WO2024186641A1

WO2024186641A1 - Methods and compositions for treating cancer

Info

Publication number: WO2024186641A1
Application number: PCT/US2024/018086
Authority: WO
Inventors: Matthew PARRIS; Mark S. GELDER
Original assignee: Onconova Therapeutics Inc
Current assignee: Traws Pharma Inc
Priority date: 2023-03-03
Filing date: 2024-03-01
Publication date: 2024-09-12
Anticipated expiration: 2025-09-03

Abstract

RAS proteins are frequently mutated in human cancers. Disclosed herein are compounds that disrupt RAS effectors and inhibits Ras/Raf/MEK/ERK pathway signaling. Further disclosed herein are methods of using compounds in combination with MEK inhibitors and/or BRAF inhibitors to treat cancer.

Description

METHODS AND COMPOSITIONS FOR TREATING CANCER

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63/488,462, filed March 3, 2023, which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] Melanoma is the fifth most common malignancy in males and the sixth most common malignancy in females. While most melanomas are detected at an early stage, a proportion of patients have metastatic disease at the time of diagnosis or develop metastasis at a later stage. The most common sites of metastasis are skin and subcutaneous tissue, followed by lungs, liver, bones, and brain.

INCORPORATION BY REFERENCE

[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

SUMMARY OF THE DISCLOSURE

[0004] Disclosed herein is a method of treating a condition comprising administering to a subject in need thereof a) a therapeutically-effective amount of a compound of the formula:

or a pharmaceutically-acceptable salt or zwitterion thereof, wherein: each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^{l la}, R^{l lb}, R¹², and R¹³ is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -

C(O)R^X, -C(O)OR^X, -C(O)NR^xR^y, -OR^X, -SR^X, -NR^xR^y, -NR^xC(O)R^y, -OC(O)R^X, or - SiR^xR^yR^z, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and each R^x, R^y, and R^z is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and b) a therapeutically-effective amount of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor selected from MEK inhibitor or an BRAF inhibitor.

[0005] In some embodiments, the second therapeutic agent is an MEK inhibitor, e.g., a MEK inhibitor selected from trametinib (GSK1120212), selumetinib, cobimetinib (i.e., XL518), and binimetinib (i.e., MEK162). In some embodiments, the second therapeutic agent is trametinib.

[0006] In some embodiments, the condition is an infectious disease, a proliferative disease, a cancer, a solid tumor, a liquid tumor, non-small cell lung cancer, melanoma, colorectal cancer, head and neck cancer, bladder cancer, pancreatic cancer, hairy cell leukemia, nonHodgkin lymphoma, thyroid cancer, ovarian cancer, lung adenocarcinoma, or brain cancer. In some embodiments, the cancer is a BRAF positive cancer, e.g., a cancer selected from melanoma, hairy cell leukemia, non-Hodgkin lymphoma, thyroid cancer, ovarian cancer, lung adenocarcinoma, colorectal cancer, brain cancer. In some embodiments, the cancer is a melanoma, e.g., an advanced melanoma, e.g., an unresectable or metastatic refractory melanoma, e.g., a BRAFV600-mutant metastatic melanoma, e.g., a BRAFV600E/K mutant metastatic melanoma.

[0007] In some embodiments, the method further comprises administering a third therapeutic agent to the subject. In some embodiments, the third therapeutic agent is an BRAF inhibitor, e.g., a BRAF inhibitor selected from vemurafenib, dabrafenib, and encorafenib. In some embodiments, the third therapeutic agent is dabrafenib.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 is a schematic of a dose escalation study of a compound disclosed herein.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0009] A mechanism of action for a compound disclosed herein, for example, rigosertib, is to down-modulate the mutated rat sarcoma (RAS) pathway. This modulation of the RAS pathway can result in less production of extracellular signal-regulated kinase (ERK), a protein involved in cell proliferation. When ERK is over expressed, ERK can provide a proliferative advantage to cells, thus leading to cancer. NRAS proto-oncogene (NRAS)-, Kirsten rat sarcoma virus (KRAS)-, or Harvey rat sarcoma virus (HRAS, HRAS proto- oncogene)-mutated cancers can be managed with, for example, an inhibitor, e.g., a mitogen- activated protein kinase kinase (MEK) inhibitor, a serine/threonine kinase B-raf (BRAF) inhibitor or a combination of one or more inhibitors disclosed herein.

[0010] Rigosertib ((E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2- methoxyphenylamino)acetic acid, or a pharmaceutically-acceptable salt or zwitterion thereof) can block the RAS cascade and promote the expression of novel antigens on the tumor’s surface. This process can turn cold tumors that are not surrounded by host lymphocytes into hot tumors that are surrounded by host lymphocytes. This modulation of the tumor microenvironment (TME) in combination with the MEK pathway modulation can facilitate the host immune system to contribute to tumor control. The host lymphocytes can contribute to tumor control when exposed to MEK modulation.

[0011] The present disclosure provides a compound disclosed herein in combination with a MEK inhibitor. For example, rigosertib can be in combination with a MEK inhibitor. A MEK inhibitor disclosed herein can be, for example, trametinib that blocks MEK. In some embodiments, the dose of the combination partner of the MEK inhibitor is trametinib, given at 2 milligram (mg) per day.

[0012] In some embodiments, a MEK inhibitor can comprise trametinib (GSK1120212), selumetinib, cobimetinib (i.e., XL518), and binimetinib (i.e., MEK162). A MEK inhibitor disclosed herein can be, for example, trametinib.

[0013] In some embodiments, rigosertib can cause genitourinary toxicity including dysuria and hematuria. In some embodiments, risk mitigation strategies can minimize these effects. [0014] In some embodiments, the dose of the MEK inhibitor is 2 mg once daily.

[0015] In some embodiments, present disclosure provides a combination of a compound disclosed herein, for example, rigosertib, with two additional therapeutic agents or two additional inhibitors. In some embodiments, the two additional therapeutic agents or two additional inhibitors can be a MEK inhibitor, and a BRAF inhibitor. In some embodiments, the MEK inhibitor can comprise trametinib (GSK1120212), selumetinib, cobimetinib (i.e., XL518), and binimetinib (i.e., MEK162). In some embodiments, the BRAF inhibitor can comprise vemurafenib, dabrafenib, and encorafenib. In some embodiments, the dose of the MEK inhibitor is 2 mg once daily. In some embodiments, the dose of the BRAF inhibitor is 150 mg twice daily.

Compounds of the disclosure

[0016] In some embodiments, disclosed herein is a compound of the formula:

wherein: each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^{l la}, R^{l lb}, R¹², and R¹³ is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -

C(O)R^X, -C(O)OR^X, -C(O)NR^xR^y, -OR^X, -SR^X, -NR^xR^y, -NR^xC(O)R^y, -OC(O)R^X, or - SiR^xR^yR^z, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and each R^x, R^y, and R^z is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen or halogen, or a pharmaceutically-acceptable salt or zwitterion thereof.

[0017] In some embodiments, R¹, R³, and R⁵ are the same. In some embodiments, R¹, R³, R⁵, and R⁸ are the same. In some embodiments, each R¹, R³, and R⁵ is independently OR^X. In some embodiments, each R¹, R³, R⁵, and R⁸ is independently OR^X. In some embodiments, each R^x is independently alkyl, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R^x is independently hydrogen. In some embodiments, each R^x is independently unsubstituted Ci-6 alkyl. In some embodiments, each R^x is independently unsubstituted C1-3 alkyl. In some embodiments, each R^x is independently methyl. In some embodiments, each R^x is independently ethyl. In some embodiments, each R^x is independently substituted C1-6 alkyl. In some embodiments, each R^x is independently substituted C1-3 alkyl. In some embodiments, each R^x is Ci alkyl substituted with hydroxy, sulfhydryl, halogen, an amino group, a nitro group, cyano, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxylic acid, a carboxaldehyde group, alkoxy, aryl, heterocyclyl groups, acyl groups, amide, or an ester.

[0018] In some embodiments, R² is hydrogen. In some embodiments, R⁴ is hydrogen. In some embodiments, R⁶ is hydrogen. In some embodiments, R⁹ is hydrogen. In some embodiments, R¹⁰ is hydrogen.

[0019] In some embodiments, R⁷ is alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, OR^X, or NR^xR^y. In some embodiments, R⁷ is NR^xR^y. In some embodiments, R^x is hydrogen. In some embodiments, R^y is hydrogen. In some embodiments, R^y is substituted alkyl. In some embodiments, R^y is substituted C1-6 alkyl. In some embodiments, R^y is Ci alkyl substituted with hydroxy, sulfhydryl, halogen, an amino group, a nitro group, cyano, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxylic acid, a carboxaldehyde group, alkoxy, aryl, a heterocyclyl group, an acyl group, amide, or an ester. In some embodiments, R^y is CH2COOH.

[0020] In some embodiments, each R^{l la} and R^llb is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R^{l la} and R^{l lb} is independently substituted C1-6 alkyl. In some embodiments, each R^{l la} and R^{l lb} is independently unsubstituted C1-6 alkyl. In some embodiments, each R¹² and R¹³ is independently alkyl, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R¹² and R¹³ is independently substituted C1-6 alkyl. In some embodiments, each R¹² and R¹³ is independently unsubstituted C1-6 alkyl. In some embodiments, R^lla is hydrogen. In some embodiments, R^llb is hydrogen. In some embodiments, R¹² is hydrogen. In some embodiments, R¹³ is hydrogen.

[0021] In some embodiments, disclosed herein is a compound of the formula:

[0022] In some embodiments, the compound has the formula:

[0023] In some embodiments, each R¹, R³, R⁵, and R⁸ is independently OR^X. In some embodiments, each R^x is independently alkyl, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R^x is independently hydrogen. In some embodiments, each R^x is independently unsubstituted Ci-6 alkyl. In some embodiments, each R^x is independently unsubstituted C1-3 alkyl. In some embodiments, each R^x is independently methyl. In some embodiments, each R^x is independently ethyl. In some embodiments, each R^x is independently substituted C1-6 alkyl. In some embodiments, each R^x is independently substituted C1-3 alkyl. In some embodiments, each R^x is independently methyl that is substituted.

[0024] In some embodiments, each R¹⁴ and R¹⁵ is independently alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen. In some embodiments, R¹⁴ is H. In some embodiments, R¹⁵ is H. In some embodiments, R¹⁵ is substituted alkyl. In some embodiments, R¹⁵ is substituted C1-6 alkyl. In some embodiments, R¹⁵ is substituted Ci alkyl. In some embodiments, R¹⁵ is CH2COOH.

[0025] In some embodiments, the compound has the formula:

[0026] In some embodiments, each R^la, R^3a, R^5a, and R^8a is the same. In some embodiments, each R^la, R^3a, R^5a, and R^8a is different. In some embodiments, each R^la, R^3a, R^5a, and R^8a is independently substituted or unsubstituted alkyl. In some embodiments, each R^la, R^3a, R^5a, and R^8a is independently substituted or unsubstituted C1-8 alkyl. In some embodiments, each R^la, R^3a, R^5a, and R^8a is independently substituted or unsubstituted C1-3 alkyl. In some embodiments, each R^la, R^3a, R^5a, and R^8a is independently substituted or unsubstituted Ci alkyl. In some embodiments, each R^la, R^3a, R^5a, and R^8a is independently methyl. In some embodiments, each R^la, R^3a, R^5a, and R^8a is independently ethyl.

[0027] In some embodiments, each R¹⁴ and R¹⁵ is independently alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen. In some embodiments, R¹⁴ is H. In some embodiments, R¹⁵ is H. In some embodiments, R¹⁵ is substituted alkyl. In some embodiments, R¹⁵ is substituted C1-6 alkyl. In some embodiments, R¹⁵ is substituted Ci alkyl. In some embodiments, R¹⁵ is CH2COOH.

[0028] In some embodiments, the compound has the formula:

[0029] In some embodiments, each R^la, R^3a, R^5a, and R^8a is independently substituted or unsubstituted alkyl. In some embodiments, each R^la, R^3a, R^5a, and R^8a is independently substituted or unsubstituted Ci-s alkyl. In some embodiments, R^la is Ci-6 alkyl. In some embodiments, R^3a is Ci-6 alkyl. In some embodiments, R^5a is Ci-6 alkyl. In some embodiments, R^8a is Ci-6 alkyl. In some embodiments, R^la is methyl. In some embodiments, R^3a is methyl. In some embodiments, R^5a is methyl. In some embodiments, R^8a is methyl. [0030] In some embodiments, R¹⁵ is substituted alkyl. In some embodiments, R¹⁵ is substituted Ci-6 alkyl. In some embodiments, R¹⁵ is substituted Ci alkyl. In some embodiments, R¹⁵ is CH2COOH.

[0031] In some embodiments, disclosed herein is a compound of the formula:

(E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid, or a pharmaceutically-acceptable salt or zwitterion thereof. In some embodiments, the compound is

sodium (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetate. In some embodiments, a compound disclosed herein is a sodium salt.

[0032] Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, ureido groups, epoxy groups, and ester groups. [0033] Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups. An alkyl or alkylene group can be, for example, a Ci, C2, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, c₂₅, C26, C27, C28, C29, C30, C31, C32, C33, C34, c₃₅, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. In some embodiments, alkyl or alkylene is C1-8 alkyl or C1-8 alkylene that is substituted or unsubstituted. In some embodiments, alkyl or alkylene is C1-6 alkyl or C1-6 alkylene that is substituted or unsubstituted. In some embodiments, alkyl or alkylene is C1-3 alkyl or C1-3 alkylene that is substituted or unsubstituted.

[0034] Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0035] Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.

[0036] Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2 -hydroxy ethyl, 1,2- difluoroethyl, and 3-carboxypropyl.

[0037] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups. Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl- cycloprop-l-yl, cycloprop-2-en-l-yl, cyclobutyl, 2,3-dihydroxycyclobut-l-yl, cyclobut-2-en- 1-yl, cyclopentyl, cyclopent-2-en-l-yl, cyclopenta-2,4-dien-l-yl, cyclohexyl, cyclohex-2-en- 1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-l-yl, 3,5-dichlorocyclohex-l-yl, 4- hydroxycyclohex-l-yl, 3,3,5-trimethylcyclohex-l-yl, octahydropentalenyl, octahydro- 1/7- indenyl, 3a,4,5,6,7,7a-hexahydro-3J/-inden-4-yl, decahydroazulenyl, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0038] Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups. The olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. An alkenyl or alkenylene group can be, for example, a C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, c₂₅, C26, C27, C28, C29, C30, C31, C₃₂, C33, C34, c₃₅, C₃₆, C37, C₃8, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. Non-limiting examples of alkenyl and alkenylene groups include ethenyl, prop-l-en-l-yl, isopropenyl, but- l-en-4-yl; 2-chloroethenyl, 4-hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7- hy droxy-7 -methyloct-3 , 5 -dien-2-yl .

[0039] Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkylnyl or alkynylene group can be internal or terminal. An alkylnyl or alkynylene group can be, for example, a C2, C3, C4, C5, Ce, C7, Cs, C₉, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C₂0, C₂1, C₂2, C₂3, C₂4, C₂₅, C₂6, C₂7, C₂8, C₂₉, C₃₀, C₃1, C₃₂, C33, C34, C₃₅, C₃6, C37, C₃8, C39, C₄0, C₄1, C₄2, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. Non-limiting examples of alkynyl or alkynylene groups include ethynyl, prop-2-yn-l-yl, prop-l-yn-l-yl, and 2-methyl-hex-4-yn-l- yl; 5-hydroxy-5-methylhex-3-yn-l-yl, 6-hydroxy-6-methylhept-3-yn-2-yl, and 5-hydroxy-5- ethylhept-3 -yn- 1 -yl .

[0040] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.

[0041] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or an ether group comprises an alkoxy group. Nonlimiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

[0042] An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be monocyclic or polycyclic. An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl. Non-limiting examples of substituted aryl groups include 3,4-dimethylphenyl, 4-/c/7-butyl phenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)-phenyl, 4-(trifluoromethoxy)phenyl, 3- chlorophenyl, 4-chlorophenyl, 3, 4-di chlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 2- iodophenyl, 3 -iodophenyl, 4-iodophenyl, 2-m ethylphenyl, 3 -fluorophenyl, 3 -methylphenyl, 3 -methoxy phenyl, 4-fluorophenyl, 4-methylphenyl, 4-m ethoxyphenyl, 2,3 -difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3, 4-di chlorophenyl, 3,5- di chlorophenyl, 2-hydroxyphenyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5- dimethoxyphenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4- trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6- trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4- di chlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5- tri chlorophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3 -dimethylphenyl, 2,4- dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5- trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2- ethylphenyl, 3 -ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5- diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5- triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 2- isopropylphenyl, 3-isopropylphenyl, and 4-isopropylphenyl.

[0043] Non-limiting examples of substituted aryl groups include 2-aminophenyl, 2-(N- methylamino)phenyl, 2-(7V,7V-dimethylamino)phenyl, 2-(7V-ethylamino)phenyl, 2-(N,N- diethylamino)phenyl, 3 -aminophenyl, 3-(7V-methylamino)phenyl, 3-(N,N- dimethylamino)phenyl, 3-(7V-ethylamino)phenyl, 3-(A,A-diethylamino)phenyl, 4- aminophenyl, 4-(A-methylamino)phenyl, 4-(A,A-dimethylamino)phenyl, 4-(N- ethylamino)phenyl, and 4-(7V,7V-diethylamino)phenyl.

[0044] A heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.

[0045] Non-limiting examples of heterocycles include: i) heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-l/Z-azepinyl, 2,3-dihydro-l/Z-indole, and 1, 2,3,4- tetrahydroquinoline; and ii) heterocyclic units having 2 or more rings one of which is a heterocyclic ring, non-limiting examples of which include hexahydro- I //-pyrrol izinyl, 3a,4,5,6,7,7a-hexahydro-l/7-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-l/7-indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro- l//-cycloocta[b]pyrrolyl. [0046] Non-limiting examples of heteroaryl include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, 1/7-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4- dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non-limiting examples of which include: 77/-purinyl, 97/-purinyl, 6-amino-9Z7-purinyl, 5Z7-pyrrolo[3,2- ]pyrimidinyl, 7Z7-pyrrolo[2,3- ]pyrimidinyl, pyrido[2,3-t ]pyrimidinyl, 4,5,6,7-tetrahydro-l-Z7-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.

[0047] Any compound herein can be purified. A compound herein can be at least about 1% pure, at least about 2% pure, at least about 3% pure, at least about 4% pure, at least about 5% pure, at least about 6% pure, at least about 7% pure, at least about 8% pure, at least about 9% pure, at least about 10% pure, at least about 11% pure, at least about 12% pure, at least about 13% pure, at least about 14% pure, at least about 15% pure, at least about 16% pure, at least about 17% pure, at least about 18% pure, at least about 19% pure, at least about 20% pure, at least about 21% pure, at least about 22% pure, at least about 23% pure, at least about 24% pure, at least about 25% pure, at least about 26% pure, at least about 27% pure, at least about 28% pure, at least about 29% pure, at least about 30% pure, at least about 31% pure, at least about 32% pure, at least about 33% pure, at least about 34% pure, at least about 35% pure, at about least 36% pure, at least about 37% pure, at least about 38% pure, at least about 39% pure, at least about 40% pure, at least about 41% pure, at least about 42% pure, at least about 43% pure, at least about 44% pure, at least about 45% pure, at least about 46% pure, at least about 47% pure, at least about 48% pure, at least about 49% pure, at least about 50% pure, at least about 51% pure, at least about 52% pure, at least about 53% pure, at least about 54% pure, at least about 55% pure, at least about 56% pure, at least about 57% pure, at least about 58% pure, at least about 59% pure, at least about 60% pure, at least about 61% pure, at least about 62% pure, at least about 63% pure, at least about 64% pure, at least about 65% pure, at least about 66% pure, at least about 67% pure, at least about 68% pure, at least about 69% pure, at least about 70% pure, at least about 71% pure, at least about 72% pure, at least about 73% pure, at least about 74% pure, at least about 75% pure, at least about 76% pure, at least about 77% pure, at least about 78% pure, at least about 79% pure, at least about 80% pure, at least about 81% pure, at least about 82% pure, at least about 83% pure, at least about 84% pure, at least about 85% pure, at least about 86% pure, at least about 87% pure, at least about 88% pure, at least about 89% pure, at least about 90% pure, at least about 91% pure, at least about 92% pure, at least about 93% pure, at least about 94% pure, at least about 95% pure, at least about 96% pure, at least about 97% pure, at least about 98% pure, at least about 99% pure, at least about 99.1% pure, at least about 99.2% pure, at least about 99.3% pure, at least about 99.4% pure, at least about 99.5% pure, at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, or at least about 99.9% pure.

[0048] In some embodiments, the compound is at least about 85% pure. In some embodiments, the compound is at least about 90% pure. In some embodiments, the compound is at least about 95% pure. In some embodiments, the compound is at least about 98% pure. In some embodiments, the compound is at least about 99% pure. In some embodiments, the compound is at least about 99.5% pure.

[0049] A compound herein can be at most about 1% pure, at most about 2% pure, at most about 3% pure, at most about 4% pure, at most about 5% pure, at most about 6% pure, at most about 7% pure, at most about 8% pure, at most about 9% pure, at most about 10% pure, at most about 11% pure, at most about 12% pure, at most about 13% pure, at most about 14% pure, at most about 15% pure, at most about 16% pure, at most about 17% pure, at most about 18% pure, at most about 19% pure, at most about 20% pure, at most about 21% pure, at most about 22% pure, at most about 23% pure, at most about 24% pure, at most about 25% pure, at most about 26% pure, at most about 27% pure, at most about 28% pure, at most about 29% pure, at most about 30% pure, at most about 31% pure, at most about 32% pure, at most about 33% pure, at most about 34% pure, at most about 35% pure, at most about 36% pure, at most about 37% pure, at most about 38% pure, at most about 39% pure, at most about 40% pure, at most about 41% pure, at most about 42% pure, at most about 43% pure, at most about 44% pure, at most about 45% pure, at most about 46% pure, at most about 47% pure, at most about 48% pure, at most about 49% pure, at most about 50% pure, at most about 51% pure, at most about 52% pure, at most about 53% pure, at most about 54% pure, at most about 55% pure, at most about 56% pure, at most about 57% pure, at most about 58% pure, at most about 59% pure, at most about 60% pure, at most about 61% pure, at most about 62% pure, at most about 63% pure, at most about 64% pure, at most about 65% pure, at most about 66% pure, at most about 67% pure, at most about 68% pure, at most about 69% pure, at most about 70% pure, at most about 71% pure, at most about 72% pure, at most about 73% pure, at most about 74% pure, at most about 75% pure, at most 76% pure, at most about 77% pure, at most about 78% pure, at most about 79% pure, at most about 80% pure, at most about 81% pure, at most about 82% pure, at most about 83% pure, at most about 84% pure, at most about 85% pure, at most about 86% pure, at most about 87% pure, at most about 88% pure, at most about 89% pure, at most about 90% pure, at most about 91% pure, at most about 92% pure, at most about 93% pure, at most about 94% pure, at most about 95% pure, at most about 96% pure, at most about 97% pure, at most about 98% pure, at most about 99% pure, at most about 99.1% pure, at most about 99.2% pure, at most about 99.3% pure, at most about 99.4% pure, at most about 99.5% pure, at most about 99.6% pure, at most about 99.7% pure, at most about 99.8% pure, or at most about 99.9% pure.

[0050] In some embodiments, the compound is at most about 85% pure. In some embodiments, the compound is at most about 90% pure. In some embodiments, the compound is at most about 95% pure. In some embodiments, the compound is at most about 98% pure. In some embodiments, the compound is at most about 99% pure. In some embodiments, the compound is at most about 99.5% pure.

[0051] A compound herein can about 1% pure, about 2% pure, about 3% pure, about 4% pure, about 5% pure, about 6% pure, about 7% pure, about 8% pure, about 9% pure, about 10% pure, about 11% pure, about 12% pure, about 13% pure, about 14% pure, about 15% pure, about 16% pure, about 17% pure, about 18% pure, about 19% pure, about 20% pure, about 21% pure, about 22% pure, about 23% pure, about 24% pure, about 25% pure, about 26% pure, about 27% pure, about 28% pure, about 29% pure, about 30% pure, about 31% pure, about 32% pure, about 33% pure, about 34% pure, about 35% pure, about 36% pure, about 37% pure, about 38% pure, about 39% pure, about 40% pure, about 41% pure, about 42% pure, about 43% pure, about 44% pure, about 45% pure, about 46% pure, about 47% pure, about 48% pure, about 49% pure, about 50% pure, about 51% pure, about 52% pure, about 53% pure, about 54% pure, about 55% pure, about 56% pure, about 57% pure, about 58% pure, about 59% pure, about 60% pure, about 61% pure, about 62% pure, about 63% pure, about 64% pure, about 65% pure, about 66% pure, about 67% pure, about 68% pure, about 69% pure, about 70% pure, about 71% pure, about 72% pure, about 73% pure, about 74% pure, about 75% pure, about 76% pure, about 77% pure, about 78% pure, about 79% pure, about 80% pure, about 81% pure, about 82% pure, about 83% pure, about 84% pure, about 85% pure, about 86% pure, about 87% pure, about 88% pure, about 89% pure, about 90% pure, about 91% pure, about 92% pure, about 93% pure, about 94% pure, about 95% pure, about 96% pure, about 97% pure, about 98% pure, about 99% pure, about 99.1% pure, about 99.2% pure, about 99.3% pure, about 99.4% pure, about 99.5% pure, about 99.6% pure, about 99.7% pure, about 99.8% pure, or about 99.9% pure.

[0052] In some embodiments, the compound is about 85% pure. In some embodiments, the compound is about 90% pure. In some embodiments, the compound is about 95% pure. In some embodiments, the compound is about 98% pure. In some embodiments, the compound is at most about 99% pure. In some embodiments, the compound is about 99.5% pure.

Pharmaceutically acceptable salts

[0053] The method disclosed herein provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is a sodium salt.

[0054] Metal salts can arise from the addition of an inorganic base to a compound disclosed herein. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0055] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0056] Acid addition salts can arise from the addition of an acid to a compound disclosed herein. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0057] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt.

Pharmaceutical compositions of the disclosure

[0058] A pharmaceutical composition of a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, intravitreal, intranasal, inhalation, nasal inhalation, mouth inhalation, intratracheal, intrapulmonary, transmucosal, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, optic, nasal, and topical administration.

[0059] A pharmaceutical composition can be administered in a local or systemic manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release. [0060] For oral administration, pharmaceutical compositions can be formulated readily by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, or suspensions for oral ingestion by a subject.

[0061] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can contain an excipient such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or to characterize different combinations of active compound doses.

[0062] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the capsule comprises a hard gelatin capsule comprising one or more of pharmaceutical, bovine, and plant gelatins. A gelatin can be alkaline- processed. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, or lubricants such as talc or magnesium stearate, and stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers can be added. All formulations for oral administration are provided in dosages suitable for such administration.

[0063] For buccal or sublingual administration, the compositions can be tablets, lozenges, or gels.

[0064] Parenteral injections can be formulated for bolus injection or continuous infusion. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0065] An active compound can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives. [0066] Formulations suitable for transdermal administration of the active compounds can employ transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsions or buffered aqueous solutions, dissolved or dispersed in a polymer or an adhesive. Such patches can be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical compounds. Transdermal delivery can be accomplished by iontophoretic patches. Additionally, transdermal patches can provide controlled delivery. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. An absorption enhancer or carrier can include absorbable pharmaceutically- acceptable solvents to assist passage through the skin. For example, transdermal devices can be in the form of a bandage comprising a backing member, a reservoir containing compounds and carriers, a rate controlling barrier to deliver the compounds to the skin of the subject at a controlled and predetermined rate over a prolonged period of time, and adhesives to secure the device to the skin or the eye.

[0067] For administration by inhalation, the active compounds can be in a form as an aerosol, a vapor, a mist, or a powder. Inhalation can occur through by nasal delivery, oral delivery, or both. Nasal or intranasal administration involves insufflation of compounds through the nose, for example, nasal drops and nasal sprays. This route of administration can result in local and/or systemic effects. Inhaler or insufflator devices can be used for nose-to-lung delivery of compounds described herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor).

[0068] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone and polyethylene glycol (PEG). In suppository forms of the compositions, a low-melting point wax such as a mixture of fatty acid glycerides or cocoa butter, can be used. In some embodiments, a pharmaceutical composition of the disclosure comprises PEG. In some embodiments, a pharmaceutical composition of the disclosure comprises PEG-400. In some embodiments, a pharmaceutical composition of the disclosure comprises PEG-4000.

[0069] In practicing a method of treatment or use provided herein, therapeutically-effective amounts of a compound described herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically- effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures. [0070] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound described herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be manufactured, for example, by mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0071] The pharmaceutical compositions can include at least one pharmaceutically- acceptable carrier, diluent, or excipient and compound described herein as free-base or pharmaceutically-acceptable salt form. The methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity.

[0072] Methods for the preparation of compositions comprising a compound described herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) include formulating a composition with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.

[0073] Non-limiting examples of dosage forms suitable for use in a method disclosed herein include feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, creams, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, phytoceuticals, nutraceuticals, and any combination thereof.

[0074] Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the method disclosed herein include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, plant cellulosic material and spheronization agents, and any combination thereof. [0075] A composition of a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow a compound to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that drug release rates and drug release profiles can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of a drug at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.

[0076] The disclosed compositions can optionally comprise from about 0.001% to about 0.005% weight by volume pharmaceutically-acceptable preservatives.

[0077] In some, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours. [0078] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.

[0079] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), each of which is incorporated by reference in its entirety.

[0080] A method disclosed herein includes, for example, administration of a compound disclosed herein, a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor), or a pharmaceutically-acceptable salt thereof, in combination with a pharmaceutically-acceptable carrier. The carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject.

[0081] A compound disclosed herein, a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor), or a pharmaceutically-acceptable salt thereof disclosed herein can be conveniently formulated into pharmaceutical compositions composed of one or more pharmaceutically-acceptable carriers. See e.g., Remington ’s Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co., Easton, PA, which discloses carriers and methods of preparing pharmaceutical compositions that can be used in conjunction with the preparation of formulations of the compound described herein and which is incorporated by reference herein. Such pharmaceuticals can be standard carriers for administration of compositions to humans and non-humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Other compositions can be administered according to standard procedures. For example, pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, and anesthetics.

[0082] Non-limiting examples of pharmaceutically-acceptable carriers include saline solution, Ringer’s solution and dextrose solution. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the compound disclosed herein or a pharmaceutically-acceptable salt thereof, where the matrices are in the form of shaped articles, such as films, liposomes, microparticles, and microcapsules.

[0083] A method disclosed herein relates to administering a compound disclosed herein, a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor), or a pharmaceutically-acceptable salt thereof as part of a pharmaceutical composition. In various embodiments, compositions of a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can comprise a liquid comprising an active agent in solution, in suspension, or both. Liquid compositions can include gels. In one embodiment, the liquid composition is aqueous. Alternatively, the composition can take form of an ointment. In another embodiment, the composition is an in situ gellable aqueous composition. In some embodiments, the composition is an in situ gellable aqueous solution. [0084] Pharmaceutical formulations can include additional carriers, as well as thickeners, diluents, buffers, preservatives, and surface active agents in addition to a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor). Pharmaceutical formulations can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, and anesthetics.

[0085] An excipient can fill a role as simple and direct as being an inert filler, or an excipient as used herein can be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.

[0086] The compound disclosed herein, a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor), or a pharmaceutically-acceptable salt thereof can also be present in liquids, emulsions, or suspensions for delivery of active therapeutic agents in aerosol form to cavities of the body such as the nose, throat, or bronchial passages.

[0087] Depending on the intended mode of administration, the pharmaceutical compositions administered as part of a method disclosed herein can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, for example, in unit dosage form suitable for single administration of a precise dosage. The compositions can contain, as noted above, an effective amount of the compound disclosed herein or a pharmaceutically-acceptable salt thereof in combination with a pharmaceutically-acceptable carrier and, in addition, can include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc. [0088] In some embodiments, a pharmaceutical composition can have a pH of from about 7 to about 12, from about 9 to about 13, from about 3 to about 4, from about 4 to about 5, from about 5 to about 6, from about 6 to about 7, from about 7 to about 8, from about 8 to about 9, from about 9 to about 10, from about 10 to about 11, from about 11 to about 12, from about 12 to about 13, or from about 13 to about 14. In some embodiments, a pharmaceutical composition can have a pH of at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, or at least about 13. In some embodiments, a pharmaceutical composition can have a pH of at most about 4, at most about 5, at most about 6, at most about 7, at most about 8, at most about 9, at most about 10, at most about 11, at most about 12, or at most about 13. In some embodiments, a pharmaceutical composition can have a pH of about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or about 13.

[0089] A compound described herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be present in a composition in a range of from about 1 milligram (mg) to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about 65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg, from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, from about 85 mg to about 90 mg, from about 90 mg to about 95 mg, from about 95 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 225 mg, from about 225 mg to about 250 mg, or from about 250 mg to about 300 mg. [0090] A compound described herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be present in a composition in an amount of at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 225 mg, at least about 250 mg, or at least about 300 mg. A compound described herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be present in a composition in an amount of at most about 5 mg, at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 35 mg, at most about 40 mg, at most about 45 mg, at most about 50 mg, at most about 55 mg, at most about 60 mg, at most about 65 mg, at most about 70 mg, at most about 75 mg, at most about 80 mg, at most about 85 mg, at most about 90 mg, at most about 95 mg, at most about 100 mg, at most about 125 mg, at most about 150 mg, at most about 175 mg, at most about 200 mg, at most about 225 mg, at most about 250 mg, or at most about 300 mg. A compound described herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be present in a composition in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or about 300 mg. [0091] In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of from about 25 mg/milliliter (mL) to about 3000 mg/mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of from about 25 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 100 mg/mL, from about 100 mg/mL to about 250 mg/mL, from about 250 mg/mL to about 500 mg/mL, from about 500 mg/mL to about 750 mg/mL, from about 750 mg/mL to about 1000 mg/mL, from about 1000 mg/mL to about 1500 mg/mL, from about 1500 mg/mL to about 2000 mg/mL, from about 2000 mg/mL to about 2500 mg/mL, or from about 2500 mg/mL to about 3000 mg/mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of at least about 25 mg/mL, at least about 50 mg/mL, at least about 100 mg/mL, at least about 250 mg/mL, at least about 500 mg/mL, at least about 750 mg/mL, at least about 1000 mg/mL, at least about 1250 mg/mL, at least about 1500 mg/mL, at least about 1750 mg/mL, at least about 2000 mg/mL, at least about 2250 mg/mL, at least about 2500 mg/mL, at least about 2750 mg/mL, or at least about 3000 mg/mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of at most about 25 mg/mL, at most about 50 mg/mL, at most about 100 mg/mL, at most about 250 mg/mL, at most about 500 mg/mL, at most about 750 mg/mL, at most about 1000 mg/mL, at most about 1250 mg/mL, at most about 1500 mg/mL, at most about 1750 mg/mL, at most about 2000 mg/mL, at most about 2250 mg/mL, at most about 2500 mg/mL, at most about 2750 mg/mL, or at most about 3000 mg/mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of about 25 mg/mL, about 50 mg/mL, about 100 mg/mL, about 250 mg/mL, about 500 mg/mL, about 750 mg/mL, about 1000 mg/mL, about 1250 mg/mL, about 1500 mg/mL, about 1750 mg/mL, about 2000 mg/mL, about 2250 mg/mL, about 2500 mg/mL, about 2750 mg/mL, or about 3000 mg/mL.

[0092] In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of about 35 mg/mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of about 70 mg/mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of about 75 mg/mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of about 140 mg/mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) in an amount of about 280 mg/mL.

[0093] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Nonlimiting examples are packaged injectables, vials, or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative. Formulations for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.

[0094] Intravenous (IV) Formulation: In some embodiments, a compound, a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor), or pharmaceutical composition of the disclosure can be administered intravenously. In some embodiments, a formulation disclosed herein can be, for example, a parenteral formulation of a solution of the active pharmaceutical ingredient (API) at a concentration of about 75 mg/mL in a liquid vehicle of polyethylene glycol (PEG) 400 with pH 7-13 or pH 12-13 adjusted by use of sodium hydroxide (NaOH) solution. The solution can be a clear, colorless to pale yellow, sterile, preservative-free solution packaged in a clear glass vial sealed with a Teflon-coated rubber stopper. A vial disclosed herein can be a 30-mL clear glass vial containing, for example, 24 mL of the parenteral formulation. Dilution with IV saline can be required when the parenteral formulation is administered IV. [0095] Oral Capsule Formulation: In some embodiments, a compound, a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor), or pharmaceutical composition of the disclosure can be administered orally. In some embodiments, a compound or pharmaceutical composition of the disclosure can be formulated as a soft gelatin capsules in 2 strengths: 1) about 70 mg/mL solution of the compound in PEG 400; or 2) about 280 mg/mL suspension of the compound in PEG 400 and PEG 4000. The 70 mg capsules contain 1 mL of a 70 mg/mL solution of a compound or a pharmaceutical composition and can be, for example, clear, transparent, and oblong. The 280 mg capsules contain 1 mL of a 280 mg/mL solution of a compound or pharmaceutical composition and can be, for example, of an opaque yellow-orange color.

Dosing

[0096] The present disclosure provides a maximally tolerated dose (MTD) of a compound disclosed herein in combination with a mitogen-activated protein kinase kinase (MEK) inhibitor (e.g., trametinib) a serine/threonine kinase B-raf (BRAF) inhibitor (dabrafenib), or any combination thereof. In some embodiments, a MTD can be of a compound disclosed herein in combination with a MEK inhibitor e.g., trametinib. In some embodiments, a MTD can be of a compound disclosed herein in combination with a MEK inhibitor and a BRAF inhibitor e.g., dabrafenib. In some embodiments, a MTD can be of a compound disclosed herein in combination with a BRAF inhibitor e.g., dabrafenib.

[0097] In some embodiments, an individual dose can comprise a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor). In some embodiments, the individual dose administered to a subject can be in an amount of from about 1 milligram (mg) to about 3000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of from about 1 mg to about 250 mg, from about 250 mg to about 500 mg, from about 500 mg to about 750 mg, from about 750 mg to about 1000 mg, from about 1000 mg to about 1250 mg, from about 1250 mg to about 1500 mg, from about 1500 mg to about 1750 mg, from about 1750 mg to about 2000 mg, from about 2000 mg to about 2250 mg, from about 2250 mg to about 2500 mg, from about 2500 mg to about 2750 mg, or from about 2750 mg to about 3000 mg.

[0098] In some embodiments, the individual dose administered to a subject can be in an amount of at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg, at least about

280 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about

450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about

650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about

850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, at least about 1800 mg, at least about 1850 mg, at least about 1900 mg, at least about 1950 mg, at least about 2000 mg, at least about 2050 mg, at least about 2100 mg, at least about 2150 mg, at least about 2200 mg, at least about 2250 mg, at least about 2300 mg, at least about 2350 mg, at least about 2400 mg, at least about 2450 mg, at least about 2500 mg, at least about 2550 mg, at least about 2600 mg, at least about 2650 mg, at least about 2700 mg, at least about 2750 mg, at least about 2800 mg, at least about 2850 mg, at least about 2900 mg, at least about 2950 mg, or at least about 3000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 1 mg, at most about 2 mg, at most about 3 mg, at most about 4 mg, at most about 5 mg, at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 35 mg, at most about 40 mg, at most about 45 mg, at most about 50 mg, at most about 55 mg, at most about 60 mg, at most about 65 mg, at most about 70 mg, at most about 75 mg, at most about 80 mg, at most about 85 mg, at most about 90 mg, at most about 95 mg, at most about 100 mg, at most about 125 mg, at most about 150 mg, at most about 175 mg, at most about 200 mg, at most about 250 mg, at most about 280 mg, at most about 300 mg, at most about 350 mg, at most about 400 mg, at most about 450 mg, at most about 500 mg, at most about 550 mg, at most about 600 mg, at most about 650 mg, at most about 700 mg, at most about 750 mg, at most about 800 mg, at most about 850 mg, at most about 900 mg, at most about 950 mg, at most about 1000 mg, at most about 1050 mg, at most about 1100 mg, at most about 1150 mg, at most about 1200 mg, at most about 1250 mg, at most about 1300 mg, at most about 1350 mg, at most about 1400 mg, at most about 1450 mg, at most about 1500 mg, at most about 1550 mg, at most about 1600 mg, at most about 1650 mg, at most about 1700 mg, at most about 1750 mg, at most about 1800 mg, at most about 1850 mg, at most about 1900 mg, at most about 1950 mg, at most about 2000 mg, at most about 2050 mg, at most about 2100 mg, at most about 2150 mg, at most about 2200 mg, at most about 2250 mg, at most about 2300 mg, at most about 2350 mg, at most about 2400 mg, at most about 2450 mg, at most about 2500 mg, at most about 2550 mg, at most about 2600 mg, at most about 2650 mg, at most about 2700 mg, at most about 2750 mg, at most about 2800 mg, at most about 2850 mg, at most about 2900 mg, at most about 2950 mg, or at most about 3000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, or about 3000 mg.

[0099] In some embodiments, the individual dose administered to a subject can be in 280 mg increments. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 280 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 560 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 840 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 1120 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 1200 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 1400 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 1500 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 1680 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 1800 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 1960 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 2000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 2200 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 2240 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 2500 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 2520 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 2800 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 3000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at least about 3080 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 280 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 560 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 840 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 1120 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 1200 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 1500 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 1800 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 2000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 2200 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 2500 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 2800 mg. In some embodiments, the individual dose administered to a subject can be in an amount of about 3000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 280 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 560 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 840 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 1120 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 1200 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 1500 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 1800 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 2000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 2200 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 2500 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 2800 mg. In some embodiments, the individual dose administered to a subject can be in an amount of at most about 3000 mg. [0100] In some embodiments, a compound described herein can be in an amount of from about 1 mg to about 3000 mg. In some embodiments, the individual dose administered to a subject can be in an amount of from about 1 mg to about 250 mg, from about 250 mg to about 500 mg, from about 500 mg to about 750 mg, from about 750 mg to about 1000 mg, from about 1000 mg to about 1250 mg, from about 1250 mg to about 1500 mg, from about 1500 mg to about 1750 mg, from about 1750 mg to about 2000 mg, from about 2000 mg to about 2250 mg, from about 2250 mg to about 2500 mg, from about 2500 mg to about 2750 mg, or from about 2750 mg to about 3000 mg.

[0101] In some embodiments, a compound described herein can be in an amount of at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg, at least about 280 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, at least about 1800 mg, at least about 1850 mg, at least about 1900 mg, at least about 1950 mg, at least about 2000 mg, at least about 2050 mg, at least about 2100 mg, at least about 2150 mg, at least about 2200 mg, at least about 2250 mg, at least about 2300 mg, at least about 2350 mg, at least about 2400 mg, at least about 2450 mg, at least about 2500 mg, at least about 2550 mg, at least about 2600 mg, at least about 2650 mg, at least about 2700 mg, at least about 2750 mg, at least about 2800 mg, at least about 2850 mg, at least about 2900 mg, at least about 2950 mg, or at least about 3000 mg. In some embodiments, a compound described herein can be in an amount of at most about 1 mg, at most about 2 mg, at most about 3 mg, at most about 4 mg, at most about 5 mg, at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 35 mg, at most about 40 mg, at most about 45 mg, at most about 50 mg, at most about 55 mg, at most about 60 mg, at most about 65 mg, at most about 70 mg, at most about 75 mg, at most about 80 mg, at most about 85 mg, at most about 90 mg, at most about 95 mg, at most about 100 mg, at most about 125 mg, at most about 150 mg, at most about 175 mg, at most about 200 mg, at most about 250 mg, at most about 280 mg, at most about 300 mg, at most about 350 mg, at most about 400 mg, at most about 450 mg, at most about 500 mg, at most about 550 mg, at most about 600 mg, at most about 650 mg, at most about 700 mg, at most about 750 mg, at most about 800 mg, at most about 850 mg, at most about 900 mg, at most about 950 mg, at most about 1000 mg, at most about 1050 mg, at most about 1100 mg, at most about 1150 mg, at most about 1200 mg, at most about 1250 mg, at most about 1300 mg, at most about 1350 mg, at most about 1400 mg, at most about 1450 mg, at most about 1500 mg, at most about 1550 mg, at most about 1600 mg, at most about 1650 mg, at most about 1700 mg, at most about 1750 mg, at most about 1800 mg, at most about 1850 mg, at most about 1900 mg, at most about 1950 mg, at most about 2000 mg, at most about 2050 mg, at most about 2100 mg, at most about 2150 mg, at most about 2200 mg, at most about 2250 mg, at most about 2300 mg, at most about 2350 mg, at most about 2400 mg, at most about 2450 mg, at most about 2500 mg, at most about 2550 mg, at most about 2600 mg, at most about 2650 mg, at most about 2700 mg, at most about 2750 mg, at most about 2800 mg, at most about 2850 mg, at most about 2900 mg, at most about 2950 mg, or at most about 3000 mg. In some embodiments, a compound described herein can be in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, or about 3000 mg.

[0102] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered to a subject in an amount of about 0.1 mg/kilogram (kg) to about 500 mg/kg, about 1 mg/kg to about 500 mg/kg, about 0.1 mg/kg to about 300 mg/kg, about 1 mg/kg to about 300 mg/kg, or about 0.1 mg/kg to about 30 mg/kg. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered to a subject in an amount of at least about 1 mg/kg, at least about 2 mg/kg, at least about 3 mg/kg, at least about 4 mg/kg, at least about 5 mg/kg, at least about 6 mg/kg, at least about 7 mg/kg, at least about 8 mg/kg, at least about 9 mg/kg, at least about 10 mg/kg, at least about 11 mg/kg, at least about 12 mg/kg, at least about 13 mg/kg, at least about 14 mg/kg, at least about 15 mg/kg, at least about 16 mg/kg, at least about 17 mg/kg, at least about 18 mg/kg, at least about 19 mg/kg, at least about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg, at least about 40 mg/kg, at least about 45 mg/kg, at least about 50 mg/kg, at least about 55 mg/kg, at least about 60 mg/kg, at least about 65 mg/kg, at least about 70 mg/kg, at least about 75 mg/kg, at least about 80 mg/kg, at least about 85 mg/kg, at least about 90 mg/kg, at least about 95 mg/kg, at least about 100 mg/kg, at least about 120 mg/kg, at least about 150 mg/kg, at least about 160 mg/kg, at least about 180 mg/kg, at least about 200 mg/kg, at least about 240 mg/kg, at least about 250 mg/kg, at least about 300 mg/kg, at least about 350 mg/kg, at least about 360 mg/kg, at least about 400 mg/kg, at least about 450 mg/kg, at least about 500 mg/kg, or at least about 600 mg/kg of the subject. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered to a subject in an amount of at most about 1 mg/kg, at most about 2 mg/kg, at most about 3 mg/kg, at most about 4 mg/kg, at most about 5 mg/kg, at most about 6 mg/kg, at most about 7 mg/kg, at most about 8 mg/kg, at most about 9 mg/kg, at most about 10 mg/kg, at most about 11 mg/kg, at most about 12 mg/kg, at most about 13 mg/kg, at most about 14 mg/kg, at most about 15 mg/kg, at most about 16 mg/kg, at most about 17 mg/kg, at most about 18 mg/kg, at most about 19 mg/kg, at most about 20 mg/kg, at most about 25 mg/kg, at most about 30 mg/kg, at most about 35 mg/kg, at most about 40 mg/kg, at most about 45 mg/kg, at most about 50 mg/kg, at most about 55 mg/kg, at most about 60 mg/kg, at most about 65 mg/kg, at most about 70 mg/kg, at most about 75 mg/kg, at most about 80 mg/kg, at most about 85 mg/kg, at most about 90 mg/kg, at most about 95 mg/kg, at most about 100 mg/kg, at most about 120 mg/kg, at most about 150 mg/kg, at most about 160 mg/kg, at most about 180 mg/kg, at most about 200 mg/kg, at most about 240 mg/kg, at most about 250 mg/kg, at most about 300 mg/kg, at most about 350 mg/kg, at most about 360 mg/kg, at most about 400 mg/kg, at most about 450 mg/kg, at most about 500 mg/kg, or at most about 600 mg/kg of the subject. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered to a subject in an amount of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 120 mg/kg, about 150 mg/kg, about 160 mg/kg, about 180 mg/kg, about 200 mg/kg, about 240 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 360 mg/kg, about 400 mg/kg, about 450 mg/kg, about 500 mg/kg, or about 600 mg/kg of the subject.

[0103] In some embodiments, dose escalation can be implemented in 70 mg increments to arrive at an effective dose to treat a condition disclosed herein (e.g., melanoma). In some embodiments, a dose disclosed herein with a maximum biological effect can be administered to a subject in need thereof.

[0104] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered intravenously. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, or at least about 40 consecutive days. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for at most about 2, at most about 3, at most about 4, at most about 5, at most about 6, at most about 7, at most about 8, at most about 9, at most about 10, at most about 11, at most about 12, at most about 13, at most about 14, at most about 15, at most about 16, at most about 17, at most about 18, at most about 19, at most about 20, at most about 21, at most about 22, at most about 23, at most about 24, at most about 25, at most about 26, at most about 27, at most about 28, at most about 29, at most about 30, at most about 31, at most about 32, at most about 33, at most about 34, at most about 35, at most about 36, at most about 37, at most about 38, at most about 39, or at most about 40 consecutive days. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 consecutive days. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 7 consecutive days. In some embodiments, a compound of the disclosure can be administered for about 14 consecutive days. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 21 consecutive days. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 28 consecutive days.

[0105] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28 consecutive days of a 28-day cycle. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for at most about 2, at most about 3, at most about 4, at most about 5, at most about 6, at most about 7, at most about 8, at most about 9, at most about 10, at most about 11, at most about 12, at most about 13, at most about 14, at most about 15, at most about 16, at most about 17, at most about 18, at most about 19, at most about 20, at most about 21, at most about 22, at most about 23, at most about 24, at most about 25, at most about 26, at most about 27, at most about 28 consecutive days of a 28-day cycle. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28 consecutive days of a 28-day cycle. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 7 consecutive days of a 28-day cycle. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 14 consecutive days of a 28-day cycle. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 21 consecutive days of a 28-day cycle. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered for about 28 consecutive days of a 28-day cycle.

[0106] A compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered via subcutaneous or intravenous injection. The volume of an injection can be at least about 0.1 milliliter (mL), at least about 0.2 mL, at least about 0.3 mL, at least about 0.4 mL, at least about 0.5 mL, at least about 0.6 mL, at least about 0.7 mL, at least about 0.8 mL, at least about 0.9 mL, at least about 1 mL, at least about 1.1 mL, at least about 1.2 mL, at least about 1.3 mL, at least about 1.4 mL, at least about 1.5 mL, at least about 1.6 mL, at least about 1.7 mL, at least about 1.8 mL, at least about 1.9 mL, at least about 2 mL, at least about

2.1 mL, at least about 2.2 mL, at least about 2.3 mL, at least about 2.4 mL, at least about 2.5 mL, at least about 2.6 mL, at least about 2.7 mL, at least about 2.8 mL, at least about 2.9 mL, or at least about 3 mL. The volume of an injection can be at most about 0.1 mL, at most about 0.2 mL, at most about 0.3 mL, at most about 0.4 mL, at most about 0.5 mL, at most about 0.6 mL, at most about 0.7 mL, at most about 0.8 mL, at most about 0.9 mL, at most about 1 mL, at most about 1.1 mL, at most about 1.2 mL, at most about 1.3 mL, at most about 1.4 mL, at most about 1.5 mL, at most about 1.6 mL, at most about 1.7 mL, at most about 1.8 mL, at most about 1.9 mL, at most about 2 mL, at most about 2.1 mL, at most about 2.2 mL, at most about 2.3 mL, at most about 2.4 mL, at most about 2.5 mL, at most about 2.6 mL, at most about 2.7 mL, at most about 2.8 mL, at most about 2.9 mL, or at most about 3 mL. The volume of an injection can be about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about

1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, or about 3 mL.

[0107] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 560 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 840 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 1120 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 1400 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 1680 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 1960 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 2240 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 2520 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 2800 mg twice a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 3080 mg twice a day.

[0108] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 560 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 840 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 1120 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 1400 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 1680 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 1960 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 2240 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 2520 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 2800 mg split in two doses throughout a day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of 3080 mg split in two doses throughout a day. [0109] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered one or more doses during one day. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a first dose in the morning or early afternoon, and a second dose in the afternoon or evening. In some embodiments, the first dose is at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 280 mg, at least about 300 mg, at least about 560 mg, at least about 840 mg, at least about 1120 mg, at least about 1400 mg, at least about 1680 mg, at least about 1960 mg, at least about 2240 mg, at least about 2520 mg, at least about 2800 mg, or at least about 3080 mg. In some embodiments, the first dose is at most about 50 mg, at most about 100 mg, at most about 150 mg, at most about 200 mg, at most about 250 mg, at most about 280 mg, at most about 300 mg, at most about 560 mg, at most about 840 mg, at most about 1120 mg, at most about 1400 mg, at most about 1680 mg, at most about 1960 mg, at most about 2240 mg, at most about 2520 mg, at most about 2800 mg, or at most about 3080 mg. In some embodiments, the first dose is about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg, about 900 mg to about 1000 mg, about 1000 mg to about 1100 mg, about 1100 mg to about 1200 mg, about 1200 mg to about 1300 mg, about 1300 mg to about 1400 mg, about 1400 mg to about 1500 mg, about 1500 mg to about 2000 mg, about 2000 mg to about 2500 mg, about 2500 mg to about 3000 mg or about 3000 mg to about 3500 mg. In some embodiments, the first dose is about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 280 mg, about 300 mg, about 560 mg, about 840 mg, about 1120 mg, about 1400 mg, about 1680 mg, about 1960 mg, about 2240 mg, about 2520 mg, about 2800 mg, or about 3080 mg. In some embodiments, the second dose is at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 280 mg, at least about 300 mg, at least about 560 mg, at least about 840 mg, at least about 1120 mg, at least about 1400 mg, at least about 1680 mg, at least about 1960 mg, at least about 2240 mg, at least about 2520 mg, at least about 2800 mg, or at least about 3080 mg. In some embodiments, the second dose is at most about 50 mg, at most about 100 mg, at most about 150 mg, at most about 200 mg, at most about 250 mg, at most about 280 mg, at most about 300 mg, at most about 560 mg, at most about 840 mg, at most about 1120 mg, at most about 1400 mg, at most about 1680 mg, at most about 1960 mg, at most about 2240 mg, at most about 2520 mg, at most about 2800 mg, or at most about 3080 mg. In some embodiments, the second dose is at most about 50 mg, at most about 100 mg, at most about 150 mg, at most about 200 mg, at most about 250 mg, at most about 280 mg, at most about 300 mg, at most about 560 mg, at most about 840 mg, at most about 1120 mg, at most about 1400 mg, at most about 1680 mg, at most about 1960 mg, at most about 2240 mg, at most about 2520 mg, at most about 2800 mg, or at most about 3080 mg. In some embodiments, the first dose is about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg, about 900 mg to about 1000 mg, about 1000 mg to about 1100 mg, about 1100 mg to about 1200 mg, about 1200 mg to about 1300 mg, about 1300 mg to about 1400 mg, about 1400 mg to about 1500 mg, about 1500 mg to about 2000 mg, about 2000 mg to about 2500 mg, about 2500 mg to about 3000 mg or about 3000 mg to about 3500 mg. In some embodiments, the second dose is about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 280 mg, about 300 mg, about 560 mg, about 840 mg, about 1120 mg, about 1400 mg, about 1680 mg, about 1960 mg, about 2240 mg, about 2520 mg, about 2800 mg, or about 3080 mg. In some embodiments, the second dose is about 280 mg, about 560 mg, about 840 mg, about 1120 mg, about 1400 mg, about 1680 mg, about 1960 mg, about 2240 mg, about 2520 mg, about 2800 mg, or about 3080 mg. In some embodiments, one or more doses can be administered in the morning or early afternoon, and one or more doses can be administered in the afternoon or evening.

[0110] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of about 800 mg for 2 to 5 days every other week. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of from about 650 mg to about 1700 mg for 3 to 6 days every other week. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of from about 800 mg to about 1500 mg for 2 days every week for 3 weeks, followed by 1 week without treatment. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of about 1800 mg per day for 3 days every other week. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of about 70 mg, about 140 mg, about 280 mg, about 560 mg, or about 700 mg once a day for one week. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of about 70 mg, about 140 mg, about 280 mg, about 560 mg, about 700 mg, or about 1120 mg per day twice a day for the first 14 days of a 21 day cycle.

[OHl] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered at a dose of about 560 mg once in the morning and about 280 mg in the evening for 2 weeks, followed by one week off. In some embodiments, the compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered in the fasting state, about 1-2 hours before or after a meal.

[0112] In some embodiments, a 3+3 dose escalation can be incorporated to determine a toxic dose, maximally tolerated dose (MTD), or recommended phase 2 dose (RP2D) or a compound of the disclosure, as shown in FIG. 1. A 3+3 dose escalation can be carried out with a cohort of three subjects, assigned to a given dose. If all of the subjects experience no dose limiting toxi cities (DLTs), additional subjects can be enrolled into the next higher dose cohort. However, if one subject develops dose limiting toxi cities at a specific dose, then an additional three subjects are enrolled into the same dose cohort. Dose escalation cohorts can orally receive 840 mg of rigosertib in the morning and 560 mg of rigosertib in the afternoon. If there are no DLTs, the dosage can be increased to 840 mg of rigosertib in the morning and 840 mg of rigosertib in the afternoon. Further, the dosage can be increased to 1,120 mg of rigosertib in the morning and 840 mg of rigosertib in the afternoon. The 3+3 dose escalation can further include standard dose of MEK inhibitor and/or BRAF inhibitor. The 3+3 dose escalation can be carried out until the toxic dose, MTD, or RP2D is determined.

[0113] In some embodiments, the dose escalation cohorts can receive rigosertib intravenously. Dose escalation cohorts can receive continuous intravenous infusion of (CIV) of rigosertib of 1,200 mg/day, given on days 1-3 of a 14-day cycle. If there are no DLTs, the dosage can be increased to 1,500 mg/day, given on days 1-3 of a 14-day cycle. Further, the dosage can be increased to 1,800 mg/day, given on days 1-3 of a 14-day cycle. The 3+3 dose escalation can further include standard dose of MEK inhibitor and/or BRAF inhibitor. The 3+3 dose escalation can be carried out until the toxic dose, MTD, or RP2D is determined. [0114] A dosing regimen for intravenous administration of a compound can be, for example, 1,800 mg/day, given on days 1-3 of a 14-day cycle for 8 cycles and then every on days 1-3 of a 28-day cycle thereafter. In combination with a dose of an immune MEK inhibitor, e.g., trametinib, a 3+3 dose escalation can be incorporated to find the recommended phase 2 dose (RP2D). Dose escalation cohorts can receive the full dose of a MEK inhibitor, e.g., trametinib, and initially reduced doses of rigosertib, for example, 1,200 mg/day, then 1500 mg/day, then 1800 mg/day given on days 1-3 of a 14-day cycle for 8 cycles and then every on days 1-3 of a 28-day cycle thereafter. In solid tumor studies, where there is less risk of bone marrow toxicity, the dose can be further incrementally increased to 2,100 mg/day, 2,400 mg/day until the MTD and RP2D are established according to 3+3 dose escalation.

[0115] A dosing regimen for intravenous administration of a compound can be, for example, 1,800 mg/day, given on days 1-3 of a 14-day cycle for 8 cycles and then every on days 1-3 of a 28-day cycle thereafter. In combination with a dose of MEK inhibitor, e.g., trametinib or a dose of a MEK inhibitor, e.g., trametinib + a dose of a BRAF inhibitor, e.g., dabrafenib, a 3+3 dose escalation can be incorporated to find the RP2D. Dose escalation cohorts can receive the full dose of trametinib or trametinib + dabrafenib and initially reduced doses of rigosertib, for example, 1,200 mg/day, then 1500 mg/day, then 1800 mg/day given on days 1- 3 of a 14-day cycle for 8 cycles and then every on days 1-3 of a 28-day cycle thereafter. In solid tumor studies, the dose can be further incrementally increased to 2,100 mg/day, 2,400 mg/day until the MTD and RP2D are established according to 3+3 dose escalation.

[0116] In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered in a first dose of about 840 mg administered approximately 1-2 hours before breakfast, followed by a second dose of about 280 mg administered about 2 hours after lunch or about 6-8 hours after the first dose. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered in a first dose of about 560 mg administered approximately 1-2 hours before breakfast, followed by a second dose of about 280-560 mg administered about 2 hours after lunch or about 6-8 hours after the first dose.

[0117] A dosing regimen disclosed herein can be, for example, one dose of 840 mg of oral rigosertib in the morning and 560 mg in the afternoon. Dose escalation can continue, depending on the observed number of dose limiting toxicities (DLT). A dosing regimen disclosed herein can be, for example, 840 mg twice daily, then 1,120 mg in the morning and then 840 mg in the afternoon. Dose escalation can continue by, for example, 280 mg increments. For example, a morning dose can be increased by 280 mg, and then the afternoon dose can be increased by 280 mg.

[0118] A dose escalation can continue until two or more DLTs are observed in a single cohort. At that point, a prior dose cohort can be expanded to 6 patients and if less than 2 DLTs occur in those 6 patients, then that dose can be considered the MTD.

[0119] Alternatively, the dose escalation can occur in 70 mg increments. Additionally, a much larger percentage of the total daily dose can be administered in the morning dose and a lower percentage in the afternoon dose (i.e., 1,400 mg in the a.m. and 560 mg in the afternoon).

[0120] In some embodiments, administering of a compound described herein or a compound described herein in combination with one or more inhibitors described herein (e.g., MEK inhibitor, BRAF inhibitor) can occur at least one hour before the subject consumes a liquid, for example, a drink. In some embodiments, administering of a compound described herein or a compound described herein in combination with one or more inhibitors described herein (e.g., MEK inhibitor, BRAF inhibitor) can occur at least one hour after the subject consumes a liquid, for example, a drink. In some embodiments, a subject is encouraged to drink at least 2 L of fluids per day. In some embodiments, a subject is advised to take 650 mg sodium bicarbonate three times per day, particularly if the urine pH is less than about 7.5.

Methods of administration

[0121] A compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can vary. For example, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases to lessen or reduce a likelihood of the occurrence of the disease or condition. A compound disclosed herein, a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor), or a composition can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of a compound disclosed herein, a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein.

[0122] A compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered as soon as is practical after the onset of a disease or condition (e.g., melanoma) is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered can be at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about

2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about

5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 2 months, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 3 months, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 4 months, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, at least about 20 weeks, at least about 5 months, at least about 21 weeks, at least about 22 weeks, at least about 23 weeks, at least about 24 weeks, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months at least about 23 months, at least about 2 years, at least about 2.5 years, at least about 3 years, at least about 3.5 years, at least about 4 years, at least about 4.5 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 11 years, at least about 12 years, at least about 13 years, at least about 14 years, at least about 15 years, at least about 16 years, at least about 17 years, at least about 18 years, at least about 19 years, at least about 20 years, at least about 21 years, at least about 22 years, at least about 23 years, at least about 24 years, or at least about 25 years. In some embodiments, the length of time a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered can be at most about 1 day, at most about 2 days, at most about

3 days, at most about 4 days, at most about 5 days, at most about 6 days, at most about 1 week, at most about 2 weeks, at most about 3 weeks, at most about 4 weeks, at most about 1 month, at most about 5 weeks, at most about 6 weeks, at most about 7 weeks, at most about 8 weeks, at most about 2 months, at most about 9 weeks, at most about 10 weeks, at most about 11 weeks, at most about 12 weeks, at most about 3 months, at most about 13 weeks, at most about 14 weeks, at most about 15 weeks, at most about 16 weeks, at most about 4 months, at most about 17 weeks, at most about 18 weeks, at most about 19 weeks, at most about 20 weeks, at most about 5 months, at most about 21 weeks, at most about 22 weeks, at most about 23 weeks, at most about 24 weeks, at most about 6 months, at most about 7 months, at most about 8 months, at most about 9 months, at most about 10 months, at most about 11 months, at most about 1 year, at most about 13 months, at most about 14 months, at most about 15 months, at most about 16 months, at most about 17 months, at most about 18 months, at most about 19 months, at most about 20 months, at most about 21 months, at most about 22 months at most about 23 months, at most about 2 years, at most about 2.5 years, at most about 3 years, at most about 3.5 years, at most about 4 years, at most about 4.5 years, at most about 5 years, at most about 6 years, at most about 7 years, at most about 8 years, at most about 9 years, at most about 10 years, at most about 11 years, at most about 12 years, at most about 13 years, at most about 14 years, at most about 15 years, at most about 16 years, at most about 17 years, at most about 18 years, at most about 19 years, at most about 20 years, at most about 21 years, at most about 22 years, at most about 23 years, at most about 24 years, or at most about 25 years. In some embodiments, the length of time a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, about 20 years, about 21 years, about 22 years, about 23 years, about 24 years, or about 25 years. The length of treatment can vary for each subject.

[0123] In some embodiments, a compound of the disclosure or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered once a day. In some embodiments, a compound of the disclosure or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered twice a day. In some embodiments, a compound of the disclosure or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered three times a day. In some embodiments, compound or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) absorption can be interfered by food. In some embodiments, the dosing is separated from a meal by at least about 15 minutes (min), at least about 30 min, at least about 45 min, at least about 1 hour (hr), at least about 1.5 hr, at least about 2 hr, at least about 2.5 hr, at least about 3 hr, at least about 3.5 hr, at least about 4 hr, at least about 4.5 hr, at least about 5 hr, at least about 5.5 hr, or at least about 6 hr. In some embodiments, the dosing is separated from a meal by at least about 30 min. In some embodiments, the dosing is separated from a meal by at least about 1 hr. In some embodiments, the dosing is separated from a meal by at least about 2 hr. In some embodiments, the dosing is separated from a meal by at most about 15 min, at most about 30 min, at most about 45 min, at most about 1 hour (hr), at most about 1.5 hr, at most about 2 hr, at most about 2.5 hr, at most about 3 hr, at most about 3.5 hr, at most about 4 hr, at most about 4.5 hr, at most about 5 hr, at most about 5.5 hr, or at most about 6 hr. In some embodiments, the dosing is separated from a meal by at most about 30 min. In some embodiments, the dosing is separated from a meal by at most about 1 hr. In some embodiments, the dosing is separated from a meal by at most about 2 hr. In some embodiments, the dosing is separated from a meal by about 15 min, about 30 min, about 45 min, about 1 hr, about 1.5 hr, about 2 hr, about 2.5 hr, about 3 hr, about 3.5 hr, about 4 hr, about 4.5 hr, about 5 hr, about 5.5 hr, or about 6 hr. In some embodiments, the dosing is separated from a meal by about 30 min. In some embodiments, the dosing is separated from a meal by about 1 hr. In some embodiments, the dosing is separated from a meal by about 2 hr. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered before the subject consumes food. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered after the subject consumes food. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered before the subject consumes a drink. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered after the subject consumes a drink. [0124] In some embodiments, the morning dose of a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is taken after an overnight fast and an hour before breakfast. In some embodiments, an afternoon dose of a compound is taken 2 hours after lunch and an hour before dinner or other food. In some embodiments, a first therapeutically-effective amount of the compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered to the subject in a morning of a day, and a second therapeutically-effective amount of the compound is administered to the subject in an afternoon of the day. In some embodiments, a first therapeutically-effective amount of a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered to the subject in a morning of a day, and a second therapeutically-effective amount of a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered to the subject in an evening of the day. In some embodiments, the first therapeutically-effective amount and the second therapeutically- effective amount are the same. In some embodiments, the first therapeutically-effective amount and the second therapeutically-effective amount are different. In some embodiments, the first therapeutically-effective amount is greater than the second therapeutically-effective amount. In some embodiments, the first therapeutically-effective amount is lesser than the second therapeutically-effective amount.

[0125] Intravenous rigosertib can be given through a large bore intravenous catheter to avoid the risks of extravasation. The IV infusion can be continuous (continuous intravenous (CIV)) for 72 hours with three separate infusion bags delivered for 24 hours each via a standard infusion pump.

[0126] To mitigate a risk of a genitourinary adverse event, a second dose of a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can be administered in the afternoon, a subject disclosed herein can be instructed to hydrate orally prior to bedtime, a subject disclosed herein can be instructed to empty the bladder prior to bedtime, or any combination thereof.

[0127] The urine pH of a subject disclosed herein can be monitored. If the urine pH is acidic, the subject can be administered oral bicarbonate. A urine dipstick obtained from a subject disclosed herein can further be monitored for evidence of microscopic hematuria. [0128] A dosing schedule for administration of a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) include, but are not limited to, once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once weekly, twice weekly, three times weekly, once monthly, twice monthly, and once every other month. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered once daily. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered twice daily. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered three times daily. In some embodiments, a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is administered four times daily.

[0129] An approximate dose can be predicted or determined on the basis of data existing in other species. In some embodiments, allometric scaling can be used to exchange a drug dose based on normalization of dose to body surface area. Allometric scaling considers the sizes of individual species based on body surface area, which is related to metabolic rate of an animal that is established through evolutionary adaptation of animals to their size. A no observed adverse effect level (NOAEL) is first determined in an animal species, the NOAEL is converted to a human equivalent dose (HED), an appropriate animal species is selected, a safety factor is applied, and a pharmacologically active dose is determined.

[0130] NOAEL, the highest dose level that does not cause significant adverse effects, is a typical index for safety obtained from animal experiments to determine a safe starting dose. NOAEL values can be converted to HED on the basis of the body surface correction factor using appropriate scaling factors from animal species. Table 1 lists HED calculation guidelines based on body surface areas. HED is determined using the equation:

HED (mg/kg) = Animal NOAEL (mg/kg) x (Weightanimai[kg]/Weighthuman[kg])⁽¹’°-⁶⁷⁾ [0131] The HED is divided by a factor value of 10 to increase safety of the first human dose. The safety factor is accountable for differences in physiological and biological processes between human and animal species. [0132] The correction factor (K_m) is estimated by dividing the average body weight (kg) of a species to its body surface area (m²). The K_m factor values of various animal species of Table 1 is used to estimate the HED as:

HED (mg/kg) = Animal doses (mg/kg) x (Animal K_m/Human K_m); or HED (mg/kg) = Animal doses (mg/kg) x K_m ratio

Table 1

[0133] Table 2 provides animal equivalent dose (AED) calculation guidelines based on body surface area. The animal equivalent dose (AED) can also be calculated on the basis of body surface area by either dividing or multiplying the human dose (mg/kg) by the K_m ratio provided in Table 2. AED can be calculated using the equation: AED (mg/kg) = Human doses (mg/kg) x K_m ratio

Table 2

[0134] For parenteral administration, HED conversion (mg/kg) is also based on body surface area normalization. The conversion can be made by dividing the NOAEL in appropriate species by the conversion factor. Table 3 provides guidelines for maximum injection volume, by species, site location, and gauge size. Injection volume of parenteral formulation is calculated by the following equation:

Injection volume (mL) = [Animal weight (kg) x Animal doses (mg/kg)] / Concentration (mg/kg)

Table 3

MEK and BRAE inhibitors

[0135] In some embodiments, disclosed herein is a method of treating a cancer (e.g., melanoma) by administering to a subject in need thereof a compound of the disclosure and an inhibitor of the RAS-RAF-MEK-ERK pathway.

[0136] In some embodiments, disclosed herein is a method of treating a cancer (e.g., melanoma) by administering to a subject in need thereof a compound of the disclosure and an extracellular signal -regulated kinase 1/2 (ERK1/2) inhibitor or a mitogen-activated protein kinase kinase (MEK) inhibitor. In some embodiments, the MEK inhibitor can be trametinib, selumetinib, cobimetinib, XL518, binimetinib (MEK162), or refametinib. In some embodiments, the MEK inhibitor is trametinib. In some embodiments, the MEK inhibitor is selumetinib. In some embodiments, the MEK inhibitor is cobimetinib or XL518. In some embodiments, the MEK inhibitor is binimetinib (MEK162). In some embodiments, the MEK inhibitor is refametinib.

[0137] In some embodiments, disclosed herein is a method of treating a cancer by administering to a subject in need thereof a compound of the disclosure, a MEK inhibitor, and/or a serine/threonine kinase B-raf (BRAF) inhibitor, or any combination thereof. In some embodiments, disclosed herein is a method of treating a cancer by administering to a subject in need thereof a compound of the disclosure, a MEK inhibitor, and a B-Raf (BRAF) inhibitor. In some embodiments, the BRAF inhibitor is vemurafenib, dabrafenib, or encorafenib. In some embodiments, the BRAF inhibitor is vemurafenib. In some embodiments, the BRAF inhibitor is dabrafenib. In some embodiments, the BRAF inhibitor is encorafenib.

[0138] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 0.1 milligram (mg)/kilogram (kg) to about 10 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1 mg/kg, from about 1 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2 mg/kg, from about 2 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3 mg/kg, from about 3 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4 mg/kg, from about 4 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5 mg/kg, from about 5 mg/kg to about 5.5 mg/kg, from about 5.5 mg/kg to about 6 mg/kg, from about 6 mg/kg to about 6.5 mg/kg, from about 6.5 mg/kg to about 7 mg/kg, from about 7 mg/kg to about 7.5 mg/kg, from about 7.5 mg/kg to about 8 mg/kg, from about 8 mg/kg to about 8.5 mg/kg, from about 8.5 mg/kg to about 9 mg/kg, from about 9 mg/kg to about 9.5 mg/kg, or from about 9.5 mg/kg to about 10 mg/kg. In some embodiments, a MEK inhibitor ,a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 0.1 mg/kg to about 0.5 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 0.5 mg/kg to about 1 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 1 mg/kg to about 1.5 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 1.5 mg/kg to about 3 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 3 mg/kg to about 5 mg/kg.

[0139] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 0.1 mg/kg, at least about 0.5 mg/kg, at least about 1 mg/kg, at least about 1.5 mg/kg, at least about 2 mg/kg, at least about 2.5 mg/kg, at least about 3 mg/kg, at least about 3.5 mg/kg, at least about 4 mg/kg, at least about 4.5 mg/kg, at least about 5 mg/kg, at least about 5.5 mg/kg, at least about 6 mg/kg, at least about 6.5 mg/kg, at least about 7 mg/kg, at least about 7.5 mg/kg, at least about 8 mg/kg, at least about 8.5 mg/kg, at least about 9 mg/kg, at least about 9.5 mg/kg, or at least about 10 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8.5 mg/kg, about 9 mg/kg, about 9.5 mg/kg, or about 10 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 1 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 2.5 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 3 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 3.5 mg/kg.

[0140] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 0.1 mg/kg, at most about 0.5 mg/kg, at most about 1 mg/kg, at most about 1.5 mg/kg, at most about 2 mg/kg, at most about 2.5 mg/kg, at most about 3 mg/kg, at most about 3.5 mg/kg, at most about 4 mg/kg, at most about 4.5 mg/kg, at most about 5 mg/kg, at most about 5.5 mg/kg, at most about 6 mg/kg, at most about 6.5 mg/kg, at most about 7 mg/kg, at most about 7.5 mg/kg, at most about 8 mg/kg, at most about 8.5 mg/kg, at most about 9 mg/kg, at most about

9.5 mg/kg, or at most about 10 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 1 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 2 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 3 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 4 mg/kg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 5 mg/kg.

[0141] In some embodiments, a MEK inhibitor or a BRAF inhibitor can be administered at a dose of from about 0.1 mg to about 0.5 mg, from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, from about 4.5 mg to about 5.0 mg, from about 5.0 mg to about 5.5 mg, from about 5.5 mg to about 6.0 mg, from about 6.0 mg to about 6.5 mg, from about 6.5 mg to about 7.0 mg, from about 7.0 mg to about 7.5 mg, or from about 7.5 mg to about 8.0 mg, per dose administered. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 0.1 mg, at most about 0.5 mg, at most about 1.0 mg, at most about 1.5 mg, at most about 2.0 mg, at most about 2.5 mg, at most about 3.0 mg, at most about 3.5 mg, at most about 4.0 mg, at most about 4.5 mg, at most about 5.0 mg, at most about 5.5 mg, at most about 6.0 mg, at most about 6.5 mg, at most about 7.0 mg, at most about 7.5 mg, or at most about 8.0 mg, per dose administered. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at about 0.1 mg, at about 0.5 mg, at about 1.0 mg, at about

1.5 mg, at about 2.0 mg, at about 2.5 mg, at about 3.0 mg, at about 3.5 mg, at about 4.0 mg, at about 4.5 mg, at about 5.0 mg, at about 5.5 mg, at about 6.0 mg, at about 6.5 mg, at about 7.0 mg, at about 7.5 mg, or at about 8.0 mg, per dose administered. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 0.5 mg to about 2.0 mg per dose administered. In some embodiments, more than one, e.g., 2, 3, or 4 doses can be administered per day. In some embodiments, a dose of from about 1.0-2.0 mg, e.g., 2.0 mg is administered once per day. In some embodiments, a MEK inhibitor can be administered at a dose of 2.0 mg once per day.

[0142] In some embodiments, a BRAF inhibitor can be administered at a dose of from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1,000 mg per dose administered. In some embodiments, a BRAF inhibitor can be administered at a dose of from about 50 mg to about 250 mg per dose, e.g., 150 mg administered. In some embodiments, more than one, e.g., 2, 3, or 4 doses can be administered per day. In some embodiments, a dose of from about 50 mg to about 250 mg per dose, e.g., 150 mg is administered twice per day. In some embodiments, a BRAF inhibitor can be administered at a dose of 150 mg twice per day.

[0143] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1,000 mg per dose administered. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 50 mg to about 250 mg per dose administered. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 250 mg to about 500 mg per dose administered. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of from about 500 mg to about 750 mg per dose administered. [0144] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 25 mg, at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, or at least about 1,000 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 240 mg. In some embodiments, a MEK inhibitor or a BRAF inhibitor can be administered at a dose of at least about 250 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 300 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 450 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 480 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 500 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 25 mg, at most about 50 mg, at most about 100 mg, at most about 150 mg, at most about 200 mg, at most about 250 mg, at most about 300 mg, at most about 350 mg, at most about 400 mg, at most about 450 mg, at most about 500 mg, at most about 550 mg, at most about 600 mg, at most about 650 mg, at most about 700 mg, at most about 750 mg, at most about 800 mg, at most about 850 mg, at most about 900 mg, at most about 950 mg, or at most about 1,000 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 240 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 250 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 300 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 450 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 480 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at most about 500 mg. [0145] In some embodiments a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor be administered at a dose of about 240 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 250 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 300 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 450 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 480 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of about 500 mg.

[0146] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered at a concentration of from about 1 mg/mL to about 2 mg/mL, from about 2 mg/mL to about 3 mg/mL, from about 3 mg/mL to about 4 mg/mL, from about 4 mg/mL to about 5 mg/mL, from about 5 mg/mL to about 6 mg/mL, from about 6 mg/mL to about 7 mg/mL, from about 7 mg/mL to about 8 mg/mL, from about 8 mg/mL to about 9 mg/mL, or from about 9 mg/mL to about 10 mg/mL. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered at a concentration of from about 9 mg/mL to about 10 mg/mL. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered at a concentration of at least about 1 mg/mL, at least about 1.5 mg/mL, at least about 2 mg/mL, at least about 2.5 mg/mL, at least about 3 mg/mL, at least about 3.5 mg/mL, at least about 4 mg/mL, at least about 4.5 mg/mL, at least about 5 mg/mL, at least about 5.5 mg/mL, at least about 6 mg/mL, at least about 6.5 mg/mL, at least about 7 mg/mL, at least about 7.5 mg/mL, at least about 8 mg/mL, at least about 8.5 mg/mL, at least about 9 mg/mL, at least about 9.5 mg/mL, or at least about 10 mg/mL. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered at a concentration of about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 5.5 mg/mL, about 6 mg/mL, about

6.5 mg/mL, about 7 mg/mL, about 7.5 mg/mL, about 8 mg/mL, about 8.5 mg/mL, about 9 mg/mL, about 9.5 mg/mL, or about 10 mg/mL. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered at a concentration of about 10 mg/mL.

[0147] In some embodiments, the volume of infusion is at most about 5 mL/kg, at most about

4.5 mL/kg, at most about 4 mL/kg, at most about 3.5 mL/kg, at most about 3 mL/kg, at most about 2.5 mL/kg, at most about 2 mL/kg, at most about 1.5 mL/kg, at most about 1 mL/kg, or at most about 0.5 mL/kg of body weight. In some embodiments, the volume of infusion is at most about 4 mL/kg of body weight. In some embodiments, the volume of infusion is at most about 3 mL/kg of body weight.

[0148] In some embodiments, the total volume of infusion is at most about 200 mL, at most about 175 mL, at most about 150 mL, at most about 125 mL, at most about 100 mL, at most about 75 mL, at most about 50 mL, or at most about 25 mL. In some embodiments, the total volume of infusion is at most about 160 mL. In some embodiments, the total volume of infusion is at most about 125 mL. In some embodiments, the total volume of infusion is at most about 100 mL.

[0149] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 240 mg. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor can be administered at a dose of at least about 480 mg.

[0150] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered intravenously. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered orally.

[0151] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered once every day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, or once every 12 weeks. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered once every week. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered once every week. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered once every 2 weeks. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered once every

4 weeks. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered once every 6 weeks. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered once every 8 weeks. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered once every 12 weeks.

[0152] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, or at least about 28 times over a 28-day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered at most about 1, at most about 2, at most about 3, at most about 4, at most about 5, at most about 6, at most about 7, at most about 8, at most about 9, at most about 10, at most about 11, at most about 12, at most about 13, at most about 14, at most about 15, at most about 16, at most about 17, at most about 18, at most about 19, at most about 20, at most about 21, at most about 22, at most about 23, at most about 24, at most about 25, at most about 26, at most about 27, or at most about 28 times over a 28-day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, or about 28 times over a 28-day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered 1 time over a 28-day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered 2 times over a 28-day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered 3 times over a 28-day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered 4 times over a 28-day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered on day 1 of a 28 day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered on day 15 of a 28 day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered on day 22 of a 28 day cycle. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered on day 1 and day 15 of a 28 day cycle.

[0153] In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered over at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 90 minutes, or at least about 120 minutes. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered over at most about 15 minutes, at most about 30 minutes, at most about 45 minutes, at most about 60 minutes, at most about 90 minutes, or at most about 120 minutes. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered over about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered over 30 minutes. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered over 60 minutes. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered over 90 minutes. In some embodiments, a MEK inhibitor, a BRAF inhibitor, or a combination of MEK inhibitor and BRAF inhibitor is administered over 120 minutes.

[0154] In some embodiments, a compound of the present disclosure can promote CD40 expression in cancer cells (e.g., melanoma cells). In some embodiments, combination of a compound of the disclosure with a MEK inhibitor can inhibit a PI3K-AKT-mT0R oncogenic pathway. In some embodiments, the combination of a compound of the disclosure with a MEK inhibitor can inhibit an oncogenic pathway. In some embodiments, the combination of a compound of the disclosure with a MEK inhibitor can inhibit a RAS-RAF-MEK-ERK pathway. In some embodiments, the combination of a compound of the disclosure with a MEK inhibitor can inhibit a PI3K-AKT-mTOR pathway. In some embodiments, combination of a compound of the disclosure with a MEK inhibitor can reduce phosphorylation of ERK, AKT^T308, mTOR, S6, or any combination thereof. In some embodiments, combination of a compound of the disclosure with a MEK inhibitor can reduce tumor progression. In some embodiments, the combination of a compound of the disclosure with a MEK inhibitor can show greater reduction in tumor size than does a monotherapy of either agent.

Other agents

[0155] In some embodiments, the compounds of this disclosure can be administered with other therapeutic agents or treatments to treat a cancer. For example, the compounds of this disclosure can be administered with other therapeutic agents or treatments to treat a melanoma, an advanced melanoma, or an unresectable or metastatic refractory melanoma. In some embodiments, a therapeutic agent can be an antibody. In some embodiments, a therapeutic agent can comprise a chemotherapeutic agent. In some embodiments, a therapeutic agent can comprise an imidazole carboxamide. For example, the imidazole carboxamide can comprise adacarbazine (DTIC and DIC).In some embodiments, a therapeutic agent can comprise a histone deacetylase (HD AC) inhibitor. For example, the HD AC inhibitor can comprise an Entinostat. In some embodiments, a therapeutic agent can comprise a CD-40 agonistic antibody. For example, the CD-40 agonistic antibody can comprise a APX005M. In some embodiments, a therapeutic agent can comprise an interleukin 2 (IL-2). In some embodiments, a therapeutic agent can comprise a bempegaldesleukin (NKTR-214). In some embodiments, a therapeutic agent can comprise a Talimogene Laherparepvec (TVEC). In some embodiments, a therapeutic agent can comprise Chimeric antigen receptor (CAR) T-cell (CART). For example, the CART can comprise a CD-19 CART. In some embodiments, a therapeutic agent can comprise T-cell receptors (TCRs). In some embodiments, another treatment can comprise an adoptive cell therapy. For example, the adoptive cell therapy can be with Tumor Infiltrating Lymphocytes (optionally, with IL-2). In some embodiments, another treatment can comprise surgery, radiotherapy, or oral microbiome study intervention.

[0156] A method disclosed herein can be used to treat, for example, an infectious disease, a proliferative disease, a cancer, a solid tumor, a liquid tumor, non-small cell lung cancer, melanoma, colorectal cancer, head and neck cancer, bladder cancer, pancreatic cancer, hairy cell leukemia, non-Hodgkin lymphoma, thyroid cancer, ovarian cancer, lung adenocarcinoma, or brain cancer. In some embodiments, the cancer is a skin cancer. In some embodiments, the cancer is a BRAF positive cancer. For example, the BRAF positive cancer can comprise melanoma, hairy cell leukemia, non-Hodgkin lymphoma, thyroid cancer, ovarian cancer, lung adenocarcinoma, colorectal cancer, or brain cancer. In some embodiments, the cancer is a melanoma. In some embodiments, melanoma can comprise a superficial spreading melanoma, a nodular melanoma, a lentigo maligna melanoma, an acral lentiginous melanoma, a desmoplastic melanoma, a cutaneous melanoma, an acral melanoma, an uveal melanoma, or a mucosal melanoma. In some embodiments, melanoma can comprise an advanced melanoma, an unresectable or metastatic refractory melanoma, a BRAFV600- mutant metastatic melanoma, or a BRAFV600E/K mutant metastatic melanoma. In some embodiments, melanoma can comprise mutated serine/threonine-protein kinase B-raf (BRAF), G protein subunit alpha 11 (GNA11), G protein subunit alpha q (GNAQ), KIT proto-oncogene (KIT), MAP kinase/ERK kinase 1 (MEK1), Harvey rat sarcoma virus (HRAS, HRAS proto-oncogene) or NRAS proto-oncogene (NRAS) protein.

[0157] Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient.

[0158] A compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can, for example, slow the proliferation of cancer cell lines, or kill cancer cells. In some embodiments, the cancer comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mutations. In some embodiments, the cancer comprises 1 mutation. In some embodiments, the cancer comprises 2 mutations. In some embodiments, the cancer comprises 3 mutations. In some embodiments, the cancer comprises 4 mutations. In some embodiments, the cancer comprises 5 mutations. [0159] In some embodiments, the cancer comprises a NRAS mutation. In some embodiments, the cancer comprises a HRAS mutation. In some embodiments, the cancer comprises a KRAS mutation. In some embodiments, the cancer comprises a G12V mutation. In some embodiments, the cancer comprises a G12D mutation. In some embodiments, the cancer comprises a G12C mutation. In some embodiments, the cancer comprises a I46T mutation. [0160] In some embodiments, the cancer comprises a BRAF mutation. In some embodiments, the cancer comprises a BRAF V600E mutation. In some embodiments, the cancer comprises a BRAF V600K mutation. In some embodiments, the cancer is a BRAF positive cancer. In some embodiments, the cancer can be a BRAF positive melanoma. In some embodiments, the cancer can be a BRAFV600-mutant metastatic melanoma. In some embodiments, melanoma can be an unresectable refractory melanoma. In some embodiments, melanoma can be metastatic refractory melanoma.

[0161] Non-limiting examples of cancer that can be treated by a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas, Burkitt lymphoma, carcinoma of unknown primary origin, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, germ cell tumors, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gliomas, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, Hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liposarcoma, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, lymphomas, leukemias, macroglobulinemia, malignant fibrous histiocytoma of bone/osteosarcoma, medulloblastoma, melanomas, mesothelioma, metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndromes, myeloid leukemia, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma/malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pituitary adenoma, pleuropulmonary blastoma, plasma cell neoplasia, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, skin cancers, skin carcinoma merkel cell, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, T-cell lymphoma, throat cancer, thymoma, thymic carcinoma, thyroid cancer, trophoblastic tumor (gestational), cancers of unknown primary site, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor. In some embodiments, the cancer is a BRAF positive cancer. For example, the BRAF positive cancer can comprise melanoma, hairy cell leukemia, non-Hodgkin lymphoma, thyroid cancer, ovarian cancer, lung adenocarcinoma, colorectal cancer, or brain cancer. In some embodiments, the cancer is a melanoma. In some embodiments, melanoma can comprise a superficial spreading melanoma, a nodular melanoma, a lentigo maligna melanoma, an acral lentiginous melanoma, a desmoplastic melanoma, a cutaneous melanoma, an acral melanoma, an uveal melanoma, or a mucosal melanoma. In some embodiments, melanoma can comprise an advanced melanoma, an unresectable or metastatic refractory melanoma, a BRAFV600-mutant metastatic melanoma, or a BRAFV600E/K mutant metastatic melanoma. In some embodiments, melanoma can comprise mutated serine/threonine-protein kinase B-raf (BRAF), G protein subunit alpha 11 (GNA11), G protein subunit alpha q (GNAQ), KIT proto-oncogene (KIT), MAP kinase/ERK kinase 1 (MEK1), Harvey rat sarcoma virus (HRAS, HRAS proto-oncogene) or NRAS protooncogene (NRAS) protein.

[0162] A tumor response due to a method disclosed herein can be measured based on the RECIST classification of responses.

[0163] In some embodiments, an overall response rate of a population of subjects administered a compound disclosed herein or a compound disclosed herein in combination with an inhibitor disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% when evaluated after a suitable amount of time post-treatment (e.g., at about 1 year post-treatment). In some embodiments, an overall response rate of a population of subjects administered a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is at most about 5%, at most about 10%, at most about 15%, at most about 20%, at most about 30%, at most about 40%, at most about 50%, at most about 55%, at most about 60%, at most about 65%, at most about 70%, at most about 75%, at most about 80%, at most about 85%, at most about 90%, or at most about 95% when evaluated after a suitable amount of time post-treatment (e.g., at about 1 year post-treatment). In some embodiments, an overall response rate of a population of subjects administered a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) is about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% when evaluated after a suitable amount of time post-treatment (e.g., at about 1 year post-treatment).

[0164] A population of subjects treated or provided with a compound disclosed herein, a compound disclosed herein in combination with an inhibitor disclosed herein (e.g., MEK inhibitor, BRAF inhibitor), and/or methods disclosed herein exhibit a high progression-free survival rate, for example, a higher progression-free survival rate compared to a subject that is administered an alternate compound or treated via an alternate method. In some embodiments, at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of subjects that are administered a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) exhibit progression-free after about 1 year post-treatment. In some embodiments, at most about 40%, at most about 50%, at most about 55%, at most about 60%, at most about 65%, at most about 70%, at most about 75%, at most about 80%, at most about 85%, at most about 90%, or at most about 95% of subjects that are administered a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) exhibit progression-free after about 1 year post-treatment. In some embodiments, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of subjects that are administered a compound disclosed herein or a compound disclosed herein in combination with an inhibitor disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) exhibit progression-free after about 1 year posttreatment.

[0165] A population of subjects administered a compound disclosed herein or a compound disclosed herein in combination with an inhibitor disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) can exhibit a low incidence of progressive disease, for example, a lower incidence compared to a population of subjects that is administered an alternate compound. In some embodiments, less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 11%, less than about 12%, less than about 13%, less than about 14%, less than about 15%, less than about 16%, less than about 17%, less than about 18%, less than about 19%, less than about 20%, less than about 21%, less than about 22%, less than about 23%, less than about 24%, less than about 25%, less than about 26%, less than about 27%, less than about 28%, less than about 29%, less than about 30%, less than about 31%, less than about 32%, less than about 33%, less than about 34%, less than about 35%, less than about 36%, less than about 37%, less than about 38%, less than about 39%, less than about 40%, less than about 41%, less than about 42%, less than about 43%, less than about 44%, less than about 45%, less than about 46%, less than about 47%, less than about 48%, less than about 49%, or less than about 50% of a population of subjects that is administered a compound disclosed herein or a compound disclosed herein in combination with one or more inhibitors disclosed herein (e.g., MEK inhibitor, BRAF inhibitor) exhibit progressive disease, for example, according to iRECIST criteria when assessed at 1 year post-treatment.

EXAMPLES

EXAMPLE 1: Study to Evaluate an Oral Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.

[0166] Approximately 30 patients are enrolled in a dose escalation study of rigosertib in metastatic melanoma to investigate doses of rigosertib in combination with trametinib. The patients are divided in three cohorts. The dose of trametinib is 2 mg once daily. The next rigosertib dose cohort is 840 mg in the morning and 560 mg in the afternoon, given at least 2 hours after the prior meal and 1 hour before each subsequent meal. Dose increments in the dose escalation 3+3 study are 280 mg each, with the morning dose being raised first, then the afternoon dose being raised in the next cohort, for example, 840 mg/560 mg, then 840 mg/840 mg, then 1,120 mg/840 mg, etc. (morning and afternoon, respectively). Per 3+3 dose escalation studies, the MTD (maximally tolerated dose) and RP2D (recommended phase 2 dose) are determined based on DLTs (dose limiting toxi cities) and after determination of the RP2D, an expansion cohort of up to 12 patients is enrolled. In addition to the assessment of safety and tolerability, efficacy is measured by the overall response rate as assessed by iRECIST. [0167] Following determination of the RP2D, a randomized, controlled phase 2 study is performed with rigosertib combination with trametinib. Approximately 200 patients are enrolled in a 1 : 1 ratio to receive either rigosertib+placebo, or trametinib + placebo, or trametinib + rigosertib. Primary outcome is the statistical comparison between progression- free survival (PFS) rates, with overall survival (OS) as the secondary endpoint.

EXAMPLE 2: Study to Evaluate an Intravenous Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.

[0168] Approximately 30 patients are enrolled in a dose escalation study of IV rigosertib in metastatic melanoma to determine the MTD in combination with trametinib. The study is performed in combination with standard dose MEK inhibition as per the label. The dose of trametinib is 2 mg once daily. The initial dose of IV rigosertib given in combination is 1,200 mg/24 hours given as a continuous infusion (CIV) for days 1-3 of a 14-day cycle. The next rigosertib dose cohort is 1,500 mg/24 hours as a continuous infusion (CIV) for days 1-3 of a 14-day cycle. Dose increments in the dose escalation 3+3 study are 300 mg/24 hours each. (1,800 mg, 2,100 mg, 2,400 mg, etc.). Per 3+3 dose escalation studies, the MTD and RP2D are determined based on DLTs and after determination of the RP2D, an expansion cohort of up to 12 patients is enrolled at the RP2D. In addition to the assessment of safety and tolerability, efficacy is measured by the overall response rate as assessed by iRECIST.

[0169] Following determination of the RP2D a randomized, controlled phase 2 study is performed in combination with trametinib. Approximately 200 patients are enrolled in a 1 : 1 ratio to receive either rigosertib+placebo, trametinib + placebo or trametinib + rigosertib. Primary outcome is the statistical comparison between progression-free survival (PFS) rates, with overall survival (OS) as the secondary endpoint.

EXAMPLE 3: Study to Evaluate PK/PD results for a Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.

[0170] Levels of a biomarker or protein are measured in a cancer cell specimen collected before beginning treatment and at the end of treatment. The effects of rigosertib on the RAS mutation in the tumor and circulating tumor cells are studied, along with the immunological milieu of the patients responding and compared to those who do not respond to the treatment. The specific time points for blood and tissue collection for pharmacodynamic assessments are determined by the protocol. Pharmacodynamic data are tabulated and summarized by individual patient and collectively by dose level. Graphical displays are provided where useful in the interpretation of results. [0171] Results available from previous genetic and biomarker tests, and additional tests of the blood and liquid cancer cell samples for biomarkers relevant to the safety and efficacy of a pharmaceutical composition described herein can be investigated for possible correlation with patient outcome.

EXAMPLE 4: Animal models to test activity of rigosertib in RAS mutated cancers with MEK inhibitors

[0172] Genetic mutations in RAS isoforms, such as NRAS, KRAS, and HRAS, are known to be detected in cancers, such as melanomas. Among NRAS, KRAS, and HRAS mutations, NRAS mutations are found in most melanoma cases. KRAS has been identified to be mutated in a number of tumor types including lung, GI Tract (colon), pancreas, skin, breast, hematopoietic tissues, gynecological, testis, and urinary tumors. In addition to mutations, other perturbations of KRAS pathway can occur leading to activation of the pathway such as amplification of wild-type KRAS. Identification of specific KRAS show that most mutations primarily occur at the G12 and G13 amino acids with mutations changing the G to a C (G12C and G13C, respectively). In addition, G12D, G12V, G12R and G12A mutations are also clinically relevant and seem to be cancer specific.

[0173] Multiple mouse models are employed to test the efficacy of rigosertib in RAS mutated cancers in combination with a MEK inhibitor. A patient-derived xenograft (PDX) model is used for the experiments, including samples obtained from melanoma, lung adenocarcinoma, colorectal, and pancreatic cancer patient. The specific PDX model used is determined based on the RAS mutation, such as mutation of NRAS, KRAS, HRAS, status of the patient sample. The tumors are analyzed via genomic sequencing to determine the RAS mutation and any other driver mutations or amplifications in other known cell cycle or survival signaling pathways.

[0174] Patient derived samples are studied in humanized mice. The studies are run in specific immunocompetent mouse models. Humanized mouse models routinely use mice with severe combined immunodeficiency that have been transplanted with hematopoietic stem cells or human peripheral blood cells. After transplantation, the mice are engrafted with the KRAS driven PDX line and treated as described below.

[0175] In addition to the humanized models employing PDX models, rigosertib and MEK inhibitor combinations are studied in murine syngeneic models. Syngeneic models utilize allografts of RAS driven tumor cells derived from the exact strain of mouse that are engrafted, which protects the tumors from rejection. A third model uses murine models that are genetically engineered to express human immune components (GEMMS) that also have genetically defined RAS mutation driven cancers.

[0176] The animal assays establish the ability of rigosertib to synergize the activity of the MEK inhibitor or act in an additive manner. The studies also address the various dosing and scheduling of rigosertib and how dosing affects the efficacy of the rigosertib-MEKinhibitor combination treatments.

[0177] The humanized mice are implanted either subcutaneously or orthotopically with patient derived tumor tissue. Syngeneic mice are implanted subcutaneously with RAS activated cells with a genetic background is identical to the mouse strain being implanted. The tumors are permitted to grow to a tumor volume is greater than or equal to 50 mm³. Once are enough animals harbor tumors with similar tumor volumes, the mice are treated with rigosertib and the MEK inhibitor.

[0178] Rigosertib is administered at various doses and schedules. Rigosertib is administered by oral gavage at 50 mg/kg (HED=243.9), 100 mg/kg (HED: 487.8 mg), 150 mg/kg (HED 731.7 mg), 200 mg/kg (HED=975 mg), 250 mg/kg (HED=1219.8 mg), or 300 mg/kg (HED=1463.4 mg). The schedule is BID at each dose. The schedule is further modified to mimic the scheduling in humans and reduce possible toxicity, such that the schedules follow: 150 mg/kg, 200 mg/kg, 250 mg/kg, and 300 mg/kg in the morning followed by pairing with a higher dose in the afternoon (Table 4).

Table 4

[0179] The animals dosed with MEK inhibitors are administered a dose at a schedule that is clinically relevant. For example, trametinib is tested in a dose range between 0.3 mg/kg-30 mg/kg via intraperitoneal injection. Selumetinib was suspended in 0.5% v/v Tween 80 and 0.5% methylcellulose and administered orally at a dose of 25 mg/kg, BID (bis in die, twice a day), 5 days/week. Cobimatinib is tested in a dose range between 0.3 mg/kg-30 mg/kg via intraperitoneal injection. Binimetinib is administered at 30 orlOO mg/kg, PO, BID for 14 days; or 300 mg/kg, PO (orally) BID for 3 days, weekly x 2. In addition to the combination groups, control groups consist of rigosertib alone, the MEK inhibitor alone, and an appropriate vehicle control.

Assessment of the growth inhibitory activity of each agent is determined by two criteria: tumor growth and increase in life span (ILS). Tumor growth is monitored by determining a tumor volume. Tumor sizes are calculated according to the formula W² x L/2 (L = length and W = the perpendicular width of the tumor, L > W). The second criteria (used for the leukemia model) measures an increase in ILS. ILS is calculated using the following formula: (mean survival of treated/(mean survival of vehicle control)- 1 x 100.

EXAMPLE 5: Study to Evaluate an Oral Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.

[0180] Approximately 60 patients are enrolled in a dose escalation study of rigosertib in BRAF positive cancer to investigate doses of rigosertib in combination with trametinib, and rigosertib in combination with trametinib and dabrafenib. Patients with presence of BRAF V600E or V600K mutations are selected to undergo treatment. The patients are divided in three cohorts. Patients of group A received a combination of rigosertib and trametinib. Patients of group B received a combination of rigosertib, trametinib, and dabrafenib. The dose of trametinib is 2 mg once daily. The dose of dabrafenib is 150 mg twice daily. The next rigosertib dose cohort is 840 mg in the morning and 560 mg in the afternoon, given at least 2 hours after the prior meal and 1 hour before each subsequent meal. Dose increments in the dose escalation 3+3 study are 280 mg each, with the morning dose being raised first, then the afternoon dose being raised in the next cohort, for example, 840 mg/560 mg, then 840 mg/840 mg, then 1,120 mg/840 mg, etc. (morning and afternoon, respectively). Per 3+3 dose escalation studies, the MTD (maximally tolerated dose) and RP2D (recommended phase 2 dose) are determined based on DLTs (dose limiting toxi cities) and after determination of the RP2D, an expansion cohort of up to 12 patients is enrolled. In addition to the assessment of safety and tolerability, efficacy is measured by the overall response rate as assessed by iRECIST.

[0181] Following determination of the RP2D, a randomized, controlled phase 2 study is performed with rigosertib combination with trametinib, and rigosertib combination with trametinib and dabrafinib. Approximately 200 patients are enrolled in a 1 : 1 ratio to receive either rigosertib+placebo, dabrafinib+placebo, trametinib + placebo or trametinib + rigosertib, rigosertib+dabrafenib, or trametinib + dabrafinib + rigosertib. Primary outcome is the statistical comparison between progression-free survival (PFS) rates, with overall survival (OS) as the secondary endpoint. EXAMPLE 6: Study to Evaluate an Intravenous Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.

[0182] Approximately 60 patients are enrolled in a dose escalation study of IV rigosertib in BRAF positive cancer to determine the MTD in combination with trametinib or in combination with trametinib and dabrafinib. Patients with presence of BRAF V600E or V600K mutations are selected to undergo treatment. The study is performed in combination with standard dose MEK inhibition or BRAF inhibition as per the label. The dose of trametinib is 2 mg once daily. The dose of dabrafenib is 150 mg twice daily. The initial dose of IV rigosertib given in combination is 1,200 mg/24 hours given as a continuous infusion (CIV) for days 1-3 of a 14-day cycle. The next rigosertib dose cohort is 1,500 mg/24 hours as a continuous infusion (CIV) for days 1-3 of a 14-day cycle. Dose increments in the dose escalation 3+3 study are 300 mg/24 hours each. (1,800 mg, 2,100 mg, 2,400 mg, etc.). Per 3+3 dose escalation studies, the MTD and RP2D are determined based on DLTs and after determination of the RP2D, an expansion cohort of up to 12 patients is enrolled at the RP2D. In addition to the assessment of safety and tolerability, efficacy is measured by the overall response rate as assessed by iRECIST.

[0183] Following determination of the RP2D a randomized, controlled phase 2 study is performed in combination with trametinib and dabrafenib. Approximately 200 patients are enrolled in a 1 : 1 ratio to receive either rigosertib + placebo, dabrafenib + placebo, trametinib + placebo, trametinib + rigosertib, rigosertib + dabrafenib, or trametinib + dabrafinib + rigosertib. Primary outcome is the statistical comparison between progression-free survival (PFS) rates, with overall survival (OS) as the secondary endpoint.

EXAMPLE 7: Animal models to test activity of rigosertib in serine/threonine kinase B-raf (BRAF) positive cancers with mitogen-activated protein kinase kinase (MEK) inhibitors and BRAF inhibitors

[0184] BRAF is mutated in a number of tumor types including those of melanoma, hairy cell leukemia, non-Hodgkin lymphoma, thyroid cancer, ovarian cancer, lung adenocarcinoma, colorectal cancer, brain cancer. In addition to mutations, other perturbations of RAS-RAF- MEK-ERK and/or PI3K-AKT-mTOR pathway can occur leading to activation of the pathway. BRAF positive cancers can have BRAF V600E or V600K mutations.

[0185] Multiple mouse models are employed to test the efficacy of rigosertib in BRAF positive cancers in combination with a MEK inhibitor. A patient-derived xenograft (PDX) model is used for the experiments, including samples obtained from BRAF positive cancer patient. The specific PDX model used is determined based on the BRAF mutation status of the patient sample. The tumors are analyzed via genomic sequencing to determine the BRAF mutation and any other driver mutations or amplifications in other known cell cycle or survival signaling pathways.

[0186] Patient derived samples are studied in humanized mice. Since optimal activity of MEK inhibitors requires an intact immune system, the studies are run in specific immunocompetent mouse models. Humanized mouse models routinely use mice with severe combined immunodeficiency that have been transplanted with hematopoietic stem cells or human peripheral blood cells. After transplantation, the mice are engrafted with the BRAF driven PDX line and treated as described below.

[0187] In addition to the humanized models employing PDX models, rigosertib, BRAF inhibitor, and MEK inhibitor combinations are studied in murine syngeneic models. Syngeneic models utilize allografts of BRAF driven tumor cells derived from the exact strain of mice that are engrafted. This strategy protects the tumors from rejection. A third model uses murine models that are genetically engineered to express human immune components (GEMMS) that also have genetically defined BRAF mutation driven cancers.

[0188] The animal assays establish the ability of rigosertib to synergize with the other agent or act in an additive manner. The studies also address the various dosing and scheduling of rigosertib and how dosing affects the efficacy of the rigosertib-MEK inhibitor combination treatments.

[0189] The humanized mice are implanted either subcutaneously or orthotopically with patient derived tumor tissue. Syngeneic mice are implanted subcutaneously with BRAF mutated cells with a genetic background is identical to the mouse strain being implanted. The tumors are permitted to grow to a tumor volume greater than or equal to 50 mm³. Once are enough animals harbor tumors with similar tumor volumes, the mice are treated with rigosertib, and the BRAF inhibitor, and the MEK inhibitor.

[0190] Rigosertib is administered at various doses and schedules. Rigosertib is administered by oral gavage at 50 mg/kg (HED=243.9), 100 mg/kg (HED: 487.8 mg), 150 mg/kg (HED 731.7 mg), 200 mg/kg (HED=975 mg), 250 mg/kg (HED=1219.8 mg), or 300 mg/kg (HED=1463.4 mg). The schedule is BID at each dose. The schedule is further modified to mimic the scheduling in humans and reduce possible toxicity, such that the schedules follow: 150 mg/kg, 200 mg/kg, 250 mg/kg, and 300 mg/kg in the morning followed by pairing with a higher dose in the afternoon (Table 5). Table 5

[0191] The animals dosed with MEK and BRAF inhibitors are administered a dose at a schedule that is clinically relevant. For example, trametinib is tested in a dose range between 0.3 mg/kg-30 mg/kg via intraperitoneal injection. Dabrafenib is tested in a dose range between 10mg/kg-30 mg/kg via intraperitoneal injection. In addition to the combination groups, control groups consist of rigosertib alone, the MEK inhibitor alone, the BRAF inhibitor alone, a combination of rigosertib and the MEK inhibitor, a combination of rigosertib and the BRAF inhibitor, a combination of the MEK inhibitor and the BRAF inhibitor and an appropriate vehicle control.

[0192] Assessment of the growth inhibitory activity of each agent is determined by two criteria: tumor growth and increase in life span (ILS). Tumor growth is monitored by determining a tumor volume. Tumor sizes are calculated according to the formula W² x L/2 (L = length and W = the perpendicular width of the tumor, L > W). The second criteria (used for the leukemia model) measures an increase in ILS. ILS is calculated using the following formula: (mean survival of treated/(mean survival of vehicle control)- 1 x 100.

Example 8: Clinical Trial design to test efficacy of a combinatory treatment with rigosertib and trametinib for treating refractory metastatic melanoma [0193] 1.0 TRIAL DESIGN [0194] Trial Design

[0195] This is an open-label, two-stage, single-arm study of oral (PO) rigosertib in combination with oral trametinib in patients with metastatic melanoma that is refractory. The primary endpoint of the study will be overall response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), safety and tolerability, and correlation of response rate with biomarkers (change in tumor infiltrating lymphocytes). [0196] This study enrolls 6 patients in the lead-in phase of stage I of this two-stage design; toxicity is assessed, with potential down titration of rigosertib. After toxicity assessment, an additional 4 patients are enrolled in stage I. The sample size is designed to test whether rigosertib plus trametinib has a >30% response rate in refractory metastatic melanoma with a clinically uninteresting response rate of 10%. If >2 patients experience disease response, then the study proceeds to stage II.

[0197] The primary objective of the study is to evaluate the activity of rigosertib in combination with trametinib in terms of ORR. The overall type I error rate for this study is strictly controlled at 5% (one-sided) and the study has a power of 80%. The study is considered to be positive if at least 20% patients treated with rigosertib plus trametinib experience an objective response. All patients receiving study drugs receive rigosertib at 560 mg po (per os/orally) twice daily on days 1-21 of a 28-day cycle as well as trametinib 2 mg/day orally. Patients receive study drugs until confirmed disease progression, intolerable toxicity, confirmed complete response, withdrawal of consent, completion of two years of therapy, or until the patients require another form of antineoplastic therapy as determined by the Investigator.

[0198] After the baseline tumor evaluation, tumor assessment during the study is performed by radiological scans every eight weeks starting from week 8 to week 24. Patients who remain on study after 24 weeks and are clinically stable decrease imaging frequency to every 12 weeks in the following schedule:

-First scheduled disease assessment: week 8

-Disease assessments every 8 week from week 16-24

-Disease assessment every 12 weeks from week 24-48

[0199] Patients are evaluated for tumor response based on the iRECIST criteria by the treating physician review. On-study assessments by iRECIST take into account the observation that some patients with melanoma can experience a transient tumor flare in the first few months after immunotherapy treatment with subsequent disease response. Clinical decisions are based on the interpretation of the Investigator treating the patient in real time using the iRECIST criteria.

[0200] All patients have at least one baseline measurable lesion by iRECIST 1.1 definition on CT or MRI (as assessed by Investigator). The timing for tumor assessments is based on calendar and not adjusted for delays or variation in cycle starts.

[0201] Patients are monitored regularly for safety and efficacy throughout the study. [0202] 1. Routine laboratory tests (serum chemistry; hematology) for screening are performed within 10 days of first dose of study treatment. [0203] 2. The mandatory Safety Follow-Up Visit is conducted approximately 30 days after the last dose of study intervention or before the initiation of a new anti-cancer treatment, whichever comes first.

[0204] 3. Written consent is obtained prior to performing any protocol specific procedure. Results of a test performed as part of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to Cycle 1, Day 1).

[0205] 4. Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment, and best response to prior systemic treatments. Date of last prior cancer treatment is documented. Radiographic studies performed prior to study entry are collected for review by the investigator. Report complete medication history for 30 days prior to the screening visit (Visit 1).

[0206] 5. Adverse experiences and laboratory safety measurements are graded per NCI CTCAE Version 5.0. All adverse experiences, whether gradable by CTCAE or not, are evaluated for seriousness.

[0207] 6. Vital signs to include temperature, pulse, respiratory rate, and blood pressure; height required only at screening.

[0208] 7. For women of reproductive potential, a urine pregnancy test are performed within 72 hours of the first dose. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test is required. Pregnancy testing is obtained q3m on study and at discontinuation. [0209] 8. Routine laboratory tests (e.g., CBC with differential; comprehensive serum chemistry panel) are performed by the local study site laboratory or contract laboratory. [0210] 9. Up to 10 mL of blood for research to be collected at indicated time points.

[0211] 10. Tumor imaging is performed within 30 days prior to first dose of study treatment. CT scans are the required modality for measurable disease unless a patient has a clinical condition e.g., severe contrast allergy, or the lesions are significantly better visualized through the use of an MRI. The same imaging technique is used in a patient throughout the study. Patients with an objective response have repeat imaging at least 4 weeks later to confirm the objective response. In addition, patients with progressive disease undergo a second scan at least 4 weeks later to confirm progression and exclude the possibility of a tumor flare reaction, according to iRECIST guidelines . Response status is assessed by the investigator. Tumor imaging is performed every 8 weeks starting at Week 8 through Week 24. Following Week 24, tumor imaging is performed approximately every 12 weeks (or whenever clinically indicated) while the patient remains on study therapy at the discretion of the investigator (Weeks 36, 48). Timing of imaging scans follows the calendar and not be adjusted for treatment delays.

[0212] 11. Rigosertib oral tablets scheduled for administration twice daily on Days 1-21 of 28-day cycles (3 weeks-on, 1 week-off) in a fasting state. The first daily dose is taken on an empty stomach after an overnight fast, and patients wait 1 hour after dosing to eat breakfast. The second daily rigosertib dose is administered at approximately 3pm (+/- 1 hour), at least 2 hours after lunch, on an empty stomach, and patients wait at least 1 hour before next meal.

[0213] 12. Trametinib scheduled as a 2 mg/day administered orally. There are no restrictions regarding the sequential dosing of rigosertib and trametinib, though rigosertib is taken in a fasting state as described in (11).

[0214] * On-treatment biopsy is required for at least 10 patients on study, including 5 patients in the Stage 1. Preference for on-treatment biopsy is given to those patients whose tumor is easily accessible (e.g., cutaneous lesion, subcutaneous nodules). A maximum of three biopsies per patient are obtained.

[0215] 13. Vital signs, labs, ECOG PS are evaluated every 2 weeks through week 14, then move to every 6 weeks with trametinib dosing. Patients who are having treatment related toxi cities or complications are seen more frequently as per protocol.

[0216] 2.0 OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S)

[0217] 2.1 Primary Objective(s), Hypothesis(es), and Endpoint(s)

[0218] Objective: To determine the efficacy of rigosertib plus trametinib in patients with a refractory metastatic melanoma.

[0219] Hypothesis: Response rate to rigosertib plus trametinib in patients with a refractory metastatic melanoma is at least 30%.

[0220] Primary Endpoint: Overall response rate (ORR)

[0221] 2.2 Secondary Objective(s), Hypothesis(es), and Endpoint(s)

[0222] Objective:

[0223] 1. To evaluate progression-free survival (PFS) in patients with refractory metastatic melanoma receiving rigosertib plus trametinib.

[0224] 2. To evaluate safety, tolerability and adverse event profile of rigosertib plus trametinib in patients with refractory metastatic melanoma.

[0225] 3. To evaluate overall survival (OS) in patients with refractory metastatic melanoma receiving rigosertib plus trametinib.

[0226] Secondary Endpoint: [0227] 1. Progression-free survival.

[0228] 2. Rate of any-grade toxicity.

[0229] 3. Overall Survival.

[0230] 2.3 Exploratory Objective(s)

Objective: To evaluate change in tumor-infiltrating lymphocytes (TILs) upon treatment with rigosertib plus trametinib in patients with refractory metastatic melanoma.

[0231] 3.0 BACKGROUND & RATIONALE

[0232] 3.1 Background

[0233] Rigosertib sodium (ON O191O.Na) is the sodium salt of (E)-2,4,6-trimethoxysteyryl- 3 -carboxymethylamino-4-m ethoxybenzyl sulfone, a member of the broader class of styrylbenzyl sulfones.

[0234] Trametinib is a potent a kinase inhibitor. Trametinib is a MEK inhibitor approved both as a single agent and in combination with dabrafenib for the treatment of metastatic refractory and/or mutated melanoma. It is a once-daily oral medication that was approved based on progression-free survival and overall survival advantage compared to chemotherapy.

[0235] 3.2 Rationale

[0236] 3.2.1 Dose of Agents

[0237] The dose of rigosertib for this study is 560 mg BID (bis in die, twice a day) on days 1- 21 of a 28-day cycle. For this trial, a PO (per os, by mouth) formulation is used.

[0238] The dose of trametinib for this study is 2 mg/day.

[0239] 3.2.2 Rationale for Endpoints

[0240] 3.2.2.1 Efficacy Endpoints

[0241] The primary endpoint for this study is the overall response rate.

[0242] 3.2.3 Planned Exploratory Biomarker Research

[0243] Blood samples (lOmL each) are collected. Blood is processed to isolate both PBMCs and serum for future biomarker analyses at the conclusion of the study, as to be determined by the Investigator based on the state of knowledge at that time and available molecular analysis platforms. Possible analyses include, but are not limited to, immune cell populations, circulating free DNA (cfDNA), circulating miRNA and protein/cytokine arrays.

[0244] On-treatment biopsies are mandatory for 10 of the 29 patients enrolled, including 5 patients from the stage I of study. On-treatment biopsy is obtained from those patients with accessible tumors (e.g., cutaneous lesions, subcutaneous nodules). On-treatment biopsies are obtained with patient consent. A maximum of three on-treatment biopsies are obtained per individual patient. These samples are interrogated to determine change in T-cell infiltration induced by rigosertib plus trametinib (as compared to archival pre-treatment tumor biopsies). RNA sequencing is performed on biopsy specimens to evaluate T-cell receptor evolution.

[0245] 4.0 METHODOLOGY

[0246] 4.1 Study Population

[0247] 4.1.1 Participant Inclusion Criteria

[0248] Participants are eligible to be included in the study if all of the following criteria apply:

[0249] 1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of unresectable or metastatic cutaneous melanoma are enrolled in this study.

[0250] Male participants:

[0251] A male participant agree to use a contraception during the treatment period and for at least 6 days (140 hours) plus an additional 90 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period.

[0252] Female participants:

[0253] A female participant is eligible to participate if not pregnant, not breastfeeding, and at least one of the following conditions applies:

[0254] a. Not a woman of childbearing potential (WOCBP)

[0255] OR

[0256] b. A WOCBP who agrees to follow the contractive guidance during the treatment period and for at least 6 days (140 hours) plus 120 days after the last treatment dose of study. [0257] 2. Participants whose disease harbors BRAF V600 mutation are exposed to BRAF- targeted therapy, with BRAF-targeted treatment discontinued for either progressive disease or intolerable toxicity.

[0258] 3. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

[0259] 4. Have measurable disease based on iRECIST. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

[0260] 5. Have provided archival tumor tissue sample or newly obtained (within 3 months of enrollment) core or excisional biopsy of a tumor lesion not previously irradiated. Formalin- fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.

[0261] 6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.

[0262] 7. Have adequate organ function as defined in the following table (Table 6).

Laboratory values are collected within 10 days prior to the start of study intervention (i.e., first dose of study treatment).

Table 6 Adequate Organ Function Laboratory Values

[0263] 4.1.2 Participant Exclusion Criteria

[0264] Participants can be excluded from the study if any of the following criteria apply: [0265] 1. Has a diagnosis of primary uveal or mucosal melanoma.

[0266] 2 A WOCBP who has a positive urine pregnancy test within 72 hours of the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) is performed and is negative in order for subject to start receiving study medication.

Pregnancy testing is obtained every three months while on study treatment; patients are withdrawn from the study if pregnancy occurs.

[0267] 3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (for immunotherapeutic agents) or within 2 weeks (for targeted therapeutics) prior to the first dose of study drug. If a subject has experienced adverse event (AE) from prior treatment, he/she has recovered from all AEs to <Grade 1 or baseline. Patients with <Grade 2 neuropathy may be eligible. Patients with endocrine-related AEs <2 requiring treatment or physiologic steroid replacement may be eligible.

[0268] 4. Has received prior radiotherapy within 2 weeks of the first dose of study drug. Participants have recovered from all radiation-related toxicities, do not require corticosteroids, and have not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (<2 weeks of radiotherapy) to non-CNS disease.

[0269] 5. If participant has had recent major surgery, the participant has recovered adequately from the procedure and/or any complications from the surgery prior to the first dose of study drug.

[0270] 6. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.

[0271] 7. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study drug. Participants who have entered the follow-up phase of an investigational study may participate as long as 4 weeks passed since the last dose of the previous investigational agent.

[0272] 8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

[0273] 9. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Participants with non-melanoma skin cancer (e.g., basal cell carcinoma of the skin, squamous cell carcinoma of the skin) or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

[0274] 10. Subjects with untreated active central nervous system (CNS) metastases, active brain metastases or leptomeningeal metastatic foci. For the subjects with brain metastases, if the subjects have received treatment and have no evidence of progressive disease on magnetic resonance imaging (MRI) at least 4 weeks after completion of the treatment and within 30 days prior to the first dose, the subjects are eligible to participate in the study.

[0275] 11. Has a history of severe hypersensitivity (>Grade 3), specifically infusion reaction, or anaphylaxis to trametinib and/or any related excipients.

[0276] 12. Has a history of severe hypersensitivity (>Grade 3 reactions including wheezing, rash, or hypotension) to rigosertib and/or any related excipients (including polyethylene glycol), or anaphylaxis.

[0277] 13. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.

[0278] 14. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

[0279] 15. Has an active infection requiring systemic therapy.

[0280] 16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.

[0281] 17. Has a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). [0282] 18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’ s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

[0283] 19. Has known psychiatric or substance abuse disorders that interfere with cooperation with the requirements of the trial.

[0284] 20. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

[0285] 21. Has had an allogenic tissue/solid organ transplant.

[0286] 4.1.3 Lifestyle Considerations

[0287] 4.1.3.1 Meals and Dietary Restrictions

[0288] Participants maintain a normal diet unless modifications are required to manage an AE such as diarrhea, nausea or vomiting. Participants ensure hydration status with at least 2 liters of oral fluid intake per day to minimize risk of urinary toxicity from rigosertib.

Rigosertib should be administered in the fasting state between meals (i.e., at least two hours after meals and one hour before next meal).

[0289] 4.2 Trial Intervention(s)

[0290] The intervention(s) used in this trial is outlined below in Table 7:

Table 7 Trial Intervention(s)

[0291] Trial interventions begin as close as possible to the date on which study eligibility is confirmed by the Coordinating Center.

[0292] 4.2.1 Timing of Dose Administration

[0293] Trial interventions are administered on Day 1 of each cycle after all procedures/assessments have been completed. Trial interventions are administered up to 2 days before or after the scheduled Day 1 of each cycle due to administrative reasons.

[0294] All trial interventions are administered on an outpatient basis. [0295] Rigosertib is administered as 560 mg (2x 280 mg tablets) taken twice daily (1,120 mg total daily dose) on days 1-21 on a 28-day cycle. Rigosertib is taken in a fasting state twice daily as follows:

• Patients are instructed to take a morning dose after an overnight fast, on an empty stomach, and wait 1 hr after dosing to have breakfast.

• The afternoon dose is taken at approximately 3 PM (±1 hr) at least 2 hours after lunch, on an empty stomach, and patients wait 1 hr before the next meal.

[0296] Water is permitted during the fasting period. Any vomited dose is reported as a missed dose. Good hydration (i.e., at least 2 liters of water per day) is recommended for all patients.

[0297] All study drug is maintained in the original container and brought to all clinic appointments for usage review by study administrator.

[0298] Trametinib is administered as 2 mg (lx 2 mg tablet) taken once daily (2 mg total daily dose) on days 1-21 on a 28 day cycle.

[0299] 4.2.2 Dose Modification and toxicity management for immune-related AEs associated with trametinib and AEs associated with rigosertib therapy

[0300] 4.2.2.1 Trametinib Toxicity and Management

[0301] AEs associated with trametinib exposure, including coadministration with additional compounds, represent an immunologic etiology. These immune-related AEs (irAEs) occur shortly after the first dose or several months after the last dose of trametinib/combination treatment and often affect more than one body system simultaneously. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy are included as part of the evaluation. Dose modification and toxicity management guidelines for irAEs associated with trametinib/combination treatment are provided in Table 8.

Table 8 Dose modification and toxicity management guidelines for AEs (immune and non-immune) associated with trametinib monotherapy and immune-oncology (IO) combinations

[0302] Infusion reactions related to trametinib

Trametinib may cause severe or life-threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose modification and toxicity management guidelines on trametinib associated infusion reaction are provided in Table 9.

Table 9 Trametinib Reaction Dose modification and Treatment Guidelines

Table 10 Adverse Events associated with oral rigosertib

[0303] 4.2.2.1.1 Rigosertib Dose Modification

[0304] Dose reduction in rigosertib is allowed. Stage 1 of the Simon Two-Stage design allows for a Lead-in Phase to assess for treatment-related toxicity. During the Lead-in phase, 6 patients are enrolled, evaluated for toxicity prior to initiation of cycle 2 (C1D2 of 28-day cycle) based on laboratory studies. Toxicity assessment includes blood and urine tests, including CBC, CMP, magnesium, phosphorus, and urinalysis. Table 10 provides adverse events associated with oral rigosertib.

[0305] Dose-limiting toxi cities (DLTs) are defined as the following:

• Grade 3-4 febrile neutropenia

• Grade 4 neutropenia lasting longer than 5 days

• Grade 4 thrombocytopenia

• Grade 3 thrombocytopenia with bleeding

• ALT/AST > 3xULN with bilirubin >2xULN without another explanation (e.g., cholestasis)

• Grade 4 nausea/vomiting/diarrhea of any duration

• Grade > 3 non-hematologic toxicity with the following exceptions: o Grade 3 nausea managed with maximal medical therapy that has persisted < 72 hours o Grade 3 vomiting and/or diarrhea managed with maximal medical therapy that has persisted < 72 hours o Grade 3 fatigue < 7 days

• Any toxicity that delays administration of rigosertib for more than 2 weeks

• Any toxicity that results in a patient receiving < 80% of the anticipated dose in the first 28-day cycle (DLT observation period)

[0306] If treatment-related toxicity (as defined above) is observed, rigosertib is held for up to 4 weeks until toxicity resolved to < Grade 1, then rigosertib is resumed at reduced dosage. Two dose reductions are permitted on study for the individual patient: first dose reduction to 560 mg AM / 280 mg PM, and second dose reduction to 280mg BID. Re-assessment of toxicity occurs to ensure that toxicity has improved to < Grade 1 prior to rigosertib resumption, and after an additional 28-day cycle of treatment following dose reduction. If AE resolves to G1 or baseline at the reduced level, and no additional toxi cities are seen at the reduced dose, the dose of rigosertib is increased in a step-wise manner (i.e., second dose reduction [280mg BID] increased to first dose reduction [560 mg AM/280 mg PM], or first dose reduction [560 mg AM/280 mg PM] increased to full starting dose [560 mg BID], Table 11). If toxicity persists as G2, rigosertib is continued at reduced dose. If toxicity persists for greater than four weeks as G>3, rigosertib is withheld. If G4 toxicity is observed, rigosertib is permanently discontinued, except for G4 neutropenia, thrombocytopenia, nausea/vomiting, and diarrhea.

Table 11

[0307] 4.3 Randomization or Treatment Allocation

[0308] All patients are scheduled to receive rigosertib 560 mg BID on day 1-21 of a 28 day cycle plus trametinib 2mg on day 1-21 of a 28 day cycle. There is no randomization in this study.

[0309] 4.4 Stratification

[0310] No treatment stratification is performed.

[0311] 4.4.1 Prohibited Concomitant Medications [0312] Participants are prohibited from receiving the following therapies during the Screening and Treatment Phase of this trial:

• Antineoplastic systemic chemotherapy or biological therapy

• Immunotherapy not specified in this protocol

• Chemotherapy not specified in this protocol

• Investigational agents other than rigosertib and trametinib

• Radiation therapy

• Live vaccines within 30 days prior to the first dose of study treatment and while participating in the study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection can be generally killed virus vaccines and can be allowed, as are mRNA such as the COVID-19 vaccines. However, intranasal influenza vaccines (e.g., FluMist®) can be live attenuated vaccines and are not allowed.

• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.

• Participants who, in the assessment by the investigator, require the use of any of the aforementioned treatments for clinical management are removed from the study. All treatments that the Investigator considers necessary for a participant’s welfare can be administered at the discretion of the Investigator in keeping with the community standards of medical care.

[0313] There are no prohibited therapies during the Post-Treatment Follow-up Phase.

[0314] Completion of intervention therapy includes 18 treatments of trametinib Q6W plus 24 twenty-eight day cycles of rigosertib (approximately 2 years). Discontinuation of treatment is considered for participants who have attained a confirmed complete response (CR) and have been treated for at least 24 weeks (4 Q6W cycles of trametinib plus 6 twenty-eight day cycles of rigosertib) and have been treated for at least two 28-day cycles of rigosertib plus at least one doses of trametinib beyond the date when the initial CR was declared.

[0315] 4.4.2 Tumor Imaging and Assessment of Disease

[0316] Tumor imaging is acquired by computed tomography (CT). For the abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) is used when CT with iodinated contrast is contraindicated, or when local practice mandates. MRI is the modality for imaging the brain. The same imaging technique regarding modality and the use of contrast are used in a participant throughout the study to optimize the reproducibility of the assessment of existing and new tumor burden and improve the accuracy of the assessment of response or progression based on imaging. Imaging includes chest, abdomen and pelvis.

[0317] Expedited confirmation of measurable disease based on RECIST 1.1 at screening is used to determine participant eligibility. Confirmation that the participant’s imaging shows at least 1 lesion that is appropriate for selection as a target lesion per RECIST 1.1 is done prior to screening for the study.

[0318] 4.4.2.1 Initial Tumor Imaging

[0319] Initial tumor imaging at Screening is performed within 30 days prior to first dose of study treatment. The site study team reviews screening images to confirm that the participant has measurable disease and confirms patient’s status as refractory per iRECIST.

[0320] Brain imaging, if performed to document the stability of existing metastases, is by MRI if possible. If MRI is medically contraindicated, CT with contrast is an acceptable alternative.

[0321] 4.4.2.1.2 Tumor Imaging During the Study

[0322] The first on-study imaging assessment is performed 8 weeks (56 days ±7 days]) after the first dose of rigosertib or trametinib (whichever is administered first). Subsequent tumor imaging is performed every 8 weeks (56 days ±7 days) after the previous imaging or more frequently if clinically indicated. After 24 weeks (168 days ±7 days) since first dose of study treatment, participants who remain on treatment have imaging performed every 12 weeks (84 days ±7 days). Imaging timing follows calendar days and is not adjusted for delays in cycle starts. Imaging continues to be performed until disease progression is identified by the Investigator.

[0323] Objective response is confirmed by a repeat imaging assessment. Tumor imaging to confirm partial response (PR) or complete response (CR) is performed at least 4 weeks after the first indication of a response is observed. Participants then return to regular scheduled imaging every 8 weeks (or 12 weeks as outlined above), starting with the next scheduled imaging time point. Participants who receive additional imaging for confirmation do not need to undergo the next scheduled tumor imaging if less than 4 weeks later; tumor imaging resumes at the subsequent scheduled imaging time point.

[0324] Per iRECIST (Section 6.1.4.5), disease progression is confirmed by the site 4 to

8 weeks after first radiologic evidence of PD in clinically stable participants. Participants who have unconfirmed disease progression continue on treatment at the discretion of the investigator until progression is confirmed by the site. Participants who receive confirmatory imaging do not need to undergo the next scheduled tumor imaging if less than 4 weeks later; tumor imaging resumes at the subsequent scheduled imaging time point, if clinically stable. Participants who have confirmed disease progression by iRECIST, as assessed by the site, discontinue study treatment.

[0325] 4.4.2.1.3 End of Treatment and Follow-up Tumor Imaging

[0326] In participants who discontinue study treatment, tumor imaging is performed at the time of treatment discontinuation (±4 week window). If previous imaging is obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not mandatory. In participants who discontinue study treatment due to documented disease progression and the investigator elects not to implement iRECIST, this is the final required tumor imaging.

[0327] For participants who discontinue study treatment without documented disease progression, every reasonable effort is made to continue monitoring disease status by tumor imaging using the same imaging schedule used while on treatment to monitor disease status until the start of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first.

[0328] 4.4.3 iRECIST 1.1 Assessment of Disease

[0329] iRECIST 1.1 is used as the initial measure for assessment of tumor response, date of disease progression, and as a basis for all protocol guidelines related to disease status (e.g., discontinuation of study treatment). Although iRECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.

[0330] 4.4.3.1 iRECIST Assessment of Disease

[0331] iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen with immunotherapeutic drugs. iRECIST is used by the investigator to assess tumor response and progression and make treatment decisions. When clinically stable, participants are not discontinued until progression is confirmed by the investigator, working with local radiology. This allowance to continue treatment despite initial radiologic disease progression takes into account the observation that some participants can have a transient tumor flare in the first few months after the start of immunotherapy, and then experience subsequent disease response. These data are captured in the clinical database.

[0332] Clinical stability is defined as the following: Absence of symptoms and signs indicating clinically significant progression of disease

• No decline in ECOG performance status

• No requirements for intensified management, including increased analgesia, radiation, or other palliative care

[0333] Any participant deemed clinically unstable is discontinued from study intervention at first radiologic evidence of disease progression, and is not required to have repeat tumor imaging for confirmation of disease progression by iRECIST.

[0334] If the investigator decides to continue treatment, the participant continues to receive study intervention and the tumor assessment is repeated 4 to 8 weeks later to confirm disease progression by iRECIST, per investigator assessment.

[0335] If repeat imaging does not confirm disease progression per iRECIST, as assessed by the investigator, and the participant continues to be clinically stable, study intervention continues and follows the regular imaging schedule. If disease progression is confirmed, participants are discontinued from study intervention.

[0336] If a participant has confirmed radiographic progression (iCPD), study intervention is discontinued; however, if the participant is achieving a clinically meaningful benefit, an exception to continue study intervention is considered following consultation with the Sponsor. In this case, if study intervention is continued, tumor imaging continues to be performed following the intervals.

Table 12 Imaging and Treatment After First Radiologic Evidence of Progressive Disease

[0337] 4.4.4 Tumor Tissue Collection and Correlative Studies Blood Sampling

[0338] Blood samples (lOmL) are collected from all patients. Blood is processed to isolate both PBMCs and serum for biomarker analyses at the conclusion of the study. Analyses include, but are not limited to, immune cell populations, circulating free DNA (cfDNA), circulating miRNA and protein/cytokine arrays.

[0339] Upon collection, blood is maintained at room temperature for up to two hours before delivered to the Biospecimen Core for processing. Blood is processed using standard Ficoll extraction for isolation of peripheral blood mononuclear cells (PBMCs) and serum. Briefly, blood is decanted into a large 50 mL conical tube and diluted 1 : 1 with phosphate buffered saline. Ficoll is layered at the bottom of the conical, then spun at 2000 rpm for 30 minutes with no brake deceleration. After centrifugation, serum is aliquoted in ImL amounts to labeled cryovials. Labels include patient identifier, date of collection, study date, and series/number of tube per sample.

[0340] Buffy coat is carefully aspirated into new tube, then spun at 2000 rpm for 2 minutes. After disposal of supernatant, PBMC pellet is washed in PBS twice and counted using standard hemocytometer. PBMCs are suspended in fetal bovine serum (FBS) containing 10% DMSO, then aliquoted into labeled cryovials with a maximum of 1 million cells per tube. Labels include patient identifier, date of collection, study date, and series/number of tube per sample.

[0341] Both serum and PBMCs are slow-frozen in ethanol before long-term storage in liquid nitrogen in secured freezers. Banked serum is used to perform cytokine array upon completion of collection. PBMCs are used to perform bulk RNA sequencing for T-cell receptor (TCR) interrogation as well as fluorescence automated cell cytometry to characterize changes to peripheral immune milieu upon study treatment.

[0342] Preference for on-treatment biopsy is given to those patients whose tumor is easily accessible (i.e., cutaneous lesions, subcutaneous nodules). A maximum of three on-treatment biopsies are obtained per patient. These samples are interrogated to determine change in T- cell infiltration induced by rigosertib plus trametinib (as compared to archival pre-treatment tumor biopsies). RNA sequencing is performed on biopsy specimens to evaluate T-cell receptor evolution.

[0343] The first on-treatment biopsy specimen (week 8) is prioritized for FACS analysis. Depending on biopsy specimen size, 50 mm3 tissue specimen (approximately 1 million cells) are reserved for tumor digestion in anticipation of surface and intracellular staining. Remaining tissue, if available, is frozen in RNALater for RNA sequencing and/or formalin fixed and paraffin embedded in anticipation of immunohistochemical staining.

[0344] Pre-treatment biopsy and, if available, second on-treatment biopsy (week 16) is divided, with half of the biopsy specimen frozen in RNALater for RNA sequencing, and half of the specimen used fresh for development of tumor organoids using existing Richmond laboratory protocols.

[0345] 4.4.5 Post-Treatment Visits

[0346] 4.4.5.1 Safety Follow-Up Visit

[0347] The Safety Follow-Up Visit is conducted approximately 30 days after the last dose of study intervention or before the initiation of a new anti-cancer treatment, whichever comes first.

[0348] 4.4.5.2 Efficacy Follow-up Visits

[0349] Participants who complete the protocol-required cycles of study intervention or who discontinue study intervention for a reason other than disease progression begin the Efficacy Follow-Up Phase and are assessed every 8 weeks (56 ± 7 days) by radiologic imaging to monitor disease status. After 6 months, the imaging time point occurs every 12 weeks (± 7 days). Information is collected regarding disease status until the start of new anti-cancer therapy, disease progression, death, or end of the study. Information regarding post-study anti-cancer treatment is collected if new treatment is initiated. Participants who completed all efficacy assessments do not have further efficacy assessments and enter the Survival Followup Phase.

[0350] 4.4.5.3 Survival Follow-up Contacts [0351] Participant survival follow-up status are assessed approximately every 12 weeks to assess for survival status until death, withdrawal of consent, three years follow-up, or the end of the study, whichever occurs first.

[0352] All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but before first dose of protocol-indicated treatment are reported, including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.

• All AEs from the time of initiation of rigosertib or trametinib (whichever dose occurs first) through 30 days following patient’s final dose of rigosertib or trametinib (whichever dose occurs last) are reported by the investigator.

• All AEs meeting serious criteria from the time of initiation of rigosertib or trametinib (whichever dose occurs first) through 90 days following patient’s final study- indicated treatment with rigosertib or trametinib (whichever dose occurs last), or through 30 days following last dose of study treatment if the participant initiates new anticancer therapy, are reported by the investigator.

[0353] 5.0 STATISTICAL ANALYSIS PLAN

[0354] 5.1 Baseline Characteristics and Other Analyses

[0355] Each relevant clinical characteristic is recorded by the use of tables and/or graphs. No statistical hypothesis tests are performed on these characteristics. The number and percentage of patients treated, and the primary reason for discontinuation are displayed. Demographic variables (such as age) and baseline characteristics are summarized by descriptive statistics.

[0356] Drug accountability data for trametinib and rigosertib are collected during the study. Compliance with trametinib administration is measured by patients: 1) receiving unscheduled study agent; 2) missing a dose. Numbers and percentages of patients and infusion/inj ection visits with any deviation in these measures is reported. Compliance with rigosertib is measured by: 1) pill counts performed to document usage; 2) monitoring of patient-specific home administration log. Number and percentages of patients and rigosertib drug cycles with any deviations are reported.

[0357] 5.2 Efficacy

Endpoints

[0358] 5.2.1 Endpoint [0359] 5.2.2 Objective response rate (ORR) as defined by immune-related response criteria is the primary endpoint of the study.

[0360] Secondary Endpoints

[0361] 5.2.2.1 Progression Free Survival

[0362] Progression-free survival (PFS) is the time from the first dose of trametinib to progression as defined by iRECIST criteria or death for any reason, whichever comes first. PFS is summarized in the method of Kaplan and Meier. Median PFS and PFS at one year is reported with 95% confidence intervals. PFS analysis based on investigator’s assessment using irRC is carried out.

[0363] Since disease progression is assessed periodically, progressive disease (PD) can occur any time in the time interval between the last assessment where PD was not documented and the assessment when PD is documented.

[0364] 6.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES

[0365] 6.1 Investigational Product

Table 13 Product Descriptions

[0366] 6.2 Packaging and Handling Information

[0367] 6.2.1 Trametinib

[0368] Each site is provided trametinib.

[0369] Trametinib is available in a single-dose vial as a clear to slightly opalescent, colorless to slightly yellow solution (100 mg/4 mL = 25 mg/mL).

[0370] Trametinib product does not contain a preservative. After preparation, the diluted solution from the trametinib 100 mg/4 mL vial is stored either:

• At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion. • Under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for no more than 96 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not shake.

[0371] Discard after 6 hours at room temperature or after 96 hours under refrigeration.

[0372] Do not freeze.

[0373] 6.2.2 Rigosertib

[0374] Rigosertib is supplied as soft gelatin capsules 280 mg/mL suspension of rigosertib in PEG 400 and PEG 4000. The 280 mg capsules are of an opaque yellow-orange color.

• Vials of concentrate 75 mg/mL and oral soft gelatin capsules of rigosertib are stored under refrigeration (2 °C to 8 °C) and protected from light.

[0375] 6.3 Clinical Supplies Disclosure

[0376] This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text.

[0377] 6.4 Storage and Handling Requirements

[0378] Clinical supplies are stored in a secure, limited-access location under the storage conditions specified on the label.

[0379] Receipt and dispensing of trial medication are recorded by an authorized person at the trial site.

[0380] Clinical supplies are not be used for any purpose other than that stated in the protocol. [0381] 6.5 Returns and Reconciliation

[0382] A record of the number of rigosertib capsules dispensed to and taken by each subject is maintained and reconciled with study treatment and compliance records. Treatment start and stop dates, including dates for treatment delay are recorded.

[0383] Appendix 1 : Clinical Laboratory Tests

• The tests detailed in Table 14 are performed by the local laboratory.

• Additional tests are performed at any time during the study as determined necessary by the investigator or required by local regulations.

Table 14 Protocol-required Safety Laboratory Assessments

[0384] Appendix 2: Description of the RECIST Process for Assessment of Disease Progression

[0385] Assessment at Screening and Prior to iRECIST Progression

[0386] Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment.

[0387] Assessment and Decision at PECIST 1.1 Progression

[0388] In participants who show evidence of radiological progressive disease (PD) by RECIST 1.1 the Investigator decides whether to continue a participant on study treatment until repeat imaging 4 to 8 weeks later is obtained (using iRECIST for participant management). This decision by the Investigator is based on the participant’s overall clinical condition.

[0389] Clinical stability can be defined as the following:

• Absence of symptoms and signs indicating clinically significant progression of disease

• No decline in ECOG performance status • No requirements for intensified management, including increased analgesia, radiation, or other palliative care

[0390] Any participant deemed clinically unstable is discontinued from study treatment at site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging for confirmation of PD by iRECIST.

[0391] If the Investigator decides to continue treatment, the participant continues to receive study treatment and the tumor assessment is repeated 4 to 8 weeks later to confirm PD by iRECIST, per Investigator assessment.

[0392] Tumor flare manifests as any factor causing radiographic progression per RECIST 1.1, including:

• Increase in the sum of diameters of target lesion(s) identified at baseline to > 20% and > 5 mm from nadir

• Unequivocal progression of non-target lesion(s) identified at baseline

• Development of new lesion(s)

[0393] iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first visit showing progression according to RECIST 1.1 is assigned a visit (overall) response of iUPD, regardless of which factors caused the progression.

[0394] New lesions are classified as measurable or non-measurable, using the same size thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up to 5 lesions total (up to 2 per organ), are selected as New Lesions - Target. The sum of diameters of these lesions is calculated and kept distinct from the sum of diameters for target lesions at baseline. All other new lesions are followed qualitatively as New Lesions - Non-target.

[0395] Assessment at the Confirmatory Imaging

[0396] On the confirmatory imaging, the participant is classified as progression confirmed (with an overall response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). [0397] Confirmation of Progression

[0398] Progression is considered confirmed, and the overall response is iCPD, if any of the following occurs:

• Any of the factors that are the basis for the initial iUPD show worsening o For target lesions, worsening is a further increase in the sum of diameters of

> 5 mm, compared to any prior iUPD time point o For non-target lesions, worsening is any significant growth in lesions overall, compared to a prior iUPD time point; this does not have to meet the unequivocal standard of RECIST 1.1 o For new lesions, worsening is any of these:

■ An increase in the new lesion sum of diameters by > 5 mm from a prior iUPD time point

■ Visible growth of new non-target lesions

■ The appearance of additional new lesions

• Any new factor appears that triggered PD by RECIST 1.1

[0399] Persistent iUPD

[0400] Progression is considered not confirmed, and the overall response remains iUPD, if:

• None of the progression-confirming factors identified above occurs AND

• The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold (by RECIST 1.1)

[0401] Additional imaging for confirmation is scheduled 4 to 8 weeks from the scan on which iUPD is seen. The assessment of the subsequent confirmation scan proceeds in an identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.

[0402] Resolution of iUPD

[0403] Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

• None of the progression-confirming factors identified above occurs, AND

• The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.

[0404] The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR if all lesions resolve.

EMBODIMENTS

[0405] The following non-limiting embodiments provide illustrative examples of the disclosure, but do not limit the scope of the disclosure.

[0406] Embodiment 1. A method of treating a condition comprising administering to a subject in need thereof: a) a therapeutically-effective amount of a compound of the formula:

C(O)R^X, -C(O)OR^X, -C(O)NR^xR^y, -OR^X, -SR^X, -NR^xR^y, -NR^xC(O)R^y, -OC(O)R^X, or - SiR^xR^yR^z, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and each R^x, R^y, and R^z is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and b) a therapeutically-effective amount of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor selected from MEK inhibitor or an BRAF inhibitor. [0407] Embodiment 2. The method of embodiment 1, wherein the condition is a cancer. [0408] Embodiment 3. The method of embodiment 2, wherein the cancer comprises a KRAS mutation.

[0409] Embodiment 4. The method of embodiment 3, wherein the KRAS mutation is G12V. [0410] Embodiment 5. The method of embodiment 3, wherein the KRAS mutation is G12D. [0411] Embodiment 6. The method of embodiment 3, wherein the KRAS mutation is G12C. [0412] Embodiment 7. The method of embodiment 3, wherein the KRAS mutation is I46T.

[0413] Embodiment 8. The method of embodiment 2, wherein the cancer does not comprise a G12C KRAS mutation.

[0414] Embodiment 9. The method of any one of embodiments 1-8, wherein the condition is a BRAF positive cancer, e.g., a cancer selected from melanoma, hairy cell leukemia, nonHodgkin lymphoma, thyroid cancer, ovarian cancer, lung adenocarcinoma, colorectal cancer, brain cancer.

[0415] Embodiment 10. The method of any one of embodiments 1-8, wherein the condition is a melanoma, e.g., an advanced melanoma, e.g., an unresectable or metastatic refractory melanoma, e.g., a BRAFV600-mutant metastatic melanoma, e.g., a BRAFV600E/K mutant metastatic melanoma.

[0416] Embodiment 11. The method of any one of embodiments 1-10, wherein the administering the compound is intravenous.

[0417] Embodiment 12. The method of any one of embodiments 1-10, wherein the administering the compound is oral.

[0418] Embodiment 13. The method of any one of embodiments 1-12, wherein the therapeutically-effective amount of the compound is from about 100 mg to about 3,000 mg. [0419] Embodiment 14. The method of any one of embodiments 1-12, wherein the therapeutically-effective amount of the compound is at least about 560 mg.

[0420] Embodiment 15. The method of any one of embodiments 1-12, wherein the therapeutically-effective amount of the compound is at least about 840 mg.

[0421] Embodiment 16. The method of any one of embodiments 1-12, wherein the therapeutically-effective amount of the compound is at least about 1,120 mg.

[0422] Embodiment 17. The method of any one of embodiments 1-12, wherein the therapeutically-effective amount of the compound is at least about 1,200 mg.

[0423] Embodiment 18. The method of any one of embodiments 1-12, wherein the therapeutically-effective amount of the compound is at least about 1,500 mg.

[0424] Embodiment 19. The method of any one of embodiments 1-12, wherein the therapeutically-effective amount of the compound is at least about 1,800 mg.

[0425] Embodiment 20. The method of any one of embodiments 1-19, wherein the compound is administered once a day.

[0426] Embodiment 21. The method of any one of embodiments 1-19, wherein the compound is administered twice a day.

[0427] Embodiment 22. The method of any one of embodiments 1-19 or 21, wherein a first therapeutically-effective amount of the compound is administered to the subject in a morning of a day, and a second therapeutically-effective amount of the compound is administered to the subject in an afternoon of the day.

[0428] Embodiment 23. The method of any one of embodiments 1-19 or 21, wherein a first therapeutically-effective amount of the compound is administered to the subject in a morning of a day, and a second therapeutically-effective amount of the compound is administered to the subject in an evening of the day.

-I l l- [0429] Embodiment 24. The method of embodiment 22 or 23, wherein the first therapeutically-effective amount and the second therapeutically-effective amount are the same.

[0430] Embodiment 25. The method of embodiment 22 or 23, wherein the first therapeutically-effective amount and the second therapeutically-effective amount are different.

[0431] Embodiment 26. The method of embodiment 22 or 23, wherein the first therapeutically-effective amount is greater than the second therapeutically-effective amount. [0432] Embodiment 27. The method of embodiment 22 or 23, wherein the first therapeutically-effective amount is lesser than the second therapeutically-effective amount.

[0433] Embodiment 28. The method of any one of embodiments 1-19, wherein the administering the compound occurs three times a day.

[0434] Embodiment 29. The method of any one of embodiments 1-28, wherein the administering the compound occurs at least an hour before the subject consumes food.

[0435] Embodiment 30. The method of any one of embodiments 1-28, wherein the administering the compound occurs at least hour after the subject consumes food.

[0436] Embodiment 31. The method of any one of embodiments 1-30, wherein the administering the compound occurs at least one hour before the subject consumes a drink. [0437] Embodiment 32. The method of any one of embodiments 1-30, wherein the administering the compound occurs at least one hour after the subject consumes a drink.

[0438] Embodiment 33. The method of any one of embodiments 1-32, wherein each R¹, R³, and R⁵ is independently OR^X.

[0439] Embodiment 34. The method of any one of embodiments 1-33, wherein each R^x is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0440] Embodiment 35. The method of any one of embodiments 1-33, wherein each R^x is independently substituted or unsubstituted Ci-6 alkyl.

[0441] Embodiment 36. The method of any one of embodiments 1-35, wherein each R^x is independently Ci alkyl substituted with hydroxy, sulfhydryl, halogen, an amino group, a nitro group, cyano, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxylic acid, a carboxaldehyde group, alkoxy, aryl, a heterocyclyl group, an acyl group, an amide, or an ester.

[0442] Embodiment 37. The method of any one of embodiments 1-36, wherein each R^x is independently methyl. [0443] Embodiment 38. The method of any one of embodiments 1-37, wherein each R², R⁴, R⁶, R⁹, and R¹⁰ is independently hydrogen.

[0444] Embodiment 39. The method of any one of embodiments 1-38, wherein each R^{l la} and R^{l lb} is independently hydrogen.

[0445] Embodiment 40. The method of any one of embodiments 1-39, wherein each R¹² and R¹³ is independently hydrogen.

[0446] Embodiment 41. The method of any one of embodiments 1-40, wherein the compound has the formula:

wherein: each R^la, R^3a, R^5a, and R^8a is independently substituted or unsubstituted Ci-8 alkyl; and each R¹⁴ and R¹⁵ is independently alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen.

[0447] Embodiment 42. The method of embodiment 41, wherein each R^la, R^3a, R^5a, and R^8a is independently methyl.

[0448] Embodiment 43. The method of embodiment 41, wherein R¹⁴ is hydrogen.

[0449] Embodiment 44. The method of embodiment 41, wherein R¹⁵ is Ci alkyl substituted with hydroxy, sulfhydryl, halogen, an amino group, a nitro group, cyano, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxylic acid, a carboxaldehyde group, alkoxy, aryl, a heterocyclyl group, an acyl group, an amide, or an ester.

[0450] Embodiment 45. The method of embodiment 41, wherein R¹⁵ is CH2COOH.

[0451] Embodiment 46. The method of any one of embodiments 1-45, wherein the compound is ((E)-2-(5-((2,4,6-trimethoxystyryl sulfonyl)methyl)-2- methoxyphenylamino)acetic acid or a pharmaceutically-acceptable salt or zwitterion thereof. [0452] Embodiment 47. The method of any one of embodiments 1-45, wherein the compound is sodium (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2- methoxyphenylamino)acetate.

[0453] Embodiment 48. The method of any one of embodiments 1-47, wherein the second therapeutic agent is a MEK inhibitor. [0454] Embodiment 49. The method of any one of embodiments 1-48, wherein the MEK inhibitor affects the MAPKZERK pathway.

[0455] Embodiment 50. The method of any one of embodiments 1-49, wherein the MEK inhibitor is a MEK1 inhibitor.

[0456] Embodiment 51. The method of any one of embodiments 1-49, wherein the MEK inhibitor is a MEK2 inhibitor.

[0457] Embodiment 52. The method of any one of embodiments 1-49, wherein the MEK inhibitor is selected from is trametinib, selumetinib, cobimetinib, or binimetinib.

[0458] Embodiment 53. The method of any one of embodiments 1-49, wherein the MEK inhibitor is trametinib.

[0459] Embodiment 54. The method of any one of embodiments 1-49, wherein the MEK inhibitor is binimetinib.

[0460] Embodiment 55. The method of any one of embodiments 1-49, wherein the MEK inhibitor is cobimetinib.

[0461] Embodiment 56. The method of any one of embodiments 1-49, wherein the MEK inhibitor is selumetinib.

[0462] Embodiment 57. The method of any one of embodiments 1-47, wherein the method comprises administering a third therapeutic agent wherein the third therapeutic agent is a BRAF inhibitor.

[0463] Embodiment 58. The method of embodiment 57, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, or encorafenib.

[0464] Embodiment 59. The method of embodiment 57, wherein the MEK inhibitor is trametinib and the BRAF inhibitor is dabrafenib.

[0465] Embodiment 60. The method of any one of embodiments 1-59, wherein the administering of the MEK inhibitor occurs on day 1-21 of a 28 day cycle.

[0466] Embodiment 61. The method of any one of the embodiments 1-60, wherein the therapeutically-effective amount of the MEK inhibitor is from about 2 mg.

[0467] Embodiment 62. The method of any one of the embodiments 1-61, wherein the condition is an unresectable refractory melanoma.

[0468] Embodiment 63. The method of any one of the embodiments 1-62, wherein the condition is a BRAF positive cancer.

[0469] Embodiment 64. The method of embodiment 57-63, wherein the BRAF inhibitor is vemurafenib. [0470] Embodiment 65. The method of any one of embodiments 57-63, wherein the BRAF inhibitor is dabrafenib.

[0471] Embodiment 66. The method of any one of embodiments 57-63, wherein the BRAF inhibitor is encorafenib.

[0472] Embodiment 67. The method of any one of embodiments 57-66, wherein the BRAF inhibitor affects intracellular signaling involved in directing cell growth.

[0473] Embodiment 68. The method of any one of the embodiments 57-67, wherein the BRAF inhibitor affects mitogen-activated protein kinase (MAPK) signaling pathway.

[0474] Embodiment 69. The method of any one of embodiments 57-68, wherein the BRAF inhibitor targets BRAF kinase.

[0475] Embodiment 70. The method of any one of the embodiments 1-69, wherein administering of the MEK inhibitor occurs once a day.

[0476] Embodiment 71. The method of any one of the embodiments 1-70, wherein the therapeutically-effective amount of the MEK inhibitor is from about 2 mg.

[0477] Embodiment 72. The method of any one of the embodiments 1-71, wherein the therapeutically-effective amount of the BRAF inhibitor is from about 150 mg.

[0478] Embodiment 73. The method of any one of the embodiments 1-72, wherein the administering of the MEK inhibitor is twice a day.

[0479] Embodiment 74. The method of any one of embodiments 1-73, wherein the administering the MEK inhibitor and/or the BRAF inhibitor is intravenous.

[0480] Embodiment 75. The method of any one of embodiments 1-73, wherein the administering the MEK inhibitor and/or the BRAF inhibitor is oral.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a condition comprising: a) administering to a subject in need thereof a therapeutically-effective amount of a compound of the formula:

C(O)R^X, -C(O)OR^X, -C(O)NR^xR^y, -OR^X, -SR^X, -NR^xR^y, -NR^xC(O)R^y, -OC(O)R^X, or - SiR^xR^yR^z, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and each R^x, R^y, and R^z is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and b) administering to the subject a therapeutically-effective amount of a second therapeutic agent, wherein the second therapeutic agent is an inhibitor selected from a MEK inhibitor or a BRAF inhibitor.

2. The method of claim 1, wherein the condition is a cancer.

3. The method of claim 2, wherein the cancer comprises a KRAS mutation.

4. The method of claim 3, wherein the KRAS mutation is G12V.

5. The method of claim 3, wherein the KRAS mutation is G12D.

6. The method of claim 3, wherein the KRAS mutation is G12C.

7. The method of claim 3, wherein the KRAS mutation is I46T.

8. The method of claim 2, wherein the cancer does not comprise a G12C KRAS mutation.

9. The method of claim 1, wherein the condition is non-small cell lung carcinoma.

10. The method of claim 1, wherein the condition is lung adenocarcinoma.

11. The method of claim 1, wherein the administering the compound is intravenous.

12. The method of claim 1, wherein the administering the compound is oral.

13. The method of claim 1, wherein the therapeutically-effective amount of the compound is from about 100 mg to about 3,000 mg.

14. The method of claim 1, wherein the therapeutically-effective amount of the compound is at least about 560 mg.

15. The method of claim 1, wherein the therapeutically-effective amount of the compound is at least about 840 mg.

16. The method of claim 1, wherein the therapeutically-effective amount of the compound is at least about 1,120 mg.

17. The method of claim 1, wherein the therapeutically-effective amount of the compound is at least about 1,200 mg.

18. The method of claim 1, wherein the therapeutically-effective amount of the compound is at least about 1,500 mg.

19. The method of claim 1, wherein the therapeutically-effective amount of the compound is at least about 1,800 mg.

20. The method of claim 1, wherein the administering of the compound is once a day.

21. The method of claim 1, wherein the administering of the compound is twice a day.

22. The method of claim 1, wherein the administering to the subject in need thereof the therapeutically-effective amount of the compound comprises administering to the subject a first therapeutically-effective amount of the compound in a morning of a day, and administering to the subject a second therapeutically-effective amount of the compound in an afternoon of the day.

23. The method of claim 1, wherein the administering to the subject in need thereof the therapeutically-effective amount of the compound comprises administering to the subject a first therapeutically-effective amount of the compound in a morning of a day, and administering to the subject a second therapeutically-effective amount of the compound in an evening of the day.

24. The method of claim 22 or 23, wherein the first therapeutically-effective amount and the second therapeutically-effective amount are same.

25. The method of claim 22 or 23, wherein the first therapeutically-effective amount and the second therapeutically-effective amount are different.

26. The method of claim 22 or 23, wherein the first therapeutically-effective amount is greater than the second therapeutically-effective amount.

27. The method of claim 22 or 23, wherein the first therapeutically-effective amount is lesser than the second therapeutically-effective amount.

28. The method of claim 1, wherein the administering the compound occurs three times a day.

29. The method of claim 1, wherein the administering the compound occurs at least an hour before the subject consumes food.

30. The method of claim 1, wherein the administering the compound occurs at least hour after the subject consumes food.

31. The method of claim 1, wherein the administering the compound occurs at least one hour before the subject consumes a drink.

32. The method of claim 1, wherein the administering the compound occurs at least one hour after the subject consumes a drink.

33. The method of claim 1, wherein each R¹, R³, and R⁵ is independently OR^X.

34. The method of claim 33, wherein each R^x is independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

35. The method of claim 33, wherein each R^x is independently substituted or unsubstituted Ci-6 alkyl.

36. The method of claim 35, wherein each R^x is independently Ci alkyl substituted with hydroxy, sulfhydryl, halogen, an amino group, a nitro group, cyano, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxylic acid, a carboxaldehyde group, alkoxy, aryl, a heterocyclyl group, an acyl group, an amide, or an ester.

37. The method of claim 33, wherein each R^x is independently methyl.

38. The method of claim 1, wherein each R², R⁴, R⁶, R⁹, and R¹⁰ is independently hydrogen.

39. The method of claim 1, wherein each R^{l la} and R^llb is independently hydrogen.

40. The method of claim 1, wherein each R¹² and R¹³ is independently hydrogen.

41. The method of claim 1, wherein the compound has the formula:

42. The method of claim 41, wherein each R^la, R^3a, R^5a, and R^8a is independently methyl.

43. The method of claim 41, wherein R¹⁴ is hydrogen.

44. The method of claim 41, wherein R¹⁵ is Ci alkyl substituted with hydroxy, sulfhydryl, halogen, an amino group, a nitro group, cyano, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxylic acid, a carboxaldehyde group, alkoxy, aryl, a heterocyclyl group, an acyl group, an amide, or an ester.

45. The method of claim 41, wherein R¹⁵ is CH2COOH.

46. The method of claim 1, wherein the compound is ((E)-2-(5-((2,4,6-trimethoxystyryl sulfonyl)methyl)-2-methoxyphenylamino)acetic acid or a pharmaceutically-acceptable salt or zwitterion thereof.

47. The method of claim 1, wherein the compound is sodium (E)-2-(5 -((2,4,6- trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetate.

48. The method of any one of claims 1-47, wherein the condition is a BRAF positive cancer.

49. The method of any one of claims 1-47, wherein the condition is a melanoma.

50. The method of any one of claims 1-47, wherein the condition is an unresectable melanoma.

51. The method of any one of claims 1-47, wherein the condition is an unresectable refractory melanoma.

52. The method of any one of claims 1-47, wherein the condition is associated with a BRAF mutation.

53. The method of claim 52, wherein the BRAF mutation is BRAF V600E mutation or a BRAF V600K mutation.

54. The method of any one of claims 1-53, wherein the inhibitor is the MEK inhibitor.

55. The method of any one of claims 1-54, wherein the MEK inhibitor is trametinib.

56. The method of any one of claims 1-54, wherein the MEK inhibitor is binimetinib.

57. The method of any one of claims 1-54, wherein the MEK inhibitor is cobimetinib.

58. The method of any one of claims 1-54, wherein the MEK inhibitor is selumetinib.

59. The method of any one of claims 1-58, wherein the therapeutically-effective amount of the MEK inhibitor is about 2 mg.

60. The method of any one of claims 1-59, wherein the administering of the MEK inhibitor occurs once a day.

61. The method of any one of claims 1-60, further comprising administering to the subject a therapeutically-effective amount of a BRAF inhibitor.

62. The method of any one of claims 1-61, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, and encorafenib.

63. The method of claim any one of claims 1-61, wherein the BRAF inhibitor is vemurafenib.

64. The method of claim any one of claims 1-61, wherein the BRAF inhibitor is dabrafenib.

65. The method of claim any one of claims 1-61, wherein the BRAF inhibitor is encorafenib.

66. The method of any of claims 1-65, wherein the therapeutically-effective amount of the BRAF inhibitor is about 150 mg.

67. The method of any of claims 1-66, wherein the administering of the BRAF inhibitor is twice a day.

68. The method of any of claims 1-67, wherein the administering of the MEK inhibitor is oral.

69. The method of any of claims 1-68, wherein the administering of the BRAF inhibitor is oral.