Evaluation of Pembrolizumab, Lenvatinib, Tretinoin, Vibostolimab, and Quavonlimab in PD-1 Refractory Melanoma: A Phase 1/2 Open-label Study

The primary objectives of this study are to assess the **safety** and tolerability of investigational treatment combinations in participants with PD-1 refractory melanoma, as determined by the proportion of participants experiencing adverse events. Additionally, the study aims to evaluate the objective response rate (ORR) as assessed by blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). These objectives are clinically relevant as they provide critical insights into the potential risks and therapeutic efficacy of the treatment combinations, which are essential for determining their viability as treatment options for this challenging condition.

The secondary objective is to evaluate the duration of response (DOR) as assessed by BICR per RECIST 1.1. This objective is important for understanding the sustainability of the treatment effects over time, which is crucial for long-term management strategies in patients with PD-1 refractory melanoma.

The clinical trial involves a total of **42 participants** diagnosed with **PD-1 refractory melanoma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having histologically or cytologically confirmed melanoma, and having progressed on treatment with an anti-PD-1/L1 monoclonal antibody. The trial includes individuals with unresectable Stage III or Stage IV melanoma, as per the AJCC 8th Edition Staging Criteria, who have not received more than three lines of therapy for their advanced melanoma. Participants are required to have adequate organ function and must adhere to specific contraceptive guidelines if applicable. The trial population is characterized by a vulnerable group, indicating that additional ethical considerations are in place to protect the participants. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **safety** and **efficacy** of investigational agents in combination with **pembrolizumab** or pembrolizumab alone in participants with **PD-1 refractory melanoma**. This is a Phase 1/2 open-label, rolling-arm, umbrella platform trial. The trial employs a randomized, controlled design to ensure robust data collection and analysis. The estimated duration of the trial is from July 31, 2020, to June 24, 2030, allowing for comprehensive assessment of long-term outcomes.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed melanoma and progression on prior anti-PD-1/L1 therapy. Following the screening, participants will be randomized to receive either the investigational treatment combinations or pembrolizumab alone. The trial includes regular follow-up visits to monitor safety, tolerability, and response to treatment, as assessed by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). The end-of-study visit will conclude the participant's involvement, with a focus on final safety assessments and overall response evaluation.

The expected length of participant involvement varies depending on individual response and tolerability, but it is anticipated to last until the end of the trial or until specific criteria for early termination are met. Conditions that may lead to early termination include the occurrence of adverse events, lack of efficacy, or withdrawal of consent. The primary endpoints of the trial are the percentage of participants experiencing adverse events and the objective response rate, while secondary endpoints include the duration of response. The trial aims to provide valuable insights into the potential benefits and risks of these investigational treatments for patients with advanced melanoma.

The clinical trial involves the administration of several investigational agents, each with specific pharmaceutical forms, routes, and frequencies of administration. **Lenvatinib** is provided in a **capsule** form for **oral use**. It is a chemical-origin medication developed by Merck & Co. Inc., identified by the sponsor product code MK-7902. The dosage and frequency of administration are determined based on the trial protocol, and participant compliance is monitored throughout the study.

**Tretinoin** is also administered in a **capsule** form for **oral use**. This chemical-origin compound is included in the study to evaluate its effects in combination with other investigational agents. The specific dosing schedule is outlined in the trial protocol, ensuring adherence to the study's objectives.

**Vibostolimab** is administered as a **solution for infusion** via **intravenous infusion**. This biological agent, also developed by Merck & Co. Inc., is identified by the sponsor product code MK-7684. The infusion schedule is carefully managed to maintain participant safety and to assess the investigational treatment's efficacy.

**Pembrolizumab**, marketed as **KEYTRUDA 25 mg/mL concentrate for solution for infusion**, is another biological agent used in the trial. It is administered through **intravenous infusion**. The product is developed by Merck Sharp & Dohme B.V. and is identified by the sponsor product code MK-3475. The administration schedule is designed to optimize therapeutic outcomes while monitoring for adverse events.

**Quavonlimab** is provided as a **solution for infusion** and is administered via **intravenous infusion**. This biological agent, with the sponsor product code MK-1308, is developed by Merck & Co. Inc. The infusion protocol is established to ensure participant safety and to evaluate the investigational treatment's potential benefits.

Throughout the trial, participant compliance with the dosing schedules is closely monitored, and any deviations are documented to ensure the integrity of the study data. The trial also includes standard-of-care therapies as comparators, where applicable, to assess the investigational agents' efficacy and safety profiles.

The efficacy of the investigational treatment combinations in the clinical trial will be assessed using the **Objective Response Rate (ORR)** as a primary endpoint. The ORR will be evaluated by a Blinded Independent Central Review (BICR) according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). This criterion is a standardized set of guidelines used to measure tumor response to treatment, providing a consistent method for evaluating changes in tumor size.

Secondary efficacy assessments will include the **Duration of Response (DOR)**, also evaluated per RECIST 1.1. The DOR measures the length of time that a tumor continues to respond to treatment without growth. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the effectiveness of the treatment combinations in participants with melanoma.