Inclusion Criteria:

• Histologically confirmed diagnosis of a solid tumor malignancy harboring KRAS G12D mutation in tumor tissue or ctDNA.
• Unresectable or metastatic disease.
• Available and prior therapy:
  • (all Phases) no available treatment with curative intent;
  • (all Phases with the exception of Phase 2 Cohort A3 [PDAC with no prior systemic treatment in the advanced disease setting]) no available standard-of-care treatment or patient is ineligible or declines treatment;
  • (Phase 2): i. Cohort A1 (NSCLC): patients must have previously received treatment with at least a platinum-containing chemotherapy regimen and CIT, and have exhausted approved targeted therapies for actionable genomic tumor aberrations, but not > 3 prior therapies in the advanced disease setting; ii. Cohort A2 (PDAC): patients must have previously received treatment with at least 1 but not > 2 prior gemcitabine- or fluoropyrimidine-based therapies in the advanced disease setting;
  • Cohort A3 (PDAC): patients must not have previously received systemic treatment in the advanced disease setting;
  • Cohort A4 (CRC): patients must have previously received at least a fluoropyrimidine, irinotecan, oxaliplatin, and a vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) inhibitor. Patients known to have MSI-H or deficient mismatch repair (dMMR) metastatic CRC must have previously received or not be eligible to receive a programmed cell death 1 (PD-1) inhibitor (e.g., pembrolizumab). Patients known to have metastatic CRC with a BRAF V600E mutation must have previously received a BRAF inhibitor (e.g., encorafenib).
• Presence of tumor lesions to be evaluated per RECIST v1.1:
  • in the Phase 1 dose escalation cohorts, patients must have measurable or evaluable disease;
  • in the Phase 1b and Phase 2 cohorts, patients must have measurable disease.
• Age ≥ 18 years.
• Life expectancy of at least 3 months.
• Most recent prior systemic therapy (eg, chemotherapy, immunotherapy or, investigational agent) and radiation therapy discontinued at least 2 weeks before first dose of study treatment.
• Recovery from the treatment-related adverse effects of prior therapy at the time of enrollment to ≤ Grade 1 (excluding alopecia, peripheral neuropathy, and parameters superseded by other eligibility criteria [eg, hematology parameters]).
  • Note: Patients with prior endocrine adverse effects are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate organ function.
• Women of childbearing potential (WOCBP) or men whose partner is a WOCBP agree to use contraception while participating in this study, and for a period of 6 months following termination of study treatment.
• Completed informed consent process, including signing IRB/EC/REB-approved Informed Consent Form (ICF).

Exclusion Criteria:

• Active brain metastases or carcinomatous meningitis. Patients are eligible if brain metastases are adequately treated, and patients are neurologically stable for at least 2 weeks prior to enrollment without the use of corticosteroids or are on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent). 2. (Phase 1b dose optimization cohorts of MRTX1133, and Phase 2 cohorts only): Prior treatment with a KRAS G12D inhibitor. 3. History of significant hemoptysis or hemorrhage within 4 weeks of the first dose of study treatment. 4. Major surgery within 4 weeks of first dose of study treatment. 5. History of intestinal disease, inflammatory bowel disease, major gastric surgery, or other gastrointestinal conditions (eg, uncontrolled nausea, vomiting, malabsorption syndrome) likely to alter absorption of study treatment or result in inability to swallow oral medications. 6. History of malignant small bowel obstruction. 7. Clinically significant ascites, defined as palpable on exam or requiring a paracentesis, within 4 weeks of first dose of study treatment. 8. Any of the following cardiac abnormalities: a. Unstable angina pectoris or myocardial infarction within 6 months prior to enrollment. b. Congestive heart failure ≥ New York Heart Association (NYHA) Class 3 within 6 months prior to enrollment. c. Left ventricular ejection fraction (LVEF) < 50%. d. QTc ≥ 470 milliseconds or medical or immediate family history of congenital Long QT Syndrome. e. Symptomatic or uncontrolled atrial fibrillation or other arrhythmia within 6 months prior to enrollment. 9. Uncontrolled hypertension, defined as: BP measured in a rested and relaxed condition, where systolic BP ≥ 150 mmHg, or diastolic BP ≥ 90 mmHg, with or without medication, on multiple observations. 10. History of stroke or transient ischemic attack within the previous 6 months. 11. Ongoing need for a medication with any of the following characteristics that cannot be switched to alternative treatment prior to study entry:
  • Patients receiving MRTX1133: known risk of Torsades de Pointes; inhibitor or inducer of P-gp; and proton pump inhibitors.
• Patients receiving MRTX1133 DIC/r: known risk of Torsades de Pointes; inhibitor or inducer of CYP3A and/or P-gp; proton pump inhibitors, and moderate sensitive or sensitive CYP3A substrates.
• Known severe hypersensitivity to study drug(s) and/or any of its excipients.
• Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments.
• Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B (HBV) or C (HCV) infection. Note that the following are permitted:
  • Patients treated for HCV with no detectable viral load
  •  Patients treated for HIV with no detectable viral load on current regimen for at least 1 month prior to treatment.
  • Note: Refer to Exclusion Criterion 11 regarding drug-drug interactions of concomitant anti-HIV agents and in particular P-gp inhibitors.
  • Patients with prior HBV infections who are considered: − Considered to have past or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of hepatitis B surface antigen [HBsAg]); or − Considered to be in an inactive HBV carrier state (defined as HBsAg-positive, with normal ALT, and HBV DNA < 2000 IU/mL or < 10,000 copies/mL).
  • Note: For patients in an inactive HBV carrier state or with a resolved HBV infection, the risk of HBV reactivation should be considered and the need for anti-HBV prophylaxis prior to initiation of treatment should be carefully assessed in accordance with local guidelines.
• Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior to start of study drug.
• Breastfeeding or planning to breast feed during the study or within 6 months after study treatment.
• Any serious illness, uncontrolled intercurrent illness, psychiatric illness, active or uncontrolled infection, or other medical condition or history, including laboratory results, which, in the Investigator’s opinion, interferes with the patient’s capacity to provide informed consent, or would be likely to interfere with the patient’s participation in the study, or with the interpretation of the results.
• Decompensated cirrhosis (e.g., jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal bleeding).

Eligibility last updated 1/18/24. Questions regarding updates should be directed to the study team contact.