A Phase 2, Multicenter, Multi Arm, Study to Evaluate MK-1308A (Coformulated quavonlimab (MK-1308)/pembrolizumab) Versus Other Treatments in Participants with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer: (MK-1308A-008)

The primary objective of this study is to compare **MK-1308A** and pembrolizumab monotherapy with respect to the Objective Response Rate per **RECIST 1.1** as assessed by Blinded Independent Central Review in participants with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer. This is clinically relevant as it aims to determine the efficacy of these treatments in achieving a measurable response in tumor size reduction, which is a critical factor in the management of advanced colorectal cancer.

Secondary objectives include: - Evaluating the Duration of Response per RECIST 1.1 as assessed by Blinded Independent Central Review in Cohorts A and B. - Comparing MK-1308A and pembrolizumab monotherapy with respect to Progression-Free Survival per RECIST 1.1 as assessed by Blinded Independent Central Review in Cohort A. - Comparing MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Progression-Free Survival per RECIST 1.1 as assessed by Blinded Independent Central Review in Cohort B. - Comparing MK-1308A and pembrolizumab monotherapy with respect to Progression-Free Survival per RECIST 1.1 as assessed by the investigator in Cohort A. - Comparing MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Progression-Free Survival per RECIST 1.1 as assessed by the investigator in Cohort B. - Comparing MK-1308A and pembrolizumab monotherapy with respect to Objective Response Rate per RECIST 1.1 as assessed by the investigator in Cohort A. - Comparing MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Objective Response Rate per RECIST 1.1 as assessed by the investigator in Cohort B. - Evaluating the Duration of Response per RECIST 1.1 as assessed by the investigator in Cohorts A and B. - Comparing MK-1308A and pembrolizumab monotherapy with respect to Overall Survival in Cohort A. - Comparing MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, and pembrolizumab monotherapy with respect to Overall Survival in Cohort B. - Evaluating the safety and tolerability of MK-1308A compared to pembrolizumab monotherapy in Cohort A. - Evaluating the safety and tolerability of MK-1308A, MK-4280A, MK-7684A, MK-4830+Pembrolizumab, compared to pembrolizumab monotherapy in Cohort B.

The clinical trial involves a total of **158 participants** diagnosed with **Stage IV Colorectal Cancer** characterized by **Microsatellite Instability-High (MSI-H)** or **Mismatch Repair Deficient (dMMR)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of Stage IV colorectal adenocarcinoma, locally confirmed dMMR/MSI-H status, and a life expectancy of at least three months. The trial includes individuals who have either been previously treated and progressed on standard treatments or those who are untreated for this condition. Participants are required to have measurable disease and adequate organ function. The study population is diverse, including vulnerable groups, and considers lifestyle factors such as the ability to adhere to contraceptive guidelines for women of childbearing potential. The selection process ensures that participants have not received prior chemotherapy or immunotherapy for untreated cases, while those previously treated must have progressed after standard therapies.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy and safety of various treatment regimens in participants with **microsatellite instability-high** (MSI-H) or **mismatch repair deficient** (dMMR) Stage IV colorectal cancer. The trial involves multiple arms, comparing the investigational product MK-1308A, a coformulation of **quavonlimab** and **pembrolizumab**, against other treatments, including pembrolizumab monotherapy and combinations with other investigational agents such as MK-4280A, MK-7684A, and MK-4830. The primary objective is to assess the Objective Response Rate (ORR) per RECIST 1.1, as evaluated by a Blinded Independent Central Review (BICR). Secondary endpoints include Duration of Response (DOR), Progression-Free Survival (PFS), and Overall Survival (OS), among others.

The trial is expected to last until November 18, 2025, with recruitment having commenced on June 25, 2021. Participants will be involved in the study for a maximum treatment period of 36 months. The study visits are structured as follows: an initial inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of Stage IV colorectal cancer and adequate organ function. Follow-up visits will be conducted to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participants may be withdrawn from the study early if they experience unacceptable adverse events, disease progression, or if they withdraw consent. The study is conducted under strict ethical guidelines, ensuring that all participants provide informed consent before any study-related procedures. The investigational products are administered via **intravenous infusion**, with dosing regimens tailored to each treatment arm. The trial is not classified as low intervention, given its focus on safety, efficacy, and dosing regimens in a specific patient population.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **KEYTRUDA** (pembrolizumab) is provided as a 25 mg/mL concentrate for solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 400 mg and a total dose not exceeding 10,400 mg over a treatment period of up to 36 months. This medication is classified as a biological product and is not a pediatric formulation.

**MK-7684A** is another investigational product, consisting of pembrolizumab and vibostolimab, formulated as a solution for infusion. It is also administered intravenously, with a maximum daily dose of 400 mg and a total dose limit of 20,800 mg over 36 months. This combination is categorized as a biological product.

**MK-4830** is available in two forms: a solution for infusion and a concentrate and solvent for concentrate for solution for infusion. Both forms are administered via intravenous infusion. The maximum daily dose is 800 mg, with a total dose cap of 41,600 mg over the treatment period. This product is also classified as a biological agent.

**MK-1308A** combines pembrolizumab and quavonlimab in a solution for infusion, administered intravenously. The maximum daily dose is 425 mg, with a total dose limit of 11,050 mg over 36 months. This formulation is a biological product.

**MK-4280A** includes pembrolizumab and favezelimab, provided as a solution for infusion. It is administered via intravenous infusion, with a maximum daily dose of 1,000 mg and a total dose not exceeding 52,000 mg over the treatment period. This product is also classified as a biological agent.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

Efficacy in this clinical trial will be assessed using the **Objective Response Rate (ORR)** as the primary endpoint, evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). This assessment will be conducted by a Blinded Independent Central Review (BICR). Secondary endpoints include Duration of Response (DOR), Progression-Free Survival (PFS), and Overall Survival (OS), all evaluated per RECIST 1.1 by both BICR and the Investigator. Additionally, the trial will monitor the number of participants experiencing adverse events and those discontinuing treatment due to adverse events.

The trial involves multiple treatment arms, including MK-1308A, MK-4280A, MK-7684A, MK-4830 combined with pembrolizumab, and pembrolizumab monotherapy. The efficacy parameters will be measured at various timepoints throughout the study, with the trial estimated to conclude by November 18, 2025. The study is designed to compare these treatments in participants with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer, with specific objectives for different cohorts within the trial.