A Multicenter Phase 1b/2 Study of Adagrasib, Cetuximab, and Cemiplimab for Metastatic Colorectal Cancer Harboring KRAS G12C Mutations

Histologically confirmed diagnosis of advanced/metastatic microsatellite stable colorectal cancer with KRASG12C mutation with 1+ prior line(s) of therapy

Confirmed KRASG12C mutation status. If a molecular profiling report is not available, a representative paraffin-embedded tumor block or a minimum of 10 unstained slides will be requested for retrospective KRASG12C mutation testing.

Unresectable or metastatic disease.

Participants must have received at least one prior line of chemotherapy for metastatic disease with progression on treatment or intolerance to therapy.

Presence of measurable disease per RECIST 1.1

Willingness to participate in on-study related procedures, including mandatory biopsies (one baseline and one on-treatment biopsy).

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, 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 7 days before first dose.

Recovery from the treatment-related 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 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 ≤ 1.5x upper limit of normal (ULN) (if associated with Gilbert's disease or UGT1A1\*28 homozygosity, ≤ 3x ULN)

* Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0x ULN (if associated with liver metastases ≤5x ULN)

* Calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 60mL/min at screening

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

Willing and able to comply with clinical trial instructions and requirements. Individuals lacking the ability, based on reasonable medical judgment, to understand and appreciate the nature and consequences of participation in this study will not be eligible for participation.

Participants who are biologically capable of having children and sexually active must agree to use an acceptable method of contraception for the duration of the treatment period and for at least 6 months after the last dose of study treatment. The Investigator will counsel the patient on selection of contraception method and instruct the participant in its consistent and correct use. Examples of acceptable forms of contraception include:

* Oral, inserted, injected or implanted hormonal methods of contraception, provided it has been used for an adequate period of time to ensure effectiveness.

* Correctly placed copper containing intrauterine device (IUD).

* Male condom or female condom used WITH a spermicide.

* Male sterilization with confirmed absence of sperm in the post-vasectomy ejaculate.

* Bilateral tubal ligation or bilateral salpingectomy.

The Investigator will instruct the participant to call immediately if the selected birth control method is discontinued or if pregnancy is known or suspected.

* Note: Women are considered post-menopausal and/or not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 months ago. In case of any ambiguity, the reproductive status of the woman should be confirmed by hormone level assessment.

What this study is about