Methods and compositions for treating cancer

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 checkpoint inhibitors to treat cancer.

Description

METHODS AND COMPOSITIONS FOR TREATING CANCERCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Patent Application No. 63 / 425,142, filed November 14, 2022, which is entirely incorporated herein by reference.BACKGROUND

[0002] A large subset of lung adenocarcinomas has a KRAS mutation as the predominant genetic driver. Tumors carrying a mutation in KRAS can have a worse prognosis than KRAS wild-type tumors. Thus, therapies that can target the KRAS pathway could be beneficial for patients with cancers having KRAS mutations.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 INVENTION

[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, Rlla, Rllb, R12, and R13is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -C(O)RX, -C(O)ORX, -C(O)NRxRy, -ORX, -SRX, -NRxRy, -NRxC(O)Ry, -OC(O)RX, or -SiRxRyRz, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and each Rx, Ry, and Rzis independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen or halogen, andb) a therapeutically-effective amount of a checkpoint inhibitor.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] FIG. 1 is a schematic of a dose escalation study of a compound disclosed herein.DETAILED DESCRIPTION OF THE INVENTION

[0006] Ras is the most frequently mutated gene causing cancer. Approximately 40% of patients with non-small cell lung cancer (NSCLC) have a mutation of RAS, most frequently KRAS. A mechanism of action for a compound disclosed herein, for example, rigosertib, is to down- modulate the mutated RAS pathway. This modulation of the RAS pathway can result in less production of ERK, a protein involved in cell proliferation. When ERK is overexpressed, ERK can provide a proliferative advantage to cells, thus leading to cancer. KRAS-mutated NSCLC can be managed with, for example, a checkpoint inhibitor.

[0007] Rigosertib ((E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2- methoxyphenylamino)acetic acid, (E)-2,4,6-trimethoxysteyryl-3-carboxymethylamino-4- methoxybenzyl sulfone, 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 micro-environment (TME) in combination with the checkpoint blockade can facilitate the host immune system to contribute to tumor control. The host lymphocytes can contribute to tumor control when exposed to a checkpoint inhibitor.

[0008] The present disclosure provides a combination of a compound disclosed herein, for example, rigosertib, with a checkpoint inhibitor. A checkpoint inhibitor disclosed herein can be, for example, nivolumab, which blocks PD-1. A checkpoint inhibitor disclosed herein can be, for example, pembrolizumab.

[0009] In some embodiments, rigosertib can cause genitourinary toxicity including dysuria and hematuria. In some embodiments, risk mitigation strategies can minimize these effects.

[0010] In some embodiments, the dose of the combination partner of the checkpoint inhibitor is the dose as per the FDA label. In some embodiments, patient safety requires a deviation from the label dose.Compounds of the disclosure

[0011] In some embodiments, disclosed herein is a compound of the formula:wherein: each R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rlla, Rllb, R12, and R13is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -C(O)RX, -C(O)ORX, -C(O)NRxRy, -ORX, -SRX, -NRxRy, -NRxC(O)Ry, -OC(O)RX, or -SiRxRyRz, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and each Rx, Ry, and Rzis 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.

[0012] In some embodiments, R1, R3, and R5are the same. In some embodiments, R1, R3, R5, and R8are the same. In some embodiments, each R1, R3, and R5is independently ORX. In some embodiments, each R1, R3, R5;and R8is independently ORX. In some embodiments, each Rxis independently alkyl, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each Rxis independently hydrogen. In some embodiments, each Rxis independently unsubstituted Ci-6 alkyl. In some embodiments, each Rxis independently unsubstituted C1.3 alkyl. In some embodiments, each Rxis independently methyl. In some embodiments, each Rxis independently ethyl. In some embodiments, each Rxis independently substituted Ci-6 alkyl. In some embodiments, each Rxis independently substituted C1.3 alkyl. In some embodiments, each Rxis 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.

[0013] In some embodiments, R2is hydrogen. In some embodiments, R4is hydrogen. In some embodiments, R6is hydrogen. In some embodiments, R9is hydrogen. In some embodiments, R10is hydrogen.

[0014] In some embodiments, R7is alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, ORX, or NRxRy. In some embodiments, R7is NRxRy. In some embodiments, Rxis hydrogen. In some embodiments, Ryis hydrogen. In some embodiments, Ryis substituted alkyl. In some embodiments, Ryis substituted Ci-6 alkyl. In some embodiments, Ryis Ci alkyl substituted withhydroxy, 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, RyisCH2COOH.

[0015] In some embodiments, each Rllaand Rllbis independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each Rllaand Rllbis independently substituted Ci-6 alkyl. In some embodiments, each Rllaand Rllbis independently unsubstituted Ci-6 alkyl. In some embodiments, each R12and R13is independently alkyl, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each R12and R13is independently substituted Ci-6 alkyl. In some embodiments, each R12and R13is independently unsubstituted Ci-6 alkyl. In some embodiments, Rllais hydrogen. In some embodiments, Rllbis hydrogen. In some embodiments, R12is hydrogen. In some embodiments, R13is hydrogen.

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

[0017] In some embodiments, the compound has the formula:

[0018] In some embodiments, each R1, R3, R5, and R8is independently ORX. In some embodiments, each Rxis independently alkyl, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, each Rxis independently hydrogen. In some embodiments, each Rxis independently unsubstituted Ci-6 alkyl. In some embodiments, each Rxis independently unsubstituted C1.3 alkyl. In some embodiments, each Rxis independently methyl. In some embodiments, each Rxis independently ethyl. In some embodiments, each Rxis independently substituted Ci-6 alkyl. In some embodiments, each Rxisindependently substituted C1.3 alkyl. In some embodiments, each Rxis independently methyl that is substituted.

[0019] In some embodiments, each R14and R15is independently alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen. In some embodiments, R14is H. In some embodiments, R15is H. In some embodiments, R15is substituted alkyl. In some embodiments, R15is substituted Ci-6 alkyl. In some embodiments, R15is substituted Ci alkyl. In some embodiments, R15is CH2COOH.

[0020] In some embodiments, the compound has the formula:

[0021] In some embodiments, each Rla, R3a, R5a, and R8ais the same. In some embodiments, each Rla, R3a, R5a, and R8ais different. In some embodiments, each Rla, R3a, R5a, and R8ais independently substituted or unsubstituted alkyl. In some embodiments, each Rla, R3a, R5a, and R8ais independently substituted or unsubstituted Ci-s alkyl. In some embodiments, each Rla, R3a, R5a, and R8ais independently substituted or unsubstituted C1.3 alkyl. In some embodiments, each Rla, R3a, R5a, and R8ais independently substituted or unsubstituted Ci alkyl. In some embodiments, each Rla, R3a, R5a, and R8ais independently methyl. In some embodiments, each Rla, R3a, R5a, and R8ais independently ethyl.

[0022] In some embodiments, each R14and R15is independently alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen. In some embodiments, R14is H. In some embodiments, R15is H. In some embodiments, R15is substituted alkyl. In some embodiments, R15is substituted Ci-6 alkyl. In some embodiments, R15is substituted Ci alkyl. In some embodiments, R15is CH2COOH.

[0023] In some embodiments, the compound has the formula:

[0024] In some embodiments, each Rla, R3a, R5a, and R8ais independently substituted or unsubstituted alkyl. In some embodiments, each Rla, R3a, R5a, and R8ais independently substituted or unsubstituted Ci-s alkyl. In some embodiments, Rlais Ci-6 alkyl. In some embodiments, R3ais Ci-6 alkyl. In some embodiments, R5ais Ci-6 alkyl. In some embodiments, R8ais Ci-6 alkyl. In some embodiments, Rlais methyl. In some embodiments, R3ais methyl. In some embodiments, R5ais methyl. In some embodiments, R8ais methyl.

[0025] In some embodiments, R15is substituted alkyl. In some embodiments, R15is substituted Ci-6 alkyl. In some embodiments, R15is substituted Ci alkyl. In some embodiments, R15is CH2COOH.

[0026] In some embodiments, disclosed herein is a compound of the formula:(E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid, (E)-2,4,6- trimethoxysteyryl-3-carboxymethylamino-4-m ethoxybenzyl sulfone, or a pharmaceutically- acceptable salt or zwitterion thereof. In some embodiments, the compound issodium (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetate. In some embodiments, the compound is sodium (E)-2,4,6-trimethoxystyryl-3-carboxy- methylamino-4-methoxybenzyl sulfone. In some embodiments, a compound disclosed herein is a sodium salt.

[0027] 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.

[0028] 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, Cn, C12, C13, C14, C15, Ci6, C17, Ci8, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C4i, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. In some embodiments, alkyl or alkylene is Ci-8alkyl or Ci-8alkylene that is substituted or unsubstituted. In some embodiments, alkyl or alkylene is Ci-6 alkyl or Ci-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.

[0029] Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0030] 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, secbutyl, and t-butyl.

[0031] Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2 -hydroxy ethyl, 1,2-difluoroethyl, and 3 -carb oxy propyl.

[0032] 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-l-yl, cyclopentyl, cyclopent-2-en-l-yl, cyclopenta-2,4-dien-l-yl, cyclohexyl, cyclohex-2-en-l-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-3J7-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.

[0033] 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, Cio, Cu, 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-hydroxy-7- methyloct-3 , 5 -dien-2-yl .

[0034] 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, C8, C9, Cio, Cu, 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, Cs8, 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-l-yl.

[0035] 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.

[0036] 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. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

[0037] 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-tert-butylphenyl, 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- methoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,3-difluorophenyl, 3,4- difluorophenyl, 3,5-difluorophenyl, 2,3 -dichlorophenyl, 3, 4-di chlorophenyl, 3,5-dichlorophenyl, 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- di chlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3, 4-di chlorophenyl, 2,3,4- tri chlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5- tri chlorophenyl, 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-tri ethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5- triethylphenyl, 2,4,6-triethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, and 4- isopropylphenyl.

[0038] 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-(7V,7V-dimethylamino)phenyl, 3-(7V-ethylamino)phenyl, 3-(A,A-diethylamino)phenyl, 4-aminophenyl, 4-( V- methylamino)phenyl, 4-(7V,7V-dimethylamino)phenyl, 4-(7V-ethylamino)phenyl, and 4-(N,N- di ethyl amino)pheny 1.

[0039] 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.

[0040] Non-limiting examples of heterocycles include: 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- 1 / / -pyrrol izi nyl , 3a,4,5,6,7,7a-hexahydro-l / 7-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-U / -indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro- IT / -cycloocta[b]pyrrolyl.

[0041] 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, nonlimiting examples of which include: 77 / -purinyl, 97 / -purinyl, 6-amino-9Z7-purinyl, 5H- pyrrolo[3,2-t ]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.

[0042] Any compound herein can be purified. A compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.

[0043] 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.Pharmaceutically acceptable salts

[0044] The method disclosed herein provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts include, for example, acidaddition salts and base-addition salts. The acid that is added to the compound to form an acidaddition 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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, alactate 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

[0049] A pharmaceutical composition of a compound disclosed herein 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, otic, nasal, and topical administration.

[0050] 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.

[0051] 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.

[0052] 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 differentcombinations of active compound doses.

[0053] 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.

[0054] For buccal or sublingual administration, the compositions can be tablets, lozenges, or gels.

[0055] 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.

[0056] 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.

[0057] 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 pharmaceuticalcompounds. 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.

[0058] 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.

[0059] 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 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.

[0060] In practicing a method of treatment or use provided herein, therapeutically-effective amounts of a compound described herein 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.

[0061] 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 modifieddepending upon the route of administration chosen. Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0062] 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.

[0063] Methods for the preparation of compositions comprising a compound described herein include formulating a compound 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.

[0064] 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.

[0065] 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.

[0066] A composition of a compound disclosed herein can be, for example, an immediate releaseform 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.

[0067] The disclosed compositions can optionally comprise from about 0.001% to about 0.005% weight by volume pharmaceutically-acceptable preservatives.

[0068] 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.

[0069] 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.

[0070] 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 Dru Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0071] A method disclosed herein includes, for example, administration of a compound disclosed herein, 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.

[0072] A compound disclosed herein 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.

[0073] 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.

[0074] A method disclosed herein relates to administering the compound disclosed herein or a pharmaceutically-acceptable salt thereof as part of a pharmaceutical composition. In various embodiments, compositions of a compound disclosed herein 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.

[0075] Pharmaceutical formulations can include additional carriers, as well as thickeners, diluents, buffers, preservatives, and surface active agents in addition to a compound disclosed herein. Pharmaceutical formulations can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, and anesthetics.

[0076] 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.

[0077] The compound disclosed herein 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.

[0078] 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.

[0079] 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 about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or 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.

[0080] A compound described herein can be present in a composition in a range of from about 1 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.

[0081] A compound described herein 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 40mg, 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.

[0082] In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound in an amount of from about 25 mg / mL to about 3000 mg / mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound 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 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 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. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound 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.

[0083] In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound in an amount of about 35 mg / mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound in an amount of about 70 mg / mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound in an amount of about 75 mg / mL. In some embodiments, a pharmaceutical composition of the disclosure can comprise a compound in an amount of about 140 mg / mL. In some embodiments, apharmaceutical composition of the disclosure can comprise a compound in an amount of about 280 mg / mL.

[0084] 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. Non-limiting 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.

[0085] Intravenous (IV) Formulation: In some embodiments, a compound 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.

[0086] Oral Capsule Formulation: In some embodiments, a compound 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

[0087] The present disclosure provides a maximally tolerated dose (MTD) of a compound disclosed herein in combination with a checkpoint inhibitor.

[0088] In some embodiments, the individual dose administered to a subject 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.

[0089] 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 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. 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.

[0090] In some embodiments, the individual dose administered to a subject can be in 280 mgincrements. 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 ofabout 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.

[0091] In some embodiments, a compound described herein can be administered to a subject in an amount of about 0.1 mg / 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, the compound disclosed herein 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.

[0092] In some embodiments, dose escalation can be implemented in 70 mg increments to arrive at an effective dose to treat a condition disclosed herein. In some embodiments, a dose disclosed herein with a maximum biological effect can be administered to a subject in need thereof.

[0093] In some embodiments, a compound of the disclosure is administered intravenously. In some embodiments, a compound of the disclosure 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 of the disclosure 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 of the disclosure can be administered for about 21 consecutive days. In some embodiments, a compound of the disclosure can be administered for about 28 consecutive days.

[0094] In some embodiments, a compound of the disclosure 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 of the disclosure can be administered for about 7 consecutive days of a 28-day cycle. In some embodiments, a compound of the disclosure can be administered for about 14 consecutive days of a 28-day cycle. In some embodiments, a compound of the disclosure can be administered for about 21 consecutive days of a 28-day cycle. In some embodiments, a compound of the disclosure can be administered for about 28 consecutive days of a 28-day cycle.

[0095] A compound disclosed herein can be administered via subcutaneous or intravenous injection. 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.

[0096] In some embodiments, a compound of the disclosure can be administered at a dose of 560 mg twice a day. In some embodiments, a compound of the disclosure can be administered at a dose of 840 mg twice a day. In some embodiments, a compound of the disclosure can beadministered at a dose of 1120 mg twice a day. In some embodiments, a compound of the disclosure can be administered at a dose of 1400 mg twice a day. In some embodiments, a compound of the disclosure can be administered at a dose of 1680 mg twice a day. In some embodiments, a compound of the disclosure can be administered at a dose of 1960 mg twice a day. In some embodiments, a compound of the disclosure can be administered at a dose of 2240 mg twice a day. In some embodiments, a compound of the disclosure can be administered at a dose of 2520 mg twice a day. In some embodiments, a compound of the disclosure can be administered at a dose of 2800 mg twice a day. In some embodiments, a compound of the disclosure can be administered at a dose of 3080 mg twice a day.

[0097] In some embodiments, a compound of the disclosure can be administered at a dose of 560 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 840 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 1120 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 1400 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 1680 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 1960 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 2240 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 2520 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 2800 mg split in two doses throughout a day. In some embodiments, a compound of the disclosure can be administered at a dose of 3080 mg split in two doses throughout a day.

[0098] In some embodiments, a compound of the disclosure 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 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, 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.

[0099] In some embodiments, a compound of the disclosure can be administered at a dose of about 800 mg for 2 to 5 days every other week. In some embodiments, a compound of the disclosure can be administered at a dose of from about 650 mg to about 1700 mg for 3 to 6 daysevery other week. In some embodiments, a compound of the disclosure 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 of the disclosure can be administered at a dose of about 1800 mg per day for 3 days every other week. In some embodiments, a compound of the disclosure 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 of the disclosure 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.

[0100] In some embodiments, a compound of the disclosure can be administered at a dose of about 560 mg once in the morning and about 560 mg in the evening daily for 3 weeks, followed by one week off where the compound of the disclosure is not administered. In some embodiments, the compound is administered in a fasting state, about 1-2 hours before or after a meal. In some embodiments, the compound is administered in a fasting state, wherein the first 560 mg dose is administered in the morning after an overnight fast, and the second 560 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach. In some embodiments, the compound is administered in a fasting state, wherein the first 560 mg dose is administered in the morning after an overnight fast, the second 560 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach, and the next meal is consumed at least one hour after administering the second dose.

[0101] In some embodiments, a compound of the disclosure 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 where the compound of the disclosure is not administered. In some embodiments, the compound is administered in a fasting state, about 1-2 hours before or after a meal. In some embodiments, the compound is administered in a fasting state, wherein the first 560 mg dose is administered in the morning after an overnight fast, and the second 280 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach. In some embodiments, the compound is administered in a fasting state, wherein the first 560 mg dose is administered in the morning after an overnight fast, the second 280 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach, and the next meal is consumed at least one hour after administering the second dose.

[0102] 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 a28-day cycle thereafter. In combination with a dose of nivolumab, a 3+3 dose escalation can be incorporated to find the RP2D (recommended phase 2 dose). Dose escalation cohorts can receive the full dose of nivolumab 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.

[0103] In some embodiments, a compound of the disclosure 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 of the disclosure 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.

[0104] 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.

[0105] 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.

[0106] 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).

[0107] 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.Rigosertib

[0108] Rigosertib ((E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2- methoxyphenylamino)acetic acid, (E)-2,4,6-trimethoxysteyryl-3-carboxymethylamino-4-methoxybenzyl sulfone, or a pharmaceutically-acceptable salt or zwitterion thereof) belongs to the class of styrylbenzyl sulfones. Rigosertib has anticancer activity in advanced solid tumors. Rigosertib inhibits kinase pathways involved in cellular processes governing cell cycle control and cancer cell growth and survival. Rigosertib binds directly to the Ras binding domain (RBD) in Ras effector proteins, including Raf and phosphatidyl-inositol 3 kinase (PI3K) kinases. Rigosertib acts as a Ras mimetic disrupting Ras signaling by binding to RBDs. Rigosertib disrupts protein-protein interaction between Ras and associated effector molecules, preventing the activation and transmission of Ras pathway signaling. Blockage of Ras pathway activity is believed to underlie the anti-tumor activity of rigosertib. In addition to directly binding to Ras binding domain, rigosertib activates the c-Jun N-terminal Kinase (JNK) pathway, resulting in the disruption of RAF / RAS activation and downstream signaling pathways, and interacts with protein kinase B (PKB), mitogen-activated proteins (MAPK), and extracellular-signaling regulated kinase (ERK). Rigosertib inhibits the polo-like kinase 1 (PLK1) pathway. Additional anti-tumor effects of rigosertib are due to formation of reactive oxygen species (ROS) resulting in activation of apoptotic pathways in tumor cells and potential microtubule destabilization. Rigosertib treatment induces arrest of cancer cells as the G2-M stage, resulting in increased apoptosis after dispersion of chromosomes in the cytoplasm in vitro. Cancer cells are sensitive to treatment with rigosertib, with observed IC50 values ranging from 50-250 nM in vitro, while noncancer cells have demonstrated resistance to rigosertib with observed IC50 values greater than 10,000 nM in vitro. In non-cancer cells, rigosertib treatment reversibly arrests cell cycle progress at the G1 phase, preventing cells from progressing in the cell cycle. Rigosertib can be administered as a monotherapy for treatment of cancer or in combination with other anti-cancer therapies for the treatment of cancer.

[0109] Rigosertib is available in intravenous and oral formulations. In vivo pharmacokinetic evaluation of rigosertib in mammals, including mice, rats, and dogs, following both intravenous and oral administration indicates that rigosertib accumulates in plasma at concentrations higher than concentrations necessary for anti-tumor activity in vitro. Rigosertib is predominantly eliminated via biliary elimination with minor urinary excretion.

[0110] In some embodiments, rigosertib treatment disrupts Ras signaling in cancer cells by binding to RBDs. In some embodiments, rigosertib treatment inhibits cancer cell growth with an IC50 value for inhibiting cell growth ranging from about 50 nM to about 250 nM. In some embodiments, rigosertib treatment selectively induces mitotic arrest in cancer cells. In some embodiments, rigosertib treatment selectively induced mitotic arrest at the G2-M stage of the cellcycle. In some embodiments, rigosertib treatment reversibly arrests non-cancer cells a the G1 stage of the cell cycle. In some embodiments, rigosertib treatment induces apoptosis in cancer cells. In some embodiments, rigosertib treatment induces the formation of ROS in tumor cells. In some embodiments, rigosertib treatment does not induce resistance in tumor cells. In some embodiments, rigosertib treatment has low bone marrow toxicity. In some embodiments, rigosertib treatment inhibits human hematopoietic tumor cell lines. In some embodiments, rigosertib displays an additive effect when used in combination with other anti-cancer agents. In some embodiments, rigosertib displays a synergistic effect when used in combination with other anti-cancer agents. In some embodiments, rigosertib displays synergism when used in combination with azacytidine. In some embodiments, rigosertib displays potentiating activity when used in combination with oxaliplatin. In some embodiments, rigosertib displays potentiating activity when used in combination with paclitaxel. In some embodiments, rigosertib displays potentiating activity when used in combination with irinotecan. In some embodiments, rigosertib displays potentiating activity when used in combination with vincristine. In some embodiments, rigosertib display a significant protective effect against doxorubicin-induced weight loss, cardiotoxicity, and death. In some embodiments, rigosertib treatment does not result in human-ether-a-go-go related gene (hERG) potassium ion channel activity. In some embodiments, rigosertib treatment does not result in electrocardiogram (ECG) abnormalities. In some embodiments, rigosertib treatment does not result in cardiac adverse effects.

[0111] Rigosertib treatment has been evaluated in subjects with hematologic malignancies, including myelodysplastic syndrome, acute lymphocytic leukemia, acute myeloid leukemia, transformed myeloproliferative neoplasms, chronic lymphocytic leukemia, mantle cell lymphoma, and multiple myeloma. Rigosertib treatment has been evaluated in subjects with pancreatic cancer. Rigosertib treatment has been evaluated in individuals with solid tumors. In some embodiments, treatment with rigosertib results in an overall response rate of at least about 50% in patients with a hematologic malignancy. In some embodiments, treatment with rigosertib results in an overall response rate of at least about 70% in patients with myelodysplastic syndrome. In some embodiments, treatment with rigosertib results in in an overall response rate of about 30% in patients with acute myeloid leukemia. In some embodiments, rigosertib treatment in combination with azacitidine in patients with higher-risk myelodysplastic syndromes results in an overall response rate of about 90%. In some embodiments, rigosertib treatment in combination with azacitidine in patients with higher-risk myelodysplastic syndromes results in a complete response. In some embodiments, rigosertibtreatment results in partial response in subjects with a solid tumor. In some embodiments, rigosertib treatment results in complete response in subjects with a solid tumor. In some embodiments, rigosertib treatment results in stable disease in subjects with a solid tumor. In some embodiments, rigosertib treatment results in a clinical benefit rate of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%, wherein clinical benefit rate is defined as complete response (CR) + partial response (PR) + stable disease (SD).

[0112] Rigosertib has demonstrated antitumor activity in in vitro and in vivo melanoma models. In a panel of cell lines of varying mutational status, including in NRASQ, BRAF, PTEN, TP53, and / or CDKN2A, rigosertib was observed to have IC50 values range from 0.1 pM to 1.0 pM and induce cytotoxicity in a dose-dependent manner. In some embodiments, treatment with rigosertib suppresses PI3K-AKTT308-mTORCl activation. In some embodiments, treatment with rigosertib suppresses PI3K-AKTT308-mTORCl activation in melanoma cells. In some embodiments, treatment with rigosertib suppresses mTORC2-AKTS473activation. In some embodiments, treatment with rigosertib suppresses mTORC2-AKTS473activation in melanoma cells. In some embodiments, treatment with rigosertib induces formation of cleaved caspase 3. In some embodiments, treatment with rigosertib induces formation of reactive oxygen species. In some embodiments, treatment with rigosertib inhibits cell viability. In some embodiments, treatment with rigosertib promotes apoptotic cell death. In some embodiments, treatment with rigosertib promotes inflammatory cell death.

[0113] Treatment of athymic mice subcutaneously implanted with BRAFmutmurine melanoma cell lines resulted in near-complete resistance to rigosertib treatment. Treatment of C57B1 / 6 mice subcutaneously implanted with melanoma tumors resulted in effective inhibition of tumor growth. In a dose escalation cohort study with mice dosed with rigosertib at 150 mg / kg, 200 mg / kg, 300 mg / kg, and 400 mg / kg demonstrated comparable effects of 300 mg / kg and 400 mg / kg in inhibiting tumor volume. Antitumor effects of rigosertib were observed in NRASwtand BR.AF"’ melanoma models, indicating that rigosertib efficacy is mutation independent. In some embodiments, rigosertib inhibits tumor growth in a mutation independent manner. In some embodiments, treatment with rigosertib results in about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, or about 100% decrease in tumor volume. In some embodiments, treatment with rigosertib results in about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about90%, about 95%, about 99%, or about 100% decrease in tumor volume compared to baseline tumor volume.

[0114] In some embodiments, treatment with rigosertib increases the total number of tumorinfiltrating leukocytes (TILs). In some embodiments, treatment with rigosertib increases the density of TILs. In some embodiments, treatment with rigosertib increases the frequency of CD4+ T helper cells in the tumor microenvironment. In some embodiments, treatment with rigosertib increases the activation of CD4+ T helper cells in the tumor microenvironment. In some embodiments, treatment with rigosertib increases the activation of CD4+ T helper cells in the tumor microenvironment compared to control. In some embodiments, treatment with rigosertib increases the frequency of CD8+ cytotoxic T cells in the tumor microenvironment. In some embodiments, treatment with rigosertib increases the activation of CD8+ cytotoxic T cells in the tumor microenvironment. In some embodiments, treatment with rigosertib increases the activation of CD8+ cytotoxic T cells in the tumor microenvironment compared to control. In some embodiments, treatment with rigosertib activates CD8+ T cells in tumor-draining lymph nodes. In some embodiments, treatment with rigosertib activates CD8+ T cells in tumor-draining lymph nodes to a greater extent than vehicle treatment.

[0115] In Phase I and II studies, oral administration of rigosertib and azacitadine in patients with myelodysplastic syndrome or acute myeloid leukemia was well-tolerated with the maximal tolerate dose not reached. Observed toxicities associated with rigosertib administration include diarrhea, constipation, fatigue, nausea, pneumonia, back pain, febrile neutropenia, thrombocytopenia, urinary hematuria, hyperglycemia, dysuria, urinary retention, hematuria, hydronephrosis, osteolysis, cerebral hemorrhage, leukopenia, neutropenia, abdominal pain, abdominal discomfort / distension, hypertonic bladder, pelvic pain, hyponatremia, urinary hesitancy, and Grade 3+ anemia.PD-1 and PD-L1

[0116] Intact immune surveillance function is necessary for controlling the outgrowth of neoplastic transformations. A correlation between tumor-infiltrating lymphocytes in cancer tissue and a favorable prognosis has been observed, with the presence of CD8+-T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells (T-regs) correlating with improved prognosis and long-term survival in solid malignancies including ovarion cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, malignant melanoma, and renal cell carcinoma.

[0117] Programmed cell death protein 1 (PD-1) is a member of the immunoglobulin (Ig) superfamily and is related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte- associated protein 4 (CTLA4). PD-1 is expressed on the cell surface of activated T-cells under normal conditions and down-modulates excessive or unwanted immune responses, including autoimmune reactions. In cancer, the interaction of PD-1 receptor and its ligand (PD-L1 and / or PD-L2) is hijacked by cancer cells and tumors to suppress immune control and reactions. PD-1 and related family members are type I transmembrane glycoproteins containing an Ig-variable- type (IgV-type) domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosinebased switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP- 1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3Q, protein kinase C-theta (PKCO), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade.

[0118] PD-1 is an inhibitory receptor belonging to the CD28 / CTLA4 family and is expressed on the surface of activated T lymphocytes, B cells, monocytes, DCs, NK cells, and Tregs. In contrast to CTLA4, the major role of PD-1 is limitation of activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity. Chronic antigen exposure can lead to persistently-high levels of PD-1 expression. This expression can induce a state of exhaustion or anergy of antigen-specific T-cells. This state can be at least partially reversed by PD-1 blockade.

[0119] Two ligands for PD-1, PD-L1 and PD-L2, are expressed on T cells, APCs, and malignant cells. The ligands function to suppress self-reactive lymphocytes and to inhibit the effector function of TAA-specific cytotoxic T lymphocytes (CTLs). Accordingly, a therapy that targets PD-1, PD-L1, or PD-L2 has the potential to restore the cytotoxic activity of TAA-specific T cells.

[0120] Upon engagement of ligands, PD-1 can inhibit kinases involved in T-cell activation through the phosphatase, SHP2. PD-1 can limit the activity of T-cells in peripheral tissues at the time of an inflammatory response to an infection and limit autoimmunity. The decrease in the proliferation of T-cells can lead to a decrease in IL-2 secretion. PD-1 can also be highly expressed on Tregs, which can have an immunosuppressive function, and further increase the proliferation of Tregs. Tumors can be highly infiltrated with TregS; thus, blockade of PD-1 candiminish the immunosuppressive function of the intratumoral Tregs.

[0121] Due to the broad expression pattern, PD-1 can also enhance NK activity in tumors or tissues. PD-1 can increase antibody production through PD-1+B-cells. Chronic antigen exposure observed in viral infection and cancer can lead to persistent PD-1 activation and T-cell anergy among cognate antigen-specific T-cells. This anergic state can be reversed through a blockade of PD-1.

[0122] PD-1 can also be expressed on tumor infiltrating lymphocytes (TILs) in many tumor types. The enhanced PD-1 expression of CD4+cells can reflect the high expression of PD-1 on regulatory T-cells within tumors. PD-1 can also be highly expressed on CD8+cells and can reflect an anergic state. Consistent with the increased expression of PD-1 on lymphocytes from many tumors, the ligands of PD-1 can also be highly expressed on the tumor cell surface. PD-L1 can be highly expressed on, for example, melanoma, ovarian cancer, lung cancer, and renal cancer cells. PD-L2 can be highly expressed on, for example, primary mediastinal B-cell lymphoma, follicular cell B-cell lymphoma, and Hodgkin’s lymphoma. Anti-PD-1 antibodies can induce regression of several tumor types including colon, renal, lung, and melanoma. Therapies targeting PD-1 directly or the interaction between PD-1 and a ligand include nivolumab, pembrolizumab, pidilizumab, and AMP-224.

[0123] In some embodiments, the anti-PD-1 antibody is Pembrolizumab. In some embodiments, the anti-PD-1 antibody is Nivolumab. In some embodiments, the anti-PD-1 antibody is Pidilizumab. Non-limiting examples of anti-PD-1 antibodies include AGEN-2034, AMP-224, BCD-100, BGBA-317, BI-754091, CBT-501, CC-90006, cemiplimab, durvalumab + MEDI- 0680, GLS-010, IBI-308, JNJ-3283, JS-001, MEDI-0680, MGA-012, MGD-013, pazopanib hydrochloride + pembrolizumab, PDR-001, PF-06801591, REGN-2810, SHR-1210, TSR-042, LZM-009, and ABBV-181. In some embodiments, the anti-PD-1 antibody is administered in combination with rigosertib, a pharmaceutical salt, or an analog thereof.

[0124] In some embodiments, the anti-PD-Ll antibody is, for example, Durvalumab, Atezolizumab, Avelumab, CX-072, BMS-936559, SHR- 1316, M-7824, LY-3300054, FAZ-053, KN-035, CA-170, CK-301, CS-1001, HLX-10, MCLA-145, MSB-2311, or MEDI-4736. In some embodiments, the anti-PD-Ll antibody is administered in combination with rigosertib, a pharmaceutical salt, or an analog thereof.

[0125] PD-1 inhibition has improved outcomes for patients with metastatic melanoma and other cancers. In some embodiments, PD-1 inhibition increases 5- year overall survival rates by about10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, or about 100%.

[0126] In some embodiments, subjects acquire resistance to a PD-1 inhibitor. In some embodiments, subjects have primary resistance to a PD-1 inhibitor. In some embodiments, acquired or primary resistance to PD-1 inhibition limits the clinical benefit of PD-1 inhibition. In some embodiments, acquired or primary resistance to PD-1 inhibition removes the clinical benefit of PD-1 inhibition. In some embodiments, acquired or primary resistance to PD-1 inhibition limits the clinical benefit of PD-1 inhibition in about 10%, in about 20%, in about 30%, in about 40%, in about 50%, in about 60%, in about 70%, in about 80%, in about 90%, in about 95%, in about 99%, or about 100% of subjects treated with a PD-1 inhibitor. In some embodiments, acquired or primary resistance to PD-1 inhibition limits the clinical benefit of PD- 1 inhibition in about in about 0% to about 10%, in about 10% to about 30%, in about 20% to about 40%, in about 30% to about 50%, in about 40% to about 60%, in about 50% to about 70%, in about 60% to about 80%, in about 70% to about 90%, in about 750% to about 95%, in about 80% to about 100%, in about 10% to about 40%, in about 20% to 50%, in about 30%, to about 60%, in about 40% to about 70%, in about 50% to about 80%, in about 60% to about 90%, in about 70% to about 100%, in about 10% to about 50%, in about 20% to about 60%, in about 30% to about 70%, in about 40% to about 80%, in about 50% to about 90%, in about 60% to about 100%, in about 10% to about 60%, in about 20% to about 70%, in about 30% to about 80%, in about 40% to about 90%, in about 50% to about 100%, in about 10% to about 70%, in about 20% to about 80%, in about 30% to about 90%, in about 40% to about 100%, in about 10% to about 80%, in about 20% to about 90%, in about 30% to about 100%, in about 10% to about 90%, in about 20% to about 100%, or in about 10% to about 100% of subjects treated with a PD-1 inhibitor. In some embodiments, treatment with a PD-1 inhibitor results in inadequate activation of TILs within the tumor microenvironment.Checkpoint Inhibitors

[0127] In some embodiments, disclosed herein is a method of treating a cancer by administering an immunomodulatory agent. In some embodiments, disclosed herein is a method of treating a cancer by administering a compound of a disclosure and a cancer immunotherapy. In some embodiments, the cancer immunotherapy targets an immune checkpoint. In some embodiments, the cancer immunotherapy can block an inhibitory checkpoint and restore immune system function. In some embodiments, disclosed herein is a method of treating a cancer byadministering a compound of the disclosure and an antibody. In some embodiments, disclosed herein is a method of treating a cancer by administering a compound of the disclosure and a biologic.

[0128] Immune checkpoints are co-stimulatory and inhibitory elements intrinsic to the immune system. Immune checkpoints aid in maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses to reduce injury to tissues when the immune system responds to pathogenic infection. An immune response can also be initiated when a T-cell recognizes antigens that are unique to a tumor cell (e.g. non-self antigens or tumor neo-antigens) or are characteristic of a tumor cell (e.g. tumor-associated antigens (TAAs)). The equilibrium between the co-stimulatory and inhibitory signals used to control the immune response from T- cells can be modulated by immune checkpoint proteins. After T-cells mature and activate in the thymus, T-cells can travel to sites of inflammation and injury to perform repair functions. T-cell function can occur either via direct action or through the recruitment of cytokines and membrane ligands involved in the immune system. The steps involved in T-cell maturation, activation, proliferation, and function can be regulated through co-stimulatory and inhibitory signals, namely through immune checkpoint proteins. Tumors can dysregulate checkpoint protein function as an immune-resistance mechanism. Thus, the development of modulators of checkpoint proteins can have therapeutic value. Non-limiting examples of immune checkpoint molecules include LAG3, BTLA, KIR, CTLA4, ICOS, TIM3, A2aR, PD-1, PD-L1, PD-L2, CD40L, OX40L, CD137L, CD47, B7-H3, and B7-H4. These checkpoint molecules can operate upstream of IL-2 in a pathway.

[0129] Checkpoint molecules guard against unwanted and harmful self-directed activation of the immune system (autoimmunity). Although necessary in aiding in the suppression of autoimmunity, these molecules can hinder immunotherapies aimed at targeting malignant selfcells that largely display the same array of surface molecules as the parent cells. Therapies aimed at overcoming these mechanisms of peripheral tolerance, particularly by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in combination with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system.

[0130] Immunological checkpoints can be molecules that regulate inhibitory signaling pathways (for example, LAG3, CTLA4, PD-1, and TIM3) or molecules that regulate stimulatory signaling pathways (for example, by ICOS). Several proteins in the extended immunoglobulin superfamily can be ligands for immunological checkpoints. Non-limiting examples of immune checkpointligand proteins include B7-H4, ICOSL, PD-L1, PD-L2, CD40L, OX40L, CD86, and CD137L.

[0131] In some embodiments, the checkpoint inhibitor is a cell-surface checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the checkpoint inhibitor is an intracellular checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is cytokine-inducible SH2-containing protein (CISH).

[0132] LAG3 (Lymphocyte-activation gene 3) is expressed on activated antigen-specific cytotoxic T cells and can enhance the function of regulatory T-cells and independently inhibit CD8+ effector T-cell activity. LAG3 is a CD-4-like negative regulatory protein with a high affinity binding site to MHC Class II, which is upregulated on some epithelial cancers, to provide tolerance of T cell proliferation and homeostasis. Blockage of the LAG-3 / Class II interaction using a LAG-3 -IG fusion protein enhances antitumor immune responses. Therapeutics targeting LAG3 include IMP321 and other monoclonal antibodies.

[0133] BTLA (B- and T-lymphocyte attenuator) can inhibit T-cells when associated with HVEM (herpes-virus entry mediator) as a ligand. HVEM can be expressed on melanoma and endothelial cancer cells. BTLA levels can be high on TILs from subjects with melanoma, and BTLA- expressing T-cells can be inhibited in the presence of HVEM.

[0134] KIR (killer immunoglobulin-like receptor) is expressed by Natural Killer (NK) cells and a subset of T lymphocytes. KIRs are largely cell surface inhibitory receptors specific for allelic forms of human leukocyte antigen (HLA) class I molecules. Upon engagement with HLA class I molecules, KIRs block NK cell activation and function. Blockage of KIRs can lead to blockage of NK cell activation and function.

[0135] CTLA4 (cytotoxic T-lymphocyte antigen 4) is also known as CD 152 (Cluster of differentiation 152). CTLA4 shares sequence homology and ligands (CD80 / B7-1 and CD86 / B7- 2) with the costimulatory molecule CD28, but differs by delivering inhibitory signals to T cells expressing CTLA4 as a receptor. CTLA4 has a much higher overall affinity for both ligands and can out-compete CD28 for binding when ligand densities are limiting.

[0136] CTLA4 is expressed on the surface of CD8+ effector T-cells and plays a functional role in the initial activation stages of both naive and memory T cells. CTLA4 counteracts the activity of CD28 via increased affinity for CD80 and CD86 during the early stages of T-cell activation. The major functions of CTLA4 include downmodulation of helper T-cells and enhancement of regulatory T-cell immunosuppressive activity. Evidence for the importance of CTLA4 can be demonstrated through the lethal systemic immune hyperactivation phenotype in Ctla4 -I- mice.

[0137] CTLA4 can also downregulate immune system functions via inhibition of IL-2 production and IL-2 receptor expression. CTLA4 can inhibit CD28-dependent upregulation of IL-2, and the inhibition of IL-2 production can lead to cell cycle arrest. The decrease in IL-2 and subsequent cell cycle arrest can account for the reduced T-cell proliferation observed in the presence of CTLA4.

[0138] CTLA4 includes an extracellular domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants encoding different isoforms exist. The membranebound isoform can function as a homodimer interconnected by a disulfide bond, and the soluble isoform can function as a monomer. Mutations in CTLA4 can be associated with, for example, insulin-dependent diabetes mellitus, Graves’ disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases.

[0139] Therapies targeting CTLA4 can be developed to circumvent tumor resistance mechanisms. Inhibition of CTLA4 can lead to a broad enhancement of immune responses that are dependent on helper T-cells. Thus, therapeutics aimed at blocking CTLA4 can assist in evading tumor cell resistance mechanisms. Examples of therapies targeting CTLA4 include ipilimumab and tremelimumab, monoclonal antibodies that can target CTLA4 and can be used in the treatment of, for example, melanoma. Therapies can also be directed toward increasing the activity of CTLA4 for the treatment of autoimmune diseases. Fusion proteins of CTLA4 and antibodies can increase the immune response in patients with, for example, rheumatoid arthritis, or patients sensitized to the Epstein Barr Virus (EPV) undergoing renal transplantation.

[0140] ICOS (Inducible T-cell COStimulator), also known as CD278, is a CD28-superfamily costimulatory molecule that is expressed on activated T cells. CD40 and CD134 are examples of additional co-stimulatory molecules.

[0141] TIM3 (T-cell immunoglobulin and mucin domain-containing protein 3), also known as Hepatitis A virus cellular receptor 2 (HAVCR2) is a Thl-specific cell surface protein that regulates macrophage activation. TIM3 can inhibit helper T-cell responses via association with the TIM3 ligand, galectin 9. Galectin 9 can be upregulated in various types of cancer, including breast cancer. TIM3 can be co-expressed with PD-1 on tumor specific CD8+ T-cells and inhibition of both molecules can significantly enhance the proliferation and cytokine production of T-cells.

[0142] Four types of adenosine receptors, Al, A2A, A2B, and A3 receptors, are expressed on the surface of immune cells. On T cells, the predominant subtype expressed is A2A adenosine receptor (A2aR). Immunosuppressive signaling through the A2aR receptor can control thecytokine secretion pattern of NK cells and function to protect inflamed tissues from excessive damage by immune cells. A2aR receptors inhibit T-cell responses by driving CD4+ T-cells to express F0XP3 (forkhead box P3). F0XP3 can then cause the CD4+ T-cells to develop into regulatory T-cells. Deletion of A2aR can lead to pathological inflammatory responses to infection.

[0143] B7-H3 can costimulate proliferation of both CD4+ and CD8+ T cells, enhance the induction of cytotoxic T cells, and selectively stimulate interferon (IFN-y) production in the presence of T cell receptor signaling. The B7-H3 receptor can be expressed in dendritic cells and monocytes.

[0144] B7-H4, also known as B7S1 or B7x, is a coinhibitory member of the B7 family that negatively regulates neutrophil-mediated innate immune responses. The B7-H4 receptor can be expressed in B cells and antigen presenting cells. The B7-H4 receptor can also be overexpressed in breast, ovarian, lung cancer, and other solid tumors.

[0145] Immunotherapies disclosed herein include those that modulate a checkpoint molecule or a checkpoint protein. Non-limiting examples of agents that modulate a checkpoint molecule or a checkpoint protein include cytokines, immunotoxins, recombinant proteins, antibodies, monoclonal antibodies, tumor-specific monoclonal antibodies, antibody-drug conjugates, immunotoxins, and any agent that modulates, up-regulates, down-regulates, agonizes, antagonizes, inhibits, or induces one or more of LAG3, BTLA, KIR, CTLA4, ICOS, TIM3, A2aR, PD-1, B7-H3, B7-H4, ICOSL, PD-L1, PD-L2, CD40L, OX40L, CD47, CD86, and CD137L. In some embodiments, the immunotoxin therapy is a therapy against one or more of CD5, CD7, CD19, CD22, CD25 (T-NHL), CD30, and CD38 (B-NHL). In some embodiments, the immunotherapy is ipilimumab, nivolumab, tremelimumab, pembrolizumab, pidilizumab, AMP -224 or ResimmuneTM (also called A-dmDT390-bisFv(UCHTl)). The agent can be administered in the same unit dosage form as a compound described herein, or in a separate dosage form in any order or concurrently.

[0146] Non-limiting examples of cells whose activity can be modulated by a combination therapy include: endothelial cells; B cells; CD4; CD8; blood cells, including red blood cells and white blood cells; dendritic cells, including dendritic antigen presenting cells; leukocytes; macrophages; memory B cells; memory T cells; monocytes; NK cells; neutrophil granulocytes; helper T cells; and cytotoxic T cells.

[0147] In some embodiments, the checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, or cemiplimab. In some embodiments,the checkpoint inhibitor is nivolumab. In some embodiments, the checkpoint inhibitor is pembrolizumab. In some embodiments, the checkpoint inhibitor is avelumab. In some embodiments, the checkpoint inhibitor is durvalumab.

[0148] In some embodiments, a checkpoint inhibitor can be administered at a dose of from about 0.1 mg / kg to about 10 mg / kg. In some embodiments, a checkpoint 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 about3.5 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 checkpoint inhibitor can be administered at a dose of from about 0.1 mg / kg to about 0.5 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of from about 0.5 mg / kg to about 1 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of from about 1 mg / kg to about 1.5 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of from about 1.5 mg / kg to about 3 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of from about 3 mg / kg to about 5 mg / kg.

[0149] In some embodiments, a checkpoint 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 checkpoint 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, about2.5 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 checkpoint inhibitor can be administered at a dose of about 1 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of about 2.5 mg / kg. In someembodiments, a checkpoint inhibitor can be administered at a dose of about 3 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of about 3.5 mg / kg.

[0150] In some embodiments, a checkpoint 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 checkpoint inhibitor can be administered at a dose of at most about 1 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at most about 2 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at most about 3 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at most about 4 mg / kg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at most about 5 mg / kg.

[0151] In some embodiments, a checkpoint 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 checkpoint inhibitor can be administered at a dose of from about 50 mg to about 250 g per dose administered. In some embodiments, a checkpoint inhibitor can be administered at a dose of from about 250 mg to about 500 mg per dose administered. In some embodiments, a checkpoint inhibitor can be administered at a dose of from about 500 mg to about 750 mg per dose administered.

[0152] In some embodiments, a checkpoint 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 leastabout 850 mg, at least about 900 mg, at least about 950 mg, or at least about 1,000 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 240 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 250 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 300 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 400 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 450 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 480 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 500 mg.

[0153] In some embodiments, a checkpoint 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 checkpoint inhibitor can be administered at a dose of about 240 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of about 250 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of about 300 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of about 450 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of about 480 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of about 500 mg.

[0154] In some embodiments, a checkpoint 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 checkpoint inhibitor is administered at a concentration of from about 9 mg / mL to about 10 mg / mL. In some embodiments, a checkpoint 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 checkpoint inhibitor is administered at a concentration of about1 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 checkpoint inhibitor is administered at a concentration of about 10 mg / mL.

[0155] 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.

[0156] 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.

[0157] In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 240 mg. In some embodiments, a checkpoint inhibitor can be administered at a dose of at least about 480 mg.

[0158] In some embodiments, the checkpoint inhibitor is administered intravenously. In some embodiments, the checkpoint inhibitor is administered orally.

[0159] In some embodiments, the checkpoint 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, the checkpoint inhibitor is administered once every week. In some embodiments, the checkpoint inhibitor is administered once every week. In some embodiments, the checkpoint inhibitor is administered once every 2 weeks. In some embodiments, nivolumab is administered once every 4 weeks. In some embodiments, the checkpoint inhibitor is administered once every 6 weeks. In some embodiments, the checkpoint inhibitor is administered once every 8 weeks. In some embodiments, the checkpoint inhibitor is administered once every 12 weeks.

[0160] In some embodiments, the checkpoint inhibitor is administered 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, the checkpoint inhibitor is administered 1 time over a 28-day cycle. In some embodiments, the checkpoint inhibitor is administered 2 times over a 28-day cycle. In some embodiments, the checkpoint inhibitor is administered 3 times over a 28-day cycle. In some embodiments, the checkpoint inhibitor is administered 4 times over a 28-day cycle. In some embodiments, the checkpoint inhibitor is administered on day 1 of a 28 day cycle. In some embodiments, the checkpoint inhibitor is administered on day 15 of a 28 day cycle. In some embodiments, the checkpoint inhibitor is administered on day 22 of a 28 day cycle. In some embodiments, the checkpoint inhibitor is administered on day 1 and day 15 of a 28 day cycle.

[0161] In some embodiments, the checkpoint 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, the checkpoint inhibitor is administered over 30 minutes. In some embodiments, the checkpoint inhibitor is administered over 60 minutes. In some embodiments, the checkpoint inhibitor is administered over 90 minutes. In some embodiments, the checkpoint inhibitor is administered over 120 minutes.

[0162] In some embodiments, nivolumab is administered over 30 minutes. In some embodiments, nivolumab is administered over 60 minutes. In some embodiments, nivolumab is administered at a dose of about 240 mg every 2 weeks over 30 minutes. In some embodiments, nivolumab is administered at a dose of about 480 mg every 2 weeks over 60 minutes. In some embodiments, nivolumab is administered at a dose of about 480 mg every 4 weeks over 30 minutes for the first 16 weeks, followed by 480 mg every 4 weeks over 30 minutes.Pembrolizumab

[0163] Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4 / kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab contains a S228P stabilizing mutation and has no reported antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activity. Pembrolizumab has been demonstrated to strongly enhance T lymphocyte immune responses in cultured blood cells from healthy human donors, cancer patients, and primates, with a reported ECso value of 0.1 to 0.3 nM in T- cell activation assaysusing human donor blood cells. Pembrolizumab modulates cytokine levels, including interleukin- 2 (IL-2), tumor necrosis factor alpha (TNFa), interferon gamma (IFNy), and other cytokines. Pembrolizumab potentiates existing immune responses only in the presence of antigen and does not nonspecifically activate T- cells. Pembrolizumab is approved for use in metastatic melanoma, adjuvant settings, and in 17 other malignancies, including NSCLC, head & neck cancer, Hodgkin Lymphoma, urothelial cell carcinoma, renal cell, gastric and GEJ, cervical cancer, endometrial cancer, hepatocellular carcinoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma, triple-negative breast cancer primary mediastinal B cell lymphoma. Pembrolizumab is also approved in the tumor-agnostic setting for mismatch repair deficient (dMMR) / microsatellite instability high (MSI-H) as well as tumor mutational burden-high (TMB) solid tumors. Pembrolizumab is well-tolerated in patients with a reported no observed advent level (NOAEL) greater than 200 mg / kg and no major safety findings observed in a repeat dose GLP -toxicity study with four months observation post dosing.

[0164] In some embodiments, pembrolizumab is administered over 30 minutes. In some embodiments, pembrolizumab is administered over 60 minutes. In some embodiments, pembrolizumab is administered at a dose of about 200 mg every 3 weeks over 30 minutes. In some embodiments, pembrolizumab is administered at a dose of about 200 mg every 3 weeks over 60 minutes. In some embodiments, pembrolizumab is administered at a dose of about 400 mg every 6 weeks over 30 minutes. In some embodiments, pembrolizumab is administered at a dose of about 400 mg every 6 weeks over 60 minutes.

[0165] In some embodiments, a dose of pembrolizumab can be modified. In some embodiments, a dose of pembrolizumab can be decreased. In some embodiments, administration of pembrolizumab can be stopped. In some embodiments, a dose of pembrolizumab can be modified in response to an infusion reaction. In some embodiments, a dose of pembrolizumab can be decreased in response to to an infusion reaction. In some embodiments, administration of pembrolizumab can be stopped in response to an infusion reaction. In some embodiments, administration of pembrolizumab can be stopped in response to an infusion reaction and resumed following cessation of or improvement in an infusion reaction. In some embodiments, administration of pembrolizumab can be stopped in response to a Grade 2 infusion reaction. In some embodiments, administration of pembrolizumab can be stopped in response to a Grade 2 infusion reaction and a subject administered an additional medical therapy comprising intravenous fluids, antihistamines, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or narcotics. In some embodiments, administration of pembrolizumab can bestopped in response to a Grade 2 infusion reaction, a subject administered an additional medical therapy, and administration of pembrolizumab resumed at a decreased infusion rate. In some embodiments, a subject can be administered an additional medical therapy comprising an antihistamine or an analgesic prior to administration of pembrolizumab. In some embodiments, administration of pembrolizumab can be stopped in response to a Grade 3 infusion reaction. In some embodiments, administration of pembrolizumab can be stopped in response to a Grade 4 infusion reaction. In some embodiments, administration of pembrolizumab can be stopped in response to a Grade 3 infusion reaction and a subject administered an additional medical therapy comprising epinephrine, intravenous fluids, antihistamines, non-steroidal anti-inflammatory drugs, acetaminophen, narcotics, oxygen, pressors, or corticosteroids. In some embodiments, administration of pembrolizumab can be stopped in response to a Grade 4 infusion reaction and a subject administered an additional medical therapy comprising epinephrine, intravenous fluids, antihistamines, non-steroidal anti-inflammatory drugs, acetaminophen, narcotics, oxygen, pressors, or corticosteroids.Rigosertib and and immune checkpoint inhibition

[0166] Rigosertib in combination with nivolumab has been evaluated in KRAS-positive lung adenocarcinoma after progression on standard first-line therapy. Manageable safety was observed in patients treated with rigosertib and nivolumab dosed with rigosertib twice daily at 560 mg and 240 mg nivolumab dosed every 14 days.

[0167] In some embodiments, a response rate in subjects treated with rigosertib and an immune checkpoint inhibitor is at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%. In some embodiments, the rate of clinical benefit in subjects treated with rigosertib and an immune checkpoint inhibitor is at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%. In some embodiments, a subject treated with rigosertib and an immune checkpoint inhibitor may show some adverse events including but not limited to dysuria, hematuria, problems with urinary frequency, abdominal pain, fatigue, anemia, lymphopenia, thrombocytopenia, hyponatremia, hyperglycemia, AST elevation, ALT elevation, ALK elevation, nausea and / or vomiting, constipation, diarrhea, anorexia, pruritis, or an infusion-related reaction.

[0168] In some embodiments, a response rate in subjects treated with rigosertib and a PD-1inhibitor is at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%. In some embodiments, the rate of clinical benefit in subjects treated with rigosertib and a PD-1 inhibitor is at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%. In some embodiments, a subject treated with rigosertib and a PD-1 inhibitor may show some adverse events including but not limited to dysuria, hematuria, problems with urinary frequency, abdominal pain, fatigue, anemia, lymphopenia, thrombocytopenia, hyponatremia, hyperglycemia, AST elevation, ALT elevation, ALK elevation, nausea and / or vomiting, constipation, diarrhea, anorexia, pruritis, or an infusion-related reaction.

[0169] In some embodiments, treatment with rigosertib and an immune checkpoint inhibitor inhibits tumor growth. In some embodiments, treatment with rigosertib and an immune checkpoint inhibitor results in about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 99%, or about 100% inhibition of tumor growth. In some embodiments, rigosertib and immune checkpoint inhibition inhibits tumor growth to a greater extent than rigosertib treatment alone. In some embodiments, rigosertib and immune checkpoint inhibition inhibits tumor growth to a greater extent than PD-1 inhibition alone. In some embodiments, rigosertib and an immune checkpoint inhibition synergize to inhibit tumor growth. In some embodiments, treatment with rigosertib and an immune checkpoint inhibitor does not result in significant weight loss in a treated subject compared to control. In some embodiments, treatment with rigosertib and an immune checkpoint inhibitor does not result in changes in liver function tests in a treated subject compared to control. In some embodiments, treatment with rigosertib and an immune checkpoint inhibitor results in low toxicity. In some embodiments, treatment with rigosertib and an immune checkpoint inhibitor results in results in a tumor-immune microenvironment primed for tumor cell targeting. In some embodiments, treatment with rigosertib and an immune checkpoint inhibitor results in increased immunogenicity of the tumor microenvironment. In some embodiments, treatment with rigosertib and an immune checkpoint inhibitor increases immunogenicity of the tumor microenvironment.

[0170] In some embodiments, treatment with rigosertib and a PD-1 inhibitor inhibits tumor growth. In some embodiments, treatment with rigosertib and a PD-1 inhibitor results in a about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 99%, or about 100% inhibition of tumor growth. In some embodiments, rigosertiband PD-1 inhibition inhibits tumor growth to a greater extent than rigosertib treatment alone. In some embodiments, rigosertib and PD-1 inhibition inhibits tumor growth to a greater extent than PD-1 inhibition alone. In some embodiments, rigosertib and a PD-1 inhibitor synergize to inhibit tumor growth. In some embodiments, treatment with rigosertib and a PD-1 inhibitor does not result in significant weight loss in a treated subject compared to control. In some embodiments, treatment with rigosertib and a PD-1 inhibitor does not result in changes in liver function tests in a treated subject compared to control. In some embodiments, treatment with rigosertib and a PD- 1 inhibitor results in low toxicity.

[0171] In some embodiments, pembrolizumab is administered intravenously over 30 minutes. In some embodiments, pembrolizumab is administered intravenously over 60 minutes. In some embodiments, pembrolizumab is administered intravenously at a dose of about 200 mg every 3 weeks over 30 minutes. In some embodiments, pembrolizumab is administered intravenously at a dose of about 200 mg every 3 weeks over 60 minutes. In some embodiments, pembrolizumab is administered intravenously at a dose of about 400 mg every 6 weeks over 30 minutes. In some embodiments, pembrolizumab is administered intravenously at a dose of about 400 mg every 6 weeks over 60 minutes.

[0172] In some embodiments, pembrolizumab is administered intravenously in combination with oral rigosertib. In some embodiments, pembrolizumab is administered via intravenous infusion at a dose of about 400 mg every 6 weeks over 30 minutes and rigosertib is administered at a dose of about 560 mg twice daily every day for 21 days followed by 7 days of no rigosertib administration in a 28-day treatment cycle. In some embodiments, pembrolizumab is administered intravenously in combination with oral rigosertib. In some embodiments, pembrolizumab is administered via intravenous infusion at a dose of about 400 mg every 6 weeks over 30 minutes and rigosertib is administered at a dose of about 560 mg in the morning and at a dose of about 280 mg in the afternoon every day for 21 days followed by 7 days of no rigosertib administration in a 28-day treatment cycle. In some embodiments, pembrolizumab is administered intravenously in combination with oral rigosertib. In some embodiments, pembrolizumab is administered via intravenous infusion at a dose of about 400 mg every 6 weeks over 30 minutes and rigosertib is administered at a dose of about 280 mg twice daily every day for 21 days followed by 7 days of no rigosertib administration in a 28-day treatment cycle. In some embodiments, pembrolizumab is administered via intravenous infusion at a dose of about 200 mg every 3 weeks over 30 minutes and rigosertib is administered at a dose of about 560 mg twice daily every day for 21 days followed by 7 days of no rigosertib administration in a 28-daytreatment cycle. In some embodiments, pembrolizumab is administered via intravenous infusion at a dose of about 200 mg every 3 weeks over 30 minutes and rigosertib is administered at a dose of about 560 mg in the morning and at a dose of about 280 mg in the afternoon every day for 21 days followed by 7 days of no rigosertib administration in a 28-day treatment cycle. In some embodiments, pembrolizumab is administered via intravenous infusion at a dose of about 200 mg every 3 weeks over 30 minutes and rigosertib is administered at a dose about 280 mg twice daily every day for 21 days followed by 7 days of no rigosertib administration in a 28-day treatment cycle.

[0173] Diseases

[0174] 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, or pancreatic cancer. In some embodiments, compounds of the invention can be used to treat cancer in a subject.

[0175] 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.

[0176] A compound of the invention 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.

[0177] 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.

[0178] Non-limiting examples of cancer that can be treated by a compound of the invention 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.Melanoma

[0179] Melanoma is the fifth most common malignancy in men and the seventh most common malignancy in women. Melanoma incidence is increasing worldwide, with a growing fraction of patients with advanced disease for which prognosis remains poor. The median survival for patients with metastatic melanoma has traditionally been under 1 year and the 5-year survival rate of patients with visceral involvement has been under 10%. Treatment options for metastatic melanoma have been limited to chemotherapeutic agents such as dacarbazine and high-dose interleukin-2 immunotherapy in a small percentage of patients. Recently progress in thedevelopment of targeted therapy and immunotherapy for metastatic melanoma. Has included Vemurafenib, a BRAF inhibitor, which was approved in 2011 for the treatment of patients with unresectable or metastatic melanoma with BRAFV600Emutation, and ipilimumab, an anti-CTLA4 monoclonal antibody, which was approved in 2011 for the treatment of patients with unresectable or metastatic melanoma. About half of patients with metastatic melanoma have tumors which harbor activating mutations at the BRAFV600locus, rendering them sensitive to targeted therapy with BRAF / MEK inhibitors. Mutually exclusive of BRAF driver mutations, another 30% of patients with metastatic melanoma have tumors which are driven by activating mutations in NRAS. The remaining 20% of melanoma patients have tumors without either of these driver mutations.

[0180] Patients with unresectable / metastatic melanoma are typically initially treated with checkpoint inhibitor therapy (barring contraindication) regardless of underlying BRAF mutation, as checkpoint inhibitor therapy is associated with a greater potential for durable response. Upon disease progression, patients whose disease has an underlying BRAF mutation are eligible for targeted therap. BRAF inhibition has been shown to induce TIL invasion into the tumor-immune environment. However, approximately half of all patients with metastatic melanoma lack effective treatment options after progression on checkpoint inhibitor therapy due to the absence of BRAFV600activating mutations. Once disease progresses on PD-1 / L1 inhibitor treatment, effective treatment options are limited. One strategy is to continue PD-1 / L1 inhibitor treatment can be continued in combination with ipilimumab; this has shown to result in objective response rates higher than single-agent ipilimumab treatment with similar rates of Grade 3+ toxicity.Methods of administration

[0181] A compound described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary. For example, a compound 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 and composition can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of a compound 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 formulationdescribed herein.

[0182] A compound can be administered as soon as is practical after the onset of a disease or condition 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 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.

[0183] In some embodiments, a compound of the disclosure can be administered once a day. In some embodiments, a compound of the disclosure can be administered twice a day. In some embodiments, a compound of the disclosure can be administered three times a day. In some embodiments, compound absorption can be interfered by food. In some embodiments, a compound of the disclosure can be administered in a fasting state. In some embodiments, the dosing is separated from a meal by at least about 15 min, at least about 30 min, at least about 45 min, at least about 1 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 compound is administered before the subject consumes food. In some embodiments, the compound is administered after the subject consumes food. In someembodiments, the compound is administered before the subject consumes a drink. In some embodiments, the compound is administered after the subject consumes a drink.

[0184] In some embodiments, the morning dose of a compound 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 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 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. 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.

[0185] Intravenous rigosertib can be given through a large bore intravenous catheter to avoid the risks of extravasation. The IV infusion can continuous (CIV) for 72 hours with three separate infusion bags delivered for 24 hours each via a standard infusion pump.

[0186] To mitigate a risk of a genitourinary adverse event, a second dose of a compound disclosed herein 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.

[0187] 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.

[0188] A dosing schedule for administration of a compound described herein 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 of the disclosure is administered once daily. In some embodiments, a compound of the disclosure is administered twice daily. In some embodiments, a compound of the disclosure is administered three times daily. In some embodiments, a compound of the disclosure is administered four times daily.

[0189] 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.

[0190] 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])(1'0 67)

[0191] 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.

[0192] The correction factor (Km) is estimated by dividing the average body weight (kg) of a species to its body surface area (m2). The Kmfactor values of various animal species of TABLE 1 is used to estimate the HED as:HED (mg / kg) = Animal doses (mg / kg) x (Animal Km / Human Km); or HED (mg / kg) = Animal doses (mg / kg) x KmratioTABLE 1

[0193] 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 Kmratio provided in TABLE 2. AED can be calculated using the equation:AED (mg / kg) = Human doses (mg / kg) x KmratioTABLE 2

[0194] 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

[0195] 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, or pancreatic cancer. In some embodiments, compounds of the invention can be used to treat cancer in a subject.

[0196] 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.

[0197] In some embodiments, a cancer that can be treated by a compound of the invention is melanoma. In some embodiments, the melanoma is metastatic melanoma. In some embodiments, the melanoma is metastic melanoma harboring activating mutations the BRAFV600locus. In some embodiments, the melanoma is metastic melanoma with activating mutations in NBAS. In some embodiments, the melanoma is metastatic melanoma without activating mutations in the BRAFV600locus or in NRAS. In some embodiments, the melanoma is metastatic melanoma refractory to treatment. In some embodiments, the melanoma is metastatic melanoma refractory to treatment with a PD-1 inhibitor. In some embodiments, the melanoma is metastatic melanoma refractory to treatment with a PD-L1 inhibitor. In some embodiments, the melanoma is metastatic melanoma refractory to treatment with an anti-PD-1 antibody. In some embodiments, the melanoma is metastatic melanoma refractory to treatment with an anti-PD-Ll antibody. In some embodiments, the melanoma is metastatic melanoma refractory to PD-1 inhibition. In some embodiments, the melanoma is metastatic melanoma refractory to PD-L1 inhibition. In some embodiments, the melanoma is unresectable melanoma. In some embodiments, the melanoma is unresectable melanoma refractory to treatment. In some embodiments, the melanoma is unresectable melanoma refractory to treatment with a PD-1 inhibitor. In some embodiments, the melanoma is unresectable melanoma refractory to treatment with a PD-L1 inhibitor. In some embodiments, the melanoma is unresectable melanoma refractory to treatment with an anti-PD-1 antibody. In some embodiments, the melanoma is unresectable melanoma refractory to treatment with an anti-PD-Ll antibody. In some embodiments, the melanoma is unresectable melanoma refractory to PD-1 inhibition. In some embodiments, the melanoma is unresectable melanoma refractory to PD-L1 inhibition.

[0198] A tumor response due to a method disclosed herein can be measured based on the iRECIST classification of responses. In some embodiments, a tumor response due to a method disclosed herein can be measured based on the iRECIST classification of response, wherein clinical stability can be defined as the absence of symptoms and signs indicating clinically significant progression of disease; no decline in ECOG performance status; and no requirements for intensified disease management, including increased analgesia, radiation, or other palliative care. In some embodiments, a tumor response due to a method disclosed herein can be measured based on the iRECIST classification of responses, wherein tumor flare can be defined as any factor causing radiographic progression including: increase in the sum of measurements / diameters of target lesion(s) identified at baseline to greater than 20% and greater than 5 mm from nadir; unequivocal progression of non-target lesion(s) identified at baseline, ordevelopment of new lesions(s). In some embodiments, a tumor response due to a method disclosed herein can be measured based on the iRECIST classification of responses, wherein confirmed progressions can be defined as an increase in the sum of measurements / diameters greater than 5 mm for target lesion(s); any significant growth in lesions overall; an increase in the new lesion sum of measurements / diameters greater than 5 mm; visible growth of new non-target lesions; or the appearance of additional new lesions.

[0199] In some embodiments, a tumor response rate can be measured based on the iRECIST classification of responses. In some embodiments, a tumor response rate can be at least or about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%. In some embodiments, a tumor response rate can be at least about 30%. In some embodiments, a tumor response rate can be at least about 50%. In some embodiments, a tumor response rate can be at least about 70%. In some embodiments, a tumor response rate can be at least about 90%.

[0200] In some embodiments, tumor response due to a method disclosed herein can be assessed by radiological scans. In some embodiments, radiological scans can be performed every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, every 16 weeks, every 17 weeks, every 18 weeks, every 19 weeks, every 20 weeks, every 21 weeks, every 22 weeks, every 23 weeks, every 24 weeks, every 28 weeks, every 32 weeks, every 36 weeks, every 40 weeks, every 48 weeks, or every 52 weeks during treatment with a method disclosed herein. In some embodiments, radiological scans can be performed every 8 weeks during treatment with a method disclosed herein. In some embodiments, radiological scans can be performed every 12 weeks during treatment with a method disclosed herein. In some embodiments, radiological scans can be performed every 16 weeks during treatment with a method disclosed herein. In some embodiments, radiological scans can be performed after 1 week, after 2 weeks, after 3 weeks, after 4 weeks, after 5 weeks, after 6 weeks, after 7 weeks, after 8 weeks, after 9 weeks, after 10 weeks, after 11 weeks, after 12 weeks, after 13 weeks, after 14 weeks, after 15 weeks, after 16 weeks, after 17 weeks, after 18 weeks, after 19 weeks, after 20 weeks, after 21 weeks, after 22 weeks, after 23 weeks, after 24 weeks, after 28 weeks, after 32 weeks, after 36 weeks, after 40 weeks, after 44 weeks, after 48 weeks, or after 52 weeks after beginning treatment with a method disclosed herein. In some embodiments, radiological scans can be performed 8 weeks after beginning treatment with amethod disclosed herein. In some embodiments, radiological scans can be performed 16 weeks after beginning treatment with a method disclosed herein. In some embodiments, radiological scans can be performed 24 weeks after beginning treatment with a method disclosed herein. In some embodiments, radiological scans can be performed 36 weeks after beginning treatment with a method disclosed herein. In some embodiments, radiological scans can be performed 48 weeks after beginning treatment with a method disclosed herein.

[0201] In some embodiments, a method disclosed herein can be used to treat a cancer in a subject with measured disease, wherein the disease measurement is measured based on iRECIST criteria. In some embodiments, a method disclosed herein can be used to treat a cancer in a subject, wherein the subject has ECOG performance status of 0 or 1.

[0202] In some embodiments, a method disclosed herein can further comprise measuring progression-free survival of a subject, wherein progression-free survival is as defined as the time from the first dose of a PD-1 inhibitor to progression as defined by iRECIST criteria or death. In some embodiments, a method disclosed herein can further comprise assessing overall survival of subjects undergoing treatment disclosed herein. In some embodiments, a method disclosed herein can further comprise assessing the rate of toxicity in subjects undergoing treatment disclosed herein, wherein the rate of toxicity is as determined by the number of adverse events attributed to treatment disclosed herein.

[0203] In some embodiments a method disclosed herein can be used to treat a cancer in an adult subject over the age of 18 years of age. In some embodiments, a method disclosed herein can be used to treat a cancer in an adult subject over the age of 18 years of age with a histologically confirmed diagnosis of unresectable cutaneous melanoma. In some embodiments, a method disclosed herein can be used to treat a cancer in an adult subject over the age of 18 years of age with a histologically confirmed diagnosis of metastatic cutaneous melanoma. In some embodiments, a method disclosed herein can be used to treat metastatic or unresectable melanoma in a subject who has progressed on treatment with an anti -PD-1 or anti-PD-Ll monoclonal antibody (mAb) administered either as a monotherapy or in combination with other checkpoint inhibitors. In some embodiments, a subject who has progressed on treatment with an anti -PD-1 or an anti-PD-Ll mAb has received at least 2 doses of an anti -PD-1 or an anti-PD-Ll mAb. In some embodiments, a subject who has progressed on treatment with an anti -PD-1 or an anti-PD-Ll mAb has demonstrated disease progression after treatment as defined by iRECIST. In some embodiments, a subject who has progressed on treatment with an anti -PD-1 or an anti-PD- Ll mAb has documented progressive disease within 12 weeks of the last dose of the anti-PD-1 oranti-PD-Ll mAb. In some embodiments, a subject who has progressed on treatment with an anti- PD-1 or an anti-PD-Ll mAb develops recurrent disease during active adjuvant treatment with an anti-PD-1 or an anti-PD-Ll mAb or develops recurrent disease within 6 weeks of the last dose of an anti-PD-1 or an anti-PD-Ll antibody.

[0204] In some embodiments, a method disclosed herein can be used to treat a cancer in a subject, wherein the cancer harbors a BRAFV600mutation. In some embodiments, a method disclosed herein can be used to treat a cancer in a subject, wherein the cancer harbors a BRAFV600mutation and the subject has been exposed to BRAF -targeted therapy. In some embodiments, a method disclosed herein can be used to treat a cancer in a subject, wherein the cancer harbors a BRAFV600mutation, the subject has been exposed to BRAF -targeted therapy, and the BRAF-targeted therapy has been discontinued for progressive disease or intolerable toxicity.

[0205] In some embodiments, a method disclosed herein can be used to treat a cancer in a subject, wherein the subject has adequate organ function. In some embodiments, adequate organ function can be defined by hematological, renal, hepatic, coagulation, and urinary function laboratory values. In some embodiments, hematological laboratory values for adequate organ function include but are not limited to: a white blood cell count of at least 3,000 / p.L, an absolute neutrophil count of at least 1,500 / p.L, a platelet count of at least 75,000 / pL, and a hemoglobin concentration of at least 9 g / dL or at least 5.6 mmol / L. In some embodiments, renal laboratory values for adequate organ function include but are not limited to: serum creatinine or measured or calculated creatinine clearance or glomerular filtration rate of at or less than 1.5-times the upper limit of normal or at or greater than 30 mL / min for a subject with creatinine levels greater than 1.5-times the upper limit of normal. In some embodiments, hepatic laboratory values for adequate organ function include but are not limited to: a serum total bilirubin value of at or less than 1.5-times the upper limit of normal or at or less than 3.0 mg / dL for patients with Gilbert syndrome, and alanine aminotransferase (serum glutamic pyruvic transaminase) and aspartate aminotransferase (serum glutamic oxaloacetic transaminase) values at or less than 2.5-times the upper limit of normal for subjects without liver metastases or at or less than 5-times that upper limit of normal for subjects with liver metastases. In some embodiments, coagulation laboratory values for adequate organ function include but are not limited to an international normalized ration (INR) or prothrombin (PT) and activated partial thromboplastin time (aPTT) value of at or less than 1.5-times the upper limit of normal unless the subject is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range. In some embodiments, urinary functionlaboratory values for adequate organ function include but are not limited to urinalysis results indicating the absence of hematuria with negative blood and 0 red blood cells detected in the urine of the subject.

[0206] In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have a diagnosis of primary uveal or mucosal melanoma. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received prior systemic anti-cancer therapy within 4 weeks for immunotherapeutic agents or within 2 weeks for targeted therapeutics prior to the onset of treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received prior radiotherapy within 2 weeks prior to onset of treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received radiotherapy within 2 weeks prior to the onset of treatment disclosed herein and the subject has not recovered from radiation- related toxicities, requires corticosteroids, or has had radiation pneumonitis. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has recovered from a recent surgery and is not experiencing complications form the surgery. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received a live vaccine or live-attenuated vaccine within 30 days prior to the onset of treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject is not currently participating in, has not participated in a study of an investigation agent, or has used an investigation device within 4 weeks prior to the onset of treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have a diagnosis of immunodeficient or is not receiving chronic system steroid or a form of immunosuppressive therapy within 7 days prior to onset of treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have an additional non-melanoma malignancy that is progressing or has required active treatment within 2 years of onset of treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have untreated active central nervous system metastases, active brain metastases, or leptomeningeal metastatic foci. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have a history of severe hypersensitivity greater than grade 3 to a treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer ina subject wherein the subject does not have an active autoimmune disease requiring systemic treatment within two years of onset of treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have a history of or has pneumonitis or interstitial lung disease requiring steroids. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have an active infection requiring systemic therapy. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have a history of hepatitis B or active Hepatitis C viral infection. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject does not have a history of or positive human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome infection. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not had an allogenic tissue or solid organ transplant. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received or is not undergoing antineoplastic systemic chemotherapy or biological therapy immediately prior to and during treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received or is not undergoing immunotherapy not disclosed herein immediately prior to and during treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received or is not undergoing chemotherapy not disclosed herein immediately prior to and during treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received treatment or is not being treated with investigational agents not disclosed herein immediately prior to and during treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject has not received a live vaccine within 30 days prior to onset of and during treatment, wherein a live vaccine comprises measles, mumps, rubella, varicella / zoster, yellow fever, rabies, BCG, and typhoid vaccines. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject is not receiving treatment with systemic glucocorticoids for a condition not resulting from treatment disclosed herein.

[0207] In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject is not a woman of childbearing potential (WOCBP). In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject is a WOCBP that not is not pregnant or breastfeeding. In some embodiments, a method disclosed herein can beused to treat cancer in a subject wherein the subject is a WOCBP with a negative urine or serum pregnancy test within 72 hours prior to onset of treatment disclosed herein. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject is a WOCBP utilizing contraception prior to and at least four months after termination of treatment disclosed herein, wherein the contraception method comprises a progestogen contraceptive implant, an intrauterine hormone-releasing system, an intrauterine device, bilateral tubal occlusion, or sexual abstinence. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject is a WOCBP with a vasectomized partner. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject is a male of reproductive age utilizing contraception throughout the course of treatment and for at least 90 days after termination of treatment. In some embodiments, a method disclosed herein can be used to treat cancer in a subject wherein the subject is a male of non- reproductive potential, wherein the male subject has azoospermia.

[0208] In some embodiments, a method disclosed herein can further comprise administration of a BRAF inhibitor. In some embodiments, a method disclosed herein can further comprise administration of corticosteroids or equivalents thereof. In some embodiments, a method disclosed herein can further comprise administration of corticosteroids or equivalents thereof, wherein corticosteroid administration decreases adverse events resulting from treatment disclosed herein. In some embodiments, a method disclosed herein can further comprises administration of corticosteroids or equivalents thereof and steroid tapering. In some embodiments, a method disclosed herein can further comprise administration of an antiinflammatory agent. In some embodiments, a method disclosed herein can further comprise bronchoscopy. In some embodiments, a method disclosed herein can further comprise endoscopy. In some embodiments, a method disclosed herein can further comprise performing blood tests on blood samples collected from a subject prior to and throughout treatment, wherein the blood tests include but are not limited to complete blood count, complete metabolic panel, analysis of magnesium levels, and analysis of phosphorous levels. In some embodiments, a method disclosed herein can further comprise performing urine tests on urine samples collected from a subject prior to and throughout treatment, wherein the urine tests include but are not limited to urinalysis. In some embodiments, a method disclosed herein can further comprise molecular analysis of blood and tumor samples obtained from a subject prior to throughout treatment disclosed herein. In some embodiments, molecular analysis of blood and tumor samples comprises analysis of immune cell populations and activation, analysis of T-cellinfiltration, analysis of circulating free DNA (cfDNA), analysis of circulating micro RNA (miRNA), RNA sequencing, analysis of T-cell receptor evolution, and protein and / or cytokine arrays.

[0209] In some embodiments, a dose of a compound disclosed herein can be modified. In some embodiments, a dose of a compound disclosed herein can be modified in response to adverse events, wherein an adverse event is an undesirable sign, symptom, or medical condition or experience that develops or worsens in severity after beginning treatment disclosed herein. In some embodiments, a dose of a compound disclosed herein can be decreased in response to development of an adverse event. In some embodiments, a dose of a compound disclosed herein can be decreased in response to development of an adverse event and increased following cessation of or improvement in an adverse event. In some embodiments, administration of a dose of a compound disclosed herein can be stopped in response to development of an adverse event. In some embodiment, administration of a dose of a compound disclosed herein can be stopped in response to development of an adverse event and resumed following cessation of or improvement in an adverse event. In some embodiment, administration of a dose of a compound disclosed herein can be stopped in response to development of an adverse event and resumed at a lower dose following cessation of or improvement in an adverse event In some embodiments, an adverse event can be a serious adverse event, wherein the serious adverse event comprises an undesirable sign, symptom, or medical condition which is fatal or life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability or incapacity, constitutes a congenital anomaly or birth defect, or jeopardizes a subject and requires medical or surgical intervention. In some embodiments, a dose of a compound disclosed herein can be decreased in response to development of a serious adverse event. In some embodiments, a dose of a compound disclosed herein can be decreased in response to development of a serious adverse event and increased following cessation of or improvement in a serious adverse event. In some embodiments, administration of a dose of a compound disclosed herein can be stopped in response to development of a serious adverse event. In some embodiment, administration of a dose of a compound disclosed herein can be stopped in response to development of a serious adverse event and resumed following cessation of or improvement in a serious adverse event. Severity of adverse events can be evaluated according to NCI CTCAE guidelines, with adverse events scored as Grade 1, Grade 2, Grade 3, Grade 4, or Grade 5 or as mild, moderate, severe, life-threatening, or fatal.

[0210] In some embodiments, a dose of a treatment disclosed herein can be modified. In some embodiments, a dose of a treatment disclosed herein can be modified in response to adverse events, wherein an adverse event is an undesirable sign, symptom, or medical condition or experience that develops or worsens in severity after beginning treatment disclosed herein. In some embodiments, a dose of a treatment disclosed herein can be decreased in response to development of an adverse event. In some embodiments, a dose of a treatment disclosed herein can be decreased in response to development of an adverse event and increased following cessation of or improvement in an adverse event. In some embodiments, administration of a dose of a treatment disclosed herein can be stopped in response to development of an adverse event. In some embodiment, administration of a dose of a treatment disclosed herein can be stopped in response to development of an adverse event and resumed following cessation of or improvement in an adverse event. In some embodiment, administration of a dose of a treatment disclosed herein can be stopped in response to development of an adverse event and resumed at a lower dose following cessation of or improvement in an adverse event In some embodiments, an adverse event can be a serious adverse event, wherein the serious adverse event comprises an undesirable sign, symptom, or medical condition which is fatal or life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability or incapacity, constitutes a congenital anomaly or birth defect, or jeopardizes a subject and requires medical or surgical intervention. In some embodiments, a dose of a treatment disclosed herein can be decreased in response to development of a serious adverse event. In some embodiments, a dose of a treatment disclosed herein can be decreased in response to development of a serious adverse event and increased following cessation of or improvement in a serious adverse event. In some embodiments, administration of a dose of a treatment disclosed herein can be stopped in response to development of a serious adverse event. In some embodiment, administration of a dose of a treatment disclosed herein can be stopped in response to development of a serious adverse event and resumed following cessation of or improvement in a serious adverse event. Severity of adverse events can be evaluated according to NCI CTCAE guidelines, with adverse events scored as Grade 1, Grade 2, Grade 3, Grade 4, or Grade 5 or as mild, moderate, severe, life-threatening, or fatal.

[0211] In some embodiments, a dose of a compound disclosed herein can be modified in response to development of a dose-limiting toxicity. In some embodiments, a dose of a compound disclosed herein can be decreased in response to development of a dose-limiting toxicity. In some embodiments, administration of a compound disclosed herein can be stopped inresponse to development of a dose-limiting toxicity. In some embodiments, administration of a compound can be stopped in response to development of a dose-limiting toxicity and resumed following the cessation of or improvement in a dose-limiting toxicity. In some embodiments, a dose-limiting toxicity comprises: Grade 3-4 febrile neutropenia; Grade 4 neutropenia lasting longer than 5 days; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; ALT and / or AST levels greater than 3-times ULN (upper limit of normal) with bilirubin greater than 2-times ULN without another explanation; Grade 4 nausea / vomiting / diarrhea of any duration; or Grade 3 or above non-hematologic toxicity excluding Grade 3 nausea managed with maximal medical therapy that has persisted < 72 hours, Grade 3 vomiting and / or diarrhea managed with maximal medical therapy that has persisted < 72 hours, or Grade 3 fatigue < 7 days.

[0212] In some embodiments, a dose of a treatment disclosed herein can be modified in response to development of a dose-limiting toxicity. In some embodiments, a dose of a treatment disclosed herein can be decreased in response to development of a dose-limiting toxicity. In some embodiments, administration of a treatment disclosed herein can be stopped in response to development of a dose-limiting toxicity. In some embodiments, administration of a treatment can be stopped in response to development of a dose-limiting toxicity and resumed following the cessation of or improvement in a dose-limiting toxicity. In some embodiments, a dose-limiting toxicity comprises: Grade 3-4 febrile neutropenia; Grade 4 neutropenia lasting longer than 5 days; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; ALT and / or AST levels greater than 3-times ULN with bilirubin greater than 2-times ULN without another explanation; Grade 4 nausea / vomiting / diarrhea of any duration; or Grade 3 or above non- hematologic toxicity excluding Grade 3 nausea managed with maximal medical therapy that has persisted < 72 hours, Grade 3 vomiting and / or diarrhea managed with maximal medical therapy that has persisted < 72 hours, or Grade 3 fatigue < 7 days.

[0213] In some embodiments, administration of a treatment disclosed herein can be stopped. In some embodiments, administration of a treatment disclosed herein can be stopped in response to development of an adverse event, severe adverse event, toxicity, or dose-limiting toxicity. In some embodiments, administration of a treatment disclosed herein can be stopped following observation of disease progression. In some embodiments, administration of a treatment disclosed herein can be stopped following observation of disease progression, wherein the observing is radiographically. In some embodiments, administration of a treatment disclosed herein can be stopped following progression or recurrence of a malignancy. In some embodiments, administration of a treatment disclosed herein can be stopped followingoccurrence of a malignancy requiring active treatment. In some embodiments, administration of a treatment disclosed herein can be stopped following a confirmed positive serum pregnancy test. In some embodiments, administration of a treatment disclosed herein can be interrupted and restarted following the interruption. In some embodiments, administration of rigosertib can be interrupted and resumed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, administration of rigosertib can be interrupted and restarted within 4 days of the originally scheduled dose or within 4 days of the previously administered dose if the interruption occurs during days 1-21 of the treatment cycle. In some embodiments, administration of rigosertib can be interrupted and restarted within 7 days of the planned cycle initiation if the interruption occurs during days 22-28 of the treatment cycle. In some embodiments, administration of pembrolizumab or a PD-1 inhibitor can be interrupted and restarted within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks of the originally scheduled dose. In some embodiments, administration of pembrolizumab or a PD-1 inhibitor can be interrupted and restarted within 6 weeks of the originally scheduled dose. In some embodiments, administration of pembrolizumab or a PD-1 inhibitor can be interrupted and restarted within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks of the previously administered dose. In some embodiments, administration of pembrolizumab or a PD-1 inhibitor can be interrupted and restarted within 8 weeks of the previously administered dose.

[0214] In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject. In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject, wherein the subject has a cancer. In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject, wherein the subject has unresectable or metastatic melanoma refractory to PD-1. In some embodiments, rigosertib can be administered at a dose of 280 mg twice a day. In some embodiments, rigosertib can be administered at a dose of 560 mg twice a day. In some embodiments, a rigosertib can be administered in two doses. In some embodiments, rigosertib can be administered as one 280 mg dose and one 560 mg dose. In some embodiments, rigosertib 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, rigosertib can be administered at a first dose of 280 mg in the morning or early afternoon, and a second dose of 280 mg in the afternoon or evening. In some embodiments, rigosertib can be administered at a first dose of 280 mg in themorning or early afternoon, and a second dose of 560 mg in the afternoon or evening. In some embodiments, rigosertib can be administered at a first dose of 560 mg in the morning or early afternoon, and a second dose of 280 mg in the afternoon or evening. In some embodiments, rigosertib can be administered at a first dose of 280 mg in the morning or early afternoon, and a second dose of 560 mg in the afternoon or evening. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 560 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered. In some embodiments, rigosertib is administered in a fasting state, about 1-2 hours before or after a meal. In some embodiments, rigosertib is administered in a fasting state, wherein the first 560 mg dose is administered in the morning after an overnight fast, and the second 560 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach. In some embodiments, rigosertib is administered in a fasting state, wherein the first 560 mg dose is administered in the morning after an overnight fast, the second 560 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach, and the next meal is consumed at least one hour after administering the second dose. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered. In some embodiments, rigosertib is administered in a fasting state, about 1-2 hours before or after a meal. In some embodiments, rigosertib is administered in a fasting state, wherein the first 560 mg dose is administered in the morning after an overnight fast, and the second 280 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach. In some embodiments, rigosertib is administered in a fasting state, wherein the first 560 mg dose is administered in the morning after an overnight fast, the second 280 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach, and the next meal is consumed at least one hour after administering the second dose. In some embodiments, rigosertib can be administered at a dose of about 280 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered. In some embodiments, rigosertib is administered in a fasting state, about 1-2 hours before or after a meal. In some embodiments, rigosertib is administered in a fasting state, wherein the first 280 mg dose is administered in the morning after an overnight fast, and the second 280 mg dose is administered in the afternoon at least two hours after a meal on an empty stomach. In some embodiments, rigosertib is administered in a fasting state, wherein the first 280 mg dose is administered in the morning after an overnight fast, the second 280 mg dose is administered inthe afternoon at least two hours after a meal on an empty stomach, and the next meal is consumed at least one hour after administering the second dose.

[0215] In some embodiments, rigosertib is administered in a 28-day cycle, wherein on days 1-21 of the cycle rigosertib is administered twice daily and on days 22-28 rigosertib is not administered. In some embodiments, the 28-day administration cycle for rigosertib repeats 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45 times, 46 times, 47 times, or 48 times. In some embodiments, the28-day administration cycle for rigosertib repeats 6 times. In some embodiments, the 28-day administration cycle for rigosertib repeats 8 times. In some embodiments, the 28-day administration cycle for rigosertib repeats 12 times. In some embodiments, the 28-day administration cycle for rigosertib repeats 24 times.

[0216] In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject. In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject, wherein the subject has a cancer. In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject, wherein the subject has unresectable or metastatic melanoma refractory to PD-1. In some embodiments, pembrolizumab is administered over 30 minutes. In some embodiments, pembrolizumab is administered over 60 minutes. In some embodiments, pembrolizumab is administered at a dose of about 200 mg every 3 weeks over 30 minutes. In some embodiments, pembrolizumab is administered at a dose of about 200 mg every 3 weeks over 60 minutes. In some embodiments, pembrolizumab is administered at a dose of about 400 mg every 6 weeks over 30 minutes. In some embodiments, pembrolizumab is administered at a dose of about 400 mg every 6 weeks over 60 minutes. In some embodiments, pembrolizumab is administered every 6 weeks in a cycle for 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, 20 cycles, 21 cycles, 22 cycles, 23 cycles, or 24 cycles. In some embodiments, pembrolizumab is administered for 4 cycles. In some embodiments, pembrolizumab is administered for 5 cycles. In some embodiments, pembrolizumab is administered for 12 cycles. In some embodiments, pembrolizumab is administered for 18 cycles.

[0217] In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject. In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject, wherein the subject has a cancer. In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject, wherein the subject has unresectable or metastatic melanoma refractory to PD-1. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 560 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 24 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 30 minutes in a 6-week cycle for 18 cycles. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 24 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 30 minutes in a 6-week cycle for 18 cycles. In some embodiments, rigosertib can be administered at a dose of about 280 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 24 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 30 minutes in a 6-week cycle for 18 cycles. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 560 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 24 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 60 minutes in a 6-week cycle for 18 cycles. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 24 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 60 minutes in a 6-week cycle for 18 cycles. In some embodiments, rigosertib can be administered at a dose of about 280 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 24 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 60 minutes in a 6-week cycle for 18 cycles.

[0218] In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject. In some embodiments, amethod disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject, wherein the subject has a cancer. In some embodiments, a method disclosed herein comprises oral administration of rigosertib and intravenous infusion of pembrolizumab to a subject, wherein the subject has unresectable or metastatic melanoma refractory to PD-1. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 560 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 8 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 30 minutes in a 6-week cycle for 5 cycles. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 8 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 30 minutes in a 6-week cycle for 5 cycles. In some embodiments, rigosertib can be administered at a dose of about 280 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 8 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 30 minutes in a 6-week cycle for 5 cycles. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 560 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 8 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 60 minutes in a 6-week cycle for 5 cycles. In some embodiments, rigosertib can be administered at a dose of about 560 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 8 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 60 minutes in a 6-week cycle for 5 cycles. In some embodiments, rigosertib can be administered at a dose of about 280 mg once in the morning and about 280 mg in the evening daily for 3 weeks, followed by one week off where rigosertib of the disclosure is not administered in a 28-day cycle for 8 cycles and pembrolizumab can be administered at a dose of about 400 mg every 6 weeks over 60 minutes in a 6-week cycle for 5 cycles.EXAMPLESEXAMPLE 1: Study to Evaluate an Oral Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.

[0219] Approximately 30 patients are enrolled in a dose escalation study of rigosertib in nonsmall cell lung cancer to investigate doses of rigosertib in combination with nivolumab. The dose of nivolumab is 240 mg every two weeks or 480 mg every four weeks. 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 and RP2D are determined based on DLTs 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.

[0220] Following determination of the RP2D a randomized, controlled phase 2 study is performed with rigosertib combination with nivolumab. Approximately 200 patients are enrolled in a 1 : 1 ratio to receive either nivolumab + placebo or nivolumab + 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.

[0221] Approximately 30 patients are enrolled in a dose escalation study of IV rigosertib in colorectal cancer to determine the MTD in combination with nivolumab. The study is performed in combination with standard dose check point inhibition as per the label. 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.

[0222] Following determination of the RP2D a randomized, controlled phase 2 study is performed in combination with nivolumab. Approximately 200 patients are enrolled in a 1 : 1 ratio to receive either nivolumab + placebo or nivolumab + 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.

[0223] 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.

[0224] 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 immune checkpoint inhibitors

[0225] 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 a 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.

[0226] Multiple mouse models are employed to test the efficacy of rigosertib in RAS mutated cancers in combination with an immune checkpoint inhibitor. A patient-derived xenograft (PDX) model is used for the experiments, including samples obtained from NSCLC, colo-rectal, and pancreatic cancer patient. The specific PDX model used is determined based on the KRAS mutation status of the patient sample. The tumors are analyzed via genomic sequencing to determine the KRAS mutation and any other driver mutations or amplifications in other known cell cycle or survival signaling pathways.

[0227] Patient derived samples are studied in humanized mice. Since optimal activity of checkpoint 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 humanperipheral blood cells. After transplantation, the mice are engrafted with the KRAS driven PDX line and treated as described below.

[0228] In addition to the humanized models employing PDX models, rigosertib and checkpoint inhibitor combinations are studied in murine syngeneic models. Syngeneic models utilize allografts of KRAS 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 KRAS mutation driven cancers.

[0229] The animal assays establish the ability of rigosertib to synergize the activity of the checkpoint 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-checkpoint inhibitor combination treatments.

[0230] The humanized mice are implanted either subcutaneously or orthotopically with patient derived tumor tissue. Syngeneic mice are implanted subcutaneously with KRAS 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 checkpoint inhibitor.

[0231] 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

[0232] The animals dosed with checkpoint inhibitors are administered a dose at a schedule that is clinically relevant. For example, nivolumab is tested in a dose range between 5-30 mg / kgadministered 1-2 times per week by intraperitoneal injection. Pembrolizumab is administered 5- 10 mg / kg every 3-5 days by intraperitoneal injection. For syngeneic models, mouse anti-PD-1, PD-L1 and CTLA-4 clones are used for optimal antigen specific recognition. In addition to the combination groups, control groups consist of rigosertib alone, the checkpoint inhibitor alone, and an appropriate vehicle control.

[0233] 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 W2x 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 oral rigosertib in combination with intravenous pembrolizumab in patients with metastatic melanoma refractory to PD-1 inhibitor therapy.

[0234] The efficacy of rigosertib in combination with pembrolizumab is evaluated in patients with metastatic melanoma who are refractory to treatment with a PD-1 inhibitor. All patients have at least one baseline measurable lesions by iRECIST 1.1 definition on CT or MRI. Patients are administered rigosertib beginning on Day 1 of each 28-day treatment cycle at a dose of 560 mg orally twice daily, once in the morning after an overnight fast and on an empty stomach waiting an hour after administering to consume food and once in the afternoon on an empty stomach at least 2 hours after the last meal, waiting an hour after administering to consume a meal. Rigosertib is administered twice daily for a period of 21 days followed by 1 week of no rigosertib administration in a 28-day cycle. The PD-1 inhibitor pembrolizumab is administered at a dose of 400 mg via intravenous infusion over a period of 30 minutes on the first day of a 6- week cycle. Throughout the administration period, patients are instructed to maintain good hydration, e.g., consuming at least 2 liters of water per day. Trial interventions are detailed in TABLE 5.TABLE 5Rigosertib is supplied as oral capsules of an opaque yellow-orange capsule with rigosertib suspended at a concentration of 280 mg / mL in PEG 400 and PEG 4000. Each capsule of rigosertib contains a total of 280 mg of rigosertib. For a 560 mg dose of rigosertib, a patient consumes two capsules of rigosertib. Pembrolizumab is supplied as a solution for injection in a vial at a concentration of 100 mg pembrolizumab / 4 mL corresponding to 25 mg / mL.

[0235] Patients will receive treatment until one of the following conditions has been met: confirmed disease progression, intolerable toxicity, confirmed complete response, withdrawal of consent, completion of two years of therapy, or until requirement of antineoplastic therapy. Throughout the course of the study, tumor assessment is performing by radiological scans taken every eight weeks beginning after 8 weeks of administration and every 8 weeks thereafter for the first 24 weeks of the study, followed by every 12 weeks thereafter. Tumor response is evaluated based on the iRECIST criteria.

[0236] Exclusion Criteria

[0237] Patients are excluded from participating in the study if they meet any one of the following criteria:• Have a diagnosis of primary uveal or mucosal melanoma.• Are a woman of childbearing potential with 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 will be required. Patients who receive a positive pregnancy test during the course of the study will be withdrawn from the study.• Have previously received one or more immunotherapeutic agents as an investigational anti-cancer therapeutic agent within 4 weeks of the first dose of rigosertib.• Have previously received a one or more targeted therapeutic as an investigational anticancer therapeutic agent within 2 weeks of the first dose of rigosertib.• Have experienced a prior adverse event from a prior anti-cancer treatment that has not recovered to less than Grade 1 or at baseline. Patients with less than Grade 2 neuropathy or patients with endocrine-related adverse events less than Grade 2 requiring treatment or physiological steroid replacement may be eligible.• Have previously received radiotherapy within 2 weeks of the first dose of rigosertib. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation consisting of at most of 2 weeks of radiotherapy for non-central nervous system disease.• If, having undergone recent major surgery, are not adequately from the procedure or are experiencing complications from the surgery prior to receiving the first dose of rigosertib.• Have received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of rigosertib; a patient who has received a killed vaccine is eligible.• Are participating or have participate in a study of an investigational agent or used an investigational device within 4 weeks prior to the first dose of rigosertib. Patients in the follow-up phase of an investigational study are eligible as long as 4 weeks have passed after the last dose of the previous investigational agent.• Have a diagnosis of immunodeficiency or are receiving chronic system steroid therapy in a dose exceeding 10 mg daily of prednisone or an equivalent or are receiving any other form of immunosuppressive therapy within 7 days prior to the first dose of rigosertib.• Have a known additional malignancy that is progressing or has required active treatment within 2 years of the first dose of rigosertib. Patients 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.• Have untreated active central nervous system (CNS) metastases, active brain metastases, or leptomeningeal metastatic foci. Patients with brain metastases are eligible if they have received treatment and have no evidence of progressive disease on MRI at least 4 weeks after completion of the treatment and within 30 days prior to the first dose of rigosertib.• Have a history of severe hypersensitivity (>Grade 3), specifically infusion reaction or anaphylaxis to pembrolizumab and / or any of its excipients.• Have a history of severe hypersensitivity (>Grade 3 reactions including wheezing, rash, or hypotension) to rigosertib and / or any of its excipients (including polyethylene glycol), or anaphylaxis.• Have 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.• Have a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.-n-• Have an active infection requiring systemic therapy.• Have 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.• Have a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).• Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with participation for the full duration of the study, or is not in the best interest to participate, in the opinion of the treating investigator.• Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.• Are 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.• Have had an allogenic tissue / solid organ transplant.

[0238] irAEs and Dose Modification and Toxicity Management Guidelines

[0239] Adverse events associated with pembrolizumab exposure may represent an immunologic etiology, with the immune-related adverse events (irAEs) occurring shortly after the first of pembrolizumab or after the last dose. Suspected irAEs are evaluated to confirm etiology or exclude other potential causes, with additional procedures or tests (e.g., bronchoscopy, endoscopy, or skin biopsy) potentially utilized as part of the evaluating. Confirmed irAEs are managed with interruptions of pembrolizumab or combination therapy, administration of corticosteroids, and / or administration of other supportive care.

[0240] Patients are monitored for signs and symptoms of pneumonitis and patients with suspected pneumonitis are evaluated with radiographic imaging to confirm. For patients with pneumonitis with a Toxicity Grade (CTCAE v5.0) Grade 2, pembrolizumab is withheld until the dissipation of the irAE and for patients with recurrent Grade 2, Grade 3, or Grade 4 pneumonitis pembrolizumab administration is permanently discontinued. In addition to modifying pembrolizumab administration, patients with pneumonitis are administered corticosteroids (e.g., prednisone or an equivalent at a dose of 1 to 2 mg / kg) followed by taper. Corticosteroidadministration can be combined with administration of prophylactic antibiotics for opportunistic infections.

[0241] Patients are monitored for signs and symptoms of enterocolitis (e.g., diarrhea, abdominal pain, blood or mucus in stool with or without fever) and for signs of symptoms of bowel perforation (e.g., peritoneal signs and ileus). For patients with Grade 2 or Grade 3 diarrhea and / or colitis, pembrolizumab administration is withheld until dissipation of diarrhea / colitis and for patients with recurrent Grade 3 or Grade 4 diarrhea and / or colitis, pembrolizumab administration is permanently discontinued. In addition to modifying pembrolizumab administration, patients with diarrhea and / or colitis are administered corticosteroids (e.g., prednisone or equivalent at an initial dose of 1 to 2 mg / kg) followed by tape. Patients with Grade 2 diarrhea or above with suspected colitis can receive GI consultation and undergo endoscopy to rule out colitis. Patients with diarrhea and / or colitis should maintain adequate hydration (e.g., oral fluid intake of clear fluids or IV infusion of fluid and electrolytes when oral fluid intake is not feasible.

[0242] Patient are monitored with liver function tests for AST or ALT elevation or increased bilirubin. AST or ALT elevation or increased bilirubin Grades are defined by the following liver function test values:• Grade 2: o AST / ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal o bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal• Grade 3 : o AST / ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal o bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal• Grade 4: o AST / ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal o bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormalFor patients with Grade 2 AST or ALT elevation or increased bilirubin, pembrolizumab is withheld and corticosteroids (e.g., prednisone or equivalent at an initial dose of 0.5 to 1 mg / kg) followed by taper are administered. For patients with Grade 3 or Grade 4 AST or ALT elevationor increased bilirubin, pembrolizumab administration is permanently discontinued and corticosteroids (e.g., prednisone or equivalent at an initial dose of 1 to 2 mg / kg) followed by taper are administered. Throughout, liver function tests are performed (e.g., weekly or more frequently) until liver enzyme values are returned to baseline or are stable.

[0243] Patient are monitored for hyperglycemia or other signs and symptoms of diabetes. For participants with new onset type 1 diabetes mellitus (T1DM) or Grade 3 or Grade 4 hyperglycemia associated with evidence of -cell failure, pembrolizumab administration is withheld and for patients with T1DM, insulin replacement therapy is initiated and for patients with hyperglycemia, antihyperglycemics are administered.

[0244] Patients are monitored for signs and symptoms of hypophysitis (e.g., hypopituitarism and adrenal insufficiency). For patients with Grade 2 hypophysitis, pembrolizumab administration is withheld and for patients with Grade 3 or Grade 4 hypophysitis, pembrolizumab administration is withheld or permanently discontinued. Concurrent with pembrolizumab dose management, corticosteroids are administered, and hormonal replacement treatment is initiated per clinical indications.

[0245] Patients are monitored for signs and symptoms of thyroid disorders. For patients with Grade 2 hyperthyroidism, pembrolizumab administration is continued and for patients with Grade 3 or Grade 4 hyperthyroidism, pembrolizumab administration is withheld or permanently discontinued. Concurrently, nonselective beta-blockers (e.g., propranolol) or thionamides are administered.

[0246] Patients are monitored for signs and symptoms of thyroid disorders. For patients with Grade 2, Grade 3, or Grade 4 hypothyroidism, pembrolizumab administration is continued. Concurrently, thyroid replacement hormones (e.g., levothyroxine or liothyronine) are administered.

[0247] Patients are monitored for changes of renal function. Nephritis is graded accorded according to increased creatinine or acute kidney injury. For patients with Grade 2 nephritis, pembrolizumab administration is withheld and for patients with Grade 3 or Grade 4 nephritis, pembrolizumab administration is permanently discontinued. In addition to pembrolizumab dose management, corticosteroids (e.g., prednisone or equivalent at an initial dose of 1 to 2 mg / kg) followed by taper are administered.

[0248] Patients are monitored for neurological toxicities. Adequate evaluation to confirm etiology and / or exclude other causes of neurological toxicity is necessary. For patients with Grade 2 neurological toxicities, pembrolizumab administration is withheld and for patients with Grade 3 or Grade 4 neurological toxicities, pembrolizumab administration is permanentlydiscontinued. Corticosteroids are concurrently administered in combination with pembrolizumab dose management based on the severity of the neurological toxicity adverse event.

[0249] Patients are monitored for myocarditis. Adequate evaluation to confirm etiology and / or exclude other causes of myocarditis is necessary. For patients with Grade 1 myocarditis, pembrolizumab administration is withheld and for patients with Grade 2, Grade 3, or Grade 4 myocarditis, pembrolizumab administration is permanently discontinued. Corticosteroids are concurrently administered in combination with pembrolizumab dose management based on the severity of the myocarditis adverse event.

[0250] Patients are evaluated for exfoliative dermatologic conditions. Adequate evaluation to confirm etiology and / or exclude other causes is necessary. For patients with suspected Stevens- Johnsons syndrome (SJS), Toxic epidermal necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) pembrolizumab administration is withheld. For patients with confirmed SJS, TEN, or DRESS pembrolizumab administration is permanently discontinued. Corticosteroids are concurrently administered in combination with pembrolizumab dose management based on severity of the adverse event.

[0251] Patients are evaluated for other irAEs with adequate evaluation to confirm etiology and / or exclude other causes. For patients with persistent Grade 2 irAEs, pembrolizumab administration is withheld. For patients with Grade 3 irAEs, pembrolizumab administration is withheld or discontinued, depending on the irAEs. Grade 3 irAEs warranting discontinuation of pembrolizumab administration include but are not limited to encephalitis, vasculitis, and sclerosing cholangitis. For patients with recurrent Grade 3 or Grade 4 irAEs, pembrolizumab administration is permanently discontinued. Corticosteroids are concurrently administered in combination with pembrolizumab dose management based on the severity of the adverse event.

[0252] The dose of corticosteroid should not exceed 10 mg / day within 12 weeks of the last study intervention treatment. Failure for the irAE to resolve warrants in permanent discontinuation of pembrolizumab administration. Corticosteroid taper should begin when the irAE is at or less than Grade 1 and continue for at least 4 weeks. For all irAEs, other immunosuppressive treatments should be initiated if the irAE is not controlled by corticosteroids. For irAEs where pembrolizumab administration has been withheld, pembrolizumab administration may resume after the irAE has decreased to at or less than Grade 1 following corticosteroid taper.

[0253] Rigosertib adverse events and dose modification

[0254] Adverse events associated with oral rigosertib administration include urinary toxicity and hyponatremia. Dose administration strategies, including urinary management strategies of maintaining good hydration status (at least 2 L per day), afternoon dosing of the second dailydose, and emptying of the bladder before sleep minimize bladder dwell of rigosertib and mitigate risk of urinary toxicity.

[0255] Patients are monitored for signs and symptoms of renal dysfunction (e.g., serum creatinine, or renal ultrasound) and serial urinalysis is monitored in combination with potential urine cytology and urology consultation. For patients with urinary toxicity including: dysuria, hematuria, pollakiuria, proteinuria, urinary retention, or cystitis rigosertib administration is modified according to Toxicity Grade (CTCAE v5.0).• For patients with an initial Grade 2 urinary toxicity episode, the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following resolving of the urinary toxicity, rigosertib administration is resumed at 560 mg twice daily, corresponding to the full starting dose of rigosertib.• For patients with recurrent Grade 2 urinary toxicity experiencing a second episode or an initial episode of Grade 3 urinary toxicity, the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following resolving the urinary toxicity, rigosertib administration is resumed at 560 mg administered in the morning followed by 280 mg in the afternoon, corresponding to the first dose reduction.• For patients with recurrent Grade 2 urinary toxicity experiencing a third episode or a second episode of recurrent Grade 3 urinary toxicity, the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following resolving the urinary toxicity, rigosertib administration is resumed at a dose 280 mg twice daily, corresponding to the second dose reduction.• For patients with recurrent Grade 3 urinary toxicity experiencing a third episode or Grade 4 urinary toxicity, rigosertib administration is permanently discontinued.

[0256] In addition to dose reduction, supportive care for urinary toxicity including hydration (e.g., oral and / or intravenous, urinary alkinazation and / or bladder anti-spasmodics (e.g., mirabegron, darifenacin, oxybutynin) can be administered.

[0257] Patients are evaluated for signs and symptoms of hyponatremia. Patients can be monitors with serial electrolyte evaluation.• For patients with an initial Grade 2 hyponatremia episode, the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following resolving of the hyponatremia, rigosertib administration is resumed at 560 mg twice daily, corresponding to the full starting dose of rigosertib.• For patients with recurrent Grade 2 hyponatremia experiencing a second episode or an initial episode of Grade 3 hyponatremia, the rigosertib dose is delayed for up to 4 weeksuntil toxicity resolves to at or less than Grade 1. Following resolving of the hyponatremia, rigosertib administration is resumed at 560 mg administered in the morning followed by 280 mg in the afternoon, corresponding to the first dose reduction.• For patients with recurrent Grade 2 hyponatremia experiencing a third episode or a second episode of recurrent Grade 3 hyponatremia, the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following resolving of the hyponatremia, rigosertib administration is resumed at a dose 280 mg twice daily, corresponding to the second dose reduction.• For patients with recurrent Grade 3 hyponatremia experiencing a third episode or Grade 4 hyponatremia, rigosertib administration is permanently discontinued.

[0258] In addition to rigosertib dose reduction, additional measures including supportive care and general of ICU admission for symptomatic or significant derangement can be applied to the patient.

[0259] Patients are evaluated for the presence of other adverse events. Additionally, patients are evaluated to confirm etiology and / or exclude other causes.• For patients with an initial Grade 2 AE, the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following resolving of the AE, rigosertib administration is resumed at 560 mg twice daily, corresponding to the full starting dose of rigosertib.• For patients with a recurrent Grade 2 AE experiencing a second episode or an initial episode of a Grade 3 AE, the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following resolving of the AE, rigosertib administration is resumed at 560 mg administered in the morning followed by 280 mg in the afternoon, corresponding to the first dose reduction.• For patients with a recurrent Grade 2 AE experiencing a third episode or a second episode of a recurrent Grade 3 AE, the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following resolving of the AE, rigosertib administration is resumed at a dose 280 mg twice daily, corresponding to the second dose reduction.• For patients with a recurrent Grade 3 AE experiencing a third episode or a Grade 4 AE excluding neutropenia, thrombocytopenia, nausea, vomiting, or diarrhea rigosertib administration is permanently discontinued.• For patients with a Grade 4 neutropenia, thrombocytopenia, nausea, vomiting, or diarrhea the rigosertib dose is delayed for up to 4 weeks until toxicity resolves to at or less than Grade 1. Following the resolving of the AE, rigosertib administration is resumed at a reduced dose.

[0260] In addition to rigosertib dose reduction, additional measures including supportive care and general of ICU admission for symptomatic or significant derangement can be applied to the patient.

[0261] Patients are monitored and evaluated for SJS, TEN, or DRESS. For patients with confirmed SJS, TEN, or DRESS rigosertib administration is permanently discontinued. Supportive care, dermatology consultation, and general or ICU admission for symptomatic or significant derangement can be combined with rigosertib dose discontinuation.

[0262] Dose-limiting and treatment toxicities for oral rigosertib administration include 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)

[0263] Following observation of a treatment-related toxicity, rigosertib administration is held for up to 4 weeks until the toxicity is resolved to at or less than Grade 1. Following resolving of the toxicity, rigosertib administration will resume at a reduced dosage according to the dose reduction detailed in TABLE 6.TABLE 6Toxicity is re-assessed prior to resuming administration of rigosertib administration and after a 28 day cycle of treatment following the dose reduction. If toxicity or adverse events resolve to Grade 1 or baseline at the reduced level with no additional toxicities observed at the reduced dose, the rigosertib dose may be increased in a step-wise manner (e.g., second dose reduction to first dose reduction, first dose reduction to full starting dose). If toxicity persists at Grade 2, rigosertib administration is continued at a reduce dose and if toxicity persists for greater than four weeks at or above Grade 2, rigosertib is withheld.

[0264] Infusion reactions related to pembrolizumab

[0265] Participants are monitored for adverse reactions related to pembrolizumab infusion. Reactions are graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading scheme and treatment modified according to the guidelines in TABLE 7.TABLE 7.

[0266] Clinical and Laboratory Procedures and Assessments

[0267] Throughout the course of the trial, clinical and laboratory procedures and assessments are performed. Patients are screened for adverse events every two weeks throughout the administration period beginning with the first 28-day administration cycle and continuing for the first four administration cycles. Thereafter, patients are screened for adverse events on day 1 of cycles 7, 10, 13, 16, 19, and 22 on day 15 of cycles 5, 8, 11, 14, 15, 20, and 23, following discontinuation of treatment, and during the safety follow-up and follow up periods. Patients are assessed for concomitant medications during the screening phase prior to initiation of treatment with rigosertib and pembrolizumab, and every two weeks throughout the administration period beginning with the first 28-day administration cycle and continuing for the first four administration cycles. Thereafter patients are evaluated on day 1 of cycles 7, 10, 13, 16, 19, and 22 on day 15 of cycles 8, 11, 14, 15, 20, and 23, and following discontinuation of treatment. Patients’ vital signs and weight are measured and recorded during the screening phase prior to initiation of treatment with rigosertib and pembrolizumab, and every two weeks throughout the administration period beginning with the first 28-day administration cycle and continuing for thefirst four administration cycles. Thereafter patients are evaluated on day 1 of cycles 7, 10, 13, 16, 19, and 22 on day 15 of cycles 8, 11, 14, 15, 20, and 23, and following discontinuation of treatment. The Eastern Cooperative Oncology Group (ECOG) performance status is recorded during the screening phase prior to initiation of treatment with rigosertib and pembrolizumab, and every two weeks throughout the administration period beginning with the first 28-day administration cycle and continuing for the first four administration cycles. Thereafter patients are evaluated on day 1 of cycles 7, 10, 13, 16, 19, and 22 on day 15 of cycles 8, 11, 14, 15, 20, and 23, and following discontinuation of treatment. For women of reproductive potential, a pregnancy test (e.g., urine or serum) will be performed during the screening phase and within 72 hours of the first dose of rigosertib. Patients will receive a physical exam during the screening phase prior to initiation of treatment with rigosertib and pembrolizumab, and every two weeks throughout the administration period beginning with the first 28-day administration cycle and continuing for the first four administration cycles. Thereafter patients are evaluated on day 1 of cycles 7, 10, 13, 16, 19, and 22 on day 15 of cycles 8, 11, 14, 15, 20, and 23, and following discontinuation of treatment. For women of reproductive potential, a pregnancy test (e.g., urine or serum) will be performed during the screening phase and within 72 hours of the first dose of rigosertib. Thereafter, women of reproductive potential will be required to take a pregnancy test every 3 months of treatment and following discontinuation of treatment. A complete blood count with differential will be obtained during the screening phase and every two weeks for the first two treatment cycles, on day 1 of treatment cycles 3, 4, 7, 10, 13, 16, 19, and 22 and on day 15 of treatment cycles 5, 8, 11, 14, 15, 20, and 23, and following discontinuation of treatment. A comprehensive metabolic panel (CMP) will be obtained during the screening phase, every two weeks throughout the administration period beginning with the first 28-day administration cycle and continuing for the first four cycles. Thereafter, a CMP will be obtained on day 1 of administration cycles 7, 10, 13, 16, 19, and 21, on day 15 of administration cycles 5, 8, 11, 14, 15, 20, and 23, and following discontinuation of treatment. Patients will undergo urinalysis beginning at the screening phase prior to administration of rigosertib and pembrolizumab, and on day 1 of administration cycles 1, 2, 3, 4, 7, 10, 13, 16, 19, and 22. Magnesium and phosphorus levels will be measured during the screening phase, every two weeks throughout the administration period beginning with the first 28-day administration cycle and continuing for the first four cycles. Thereafter, a magnesium and phosphorous levels will be measured on day 1 of administration cycles 7, 10, 13, 16, 19, and 21, on day 15 of administration cycles 5, 8, 11, 14, 15, 20, and 23, following discontinuation of treatment, and during safety follow-up. Troponin levels will be measured during the screening phase prior to administration of rigosertib andpembrolizumab and on day 1 of cycle 3 of the administration cycle. Thyroid testing will be performed during the screening phase, on day 1 of administration cycle 3, on day 15 of administration cycles 5, 8, 11, 14, 15, 20, and 23, following discontinuation of treatment, and during safety follow-up screening. Lactate dehydrogenase levels will be measured during the screening visit prior to administration of rigosertib and pembrolizumab, following discontinuation of treatment, and during safety follow-up screening.

[0268] Exploratory Biomarkers

[0269] A blood sample (e.g., a 10 mL sample) will be collected from patients every two weeks during the administration period for the first two administration cycles, on day 1 of administration cycles 3, 4, 7, 10, 13, 16, 19, and 22, and on day 15 of administration cycles 5, 8, 11, 14, 15, 20, and 23. Following collection, blood samples will be processed with standard Ficoll extraction procedures to isolate peripheral blood mononuclear cells (PMBCs) and serum. Serum will be aliquoted into 1 mL labeled cryovials, and slow-frozen in ethanol prior to longterm storage in liquid nitrogen. Cytokine levels will be measured in banked serum via a cytokine array. Following isolation of PBMCs, the PBMCs will be washed in PBS twice, counted, and suspended in fetal bovine serum containing 10% DMSO prior to aliquoting into labeled cryovials. Isolated PBMCs will be slow-frozen in ethanol prior to long-term storage in liquid nitrogen. Bull RNA sequencing for T-cell receptor interrogation and fluorescence automated cell cytometry will be used to characterize change to the peripheral immune milieu in response to treatment with rigosertib and pembrolizumab. Additional analyses can include analysis of immune cell population, circulating free DNA, circulating micro RNA, and protein and cytokine arrays.

[0270] On-treatment biopsies are obtained from patients and interrogated to determine changes in T-cell infiltration induced by treatment with rigosertib and pembrolizumab and compared to archival pre-treatment tumor biopsies. On-treatment biopsies will be evaluated for T-cell receptor evolution by RNA-sequencing. In addition, biopsy samples will be formalin fixed and paraffin embedded and analyzed with immunohistochemical staining or used in the development of tumor organoids for downstream analyses.

[0271] Endpoints

[0272] The primary endpoint for the study is object response rate (ORR) as defined by immune- related response criteria. Secondary endpoints include progression free survival, as defined as the time from the first dose of pembrolizumab to progression as defined by iRECIST criteria or death; overall survival as defined as the interval between the first dose of pembrolizumab and death; and rate of toxicity with adverse events attributed to study drugs listed by CTCAE gradeand reported in terms of the number of patients who experience adverse events as a percentage of all treated patients. An exploratory object is to evaluate change in tumor-infiltrating lymphocytes upon treatment with rigosertib and pembrolizumab.EMBODIMENTS

[0273] The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention.

[0274] 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:or a pharmaceutically-acceptable salt or zwitterion thereof, wherein: each R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rlla, Rllb, R12, and R13is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -C(O)RX, -C(O)ORX, -C(O)NRxRy, -ORX, -SRX, -NRxRy, -NRxC(O)Ry, -OC(O)RX, or -SiRxRyRz, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and each Rx, Ry, and Rzis 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 checkpoint inhibitor.

[0275] Embodiment 2. The method of embodiment 1, wherein the condition is a cancer.

[0276] Embodiment 3. The method of embodiment 2, wherein the cancer comprises a KRAS mutation.

[0277] Embodiment 4. The method of embodiment 3, wherein the KRAS mutation is G12V.

[0278] Embodiment 5. The method of embodiment 3, wherein the KRAS mutation is G12D.

[0279] Embodiment 6. The method of embodiment 3, wherein the KRAS mutation is G12C.

[0280] Embodiment 7. The method of embodiment 3, wherein the KRAS mutation is I46T.

[0281] Embodiment 8. The method of embodiment 2, wherein the cancer does not comprise a G12C KRAS mutation.

[0282] Embodiment 9. The method of any one of embodiments 1-8, wherein the condition is non-small cell lung carcinoma.

[0283] Embodiment 10. The method of any one of embodiments 1-8, wherein the condition is lung adenocarcinoma.

[0284] Embodiment 11. The method of any one of embodiments 1-10, wherein the administering the compound is intravenous.

[0285] Embodiment 12. The method of any one of embodiments 1-10, wherein the administering the compound is oral.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] Embodiment 20. The method of any one of embodiments 1-19, wherein the compound is administered once a day.

[0294] Embodiment 21. The method of any one of embodiments 1-19, wherein the compound is administered twice a day.

[0295] 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.

[0296] 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.

[0297] Embodiment 24. The method of embodiment 22 or 23, wherein the first therapeutically- effective amount and the second therapeutically-effective amount are the same.

[0298] Embodiment 25. The method of embodiment 22 or 23, wherein the first therapeutically- effective amount and the second therapeutically-effective amount are different.

[0299] Embodiment 26. The method of embodiment 22 or 23, wherein the first therapeutically- effective amount is greater than the second therapeutically-effective amount is.

[0300] Embodiment 27. The method of embodiment 22 or 23, wherein the first therapeutically- effective amount is lesser than the second therapeutically-effective amount is.

[0301] Embodiment 28. The method of any one of embodiments 1-19, wherein the administering the compound occurs three times a day.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] Embodiment 33. The method of any one of embodiments 1-32, wherein each R1, R3, and R5is independently ORX.

[0307] Embodiment 34. The method of any one of embodiments 1-33, wherein each Rxis independently alkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0308] Embodiment 35. The method of any one of embodiments 1-33, wherein each Rxis independently substituted or unsubstituted Ci-6 alkyl.

[0309] Embodiment 36. The method of any one of embodiments 1-35, wherein each Rxis 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.

[0310] Embodiment 37. The method of any one of embodiments 1-36, wherein each Rxis independently methyl.

[0311] Embodiment 38. The method of any one of embodiments 1-37, wherein each R2, R4, R6, R9, and R10is independently hydrogen.

[0312] Embodiment 39. The method of any one of embodiments 1-38, wherein each Rllaand Rllbis independently hydrogen.

[0313] Embodiment 40. The method of any one of embodiments 1-39, wherein each R12and R13is independently hydrogen.

[0314] Embodiment 41. The method of any one of embodiments 1-40, wherein the compound has the formula:wherein: each Rla, R3a, R5a, and R8ais independently substituted or unsubstituted Ci-s alkyl; and each R14and R15is independently alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen.

[0315] Embodiment 42. The method of embodiment 41, wherein each Rla, R3a, R5a, and R8ais independently methyl.

[0316] Embodiment 43. The method of embodiment 41, wherein R14is hydrogen.

[0317] Embodiment 44. The method of embodiment 41, wherein R15is 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.

[0318] Embodiment 45. The method of embodiment 41, wherein R15is CH2COOH.

[0319] 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, (E)- 2,4,6-trimethoxystyryl-3-carboxy-methylamino-4-methoxybenzyl sulfone, or a pharmaceutically- acceptable salt or zwitterion thereof.

[0320] 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 or sodium (E)-2,4,6-trimethoxystyryl-3-carboxy-methylamino-4-methoxybenzyl sulfone.

[0321] Embodiment 48. The method of any one of embodiments 1-47, wherein the administering the checkpoint inhibitor is intravenous.

[0322] Embodiment 49. The method of any one of embodiments 1-47, wherein the administering the checkpoint inhibitor is oral.

[0323] Embodiment 50. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is a cell-surface checkpoint inhibitor.

[0324] Embodiment 51. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is a CTLA-4 inhibitor.

[0325] Embodiment 52. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is a PD-1 inhibitor.

[0326] Embodiment 53. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is a PD-L1 inhibitor.

[0327] Embodiment 54. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is an intracellular checkpoint inhibitor.

[0328] Embodiment 55. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is cytokine-inducible SH2-containing protein (CISH).

[0329] Embodiment 56. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is Nivolumab.

[0330] Embodiment 57. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is pembrolizumab.

[0331] Embodiment 58. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is ipilimumab.

[0332] Embodiment 59. The method of any one of embodiments 1-49, wherein the checkpoint inhibitor is atezolizumab.

[0333] Embodiment 60. The method of any one of embodiments 1-59, wherein the therapeutically-effective amount of the checkpoint inhibitor is from about 100 mg to about 1,000 mg.

[0334] Embodiment 61. The method of any one of embodiments 1-59, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 240 mg.

[0335] Embodiment 62. The method of any one of embodiments 1-59, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 480 mg.

[0336] Embodiment 63. The method of any one of embodiments 1-59, wherein the therapeutically-effective amount of the checkpoint inhibitor is from about 2 mg / kg to about 12 mg / kg.

[0337] Embodiment 64. The method of any one of embodiments 1-59, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 2 mg / kg.

[0338] Embodiment 65. The method of any one of embodiments 1-59, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 3 mg / kg.

[0339] Embodiment 66. The method of any one of embodiments 1-59, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 10 mg / kg.

[0340] Embodiment 67. The method of any one of embodiments 1-66, wherein the checkpoint inhibitor is administered over 30 minutes.

[0341] Embodiment 68. The method of any one of embodiments 1-66, wherein the checkpoint inhibitor is administered over 60 minutes.

[0342] Embodiment 69. The method of any one of embodiments 1-68, wherein the checkpoint inhibitor is administered once every 2 weeks.

[0343] Embodiment 70. The method of any one of embodiments 1-68, wherein the administering of the checkpoint inhibitor occurs once every 4 weeks.

[0344] Embodiment 71. The method of any one of embodiments 1-68, wherein the administering of the compound occurs on 21 consecutive days of a 28-day cycle.

[0345] Embodiment 72. The method of any one of embodiments 1-68, wherein the administering of the checkpoint inhibitor occurs on day 1 and day 15 of a 28 day cycle.

Claims

CLAIMSWHAT IS CLAIMED IS:

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:or a pharmaceutically-acceptable salt or zwitterion thereof, wherein: each R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rlla, Rllb, R12, and R13is independently alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, -C(O)RX, -C(O)ORX, -C(O)NRxRy, -ORX, -SRX, -NRxRy, -NRxC(O)Ry, -OC(O)RX, or -SiRxRyRz, each of which is independently substituted or unsubstituted; or hydrogen or halogen; and each Rx, Ry, and Rzis 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 checkpoint 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 compound is administered once a day.

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

22. The method of claim 1, 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.

23. The method of claim 1, 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.

24. The method of claim 22 or 23, wherein the first therapeutically-effective amount and the second therapeutically-effective amount are the 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 R5is independently ORX.

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

35. The method of claim 33, wherein each Rxis independently substituted or unsubstituted Ci-6 alkyl.

36. The method of claim 35, wherein each Rx 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 Rxis independently methyl.

38. The method of claim 1, wherein each R2, R4, R6, R9, and R10is independently hydrogen.

39. The method of claim 1, wherein each Rllaand Rllbis independently hydrogen.

40. The method of claim 1, wherein each R12and R13is independently hydrogen.

41. The method of claim 1, wherein the compound has the formula:wherein: each Rla, R3a, R5a, and R8ais independently substituted or unsubstituted Ci-s alkyl; and each R14and R15is independently alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or hydrogen.

42. The method of claim 41, wherein each Rla, R3a, R5a, and R8ais independently methyl.

43. The method of claim 41, wherein R14is hydrogen.

44. The method of claim 41, wherein R15is 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 R15is CH2COOH.

46. The method of claim 1, wherein the compound is ((E)-2-(5-((2,4,6-trimethoxystyryl sulfonyl)methyl)-2-methoxyphenylamino)acetic acid, (E)-2,4,6-trimethoxystyryl-3-carboxy- methylamino-4-methoxybenzyl sulfone 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 or sodium (E)-2,4,6- trimethoxystyryl-3 -carboxy -methylamino-4-m ethoxybenzyl sulfone.

48. The method of claim 1, wherein the administering the checkpoint inhibitor is intravenous.

49. The method of claim 1, wherein the administering the checkpoint inhibitor is oral.

50. The method of claim 1, wherein the checkpoint inhibitor is a cell-surface checkpoint inhibitor.

51. The method of claim 1, wherein the checkpoint inhibitor is a CTLA-4 inhibitor.

52. The method of claim 1, wherein the checkpoint inhibitor is a PD-1 inhibitor.

53. The method of claim 1, wherein the checkpoint inhibitor is a PD-L1 inhibitor.

54. The method of claim 1, wherein the checkpoint inhibitor is an intracellular checkpoint inhibitor.

55. The method of claim 1, wherein the checkpoint inhibitor is cytokine-inducible SH2- containing protein (CISH).

56. The method of claim 1, wherein the checkpoint inhibitor is Nivolumab.

57. The method of claim 1, wherein the checkpoint inhibitor is pembrolizumab.

58. The method of claim 1, wherein the checkpoint inhibitor is ipilimumab.

59. The method of claim 1, wherein the checkpoint inhibitor is atezolizumab.

60. The method of claim 1, wherein the therapeutically-effective amount of the checkpoint inhibitor is from about 100 mg to about 1,000 mg.

61. The method of claim 1, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 240 mg.

62. The method of claim 1, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 480 mg.

63. The method of claim 1, wherein the therapeutically-effective amount of the checkpoint inhibitor is from about 2 mg / kg to about 12 mg / kg.

64. The method of claim 1, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 2 mg / kg.

65. The method of claim 1, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 3 mg / kg.

66. The method of claim 1, wherein the therapeutically-effective amount of the checkpoint inhibitor is about 10 mg / kg.

67. The method of claim 1, wherein the checkpoint inhibitor is administered over 30 minutes.

68. The method of claim 1, wherein the checkpoint inhibitor is administered over 60 minutes.

69. The method of claim 1, wherein the checkpoint inhibitor is administered once every 2 weeks.

70. The method of claim 1, wherein the administering of the checkpoint inhibitor occurs once every 4 weeks.

71. The method of claim 1, wherein the administering of the compound occurs on 21 consecutive days of a 28-day cycle.

72. The method of claim 1, wherein the administering of the checkpoint inhibitor occurs on day 1 and day 15 of a 28 day cycle.

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