Combination therapy

Abstract

The present invention relates to a combination therapy for treating KRas G12C cancer. In particular, the present invention relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PARP inhibitor and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB, a pharmaceutical composition comprising a therapeutically effective amount of said inhibitor, or a kit comprising said composition, as well as methods of use thereof.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to combination therapies useful in the treatment of cancer. In particular, the present invention relates to therapeutically effective combinations of inhibitors of the enzyme poly ADP-ribose polymerase (PARP) and KRas G12C inhibitors, pharmaceutical compositions comprising said inhibitors, kits comprising said compositions, and methods of use thereof.

[0002] BACKGROUND OF THE INVENTION Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRas) is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch, moving between inactive (GDP-bound) and active (GTP-bound) states, transducing upstream cellular signals received from multiple tyrosine kinases to downstream effectors that control various processes, including cell proliferation (e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancies was observed over 30 years ago (see, e.g., Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and result in constitutive activation of KRas and downstream signaling have been reported in 25–30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single-base substitutions resulting in missense mutations at codons 12 and 13 of the primary amino acid sequence of KRas comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi: 10.1158 / 1078-0432.CCR-11-3265).

[0004] The well-known role of KRas in malignancies, and the discovery of such frequent mutations in KRas in various tumor types, have made KRas a highly attractive target for the pharmaceutical industry for cancer therapy. Despite 30 years of extensive research efforts to develop KRas inhibitors for the treatment of cancer, no KRas inhibitor has demonstrated sufficient safety and / or efficacy to gain regulatory approval (see, e.g., McCormick (2015) Clin Cancer Res. 21 (8):1797-1801).

[0005] Despite the failure of many efforts to target KRas, recent developments in covalent targeting of KRas G12C have shown early promise (e.g., Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234), with multiple compounds recently entering human clinical trials (e.g., AMG510 and MRTX849). Nevertheless, compounds that inhibit KRas activity remain highly promising and are under investigation, including compounds that target KRas G12C, as well as compounds that interfere with effectors such as guanine nucleotide exchange factors (e.g., Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi: 10.1002 / anie201201358).

[0006] The KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzymatic activity and demonstrate single-agent activity in inhibiting the in vitro growth of cell lines harboring KRas G12C mutations. However, the relative potency and / or maximum observed effect of any given KRas G12C inhibitor may vary among KRAS mutant cell lines. The reasons or causes for the range of efficacy and maximum observed effect are not fully understood, although certain cell lines appear to differ in intrinsic resistance. Therefore, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index, and / or clinical utility of KRas G12C inhibitors in vitro and in vivo.

[0007] PARP plays a crucial role in detecting and repairing single-strand breaks in DNA through the base excision repair mechanism. PARP inhibitors disrupt the repair pathway by inhibiting PARP enzymatic activity, converting single-strand breaks into double-strand breaks during replication. Double-strand breaks are typically repaired through the homologous recombination pathway involving BRCA1 and BRCA2 (e.g., O'Connor, (2015) Mol Cell Review 60(4):547-560). BRCA1 and BRCA2 genes are tumor suppressor genes, and mutations in BRCA genes confer a high risk of certain cancers and potential resistance to certain cancer treatments. Mutations in BRCA genes result in the inability to repair broken DNA, which helps prevent the development of certain cancers. Therefore, these BRCA-mutated cancer cells are highly dependent on PARP to repair DNA strand breaks so that cell division can continue (Bryant et al. (2005) Nature 434: 913-917, and Farmer et al. (2005) Nature 434:917-921). The MAPK pathway is one of the most frequently mutated oncogenic pathways in cancer. Dysregulation of the MAPK pathway is frequently observed and plays a central role in the development and maintenance of several cancers (e.g., melanoma, pancreatic cancer, lung cancer, colorectal cancer, and breast cancer) (e.g., Neuzillet et al., (2014) Pharmacology & Therapeutics 141:160-171).

[0008] Several inhibitors have been developed that demonstrate activity against PARP, and many of these inhibitors are currently in human clinical trials or have been investigated. Examples of PARP inhibitors suitable for the provided compositions and methods include olaparib, 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one; rucaparib, 6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one, 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-; niraparib, (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide; talazoparib, 3H-pyrido[4,3,2-de]phthalazin-3-one, These include, but are not limited to, 5-fluoro-8-(4-fluorophenyl)-2,7,8,9-tetrahydro-9-(1-methyl1H-1,2,4-triazol-5-yl)-, (8S,9R)-; and veliparib, (R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide. Summary of the Invention [Problem to be solved by the invention]

[0009] The PARP inhibitors disclosed herein are potent inhibitors of PARP enzyme activity and exhibit single-agent activity in inhibiting the in vitro growth of the cancer cell lines discussed herein, although the relative potency and / or maximum observed effect of any given PARP inhibitor may vary between cancer cell lines. The reasons or causes for the range of efficacy and maximum observed effect are not fully understood, but certain cell lines appear to have different intrinsic resistance. Therefore, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index, and / or clinical utility of PARP inhibitors in vitro and in vivo.

[0010] (Summary of the Invention) In one aspect, the combination therapy of the present invention synergistically increases the potency of the KRas G12C inhibitor by co-administering the KRas G12C inhibitor with a PARP inhibitor, thereby improving the efficacy of the KRas G12C inhibitor disclosed herein. In another aspect, the combination therapy of the present invention provides improved clinical benefit to patients compared to treatment with a KRas G12C inhibitor disclosed herein as a single agent.

[0011] In one aspect of the present invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof and a compound of formula (I): [ka] [In the formula, X is a 4- to 12-membered saturated or partially saturated monocyclic ring, bridged ring, or spiro ring, and the saturated or partially saturated monocyclic ring is 8 and optionally substituted with; Y is a bond, O, S, or NR 5 and; R 1 teeth, [ka] and; R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of said Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be selected from the group consisting of one or more R 9 optionally substituted with; Z is C1-C4 alkylene; Each R 3are independently C1-C3 alkyl, oxo, or haloalkyl; L is a bond, —C(O)—, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, and each of said cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl is selected from the group consisting of one or more R 6 or R 7 optionally substituted with; Each R 5 are independently hydrogen or C1-C3 alkyl; R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl, or heteroaryl being selected from the group consisting of one or more R 7 optionally substituted with; Each R 7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, where Q is O or S; R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 )2, -N(R 5 )2, wherein the C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 ) 2 or heteroaryl, optionally substituted; Each R 9are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein said C1-C6 alkyl is optionally substituted with cycloalkyl; Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R 11 is haloalkyl; R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2 or hydroxyalkyl; Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 )2, —NHC(O)C1-C3 alkyl, —CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclyl, wherein said heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and said heteroaryl or heteroaryl portion of said heteroarylalkyl is substituted with one or more R 7 optionally substituted with; m is 0 or an integer of 1 to 2; p is 1 or 2; where: [ka] If is a triple bond, R A does not exist, and R B is present and p is 1; or [ka] is a double bond, R A exists and R B exists and p is 2, or R A , R B and the carbon atoms attached thereto may be one or more R 7 forming an optionally substituted 5- to 8-membered partially saturated cycloalkyl or a pharmaceutically acceptable salt thereof.

[0012] Also encompassed for use in the methods provided herein are compounds of formula IA: [ka] [In the formula, R 1 , R 3 , R 4 , R 5 , R 10 , R 11 , L and m are as defined for formula I, and the piperazinyl ring is 8 and R 8 is as defined for Formula I] or a pharmaceutically acceptable salt thereof.

[0013] Also encompassed for use in the methods provided herein are compounds of formula IB: [ka] [In the formula, R 1 , R 3 , R 4 , L and m are as defined for formula I, and R 2 is one or more R 9 and R is heterocyclylalkyl optionally substituted with9 is as defined for formula I, and the piperazinyl ring is R 8 and R 8 is as defined for Formula I] or a pharmaceutically acceptable salt thereof.

[0014] Also included for use in the methods provided herein are the following: [ka] and pharmaceutically acceptable salts thereof.

[0015] In another aspect of the present invention, there is provided a pharmaceutical composition for use in the methods of the present invention, comprising a combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt thereof, and a compound, or a pharmaceutically acceptable salt thereof, which is a KRas G12C inhibitor selected from Formula I, Formula IA, Formula 1-B, or any of the foregoing compounds (i.e., the compounds in the preceding paragraph); and a pharmaceutically acceptable excipient.

[0016] In one aspect of the present invention, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof and a KRAS G12C inhibitor selected from Formula (I), Formula IA, Formula IB, or the compounds thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0017] In some embodiments of the present invention, the compound that is a KRas G12C inhibitor and the PARP inhibitor are the only active agents in the compositions and methods provided.

[0018] Examples of PARP inhibitors suitable for the compositions and methods provided herein include, but are not limited to, olaparib, 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one; rucaparib, 6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one, 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-; niraparib, (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide; talazoparib, 3H-pyrido[4,3,2-de]phthalazin-3-one, 5-fluoro-8-(4-fluorophenyl)-2,7,8,9-tetrahydro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-, (8S,9R)-; and veliparib, (R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide. Other PARP inhibitors suitable for the compositions and methods provided herein include, but are not limited to, RBN-2397 (Ribon Therapeutics), I-1 (Gu, et al., J Med Chem, 2023), KMR-206 (Sanderson, et al., Cell Chemical Biology, 2023), RP14042 (Viswanadha, et al., European Journal of Cancer, 2022), and JAB-26766 (Jacobio).

[0019] In yet another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to a KRas G12C inhibitor, comprising contacting cancer cells with a therapeutically effective amount of a compound selected from Formula (I), Formula IA, Formula IB, or the compounds thereof, in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the PARP inhibitor synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0020] Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., determined using a regulatory agency-approved (e.g., FDA-approved) assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of a PARP inhibitor and a KRas G12C inhibitor compound selected from Formula I, Formula IA, Formula 1-B, or the compounds thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the PARP inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor.

[0021] Also provided herein are kits comprising a PARP inhibitor and a compound that is a KRas G12C inhibitor selected from Formula (I), Formula (IA), Formula (IB), or one of the foregoing compounds. Also provided are kits comprising a PARP inhibitor and a compound that is a KRas G12C inhibitor selected from Formula (I), Formula (IA), Formula (IB), or one of the foregoing compounds, for use in treating KRas G12C cancer.

[0022] In a related embodiment, the invention provides a kit comprising a dose of a PARP inhibitor and a compound that is a KRas G12C inhibitor selected from Formula (I), Formula IA, Formula IB, or one of the foregoing compounds, in amounts effective to inhibit the growth of cancer cells in a subject. Optionally, the kit includes instructions for administering the PARP inhibitor and the compound that is a KRas G12C inhibitor of Formula (I), Formula (IA), or Formula (IB), or a compound selected from one of the foregoing compounds. The instructions may provide the user with a set of instructions for using the PARP inhibitor and the compound that is a KRas G12C inhibitor selected from Formula (I), Formula IA, Formula IB, or one of the foregoing, in combination.

[0023] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, where optionally the prior treatment was unsuccessful; and / or the patient has undergone surgery, where optionally the surgery was unsuccessful; and / or the patient has been treated with a platinum-based chemotherapy agent, where optionally the patient has been previously determined to be non-responsive to treatment with a platinum-based chemotherapy agent; and / or the patient has been treated with a kinase inhibitor, where optionally the prior treatment with the kinase inhibitor was unsuccessful; and / or the patient has been treated with one or more other therapeutic agents. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 is a chart showing the effect of Compound 478 and / or Olaparib administration on H2122 tumor volume. Detailed Description of the Invention

[0025] The present invention relates to a combination therapy for treating KRas G12C cancer. In particular, the present invention relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition, and methods of using the same.

[0026] The combination of a PARP inhibitor and a KRas G12C inhibitor compound of Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt thereof, synergistically increases the efficacy of the KRas G12C inhibitor compound of Formula (I), Formula (IA), or Formula IB, against cancer cells expressing KRasG12C, thereby increasing the potency and therapeutic index of the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0027] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0028] As used herein, "KRas G12C" refers to a mutant containing a cysteine ​​to glycine amino acid substitution at amino acid position 12 of the mammalian KRas protein. The amino acid codon and residue position assignment for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: mutant p.Gly12Cys.

[0029] As used herein, "KRas G12C inhibitor" refers to a compound of the present invention represented by Formula (I), Formula IA, and Formula IB described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12C. The KRas G12C inhibitor of the present invention interacts with KRas G12C and irreversibly binds to KRas G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine ​​residue at position 12, thereby inhibiting the enzymatic activity of KRas G12C. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). In another embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-228 (numbered in US2019-0270743) or a pharmaceutically acceptable salt thereof.

[0030] As used herein, "KRas G12C-related disease or disorder" refers to the disease or disorder that is related to, mediated by, or has KRas G12C mutation.A non-limiting example of KRas G12C-related disease or disorder is KRas G12C-related cancer.

[0031] As used herein, "PARP" refers to poly(ADP-ribose) polymerase, a protein family involved in many cellular processes, including DNA repair, genome stability, and programmed cell death. The PARP family includes 17 members (10 putative). Their intracellular structures and functions are highly diverse. PARP1, PARP2, VPARP (PARP4), tankyrase-1, and tankyrase-2 (PARP-5a or TNKS, PARP-5b or TNKS2) have confirmed PARP activity. Other members include PARP3, PARP6, TIPARP (or "PARP7"), PARP8, PARP9, PARP10, PARP11, PARP12, PARP14, PARP15, and PARP16. PARPs are composed of four interesting domains: a DNA-binding domain, a caspase-cleavage domain (see below), an automodification domain, and a catalytic domain. The DNA-binding domain contains two zinc finger motifs. In the presence of damaged DNA (base pair breaks), the DNA-binding domain binds to DNA and induces a conformational shift. This binding is known to occur independently of other domains. This is essential for the programmed cell death model based on PARP's inhibition of caspase cleavage. The automodification domain dissociates the protein from DNA after catalytic reactions and also plays an important role in cleavage-induced inactivation. The primary role of PARP (located in the cell nucleus) is to detect metabolically, chemically, or radiation-induced single-strand DNA breaks (SSBs) and initiate an immediate cellular response by signaling the enzymatic machinery involved in SSB repair. When PARP detects an SSB, it binds to DNA and undergoes a conformational change, initiating the synthesis of polymeric adenosine diphosphate ribose (poly(ADP-ribose) or PAR) chains, which act as a signal for other DNA repair enzymes. Target enzymes include scaffolding proteins such as DNA ligase III (LigIII), DNA polymerase β (polβ), and X-ray repair cross-complementing gene 1 (XRCC1).After repair, PAR chains are degraded via poly(ADP-ribose) glycohydrolase (PARG). NAD+ is required as a substrate to generate ADP-ribose monomers. It has been thought that excessive PARP activation inhibits glucose oxidation, depleting intracellular NAD+ stores and inducing progressive ATP depletion, potentially leading to cell necrosis. However, recent studies have suggested that inhibition of hexokinase activity leads to glycolytic defects (Andrabi, PNAS 2014). Basal PARP activity also regulates basal bioenergetics. PARP is inactivated by caspase-3 cleavage during programmed cell death. PARP enzymes are essential for many cellular functions, including inflammatory gene expression: PARP1 is required for the induction of ICAM-1 gene expression by cardiomyocytes and smooth muscle cells in response to TNF.

[0032] As used herein, "PARP inhibitors" refer to compounds that can negatively regulate or inhibit all or part of the enzymatic activity of the PARP enzyme. More specifically, PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly (ADP-ribose) polymerase (PARP). They are being developed for multiple indications, including the treatment of hereditary cancers. Some forms of cancer are more dependent on PARP than normal cells, making PARPs (e.g., PARP1 and PARP2) attractive targets for cancer therapy. As evidenced by the addition of olaparib to conventional treatment, PARP inhibitors appear to improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer. In addition to their use in cancer therapy, PARP inhibitors also hold promise as treatments for acute life-threatening conditions such as stroke and myocardial infarction, as well as long-term neurodegenerative diseases.

[0033] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In certain embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12C mutation (e.g., determined using a regulatory agency-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has a tumor that is KRas G12C mutation-positive (e.g., determined using a regulatory agency-approved assay or kit). The subject may have a tumor that is KRas G12C mutation-positive (e.g., identified as positive using a regulatory agency-approved (e.g., FDA-approved) assay or kit). The subject may be a subject whose tumor has been identified or diagnosed as having a KRas G12C mutation (e.g., the tumor is determined using a regulatory agency-approved (e.g., FDA-approved) kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a KRas G12C mutation (optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0034] As used herein, a "pediatric patient" refers to a patient who is under 16 years of age at the time of diagnosis or treatment. The term "pediatric" is divided into various subgroups, including neonates (birth to 1 month of age), infants (1 month to 2 years of age), children (2 to 12 years of age), and adolescents (12 to 21 years of age up to, but not including, their 20th birthday) (Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al.).

[0035] In some embodiments of any of the methods or uses described herein, assays used to determine whether a patient has a KRas G12C mutation using a sample (e.g., a biopsy sample, such as a biological sample or a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient with one or more symptoms of a KRas G12C-associated cancer, and / or a patient at high risk of developing a KRas G12C-associated cancer) can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping, ddPCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0036] "Regulatory Authority" means the agency that approves drugs for medical use in a country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0037] The term "amino" refers to -NH2.

[0038] The term "acyl" refers to -C(O)CH3.

[0039] The term "alkyl," as used herein, refers to straight- and branched-chain aliphatic groups having 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, optionally substituted with 1, 2, or 3 substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0040] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced with halogen. Examples of haloalkyl include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0041] The term "haloalkyloxy" refers to an --O-haloalkyl.

[0042] An "alkylene" group, as defined herein, is an alkyl group that is positioned between and serves to link two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0043] The term "alkoxy" refers to -OC1-C6 alkyl.

[0044] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbon atoms, e.g., 3 to 8 carbon atoms, and further e.g., 3 to 6 carbon atoms, which cycloalkyl groups may be further optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0045] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain is replaced with a heteroatom selected from the group consisting of O, S and N.

[0046] As used herein, the term "hydroxyalkyl" refers to -alkyl-OH.

[0047] The term "dihydroxyalkyl" refers to an alkyl group, as defined herein, in which two carbon atoms are each replaced with a hydroxyl group.

[0048] The term "alkylaminyl" refers to -NR x -alkyl, where R x is hydrogen. In one embodiment, R x is hydrogen.

[0049] The term "dialkylaminyl" refers to -N(R y )2, where each R y is C1-C3 alkyl.

[0050] The term "alkylaminylalkyl" refers to -alkyl-NR x -alkyl, where R x is hydrogen. In one embodiment, R x is hydrogen.

[0051] The term "dialkylaminylalkyl" refers to -alkyl-N(R y )2, where each R y is C1-C4 alkyl, and the -alkyl-N(R y The alkyl in 2 may be optionally substituted with hydroxy or hydroxyalkyl.

[0052] An "aryl" group is a C6-C aryl group containing one to three aromatic rings. 14 In one embodiment, the aryl group is a C-C10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0053] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. Examples of aralkyl groups include (C-C) alkyl (C-C 10 ) aryl, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. Examples of substituted aralkyls include those in which the alkyl group is substituted with hydroxyalkyl.

[0054] A "heterocyclyl" or "heterocyclic" group is a ring structure having about 3 to about 12 atoms, e.g., 4 to 8 atoms, where one or more atoms are selected from the group consisting of N, O, and S, and the remainder of the ring atoms are carbon. A heterocyclyl may be monocyclic, bicyclic, spirocyclic, or bridged. A heterocyclic group may have an R on a carbon or nitrogen at one or more positions. 7 wherein R 7is as defined for formula I. Heterocyclic groups are also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, oxazepanyl, azabicyclohexane, azabicycloheptane, and oxazabicycloheptane. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0055] The term "heterocyclylalkyl" refers to a heterocyclyl group, as defined herein, connected to the remainder of the molecule via an alkyl linker, wherein the alkyl linker of said heterocyclylalkyl is optionally substituted with hydroxy or hydroxyalkyl.

[0056] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; 6, 10, or 14 pi electrons shared in a cyclic arrangement; and, in addition to carbon atoms, 1 to 3 heteroatoms selected from the group consisting of N, O, and S per ring.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, and indolinyl. phenyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl , phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuran thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0057] A "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, wherein the group is on the alkyl group, either of which may be independently optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoindolylmethyl, cinnonylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are cyclic compounds having adjacent O and / or S atoms.

[0058] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of a desired target, i.e., PARP or KRas G12C. Such an amount may be administered as a single dose or according to a regimen that is effective.

[0059] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to improve symptoms, in some way alleviate symptoms, stop or reverse the progression of a disease state, or negatively regulate or inhibit the activity of PARP or KRas G12C. Such an amount can be administered as a single dose or according to a regimen that is effective.

[0060] As used herein, a "therapeutically effective amount of a combination" of two compounds refers to an amount in which the combined amount synergistically increases the activity of the combination (i.e., greater than merely additive activity) compared to the therapeutically effective amounts of each compound in the combination. Alternatively, in vivo, a combination of a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, extends overall survival ("OS") in a subject compared to treatment with a KRas G12 inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, extends progression-free survival ("PFS") in a subject compared to treatment with a KRas G12 inhibitor alone. In one embodiment, the combination of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, improves the duration of stable disease in a subject compared to treatment with a KRas G12C inhibitor alone.The amount of each compound in the combination may be the same as or different from the therapeutically effective amount of each compound when administered alone, so long as the combination exhibits a synergistic effect. Such amounts may be administered as a single dose or according to a regimen whereby it is effective.

[0061] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0062] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief that can result from or be associated with administration of the composition, whether permanent, temporary, persistent, or transient.

[0063] As used herein, the term "about," when used to partially modify a parameter defined by a numerical value (e.g., the dose of a KRAS inhibitor or PARP inhibitor or a pharmaceutically acceptable salt thereof, or the length of treatment with a combination therapy described herein), means that the parameter may vary by about 10% above or below the stated numerical value for the parameter. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. When "about" is used at the beginning of a list of parameters, it means that the respective parameter varies. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, or 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, or about 25% or more.

[0064] Inhibitor compounds In one aspect of the present invention, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a combination of therapeutically effective amounts of a PARP inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0065] Methods for preparing PARP inhibitors or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof are well known to those skilled in the art, and PARP inhibitors can be purchased from a variety of commercial sources in forms suitable for both research and human use. Additionally, PARP inhibitors suitable for use in the compositions and methods disclosed herein, methods for preparing said inhibitors, and related uses and methods are disclosed in the following U.S. patent documents: U.S. Patent Nos. 7,151,102; 7,449,464; 7,981,889; 8,071,579; 8,143,241; 8,247,416; 8,475,842; 8,859,562; 8,912,187; 9,169,235; 9,566,276; 8,169,235; 9,566,276; 8,169,235; 9,566,276; 9 ... ,012,976; No. 8,420,650; No. 8,735,392; No. 9,820,985; No. 10,189,837; No. 6,495,541; No. 7,351,701; No. 7,531,530; No. 8,754,072; No. 9,045,487; No. 9,861,638; No. 9,987,285; No. 10,130,636; No. 10,278,974; No. 8,071,623; No. 8,436,185; No. 11,091,459; No. 7,550,603, etc.

[0066] 1. KRas G12C inhibitors In one embodiment, the KRas G12C inhibitor used in the present methods has formula (I): [ka] [In the formula, X is a 4- to 12-membered saturated or partially saturated monocyclic ring, bridged ring, or spiro ring, and the saturated or partially saturated monocyclic ring is 8 and optionally substituted with; Y is a bond, O, S, or NR 5 and; R 1 teeth, [ka] and; R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of said Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be selected from the group consisting of one or more R 9 and optionally substituted with; Z is C1-C4 alkylene; Each R 3 are independently C1-C3 alkyl, oxo, or haloalkyl; L is a bond, —C(O)—, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, and each of said cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl is selected from the group consisting of one or more R 6 or R 7 optionally substituted with; Each R 5 are independently hydrogen or C1-C3 alkyl; R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl, or heteroaryl being selected from the group consisting of one or more R 7 optionally substituted with; Each R 7 are independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, wherein Q is O or S; R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 )2, -N(R 5 )2, wherein the C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 ) 2 or heteroaryl, optionally substituted; Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein said C1-C6 alkyl is optionally substituted with cycloalkyl; Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R 11 is haloalkyl; R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2 or hydroxyalkyl; Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 ) 2、-NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and wherein the heteroaryl or heteroaryl portion of the heteroarylalkyl is substituted with one or more R 7 optionally substituted with; m is 0 or an integer of 1 to 2; p is 1 or 2; [ka] If is a triple bond, R A does not exist, and R B exists and p is 1; or [ka] is a double bond, R A exists and R B exists and p is 2, or R A , R B and the carbon atoms attached thereto may be one or more R 7 forming an optionally substituted 5- to 8-membered partially saturated cycloalkyl or a pharmaceutically acceptable salt thereof.

[0067] In one embodiment, the KRas G12C inhibitor used in the methods herein has formula IA: [ka] [In the formula, R 1 , R 3 , R 4 , R 5 , R 10 , L and m are as defined for formula I, and R 11is hydrogen, methyl or hydroxyalkyl, and the piperidinyl ring is 8 wherein R 8 is as defined for Formula I] or a pharmaceutically acceptable salt thereof.

[0068] In one embodiment, the KRas G12C inhibitor used in the methods herein has formula IB: [ka] [In the formula, R 1 , R 3 , R 4 , R 9 , R 11 , L and m are as defined for Formula I. or a pharmaceutically acceptable salt thereof.

[0069] Non-limiting examples of compounds that are KRas G12C inhibitors of Formula (I), Formula IA, and Formula IB useful in the methods disclosed herein are selected from the group consisting of Example Nos. 1-678 of WO2019 / 099524 and Example Nos. 1-228 of WO2020 / 101736, for example, compounds having the following representative structures: [ka] and pharmaceutically acceptable salts thereof.

[0070] In one embodiment, the KRas G12C inhibitor is: [ka] (also shown as Example 234 of WO2019 / 099524) or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the KRas G12C inhibitor is: [ka] (also shown as Example 359 of WO2019 / 099524) or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the KRas G12C inhibitor is: [ka] (Example 478 of WO2019 / 099524, MRTX-849 and / or adagrasib) or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the KRas G12C inhibitor is: [ka] (also shown as Example 507 in WO2019 / 099524) or a pharmaceutically acceptable salt thereof.

[0074] The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures (isomers of the same structure that differ in the arrangement of their atoms in space). The compounds may be used as mixtures, or the individual components / isomers may be resolved using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers known to those skilled in the art, such as CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to produce individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the present invention. Unless otherwise indicated, when referring to compounds of the invention in this specification, including the claims, the term "compound" is understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.

[0075] In one embodiment, the compound that is a KRas G12C inhibitor of Formula I, Formula IA, Formula IB, or the compounds used in the methods of the present application, includes the trifluoroacetate salt of the compound.

[0076] Methods for producing the KRas G12C inhibitors disclosed herein are known. For example, commonly owned PCT International Publication Nos. WO2017201161 and WO199099524, and U.S. Patent Application Publication Nos. US20180072723 and US20190270743 describe general reaction schemes for producing compounds of Formula I, Formula IA, or Formula IB, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, and also provide detailed synthetic routes for producing each of the KRas G12C inhibitors disclosed herein.

[0077] The PARP inhibitor and the KRas G12C compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, can be formulated into a pharmaceutical composition.

[0078] Pharmaceutical Composition In another aspect, the present invention provides a pharmaceutical composition comprising a PARP inhibitor or a pharmaceutically acceptable salt thereof and a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof according to the present invention, as well as a pharmaceutically acceptable carrier, excipient, or diluent that can be used in the methods disclosed herein. The PARP inhibitor or a pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof can be formulated by any method known in the art and prepared for administration by any route, including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal. In certain embodiments, the PARP inhibitor or a pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof are administered intravenously in a hospital setting. In one embodiment, administration can be oral.

[0079] The characteristics of the carrier vary depending on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not inhibit the effectiveness of the biological activity of the active ingredient. Thus, in addition to the inhibitor, the composition may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0080] As used herein, the term pharmaceutically acceptable salt refers to the salt that maintains the desired biological activity of the compound and shows minimal or no undesired toxicological effects.The examples of such salt include but are not limited to the acid addition salt that forms with inorganic acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid etc.) and the salt that forms with organic acid (for example, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid and polygalacturonic acid). The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, including quaternary ammonium salts of the formula --NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, such as chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0081] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the patient being treated. In one embodiment, the dose of the active compound for all of the above conditions ranges from about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, and, as a further example, from 0.5 to about 25 mg per kg of recipient body weight per day. Typical topical dosages range from 0.01 to 3% wt / wt in a suitable carrier. The effective dosage range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative is active in itself, the effective dosage can be estimated using the weight of the derivative as described above or by other means known to those skilled in the art.

[0082] A pharmaceutical composition comprising a PARP inhibitor, or a pharmaceutically acceptable salt thereof, and a KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, can be used in the methods of use described herein.

[0083] Coadministration PARP inhibitor or its pharmaceutically acceptable salt or its pharmaceutical composition and KRas G12C inhibitor or its pharmaceutically acceptable salt or its pharmaceutical composition can be formulated into separate or separate dosage forms, and can be administered sequentially.As another option, if the administration route is the same (for example, oral), the two active compounds can be co-administered in one dosage form.

[0084] The pharmaceutical compositions containing a PARP inhibitor or a pharmaceutically acceptable salt thereof and / or a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof for use in the present methods can be administered simultaneously, separately, or sequentially. In one embodiment, the PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered before the administration of a compound which is a KRas G12C inhibitor selected from Formula (I), Formula IA, Formula IB, or the aforementioned compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered after the administration of a compound which is a KRas G12C inhibitor selected from Formula (I), Formula IA, Formula IB, or the aforementioned compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered approximately simultaneously with the administration of a compound which is a KRas G12C inhibitor selected from Formula (I), Formula IA, Formula IB, or the aforementioned compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0085] In some cases, it may be advantageous to administer each inhibitor separately at different times and by different routes. Thus, the components in the combination, i.e., the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, do not necessarily need to be administered substantially simultaneously or in any order.

[0086] Cancer therapeutic agents are typically administered at their maximum tolerated dose (MTD), which is the maximum dose of the agent that does not cause unacceptable side effects. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, are each administered at their respective MTDs. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at its MTD, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at an amount less than its MTD. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at an amount less than its MTD, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at its MTD. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, are administered at their respective MTDs. The administration may be timed so that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other compound.

[0087] In one embodiment, a single dose of a compound selected from Formula (I), Formula IA, Formula IB, or the foregoing compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered daily (i.e., approximately 24 hours apart) (i.e., QD). In another embodiment, two doses of a compound selected from Formula (I), Formula IA, Formula IB, or the foregoing compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, are administered daily (i.e., BID). In another embodiment, three doses of a compound selected from Formula (I), Formula IA, Formula IB, or the foregoing compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, are administered daily (i.e., TID).

[0088] In one embodiment, PARP inhibitor or its pharmaceutically acceptable salt or its pharmaceutical composition is administered QD.In another embodiment, PARP inhibitor or its pharmaceutically acceptable salt or its pharmaceutical composition is administered BID.In another embodiment, PARP inhibitor or its pharmaceutically acceptable salt or its pharmaceutical composition is administered TID.

[0089] In one embodiment, a single dose of a compound which is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, are each administered once daily.

[0090] Examples of PARP inhibitors suitable for the compositions and methods provided herein include, but are not limited to, olaparib, rucaparib, niraparib, talazoparib, and veliparib. Other examples of PARP inhibitors suitable for the compositions and methods provided herein include, but are not limited to, RBN-2397, I-1, KMR-206, RP14042, and JAB-26766.

[0091] Combination therapy In one aspect of the present invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to a subject a compound selected from the group consisting of a PARP inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a KRAS G12C inhibitor represented by Formula (I), Formula IA, Formula IB, or a compound selected from the foregoing classes of compounds (i.e., [ka] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with a therapeutically effective amount. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0092] In yet another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to a KRas G12C inhibitor, the method comprising contacting the cancer cells with an effective amount of a compound selected from Formula (I), Formula IA, Formula IB, or the foregoing compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which is a KRas G12C inhibitor, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the PARP inhibitor synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0093] In one embodiment, the combination therapy comprises a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof and a PARP inhibitor. In one aspect of this embodiment, the PARP inhibitor is olaparib. In one aspect of this embodiment, the PARP inhibitor is rucaparib. In one aspect of this embodiment, the PARP inhibitor is niraparib. In one aspect of this embodiment, the PARP inhibitor is talazoparib. In one aspect of this embodiment, the PARP inhibitor is veliparib.

[0094] In one embodiment, the combination therapy comprises a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof, and a PARP inhibitor.

[0095] In one aspect of this embodiment, the PARP inhibitor is olaparib. In one aspect of this embodiment, the PARP inhibitor is rucaparib. In one aspect of this embodiment, the PARP inhibitor is niraparib. In one aspect of this embodiment, the PARP inhibitor is talazoparib. In one aspect of this embodiment, the PARP inhibitor is veliparib.

[0096] In one embodiment, the combination therapy comprises a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof, and a PARP inhibitor.

[0097] In one aspect of this embodiment, the PARP inhibitor is olaparib. In one aspect of this embodiment, the PARP inhibitor is rucaparib. In one aspect of this embodiment, the PARP inhibitor is niraparib. In one aspect of this embodiment, the PARP inhibitor is talazoparib. In one aspect of this embodiment, the PARP inhibitor is veliparib.

[0098] In one embodiment, the combination therapy comprises a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof, and a PARP inhibitor.

[0099] In one aspect of this embodiment, the PARP inhibitor is olaparib. In one aspect of this embodiment, the PARP inhibitor is rucaparib. In one aspect of this embodiment, the PARP inhibitor is niraparib. In one aspect of this embodiment, the PARP inhibitor is talazoparib. In one aspect of this embodiment, the PARP inhibitor is veliparib.

[0100] As used herein, the term "contact" refers to combining predetermined moieties together in an in vitro or in vivo system. For example, "contacting" cancer cells includes administering a combination provided herein to an individual or subject, such as a human, who has KRas G12C, as well as introducing a combination provided herein into a sample containing, for example, cells or purified preparations containing KRas G12C.

[0101] By negatively regulating the activity of KRas G12C, the methods described herein are designed to inhibit undesirable cell proliferation resulting from increased KRas G12C activity in cells. The degree of covalent modification of KRas G12C can be monitored in vitro using known methods, such as those described in PCT International Application Publication Nos. WO2012201161, WO199099524, and WO2020101736. Furthermore, to assess therapeutic efficacy, the inhibitory activity of the combination therapy in cells can be monitored, for example, by measuring the amount of phosphorylated ERK inhibited by KRas G12C activity, and the dosage can be adjusted appropriately by the attending physician.

[0102] The compositions and methods provided herein may be used to treat KRas G12C-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the PARP inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0103] In one embodiment, the combination of a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in an increase in overall survival ("OS") in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in an increase in progression-free survival ("PFS") in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and a therapeutically effective amount of a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in improved duration of stable disease in a subject compared to treatment with a KRas G12C inhibitor alone.In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). In one embodiment, the PARP inhibitor is selected from olaparib, rucaparib, niraparib, talazoparib, and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and rucaparib.In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and veliparib.

[0104] In another embodiment, a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered in combination with a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof after disease progression is observed with KRas G12C monotherapy, and the combination therapy enhances clinical benefit to the patient by prolonging OS, PFS, tumor regression, tumor growth inhibition, or duration of stable disease in the patient.

[0105] In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). In one embodiment, the PARP inhibitor is selected from olaparib, rucaparib, niraparib, talazoparib, and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and niraparib.In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and veliparib.

[0106] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors such as lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. More specifically, these compounds can be used to treat the following: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchopulmonary) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, lipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, Hamartoma, leiomyoma); Genitourinary system: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), gallbladder Ductal carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, carcinoma of the ampulla of Vater, bile duct carcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondral exostosis (osteochondroma), benign chondroma, chondroblastoma, chondrodysplastic fibroma, osteoid osteoma and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, cervical dysplasia), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysblastoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma) Cancer: adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentil dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

[0107] Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., determined using a regulatory agency-approved (e.g., FDA-approved) assay or kit); and (b) administering to the patient a combination of a PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a therapeutically effective amount of a compound that is a KRas G12C inhibitor of Formula I, Formula IA, or Formula 1-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the PARP inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (numbered as described in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). In one embodiment, the PARP inhibitor is selected from olaparib, rucaparib, niraparib, talazoparib, and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 234 and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 359 and veliparib.In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and veliparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and olaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and rucaparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and niraparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and talazoparib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and veliparib.

[0108] In one embodiment, the compound of formula I is administered as a capsule for a period of time. In one embodiment, a tablet or capsule formulation of the compound of Formula I contains from about 10 mg to about 100 mg (e.g., from about 10 mg to about 95 mg, from about 10 mg to about 90 mg, from about 10 mg to about 85 mg, from about 10 mg to about 80 mg, from about 10 mg to about 75 mg, from about 10 mg to about 70 mg, from about 10 mg to about 65 mg, from about 10 mg to about 60 mg, from about 10 mg to about 55 mg, from about 10 mg to about 50 mg, from about 10 mg to about 45 mg, from about 10 mg to about 40 mg, from about 10 mg to about 35 mg, from about 10 mg to about 30 mg, from about 10 mg to about 25 mg, from about 10 mg to about 20 mg, from about 10 mg to about 15 mg, from about 15 mg to about 100 mg, from about 15 mg to about 95 mg, from about 15 mg to about 90 mg, from about 15 mg to about 85 mg, from about 15 mg to about 80 15 mg to 75 mg, 15 mg to 70 mg, 15 mg to 65 mg, 15 mg to 60 mg, 15 mg to 55 mg, 15 mg to 50 mg, 15 mg to 45 mg, 15 mg to 40 mg, 15 mg to 35 mg, 15 mg to 30 mg, 15 mg to 25 mg, 15 mg~20 mg, 20 mg~100 mg, 20 mg~95 mg, 20 mg~90 mg, 20 mg~85 mg, 20 mg~80 mg, 20 mg~75 mg, 20 mg~70 mg, 20 mg~65 mg, 20 mg~60 mg, 20 mg~55 mg, 20 mg~50 mg, about 20 mg to about 45 mg, about 20 mg~40 mg, 20 mg~35 mg, 20 mg~30 mg, 20 mg~25 mg, 25 mg~100 mg, 25 mg~95 mg, 25 mg~90 mg, 25 mg~85 mg, 25 mg~80 mg, 25 mg~75 mg, 25 mg~70 mg, 25 mg~65 mg, about 25 mg to about 60 mg, about 25 mg to about 55 mg, about 25 mg to about 50 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30mg to about 100 mg, about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 100 mg, about 35 mg to about 95 mg, about 35 mg to about 90 mg, about 35 mg to about 85 mg, about 35 mg to about 80 mg, about 35 mg to about 75 mg, about 35 mg to about 70 mg, about 35 mg to about 65 mg, about 35 mg to about 60 mg, about 35 mg to about 55 mg, about 35 from about 40 mg to about 100 mg, from about 40 mg to about 95 mg, from about 40 mg to about 90 mg, from about 40 mg to about 85 mg, from about 40 mg to about 80 mg, from about 40 mg to about 75 mg, from about 40 mg to about 70 mg, from about 40 mg to about 65 mg, from about 40 mg to about 60 mg, from about 40 mg to about 55 mg, from about 40 mg to about 50 mg, from about 40 mg to about 45 mg, from about 45 mg to about 100 mg, from about 45 mg to about 95 mg, from about 45 mg to about 90 mg, from about 45 mg to about 85 mg, from about 45 mg to about 80 mg, from about 45 mg to about 75 mg, from about 45 mg to about 70 mg, from about 45 mg to about 65 mg, from about 45 mg to about 60 mg, From about 45 mg to about 50 mg, from about 50 mg to about 100 mg, from about 50 mg to about 95 mg, from about 50 mg to about 90 mg, from about 50 mg to about 85 mg, from about 50 mg to about 80 mg, from about 50 mg to about 75 mg, from about 50 mg to about 70 mg, from about 50 mg to about 65 mg, from about 50 mg to about 60 mg, from about 50 mg to about 55 mg, from about 55 mg to about 100 mg, from about 55 mg to about 95 mg, from about 55 mg to about 90 mg, from about 55 mg to about 85 mg, from about 55 mg to about 80 mg, from about 55 mg to about 75 mg, from about 55 mg to about 70 mg, from about 55 mg to about 65 mg, from about 55 mg to about 60 mg, from about 60 mg to about 100 mg, from about 60 mg to about 95 mg, from about 60mg~90 mg, 60 mg~85 mg, 60 mg~80 mg, 60 mg~75 mg, 60 mg~70 mg, 60 mg~65 mg, 65 mg~100 mg, 65 mg~95 mg, 65 mg~90 mg, 65 mg~85 mg, 65 mg~80 mg, 65 mg~75 65 mg to 70 mg, 70 mg to 100 mg, 70 mg to 95 mg, 70 mg to 90 mg, 70 mg to 85 mg, 70 mg to 80 mg, 70 mg to 75 mg, 75 mg to 100 mg, 75 mg to 95 mg, 75 mg to 90 mg, 75 mg to 85 mg, 75 mg~about 80 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 100 mg, about 90 mg to about 95 mg, about 95 mg to about 100 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 or about 100 mg) of a compound of Formula I (e.g., a compound selected from Compound Nos. 1-678 (compounds numbered in WO199099524, e.g., Compound Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof)). In one embodiment, the compound of Formula I is orally administered once daily (QD) every day for a period of time. In one embodiment, the compound of Formula I is orally administered twice daily (BID) every day for a period of time. In one embodiment, the compound of formula I is administered at a dose of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg) over a period of time.mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 from about 40 mg to about 320 mg, from about 40 mg to about 300 mg, from about 40 mg to about 280 mg, from about 40 mg to about 260 mg, from about 40 mg to about 240 mg, from about 40 mg to about 220 mg, from about 40 mg to about 200 mg, from about 40 mg to about 180 mg, from about 40 mg to about 160 mg, from about 40 mg to about 140 mg, from about 40 mg to about 120 mg, from about 40 mg to about 100 mg, from about 40 mg to about 80 mg, from about 40 mg to about 60 mg, from about 60 mg to about 500 mg, from about 60 mg to about 480 mg, from about 60 mg to about 460 mg, from about 60 mg to about 440 mg, from about 60 mg to about 420 mg, from about 60 mg to about 400 mg, from about 60 mg to about 380 mg, from about 60 mg to about 360 mg, from about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 from about 120 mg to about 500 mg, from about 120 mg to about 480 mg, from about 120 mg to about 460 mg, from about 120 mg to about 440 mg, from about 120 mg to about 420 mg, from about 120 mg to about 400 mg, from about 120 mg to about 380 mg, from about 120 mg to about 360 mg, from about 120 mg to about 340 mg, from about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg~about 280mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 From about 160 mg to about 200 mg, from about 160 mg to about 180 mg, from about 180 mg to about 500 mg, from about 180 mg to about 480 mg, from about 180 mg to about 460 mg, from about 180 mg to about 440 mg, from about 180 mg to about 420 mg, from about 180 mg to about 400 mg, from about 180 mg to about 380 mg, from about 180 mg to about 360 mg, from about 180 mg to about 340 mg, from about 180 mg to about 320 mg, from about 180 mg to about 300 mg, from about 180 mg to about 280 mg, from about 180 mg to about 260 mg, from about 180 mg to about 240 mg, from about 180 mg to about 220 mg, from about 180 mg to about 200 mg, from about 200 mg to about 500 mg, from about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg~about 360 mg, about 220mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg mg, about 340 mg to about 480mg, approx. 340 mg ~ approx. 460 mg, approx. 340 mg ~ approx. 440 mg, approx. 340 mg ~ approx. 420 mg, approx. 340 mg ~ approx. 400 mg, approx. 340 mg ~ approx. 380 mg, approx. mg~440 mg, 360 mg~420 mg, 360 mg~400 mg, 360 mg~380 mg, 380 mg~500 mg, 380 mg~480 mg, 380 mg~460 mg, 380 mg~440 mg, 380 mg~420 mg, 380 mg~400 mg, about 400 mg to about 500 mg, about 400 The compound is orally administered in an amount of about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25 mg, about 50 mg, about 75 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, or about 500 mg.

[0109] In one embodiment, the combination therapy involves administering a compound of Formula I once daily or twice daily on a daily basis (over a period of time), for example, about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 4 ... mg~20 mg, 20 mg~400 mg, 20 mg~380 mg, 20 mg~360 mg, 20 mg~340 mg, 20 mg~320 mg, 20 mg~300 mg, 20 mg~280 mg, 20 mg~260 mg, 20 mg~240 mg, 20 mg~220 20 mg to 200 mg, 20 mg to 180 mg, 20 mg to 160 mg, 20 mg to 140 mg, 20 mg to 120 mg, 20 mg to 100 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 40 mg, 40 mg to 400 mg, 40 mg to 380 mg, about 40 mg to about 360 40 mg to 340 mg, 40 mg to 320 mg, 40 mg to 300 mg, 40 mg to 280 mg, 40 mg to 260 mg, 40 mg to 240 mg, 40 mg to 220 mg, 40 mg to 200 mg, 40 mg to 180 mg, 40 mg to 160 mg, 40 mg~140 mg, 40 mg~120 mg, 40 mg~100 mg, 40 mg~80 mg, 40 mg~60 mg, 60 mg~400 mg, 60 mg~380 mg, 60 mg~360 mg, 60 mg~340 mg, 60 mg~320 mg, 60 mg~300 mg, about 60from about 60 mg to about 280 mg, from about 60 mg to about 260 mg, from about 60 mg to about 240 mg, from about 60 mg to about 220 mg, from about 60 mg to about 200 mg, from about 60 mg to about 180 mg, from about 60 mg to about 160 mg, from about 60 mg to about 140 mg, from about 60 mg to about 120 mg, from about 60 mg to about 100 mg, from about 60 mg to about 80 mg, from about 80 mg to about 400 mg, from about 80 mg to about 380 mg, from about 80 mg to about 360 mg, from about 80 mg to about 340 mg, from about 80 mg to about 320 mg, from about 80 mg to about 300 mg, from about 80 mg to about 280 mg, from about 80 mg to about 260 mg, from about 80 mg to about 240 mg, from about 80 mg to about 220 mg, from about 80 mg to about 200 mg, from about 80 from about 180 mg to about 180 mg, from about 80 mg to about 160 mg, from about 80 mg to about 140 mg, from about 80 mg to about 120 mg, from about 80 mg to about 100 mg, from about 100 mg to about 400 mg, from about 100 mg to about 380 mg, from about 100 mg to about 360 mg, from about 100 mg to about 340 mg, from about 100 mg to about 320 mg, from about 100 mg to about 300 mg, from about 100 mg to about 280 mg, from about 100 mg to about 260 mg, from about 100 mg to about 240 mg, from about 100 mg to about 220 mg, from about 100 mg to about 200 mg, from about 100 mg to about 180 mg, from about 100 mg to about 160 mg, from about 100 mg to about 140 mg, from about 100 mg to about 120 mg, from about 120 mg to about 400 mg. mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg~about 260 mg, about 140From about 140 mg to about 240 mg, from about 140 mg to about 220 mg, from about 140 mg to about 200 mg, from about 140 mg to about 180 mg, from about 140 mg to about 160 mg, from about 160 mg to about 400 mg, from about 160 mg to about 380 mg, from about 160 mg to about 360 mg, from about 160 mg to about 340 mg, from about 160 mg to about 320 mg, from about 160 mg to about 300 mg, from about 160 mg to about 280 mg, from about 160 mg to about 260 mg, from about 160 mg to about 240 mg, from about 160 mg to about 220 mg, from about 160 mg to about 200 mg, from about 160 mg to about 180 mg, from about 180 mg to about 400 mg, from about 180 mg to about 380 mg, from about 180 mg to about 360 mg, from about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 400mg, approx. 280 mg ~ approx. 380 mg, approx. 280 mg ~ approx. 360 mg, approx. 280 mg ~ approx. 340 mg, approx. 280 mg ~ approx. 320 mg, approx. 280 mg ~ approx. 300 mg, approx. mg~320 mg, 320 mg~400 mg, 320 mg~380 mg, 320 mg~360 mg, 340 mg~360 mg, 340 mg~400 mg, 340 mg~380 mg, 340 mg~360 mg, 360 mg~400 mg, 360 mg~380 mg, about 380 mg to about 400 mg, about 100 In one embodiment, the KRAS inhibitor is orally administered once a day. In one embodiment, the KRAS inhibitor is orally administered twice a day.

[0110] Those skilled in the art will recognize that both in vivo and in vitro testing using appropriate, known, and generally accepted cell and / or animal models will suggest the ability of a test compound combination or combinations to treat or prevent a given disorder.

[0111] Those skilled in the art will further recognize that human clinical trials, including first-in-human studies, dose-ranging studies, and efficacy studies, in healthy patients and / or patients suffering from a given disease, can be completed according to methods well known in the clinical and medical arts.

[0112] Synergy In one embodiment, the addition of a PARP inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, synergistically increases the activity of a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB against a cancer or cancer cell line that expresses KRas G12C. Any method for determining whether two compounds exhibit synergistic effects can be used to determine the synergistic effect of the combination.

[0113] Several mathematical models have been developed to determine whether two compounds act synergistically, i.e., have more than just an additive effect. For example, Loewe Additivity (Loewe (1928) Physiol. 27: 47-187), Bliss Independence (Bliss (1939) Ann. Appl. Biol. 26: 585-615), Highest Single Agent, ZIP (Yadav et al (2015) Comput Struct Biotech J 13: 504-513), and other models, such as Chou & Talalay (1984) Adv Enzyme Regul 22: 27-55. #6382953; and Greco et al. (1995) Pharmacol Rev 47(2): 331-85. #7568331), are well known in the pharmaceutical industry and can be used to calculate a "synergy score" that indicates whether synergy has been detected and the magnitude of that synergy. These synergy scores can be combined to provide a composite synergy score that can be used to evaluate and characterize compounds that are KRas G12C inhibitors of Formula (I), Formula (IA) or Formula (IB) in combination with PARP inhibitors.

[0114] Generally, mathematical models use data from the single agent values ​​to determine a predicted additive effect for the combination and compare it to the observed effect for the combination. If the observed effect is greater than the predicted effect, the combination is considered synergistic. For example, the Bliss independence model uses the observed combination response (Y O ) and the predicted combination response (Y P ) is compared. Usually, Y O Y P If it is greater, the combined effect is declared to be synergistic.

[0115] In some embodiments, the term "synergistic effect," as used herein, refers to the effect of a combination of a KRAS inhibitor, or a pharmaceutically acceptable salt thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof, resulting in any beneficial or desired result, including, for example, a clinical result or endpoint described herein, which is greater than the sum of the effects observed when the compound of Formula I, or a pharmaceutically acceptable salt thereof (e.g., a compound selected from Compounds 1-678 (as numbered in WO2019099524), e.g., Compound Nos. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof), and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, are administered alone.

[0116] In some embodiments, the methods provided herein are for a period of 1 day to 2 years (e.g., between 1 day and 22 months, between 1 day and 20 months, between 1 day and 18 months, between 1 day and 16 months, between 1 day and 14 months, between 1 day and 12 months, between 1 day and 10 months, between 1 day and 9 months, between 1 day and 8 months, between 1 day and 7 months, between 1 day and 6 months, between 1 day and 5 months, between 1 day and 4 months, between 1 day and 3 months, between 1 day and 2 months, between 1 day and 1 month, between 1 week and 2 years, between 1 week and 22 months, between 1 week and 20 months, between 1 week and 18 months, between 1 week and 16 months, between 1 week and 12 months, between 1 day ... Up to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months, 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, 1 week to 4 months, 1 week to 3 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 9 months, 2 weeks to 8 months, 2 weeks to 7 months, 2 weeks to 6 months, 2 weeks ~5 months, 2 weeks to 4 months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 9 months, 1 month to 8 months, 1 month to 7 months, 1 month to 6 months, 1 month to 5 months, 1 month to 4 months, 1 month to 3 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 1 8 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 9 months, 2 months to 8 months, 2 months to 7 months, 2 months to 6 months, 2 months to 5 months, 2 months to 4 months, 3 months to 2 years, 3 months to 22 months, 3 months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months,Between 4 months and 18 months, between 4 months and 16 months, between 4 months and 14 months, between 4 months and 12 months, between 4 months and 10 months, between 4 months and 8 months, between 4 months and 6 months, between 6 months and 2 years, between 6 months and 22 months, between 6 months and 20 months, between 6 months and 18 months, between 6 months and 16 months, between 6 months and 14 months, between 6 months and 12 months, between 6 months and 10 months, or between 6 months and 8 months) after treatment with the combination therapy, the volume of one or more solid tumors in the patient is reduced by 1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%). %, 1%~75%, 1%~70%, 1%~65%, 1%~60%, 1%~55%, 1%~50%, 1%~45%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 2%~99%, 2%~90%, 2%~85 %, 2%~80%, 2%~75%, 2%~70%, 2%~65%, 2%~60%, 2%~55%, 2%~50%, 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95 %, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~70%, 4%~65%, 4%~60%, 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~9 9%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~75%, 6%~70%, 6%~65%, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~ 10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8%~80%, 8%~75%, 8%~70%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8% ~15%, 10%~99%, 10%~95%, 10%~90%, 10%~85%, 10%~80%, 10%~75%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%,10%~25%、10%~20%、10%~15%、15%~99%、15%~95%、15%~90%、15%~85%、15%~80%、15%~75%、15%~70%、15%~65%、15%~60%、15%~55%、15%~50%、15%~55%、15%~50%、15%~45%、15%~40%、15%~35%、15%~30%、15%~25%、15%~20%、20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%, 60%~85%, 60%~80%, 60%~75%, 60%~70%, 60%~65%, 65%~99%, 60%~95%, 60%~90%, 60%~85%, 60%~80%, 60%~75%, 60%~70%, 60%~65%, 70%~99%, 70%~95%, 70%~90%, 70%~85%, 70%~80%, 70%~75%, 75% The tumor volume may be reduced by up to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100% (e.g., as compared to the volume of one or more solid tumors in the patient before treatment).

[0117] "Survival time" refers to the length of time from identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional to death of the mammal (time to death attributable to the cancer). Methods for extending survival time in a mammal afflicted with cancer are described herein.

[0118] In some embodiments, any of the methods described herein results in an increase in patient survival (e.g., between 1% and 400%, between 1% and 380%, between 1% and 360%, between 1% and 340%, between 1% and 320%, between 1% and 300%, between 1% and 280%, between 1% and 260%, between 1% and 240%, between 1% and 220%, between 1% and 200%, between 1% and 180%, between 1% and 160%, between 1% and 140%, between 1% and 120%, between 1% and 100%, between 1% and 95%, between 1% and 90%, between 1% and 85%, 1%~80%, 1%~75%, 1%~70%, 1%~65%, 1%~60%, 1%~55%, 1%~50%, 1%~45%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 5%~400%, 5%~38 0%, 5%~360%, 5%~340%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5%~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~ 80%, 5%~70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260% , 10%~240%, 10%~220%, 10%~200%, 10%~180%, 10%~160%, 10%~140%, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10% ~30%, 10%~20%, 20%~400%, 20%~380%, 20%~360%, 20%~340%, 20%~320%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20% ~160%, 20%~140%, 20%~120%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%,30%~320%、30%~300%、30%~280%、30%~260%、30%~240%、30%~220%、30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%、70%~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%, 240%~360%, 240%~340%, 240%~320%, 240%~300%, 240%~280%, 240%~260%, 260%~400%, 260%~380%, 260%~360%, 260%~340%, 260%~320%, 260%~300%, 260% to 280%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%.

[0119] In some embodiments of any of the methods described herein, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, prior to treatment with a composition or method of the invention, and optionally, the prior treatment was unsuccessful; and / or the patient has undergone surgery, and optionally, the surgery was unsuccessful; and / or the patient has been treated with a platinum chemotherapeutic agent, and optionally, was previously determined to be non-responsive to treatment with the platinum chemotherapeutic agent; and / or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful; and / or the patient has been treated with one or more other therapeutic agents.

[0120] kit The present invention also relates to a kit comprising a PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided is a kit comprising a PARP inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a compound that is a KRas G12C inhibitor of Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating hematological cancers.

[0121] In a related embodiment, the present invention provides a kit comprising a PARP inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in amounts effective to inhibit the proliferation of cancer cells (particularly KRas G12C-expressing cancer cells) in a subject. Optionally, the kit includes instructions describing how to administer the PARP inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The instructions can provide the user with a set of instructions for using the PARP inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with the compound that is a KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [Example]

[0122] Example A PARP inhibitors enhance the activity of KRas G12C inhibitors against KRas G12C-expressing cell lines This example demonstrates that the combination of a PARP inhibitor and exemplary KRas G12C inhibitor compounds of Formula I, Formula IA, and Formula 1-B synergistically inhibits the growth of tumor cell lines expressing KRas G12C.

[0123] Two lung cancer cell lines harboring the KRas G12C mutation were assembled to investigate synergistic activity when combined with a PARP inhibitor and exemplary KRas G12C inhibitors disclosed herein. The collection includes NCI-H2030 (ATCC CRL-5985) and NCI-H2122 (ATCC CRL-5985).

[0124] For each cell line, assays to determine synergy scores for pairwise combinations were performed in triplicate. Three 96-well plates, plus four additional wells of a separate 96-well control plate for measuring baseline luminescence, were seeded with 5,000 cells / well of a particular cell line in a total volume of 90 μl of growth medium appropriate for that cell line (e.g., RPMI 1640 medium supplemented with 10% FBS and cell-line-specific reagents required for growth). Plates were incubated overnight at 37°C in a 5% CO2 atmosphere.

[0125] Thirty microliters of Cell-Titer Glo reagent (CTG; Promega Corporation) was added to each well at the designated baseline, and the plate was incubated for 20 minutes with shaking at room temperature. Baseline luminescence was quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0126] Serial dilutions of working stock 1000x drugs were prepared in 100% DMSO, including 9-point single-agent dilutions of exemplary KRas G12C inhibitors of Formula (I), Formula (IA), and Formula (IB) and 5-point single-agent dilutions of PARP inhibitors. The dilutions used for KRas G12C inhibitors and PARP inhibitors varied for each individual compound, but ranged from 3-6x / serial dilution.

[0127] Exemplary KRas G12C inhibitors tested in this example include: [ka] *The above example numbers refer to the example numbers of each compound disclosed in PCT International Application Publication No. WO2019099524.

[0128] A 10X intermediate dose plate containing single agent dilutions of an exemplary KRas G12C inhibitor of Formula (I) or a PARP inhibitor was prepared in serum-free RPMI medium. Additionally, a matrix of 40 dilutions combining an exemplary KRas G12C inhibitor of Formula (I), Formula IA, or Formula IB with a PARP inhibitor was prepared as test samples.

[0129] Ten microliters of each of the 40 combinations of 10X single agent and dose matrix was added to corresponding wells of three 96-well plates seeded with the appropriate cell lines listed above, and the plates were incubated at 37°C in a 5% CO atmosphere for 72 hours. Thirty microliters of Cell-Titer Glo reagent (CTG) was added to each test well, the plates were incubated with shaking at room temperature for 20 minutes, and luminescence was quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0130] The raw data and metadata were used as input files to calculate the % effect for each treatment condition and analyzed using four independent mathematical reference models designed to determine whether two test compounds exhibit synergistic effects: Loewe additivity, Bliss independence, highest single agent effect, and ZIP (Highest Single Agent and ZIP).

[0131] The data output from each mathematical model assigned a relative synergy score. The data reported in Tables 1A and 1B are the sum of Loewe additivity, Bliss independence, highest single agent effect, and ZIP (Highest Single Agent and ZIP) synergy scores ("Composite Synergy Score"). A positive score indicates synergy between two or more compounds, while a negative score indicates no synergy. The more positive the value, the greater the synergy between two or more compounds. [Table 1] [Table 2]

[0132] These results demonstrate that a population of KRas G12C cell lines exhibits modest synergistic effects in certain cell lines in response to the combination of a PARP inhibitor and the exemplary KRas G12C inhibitor MRTX849 (Example 478 of WO2019 / 099524), justifying further investigation into combination efficacy testing in in vivo models.

[0133] Example B In vivo model for investigating the combination therapy of KRas G12C inhibitors and PARP inhibitors Immunocompromised nude / nude mice were inoculated with cells carrying the KRas G12C mutation or patient-derived tumor samples into the right hind flank. Tumor volumes were ∼300 mm 3 At this time, mice were divided into four groups of five. Group 1 received vehicle alone. Group 2 received a single KRas G12C inhibitor at a dose equivalent to the maximal biological effect, but this did not result in complete tumor regression. Group 3 received a single PARP inhibitor at a dose equivalent to the maximal biological effect, but this did not result in complete tumor regression. Group 4 received a single KRas G12C inhibitor in combination with a single PARP inhibitor, using a schedule consistent with the above. The treatment period was 17 days. Tumor volume was measured every 2–3 days using a vernier caliper and calculated using the formula: 0.5 × (length × width). 2 The combination therapy in this model demonstrated greater tumor growth suppression efficacy compared with treatment with a KRas G12C inhibitor alone, demonstrating a high likelihood of providing clinically significant benefit to treated patients.

[0134] For example, 5 x 10 in 20 nude / nude mice 6 H2122 cells were inoculated into the right hind leg. Tumor volumes were approximately 300 mm 3At the time of tumor growth (study day 1), five mice in each of five groups were administered daily p.o. for 32 days: vehicle alone (10% Captisol in 50 mM citrate buffer, pH 5.0); the KRas G12C inhibitor Compound 478 at 100 mg / kg (10% Captisol in 50 mM citrate buffer, pH 5.0); the PARP inhibitor Olaparib at 50 mg / kg (10% Captisol in 50 mM citrate buffer, pH 5.0); or the KRas G12C inhibitor Compound 478 at 100 mg / kg and Olaparib at 50 mg / kg. Treatment was discontinued in all vehicle- and Olaparib-only groups on day 17 due to large tumor growth. The average tumor volumes measured at pre-specified days for the five mice in each group are shown in Figure 1 and Table 2. [Table 3]

[0135] As shown in Figure 1 and Table 2, single-agent administration of olaparib resulted in 0% tumor growth inhibition at day 17, whereas single-agent administration of the KRas G12C inhibitor compound 478 resulted in 89% tumor growth inhibition. On the other hand, the combined use of the PARP inhibitor olaparib and compound 478 resulted in 2% tumor regression at day 17.

[0136] These results demonstrate that the combination therapy resulted in greater tumor growth inhibition compared with either single agent alone in a xenograft model derived from the H2122 cell line, and that the use of a PARP inhibitor enhanced the in vivo antitumor efficacy of the combination therapy against KRas G12C-expressing cancers.

[0137] While the invention has been described in relation to particular embodiments thereof, it will be understood that the invention is capable of further modifications, and this application generally includes such departures from the present disclosure as may be applicable to the essential features hereinabove described within the scope of the principles of the invention as come within known or customary practice in the art to which the invention pertains, and is intended to cover any such variations, uses, or adaptations of the invention within the scope of the appended claims.

Claims

1. 1. A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a PARP inhibitor and a compound of formula (I): 【Chemical 1】 [In the formula, X is a 4- to 12-membered saturated or partially saturated monocyclic, bridged, or spirocyclic ring, and the saturated or partially saturated monocyclic ring is 8 and optionally substituted with; Y is a bond, O, S, or NR 5 and R 1 teeth, 【Chemistry 2】 and R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of said Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be selected from the group consisting of one or more R 9 and optionally substituted with; each Z is C1-C4 alkylene; Each R 3 is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl, or halogen; L is a bond, —C(O)—, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, and each of said cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl is selected from the group consisting of one or more R 6 , R 7 or R 8 optionally substituted with; Each R 5 are independently hydrogen or C1-C3 alkyl; R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl, or heteroaryl being selected from the group consisting of one or more R 7 optionally substituted with; Each R 7 are independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, wherein Q is O or S; R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 ) 2 , -N(R 5 ) 2 wherein the C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 ) 2 or heteroaryl, optionally substituted; Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein said C1-C6 alkyl is optionally substituted with cycloalkyl; Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R 11 is haloalkyl; R A is absent, hydrogen, deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl; Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 ) 2 , -NHC(O)C1-C3 alkyl, -CH 2 NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and wherein the heteroaryl or heteroaryl portion of the heteroarylalkyl is substituted with one or more R 7 optionally substituted with; 【Chemistry 3】 If is a triple bond, R A does not exist, and R B is present and p is 1; or 【Chemistry 4】 is a double bond, R A exists and R B exists and p is 2, or R A , R B and the carbon atoms attached thereto may be one or more R 7 forming an optionally substituted 5-8 membered partially saturated cycloalkyl; m is 0 or an integer from 1 to 2; p is 1 or 2] or a pharmaceutically acceptable salt thereof to a subject.

2. 1. A KRas G12C inhibitor having formula IA: 【Chemistry 5】 [In the formula, R 1 , R 3 , R 4 , R 5 , R 10 , R 11 , L and m are as defined for formula I, and the piperazinyl ring is 8 and wherein R 8 is as defined for Formula I] 10. The method of claim 1, wherein the compound is a compound of Formula I having the formula:

3. 1. A KRas G12C inhibitor having formula IB: 【Chemistry 6】 [In the formula, R 1 , R 3 , R 4 , L and m are as defined for formula I, and R 2 is one or more R 9 and R is a heterocyclylalkyl optionally substituted with 9 is as defined for formula I; said piperazinyl ring is R 8 and wherein R 8 is as defined for Formula I] 10. The method of claim 1, wherein the compound is a compound of Formula I having the formula:

4. The KRas G12C inhibitor has the following formula: 【Chemistry 7】 and pharmaceutically acceptable salts thereof.

5. The KRas G12C inhibitor has the following formula: 【Chemistry 8】 or a pharmaceutically acceptable salt thereof.

6. The KRas G12C inhibitor has the following formula: 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

7. The KRas G12C inhibitor has the following formula: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

8. The KRas G12C inhibitor has the following formula: 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

9. 9. The method of any one of claims 1 to 8, wherein the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, RBN-2397, I-1, KMR-206, RP14042 and JAB-26766.

10. 6. The method of claim 5, wherein the PARP inhibitor is olaparib.

11. 6. The method of claim 5, wherein the PARP inhibitor is rucaparib.

12. 6. The method of claim 5, wherein the PARP inhibitor is niraparib.

13. 6. The method of claim 5, wherein the PARP inhibitor is talazoparib.

14. 6. The method of claim 5, wherein the PARP inhibitor is veliparib.

15. 7. The method of claim 6, wherein the PARP inhibitor is olaparib.

16. 7. The method of claim 6, wherein the PARP inhibitor is rucaparib.

17. 7. The method of claim 6, wherein the PARP inhibitor is niraparib.

18. 7. The method of claim 6, wherein the PARP inhibitor is talazoparib.

19. 7. The method of claim 6, wherein the PARP inhibitor is veliparib.

20. 8. The method of claim 7, wherein the PARP inhibitor is olaparib.

21. 8. The method of claim 7, wherein the PARP inhibitor is rucaparib.

22. 8. The method of claim 7, wherein the PARP inhibitor is niraparib.

23. 8. The method of claim 7, wherein the PARP inhibitor is talazoparib.

24. 8. The method of claim 7, wherein the PARP inhibitor is veliparib.

25. 9. The method of claim 8, wherein the PARP inhibitor is olaparib.

26. 9. The method of claim 8, wherein the PARP inhibitor is rucaparib.

27. 9. The method of claim 8, wherein the PARP inhibitor is niraparib.

28. 9. The method of claim 8, wherein the PARP inhibitor is talazoparib.

29. 9. The method of claim 8, wherein the PARP inhibitor is veliparib.

30. 10. The method of claim 9, wherein the PARP inhibitor is olaparib.

31. 10. The method of claim 9, wherein the PARP inhibitor is rucaparib.

32. 10. The method of claim 9, wherein the PARP inhibitor is niraparib.

33. 10. The method of claim 9, wherein the PARP inhibitor is talazoparib.

34. 10. The method of claim 9, wherein the PARP inhibitor is veliparib.

35. 35. The method of any one of claims 1 to 34, wherein the PARP inhibitor and the KRAS G12C inhibitor are administered on the same day.

36. 35. The method of any one of claims 1 to 34, wherein the PARP inhibitor and the KRAS G12C inhibitor are administered on different days.

37. 35. The method of any one of claims 1 to 34, wherein the KRas G12C inhibitor is administered at a maximum tolerated dose.

38. 35. The method of any one of claims 1 to 34, wherein the PARP inhibitor and the KRAS G12C inhibitor are each administered at a maximum tolerated dose.

39. 39. The method of any one of claims 1-38, wherein a therapeutically effective amount of a combination of a PARP inhibitor and a KRAS G12C inhibitor results in increased overall survival, increased progression-free survival, increased tumor growth inhibition, or increased duration of stable disease in a subject compared to treatment with a KRAS G12C inhibitor alone.

40. A pharmaceutical composition comprising a therapeutically effective amount of a combination of a PARP inhibitor and a KRas G12 inhibitor of Formula (I), Formula IA or Formula IB, and a pharmaceutically acceptable excipient.

41. the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, and veliparib; and the KRas G12C inhibitor is a compound represented by the following formula: 【Chemistry 12】 41. The pharmaceutical composition of claim 40, wherein the compound is selected from the group consisting of:

42. A method for inhibiting KRas G12C activity in a cell, comprising treating the cell in which inhibition of KRas G12C activity is desired with an effective amount of a PARP inhibitor or a pharmaceutical composition thereof or a pharmaceutically acceptable salt thereof, and a compound represented by the following formula: 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, wherein the PARP inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.

43. 43. The method of claim 42, wherein the PARP inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.

44. Below formula: 【Chemistry 14】 and pharmaceutically acceptable salts thereof, comprising administering to a subject undergoing KRas G12C therapy using said compound or its salt a therapeutically effective amount of a PARP inhibitor, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, wherein said PARP inhibitor synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor.

45. 45. The method of any one of claims 1 to 39 and 44, wherein the therapeutically effective amount of a KRas G12C inhibitor in said combination is about 0.01 to 100 mg / kg per day.

46. 46. ​​The method of claim 45, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is about 0.1 to 50 mg / kg per day.

47. 47. The method of any one of claims 45 or 46, wherein the therapeutically effective amount of the PARP inhibitor in said combination is about 0.01 to 100 mg / kg per day.

48. 48. The method of claim 47, wherein the therapeutically effective amount of the PARP inhibitor in the combination is about 0.1 to 50 mg / kg per day.

49. Cancer of the heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchopulmonary) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; digestive system: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, lipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), Colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, carcinoma of the ampulla of Vater, bile duct carcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondral exostosis (osteochondroma), benign chondroma, chondroblastoma, chondrodysplastic fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), marrow Membranes (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, cerebrospinal fluid tumor 40. The method of any one of claims 1 to 39, wherein the cancer is selected from the group consisting of: tumors of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigine dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

50. 50. The method of claim 49, wherein the cancer is a KRas G12C-associated cancer.

51. 50. The method of claim 49, wherein the cancer is non-small cell lung cancer.

52. 50. The method of claim 49, wherein the cancer is bladder cancer.

53. 50. The method of claim 49, wherein the cancer is cervical cancer.

54. 50. The method of claim 49, wherein the cancer is colon cancer.

55. 42. A kit comprising the pharmaceutical composition of claim 40 or 41 for treating KRas G12C cancer in a subject.

56. a) a pharmaceutical composition comprising a PARP inhibitor; and b) Below formula: 【Chemistry 15】 and pharmaceutically acceptable salts thereof.

57. 46. ​​The kit of claim 45, wherein the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, and veliparib.

58. 58. The kit of claim 55, 56 or 57, further comprising instructions for administering one or both of the pharmaceutical compositions.

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