Adagrasib (MRTX849) Plus Cetuximab and Irinotecan for the Treatment of Patients with Unresectable or Metastatic, KRAS positive Colorectal Cancer

Inclusion Criteria

• Histologically confirmed diagnosis of adenocarcinoma of the colon or rectum with KRAS G12C mutation. KRAS G12C on circulating tumor derived deoxyribonucleic acid (ctDNA) may also be used as basis of eligibility, with approval from study or site primary investigators (PIs)
• Unresectable or metastatic disease
• Previously treated with at least two prior chemotherapy regimens for metastatic disease (where a regimen is defined as a unique combination of fluorouracil [5-FU], oxaliplatin, irinotecan, bevacizumab [or biosimilar], capecitabine). A treatment with adjuvant therapy with progression within 6 months of completing therapy would be considered a prior chemotherapy regimen
• Presence of tumor lesions to be evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 patients must have measurable disease
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of the proposed combination in patients < 18 years of age, and because solid tumor malignancies with KRAS G12C 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 before first 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
• Absolute neutrophil count >= 1,000/mm^ 3 (>= 1.0 × 10^9/L) (within 28 days of cycle 1 day 1 [C1D1])
• Platelet count >= 100,000/mm^ 3 (>= 100 × 10^9/L) (within 28 days of C1D1)
• International normalizing ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) (within 28 days of C1D1)
• Hemoglobin >= 9 g/dL (within 28 days of C1D1), in the absence of transfusions for at least 2 weeks
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (if associated with Gilbert’s disease or UGT1A1*28 homozygosity, =< 3 x ULN) (within 28 days of C1D1)
• Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5 x ULN (if associated with liver metastases =< 5 x ULN) (within 28 days of C1D1)
• Estimated creatinine clearance >= 60 mL/min by Cockcroft-Gault or chronic kidney disease epidemiology collaboration equation (CKD-EPI) (within 28 days of C1D1)
• Women of child-bearing potential or men whose partner is a woman of child-bearing potential agree to use contraception while participating in this study, and for 6 months (females) or 4 months (males) following termination of study treatment
• Completed informed consent process, including signing of institutional review board (IRB)-approved informed consent form
• Willing and able to comply with clinical trial instructions and requirements

Exclusion Criteria

• Active brain metastases, unless adequately treated and patient is neurologically stable (except for residual symptoms of central nervous system treatment) for at least 2 weeks prior to enrollment without corticosteroids or are on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
• 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 of study 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 >= New York Heart Association (NYHA) class 3 within the last 6 months * QTc > 480 milliseconds * Left ventricular ejection fraction (LVEF) < 50%, if known
• 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 or QT prolongation; 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 (< 2 years) or suspected presence of another malignancy, with the exception of basal cell carcinoma
• Known or suspected allergy or hypersensitivity to study drugs
• 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 urine pregnancy test during screening
• Breast-feeding or planning to breast feed during the study or within 6 months after end of treatment
• History of severe obstructive pulmonary disease or interstitial lung disease
• 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 results