Combination therapy

Abstract

The present invention relates to a combination therapy for the treatment of KRas G12C cancer. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of a therapeutically effective amount of a PARP inhibitor and a KRAS G12C inhibitor of formula (I), formula (I-A) or formula (I-B), pharmaceutical compositions comprising a therapeutically effective amount of the inhibitor, kits comprising the compositions and methods of use thereof.

Description

Field of the Invention

[0001] The present invention relates to combination therapies for treating cancer. In particular, the present invention relates to therapeutically effective combinations of inhibitors of the enzyme poly ADP ribose polymerase (PARP) and inhibitors of KRas G12C, pharmaceutical compositions comprising said inhibitors, kits comprising said compositions and methods of use thereof. Background of the Invention

[0003] Kirsten rat sarcoma 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras oncogene family. KRas acts as a molecular switch that cycles between inactive (GDP-bound) and active (GTP-bound) states, transducing upstream cellular signals received from a variety of tyrosine kinases to downstream effectors, regulating a wide variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0004] The role of activated KRas in malignancies was observed more than three decades 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 lead to 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). In lung adenocarcinoma, single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations, with G12C transversion being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online on September 26, 2012. doi:10.1158 / 1078-0432.CCR-11-3265).

[0005] The well-known role of KRas in malignancies and the frequent mutations found in a variety of tumor types make KRas an attractive target for cancer therapy in the pharmaceutical industry. Despite extensive research and development efforts over the past three decades in developing KRas inhibitors for the treatment of cancer, no KRas inhibitor has been shown to be sufficiently safe and / or effective to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21(8): 1797-1801).

[0006] Although many efforts to target KRas have failed, recent progress in covalently targeting KRas G12C has shown initial promise (see, for example, Ostrem et al., (2013) Nature 503:548-551, and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234), and some compounds have recently entered human clinical trials, such as AMG510 and MRTX849. Nevertheless, compounds that inhibit KRas activity, including compounds that disrupt effectors (e.g., guanine nucleotide exchange factors) (see, for example, Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358) and compounds that target KRas G12C, are still highly desired and under investigation.

[0007] Although the KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzymatic activity and exhibit single agent activity that inhibits in vitro proliferation of cell lines carrying KRas G12C mutations, the relative potency and / or maximum observed effect of any given KRas G12C inhibitor varies between KRAS mutant cell lines. One or more reasons for the range of potency and the maximum observed effect are not fully understood, but certain cell lines appear to have different intrinsic resistances. Therefore, it is necessary to develop alternative methods to maximize the potency, efficacy, therapeutic index, and / or clinical benefit of KRas G12C inhibitors in vitro and in vivo.

[0008] PARP plays a key role in detecting and repairing single-strand breaks in DNA through the base excision repair mechanism. PARP inhibitors disrupt the repair pathway by blocking PARP enzymatic activity and convert single-strand breaks into double-strand breaks during replication. Double-strand breaks are usually repaired by the homologous recombination pathway, which involves BRCA1 and BRCA2 (e.g., O'Connor, (2015) Mol Cell Review 60(4):547-560). BRCA1 and BRCA2 genes are tumor suppressor genes, and BRCA gene mutations can bring a high risk of developing certain cancers and potential resistance to certain forms of cancer treatment. When the BRCA gene mutates, it can no longer effectively repair broken DNA to help prevent the occurrence of certain cancers. Therefore, these BRCA-mutated cancer cells rely more on PARP to repair DNA strand breaks, allowing cells to continue to divide (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 commonly mutated oncogenic pathways in cancer. Disregulation of this pathway is frequently observed and plays an important role in the development and maintenance of several cancers, including melanoma, pancreatic cancer, lung cancer, colorectal cancer, and breast cancer (e.g., Neuzillet et al., (2014) Pharmacology & Therapeutics 141: 160-171).

[0009] Several inhibitors with anti-PARP activity have been developed, and many of these inhibitors are being or have been studied in human clinical trials. Examples of PARP inhibitors suitable for use in the provided compositions and methods include, but are not limited to, olaparib, 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one; rucaparib, 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepine -6-one; niraparib, (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide; talazoparib, (8S,9R)-5-fluoro-8-(4-fluorophenyl)-2,7,8,9-tetrahydro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3H-pyrido[4,3,2-de]phthalazin-3-one; and veliparib, (R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide.

[0010] Although the PARP inhibitors disclosed herein are potent inhibitors of PARP enzymatic activity and exhibit single agent activity that inhibits in vitro proliferation of cancer cell lines of the types discussed herein, the relative potency and / or maximum observed effect of any given PARP inhibitor varies between cancer cell lines. One or more reasons for the range of potency and maximum observed effect are not fully understood, but certain cell lines appear to have different intrinsic resistances. Therefore, there is a need to develop alternative methods to maximize the potency, efficacy, therapeutic index, and / or clinical benefit of PARP inhibitors in vitro and in vivo. SUMMARY OF THE INVENTION

[0012] In one aspect, the combination therapy of the present invention improves the efficacy of the KRas G12C inhibitor disclosed herein by co-administering the KRas G12C inhibitor with a PARP inhibitor, synergistically increasing the potency of the KRas G12C inhibitor. On the other hand, the combination therapy of the present invention provides patients with improved clinical benefit compared to treatment with the KRas G12C inhibitor disclosed herein as a single active agent.

[0013] In one aspect of the present invention, provided herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof and a KRAS G12C inhibitor of formula (I) or a pharmaceutically acceptable salt thereof in combination:

[0014]

[0015] in:

[0016] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted by one or more R 8 replace;

[0017] Y is a bond, O, S or NR 5 ;

[0018] R 1 Yes -C(O)C(R A ) C(R B ) p or -SO 2 C(R A ) C(R B ) p ;

[0019] R 2is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl or heteroarylalkyl, wherein each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl may be optionally replaced by one or more R 9 replace;

[0020] Z is C1-C4 alkylene;

[0021] Each R 3 are independently C1-C3 alkyl, oxo or haloalkyl;

[0022] L is a bond, -C(O)- or C1-C3 alkylene;

[0023] R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally replaced by one or more R 6 or R 7 replace;

[0024] Each R 5 are independently hydrogen or C1-C3 alkyl;

[0025] R 6 is a cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroaryl group, wherein each of the cycloalkyl, heterocyclyl, aryl or heteroaryl group may be optionally replaced by one or more R 7 replace;

[0026] Each R 7 are independently halogen, hydroxy, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0027] 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 group may be optionally substituted with cyano, halogen, -OR 5 、-N(R 5 ) 2 or heteroaryl substituted;

[0028] Each R 9are independently hydrogen, oxo, acyl, hydroxy, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylamino, dialkylamidoalkyl or dialkylaminoalkyl, wherein the C1-C6 alkyl may be optionally substituted with a cycloalkyl group;

[0029] Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;

[0030] R 11 is a haloalkyl group;

[0031] R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl;

[0032] 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, dialkylaminoalkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted by one or more substituents independently selected from halogen, hydroxy, alkoxy and C1-C3 alkyl, wherein the heteroaryl portion of the heteroaryl or heteroarylalkyl is optionally substituted by one or more R 7 replace;

[0033] m is 0 or an integer between 1 and 2;

[0034] p is 1 or 2; and wherein,

[0035] when When it is a triple bond, R A Does not exist, R B exists and p is equal to 1,

[0036] or when When it is a double bond, R A Existence, R B exists and p is equal to 2, or R A , R B and the carbon atoms to which they are attached form a 7 Substituted 5-8 membered partially saturated cycloalkyl.

[0037] Also included for use in the methods provided herein are KRas G12C inhibitor compounds of Formula I having Formula IA:

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 5 , R 10 , R 11 , L and m are as defined in Formula I, and the piperazine ring is optionally replaced by R 8 Substitution, where R 8 As defined in Formula I.

[0040] Also included for use in the methods provided herein are KRas G12C inhibitor compounds of Formula I having Formula IB:

[0041]

[0042] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , L and m are as defined in Formula I, R 2 is optionally replaced by one or more R 9 Substituted heterocyclylalkyl, wherein R 9 As defined in formula I, and the piperazine ring is optionally replaced by R 8 Substitution, where R 8 As defined in Formula I.

[0043] For use in the methods provided herein, also included are KRas G12C inhibitor compounds selected from the following: and pharmaceutically acceptable salts thereof.

[0044] In another aspect of the present invention, a pharmaceutical composition for use in the method is provided, which comprises a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof in combination with a KRas G12C inhibitor compound of Formula I, Formula IA, Formula 1-B or selected from the foregoing chemical substances (i.e., the substances in the previous paragraph) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0045] In one aspect of the present invention, provided herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof and a combination of a KRAS G12C inhibitor of Formula (I), Formula IA, Formula IB, or a pharmaceutically acceptable salt thereof selected from the foregoing chemical substances. In one embodiment, the cancer is a cancer associated with KRas G12C. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0046] In some aspects of the invention, the KRas G12C inhibitor compound and the PARP inhibitor are the only active agents in the provided compositions and methods.

[0047] Examples of PARP inhibitors suitable for use in the provided compositions and methods include, but are not limited to: olaparib, 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one; rucaparib, 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one; niraparib, (S)-2 -(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide; talazoparib, (8S,9R)-5-fluoro-8-(4-fluorophenyl)-2,7,8,9-tetrahydro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3H-pyrido[4,3,2-de]phthalazin-3-one; and veliparib, (R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide. Other PARP inhibitors suitable for use in the provided compositions and methods include, but are not limited to, RBN-2397 (Ribon Therapeutics), 1-1 (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).

[0048] In another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to KRas G12C inhibitors, the method comprising contacting cancer cells with a therapeutically effective amount of a KRasG12C inhibitor compound of Formula (I), Formula IA, Formula IB, or a combination of a compound selected from the foregoing chemical substances and a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the PARP inhibitor synergistically increases the sensitivity of cancer cells to KRas G12C inhibitors. In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0049] Also provided herein are methods for treating cancer in an individual 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 an assay or kit approved by a regulatory agency, such as an FDA-approved assay); and (b) administering to the patient a therapeutically effective amount of a PARP inhibitor and a KRas G12C inhibitor compound of Formula I, Formula IA, Formula I-B, or selected from the foregoing chemical substances, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the PARP inhibitor synergistically increases the sensitivity of the cancer associated with KRas G12C to the KRas G12C inhibitor.

[0050] Also provided herein is a kit comprising a PARP inhibitor and a KRasG12C inhibitor of Formula (I), Formula IA, Formula IB, or one of the foregoing. Also provided is a kit comprising a PARP inhibitor and a KRasG12C inhibitor compound of Formula (I), Formula IA, Formula IB, or one of the foregoing for use in treating KRasG12C cancer.

[0051] In a related aspect, the present invention provides a kit containing a dose of a PARP inhibitor and a KRas G12C inhibitor compound of Formula (I), Formula IA, Formula IB, or one of the foregoing substances, which is effective to inhibit the proliferation of cancer cells in an individual. In some cases, the kit includes an insert containing instructions for the administration of the PARP inhibitor and the compound of Formula (I), Formula IA, Formula IB, or one of the foregoing substances. The insert can provide a user with a set of instructions for using the combination of a PARP inhibitor and a KRas G12C inhibitor compound of Formula (I), Formula IA, Formula IB, or one of the foregoing substances.

[0052] 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, and optionally, the previous 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-based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with a platinum-based chemotherapeutic agent; and / or the patient has been treated with a kinase inhibitor, and optionally, previous treatment with the kinase inhibitor was unsuccessful; and / or the patient has been treated with one or more other therapeutic agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 is a graph showing the effect of administration of Compound 478 and / or Olaparib on H2122 tumor volume. DETAILED DESCRIPTION OF THE INVENTION

[0056] The present invention relates to combination therapies for treating KRas G12C cancers. In particular, the present invention relates to methods of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof, a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition and methods of use thereof.

[0057] 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 potency of the KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition against cancer cells expressing KRas G12C, thereby increasing the efficacy 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.

[0058] definition

[0059] Unless defined otherwise, 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.

[0060] As used herein, "KRas G12C" refers to a mutant form of mammalian KRas protein comprising an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The designation of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Cys.

[0061] "KRas G12C inhibitor" as used herein refers to a compound of the present invention represented by formula (I), formula IA and formula IB as 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 KRasG12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine ​​residue at position 12 and irreversibly binds thereto, thereby inhibiting the enzymatic activity of KRas G12C. In one embodiment, the KRas G12C inhibitor is a compound selected from compound number 1-678 (such as the number in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Example No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof). In another embodiment, the KRas G12C inhibitor is a compound selected from compound number 1-228 (such as the number in US2019-0270743) or a pharmaceutically acceptable salt thereof.

[0062] As used herein, "a disease or disorder associated with KRas G12C" refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. A non-limiting example of a disease or disorder associated with KRas G12C is a cancer associated with KRas G12C.

[0063] As used herein, "PARP" refers to poly (ADP-ribose) polymerase, which is a family of proteins involved in a variety of cellular processes (e.g., DNA repair, genome stability, and programmed cell death). The PARP family contains 17 members (10 are putative). Their structures and functions in cells vary greatly. PARP1, PARP2, VPARP (PARP4), Tankyrase-1 and -2 (PARP-5a or TNKS and PARP-5b or TNKS2) have confirmed PARP activity. Others include PARP3, PARP6, TIPARP (or "PARP7"), PARP8, PARP9, PARP10, PARP11, PARP12, PARP14, PARP15 and PARP16. PARP consists of four related domains: a DNA binding domain, a caspase cleavage domain (see below), a self-modification domain, and a catalytic domain. The DNA binding domain consists of two zinc finger motifs. When damaged DNA is present (base pairs are excised), the DNA binding domain will bind to the DNA and induce a conformational transition. This binding has been shown to occur independently of the other domains. This is an integral part of the programmed cell death model based on the inhibition of caspase cleavage by PARP. The self-modification domain is responsible for releasing the protein from the DNA after catalysis. In addition, it plays an integral role in cleavage-induced inactivation. The main role of PARP (present in the nucleus) is to detect and initiate an immediate cellular response to SSBs induced by metabolites, chemicals or radiation through the enzymatic mechanism involved in signaling single-strand DNA break (SSB) repair. Once PARP detects SSB, it binds to DNA, undergoes structural changes, and begins to synthesize polymerized adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chains, which serve as signals for other DNA repair enzymes. Target enzymes include DNA ligase III (LigIII), DNA polymerase β (polβ) and scaffold proteins such as X-ray cross-complementation gene 1 (XRCC1). After repair, PAR chains are degraded by poly(ADP-ribose) glycosyl hydrolase (PARG). NAD+ is required for the generation of substrates for ADP-ribose monomers. Overactivation of PARP is thought to deplete cellular NAD+ stores and induce progressive ATP depletion and cell necrosis because glucose oxidation is inhibited. However, recent studies have shown that inhibition of hexokinase activity leads to glycolytic defects (Andrabi, PNAS 2014). Basal PARP activity also regulates basal bioenergetics. It should be noted below that during programmed cell death, PARP is cleaved and inactivated by caspase-3. PARP enzymes are critical in a variety of cellular functions, including the expression of inflammatory genes: PARP1 is required to induce expression of the ICAM-1 gene in cardiomyocytes and smooth muscle cells in response to TNF.

[0064] As used herein, "PARP inhibitors" refers to compounds that are capable of negatively regulating or inhibiting all or part of the enzymatic activity of the PARP enzyme. More particularly, PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). They are being developed for a variety of indications, including the treatment of hereditary cancers. Several forms of cancer are more dependent on PARP than conventional cells, making PARP (PARP1, PARP2, etc.) an attractive target for cancer treatment. As demonstrated primarily by adding 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 treatment, PARP inhibitors are also considered potential treatments for acute life-threatening diseases such as stroke and myocardial infarction, as well as long-term neurodegenerative diseases.

[0065] 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, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the individual has experienced and / or exhibits at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the individual has been identified or diagnosed as having a cancer with a KRas G12C mutation (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay). In some embodiments, the individual has a tumor that is positive for a KRas G12C mutation (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay). The individual may be an individual with a tumor that is positive for a KRas G12C mutation (e.g., determined to be positive using an assay or kit approved by a regulatory agency, such as an FDA-approved assay). The individual may be an individual whose tumor has a KRas G12C mutation (e.g., where the tumor is determined using a kit or assay approved by a regulatory agency, such as an FDA-approved assay). In some embodiments, the individual is suspected of having a cancer associated with the KRas G12C gene. In some embodiments, the individual has a clinical record indicating that the individual has a tumor with a KRas G12C mutation (and optionally the clinical record indicates that the individual should be treated with any of the compositions provided herein).

[0066] As used herein, the term "pediatric patient" refers to a patient under the age of 16 at the time of diagnosis or treatment. The term "pediatric" can be further divided into a variety of subgroups, including: neonates (from birth to the first month of life); infants (1 month to up to 2 years); children (2 years to up to 12 years); and adolescents (12 years to 21 years (up to but not including the 22nd birthday)). BerhmanRE, KliegmanR, ArvinAM, NelsonWE, NelsonTextbook of Pediatrics, 15th ed., Philadelphia: WBSaunders Company, 1996; RudolphAM et al., Rudolph's Pediatrics, 21st ed., New York: McGraw-Hill, 2002; and AveryMD, FirstLR, Pediatric Medicine, 2nd ed., Baltimore: Williams&Wilkins; 1994.

[0067] In some embodiments of any of the methods or uses described herein, an assay for determining whether a patient has a KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample, such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a cancer associated with KRas G12C, a patient having one or more symptoms of a cancer associated with KRas G12C, and / or a patient having an increased risk of developing a cancer associated with KRas G12C) 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, or ddPCR). As is well known in the art, these 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.

[0068] The term "regulatory body" is a national agency responsible for approving drugs for medical use in that country. For example, a non-limiting example of a regulatory body is the United States Food and Drug Administration (FDA).

[0069] The term "amino" refers to -NH 2 ;

[0070] The term "acyl" refers to -C(O)CH 3 .

[0071] The term "alkyl" as used herein refers to a straight or branched aliphatic group having 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, which is 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.

[0072] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens are replaced by halogens. Examples of haloalkyl are trifluoromethyl, difluoromethyl and fluoromethyl.

[0073] The term "haloalkoxy" refers to an -O-haloalkyl group.

[0074] "Alkylene" refers to an alkyl group as defined above that is positioned between and used to connect two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0075] The term "alkoxy" refers to an -OC1-C6 alkyl group.

[0076] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl is additionally optionally substituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0077] The term "heteroalkyl" refers to an alkyl group as defined above wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from O, S and N.

[0078] As used herein, the term "hydroxyalkyl" refers to -alkyl-OH.

[0079] The term "dihydroxyalkyl" refers to an alkyl group as defined herein wherein two carbon atoms are each replaced with hydroxy groups.

[0080] The term "alkylamino" refers to -NR x -alkyl, where R x is hydrogen. In one embodiment, R x It's hydrogen.

[0081] The term "dialkylamino" refers to -N(R y ) 2 , where each R y It is a C1-C3 alkyl group.

[0082] The term "alkylaminoalkyl" refers to an -alkyl-NR x -alkyl, where R xis hydrogen. In one embodiment, R x It's hydrogen.

[0083] The term "dialkylaminoalkyl" refers to an -alkyl-N(R y ) 2 , where each R y is a C1-C4 alkyl group, wherein -alkyl-N(R y ) 2 The alkyl group may be optionally substituted with hydroxy or hydroxyalkyl.

[0084] "Aryl" is a C 6 -C 14 An aromatic moiety, which is optionally substituted. As one embodiment, aryl is C 6 -C 10 Aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0085] "Aralkyl" or "arylalkyl" includes an aryl group covalently linked to an alkyl group, either of which is independently optionally substituted or unsubstituted. Examples of aralkyl groups are (C 1 -C 6 )alkyl(C 6 -C 10 ) aryl groups, including but not limited to benzyl, phenethyl and naphthylmethyl. An example of a substituted aralkyl group is one in which the alkyl group is substituted with a hydroxyalkyl group.

[0086] A "heterocyclyl" or "heterocyclic" group is a ring structure having about 3 to about 12 atoms (e.g., 4 to 8 atoms), one or more of which are selected from N, O and S, and the remaining ring atoms are carbon. A heterocyclyl group may be a monocyclic, bicyclic, spirocyclic or bridged ring system. A heterocyclyl group is optionally substituted at one or more positions on a carbon or nitrogen atom with R 7 Substitution, where R 7 As defined in Formula I. Heterocyclic radical is also independently optionally replaced by alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkyloxycarbonyl, or replaced by oxo or lower alkyl on sulfur. The example of heterocyclic radical includes but is not limited to epoxy, azetidinyl, aziridine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithiohexyl, trithiohexyl, dioxolane, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidone, 4-piperidone, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, oxazaheptanyl, azabicyclohexane, azabicycloheptane and oxazabicycloheptane. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0087] The term "heterocycloalkyl" refers to a heterocyclyl group as defined herein attached to the remainder of the molecule via an alkyl linker group, wherein the alkyl linker group of the heterocycloalkyl group may be optionally substituted with hydroxy or hydroxyalkyl.

[0088] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10 or 14 π electrons shared in a cyclic array; and having 1 to 3 heteroatoms per ring other than carbon atoms selected from N, O and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl , indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolyl, 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, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinine cycloalkyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthene.

[0089] " heteroaralkyl " comprises the heteroaryl that is covalently connected to alkyl, wherein free radical is located on alkyl, and any one of alkyl and heteroaryl is optionally substituted or unsubstituted independently.The example of heteroaralkyl comprises the heteroaryl with 5,6,9 or 10 ring atoms bonded with C1-C6 alkyl.The example of heteroaralkyl comprises pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolylmethyl, quinolylethyl, benzofuranylmethyl, indolylethyl, isoquinolylmethyl, isoindolylmethyl, cinnolinylmethyl and benzothienylethyl.Particularly excluded from the scope of this term are compounds with adjacent ring O and / or S atoms.

[0090] As used herein, an "effective amount" of a compound refers to an amount sufficient to negatively regulate or inhibit the activity of a desired target (ie, PARP or KRasG12C). Such an amount may be administered as a single dose or may be administered according to a regimen such that the amount is effective.

[0091] As used herein, a "therapeutically effective amount" of a compound refers to an amount sufficient to improve, alleviate symptoms, or stop or reverse the progression of a condition in some way or to negatively regulate or inhibit PARP or KRas G12C activity. Such an amount can be administered as a single dose or can be administered according to a regimen such that the amount is effective.

[0092] As used herein, a "combined therapeutically effective amount" of two compounds is an amount that together synergistically increases the activity of the combination compared to the therapeutically effective amounts of each compound in the combination, i.e., more than additive alone. Optionally, in vivo, the combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in the duration of overall survival ("OS") in the subject relative to treatment with the KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in the duration of progression-free survival ("PFS") in the subject relative to treatment with the KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor regression in the subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor growth inhibition in the subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an improvement in the duration of disease stabilization in the subject relative to treatment with a KRas G12C inhibitor alone. The amount of each compound in the combination may be the same or different than the therapeutically effective amount of each compound when it is administered alone as a monotherapy, as long as the combination has a synergistic effect. Such an amount may be administered as a single dose or may be administered according to a regimen such that the amount is effective.

[0093] As used herein, treatment refers to any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0094] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, sustained or transient, attributable to or associated with administration of the composition.

[0095] As used herein, the term "about" when used to modify a parameter defined by a numerical value (e.g., the dosage of a KRAS inhibitor or PARP inhibitor or a pharmaceutically acceptable salt, or the length of treatment for a combination therapy described herein) means that the parameter may vary between up to 10% below or above the stated value of the parameter. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. "About" when used at the beginning of a parameter list means to modify each parameter. 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, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.

[0096] Inhibitor compounds

[0097] In one aspect of the present invention, provided herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0098] Methods for preparing PARP inhibitors or pharmaceutically acceptable salts thereof or pharmaceutical compositions are well known to those skilled in the art, and PARP inhibitors are available from a wide variety of commercial suppliers in forms suitable for research or human use. In addition, PARP inhibitors suitable for use in the compositions and methods disclosed herein, methods for preparing such inhibitors, and related uses and methods are disclosed in the following U.S. Patents: U.S. Pat. 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; 8,012,976; 8,420,650; 8,735,392; 9,820,9 85; US10,189,837; US6,495,541; US7,351,701; US7,531,530; US8,754,072; US9,045,487; US9,861,638; US9,987,285; US10,130,636; US10,278,974; US8,071,623; US8,436,185; US11,091,459; US7,550,603, etc.

[0099] 1. KRas G12C inhibitors

[0100] In one embodiment, the KRas G12C inhibitor used in the method is a compound of formula (I):

[0101]

[0102] or a pharmaceutically acceptable salt thereof, wherein:

[0103] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted by one or more R 8 replace;

[0104] Y is a bond, O, S or NR 5 ;

[0105] R 1 Yes -C(O)C(R A ) C(R B ) p or -SO 2 C(RA ) C(R B ) p ;

[0106] R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl or heteroarylalkyl, wherein each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl may be optionally replaced by one or more R 9 replace;

[0107] Z is C1-C4 alkylene;

[0108] Each R 3 are independently C1-C3 alkyl, oxo or haloalkyl;

[0109] L is a bond, -C(O)- or C1-C3 alkylene;

[0110] R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally replaced by one or more R 6 or R 7 replace;

[0111] Each R 5 are independently hydrogen or C1-C3 alkyl;

[0112] R 6 is a cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroaryl group, wherein each of the cycloalkyl, heterocyclyl, aryl or heteroaryl group may be optionally replaced by one or more R 7 replace;

[0113] Each R 7 are independently halogen, hydroxy, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0114] 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 group may be optionally substituted with cyano, halogen, -OR 5 、-N(R 5 )2 or heteroaryl substituted;

[0115] Each R 9 are independently hydrogen, oxo, acyl, hydroxy, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylamino, dialkylamidoalkyl or dialkylaminoalkyl, wherein the C1-C6 alkyl may be optionally substituted with a cycloalkyl group;

[0116] Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;

[0117] R 11 is a haloalkyl group;

[0118] R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl;

[0119] 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, dialkylaminoalkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted by one or more substituents independently selected from halogen, hydroxy, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted by one or more R 7 replace;

[0120] m is 0 or an integer between 1 and 2;

[0121] p is 1 or 2; and wherein,

[0122] when When it is a triple bond, R A Does not exist, R B exists, and p is equal to 1;

[0123] or when When it is a double bond, R A Existence, R B exists, and p is equal to 2, or R A , R Band the carbon atoms to which they are attached form a 7 Substituted 5-8 membered partially saturated cycloalkyl.

[0124] In one embodiment, KRas G12C inhibitors for use in the methods herein include compounds having Formula IA:

[0125]

[0126] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 5 , R 10 , L and m are as defined in Formula I, R 11 is hydrogen, methyl or hydroxyalkyl, and the pyridyl ring is optionally replaced by R 8 Substitution, where R 8 As defined in Formula I.

[0127] In one embodiment, KRas G12C inhibitors for use in the methods herein include compounds having Formula IB:

[0128]

[0129] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 9 , R 11 , L and m are as defined in Formula I.

[0130] Non-limiting examples of KRas G12C inhibitors of Formula (I), Formula IA, and Formula IB that can be used in the methods disclosed herein are selected from Example Nos. 1-678 of WO2019 / 099524 and Example Nos. 1-228 of WO2020 / 101736, including the following representative structures:

[0131]

[0132] and pharmaceutically acceptable salts thereof.

[0133] In one embodiment, the KRas G12C inhibitor is:

[0134]

[0135] (also known as Example 234 of WO2019 / 099524) or a pharmaceutically acceptable salt thereof.

[0136] In one embodiment, the KRas G12C inhibitor is:

[0137]

[0138] (also known as Example 359 of WO2019 / 099524) or a pharmaceutically acceptable salt thereof.

[0139] In one embodiment, the KRas G12C inhibitor is:

[0140]

[0141] (also known as Example 478 of WO2019 / 099524, MRTX-849 and / or adagrasib) or a pharmaceutically acceptable salt thereof.

[0142] In one embodiment, the KRas G12C inhibitor is:

[0143]

[0144] (also referred to as Example 507 of WO2019 / 099524) or a pharmaceutically acceptable salt thereof.

[0145] The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as a mixture of stereoisomers (isomers having the same structure but differing in the arrangement of their atoms in space). The compounds may be used as a mixture or as a single component / isomer, and the individual components / isomers may be separated using commercially available reagents and conventional methods for separating stereoisomers and enantiomers that are well known to those skilled in the art, for example, using (Sigma-Aldrich) or (Diacel Corp) chiral chromatography HPLC column. Optionally, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates to prepare single isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise indicated, wherever the compounds of the present invention are mentioned in the specification, including the claims, the term "compound" is understood to cover all chiral (enantiomers and diastereomers) and racemic forms.

[0146] In one embodiment, the KRas G12C inhibitor compound of Formula I, Formula IA, Formula IB, or the foregoing used in the method comprises a trifluoroacetate salt of the above compound.

[0147] The preparation methods of the KRas G12C inhibitors disclosed herein are known. For example, co-owned published international PCT application numbers WO2017201161 and WO2019099524, and published U.S. patent application publication numbers US20180072723 and US20190270743 describe general reaction schemes for preparing 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 preparing each KRas G12C inhibitor disclosed herein.

[0148] The PARP inhibitor and the KRas G12C compound of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be formulated into a pharmaceutical composition.

[0149] Pharmaceutical composition

[0150] 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 of the present invention and 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 well known in the art and can be 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 performed by an oral route.

[0151] The carrier characteristics will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue or organism and does not interfere with the effectiveness of the biological activity of the active ingredient. Therefore, in addition to the inhibitor, the composition may also include diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials known in the art. The preparation of pharmaceutically acceptable preparations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition (A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990).

[0152] The term pharmaceutically acceptable salt used herein refers to a salt that retains the desired biological activity of the above-mentioned compounds and exhibits minimal or no undesirable toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid). The compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly including quaternary ammonium salts of the formula -NR+Z-, wherein R is hydrogen, alkyl or benzyl, and Z is a counterion including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methanesulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzoate and diphenylacetate).

[0153] 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 severe toxic effects in the treated patient. In one embodiment, for all the above-mentioned conditions, the dosage range of the active compound is about 0.01mg / kg to 300mg / kg recipient body weight / day, for example 0.1mg / kg to 100mg / kg recipient body weight / day, and further for example 0.5mg / kg to about 25mg / kg recipient body weight / day. The typical local dosage range in a suitable carrier is 0.01-3%wt / wt. The effective dosage range of the pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself shows activity, the effective dose can be estimated using the weight of the derivative as described above, or by other means known to those skilled in the art.

[0154] Pharmaceutical compositions 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.

[0155] Co-administration

[0156] The PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be independently formulated into separate or separate dosage forms that can be co-administered sequentially. Alternatively, if the route of administration is the same (e.g., oral), the two active compounds can be formulated into a single form for co-administration, however, the two co-administration methods are part of the same therapeutic treatment or regimen.

[0157] The pharmaceutical composition containing a PARP inhibitor or a pharmaceutically acceptable salt thereof and / or a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof used in the method can be used simultaneously, separately or sequentially. In one embodiment, the PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition is administered before administering a KRas G12C inhibitor compound of formula (I), formula IA, formula IB, or a KRas G12C inhibitor compound of the foregoing chemical substances, 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 is administered after administering a KRas G12C inhibitor compound of formula (I), formula IA, formula IB, or a KRas G12C inhibitor compound of the foregoing chemical substances, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the administration of the PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition is performed at about the same time as the administration of a KRas G12C inhibitor compound of formula (I), formula IA, formula IB, or a KRas G12C inhibitor compound of the foregoing chemical substances, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0158] In some cases, it will be advantageous to administer each inhibitor separately at different times and by different routes. Thus, the components of the combination, i.e., the KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, do not necessarily need to be administered substantially simultaneously or in any order.

[0159] Oncology drugs are typically administered at a maximum tolerated dose ("MTD"), which is the highest dose of a drug that does not cause unacceptable side effects. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are administered at their respective MTDs. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD, while a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD, while a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are administered in an amount less than their respective MTDs. Administration can be timed so that the peak pharmacokinetic effect of one compound is consistent with the peak pharmacokinetic effect of another compound.

[0160] In one embodiment, a single dose of a KRas G12C inhibitor of Formula (I), Formula IA, Formula IB, or a KRas G12C inhibitor selected from the aforementioned chemical substances, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered daily (i.e., at about 24-hour intervals) (i.e., QD). In another embodiment, two doses of a KRas G12C inhibitor of Formula (I), Formula IA, Formula IB, or a KRas G12C inhibitor selected from the aforementioned chemical substances, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered daily (i.e., BID). In another embodiment, three doses of a KRas G12C inhibitor of Formula (I), Formula IA, Formula IB, or a KRas G12C inhibitor selected from the aforementioned chemical substances, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered daily (i.e., TID).

[0161] In one embodiment, the PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered once daily. In another embodiment, the PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered twice daily. In another embodiment, the PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered three times daily.

[0162] In one embodiment, a single dose of a KRasG12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered separately once daily.

[0163] Examples of PARP inhibitors suitable for use in the provided compositions and methods include, but are not limited to, olaparib, rucaparib, niraparib, talazoparib, and veliparib. Other examples of PARP inhibitors suitable for use in the provided compositions and methods include, but are not limited to, RBN-2397, 1-1, KMR-206, RP14042, and JAB-26766.

[0164] Combination therapy

[0165] In one aspect of the present invention, provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a compound of formula (I), formula IA, formula IB or a compound selected from the foregoing chemical substances (i.e. ) or a combination of a KRAS G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a cancer associated with KRas G12C. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0166] In another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to KRas G12C inhibitors, the method comprising contacting cancer cells with an effective amount of a KRas G12C inhibitor compound of Formula (I), Formula IA, Formula IB, or a combination thereof selected from the foregoing chemical substances, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the PARP inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor. In one embodiment, the contact is in vitro. In one embodiment, the contact is in vivo.

[0167] In one embodiment, the combination therapy comprises a combination of: a compound having the formula

[0168]

[0169] 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.

[0170] In one embodiment, the combination therapy comprises a combination of: a compound having the formula

[0171]

[0172] or a pharmaceutically acceptable salt thereof, and a PARP inhibitor.

[0173] 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.

[0174] In one embodiment, the combination therapy comprises a combination of: a compound having the formula

[0175]

[0176] or a pharmaceutically acceptable salt thereof, and a PARP inhibitor.

[0177] 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.

[0178] In one embodiment, the combination therapy comprises a combination of: a compound having the formula

[0179]

[0180] or a pharmaceutically acceptable salt thereof, and a PARP inhibitor.

[0181] 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.

[0182] As used herein, the term "contacting" refers to bringing together specified parts in an in vitro system or an in vivo system. For example, "contacting" a cancer cell includes administering a combination provided herein to an individual or subject (e.g., a human) having KRas G12C, and, for example, introducing a combination provided herein into a sample containing cells or purified preparations containing KRas G12C.

[0183] By negatively regulating the activity of KRas G12C, the methods described herein are designed to inhibit unwanted cell proliferation caused by enhanced KRas G12C activity in cells. The degree of covalent modification of KRas G12C can be monitored in vitro using known methods, including methods described in published international PCT application numbers WO2017201161, WO2019099524, and WO2020101736. In addition, the inhibitory activity of the combination in cells can be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphorylated ERK to assess the effectiveness of the treatment, and the dosage can be adjusted accordingly by the attending physician.

[0184] The compositions and methods provided herein can be used to treat a KRas G12C-associated cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or 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.

[0185] In one embodiment, the combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in the duration of overall survival ("OS") of the individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in the duration of progression-free survival ("PFS") of the individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor regression in the individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, causes an increase in tumor growth inhibition in an individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, causes an improvement in the duration of disease stabilization in an individual relative 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 a therapeutically effective amount of Example No. 234 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and talazoparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and veliparib.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and talazopanib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and talazopanib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and talazoparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and veliparib.

[0186] In another embodiment, once disease progression is observed on KRas G12C monotherapy, 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, wherein the combination therapy provides enhanced clinical benefit to the patient by increasing the patient's OS, PFS, tumor regression, tumor growth inhibition, or duration of stable disease.

[0187] In one embodiment, the KRas G12C inhibitor is selected from compound numbers 1-678 (such as numbering 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, talazopanib and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and talazopanib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and talazopanib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and talazopanib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and talazopanib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and veliparib.

[0188] The compositions and methods provided herein can be used to treat a 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, and thyroid cancer, as well as sarcomas. More particularly, these compounds are useful in the treatment of: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; Lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchial) 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 tumors, Tumors), VIP tumor (vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, =Mesenchymal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: hepatoma (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary carcinoma, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrofibroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor;Nervous system: skull (osteomas, hemangiomas, granulomas, xanthoma, osteodegenerative diseases), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealoma), glioblastoma multiforme, oligodendrogliomas, neurothecomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecological: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors (granulosa-thecal cell carcinomas, ... Tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematologic system: 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, moles dysplasticnevi, lipoma, hemangioma, dermatofibroma, keloids, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.;

[0189] Also provided herein is a method for treating cancer in an individual in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a cancer associated with KRas G12C) (e.g., as determined using an assay or kit approved by a regulatory agency, such as FDA); and (b) administering to the patient a therapeutically effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition and a KRas G12C inhibitor compound of Formula I, Formula IA, Formula 1-B or a pharmaceutically acceptable salt thereof or a pharmaceutical composition, wherein the PARP inhibitor synergistically increases the sensitivity of the cancer associated with KRas G12C to the KRas G12C inhibitor. In one embodiment, the KRas G12C inhibitor is a compound selected from the following: 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, talazopanib and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and talazopanib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and talazopanib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and rucaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and talazoparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and veliparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and olaparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and rucaparib.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and niraparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and talazoparib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and veliparib.

[0190] In one embodiment, the compound of Formula I is administered as a capsule over a period of time. In one embodiment, a tablet or capsule formulation of the compound of Formula I comprises 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). g, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 95 mg, about 20 mg to about 90 mg g, about 20 mg to about 85 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg, about 20 mg to about 70 mg, about 20 mg to about 65 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 100 mg, about 25 mg to about 95 mg, about 25 mg to about 90 mg, about 25 mg to about 85 mg, about 25 mg to about 80 mg, about 25 mg to about 75 mg, about 25 mg to about 70 mg , about 25 mg to about 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 30 mg 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 mg to about 50 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, about 40 mg to about about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, about 45 mg to about 100 mg, about 45 mg to about 95 mg, about 45 mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45 mg to about 50 mg, about 50 mg to about 100 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 100 mg, about 55 mg to about 95 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 mg, about 55 mg to about 65 mg, about 55 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 95 mg, about 60 mg to about 90 mg, about 60 mg to about 85 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 60 mg to about 65 mg, about 65 mg to about 100 mg, about 65 mg to about 95 mg, about 65 mg to about 90 mg, about 65 mg to about 85 mg, about 65 mg to about 80 mg, about 65 mg to about 75 mg, about 65 mg to about 70 mg, about 70 mg to about 100 mg, about 70 mg to about 95 mg, about 70 mg to about 90 mg, about 70 mg to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 75 mg to about 90 mg, about 75 mg to about 85 mg,about 75 mg to 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 10 0 mg) of a compound of formula I (e.g., a compound selected from the following: compound No. 1-678 (such as the number in WO2019099524, such as compound No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof). In one embodiment, the compound of formula I is orally administered once a day (QD) during a period of time. In one embodiment, the compound of formula I is orally administered twice a day (BID) during a period of time. In one embodiment, an amount 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 4 20 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, 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 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg,about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, 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 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 340 mg, 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. 0 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 mg to about 320 mg, about 1 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 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 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 38 0mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140mg to about 240mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 500mg, about 160mg to about 480mg, about 160mg to about 460mg, about 160mg to about 440mg, about 160mg to about 420mg, about 160mg to about 400mg, about 160mg to about 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 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 18 0mg to about 360mg, about 180mg to about 340mg, about 180mg to about 320mg, about 180mg to about 300mg, about 180mg to about 280mg, about 180mg to about 260mg, about 180mg to about 240mg, about 180mg to about 220mg, about 180mg to about 200mg, about 200mg to about 500mg, about 200mg to about 480mg, about 200mg to about 460mg, about 200mg to about 440mg, about 200mg to about 420mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg,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 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 0mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 500mg, about 240mg to about 480mg, about 240mg to about 460mg, about 240mg to about 440mg, about 240mg to about 420mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 340mg, about 240mg to about 320mg, about 240mg to about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 500mg, about 260mg to about 480mg, about 260mg to about 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 380 mg 0mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 500mg, about 300mg to about 480mg, about 300mg to about 460mg, about 300mg to about 440mg, about 300mg to about 420mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300mg to about 360mg, about 300mg to about 340mg, about 300mg to about 320mg, about 320mg to about 500mg, about 320mg to about 480mg, about 320mg to about 460mg, about 320mg to about 440mg, about 320mg to about 420mg,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, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, 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. 0 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, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg) of the compound of Formula I can be administered orally.

[0191] In one embodiment, the combination therapy comprises oral administration of a compound of Formula I once or twice daily (over a period of time), for example, in an amount of 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 40 mg, about 10 mg to about 20 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, 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 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 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 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 12 0mg, about 40mg to about 100mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60mg to about 260mg, about 60mg to about 240mg, about 60mg to about 220mg, about 60mg to about 200mg, about 60mg to about 180mg, about 60mg to about 160mg, about 60mg to about 140mg, about 60mg to about 120mg, about 60mg to about 100mg,about 60 mg to about 80 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 340 mg, 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 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 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 400 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 3 20mg, about 120mg to about 300mg, about 120mg to about 280mg, about 120mg to about 260mg, about 120mg to about 240mg, about 120mg to about 220mg, about 120mg to about 200mg, about 120mg to about 180mg, about 120mg to about 160mg, about 120mg to about 140mg, about 140mg to about 400mg, about 140mg to about 380mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140 From 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 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, 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 400 mg, from about 200 mg to about 380 mg, from about 200 mg to about 360 mg, from about 200 mg to about 340 mg, from about 200 mg to about 320 mg, from about 200 mg to about 30 0mg, about 200mg to about 280mg, about 200mg to about 260mg, about 200mg to about 240mg, about 200mg to about 220mg, about 220mg to about 400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about 340mg, about 220mg to about 320mg, about 220mg to about 300mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 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 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, 0mg to about 300mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300mg to about 360mg, about 300mg to about 340mg, about 300mg to about 320mg, about 320mg to about 400mg, about 320mg to about 380mg, about 320mg to about 360mg, about 340mg to about 360mg, about 340mg to about 400mg, about 340mg to about 380mg, about 340mg to about 360mg, about 360mg to about 400mg, about 360mg to about 380mg, about 380mg to about 400mg, about 100mg, about 200mg,In one embodiment, the PARP inhibitor is administered orally, for example, once a day (over a period of time). In one embodiment, the KRAS inhibitor is administered orally once a day. In one embodiment, the KRAS inhibitor is administered orally twice a day.

[0192] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and accepted cell and / or animal models are predictive of the ability of a test compound or combination to treat or prevent a given disorder.

[0193] Those skilled in the art will also recognize that human clinical trials, including first-in-human trials, dose-ranging and efficacy trials, in healthy patients and / or patients suffering from a given disorder can be accomplished according to methods well known in the clinical and medical arts.

[0194] Synergy

[0195] In one embodiment, the addition of a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof synergistically increases the activity of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB against a cancer or cancer cell line expressing KRas G12C. Any method for determining whether two compounds exhibit synergistic effects can be used to determine the synergistic effect of the combination.

[0196] Several mathematical models have been developed to determine whether two compounds have synergistic effects, i.e., effects that exceed simple additive effects, such as the Loewe Additivity model (Loewe (1928) Physiol. 27:47-187), the Bliss Independence model (Bliss (1939) Ann. Appl. Biol. 26:585-615), the Highest Single Agent model, the ZIP model (Yadav et al. (2015) Comput Struct Biotech J 13:504-513), and other models (Chou & Talalay (1984) Adv Enzyme Regul 22:27-55. #6382953; and Greco et al. (1995) Pharmacol Rev. 47(2):331-85.#7568331) is a model well known in the pharmaceutical industry and can be used to calculate a "synergy score" that indicates whether synergy is detected and the extent of such synergy. These synergy scores are combined to produce a composite synergy score that can be used to evaluate and characterize the combination of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB and a PARP inhibitor.

[0197] Typically, mathematical models use data obtained from the single active agent values ​​to determine the predicted additive effect of the combination and compare it to the observed effect from the combination. If the observed effect is stronger than the predicted effect, the combination is considered synergistic. For example, the Bliss independence model compares the observed combination response (Y O ) and the predicted combined response (Y P ), which is based on the assumption that there are no drug-drug interactions. O Greater than Y P , the combined effect is claimed to be synergistic.

[0198] In some embodiments, "synergistic effect" as used herein means that the combination of a KRAS inhibitor or a pharmaceutically acceptable salt thereof and a PARP inhibitor or a pharmaceutically acceptable salt thereof produces an effect, for example, any beneficial or desired result, including the clinical results or endpoints described herein, that is stronger than the sum of the effects observed when a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., a compound selected from Compound Nos. 1-678 (such as the numbers in WO2019099524), such as Compound Nos. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof) and a PARP inhibitor or a pharmaceutically acceptable salt thereof is administered alone.

[0199] In some embodiments, during treatment with the combination therapy for 1 day to 2 years (e.g., 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week 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 day to 3 months, 1 day to 2 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 to 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 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 18 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, or 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 The methods provided herein can result in a reduction in the volume of one or more solid tumors in a patient by 1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months).1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70% , 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%, 4% to 95%, 4% to 90%, 4% to 85%, 4% to 80% , 4% to 75%, 4% to 70%, 4% to 65%, 4% to 60%, 4% to 55%, 4% to 50%, 4% to 45%, 4% to 40%, 4% to 35%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 6% to 99%, 6% to 95%, 6% to 90%, 6% to 85% %, 6% to 80%, 6% to 75%, 6% to 70%, 6% to 65%, 6% to 60%, 6% to 55%, 6% to 50%, 6% to 45%, 6% to 40%, 6% to 35%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 8% to 99%, 8% to 95%, 8% to 9 0%, 8% to 85%, 8% to 80%, 8% to 75%, 8% to 70%, 8% to 65%, 8% to 60%, 8% to 55%, 8% to 50%, 8% to 45%, 8% to 40%, 8% to 35%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 10% to 99%, 10% to 95%, 1 0% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15 %, 15% to 99%, 15% to 95%, 15% to 90%, 15% to 85%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 99%, 20% to 95%, 20% to 90%, 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%,20% to 40%, 20% to 35%, 20% to 30%, 20% to 25%, 25% to 99%, 25% to 95%, 25% to 90%, 25% to 85%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 4 5%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 99%, 30% to 95%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30 % to 40%, 30% to 35%, 35% to 99%, 35% to 95%, 35% to 90%, 35% to 85%, 35% to 80%, 35% to 75%, 35% to 70%, 35% to 65%, 35% to 60%, 35% to 55%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 99% , 40% to 95%, 40% to 90%, 40% to 85%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 60%, 40% to 55%, 40% to 50%, 40% to 45%, 45% to 99%, 45% to 95%, 45% to 95%, 45% to 90%, 45% to 85%, 45% to 80%, 45% to 75%, 45% to 70%, 45% to 65%, 45% to 60%, 45% to 55%, 45% to 50%, 50% to 99%, 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 75%, 5 0% to 70%, 50% to 65%, 50% to 60%, 50% to 55%, 55% to 99%, 55% to 95%, 55% to 90%, 55% to 85%, 55% to 80%, 55% to 75%, 55% to 70%, 55% to 65%, 55% to 60%, 60% to 99%, 60% to 95%, 60% to 90 %, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 65% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 70% to 99%, 70% to 95%, 70% to 90%, 70% to 85%, 70% to 80%, 70% to 75%, 75% 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., compared to the size of one or more solid tumors in the patient before treatment).

[0200] The phrase "survival time" refers to the length of time between the time a cancer (e.g., any of the cancers described herein) is identified or diagnosed in a mammal by a medical professional and the time the mammal dies (caused by the cancer). Methods of increasing the survival time of a mammal suffering from cancer are described herein.

[0201] In some embodiments, any of the methods described herein can result in an increase in the survival time of a patient (e.g., 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%, 1% to 140%, 1% to 120%, 1% to 100%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35 %, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 400%, 5% to 380%, 5% to 360%, 5% to 340%, 5% to 320%, 5% to 300%, 5% to 280%, 5% to 260%, 5% to 240%, 5% to 220%, 5% to 200%, 5% to 180%, 5% to 160%, 5% to 140%, 5% to 120%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 10%, 10% to 400%, 10% to 380 %, 10% to 360%, 10% to 340%, 10% to 320%, 10% to 300%, 10% to 280%, 10% to 260%, 10% to 240%, 10% to 220%, 10% to 200%, 10% to 180%, 10% to 160%, 10% to 140%, 10% to 120%, 10% to 10 0%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 400%, 20% to 380%, 20% to 360%, 20% to 340%, 20% to 320%, 20% to 300%, 20% to 280%, 20% to 260%, 20% to 240%, 20% to 220%, 20% to 200%, 20% to 180%, 20% to 160%, 20% to 140%, 20% to 120%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50% , 20% to 40%, 20% to 30%, 30% to 400%, 30% to 380%, 30% to 360%, 30% to 340%, 30% to 320%, 30% to 300%, 30% to 280%, 30% to 260%, 30% to 240%, 30% to 220%, 30% to 200%, 30% to 180%,30% to 160%, 30% to 140%, 30% to 120%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 400%, 40% to 380%, 40% to 360%, 40% to 340%, 40% to 320%, 40% to 300%, 40% to 280%, 40% to 260%, 40% to 240%, 40% to 220%, 40% to 200%, 40% to 180%, 40% to 160%, 40% to 140%, 40% to 120%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 7 0%, 40% to 60%, 40% to 50%, 50% to 400%, 50% to 380%, 50% to 360%, 50% to 340%, 50% to 320%, 50% to 300%, 50% to 280%, 50% to 260%, 50% to 240%, 50% to 220%, 50% to 200%, 50% to 18 0%, 50% to 160%, 50% to 140%, 50% to 140%, 50% to 120%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 400%, 60% to 380%, 60% to 360%, 60% to 340%, 60% to 320%, 60% to 300%, 60% to 280%, 60% to 260%, 60% to 240%, 60% to 220%, 60% to 200%, 60% to 180%, 60% to 160%, 60% to 140%, 60% to 120%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 7 0% to 400%, 70% to 380%, 70% to 360%, 70% to 340%, 70% to 320%, 70% to 300%, 70% to 280%, 70% to 260%, 70% to 240%, 70% to 220%, 70% to 200%, 70% to 180%, 70% to 160%, 70% to 140%, 70% to 120%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 400%, 80% to 380%, 80% to 360%, 80% to 340%, 80% to 320%, 80% to 300%, 80% to 280%, 80% to 260%, 80% to 240%, 80% to 220%, 80% to 200%, 80% to 180%, 80% to 160%, 80% to 140%, 80% to 120%, 80% to 100%, 80% to 90%, 90% to 400%, 90% to 380%, 90% to 360%, 90% to 340%, 90% to 320%, 90% to 300%, 90% to 280%,90% to 260%, 90% to 240%, 90% to 220%, 90% to 200%, 90% to 180%, 90% to 160%, 90% to 140%, 90% to 120%, 90% to 100%, 100% to 400%, 100% to 380%, 100% to 360%, 100% to 340%, 100% to 320%, 100% to 300%, 100% to 280%, 100% to 260%, 100% to 240%, 100% to 220%, 100% to 200%, 100% to 180%, 100% to 160%, 100% to 140%, 100% to 120%, 120% to 400%, 120% to 380% , 120% to 360%, 120% to 340%, 120% to 320%, 120% to 300%, 120% to 280%, 120% to 260%, 120% to 240%, 120% to 220%, 120% to 200%, 120% to 180%, 120% to 160%, 120% to 140%, 140% to 400%, 140% to 380%, 140% to 360%, 140% to 340%, 140% to 320%, 140% to 300%, 140% to 280%, 140% to 260%, 140% to 240%, 140% to 220%, 140% to 200%, 140% to 180%, 140% to 160% , 160% to 400%, 160% to 380%, 160% to 360%, 160% to 340%, 160% to 320%, 160% to 300%, 160% to 280%, 160% to 260%, 160% to 240%, 160% to 220%, 160% to 200%, 160% to 180%, 180% to 400%, 180% to 380%, 180% to 360%, 180% to 340%, 180% to 320%, 180% to 300%, 180% to 280%, 180% to 260%, 180% to 240%, 180% to 220%, 180% to 200%, 200% to 400%, 200% to 380% , 200% to 360%, 200% to 340%, 200% to 320%, 200% to 300%, 200% to 280%, 200% to 260%, 200% to 240%, 200% to 220%, 220% to 400%, 220% to 380%, 220% to 360%, 220% to 340%, 220% to 320%, 220% to 300%, 220% to 280%, 220% to 260%, 220% to 240%, 240% to 400%, 240% to 380%, 240% to 360%, 240% to 340%, 240% to 320%, 240% to 300%, 240% to 280%, 240% to 260%,260% to 400%, 260% to 380%, 260% to 360%, 260% to 340%, 260% to 320%, 260% to 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% (e.g., compared to patients with similar cancers who were given a different treatment or who received no treatment).

[0202] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient was treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, and optionally the previous treatment was unsuccessful; and / or the patient had surgery, and optionally the surgery was unsuccessful; and / or the patient had been treated with a platinum-based chemotherapeutic agent, and optionally the patient was previously determined to be non-responsive to treatment with a platinum-based chemotherapeutic agent; and / or the patient had been treated with a kinase inhibitor, and optionally the previous treatment with the kinase inhibitor was unsuccessful; and / or the patient had been treated with one or more other therapeutic agents.

[0203] Pill Box

[0204] The present invention also relates to a kit comprising a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. A kit for treating a hematological cancer is also provided, comprising a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0205] In a related aspect, the present invention provides a kit comprising a dose of a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a dose of a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells, particularly cancer cells expressing KRas G12C, in an individual. In some cases, the kit comprises an insert containing instructions for the administration of the PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The insert can provide a user with a set of instructions for using a combination of a PARP inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0206] Example A

[0207] PARP inhibitors enhance the activity of KRas G12C inhibitors against KRas G12C-expressing cell lines

[0208] 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.

[0209] Two lung cancer cell lines containing KRas G12C mutations were assembled to determine whether PARP inhibitors combined with exemplary KRas G12C inhibitors disclosed herein produce synergistic activity. The collection includes NCI-H2030 (ATCC CRL-5985) and NCLH2122 (ATCC CRL-5985).

[0210] The assays for determining the synergy score of the pairwise combinations for each cell line were performed in triplicate. The specific cell line was seeded at 5000 cells / well in three 96-well plates and in 4 wells of a separate 96-well control plate for determining baseline luminescence in a total volume of 90 μL of growth medium appropriate for the cell line, e.g., RPMI 1640 medium supplemented with 10% FBS and any cell line specific reagents required for growth. The plates were incubated at 37°C, 5% CO 2 Incubate overnight under atmosphere.

[0211] For each designated baseline well, 30 μL of Cell-Titer Gio reagent (CTG; Promega Corporation) was added to each well and the plate was incubated at room temperature with shaking for 20 minutes.Baseline luminescence was quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0212] A series of working stock 1000× drug dilutions in 100% DMSO were prepared, including 9 single active agent dilutions of exemplary KRas G12C inhibitors of Formula (I), Formula IA, and Formula IB, and 5 single active agent dilutions of PARP inhibitors. The dilutions used for KRas G12C inhibitors and PARP inhibitors varied for each compound, but ranged from 3 to 6 times per serial dilution.

[0213] Exemplary KRas G12C inhibitors tested in this example include:

[0214]

[0215]

[0216] *Example number refers to the example number of each compound disclosed in the published international PCT application publication number WO2019099524.

[0217] 10× intermediate dose plates containing a series of single active agent dilutions of an exemplary KRas G12C inhibitor or PARP inhibitor of Formula (I) were prepared in serum-free RPMI medium. In addition, a matrix of 40 dilution combinations of an exemplary KRas G12C inhibitor of Formula (I), Formula IA or Formula IB and a PARP inhibitor was prepared as a test sample.

[0218] To each corresponding well of three 96-well plates seeded with the appropriate cell lines described above, 10 μL of each 10× single active agent and 40 combination dose matrix was added and the plates were incubated at 37°C, 5% CO. 2 30 μL of Cell-Titer Gio reagent (CTG) was added to each test well, the plate was incubated with shaking at room temperature for 20 minutes, and luminescence was quantified using a BMG ClarioStar multi-mode plate reader according to the manufacturer's instructions.

[0219] The raw data and metadata files were used as input files to calculate the percent effect for each treatment condition and were analyzed using four independent mathematical reference models to determine whether two test compounds exhibited synergy: the Loewe additivity model, the Bliss independence model, the highest single active agent model, and the ZIP model.

[0220] The data output of each mathematical model is the assignment of relative synergy scores. The data reported in Table 1A and Table 1B are the sum of the scores of the Loewe additive model, the Bliss independence model, the highest single active agent model, and the ZIP model ("composite synergy score"). A positive score indicates that there is synergy between two or more compounds, while a negative score indicates a lack of synergy. The larger the positive value, the stronger the synergy between two or more compounds.

[0221] Table 1A

[0222] Composite synergy scores of exemplary PARP inhibitors in combination with exemplary KRas G12C inhibitor MRTX849 against KRas G12C cell lines

[0223]

[0224]

[0225] Table 1B

[0226] Composite synergy scores of exemplary PARP inhibitors in combination with exemplary KRasG12C inhibitors of Formula (I), Formula IA and Formula IB against KRasG12C cell lines using hypoxia or normal conditions

[0227]

[0228] These results suggest that the KRas G12C cell line panel exhibits moderate synergy in certain cell lines with the combination of a PARP inhibitor and the exemplary KRas G12C inhibitor MRTX849 (Example 478 of WO2019 / 099524), and further investigation of the combination efficacy studies in in vivo models is needed.

[0229] Example B

[0230] In vivo model for testing the combination of KRas G12C inhibitor plus PARP inhibitor

[0231] Immunocompromised nude / nude mice were inoculated with cells harboring the KRas G12C mutation or patient-derived tumor samples in the right flank. When tumors reached ∼300 mm 3When the size was measured, the mice were divided into four groups of 5 mice each. The first group was administered only the vehicle. The second group was orally administered a single active dose of the KRas G12C inhibitor every day at a concentration that produced the maximum biological effect but did not lead to complete tumor regression. The third group was orally administered a single active dose of the PARP inhibitor every day at a concentration that produced the maximum biological effect but did not lead to complete tumor regression. The fourth group was orally administered a combination of a single active dose of the KRas G12C inhibitor and a single active dose of the PARP inhibitor according to a matching regimen. The treatment period was 17 days. Tumor volume was measured every two to three days using a caliper, and tumor volume was calculated according to the following formula: 0.5×(length×width) 2 In the model, the combination resulted in a greater degree of inhibition of tumor growth, suggesting that the combination therapy may have clinically meaningful benefits for treated individuals compared with treatment with a KRas G12C inhibitor alone.

[0232] For example, 20 nude / nude mice were inoculated with 5 × 10 6 H2122 cells. When the tumor volume reaches 300 mm 3 At 14:00 (study day 1), five groups of five mice were orally administered daily for 32 days: vehicle alone (10% Captisol in 50 mM citrate buffer, pH 5.0), 100 mg / kg KRas G12C inhibitor compound 478 (10% Captisol in 50 mM citrate buffer, pH 5.0), 50 mg / kg PARP inhibitor olaparib (10% Captisol in 50 mM citrate buffer, pH 5.0), or 100 mg / kg KRas G12C inhibitor compound 478 and 50 mg / kg olaparib. Due to larger tumor growth in the vehicle group and the group using olaparib alone, dosing was stopped for all groups on day 17. Tumor volumes of five mice in each group were measured on the scheduled days, and the average values ​​were calculated and the results are reported in Figure 1 and Table 2.

[0233] Table 2

[0234] Mean tumor volume (mm) of H2122 tumor-bearing mice treated with single agents and combination therapy 3 )

[0235] Study Days vehicle Compound 478 Olaparib Combination of compound 478 + olaparib -1 284.728 284.794 292.194 294.492 3 487.382 290.578 451.342 284.33 6 641.168 301.744 558.15 266.928 10 763.78 326.222 776.514 271.178 13 890.67 345.38 848.664 263.13 17 980.99 360.308 1058.96 289.524

[0236] like Figure 1As shown in Table 2, administration of olaparib as a single agent showed 0% tumor growth inhibition on day 17, while administration of KRas G12C inhibitor compound 478 as a single agent showed 89% tumor growth inhibition. However, the combination of the PARP inhibitor olaparib and compound 478 resulted in 2% tumor regression on day 17.

[0237] These results demonstrate that in an H2122 cell line-derived xenograft model, combination treatment resulted in greater regression of tumor growth compared with either single agent or the use of a PARP inhibitor alone, suggesting enhanced in vivo antitumor efficacy of the combination against KRas G12C-expressing cancers.

[0238] Although the invention has been described in conjunction with specific embodiments, it will be understood that the invention is capable of further modifications, and this application is intended to cover any changes, uses or modifications of the invention that generally follow the principles of the invention and include departures from the present disclosure within the scope of known or customary practice in the art to which the invention pertains, and which may be applied to the basic features set forth above, and which are within the scope of the appended claims.

Claims

1. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual a combination of a therapeutically effective amount of a PARP inhibitor and a KRAS G12C inhibitor of formula (I): or a pharmaceutically acceptable salt thereof: wherein: X is a 4- to 12-membered saturated or partially saturated monocyclic, bridged or spiro ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted by one or more Rs 8 substituted; Y is a key, O, S or NR 5 ; R 1 is -C(O)C(R A ) C(R B ) p or -SO 2 C(R A ) C(R B ) p ; R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, -Z-NR 5 R 10 , heterocyclic group, heterocyclic group alkyl, aryl, heteroaryl or heteroaryl alkyl, wherein each of Z, heterocyclic group, heterocyclic group alkyl, aryl, heteroaryl and heteroaryl alkyl may optionally be substituted by one or more R 9 substituted; each Z is a C1-C4 alkylene; Each R 3 independently is C1-C3 alkyl, oxo, haloalkyl, hydroxy or halogen; L is a bond, -C(O)- or a C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclic group, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclic group, aryl, aralkyl and heteroaryl may optionally be substituted by one or more R 6 , R 7 or R 8 substituents; Each R 5 is independently hydrogen or C1-C3 alkyl; R 6 is a cycloalkyl group, a heterocyclic group, a heterocyclic alkyl group, an aryl group or a heteroaryl group, wherein each of the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group may be optionally substituted by one or more R 7 substituents; Each R 7 independently is halogen, hydroxy, 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 may optionally be substituted by cyano, halogen, -OR 5 、-N(R 5 ) 2 or heteroaryl; Each R 9 is independently hydrogen, oxo, acyl, hydroxy, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclic alkyl, alkoxy, dialkylamino, dialkylamidoalkyl or dialkylaminoalkyl, where the C1-C6 alkyl may optionally be substituted by cycloalkyl; Each R 10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl; R 11 is a haloalkyl group; R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 ) 2 or hydroxyalkyl; Each R B is 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, dialkylaminoalkyl or heterocycloalkylalkyl, wherein the heterocycloalkyl moiety is substituted with one or more substituents independently selected from halogen, hydroxy, alkoxy and C1-C3 alkyl, and wherein the heteroaryl moiety of the heteroaryl or heteroarylalkyl is optionally substituted with one or more R 7 substituents; When is a triple bond, then R A does not exist, R B exists and p is equal to 1, Or when is a double bond, then R A is present, R B is present and p is equal to 2, or R A , R B and the carbon atoms to which they are attached form a 5- to 8-membered partially saturated cycloalkyl group optionally substituted by one or more R 7 substituents; m is 0 or an integer between 1 and 2; and p is 1 or 2.

2. The method according to claim 1, wherein the KRas G12C inhibitor compound of formula I has formula I-A: or a pharmaceutically acceptable salt thereof, wherein R 1 、R 3 、R 4 、R 5 、R 10 、R 11 、L and m are as defined in formula I, and the piperazine ring is optionally substituted by R 8 wherein R 8 is as defined in formula I.

3. The method according to claim 1, wherein the KRas G12C inhibitor is a compound of formula I having formula I-B: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , L and m are as defined in formula I, R 2 is a heterocyclic alkyl optionally substituted by one or more R 9 wherein R 9 is as defined in formula I, and the piperazine ring is optionally substituted by R 8 wherein R 8 is as defined in formula I.

4. The method according to claim 1, wherein the KRas G12C inhibitor is selected from: and pharmaceutically acceptable salts thereof.

5. The method according to claim 1, wherein the KRas G12C inhibitor is: or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1, wherein the KRas G12C inhibitor is: or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1, wherein the KRas G12C inhibitor is: or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1, wherein the KRas G12C inhibitor is: or a pharmaceutically acceptable salt thereof.

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

10. The method according to claim 5, wherein the PARP inhibitor is olaparib.

11. The method according to claim 5, wherein the PARP inhibitor is rucaparib.

12. The method according to claim 5, wherein the PARP inhibitor is niraparib.

13. The method according to claim 5, wherein the PARP inhibitor is talazoparib.

14. The method according to claim 5, wherein the PARP inhibitor is veliparib.

15. The method according to claim 6, wherein the PARP inhibitor is olaparib.

16. The method according to claim 6, wherein the PARP inhibitor is rucaparib.

17. The method according to claim 6, wherein the PARP inhibitor is niraparib.

18. The method according to claim 6, wherein the PARP inhibitor is talazoparib.

19. The method according to claim 6, wherein the PARP inhibitor is veliparib.

20. The method according to claim 7, wherein the PARP inhibitor is olaparib.

21. The method according to claim 7, wherein the PARP inhibitor is rucaparib.

22. The method according to claim 7, wherein the PARP inhibitor is niraparib.

23. The method according to claim 7, wherein the PARP inhibitor is talazoparib.

24. The method according to claim 7, wherein the PARP inhibitor is veliparib.

25. The method according to claim 8, wherein the PARP inhibitor is olaparib.

26. The method according to claim 8, wherein the PARP inhibitor is rucaparib.

27. The method according to claim 8, wherein the PARP inhibitor is niraparib.

28. The method according to claim 8, wherein the PARP inhibitor is talazoparib.

29. The method according to claim 8, wherein the PARP inhibitor is veliparib.

30. The method according to claim 9, wherein the PARP inhibitor is olaparib.

31. The method according to claim 9, wherein the PARP inhibitor is rucaparib.

32. The method according to claim 9, wherein the PARP inhibitor is niraparib.

33. The method according to claim 9, wherein the PARP inhibitor is talazoparib.

34. The method according to claim 9, wherein the PARP inhibitor is veliparib.

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

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

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

38. The method according to any one of claims 1-34, wherein the PARP inhibitor and the KRAS G12C inhibitor are administered at their respective maximum tolerated doses.

39. The method according to any one of claims 1-38, wherein, relative to treatment with the KRas G12C inhibitor alone, the combination of a therapeutically effective amount of the PARP inhibitor and the KRAS G12C inhibitor results in an increased duration of overall survival, an increased duration of progression-free survival, an increased regression of tumor growth, an increased inhibition of tumor growth, or an increased duration of disease stabilization in an individual.

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

41. The pharmaceutical composition according to claim 40, wherein the PARP inhibitor is selected from olaparib, rucaparib, niraparib, talazoparib, and veliparib, and the KRas G12C inhibitor is selected from: and its pharmaceutically acceptable salts.

42. A method of inhibiting KRas G12C activity in a cell, the method comprising contacting a cell in need of inhibition of KRas G12C activity with an effective amount of a PARP inhibitor or a pharmaceutical composition thereof or a pharmaceutically acceptable salt and a KRas G12C inhibitor compound selected from: and its pharmaceutically acceptable salts, wherein the PARP inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor.

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

44. A method of increasing the sensitivity of cancer cells to a compound of a KRas G12C inhibitor, the compound selected from: and pharmaceutically acceptable salts thereof, the method comprising administering to an individual being treated with the compound or salt for KRas G12C a therapeutically effective amount of a PARP inhibitor alone or a combination of a therapeutically effective amount of a PARP inhibitor with a pharmaceutically acceptable carrier, excipient, or diluent, wherein the PARP inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor.

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

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

48. The method according to 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. The method according to any one of claims 1 - 39, wherein the cancer is selected from: 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 (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal polypeptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilms 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: carcinoma of the gallbladder, carcinoma of the ampulla of Vater, cholangiocarcinoma; Bone: Osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondrofibroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous System: Skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (cancer); Hematopoietic System: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal: Neuroblastoma.

50. The method according to claim 49, wherein the cancer is a cancer associated with KRas G12C.

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

52. The method according to claim 49, wherein the cancer is bladder cancer.

53. The method according to claim 49, wherein the cancer is cervical cancer.

54. The method according to claim 49, wherein the cancer is colorectal cancer.

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

56. A kit, comprising: a) a pharmaceutical composition comprising a PARP inhibitor, and b) a pharmaceutical composition comprising a KRas G12C inhibitor compound selected from: and pharmaceutically acceptable salts thereof.

57. The kit according to claim 45, wherein the PARP inhibitor is selected from olaparib, rucaparib, niraparib, talazoparib, and veliparib.

58. The kit according to claim 55, 56 or 57, further comprising an insert containing instructions for administration of one or both pharmaceutical compositions.

Images