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

Inclusion Criteria:

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

• Confirmed KRASG12C mutation status. If a molecular profiling report is notavailable, a representative paraffin-embedded tumor block or a minimum of 10unstained slides will be requested for retrospective KRASG12C mutation testing.

• Unresectable or metastatic disease.

• Participants must have received at least one prior line of chemotherapy formetastatic 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 mandatorybiopsies (one baseline and one on-treatment biopsy).

• 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, children areexcluded from this study.

• Able to take oral medications.

• Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy orinvestigational agent) and radiation therapy discontinued at least 7 days beforefirst dose.

• Recovery from the treatment-related adverse effects of prior therapy at the time ofenrollment to ≤ Grade 1 (excluding alopecia and prior oxaliplatin-inducedneuropathy).

• 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 withGilbert's disease or UGT1A1*28 homozygosity, ≤ 3x ULN)

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0x ULN (ifassociated with liver metastases ≤5x ULN)

• Calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 60mL/minat screening

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

• Willing and able to comply with clinical trial instructions and requirements.Individuals lacking the ability, based on reasonable medical judgment, to understandand appreciate the nature and consequences of participation in this study will notbe eligible for participation.

• Participants who are biologically capable of having children and sexually activemust agree to use an acceptable method of contraception for the duration of thetreatment 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 andinstruct the participant in its consistent and correct use. Examples of acceptableforms of contraception include:

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

• 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-vasectomyejaculate.

• Bilateral tubal ligation or bilateral salpingectomy.

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

• Note: Women are considered post-menopausal and/or not of child bearingpotential if they have had 12 months of natural (spontaneous) amenorrhea withan appropriate clinical profile (e.g., age appropriate, history of vasomotorsymptoms) or have had surgical bilateral oophorectomy (with or withouthysterectomy) or tubal ligation at least 6 months ago. In case of anyambiguity, the reproductive status of the woman should be confirmed by hormonelevel assessment.

Exclusion Criteria:

• Prior PD1 or CTLA4 inhibition therapy

• Prior KRASG12C inhibition therapy

• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any otherform of immunosuppressive therapy within 7 days prior to the first dose of trialtreatment

• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considereda form of systemic treatment

• Active brain metastases, unless adequately treated and participant 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)

• Ongoing need for a medication with any of the following characteristics that cannotbe switched to alternative treatment within 10 days prior to study entry: known riskof QTc prolongation or Torsades de Pointes; substrate of CYP3A with a narrowtherapeutic index; strong inducer or inhibitor of CYP3A and/or P-gp; stronginhibitor of BCRP; strong inhibitor or inducer of CYP2C19; and proton pumpinhibitors

• Major surgery within 4 weeks of the first dose of any study drug

• History of intestinal disease or major gastric surgery likely to alter absorption ofstudy treatment (to be determined by the treating physician)

• 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.

• Participants with symptomatic leptomeningeal disease.

• Major surgery within 4 weeks of first dose of any study drug.

• History of intestinal disease or major gastric surgery likely to alter absorption ofstudy treatment, to be determined by the treating physician

• Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B (HBV) or C (HCV) infection as tested in a CLIA certified lab using a positive HIVantibody test. For Hepatitis B and C, an antigen that is drawn and positive. Notethat the following are permitted:

• Participants treated for HIV with no detectable viral load on current regimen for atleast 1 month prior to randomization;

• Note: Please refer to exclusion criteria regarding drug-drug interactions ofconcomitant anti-HIV agents, and in particular CYP3A substrates.

• Participants with prior HBV infections who are:

• considered to have past or resolved HBV infection, defined as the presence ofhepatitis 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 withnormal ALT, and HBV DNA < 2,000 IU/mL or < 10,000 copies/mL;

• Note: For participants in an inactive HBV carrier state or with a resolved HBVinfection, the risk of HBV reactivation should be considered and the need foranti-HBV prophylaxis prior to randomization should be carefully assessed inaccordance with local guidelines.

• Participants treated for HCV with no detectable viral load.

• 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 theparticipant's participation in the study, or with the interpretation of results.