Phase I Trial of Adagrasib (MRTX849) in Combination With Cetuximab and Irinotecan in Patients With Colorectal Cancer

Inclusion Criteria:

• Histologically confirmed diagnosis of adenocarcinoma of the colon or rectum withKRASG12C mutation. KRASG12C on ctDNA may also be used as basis of eligibility, withapproval from study or site PIs.

• Unresectable or metastatic disease.

• Previously treated with at least two prior chemotherapy regimens for metastaticdisease (where a regimen is defined as a unique combination of 5-FU, oxaliplatin,irinotecan, bevacizumab (or biosimilar), capecitabine). A treatment with adjuvanttherapy with progression within 6 months of completing therapy would be considered aprior chemotherapy regimen.

• Presence of tumor lesions to be evaluated per RECIST 1.1patients must havemeasurable disease.

• Age ≥ 18 years. Because no dosing or adverse event data are currently available onthe use of the proposed combination in patients <18 years of age, and because solidtumor malignancies with KRASG12C mutation is rare among patients < 18 years of age,children are excluded from this study.

• Able to take oral medications.

• Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy or,investigational agent) and radiation therapy discontinued at least 2 weeks beforefirst dose or five half-lives whichever is shorter.

• Recovery from the adverse effects of prior therapy at the time of enrollment to ≤Grade 1 (excluding alopecia and prior oxaliplatin-induced neuropathy).

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Laboratory values within the screening period:

• Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0, 109/L)

• Platelet count ≥ 100,000/mm3 (≥ 100, 109/L)

• INR/PTT ≤ 1.5 upper limit of normal (ULN)

• Hemoglobin ≥ 9 g/dL, in the absence of transfusions for at least 2 weeks

• Total bilirubin ≤ 1.5 upper limit of normal (ULN) (if associated with Gilbert'sdisease or UGT1A1*28 homozygosity, ≤ 3 ULN)

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 ULN (ifassociated with liver metastases ≤5 ULN)

• Estimated creatinine clearance ≥ 60 mL/min by Cockcroft-Gault or CKD-EPI.

• Women of child-bearing potential or men whose partner is a woman of child-bearingpotential agree to use contraception while participating in this study, and for 6months following termination of study treatment.

• Completed informed consent process, including signing of IRB-approved informedconsent form.

• Willing and able to comply with clinical trial instructions and requirements.

Exclusion criteria:

• Active brain metastases, unless adequately treated and patient is neurologicallystable (except for residual symptoms of central nervous system treatment) for atleast 2 weeks prior to enrollment without corticosteroids or are on a stable ordecreasing dose of ≤ 10 mg daily prednisone (or equivalent).

• Prior treatment with KRASG12C inhibitor + EGFR inhibitor combo

• Patients with carcinomatous meningitis.

• History of significant hemoptysis or hemorrhage within 4 weeks of the first dose,unless resolved or stable.

• Major surgery within 4 weeks of first dose.

• History of intestinal disease or major gastric surgery likely to alter absorption ofstudy treatment.

• Any of the following cardiac abnormalities:

• Symptomatic or uncontrolled atrial fibrillation or other arrhythmia

• Unstable angina pectoris or myocardial infarction within the last 6 months.

• Congestive heart failure ≥ NYHA Class 3 within the last 6 months.

• QTc > 480 milliseconds.

• LVEF, if known, beyond the allowable window for single-agent MRTX849

• Ongoing need for a medication with any of the following characteristics that cannotbe switched to alternative treatment prior to study entry (see Appendix 2): knownrisk of Torsades de Pointes or QT prolongation; substrate of CYP3A with narrowtherapeutic index; strong inducer or inhibitor of CYP3A and/or P-gp; stronginhibitor of BCRP; and proton pump inhibitors.

• Known or suspected presence of another malignancy that could be mistaken for themalignancy under study.

• 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. Women of child-bearing potential must have a negative serum or urinepregnancy test during screening.

• Breast-feeding or planning to breast feed during the study or within 6 months afterend of treatment.

• Any serious illness, uncontrolled inter-current illness, psychiatric illness, activeor uncontrolled infection, or other medical history, including laboratory results,which, in the investigator's opinion, would be likely to interfere with thepatient's participation in the study, or with the interpretation of results.