The SEAMARK Study: Phase 2 Study of First-line Encorafenib and Cetuximab Plus Pembrolizumab in Participants With BRAF V600E-mutant,MSIH/dMMR Metastatic Colorectal Cancer

Prior treatment

• Evidence of active and uncontrolled bacterial or viral infection, with certain exceptions, as noted below, for chronic infection with hepatitis B or hepatitis C, within 2 weeks prior to start of study intervention. Note: For COVID-19/SARS-CoV-2, SARS-CoV-2 testing is not mandated for study entry, and testing should follow local clinical practice standards. Any participant with a positive test result for SARS-CoV-2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV-2, is excluded. Once the infection resolves, the participant may be considered for re-screening.
• Has active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
• History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to randomization.
• Unable to swallow, retain, and absorb oral medications.

Other illness

• Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
• Active hepatitis B or hepatitis C infection
• Leptomeningeal disease.
• Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Participants with diabetes type I, vitiligo, psoriasis, controlled asthma, Graves' disease, Hashimoto's disease or hypo- or hyperthyroid disease are exceptions and may participate. Note: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered a form of immunosuppressive agents and are permitted.
• Impaired gastrointestinal function (eg, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, small bowel resection) or disease which may significantly alter the absorption of oral study intervention or recent changes in bowel function suggesting current or impending bowel obstruction.

Lab values

• Clinically significant cardiovascular diseases, including any of the following: a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤ 6 months prior to randomization. b. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2). c. Recent history (one year) or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia). d. History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to randomization. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive) deep vein thrombosis or pulmonary emboli. Note: Participants with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks. Note: Participants with thromboembolic events related to indwelling catheters (including PICC lines) or other procedures may be enrolled e. Triplicate average QTcF interval ≥480 ms or a history of prolonged QT syndrome. Note: Participants with BBB or with an implanted cardiac pacemaker may enroll into the study upon agreement between the investigator and sponsor or designee. f. Congenital LQTS.
• Participants positive for HIV are ineligible unless they meet all of the following: a. A stable regimen of highly active anti-retroviral therapy that is not contraindicated. b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections c. A CD4 count >250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests. Note: Participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease are not eligible.
• Documented clinical disease progression (eg, worsening of performance status, clinical symptoms, or clinically significant laboratory parameters demonstrating worsening of disease) or radiographic disease progression during the screening period.

Other

• Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown.
• Presence of acute or chronic pancreatitis.

• Molecular Prescreening Inclusion Criteria: 1. Locally confirmed dMMR or MSI-H disease in tumor tissue or blood (eg. ctDNA genetic testing) as determined by a local laboratory assay in a CLIA- or similarly certified laboratory
• Screening Inclusion Criteria: 10. Adequate bone marrow function characterized by the following at screening: a. ANC ≥1.5 × 109/L b. Platelets ≥100 × 109/L c. Hemoglobin ≥9.0 g/dL (without blood transfusions 2 weeks prior to randomization)
• Screening Inclusion Criteria: 11. Adequate hepatic and renal function characterized by the following at screening: a. Serum Tbili ≤1.5 × ULN and < 2 mg/dL. Note: Tbili >1.5 × ULN is allowed if direct (conjugated) ≤ 1.5 × ULN and indirect (unconjugated) bilirubin is ≤ 4.25 × ULN. Note: Participants with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (eg, hemolysis, hematoma) may be enrolled following discussion and agreement with the sponsor or designee. b. ALT and AST ≤ 2.5 × ULN, or ≤ 5 × ULN in the presence of liver metastases.
• Screening Inclusion Criteria: 12. Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol. Note: Participants ≥ 16 years old that are under guardianship may participate with the consent of their legally authorized guardian if permitted by local regulations. When appropriate, adolescent participants will be included in all discussions (see Sectiopn 10.1.3). Note: The investigator, or a person designated by the investigator, will obtain [written/electronically signed] informed consent/assent from each study participant’s legal guardian (as defined in Appendix 1 [and the participant’s assent, when applicable,] before any study-specific activity is performed [unless a waiver of informed consent has been granted by an IRB/ EC]). All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand. The investigator will retain the original copy of each participant's signed consent[/assent document.
• Molecular Prescreening Inclusion Criteria 2. Locally confirmed BRAF V600E mutation in tumor tissue or blood (eg, ctDNA genetic testing) as determined by either PCR or NGS-based local laboratory assay in a CLIA- or similarly certified laboratory.
• Screening Inclusion Criteria - 3. Male or female participants age ≥16 years at the time of informed consent/assent (or the minimum country specific age of consent if >16). In countries or sites where enrollment of adolescents is not permitted (eg, Germany), male or female participants age ≥18 years at the time of informed consent.
• Screening Inclusion Criteria - 4. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
• Screening Inclusion Criteria: 5. Histologically or cytologically confirmed metastatic Stage IV colorectal adenocarcinoma. Note: Patients with oligometastatic disease previously treated with curative intent are eligible to participate in the study as long as they have baseline measurable disease per RECIST 1.1.
• Screening Inclusion Criteria: 6. Presence of measurable disease per RECIST v1.1, as assessed by investigator and evidenced by available baseline tumor scan. Note: Baseline scan is defined as the last scan prior to the date of randomization (Section 10.10). Note: Baseline scans will be required to be available for subsequent submission to a central radiology vendor to be assessed by the BICR.
• Screening Inclusion Criteria: 7. Availability of adequate tumor tissue (primary or metastatic; archival or newly obtained; block or slides; see Section 8.6.1). Whenever possible, the archival sample should be from the same tumor block that was used for local BRAF V600E mutation and MSI-H/dMMR testing. It is recommended that the tissue block be obtained from a biopsy or surgery that was performed within 2 years prior to study enrollment. Please consult the study clinician if samples are older. A newly obtained tumor tissue biopsy must be provided prior to randomization for participants unable to provide adequate archival tumor tissue. If a newly obtained biopsy is taken, the biopsy should be taken from a nontarget lesion when possible. Note: Participants with early stage disease (eg, Stages I-III) treated with surgery followed by chemotherapy (eg, treatment in the adjuvant setting) or have received prior systemic neoadjuvant therapy with or without radiation who present with new lesions or evidence of disease recurrence during or within 6 months of the last dose of chemotherapy would be considered as having received 1 prior systemic therapy in the metastatic setting.
• Screening Inclusion Criteria: 8. Have not received prior systemic regimens for metastatic disease. Note: Participants with early stage disease (eg, Stages I-III) treated with surgery followed by chemotherapy (eg, treatment in the adjuvant setting) or have received prior systemic neoadjuvant therapy with or without radiation who present with new lesions or evidence of disease recurrence during or within 6 months of the last dose of chemotherapy would be considered as having received 1 prior systemic therapy in the metastatic setting.
• Screening Inclusion Criteria: 9. ECOG performance status of ≤1.