Evaluation of Pembrolizumab, Quavonlimab, and Lenvatinib in Advanced Melanoma with Brain Metastases: A Phase 1/2 Open-Label Study

The primary objective of this study is to assess the **safety** and tolerability of investigational treatment combinations in participants with advanced melanoma with brain metastases, either PD-1 refractory or PD-1 naive. This is 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), with modifications allowing for measurable lesions of at least 0.5 cm in one dimension by magnetic resonance imaging (MRI) and up to five intracranial target lesions, in addition to any extracranial target lesions. These objectives are clinically relevant as they provide insights into the potential efficacy and safety profile of the treatment regimens, which is crucial for managing melanoma with brain metastases.

Secondary objectives include:

• Evaluating the duration of response (DOR) as assessed by BICR per RECIST 1.1, with similar modifications to lesion criteria.
• Assessing the brain metastasis response rate (BMRR) using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, with modifications.
• Evaluating the brain metastasis duration of response (BM-DOR) as per RANO-BM criteria.
• Assessing progression-free survival (PFS) as evaluated by BICR per RECIST 1.1, with the same lesion criteria modifications.

The clinical trial involves a total of **18 participants** diagnosed with **advanced melanoma with brain metastases**, specifically those who are either PD-1 refractory or PD-1 naive. 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 inclusion criteria, such as having American Joint Committee on Cancer (AJCC) Stage IV, M1D melanoma, being neurologically asymptomatic from brain metastases, and having adequate organ function. Both genders are represented, and the trial includes individuals from a vulnerable population. Lifestyle considerations include the requirement for male participants capable of producing sperm to use contraception or abstain from penile-vaginal intercourse, while female participants must not be pregnant or breastfeeding and must use effective contraception or abstain from heterosexual intercourse during the study period. The trial does not provide specific details on the general health status or lifestyle habits such as diet and physical activity of the participants.

The clinical trial is designed to evaluate the **safety** and **efficacy** of investigational agents, with or without **pembrolizumab**, in participants with advanced melanoma with brain metastases. This study employs a randomized, open-label, rolling-arm umbrella platform design, allowing for the assessment of multiple investigational treatments. The trial is expected to run from April 2021 to June 2031, with participant involvement varying based on the specific treatment arm and response to therapy.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having American Joint Committee on Cancer (AJCC) Stage IV, M1D melanoma, and being neurologically asymptomatic from brain metastases. Following the screening, participants will be randomized into different treatment arms, receiving either investigational agents alone or in combination with pembrolizumab. The investigational products include MK-1308A, Lenvatinib, and KEYTRUDA, administered via intravenous infusion or oral use, depending on the specific agent.

Study visits will include regular follow-up assessments to monitor safety, tolerability, and treatment efficacy. The primary endpoints focus on the percentage of participants experiencing adverse events and the objective response rate as assessed by blinded independent central review. Secondary endpoints include duration of response, brain metastasis response rate, and progression-free survival. The end-of-study visit will occur after the completion of the treatment period or upon early termination due to adverse events or disease progression.

Participant involvement is expected to last until the end of the treatment period, with specific durations depending on the investigational agent administered. Conditions that may lead to early termination from the study include significant adverse events or lack of therapeutic benefit. The trial aims to provide valuable insights into the treatment of advanced melanoma with brain metastases, contributing to the development of effective therapeutic strategies.

The clinical trial involves the administration of **MK-1308A**, a **solution for infusion** containing the active substances **pembrolizumab** and **quavonlimab**. This investigational medication is administered via **intravenous infusion**. The frequency and specific dosage of administration are determined based on the study protocol, which aims to evaluate the safety and efficacy of this combination in participants with melanoma. The pharmaceutical form is a solution for infusion, and the product is developed by Merck & Co. Inc. The active substances are proteins, with pembrolizumab being a well-known immune checkpoint inhibitor and quavonlimab being a monoclonal antibody targeting CTLA-4.

Another investigational product used in the trial is **Lenvatinib**, which is provided in **capsule** form for **oral use**. Lenvatinib is a chemical compound and acts as a multi-targeted tyrosine kinase inhibitor. It is also developed by Merck & Co. Inc. The dosing schedule for lenvatinib is determined according to the study protocol, ensuring optimal therapeutic exposure while monitoring for potential adverse effects. Compliance with the oral administration is monitored throughout the trial to ensure adherence to the prescribed regimen.

The trial also includes the use of **KEYTRUDA 25 mg/mL concentrate for solution for infusion**, which contains the active substance **pembrolizumab**. This product is administered via **intravenous infusion** and is developed by Merck Sharp & Dohme B.V. Pembrolizumab is a monoclonal antibody that targets the PD-1 receptor, enhancing the immune system's ability to detect and combat tumor cells. The administration schedule and dosage are aligned with the study's objectives to assess the safety and efficacy of pembrolizumab in combination with other investigational agents.

Throughout the trial, participant compliance with the dosing schedules is closely monitored. This includes regular assessments and documentation of adherence to the prescribed treatment regimens. The trial aims to evaluate the safety, tolerability, and objective response rate of these investigational treatments in participants with melanoma, as assessed by blinded independent central review per RECIST 1.1 criteria.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)**, which will be evaluated by a blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), with modifications for measurable lesion criteria of at least 0.5 cm in one dimension by magnetic resonance imaging (MRI) and allowance for up to five intracranial target lesions. Additionally, the percentage of participants who experience an adverse event (AE) and the percentage of participants who discontinue study treatment due to an AE will be monitored.

Secondary endpoints include the **Duration of Response (DOR)**, **Brain Metastasis Response Rate (BMRR)**, **Brain Metastasis Duration of Response (BM-DOR)**, and **Progression-free Survival (PFS)**. These parameters will provide a comprehensive evaluation of the treatment's efficacy in participants with melanoma. The trial will utilize investigational agents with or without pembrolizumab or pembrolizumab alone, and the efficacy assessments will be conducted at specified intervals throughout the study duration, which is estimated to conclude by June 17, 2031.