KRAS G12D Inhibitor and Irinotecan Combination and Related Methods of Treatment

Abstract

The present invention relates to combination therapies for treating KRas G12D cancer. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of irinotecan (or an analogue thereof) and a KRas G12D inhibitor, pharmaceutical compositions comprising such compositions, kits comprising such compositions, and methods of use thereof.

Description

[Technical field]

[0001] The present invention relates to combination therapies useful for treating cancer. In particular, the present invention relates to therapeutically effective combinations of KRas G12D inhibitors and irinotecan, as well as pharmaceutical compositions comprising these agents, kits comprising such compositions, and methods of use thereof. [Background technology]

[0002] KRas inhibitors Kirsten rat sarcoma 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch that cycles between inactive (GDP-bound) and active (GTP-bound) states, transforming upstream cellular signals received from multiple tyrosine kinases into downstream effectors that regulate a wide variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancies was observed more than 30 years ago (see, e.g., Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation and downstream signaling of KRas have been reported in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence constitute approximately 33% of these KRas driver mutations in lung adenocarcinoma, with the G12D mutation being a common activating mutation (see, e.g., Li, Balmain and Counter, (2018) Nat Rev Cancer Dec; 18(12): 767-777; Sanchez-Vega, et al, (2018) Cell; 173, 321-337).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations in KRas in various tumor types have made KRas a highly attractive target for the pharmaceutical industry for cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas to treat cancer, only a single KRas G12C inhibitor (KRas G12C inhibitor sotorasib) has demonstrated sufficient safety and / or efficacy to gain regulatory approval (see, e.g., FDA Approves First KRAS Inhibitor: Sotorasib. [No authors listed] Cancer Discov. 2021 Aug;11(8):OF4. doi:10.1158 / 2159-8290. CD-NB2021-0362. Epub 2021 Jun 22). To date, no KRas G12D inhibitor has demonstrated sufficient safety and / or efficacy to gain regulatory approval.

[0005] Compounds that inhibit KRas activity remain highly desirable, including those that disrupt effectors such as guanine nucleotide exchange factors (see, e.g., Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358) and those that target KRas G12D (see, e.g., K-Ras(G12D) Has a Potential Allosteric Small Molecule Binding Site, Feng H, Zhang Y, Bos PH, Chambers JM, Dupont MM, Stockwell BR, Biochemistry, 2019 May 28;58(21):2542-2554. doi:10.1021 / acs.biochem.8b01300. Epub 2019 May 14, and Second harmonic generation detection of Ras conformational changes and discovery of a small molecular binder, Donohue E, Khorsand S, Mercado G, Varney KM, Wilder PT, Yu W, MacKerell AD Jr, Alexander P, Van QN, Moree B, Stephen AG, Weber DJ, Salafsky J, McCormick F., Proc Natl Acad Sci USA 2019 Aug 27;116(35):17290-17297, doi:10.1073 / pnas.1905516116. Epub 2019 Aug 9) and are under investigation. Clearly, there remains a continuing interest and effort to develop inhibitors of KRas, particularly inhibitors of activated KRas mutants, including KRas G12D.

[0006] The KRas G12D inhibitors disclosed herein are potent inhibitors of KRas G12D signaling and exhibit single-agent activity in inhibiting the in vitro proliferation of cell lines with KRas G12D mutations, but the relative potency and / or maximum observed effect of any given KRas G12D inhibitor may vary between KRas mutant cell lines. The range of potency and the reason(s) for the maximum observed effect are not fully understood, although certain cell lines appear to have different inherent resistance. Thus, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index, and / or clinical benefit of KRas G12D inhibitors in vitro and in vivo.

[0007] Irinotecan Irinotecan, sold under various bean names, is a chemotherapy cytotoxic agent approved for the treatment of colon and small cell lung cancer. It is given intravenously, often with other chemotherapy drugs. Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Inhibition of topoisomerase I by the active metabolite SN-38 ultimately results in inhibition of both DNA replication and transcription. The molecular action of irinotecan occurs by trapping a subset of topoisomerase-1-DNA cleavage complexes, those with guanine +1 in the DNA sequence. One irinotecan molecule stacks against the base pair adjacent to the topoisomerase-induced cleavage site, poisoning (inactivating) the topoisomerase 1 enzyme.

[0008] Irinotecan has a large volume of distribution (400 L / m 2) at physiological pH. Irinotecan and its active metabolite ethyl-10-hydroxy-camptothecin (SN-38) exist in two pH-dependent equilibrium isoforms, the antitumor active lactone ring hydrolyzed to the carboxylic acid isoform. In plasma, irinotecan and SN-38 are mostly bound to albumin, which stabilizes their lactone forms. In blood, irinotecan and SN-38 are bound to platelets and red blood cells.

[0009] Irinotecan has a linear pharmacokinetic profile. The population pharmacokinetic model assumed a three-compartment model for irinotecan and a two-compartment model for SN-38. SN-38 has a short distribution half-life (approximately 8 min). It reached its peak plasma concentration within 2 h after injection. SN-38 also shows a second peak in plasma concentration due to its enterohepatic recirculation and its release from erythrocytes. Approximately 2-5% of the prodrug irinotecan is hydrolyzed to its active metabolite, SN-38, in the liver by two carboxylesterase converting enzymes (CES1 and CES2) and in plasma by butyrylcholinesterase (hBChE). CES2 has a 12.5-fold higher affinity for irinotecan than CES1. Meanwhile, butyrylcholinesterase has a 6-fold higher activity for irinotecan than CES. After conversion, SN-38 is actively transported to the liver by the organic anion transporting polypeptide (OATP) 1B1 transporter.

[0010] SN-38 is inactivated by glucuronidation to SN-38G (β-glucuronide conjugate) by several uridine diphosphate glucuronosyltransferase enzymes (UGTs) in the liver (UGT1A1, UGT1A9) and extrahepatically (UGT1A1, UGT1A7, UGT1A10) and excreted in the bile. Several UGT polymorphisms affect irinotecan pharmacokinetics, for example, reduced UGT1 activity can result in severe toxicity. Also, bilirubin and bilirubin glucuronidation of UGT1A1 conjugates is another risk factor for increased toxicity.

[0011] Other chemotherapy agents Other chemotherapeutic agents that are used in the same or similar manner as irinotecan and irinotecan analogs include oxaliplatin, gemcitabine, docetaxel, 5FU, pemetrexed, SN-38, Abraxane, and nab-paclitaxel.

[0012] Irinotecan is a potent anticancer drug that exhibits activity both alone and with chemotherapeutic agents, but the relative efficacy and / or maximum observed efficacy of irinotecan or irinotecan-based regimens can vary. The reasons for such variation are not fully understood, but certain cell lines appear to have different inherent resistance. Therefore, there is a need to develop alternative approaches that maximize the potency, efficacy, therapeutic index, and / or clinical benefit of irinotecan. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.13:394-401 [Non-Patent Document 2] Der et al.,(1982)Proc.Natl Acad.Sci.USA 79(11):3637-3640 [Non-Patent Document 3] Samatar and Poulikakos(2014)Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428

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[0014] The combination therapy of the present invention, in one aspect, increases the potency of the KRas G12D inhibitor, resulting in improved efficacy of the KRas G12D inhibitors disclosed herein.The combination therapy of the present invention, in another aspect, provides patients with improved clinical benefit compared to treatment with the KRas G12D inhibitors disclosed herein as single agents.

[0015] Thus, in one aspect of the invention, irinotecan: [ka] (S)-4,11-Diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-β]quinolin-9-yl ester[1,4'-bipiperidine]-1'-carboxylic acid trihydrate monohydrochloride Molecular formula:C 33 H 38 N 4 O 6 or a pharma- ceutically acceptable salt thereof (most particularly, typically, 3H 2 O·HCl, in its commercially available trihydrate monochloride form), and the KRas G12D inhibitor compound MRTX1133: [ka] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol or a pharma- ceutically acceptable salt thereof is provided.

[0016] In another aspect of the invention, there is provided a therapeutically effective combination of irinotecan or an irinotecan analog, such as topotecan, belotecan, trastuzumab deruxtecan, or camptothecin, or a pharma- ceutically acceptable salt thereof, and the KRas G12D inhibitor MRTX1133, or a pharma- ceutically acceptable salt thereof.

[0017] In another aspect of the invention, a therapeutically effective amount of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or MRTX1133 analogs and related compounds, such as, but not limited to, Ex.252 (MRTX1133), 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-yl)- ol; Ex. 243, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol; Ex. 246, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; Ex. 251, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl yl)-5-chloronaphthalen-2-ol; Ex. 253, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; Ex. 259, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; and Ex. 282, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) A pharmaceutical composition for use in the method is provided, comprising any combination of the compounds disclosed and described in WIPO Publication WO2021 / 041671, including 5-fluoro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, or a pharma- ceutically acceptable salt thereof, and a pharma-ceutically acceptable excipient.

[0018] In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of irinotecan, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor, MRTX1133, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] In another aspect of the present invention, provided herein is a method of treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a combination of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0020] In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the KRas G12D-associated cancer is pancreatic cancer, colon cancer, endometrial cancer, and non-small cell lung cancer.

[0021] In some aspects of the invention, irinotecan and a KRas G12D inhibitor compound (eg, MRTX1133) are the only active agents in the compositions and methods provided.

[0022] In addition to irinotecan or a pharmaceutically acceptable salt thereof, examples of irinotecan analogs suitable for the provided compositions and methods include, but are not limited to, topotecan, belotecan, trastuzumab deruxtecan, and camptothecin or a pharmaceutically acceptable salt thereof.

[0023] Chemotherapeutic agents other than irinotecan and irinotecan analogs that can be effectively used in combination with MRTX1133 or MRTX1133 analogs or their salts include oxaliplatin, gemcitabine, docetaxel, 5FU, pemetrexed, SN-38, Abraxane, paclitaxel, and nab-paclitaxel. Also includes gemcitabine used in combination with nab-paclitaxel (and further combination with MRTX1133 or MRTX1133 analogs or their salts).

[0024] In addition to MRTX1133, examples of KRas G12D inhibitors suitable for the provided compositions and methods include, but are not limited to, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7a S)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol, 4-(4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, and pharma- ceutically acceptable salts thereof.

[0025] In yet another aspect, the invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12D inhibitor, comprising contacting the cancer cell with a therapeutically effective amount of irinotecan (or an irinotecan analog) or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound, e.g., MRTX1133 (or an MRTX1133 analog) or a pharmaceutical composition or combination of pharmaceutical compositions, wherein the irinotecan or irinotecan analog (or salt) increases the sensitivity of the cancer cell to the KRas G12D inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0026] Also provided herein is a method for treating cancer in a subject in need of such treatment, comprising: (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor, e.g., MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the irinotecan or irinotecan analog, or a pharma- ceutically acceptable salt thereof, increases the sensitivity of the KRas G12D-associated cancer to MRTX1133 or an MRTX1133 analog.

[0027] Also provided herein is a kit comprising irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.Also provided is a kit comprising irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in treating KRas G12D cancer.

[0028] In a related aspect, the present invention provides a kit containing a dose of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition, in an amount effective to inhibit the proliferation of cancer cells in a subject. In some cases, the kit includes a package insert having instructions for administering the irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and the KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition. The package insert may provide the user with a set of instructions for using the irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof in combination with the KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition.

[0029] In some aspects 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, optionally, the previous treatment was unsuccessful, and / or the patient has undergone surgery, optionally, the surgery was unsuccessful, and / or the patient has been treated with a platinum-based chemotherapeutic agent, 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, optionally, the previous treatment with the kinase inhibitor was unsuccessful, and / or the patient has been treated with one or more other therapeutic agent(s). [Brief description of the drawings]

[0030] [Figure 1] 1 shows the mean tumor volume in mouse xenografts for MRTX1133 alone and in combination with irinotecan (LS180 colon cancer cell line). [Diagram 2] 1 shows the mean tumor volume in mouse xenografts for MRTX1133 alone and in combination with irinotecan (PANC0203 pancreatic cancer cell line). [Diagram 3] 1 shows the mean tumor volume in mouse xenografts for MRTX1133 alone and in combination with irinotecan (SNU1033 rectal cancer cell line). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The present invention relates to combination therapies for treating KRas G12D cancer. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof ("irinotecans"), and a KRas G12D inhibitor MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, a pharmaceutical composition comprising a therapeutically effective amount of the two agents, a kit comprising the composition, and methods of use thereof.

[0032] The combination of irinotecan, an analogue thereof, or a pharma- ceutically acceptable salt thereof with a KRas G12D inhibitor, such as MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, increases the potency of the KRas G12D inhibitor compound against cancer cells expressing KRas G12D, thereby increasing the efficacy and therapeutic index of the KRas G12D inhibitor compound or a pharma- ceutically acceptable salt thereof.

[0033] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0034] As used herein, "KRas G12D" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence specified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Asp.

[0035] As used herein, "KRas G12D inhibitors" refers to compounds such as those depicted and depicted in WO2021 / 041671 and other publications, or pharma- ceutically acceptable salts thereof. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12D. The KRas G12D inhibitors of the present invention interact with and non-covalently bind to KRas G12D in the switch II pocket, inhibiting the protein-protein interactions required for activation of the KRAS pathway. MRTX1133 is an example of a KRas G12D inhibitor.

[0036] As used herein, "KRas G12D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12D mutation. A non-limiting example of a KRas G12D-associated disease or disorder is a KRas G12D-associated cancer.

[0037] As used herein, "irinotecan" refers to the compound: [ka] Most typically, it refers to the trihydrate monochloride form, but may also refer to other salt and / or hydrated and / or solvated forms.

[0038] As used herein, "irinotecan analogs" refers to compounds structurally related to irinotecan, such as topotecan, belotecan, trastuzumab deruxtecan, or camptothecin.

[0039] As used herein, the terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease or disorder being treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12D mutation (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit). In some embodiments, the subject has a tumor that is positive for the KRas G12D mutation (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be a subject with tumor(s) that are positive for the KRas G12D mutation (e.g., identified as positive using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be one whose tumor has a KRas G12D mutation (e.g., the tumor has been identified as such using a regulatory approved, e.g., FDA approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12D gene-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with KRas G12D (optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0040] The term "pediatric patient" as used herein refers to a patient who is under 16 years of age at the time of diagnosis or treatment. The term "child" can be further divided into various subpopulations including neonates (birth to 1 month of age), infants (1 month to 2 years of age), children (2 to 12 years of age), and adolescents (12 to 21 years of age, including but not including their 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0041] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient has a KRas G12D 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 KRas G12D-associated cancer, a patient with one or more symptoms of a KRas G12D-associated cancer, and / or a patient with an increased risk of developing a KRas G12D-associated cancer), and 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, the assay is typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0042] The term "regulatory authority" refers to a national agency for approval of medical use of pharmaceutical agents by a country. For example, a non-limiting example of a regulatory agency is the United States Food and Drug Administration (FDA).

[0043] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of a desired target, or otherwise stop or slow the proliferation of a target cell, i.e., irinotecan or KRas G12D. Such an amount may be administered as a single dose or according to a regimen, and is thereby effective.

[0044] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to alleviate or in any way reduce symptoms, or to halt or reverse the progression of a condition, or to negatively regulate or inhibit the activity of KRas G12D. Such an amount may be administered as a single dose or may be administered according to a regimen, thereby being effective.

[0045] As used herein, a "therapeutically effective amount" of two compounds is an amount that increases the activity of the combination together, i.e., more than merely additive, compared to the therapeutically effective amount of each compound in the combination. Alternatively, in vivo, a combination of a therapeutically effective amount of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma-ceutically acceptable salt thereof or a pharmaceutical composition thereof results in an increased overall survival ("OS") in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of irinotecan or an irinotecan analog or a pharma-ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma-ceutically acceptable salt thereof or a pharmaceutical composition thereof results in an increased progression-free survival ("PFS") in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition results in increased tumor regression in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with a KRas G12D inhibitor alone.The amount of each compound in the combination may be the same or different from the therapeutically effective amount of each compound when administered alone as a monotherapy. Such amounts may be administered as a single dosage or may be administered according to a regimen whereby it is effective.

[0046] As used herein, "treatment" refers to any manner in which the symptoms or pathology of a condition, disorder, or disease are alleviated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0047] As used herein, "alleviation" of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the composition.

[0048] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dose of a KRas inhibitor or its pharma- ceutically acceptable salt, or the dose of irinotecan, or the length of treatment time with a combination therapy described herein) means that the parameter may vary up to 10% below or above the numerical value stated for that parameter. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. When used at the beginning of a list of parameters, "about" is meant to modify the respective 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.

[0049] KRas G12D inhibitor compounds In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0050] In one embodiment, the KRas G12D inhibitor is [ka] (MRTX1133, and also referred to as Example 252 in WO2021 / 041671) or a pharma- ceutically acceptable salt thereof.

[0051] The KRas G12D inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, i.e., isomers of the same constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using commercially available reagents and conventional methods for the isolation of stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare the individual 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, whenever this specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to include all chiral (enantiomers and diastereomers) and racemic forms.

[0052] In one embodiment, the KRas G12D inhibitor compound MRTX1133 used in the method is a salt of the above compounds, for example, salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and quaternary ammonium salts of the formula -NR+Z-. and Z is a counterion including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoic acid, succinic acid, acetic acid, glycolic acid, maleic acid, malic acid, citric acid, tartaric acid, ascorbic acid, benzoic acid, cinnamic acid, mandelic acid, benzilic acid, and diphenylacetic acid).

[0053] Methods for producing the KRas G12D inhibitors disclosed herein are known. For example, WO2021 / 041671 describes general reaction schemes for preparing compounds including MRTX1133 and MRTX1133 analogs, and also provides detailed synthetic routes for the preparation of these compounds.

[0054] Irinotecan and Irinotecan Analogs In one embodiment, the irinotecan or irinotecan analog of the present invention is irinotecan: [ka] It is.

[0055] In one embodiment, irinotecan is typically 2 It is in the trihydrate monochloride form, designated O·HCl.

[0056] In one embodiment, the irinotecan or irinotecan analog of the present invention is the irinotecan analog topotecan: [ka] or a pharma- ceutically acceptable salt thereof.

[0057] In one embodiment, the irinotecan or irinotecan analog of the present invention is the irinotecan analog belotecan: [ka] or a pharma- ceutically acceptable salt thereof.

[0058] In one embodiment, the irinotecan or irinotecan analog of the present invention is the irinotecan analog trastuzumab deruxtecan: [ka] or a pharma- ceutically acceptable salt thereof.

[0059] In one embodiment, the irinotecan or irinotecan analog of the present invention is an irinotecan analog camptothecin: [ka] or a pharma- ceutically acceptable salt thereof.

[0060] The irinotecan and irinotecan analogs used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, i.e., isomers of the same constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using commercially available reagents and conventional methods for the isolation of stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare the individual 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, whenever this specification, including the claims, refers to a compound of the invention, the term "compound" is to be understood to encompass all chiral (enantiomers and diastereomers) and racemic forms.

[0061] In another embodiment, the recited irinotecan and irinotecan analogs include their salts, such as salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and tetracarboxylic acids of the formula -NR+Z-. and Z is a counterion including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoic acid, succinic acid, acetic acid, glycolic acid, maleic acid, malic acid, citric acid, tartaric acid, ascorbic acid, benzoic acid, cinnamic acid, mandelic acid, benzilic acid, and diphenylacetic acid).

[0062] Methods for preparing irinotecan and irinotecan analogs are well known, and these compounds are commercially available.

[0063] Pharmaceutical Compositions The irinotecan or irinotecan analog, or a pharma- ceutically acceptable salt, and the KRas G12D compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, may be formulated into a pharmaceutical composition.

[0064] In another aspect, the present invention provides a pharmaceutical composition comprising irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof, and the KRas G12D inhibitor MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof, and one or more of a pharma- ceutically acceptable carrier, excipient, or diluent that can be used in the methods disclosed herein. The irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof, and the KRas G12D inhibitor MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof, can be independently formulated by any method known in the art and prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intravenous, or intrarectal. In certain embodiments, the two above components are administered intravenously in a hospital environment. In one embodiment, administration can be by oral route.

[0065] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutical acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, in addition to the inhibitor, the composition may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutical acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0066] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound and exhibits minimal or no undesired 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 acids formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharma- ceutically acceptable quaternary salts known to those of skill in the art, including in particular quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion that includes chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citric acid, tartaric acid, ascorbic acid, benzoate, cinnamate, mandelic acid, benzylic acid, and diphenylacetate).

[0067] The active compound is contained in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the patient being treated. In one embodiment, the dose of the active compound for all of the above conditions ranges from about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, and further examples, 0.5 to about 25 mg per kilogram of recipient body weight per day. Typical topical dosages range from 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of the pharma- ceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative is active in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

[0068] A pharmaceutical composition comprising irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and the KRas G12D compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, may be used in the methods of use described herein.

[0069] Simultaneous administration Irinotecan or an irinotecan analog or a pharmaceutically acceptable salt thereof and KRas G12D compound MRTX1133 or an MRTX1133 analog or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms, which can be co-administered one after the other.Another option is that when the route of administration is the same (e.g., oral), the two active compounds can be formulated into a single form for co-administration, but both methods of co-administration are part of the same therapeutic treatment or regimen.

[0070] The pharmaceutical composition comprising irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and the KRas G12D compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof for use in the method may be for simultaneous, separate, or sequential use. In one embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof is administered prior to administration of the KRas G12D compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof. In another embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof is administered after administration of the KRas G12D compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof. In another embodiment, irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, is administered approximately contemporaneously with the administration of the KRas G12D compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof.

[0071] Separate administration of each inhibitor at different times and by different routes may be advantageous in some cases. Thus, the components in the combination, i.e., irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and the KRas G12D compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, do not necessarily have to be administered essentially simultaneously or in any order.

[0072] Oncology drugs are typically administered at the maximum tolerated dose ("MTD"), which is the highest dose of the drug that does not cause unacceptable side effects. In one embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof, and the KRas G12D compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt or pharmaceutical composition thereof are each administered at their respective MTD. In one embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD, and the KRas G12D compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD. In one embodiment, irinotecan or an irinotecan analog or a pharmaceutically acceptable salt thereof is administered in an amount below its MTD, and the KRas G12D compound MRTX1133 or an MRTX1133 analog or a pharmaceutically acceptable salt thereof is administered at its MTD. In one embodiment, both components are each administered in an amount below their respective MTD. Administration can be timed so that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.

[0073] In one embodiment, a single dose of the KRas G12D inhibitor compound MRTX1133 or MRTX1133 analog, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof is administered per day (i.e., about 24 hours apart) (i.e., QD). In another embodiment, two doses of the KRas G12D inhibitor compound MRTX1133 or MRTX1133 analog, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof are administered per day (i.e., BID). In another embodiment, three doses of the KRas G12D inhibitor compound MRTX1133 or MRTX1133 analog, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof are administered per day (i.e., TID).

[0074] In one embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof is administered QD. In another embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof is administered BID. In another embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof of the present invention is administered TID.

[0075] In one embodiment, a single dose of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and the KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, are each administered once daily.

[0076] Examples of irinotecan and irinotecan analogs, or pharma- ceutically acceptable salts thereof, suitable for the provided compositions and methods include those mentioned herein, e.g., irinotecan, topotecan, belotecan, trastuzumab deruxtecan, and camptothecin.

[0077] Examples of KRas G12D inhibitors suitable for the provided compositions and methods include those mentioned herein, such as MRTX1133: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalene-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2 -ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7 a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol, and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, or a pharma- ceutically acceptable salt thereof and a pharma-ceutically acceptable excipient.

[0078] Combination therapy In one aspect of the present invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition. In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the KRas G12D-associated cancer is pancreatic cancer, colon cancer, endometrial cancer, and non-small cell lung cancer.

[0079] In yet another aspect, the present invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12D inhibitor, comprising contacting the cancer cell with an effective amount of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharmaceutical composition or a combination of pharmaceutical compositions, wherein the irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof increases the sensitivity of the cancer cell to the KRas G12D inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0080] In one embodiment, the combination therapy comprises a compound of the formula: [ka] and irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof.

[0081] In one embodiment, the combination therapy comprises a compound of the formula: [ka] and irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof.

[0082] In one embodiment, the combination therapy comprises a compound of the formula: [ka] and irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof.

[0083] In one embodiment, the combination therapy comprises a compound of the formula: [ka] and irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof.

[0084] In one embodiment, the combination therapy comprises a compound of the formula: [ka] and irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof.

[0085] In one embodiment, the combination therapy comprises a compound of the formula: [ka] and irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof.

[0086] In one embodiment, the combination therapy comprises a compound of the formula: [ka] and irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof.

[0087] In one embodiment, the irinotecan or irinotecan analogue or a pharma- ceutically acceptable salt thereof referred to above is irinotecan.

[0088] In one embodiment, the above-mentioned irinotecan or irinotecan analog or a pharma- ceutically acceptable salt thereof is topotecan.

[0089] In one embodiment, the above-mentioned irinotecan or irinotecan analog or a pharma- ceutically acceptable salt thereof is belotecan.

[0090] In one embodiment, the above-mentioned irinotecan or irinotecan analog or a pharma- ceutically acceptable salt thereof is trastuzumab deruxtecan.

[0091] In one embodiment, the above-mentioned irinotecan or irinotecan analog or a pharma- ceutically acceptable salt thereof is a camptothecin.

[0092] As used herein, the term "contacting" refers to bringing together the moieties indicated 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, such as a human, having a KRas G12D mutation, and introducing, for example, a combination provided herein into a sample containing a cell or purified preparation containing a KRas G12D mutation.

[0093] By negatively regulating the activity of KRas G12D, the methods described herein are designed to inhibit undesirable cell proliferation resulting from enhanced KRas G12D activity in cells. The ability of a compound to inhibit KRas G12D can be monitored in vitro using known methods, including those described in published International PCT Application No. 2021 / 041671. Similarly, the inhibitory activity of the combination in cells can be monitored, for example, by measuring the inhibition of KRas G12D activity of the amount of phosphorylated ERK to assess the effectiveness of treatment, and dosage can be adjusted accordingly by the attending physician.

[0094] The compositions and methods provided herein may be used to treat KRas G12D-associated cancer in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a combination of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition, wherein the irinotecan or irinotecan analog or a pharma- ceutically acceptable salt thereof increases the sensitivity of the KRas G12D-associated cancer to the KRas G12D inhibitor. In one embodiment, the KRas G12D-associated cancer is colorectal cancer. In one embodiment, the KRas G12D-associated cancer is pancreatic cancer. In one embodiment, the KRas G12D-associated cancer is endometrial cancer. In one embodiment, the KRas G12D-associated cancer is non-small cell lung cancer.

[0095] In one embodiment, a combination of a therapeutically effective amount of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in increased overall survival ("OS") in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in increased progression-free survival ("PFS") in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition results in increased tumor regression in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with a KRas G12D inhibitor alone.

[0096] In another embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof is administered in combination with a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt or pharmaceutical composition thereof when disease progression is observed with KRas G12D monotherapy, and the combination therapy provides enhanced clinical benefit to the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or stable disease in the patient.In one embodiment, the KRas G12D inhibitor is MRTX1133 and MRTX1133 analogs, such as 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol, 4- (4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, and pharma- ceutically acceptable salts thereof.

[0097] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of MRTX1133, or a pharma- ceutically acceptable salt thereof, and irinotecan, or a pharma- ceutically acceptable salt thereof.

[0098] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of MRTX1133, or a pharma- ceutically acceptable salt thereof, and topotecan, or a pharma- ceutically acceptable salt thereof.

[0099] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of MRTX1133, or a pharma- ceutically acceptable salt thereof, and belotecan, or a pharma- ceutically acceptable salt thereof.

[0100] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of MRTX1133, or a pharma- ceutically acceptable salt thereof, and trastuzumab deruxtecan, or a pharma- ceutically acceptable salt thereof.

[0101] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of MRTX1133, or a pharma- ceutically acceptable salt thereof, and a camptothecin, or a pharma- ceutically acceptable salt thereof.

[0102] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors such as lung, colon, pancreatic, prostate, breast, brain, skin, cervical, testicular, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, astrocytic, breast, cervical, colon, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers and sarcomas. More specifically, these compounds can be used to treat: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucocorticoid, erythroblastoma ... , gastrinoma, carcinoid 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 (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, tetanus) tumour, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampulla of Vater cancer, bile duct cancer; bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteosarcoma) steochronfroma) (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological: Uterus (endometrial cancer), Cervix (cervical cancer, preneoplastic cervical dysplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), Fallopian tubes (carcinoma); Hematologic: Hematologic Myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

[0103] Also provided herein is a method for treating cancer in a subject in need of such treatment, comprising: (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition, wherein the irinotecan or irinotecan analog, or a pharma- ceutically acceptable salt thereof, increases the sensitivity of the KRas G12D-associated cancer to the KRas G12D inhibitor.In one embodiment, the KRas G12D inhibitor is an MRX-'1133 and MRTX1133 analogue, such as 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol, 4- (4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, and pharma- ceutically acceptable salts thereof.

[0104] In one embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof, such as topotecan, belotecan, trastuzumab deruxtecan, or camptothecin, is used.

[0105] In one embodiment, the therapeutic combination comprises a therapeutically effective amount of irinotecan, or a pharma- ceutically acceptable salt thereof.

[0106] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of topotecan, or a pharma- ceutically acceptable salt thereof.

[0107] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of belotecan or a pharma- ceutically acceptable salt thereof.

[0108] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of trastuzumab deruxtecan, or a pharma- ceutically acceptable salt thereof.

[0109] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of a camptothecin, or a pharma- ceutically acceptable salt thereof.

[0110] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of MRTX1133.

[0111] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol, 4-( 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol, or 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, or a pharma- ceutically acceptable salt thereof.

[0112] In one embodiment, KRas G12D MRTX1133 or a pharma- ceutically acceptable salt thereof is administered in a parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intravenous, or intrarectal formulation for a period of time. In one embodiment, the dose of MRTX1133 administered comprises one or more of about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, and about 2000 mg. In one embodiment, MRTX1133 is administered once a day (QD) every day for a period of time. In one embodiment, MRTX1133 is administered twice a day (BID) every day for a period of time.

[0113] In one embodiment, irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof is administered over a period of time at a dose of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, 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). g, approx. 20 mg to approx. 200 mg, approx. 20 mg to approx. 180 mg, approx. 20 mg to approx. 160 mg, approx. 20 mg to approx. 140 mg, approx. 20 mg to approx. 120 mg, approx. 0mg, about 40mg to about 480mg, about 40mg to about 460mg, about 40mg to about 440mg, about 40mg to about 420mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg, about 40mg to about 340mg, about 40mg to about 320mg, about 40m g ~ about 300 mg, about 40 mg - about 280 mg, about 40 mg - about 260 mg, about 40 mg - about 240 mg, about 40 mg - about 220 mg, about 40 mg - about 200 mg, about 40 mg - about 180 mg, about 40 mg - about 160 mg, about 40 mg - about 140 mg, about 40 mg - about 120 mg , approx. 40 mg ~ approx. 100 mg, approx. 40 mg ~ approx. 80 mg, approx. 40 mg ~ approx. 60 mg, approx. 60 mg ~ approx. 500 mg, approx. 60 mg ~ approx. 480 mg, approx. 60 mg ~ approx. 460 mg, approx. 0mg, 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 60m g ~ about 180mg, about 60mg - about 160mg, about 60mg - about 140mg, about 60mg - about 120mg, about 60mg - about 100mg, about 60mg - about 80mg, about 80mg - about 500mg, about 80mg - about 480mg, about 80mg - about 460mg, about 80mg - about 440mg,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, 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 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 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mgAbout 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 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 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg,About 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, 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 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 mgIt is intravenously administered in an amount of about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg.

[0114] In one embodiment, irinotecan is administered at 125 mg / m weekly for 4 weeks every 6 weeks. 2 or 350 mg / m every 3 weeks 2 is administered intravenously via a 30 or 90 minute infusion.

[0115] In another embodiment, irinotecan is administered at 125 mg / m weekly for 4 weeks every 6 weeks. 2 or 350 mg / m every 3 weeks 2 Administered intravenously via a less than 30 or 90 minute infusion.

[0116] In one embodiment, irinotecan is infused intravenously as indicated on the CAMPTOSAR® product label.

[0117] Those skilled in the art will recognize that both in vivo and in vitro testing using suitable, known and generally accepted cellular and / or animal models are predictive of the ability of a test compound or combination to treat or prevent a given disorder.

[0118] One of ordinary skill in the art will further recognize that human clinical trials, including first-in-human, dose ranging and efficacy studies in healthy patients and / or patients suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0119] In some embodiments, the methods provided herein provide a method for determining whether or not a patient has a tumor that is refractory to treatment (e.g., relative to the size of one or more solid tumors in the patient prior to treatment) that is at least 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 years, 1 week to 1 years, 1 week to 1 years, 1 week to 2 years, 1 week to 2 years, 1 week to 2 years, 1 week to 2 years, ~12 months, 1 week ~ 10 months, 1 week ~ 9 months, 1 week ~ 8 months, 1 week ~ 7 months, 1 week ~ 6 months, 1 week ~ 5 months, 1 week ~ 4 months, 1 week ~ 3 months, 1 week ~ 2 months, 1 week ~ 1 month, 2 weeks ~ 2 years, 2 weeks ~ 22 months, 2 weeks ~ 20 months, 2 weeks ~ 18 months, 2 weeks ~ 16 months, 2 weeks ~ 14 months, 2 weeks ~ 12 months, 2 weeks ~ 10 months, 2 weeks ~ 9 months, 2 weeks ~ 8 months, 2 weeks ~ 7 months, 2 weeks ~ 6 months, 2 weeks ~ 5 months, 2 weeks ~ 4 months, 2 weeks ~ 3 months, 2 weeks ~ 2 months, 2 weeks ~ 1 month, 1 month ~ 2 years, 1 month ~ 22 months , 1 month to 20 months, 1 month to 18 months, 1 month to 16 months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 9 months, 1 month to 8 months, 1 month to 7 months, 1 month to 6 months, 1 month to 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 months, 3 months to 2 years, 3 months to 22 months, 3 months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months 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 to 8 months) of reduction in volume of one or more solid tumors in a patient after treatment with the combination therapy for a period of 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 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 85%, 2% to 60%, 2% to 6 ... 0%, 2%~55%, 2%~50%, 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95%, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~7 0%, 4%~65%, 4%~60%, 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~99%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~ 75%, 6%~70%, 6%~65%, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8% ~80%, 8%~75%, 8%~70%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8%~15%, 10%~99%, 10%~95%, 10%~90%, 10%~8 5%, 10%~80%, 10%~75%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~99%, 15 %~95%, 15%~90%, 15%~85%, 15%~80%, 15%~75%, 15%~70%, 15%~65%, 15%~60%, 15%~55%, 15%~50%, 15%~55%, 15%~50%, 15%~45%, 15%~40%, 15%~35%, 15%~30%,15%~25%、15%~20%、20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、The reduction may be 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%).

[0120] The phrase "survival time" refers to the length of time between identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional and the time of death (caused by the cancer) of the mammal. Methods of increasing survival time in a mammal with cancer are described herein.

[0121] In some embodiments, any of the methods described herein may be used to measure an increase in patient survival (e.g., between 1% and 400%, between 1% and 380%, between 1% and 360%, between 1% and 340%, between 1% and 320%, between 1% and 300%, between 1% and 280%, between 1% and 260%, between 1% and 240%, between 1% and 220%, between 1% and 200%, between 1% and 180%, between 1% and 160%, between 1% and 140%, between 1% and 120%, between 1% and 100%, between 1% and 95%, between 1% and 90%, between 1% and 85%, between 1% and 80%). ,1%~75%,1%~70%,1%~65%,1%~60%,1%~55%,1%~50%,1%~45%,1%~40%,1%~35%,1%~30%,1%~25%,1%~20%,1%~15%,1%~10%,1%~5%,5%~400%,5%~380%,5%~3 60%, 5%~340%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5%~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~ 70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~24 0%, 10%~220%, 10%~200%, 10%~180%, 10%~160%, 10%~140%, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10% ~20%, 20%~400%, 20%~380%, 20%~360%, 20%~340%, 20%~320%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20% ~140%, 20%~120%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%,30%~300%、30%~280%、30%~260%、30%~240%、30%~220%、30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%、~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%, 240%~360%, 240%~340%, 240%~320%, 240%~300%, 240%~280%, 240%~260%, 260%~400%, 260%~380%, 260%~360%, 260%~340%, 260%~320%, 260%~300%, 26 0% 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%).

[0122] 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, optionally, the previous treatment was unsuccessful, and / or the patient has undergone surgery, optionally, the surgery was unsuccessful, and / or the patient has been treated with a platinum-based chemotherapeutic agent, 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, optionally, the previous treatment with the kinase inhibitor was unsuccessful, and / or the patient has been treated with one or more other therapeutic agent(s).

[0123] kit The present invention also relates to and / or provides a kit comprising irinotecan or an irinotecan analog, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition, for use in treating cancer.

[0124] In a related aspect, the present invention provides a kit containing a dose of irinotecan or an irinotecan analog or a pharma- ceutically acceptable salt thereof, and a dose of a KRas G12D inhibitor compound MRTX1133 or an MRTX1133 analog or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells, particularly KRas G12D-expressing cancer cells, in a subject. The kit may, in some cases, include a package insert with instructions for the administration of these agents, and the package insert may provide the user with a set of instructions for using these agents in combination. EXAMPLES

[0125] The following examples are intended to further illustrate certain embodiments of the invention, but are not intended to limit the scope of the invention.

[0126] Example A In vivo model for investigating KRas G12D inhibitor and irinotecan combinations Immunodeficient nude / nude mice are inoculated with cells carrying the KRas G12D mutation in the right hind flank. Tumor volumes of 200–400 mm 3When the mice reach a size of 100x, the mice are divided into 4-5 groups of 4-5 mice each. The first group receives vehicle only. The second group receives a single dose of a KRas G12D inhibitor twice daily at a concentration that results in maximal or submaximal biological effect, depending on the cell line and single agent activity, that does not result in complete tumor regression. The second group may receive a KRas G12D inhibitor twice daily for 2 consecutive days followed by 5 days off at a concentration that results in maximal or submaximal biological effect, depending on the cell line and single agent activity, that does not result in complete tumor regression. The third group receives a single dose of irinotecan at a concentration that results in maximal or submaximal biological effect, depending on the cell line and single agent activity, that also does not result in complete tumor regression. The fourth group receives a single-agent dose of a KRas G12D inhibitor using a schedule of twice daily for 2 consecutive days followed by 5 days off in combination with a single-agent dose of irinotecan. Treatment duration varies from cell line to cell line but is typically 15-22 days. Tumor volumes are measured using calipers every 2-3 days and tumor volume is calculated by the following formula: 0.5 x (length x width). 2 The greater degree of tumor growth inhibition for the combination in this model demonstrates that combination therapy is more likely to provide a clinically significant benefit to treated subjects compared with treatment with a KRas G12D inhibitor alone.

[0127] 25 nude / nude mice were given 5 × 10 6 LS180 cells were inoculated into 20 nude / nude mice at 5 × 10 6 Panc 02.03 cells were inoculated into 20 nude / nude mice at 5 × 10 6 SNU-1033 cells were inoculated into each mouse. For all models, tumor volumes were approximately 200–400 mm 3When tumor volume reached 0 (study day 0), five mice in each of the groups were administered vehicle alone (10% Captisol in 50 mM citrate buffer, pH 5.0), 30 mg / kg of the KRas G12D inhibitor MRTX1133 (10% Captisol in 50 mM citrate buffer, pH 5.0), 100 mg / kg of irinotecan (saline vehicle), or 30 mg / kg of the KRas G12D inhibitor MRTX1133 and 100 mg / kg of irinotecan ip. MRTX1133 was treated either twice daily ip for the duration of the study or twice daily ip for two consecutive days followed by a drug holiday. Irinotecan was administered ip once every 7 days for the duration of the study. Tumor volumes, measured on a given day for five mice per group, were averaged and are reported for each xenograft in the tables provided below.

[0128] Example B KRas G12D inhibitor MRTX1133 in combination with irinotecan (LS180 colon cancer cell line) Twenty-five nude / nude mice were inoculated with LS180 cells in the posterior right flank. Tumors grew to approximately 250 mm 3 When the immunization rate reached 100%, five treatment groups were established with five mice per group. The results of this study are provided in Table 1. [Table 1]

[0129] As shown in Table 1, administration of MRTX1133 as a single agent administered twice daily showed 45% tumor growth inhibition, while MRTX1133 administered twice daily for two consecutive days showed 4% tumor growth inhibition at day 15 depending on the dosing regimen. The combination of MRTX1133 and irinotecan resulted in 83% tumor growth inhibition at day 15. See Figure 1.

[0130] Example C KRas G12D inhibitor MRTX1133 in combination with irinotecan (PANC0203 pancreatic cancer cell line) Twenty nude / nude mice were inoculated with Panc 02.03 cells in the posterior right flank. Tumors grew to approximately 300 mm 3 When the immunization rate reached 100%, four treatment groups were established with 5 mice per group. The results of this study are provided in Table 2. [Table 2]

[0131] As shown in Table 2, administration of MRTX1133 as a single agent resulted in 72% tumor growth at day 22. The combination of MRTX1133 and irinotecan resulted in -9% tumor regression at day 22. See Figure 2.

[0132] Example D KRas G12D inhibitor MRTX1133 in combination with irinotecan (SNU1033 rectal cancer cell line) Twenty nude / nude mice were inoculated with SNU1033 cells in the right hind flank. Tumors grew to approximately 300 mm 3 When the immunization rate reached 100%, four treatment groups were established with 5 mice per group. The results of this study are provided in Table 3. [Table 3]

[0133] As shown in Table 3, administration of MRTX1133 as a single agent showed 47% tumor growth inhibition at day 33. The combination of MRTX1133 and irinotecan resulted in -58% tumor regression at day 33. See Figure 3.

[0134] Example E KRas G12D inhibitor MRTX1133 in combination with gemcitabine and in combination with gemcitabine / nP (SNU1033, PANC0203, and LS180 cancer cell lines) Twenty nude / nude mice for each cell line (SNU1033, PANC0203, and LS180, and each combination MRTX1133+gemcitabine, and MRTX1133+gemcitabine / nP) are inoculated with the cells in the right hind flank. Tumors grow to approximately 300 mm 3 When the immunization rate is reached, four treatment groups are established with 5 mice per group. The results of this study are generated and are provided in the table.

[0135] These results demonstrate that the combination therapy resulted in a greater amount of tumor growth inhibition compared to either single agent alone, demonstrating enhanced in vivo antitumor efficacy of the combination against KRas G12D-expressing cancers.

[0136] While the invention has been described in relation to particular embodiments thereof, which are capable of further modification, it will be understood that this application is generally intended to cover any variation, use, or alteration of the invention in accordance with the principles of the invention, including departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and that may apply to the essential features set forth above and that fall within the scope of the following appended claims.

Claims

1. 1. A method of treating cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a combination of a KRas G12D inhibitor or a pharmaceutically acceptable salt thereof and a cytotoxic compound selected from irinotecan, topotecan, belotecan, trastuzumab deruxtecan, and camptothecin, or a pharmaceutically acceptable salt thereof; The method, wherein the KRas G12D inhibitor or a salt thereof is MRTX1133: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or a pharmaceutically acceptable salt thereof.

2. The KRas G12D inhibitor is MRTX1133: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein the cytotoxic compound is irinotecan.

3. 10. The method of claim 1, wherein the KRas G12D inhibitor or salt and the cytotoxic compound are administered on the same day.

4. 10. The method of claim 1, wherein the KRas G12D inhibitor or salt and the cytotoxic compound are administered on different days.

5. 10. The method of claim 1, wherein the KRas G12D inhibitor or salt is administered at a maximally tolerated dose.

6. 10. The method of claim 1, wherein the cytotoxic compound is administered at a maximal tolerated dose.

7. 10. The method of claim 1, wherein the KRas G12D inhibitor or salt and the cytotoxic compound are each administered at a maximally tolerated dose.

8. 10. The method of claim 1, wherein the KRas G12D inhibitor or salt is administered at less than the maximum tolerated dose.

9. 10. The method of claim 1, wherein the cytotoxic compound is administered at less than the maximum tolerated dose.

10. 10. The method of claim 1, wherein the KRas G12D inhibitor or salt and the cytotoxic compound are each administered at less than the maximum tolerated dose.

11. 2. The method of claim 1, wherein the combination of the therapeutically effective amount of the KRas G12D inhibitor or salt and the cytotoxic compound results in increased overall survival, increased progression-free survival, increased tumor growth regression, increased tumor growth inhibition, or increased stable disease duration in the subject compared to treatment with the KRas G12D inhibitor or salt alone.

12. 2. The method of claim 1, wherein the combination of the therapeutically effective amount of the KRas G12D inhibitor or salt and the cytotoxic compound results in increased overall survival, increased progression-free survival, increased tumor growth regression, increased tumor growth inhibition, or increased stable disease in the subject compared to treatment with the cytotoxic compound alone.

13. A pharmaceutical composition comprising a therapeutically effective amount of a combination of a KRas G12D inhibitor or a pharmaceutically acceptable salt thereof and a cytotoxic compound selected from irinotecan, topotecan, belotecan, trastuzumab deruxtecan, and camptothecin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, The KRas G12D inhibitor is MRTX1133: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

14. 1. A method of inhibiting KRas G12D activity in a cell, comprising: contacting the cells in which inhibition of KRas G12D activity is desired with an effective amount of a combination of a KRas G12D inhibitor or a pharmaceutically acceptable salt thereof and a cytotoxic compound selected from irinotecan, topotecan, belotecan, trastuzumab deruxtecan, and camptothecin or a pharmaceutically acceptable salt thereof; The KRas G12D inhibitor is MRTX1133: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof.

15. 10. The method of claim 1, wherein the therapeutically effective amount of the KRas G12D inhibitor in the combination is about 0.01 to 100 mg / kg per day.

16. 16. The method of claim 15, wherein the therapeutically effective amount of the KRas G12D inhibitor in the combination is about 0.1 to 50 mg / kg per day.

17. 10. The method of claim 1, wherein the therapeutically effective amount of irinotecan in the combination is about 0.01 to 100 mg / kg per day.

18. 18. The method of claim 17, wherein the therapeutically effective amount of irinotecan in the combination is about 0.1 to 50 mg / kg per day.

19. The cancer is cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; digestive tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), Colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, 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, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, carcinoma of the ampulla of Vater, bile duct carcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, vascular tumor, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, undifferentiated 10. The method of claim 1, wherein the tumor is selected from the group consisting of: carcinoid tumor, granulosa sheath cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, 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, lentil dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

20. 20. The method of claim 19, wherein the cancer is a KRas G12D-associated cancer.

21. 21. The method of claim 20, wherein the cancer is pancreatic cancer, colon cancer, endometrial cancer, and non-small cell lung cancer.

22. 14. A kit comprising the pharmaceutical composition of claim 13 for treating KRas G12D cancer in a subject.

23. 23. The kit of claim 22, further comprising a package insert having directions for administration of the pharmaceutical composition(s).

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