Phase 2 Multicenter Randomized Double-Blind Study of MK-4280A, Pembrolizumab, and Lenvatinib in Patients with Selected Malignant Neoplasms

The primary objective of this study is to evaluate the **clinical benefit** in participants with **malignant neoplasm** treated with MK-4280A or pembrolizumab in Cohort A. Additionally, in Cohort B, the study aims to assess the combination of lenvatinib with MK-4280A or pembrolizumab concerning the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by the investigator. This evaluation is clinically relevant as it seeks to determine the efficacy of these treatments in improving patient outcomes in selected solid tumors.

Secondary objectives include:

• Cohort A: To evaluate the pathologic complete response (pCR) rate of MK-4280A or pembrolizumab as assessed by local pathology review.
• Cohort A: To evaluate the Major Pathologic Response (mPR) rate as assessed by local pathology review.
• Cohort A: To evaluate the OR rate of participants treated with MK-4280A or pembrolizumab per RECIST 1.1 as assessed by the investigator prior to surgical resection.
• Cohort A: To evaluate the safety and tolerability of MK-4280A followed by surgery.
• Cohort B: To evaluate the safety and tolerability of MK-4280A in combination with lenvatinib.

The clinical trial involves a total of **141 participants** diagnosed with **neoplasm malignant**. The study population includes individuals of any sex or gender, with an age range starting from 18 years. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed diagnosis of resectable cutaneous squamous cell carcinoma or endometrial carcinoma, adequate organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial includes both male and female subjects, and it considers vulnerable populations. Participants are required to have a life expectancy greater than three years and must have adequately controlled blood pressure without antihypertensive medication. Lifestyle considerations include adherence to contraception guidelines for those of childbearing potential. The trial excludes individuals with metastatic skin involvement from another primary cancer or unknown primary cancer. Participants must be systemic treatment naïve for Cohort A and have measurable disease per RECIST 1.1 for Cohort B.

The clinical trial is a **randomized**, **double-blind**, Phase 2 study designed to evaluate the efficacy and safety of MK-4280A, a coformulation of **favezelimab** and **pembrolizumab**, in patients with selected solid tumors. The trial involves two cohorts: Cohort A focuses on evaluating the clinical benefit of MK-4280A or pembrolizumab, while Cohort B assesses the combination of **lenvatinib** with MK-4280A or pembrolizumab, specifically measuring the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The trial is expected to run until February 27, 2028, with recruitment starting on September 11, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of resectable cutaneous squamous cell carcinoma or endometrial cancer, adequate organ function, and controlled blood pressure. Following the screening, participants will be randomized to receive either the investigational product or a comparator. The trial includes regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects of the treatment.

The expected length of participant involvement varies depending on the cohort and treatment arm, with a maximum treatment period of 182 days for lenvatinib and 105 days for MK-4280A or pembrolizumab. Participants may be subject to early termination from the study if they experience significant adverse events, disease progression, or if they withdraw consent. The trial aims to provide valuable insights into the treatment of **malignant neoplasms**, contributing to the development of effective therapeutic strategies for these conditions.

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **Lenvatinib** is provided in a **capsule** form, with a maximum daily dose of 20 mg and a total maximum dose of 25,480 mg over a treatment period of up to 182 days. The route of administration is **oral**, and the substance is of chemical origin. The product is manufactured by Merck & Co. Inc. and is identified by the sponsor product code MK-7902.

**KEYTRUDA**, a concentrate for solution for infusion, contains the active substance **pembrolizumab**. It is administered via **intravenous infusion** with a maximum daily dose of 200 mg and a total maximum dose of 7,000 mg over a treatment period of up to 105 days. This biological product is produced by Merck Sharp & Dohme BV and is identified by the sponsor product code MK-3475. Pembrolizumab is a protein-based substance, and the product is authorized for use in the European Union.

Another formulation of **Lenvatinib** is also included in the trial, identical in pharmaceutical form, dosage, and administration route to the previously described Lenvatinib capsule. It is also manufactured by Merck & Co. Inc. and shares the same sponsor product code MK-7902.

**MK-4280A** is a solution for infusion containing a coformulation of **pembrolizumab** and **favezelimab**. This biological product is administered via **intravenous infusion** with a maximum daily dose of 1 g and a total maximum dose of 35 g over a treatment period of up to 105 days. The product is manufactured by Merck & Co. Inc. and is identified by the sponsor product code MK-4280A. Both active substances are protein-based.

Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment, as the focus is on evaluating the efficacy and safety of the experimental medications.

Efficacy in this clinical trial will be assessed using specific primary and secondary endpoints. The primary endpoints include the evaluation of **Clinical Benefit** in Cohort A and the **Objective Response Rate (ORR)** per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by the investigator in Cohort B. Secondary endpoints encompass a range of measures such as **Pathologic Complete Response (pCR)** and **Major Pathologic Response (mPR)** in Cohort A, as well as ORR per RECIST 1.1 as assessed by the investigator in the same cohort. Additionally, the trial will monitor the number of participants experiencing adverse events (AEs), discontinuations due to AEs, perioperative complications, and AEs that preclude surgery across both cohorts.