MC# 18-26 - A Phase I/II Multiple Expansion Cohort Trial of MRTX849 in Patients with Advanced Solid Tumors with KRAS G12C Mutation
Disease Type(s): Colorectal, Lung-NSCLC
Phase(s): I, II
Drug Classification(s): Targeted Therapy, Small Molecule
Molecular Target(s): HRAS, KRAS, NRAS
Mechanism of Action
MRTX849 is a potent, highly selective and orally available small molecule inhibitor of a form of KRAS that harbors an oncogenic substitution mutation (G12C)
In this study, the sponsor and investigators want to learn:
- How much of MRTX849 can be given with an acceptable level of side effects
- The effects of MRTX849 (good and bad)
- How much of MRTX849 is absorbed into the blood and how fast it is removed
- If research tests can be used in the future to predict who will benefit from MRTX849
- Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation (and for Cohort E, a qualifying STK11 mutation)
- in Phase 2 Cohorts A, B, and E squamous or non-squamous NSCLC
- in Phase 2 Cohorts C, F, and G adenocarcinoma of the colon or rectum
- Unresectable or metastatic disease
- Available and prior therapy:
- No available treatment with curative intent,
- No available standard-of-care treatment or patient is ineligible or declines treatment, except
- In Phase 2 NSCLC Cohorts A and B, patients must have previously received treatment with at least a platinum-containing chemotherapy regimen and checkpoint inhibitor therapy
- In Phase 2 NSCLC Cohort E, patients must be in the first-line systemic treatment setting
- In Phase 2 CRC Cohort F, patients must have previously received standard treatment for metastatic disease, and must have previously received at least a fluoropyrimidine, irinotecan, oxaliplatin, and a VEGF/VEGF receptor (VEGFR) inhibitor that is FDA-approved for treatment of CRC (bevacizumab, ramucirumab, ziv-aflibercept, or a bevacizumab biosimilar), and have progressed during or within 3 months (106 days) of the last administration of chemotherapy
- Patients known to have MSI-H or dMMR metastatic CRC must have previously received or not be eligible to receive a 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).
- Patients who had withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease are eligible.
- Patients who had received adjuvant chemotherapy and had recurrence during or within 6 months (183 days) of completion of the adjuvant chemotherapy are allowed to count the adjuvant therapy as standard treatment.
- in Phase 2 CRC in combination with cetuximab Cohort G, patients must have previously received treatment with fluoropyrimidine, irinotecan, oxaliplatin, and a VEGF/VEGF receptor (VEGFR) inhibitor. Note,
- Patients known to have MSI-H or dMMR metastatic CRC must have previously received or not be eligible to receive a 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 1.1:
- In general Phase I, Phase Ib cohorts that do not include a statistical evaluation of clinical activity, and cohort sub-studies, patients must have measurable or evaluable disease. The exception is the Phase Ib evaluation of MRTX849 tablets administered at 400 mg BID for which patients must have measurable disease.
- In Phase Ib cohorts that include a statistical evaluation of clinical activity and Phase II, patients must have measurable disease
- Age ≥ 18 years
- Life expectancy of at least 3 months
- Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy or, investigational agent) and radiation therapy discontinued at least 2 weeks before first dose date
- Recovery from the adverse effects of prior therapy at the time of enrollment to ≤ Grade 1 (excluding alopecia)
- Eastern Cooperative Oncology Group (ECOG) performance status in 0 or 1
- Laboratory values within the screening period:
- Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 x 109/L)
- Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)
- Hemoglobin ≥ 9 g/dL, in the absence of transfusions for at least 2 weeks
- Total bilirubin ≤1.5 x Upper Limit of Normal (ULN) (if associated with liver metastases or Gilbert’s disease, ≤3 x ULN)
- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤3.0 x ULN (if associated with liver metastases, ≤5 x ULN)
- Calculated creatinine clearance ≥ 60 mL/min by the Cockcroft-Gault equation
- Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees 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-approved informed consent form
- Willing to comply with clinical trial instructions and requirements
- Active brain metastases. Patients are eligible if brain metastases are adequately treated and patients are neurologically stable (except for residual signs or symptoms related to the central nervous system (CNS) treatment) 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). For the Phase 1b cohort for patients with brain metastases, patients with asymptomatic brain lesions are eligible if neurologically stable without the use of corticosteroids for two weeks or more and anti-epileptic therapy. Patients with brainstem (midbrain, pons, and medulla) metastases are excluded, metastases in the cerebellum are allowed.
- Patients with carcinomatous meningitis. Patients with focal leptomeningeal disease are allowed in the Phase 1b cohort for patients with brain metastases.
- History of significant hemoptysis or hemorrhage within 4 weeks of the first dose date
- Undergone major surgery within 4 weeks of first dose date
- History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications
- Any of the following cardiac abnormalities within the last 6 months:
- Unstable angina pectoris
- Congestive heart failure ≥ NYHA Class 3
- QTc > 480 milliseconds or family history of Long QT Syndrome
- History of stroke or transient ischemic attack within the previous 6 months
- Ongoing need for a medication with any of the following characteristics that cannot be switched to alternative treatment prior to study entry: known risk of Torsades de Pointes; substrate of CYP3A with narrow therapeutic index; strong inducer or inhibitor of CYP3A and/or P-gp; strong inhibitor of BCRP; and proton pump inhibitors.
- Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments
- Known human immunodeficiency virus (HIV) seropositivity or active Hepatitis B or C. Patients treated for hepatitis C with no detectable viral load are permitted.
- Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior start of study drug.
- Breast-feeding or planning to breast feed during the study or within 6 months after study treatment
- Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with the patient’s participation in the study, or with the interpretation of the results
Exclusion criterion specific to Phase II cohorts:
- Prior treatment with a therapy targeting KRAS G12C mutation
- Dallas, TX - Mary Crowley Cancer Research - Medical City