item 79) 77. The method of any one of items 74 to 76, wherein the amount of compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 2 mg per day. (Item 80) 77. The method of any one of items 74 to 76, wherein the amount of compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 3 mg per day. (Item 81) 81. The method of any one of items 74 to 80, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first 28 day administration cycle. (Item 82) 81. The method of any one of items 74 to 80, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the initial 28 day administration cycle. (Item 83) 81. The method according to any one of items 74 to 80, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 25 mg per day. (Item 84) 81. The method according to any one of items 74 to 80, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 20 mg per day. (Item 85) 81. The method according to any one of items 74 to 80, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 15 mg per day. (Item 86) 81. The method according to any one of items 74 to 80, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg per day. (Item 87) 81. The method according to any one of items 74 to 80, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 10 mg per day. (Item 88) 81. The method according to any one of items 74 to 80, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 15 mg per day. (Item 89) 81. The method according to any one of items 74 to 80, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 20 mg per day. (Item 90) 89. The method according to any one of items 74 to 89, wherein compound B administered during the lead-in period is in the form of a pharmaceutically acceptable salt. (Item 91) 91. The method of claim 90, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 92) Item 92. The method according to item 91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 40 mg per day. (Item 93) Item 92. The method of item 91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 30 mg per day. (Item 94) Item 92. The method of item 91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 25 mg per day. (Item 95) Item 92. The method of item 91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 7 mg per day. (Item 96) Item 92. The method of item 91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg per day. (Item 97) Item 92. The method of item 91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg per day. (Item 98) Item 92. The method of item 91, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 27 mg per day. (Item 99) 99. The method of any one of items 74-98, wherein the lead-in period begins 21 days prior to the initial 28-day administration cycle. (Item 100) 99. The method of any one of items 74-98, wherein the lead-in period begins 14 days prior to the first 28-day administration cycle. (Item 101) 99. The method of any one of items 74-98, wherein the lead-in period begins 10 days prior to the first 28-day administration cycle. (Item 102) 99. The method of any one of items 74-98, wherein the lead-in period begins 7 days prior to the first 28-day administration cycle. (Item 103) 103. The method according to any one of items 74 to 102, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are each administered daily during the lead-in period. (Item 104) 103. The method according to any one of items 74 to 102, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are each administered once daily during the lead-in period. (Item 105) 105. The method of any one of items 74 to 104, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are administered in the same or different dosage forms during said lead-in period. (Item 106) 106. The method of item 105, wherein Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt thereof are administered in the same dosage form during said lead-in period. (Item 107) 107. The method of claim 106, wherein the dosage form is a capsule. (Item 108) 106. The method of item 105, wherein Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt form thereof are administered in different dosage forms during said lead-in period. (Item 109) 109. The method of claim 108, wherein Compound A is administered during the lead-in period before, simultaneously with, or after the administration of Compound B or a pharmaceutically acceptable salt form thereof. (Item 110) 109. The method according to claim 108, wherein the dosage form of compound A or a pharmaceutically acceptable salt thereof is a capsule. (Item 111) 109. The method according to claim 108, wherein the dosage form of compound B or a pharmaceutically acceptable salt thereof is a capsule. (Item 112) 112. The method according to any one of items 74 to 111, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are orally administered during said lead-in period. (Item 113) 113. The method of any one of items 1 to 112, wherein the patient has a confirmed mutation in RASA1 and / or RAF1. (Item 114) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 1 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. (Item 115) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. (Item 116) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. (Item 117) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. (Item 118) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. (Item 119) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. (Item 120) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. (Item 121) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 20 mg per day. (Item 122) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 15 mg per day. (Item 123) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day. (Item 124) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day. (Item 125) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day. (Item 126) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day. (Item 127) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day. (Item 128) 2. The method of claim 1, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 10 mg per day. (Item 129) 129. The method according to any one of items 114 to 128, wherein compound B is in the form of a pharmaceutically acceptable salt. (Item 130) 130. The method of claim 129, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 131) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 1 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. (Item 132) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. (Item 133) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. (Item 134) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. (Item 135) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 2 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. (Item 136) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. (Item 137) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 3 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. (Item 138) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day. (Item 139) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg per day. (Item 140) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day, and the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg per day. (Item 141) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 4 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 13 mg per day. (Item 142) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 7 mg per day. (Item 143) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 13 mg per day. (Item 144) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 7 mg per day. (Item 145) Item 131. The method of item 130, wherein the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day and the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 13 mg per day. (Item 146) 146. The method according to any one of items 114 to 145, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in the same or different dosage forms. (Item 147) 147. The method of item 146, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in the same dosage form. (Item 148) Item 148. The method of item 147, wherein the dosage form is a capsule. (Item 149) 149. The method according to any one of items 114 to 148, wherein compound A or a pharmaceutically acceptable salt thereof is administered once per day. (Item 150) 149. The method according to any one of items 114 to 149, wherein compound B or a pharmaceutically acceptable salt form thereof is administered once daily. (Item 151) 147. The method of item 146, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in different dosage forms. (Item 152) 152. The method of claim 151, wherein compound A is administered before, simultaneously with, or after said administration of compound B or a pharmaceutically acceptable salt form thereof. (Item 153) Item 153. The method according to item 151 or item 152, wherein the dosage form of compound A or a pharmaceutically acceptable salt thereof is a capsule. (Item 154) Item 153. The method according to item 151 or item 152, wherein the dosage form of compound B or a pharmaceutically acceptable salt thereof is a capsule. (Item 155) 155. The method according to any one of items 114 to 154, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered orally. (Item 156) 156. The method according to any one of Items 114 to 155, 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, lung adenocarcinoma, squamous non-small cell lung carcinoma, non-squamous non-small cell lung carcinoma, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and peritoneal serous carcinoma. (Item 157) 157. The method of claim 156, wherein the patient has non-small cell lung cancer. (Item 158) 157. The method of claim 156, wherein the patient has endometrial cancer. (Item 159) 157. The method of claim 156, wherein the patient has ovarian cancer. (Item 160) 157. The method of claim 156, wherein the patient has low-grade serous ovarian cancer. (Item 161) 161. The method of any one of items 114 to 160, wherein the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1, and MEK2. (Item 162) 162. The method of any one of items 114 to 161, wherein the patient has a confirmed mutation in RASA1 and / or RAF1. (Item 163) 163. The method of any one of items 114 to 162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28 day administration cycle comprising: (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt thereof, is administered. (Item 164) 163. The method of any one of items 114 to 162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28 day administration cycle comprising: (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt thereof, are administered, followed by (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt thereof, is administered. (Item 165) 163. The method of any one of items 114 to 162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) a 5 day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (ii) two days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered; and (b) a 7 day period during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered. (Item 166) 163. The method of any one of items 114 to 162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) a 5 day period during which both Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (ii) two days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered, followed by (b) seven days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered. (Item 167) 163. The method of any one of items 114 to 162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) 4 days during which both Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered; and (ii) 3 days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered; and (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered. (Item 168) 163. The method of any one of items 114 to 162, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered in a 28 day administration cycle comprising: (a) three 7 day periods each comprising: (i) 4 days during which both Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, are administered, and (ii) 3 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt thereof, is administered, followed by (b) 7 days during which neither Compound A, or a pharmaceutically acceptable salt thereof, nor Compound B, or a pharmaceutically acceptable salt thereof, is administered. (Item 169) 169. The method of any one of items 163-168, wherein the 28-day administration cycle is repeated for a maximum of a total of 24 consecutive 28-day administration cycles. (Item 170) 169. The method of any one of items 163 to 168, wherein only Compound B or a pharmaceutically acceptable salt form thereof is administered during a lead-in period prior to the first 28 day administration cycle. (Item 171) 171. The method of claim 170, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as or less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle. (Item 172) 172. The method of claim 171, wherein the lead-in period begins 21 days prior to the initial 28-day administration cycle. (Item 173) 172. The method of claim 171, wherein the lead-in period begins 14 days prior to the initial 28-day administration cycle. (Item 174) 172. The method of claim 171, wherein the lead-in period begins 10 days prior to the initial 28-day administration cycle. (Item 175) 172. The method of claim 171, wherein the lead-in period begins 7 days prior to the initial 28-day administration cycle. (Item 176) 169. The method according to any one of items 163 to 168, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 25 mg per day. (Item 177) 169. The method according to any one of items 163 to 168, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 20 mg per day. (Item 178) 169. The method according to any one of items 163 to 168, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 15 mg per day. (Item 179) 169. The method according to any one of items 163 to 168, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg per day. (Item 180) 169. The method according to any one of items 163 to 168, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 10 mg per day. (Item 181) 169. The method according to any one of items 163 to 168, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 15 mg per day. (Item 182) 169. The method according to any one of items 163 to 168, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 20 mg per day. (Item 183) 169. The method according to any one of items 163 to 168, wherein compound B administered during the lead-in period is in the form of a pharmaceutically acceptable salt. (Item 184) 184. The method of claim 183, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 185) Item 185. The method of item 184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 40 mg per day. (Item 186) Item 185. The method of item 184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 30 mg per day. (Item 187) Item 185. The method of item 184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 25 mg per day. (Item 188) Item 185. The method of item 184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 7 mg per day. (Item 189) Item 185. The method of item 184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg per day. (Item 190) Item 185. The method of item 184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg per day. (Item 191) Item 185. The method of item 184, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 27 mg per day. (Item 192) 192. The method according to any one of items 170 to 191, wherein compound B or a pharmaceutically acceptable salt thereof is administered daily during said lead-in period. (Item 193) 193. The method according to any one of items 170 to 192, wherein compound B or a pharmaceutically acceptable salt thereof is administered once daily during said lead-in period. (Item 194) 169. The method of any one of items 163 to 168, wherein one or both of Compound A or a pharmaceutically acceptable salt form thereof and Compound B or a pharmaceutically acceptable salt form thereof are administered during a lead-in period prior to an initial 28 day administration cycle at a dose that is less than the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt form thereof and Compound B or a pharmaceutically acceptable salt form thereof administered during said initial 28 day cycle. (Item 195) 195. The method of claim 194, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the first 28-day administration cycle. (Item 196) 195. The method of claim 194, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the initial 28-day administration cycle. (Item 197) 197. The method according to any one of items 194 to 196, wherein the amount of compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg to about 5 mg per day. (Item 198) 197. The method of any one of items 194 to 196, wherein the amount of compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg per day. (Item 199) 197. The method of any one of items 194 to 196, wherein the amount of compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 2 mg per day. (Item 200) 197. The method of any one of items 194 to 196, wherein the amount of compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 3 mg per day. (Item 201) 201. The method of any one of items 194 to 200, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first 28 day administration cycle. (Item 202) 201. The method of any one of items 194 to 200, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the initial 28 day administration cycle. (Item 203) 203. The method according to any one of items 194 to 202, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 25 mg per day. (Item 204) 203. The method according to any one of items 194 to 202, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 20 mg per day. (Item 205) 203. The method according to any one of items 194 to 202, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg to about 15 mg per day. (Item 206) 203. The method according to any one of items 194 to 202, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 5 mg per day. (Item 207) 203. The method according to any one of items 194 to 202, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 10 mg per day. (Item 208) 203. The method according to any one of items 194 to 202, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 15 mg per day. (Item 209) 203. The method according to any one of items 194 to 202, wherein the amount of compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 20 mg per day. (Item 210) 209. The method according to any one of items 194 to 209, wherein compound B administered during the lead-in period is in the form of a pharmaceutically acceptable salt. (Item 211) 211. The method of claim 210, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 212) 212. The method of item 211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 40 mg per day. (Item 213) 212. The method of item 211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 30 mg per day. (Item 214) 212. The method of item 211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 5 mg to about 25 mg per day. (Item 215) 212. The method of claim 211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 7 mg per day. (Item 216) 212. The method of claim 211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg per day. (Item 217) 212. The method of claim 211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg per day. (Item 218) 212. The method of claim 211, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 27 mg per day. (Item 219) 219. The method of any one of items 194-218, wherein the lead-in period begins 21 days prior to the first 28-day administration cycle. (Item 220) 219. The method of any one of items 194-218, wherein the lead-in period begins 14 days prior to the first 28-day administration cycle. (Item 221) 219. The method of any one of items 194-218, wherein the lead-in period begins 10 days prior to the initial 28-day administration cycle. (Item 222) 219. The method of any one of items 194-218, wherein the lead-in period begins 7 days prior to the first 28-day administration cycle. (Item 223) 223. The method according to any one of items 194 to 222, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are each administered daily during the lead-in period. (Item 224) 223. The method according to any one of items 194 to 222, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are each administered once daily during the lead-in period. (Item 225) 223. The method according to any one of items 194 to 222, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are administered in the same or different dosage forms during said lead-in period. (Item 226) 226. The method of item 225, wherein Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt thereof are administered in the same dosage form during said lead-in period. (Item 227) 227. The method of claim 226, wherein the dosage form is a capsule. (Item 228) 226. The method of item 225, wherein Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt form thereof are administered in different dosage forms during said lead-in period. (Item 229) 229. The method of item 228, wherein Compound A is administered during the lead-in period before, simultaneously with, or after the administration of Compound B or a pharmaceutically acceptable salt form thereof. (Item 230) 220. The method according to item 228 or item 229, wherein the dosage form of compound A or a pharmaceutically acceptable salt thereof is a capsule. (Item 231) 220. The method according to item 228 or item 229, wherein the dosage form of compound B or a pharmaceutically acceptable salt thereof is a capsule. (Item 232) 232. The method according to any one of items 194 to 231, wherein compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt form thereof are orally administered during said lead-in period. (Item 233) 233. The method according to any one of items 1 to 232, wherein compound A is provided in the form of a pharmaceutically acceptable salt. (Item 234) 233. The method according to any one of items 1 to 232, wherein compound A is provided in free base form. (Item 235) 1. A method of treating a patient having a solid tumor, comprising administering 2 mg of Compound A as the free base and 15 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily. (Item 236) 236. The method of item 235, wherein compound B is administered as a pharmaceutically acceptable salt form. (Item 237) 237. The method of claim 236, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 238) 238. The method of claim 237, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 20 mg. (Item 239) 1. A method of treating a patient having a solid tumor, comprising administering 2 mg of Compound A as the free base and 20 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily. (Item 240) 239. The method of claim 239, wherein compound B is administered as a pharmaceutically acceptable salt form. (Item 241) 241. The method of claim 240, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 242) 242. The method of claim 241, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg. (Item 243) 1. A method of treating a patient having a solid tumor, comprising: (a) administering 3 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by a 7-day cycle comprising: (b) no administration of Compound A or Compound B for 2 consecutive days. (Item 244) 244. The method of item 243, wherein compound B is administered as a pharmaceutically acceptable salt form. (Item 245) 245. The method of claim 244, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 246) 246. The method of claim 245, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg. (Item 247) 1. A method of treating a patient having a solid tumor, comprising: The method comprises: (a) a lead-in period comprising administering 3 mg of Compound A free base and 10 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 3 mg of Compound A free base and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days. (Item 248) 248. The method of item 247, wherein compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. (Item 249) 249. The method of claim 248, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 250) 249. The method of claim 249, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg. (Item 251) 251. The method of claim 250, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the treatment period is about 27 mg. (Item 252) 1. A method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of a total of 2 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) (i) administering 1 mg of Compound A free base twice daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. (Item 253) 253. The method of item 252, wherein compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. (Item 254) 254. The method of claim 253, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 255) 255. The method of claim 254, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg. (Item 256) 256. The method of claim 255, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the treatment period is about 20 mg. (Item 257) 1. A method of treating a patient having a solid tumor, comprising: (a) administering 4 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by a 7-day cycle comprising: (a) administering 4 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form once daily for 5 consecutive days, followed by (b) administering no Compound A or Compound B for 2 consecutive days. (Item 258) 258. The method of item 257, wherein compound B is administered as a pharmaceutically acceptable salt form. (Item 259) 259. The method of claim 258, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 260) 259. The method of claim 259, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg. (Item 261) 1. A method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) administering 1 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) a 7-day treatment cycle comprising administering neither Compound A nor Compound B for 2 consecutive days. (Item 262) 262. The method of item 261, wherein compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. (Item 263) 263. The method of claim 262, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 264) 264. The method of claim 263, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg. (Item 265) 265. The method of claim 264, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the treatment period is about 27 mg. (Item 266) 1. A method of treating a patient having a solid tumor, comprising: (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) a 7-day treatment cycle comprising administering 2 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B. (Item 267) 267. The method of item 266, wherein compound B is administered as a pharmaceutically acceptable salt form during both the lead-in period and the treatment cycle. (Item 268) 268. The method of claim 267, wherein the pharmaceutically acceptable salt form is a maleate salt (which may be a sesqui-maleate salt). (Item 269) 269. The method of claim 268, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg. (Item 270) 269. The method of claim 269, wherein the amount of Compound B as the maleate sa...

Claims

1. A combination of Compound A (mirdametinib) or a pharmaceutically acceptable salt form thereof and Compound B (lifirafenib) or a pharmaceutically acceptable salt form thereof for use in treating a patient having a solid tumor, wherein Compound A and Compound B are each administered in a therapeutically effective amount.

2. 2. The combination for use according to claim 1, wherein said therapeutically effective amount of Compound A is from about 1 mg to about 5 mg per day; and / or said therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is from about 5 mg to about 40 mg per day.

3. (i) (a) the therapeutically effective amount of Compound A is about 1 mg per day, and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 15 mg per day; (ii) (a) the therapeutically effective amount of Compound A is about 2 mg per day, and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 40 mg per day; (iii) (a) the therapeutically effective amount of Compound A is about 3 mg per day, and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 5 mg to about 40 mg per day; (iv) (a) the therapeutically effective amount of Compound A is about 4 mg per day, and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 10 mg to about 40 mg per day; (v) (a) the therapeutically effective amount of Compound A is about 5 mg per day, and (b) the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 10 mg to about 40 mg per day; (vi) (a) the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and (b) the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day, or about 10 mg per day; or (vii) The combination for use according to claim 1, wherein (a) the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and (b) the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 5 mg per day, or about 10 mg per day.

4. (i) (a) the therapeutically effective amount of Compound A is about 1 mg per day, and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg per day; (ii) (a) the therapeutically effective amount of Compound A is about 2 mg per day, and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day; (iii) (a) the therapeutically effective amount of Compound A is about 3 mg per day; and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day; (iv) (a) the therapeutically effective amount of Compound A is about 4 mg per day, and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg to about 35 mg per day; or (v) The combination for use according to claim 1, wherein (a) the therapeutically effective amount of Compound A is about 5 mg per day, and (b) the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 20 mg to about 40 mg per day.

5. (ii) (a) the therapeutically effective amount of Compound A is about 2 mg per day, and (b) the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 20 mg per day or about 15 mg per day; (iii) (a) the therapeutically effective amount of Compound A is about 3 mg per day, and (b) the therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt form thereof, is about 20 mg per day or about 15 mg per day; or (iv) The combination for use according to claim 4, wherein (a) the therapeutically effective amount of Compound A is about 4 mg per day, and (b) the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt form thereof is about 20 mg per day, about 15 mg per day, about 10 mg per day, or about 5 mg per day.

6. The combination for use according to any one of claims 1 to 5, wherein compound B is in the form of a pharmaceutically acceptable salt.

7. The combination for use according to claim 6, wherein said pharmaceutically acceptable salt form is a maleate salt, which may be a sesqui-maleate salt.

8. (i) (a) the therapeutically effective amount of Compound A is about 1 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 5 mg to about 10 mg per day; (ii) (a) the therapeutically effective amount of Compound A is about 2 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 10 mg to about 30 mg per day; (iii) (a) the therapeutically effective amount of Compound A is about 3 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 15 mg to about 40 mg per day; (iv) (a) the therapeutically effective amount of Compound A is about 4 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg to about 40 mg per day; (v) (a) the therapeutically effective amount of Compound A is about 5 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 25 mg to about 40 mg per day; (vi) (a) the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 8 mg per day, and (b) the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 7 mg per day, or about 13 mg per day; or (vii) The combination for use according to claim 6 or 7, wherein (a) the therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof is about 12 mg per day, and (b) the therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof is about 7 mg per day, or about 13 mg per day.

9. (i) (a) the therapeutically effective amount of Compound A is about 1 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg per day; (ii) (a) the therapeutically effective amount of Compound A is about 2 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 13 mg per day, about 20 mg per day, or about 27 mg per day; (iii) (a) the therapeutically effective amount of Compound A is about 3 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be a sesqui-maleate salt) is about 20 mg per day, about 27 mg per day, or about 34 mg per day; (iv) (a) the therapeutically effective amount of Compound A is about 4 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg per day, about 20 mg per day, about 13 mg per day, or about 7 mg per day; or (v) The combination for use according to claim 8, wherein (a) the therapeutically effective amount of Compound A is about 5 mg per day, and (b) the therapeutically effective amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 34 mg per day.

10. The combination for use according to any one of claims 1 to 9, wherein compound A and / or compound B are administered once per day.

11. Compound A and Compound B, or pharmaceutically acceptable salt forms thereof, I. (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. II. (a) 21 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, followed by (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. III. (a) three 7-day periods each including (i) a 5-day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) two days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; and (b) a 7-day period during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. IV. (a) three 7-day periods each including (i) a 5-day period during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) two days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) a 7-day period during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered. V. (a) three 7-day periods each comprising (i) 4 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) 3 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered; or VI. (a) three 7-day periods each including (i) 4 days during which both Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, are administered, and (ii) 3 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which neither Compound A nor Compound B, or a pharmaceutically acceptable salt form thereof, is administered.

11. The combination for use according to any one of claims 1 to 10, administered in a 28 day administration cycle comprising:

12. 12. The combination for use according to claim 11, wherein the 28-day administration cycle is repeated for a total of up to 24 consecutive 28-day administration cycles.

13. The combination for use according to any one of claims 10 to 12, wherein only Compound B or a pharmaceutically acceptable salt form thereof is administered during the lead-in period prior to the first 28 day administration cycle.

14. 14. The combination for use according to claim 13, wherein the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is the same as or less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first 28-day administration cycle; and / or Compound B or a pharmaceutically acceptable salt thereof is administered daily during the lead-in period, preferably once daily during the lead-in period.

15. 13. The combination for use according to any one of claims 10 to 12, wherein one or both of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt form thereof, are administered during a lead-in period prior to an initial 28 day administration cycle at a dose that is lower than the therapeutically effective amounts of Compound A, or a pharmaceutically acceptable salt form thereof, and Compound B, or a pharmaceutically acceptable salt thereof, administered during said initial 28 day cycle.

16. the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is (i) is the same as the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the first 28-day administration cycle; or (ii) less than the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the first 28-day administration cycle.

17. (A) the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is from about 1 mg to about 5 mg per day; and / or (B) the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the lead-in period is (i) is the same as the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first 28-day administration cycle; (ii) less than the amount of Compound B or a pharmaceutically acceptable salt thereof administered during the first 28-day administration cycle; (iii) about 5 mg to about 25 mg per day, about 5 mg to about 20 mg per day, or about 5 mg to about 15 mg per day; or (iv) The combination for use according to claim 15 or 16, wherein the dose is about 5 mg per day, about 10 mg per day, about 15 mg per day, or about 20 mg per day.

18. 18. The combination for use according to claim 17, wherein the amount of Compound A or a pharmaceutically acceptable salt thereof administered during the lead-in period is about 1 mg per day, about 2 mg per day, or about 3 mg per day.

19. The combination for use according to any one of claims 15 to 18, wherein compound B administered during the lead-in period is in the form of a pharmaceutically acceptable salt.

20. 20. The combination for use according to claim 19, wherein the pharmaceutically acceptable salt form is a maleate salt, which may be a sesqui-maleate salt.

21. the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period (i) about 5 mg to about 40 mg per day, about 5 mg to about 30 mg per day, or about 5 mg to about 25 mg per day; or (ii) The combination for use according to claim 19 or 20, wherein the dose is about 7 mg per day, about 13 mg per day, about 20 mg per day, or about 27 mg per day.

22. The combination for use according to any one of claims 15 to 21, wherein the lead-in period starts 21 days, 14 days, 10 days or 7 days before the first 28 day administration cycle.

23. 23. The combination for use according to any one of claims 15 to 22, wherein said compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are each administered daily during said lead-in period.

24. 24. The combination for use according to claim 23, wherein said compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof are each administered once daily during said lead-in period.

25. The combination for use according to any one of claims 1 to 24, wherein compound A is provided in the form of a pharmaceutically acceptable salt or in the form of a free base.

26. A combination of Compound A (mirdametinib) and Compound B (lifirafenib) for use in treating patients with solid tumors, wherein the patient is administered 2 mg of Compound A as the free base and 15 mg of Compound B, or pharmaceutically acceptable salts thereof, once daily.

27. 27. The combination for use according to claim 26, wherein said compound B is administered as a pharmaceutically acceptable salt form.

28. 28. The combination for use according to claim 27, wherein the pharmaceutically acceptable salt form is a maleate salt, which may be a sesqui-maleate salt.

29. The combination for use according to any one of claims 26 to 28, wherein said amount of compound B as maleate salt (which may be sesqui-maleate salt) is about 20 mg.

30. A combination of Compound A (mirdametinib) and Compound B (lifirafenib) for use in treating patients with solid tumors, wherein the patient is administered 2 mg of Compound A as the free base and 20 mg of Compound B, or pharmaceutically acceptable salts thereof, once daily.

31. 1. A combination of Compound A (mirdametinib) and Compound B (lifirafenib) for use in treating patients with solid tumors, comprising: I. (a) 3 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form administered once daily for 5 consecutive days, followed by (b) 2 consecutive days without administration of either Compound A or Compound B; or II. (a) 4 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form administered once daily for 5 consecutive days, followed by (b) no administration of Compound A or Compound B for 2 consecutive days. a combination for said use, comprising a 7-day cycle comprising:

32. 32. The combination for use according to claim 30 or 31, wherein compound B is administered as a pharmaceutically acceptable salt form.

33. 33. The combination for use according to claim 32, wherein the pharmaceutically acceptable salt form is a maleate salt, which may be a sesqui-maleate salt.

34. 34. The combination for use according to claim 32 or 33, wherein said amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 27 mg.

35. A combination of Compound A (mirdametinib) and Compound B (lifirafenib) for use in treating patients with solid tumors, said treatment comprising a combination for said use comprising: (a) a lead-in period comprising the administration of 3 mg of Compound A free base and 10 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) the administration of 3 mg of Compound A free base and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B.

36. 36. The combination for use according to claim 35, wherein said compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

37. 37. The combination for use according to claim 36, wherein the pharmaceutically acceptable salt form is a maleate salt, which may be a sesqui-maleate salt.

38. 38. The combination for use according to any one of claims 35 to 37, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 13 mg or about 27 mg.

39. A combination of Compound A (mirdametinib) and Compound B (lifirafenib) for use in treating patients with solid tumors, said treatment comprising I. (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 1 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days without administration of either Compound A or Compound B; II. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 2 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days without administering either Compound A or Compound B; III. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 3 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; or IV. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a combination for said uses, comprising: (i) a 7-day treatment cycle comprising administering 4 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B.

40. 40. The combination for use according to claim 39, wherein said compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

41. 41. The combination for use according to claim 40, wherein the pharmaceutically acceptable salt form is a maleate salt, which may be a sesqui-maleate salt.

42. 42. The combination for use according to any one of claims 39 to 41, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg or about 27 mg.

43. A combination of Compound A (mirdametinib) and Compound B (lifirafenib) for use in treating patients with solid tumors, said treatment comprising I. (a) a lead-in period comprising administering a total of 2 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 1 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; II. (a) a lead-in period comprising administering a total of 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; or III. (a) a lead-in period comprising administering a total of 4 mg of Compound A free base and 15 mg of Compound B or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) a combination for said uses, comprising: (i) a 7-day treatment cycle comprising administering 4 mg of Compound A free base once daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of either Compound A or Compound B.

44. 44. The combination for use according to claim 43, wherein said compound B is administered as a pharmaceutically acceptable salt form during both said lead-in period and said treatment cycle.

45. 45. The combination for use according to claim 44, wherein the pharmaceutically acceptable salt form is a maleate salt, which may be a sesqui-maleate salt.

46. 46. ​​The combination for use according to any one of claims 43 to 45, wherein the amount of Compound B as the maleate salt (which may be the sesqui-maleate salt) administered during the lead-in period is about 20 mg.

47. A combination of Compound A (mirdametinib) and Compound B (lifirafenib) for use in treating patients with solid tumors, said treatment comprising (i) administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily; (ii) administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof once daily; (iii) administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof once daily; (iv) administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily; (v) administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily; or (vi) A combination for said use, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily.

48. 48. The combination for use according to claim 47, wherein compound B is in the form of a pharmaceutically acceptable salt.

49. 49. The combination for use according to claim 48, wherein the pharmaceutically acceptable salt form is a maleate salt, which may be a sesqui-maleate salt.

50. 50. The combination for use according to any one of claims 47 to 49, wherein each dose of Compound B as the maleate salt (which may be the sesqui-maleate salt) is about 7 mg.

51. Compound A and Compound B or a pharmaceutically acceptable salt form thereof are administered during the lead-in period and / or the treatment period. (i) administered in the same or different dosage forms; (ii) administered in the same dosage form, wherein said same dosage form is a capsule; or (iii) A combination for use according to any one of claims 15 to 24 or 26 to 50, which is administered in different dosage forms.

52. 52. The combination for use according to claim 51, wherein Compound A is administered before, simultaneously with, or after the administration of Compound B or a pharmaceutically acceptable salt form thereof, and / or the dosage form of Compound A and / or Compound B is a capsule.

53. 53. The combination for use according to any one of claims 15 to 52, wherein Compound A and Compound B or a pharmaceutically acceptable salt form thereof are administered orally.

54. 1. A pharmaceutical composition comprising: Compound A (mirdametinib), b. Compound B (lifirafenib) or a pharmaceutically acceptable salt form thereof; c. fillers; d. disintegrants, and e. The pharmaceutical composition, comprising a lubricant.

55. (i) Compound A is present at about 0.8 mg to about 1.2 mg, or about 1.5 mg to about 2.5 mg; (ii) said pharmaceutically acceptable salt of Compound B is a maleate salt (which may be a sesqui-maleate salt) of Compound B and is present in an amount of from about 6 mg to about 8 mg, or from about 20 mg to about 35 mg; (iii) the filler is present at about 80 wt / wt% to about 90 wt / wt%, or about 72.5 wt / wt% to about 85 wt / wt%; (iv) the disintegrant is present at about 3.5 wt / wt% to about 4.5 wt / wt%; and / or 55. The pharmaceutical composition of claim 54, wherein (v) the lubricant is present at about 1.5 wt / wt% to about 5.0 wt / wt%.

56. (i) the filler is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, dicalcium phosphate, and combinations thereof; (ii) the disintegrant is selected from the group consisting of croscarmellose, sodium starch glycolate, crospovidone, alginic acid, and combinations thereof; and / or (iii) 56. The pharmaceutical composition of claim 54 or 55, wherein the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, glyceryl dibehenate, talc, or a combination thereof.

57. 57. The pharmaceutical composition according to any one of claims 54 to 56, wherein the pharmaceutical composition is a tablet or a capsule.

58. The capsule is (i) about 1.0 mg of Compound A and about 7 mg of a maleate salt (which may be a sesqui-maleate salt) of Compound B, wherein the components of the capsule are as follows: a. about 0.8 wt / wt % to about 1.2 wt / wt % of Compound A; b. about 6 wt / wt % to about 8 wt / wt % of a maleate salt (which may be a sesqui-maleate salt) of Compound B; c. about 80 wt / wt% to about 90 wt / wt% silicified microcrystalline cellulose; d. about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium; e. about 1.5 wt / wt % to about 5.0 wt / wt % sodium stearyl fumarate, and f. a gelatin capsule encapsulating components a through e; or (ii) about 2.0 mg of Compound A and about 27 mg of a maleate salt (which may be a sesqui-maleate salt) of Compound B, wherein the components of the capsule are as follows: a. about 0.8 wt / wt % to about 1.3 wt / wt % of Compound A; b. about 12.3 wt / wt % to about 15.0 wt / wt % of a maleate salt (which may be a sesqui-maleate salt) of Compound B; c. about 72.5 wt / wt% to about 85 wt / wt% silicified microcrystalline cellulose; d. about 3.5 wt / wt% to about 4.5 wt / wt% croscarmellose sodium; e. about 1.5 wt / wt % to about 5.0 wt / wt % sodium stearyl fumarate, and f. A gelatin capsule encapsulating components a to e 58. The pharmaceutical composition of claim 57.

59. 59. A pharmaceutical composition according to any one of claims 54 to 58 for use in treating a patient with a solid tumor.

60. 60. The combination for use according to any one of claims 1 to 53, or the pharmaceutical composition for use according to claim 59, 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, lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, gastric cancer, sarcoma, bladder cancer, head and neck cancer, small cell lung 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, and serous carcinoma of the peritoneum.

61. 61. The combination for use or pharmaceutical composition for use according to claim 60, wherein the patient has non-small cell lung cancer, endometrial cancer, ovarian cancer, or low-grade serous ovarian cancer.

62. A combination for use according to any one of claims 1 to 53, 60 and 61, or a pharmaceutical composition for use according to any one of claims 59 to 61, wherein the patient has a confirmed mutation in one or more of KRAS, NRAS, HRAS, BRAF, NF1, MEK1 and MEK2; and / or a confirmed mutation in RASA1 and / or RAF1.

63. The pharmaceutical composition comprises: I. (a) 21 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (b) 7 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; II. (a) 21 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 7 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; III. (a) three 7-day periods each including (i) a 5-day period during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) a 2-day period during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, and (b) a 7-day period during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; IV. (a) three seven-day periods each comprising (i) five days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) two days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, followed by (b) seven days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; V. (a) three seven-day periods each comprising (i) four days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) three days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (b) seven days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered; or VI. (a) three seven-day periods each comprising (i) four days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, and (ii) three days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered, followed by (b) seven days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

63. The pharmaceutical composition for use according to any one of claims 59 to 62, administered in a 28 day administration cycle comprising:

64. 64. The pharmaceutical composition for use according to claim 63, wherein the 28-day administration cycle is repeated for a total of up to 24 consecutive 28-day administration cycles.

65. 63. The pharmaceutical composition for use according to any one of claims 59 to 62, wherein the pharmaceutical composition is administered in a 7-day dosing cycle comprising (a) 5 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is administered, followed by (b) 2 days during which the pharmaceutical composition comprising Compound A and Compound B, or a pharmaceutically acceptable salt form thereof, is not administered.

66. 1. A composition comprising Compound A (mirdametinib) or a pharmaceutically acceptable salt form thereof for use in treating a patient having a solid tumor, wherein the composition is administered in combination with Compound B (lifirafenib) or a pharmaceutically acceptable salt form thereof, wherein Compound A and Compound B are each administered in a therapeutically effective amount.

67. A composition comprising compound B (lifirafenib) or a pharmaceutically acceptable salt form thereof for use in treating a patient having a solid tumor, wherein the composition is administered in combination with compound A (mirdametinib) or a pharmaceutically acceptable salt form thereof, wherein compound A and compound B are each administered in a therapeutically effective amount.

68. A composition comprising Compound A (mirdametinib) for use in treating a patient having a solid tumor, wherein the composition is administered in combination with Compound B (lifirafenib), wherein the patient is administered 2 mg of Compound A as the free base and 15 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

69. A composition comprising Compound B (lifirafenib) for use in treating a patient having a solid tumor, wherein the composition is administered in combination with Compound A (mirdametinib), wherein the patient is administered 2 mg of Compound A as the free base and 15 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

70. A composition comprising Compound A (mirdametinib) for use in treating a patient having a solid tumor, wherein the composition is administered in combination with Compound B (lifirafenib), wherein the patient is administered 2 mg of Compound A as the free base and 20 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

71. A composition comprising Compound B (lifirafenib) for use in treating a patient having a solid tumor, wherein the composition is administered in combination with Compound A (mirdametinib), wherein the patient is administered 2 mg of Compound A as the free base and 20 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily.

72. A composition comprising compound A (mirdametinib) for treating a patient with a solid tumor, wherein said composition is administered in combination with compound B (lifirafenib), said treatment comprising I. (a) 3 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form administered once daily for 5 consecutive days, followed by (b) 2 consecutive days without administration of either Compound A or Compound B; or II. (a) 4 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form administered once daily for 5 consecutive days, followed by (b) no administration of Compound A or Compound B for 2 consecutive days. The composition comprising a 7-day cycle comprising:

73. A composition comprising compound B (lifirafenib) for treating a patient with a solid tumor, wherein the composition is administered in combination with compound A (mirdametinib), the treatment comprising I. (a) 3 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form administered once daily for 5 consecutive days, followed by (b) 2 consecutive days without administration of either Compound A or Compound B; or II. (a) 4 mg of Compound A free base and 20 mg of Compound B or a pharmaceutically acceptable salt form administered once daily for 5 consecutive days, followed by (b) no administration of Compound A or Compound B for 2 consecutive days. The composition comprising a 7-day cycle comprising:

74. 1. A composition comprising compound A (mirdametinib) for use in treating patients with solid tumors, wherein said composition is administered in combination with compound B (lifirafenib), wherein said treatment is (a) a lead-in period comprising the administration of 3 mg of Compound A free base and 10 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) the administration of 3 mg of Compound A free base and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days without administration of either Compound A or Compound B; The composition comprising:

75. A composition comprising compound B (lifirafenib) for use in treating patients with solid tumors, wherein said composition is administered in combination with compound A (mirdametinib), wherein said treatment is (a) a lead-in period comprising the administration of 3 mg of Compound A free base and 10 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) the administration of 3 mg of Compound A free base and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days without administration of either Compound A or Compound B; The composition comprising:

76. 1. A composition comprising compound A (mirdametinib) for use in treating patients with solid tumors, wherein said composition is administered in combination with compound B (lifirafenib), wherein said treatment is I. (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 1 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days without administration of either Compound A or Compound B; II. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 2 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days without administering either Compound A or Compound B; III. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 3 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; or IV. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) a 7-day treatment cycle comprising the administration of 4 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B.

77. A composition comprising compound B (lifirafenib) for use in treating patients with solid tumors, wherein said composition is administered in combination with compound A (mirdametinib), wherein said treatment is I. (a) a lead-in period comprising the administration of 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 1 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days without administration of either Compound A or Compound B; II. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 2 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days without administering either Compound A or Compound B; III. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 3 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; or IV. (a) a lead-in period comprising administering 15 mg of Compound B or a pharmaceutically acceptable salt form thereof once daily for 14 consecutive days, followed by (b) (i) a 7-day treatment cycle comprising the administration of 4 mg of Compound A free base once daily and 20 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B.

78. 1. A composition comprising compound A (mirdametinib) for use in treating patients with solid tumors, wherein said composition is administered in combination with compound B (lifirafenib), wherein said treatment is I. (a) a lead-in period comprising administering a total of 2 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 1 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; II. (a) a lead-in period comprising administering a total of 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; or III. (a) a lead-in period comprising administering a total of 4 mg of Compound A free base and 15 mg of Compound B or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) (i) a 7-day treatment cycle comprising the administration of 4 mg of Compound A free base once daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B.

79. A composition comprising compound B (lifirafenib) for use in treating patients with solid tumors, wherein said composition is administered in combination with compound A (mirdametinib), wherein said treatment is I. (a) a lead-in period comprising administering a total of 2 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 1 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; II. (a) a lead-in period comprising administering a total of 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, divided into two doses per day once daily for 14 consecutive days, followed by (b) a 7-day treatment cycle comprising: (i) administering 3 mg of Compound A free base and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) administering neither Compound A nor Compound B for 2 consecutive days; or III. (a) a lead-in period comprising administering a total of 4 mg of Compound A free base and 15 mg of Compound B or a pharmaceutically acceptable salt form thereof, divided into two doses per day, once daily for 14 consecutive days, followed by (b) (i) a 7-day treatment cycle comprising the administration of 4 mg of Compound A free base once daily and 15 mg of Compound B, or a pharmaceutically acceptable salt form thereof, once daily for 5 consecutive days, followed by (ii) 2 consecutive days with no administration of Compound A or Compound B.

80. 1. A composition comprising compound A (mirdametinib) for use in treating patients with solid tumors, wherein said composition is administered in combination with compound B (lifirafenib), wherein said treatment is (i) administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily; (ii) administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof once daily; (iii) administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof once daily; (iv) administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily; (v) administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily; or (vi) The composition, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily.

81. A composition comprising compound B (lifirafenib) for use in treating patients with solid tumors, wherein said composition is administered in combination with compound A (mirdametinib), wherein said treatment is (i) administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B, or a pharmaceutically acceptable salt thereof, once daily; (ii) administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof once daily; (iii) administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof once daily; (iv) administering 2 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily; (v) administering 4 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily; or (vi) The composition, comprising administering 6 mg of Compound A as the free base twice daily and 5 mg of Compound B or a pharmaceutically acceptable salt thereof twice daily.

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