Phase 3 Randomized Controlled Trial of Adjuvant mRNA-4157 and Pembrolizumab Versus Placebo and Pembrolizumab in High-Risk Stage II-IV Melanoma

The primary objective of this Phase 3 clinical study is to compare **V940** (mRNA-4157) plus **pembrolizumab** to placebo plus pembrolizumab with respect to **recurrence-free survival** (RFS) in participants with high-risk Stage II-IV melanoma. This objective is clinically relevant as it aims to determine the efficacy of the investigational combination therapy in preventing melanoma recurrence, which is critical for improving long-term patient outcomes.

Secondary objectives include:

• Comparing V940 plus pembrolizumab to placebo plus pembrolizumab with respect to **distant metastasis-free survival** (DMFS).
• Comparing V940 plus pembrolizumab to placebo plus pembrolizumab with respect to **overall survival** (OS).
• Evaluating the **safety and tolerability** of V940 plus pembrolizumab.
• Assessing V940 plus pembrolizumab versus placebo plus pembrolizumab with respect to mean change from baseline in global health status/quality of life (QoL), physical functioning, and role functioning using the EORTC QLQ-C30.

The clinical trial involves a total of **733 participants** diagnosed with **melanoma**, specifically those with resected cutaneous melanoma confirmed to be at stage IIB to IV. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult participants. The participants were selected based on specific criteria, including having undergone complete surgical resection rendering them disease-free, and having no prior systemic therapy for melanoma beyond surgical intervention. The trial excludes vulnerable populations and requires participants to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must also demonstrate adequate organ function and have no clinical evidence of brain metastases. Lifestyle factors such as diet and physical activity are not specified, but participants with controlled HIV or undetectable HCV viral load are eligible, as well as those with controlled HBV under antiviral therapy. The trial aims to compare the efficacy of V940 plus pembrolizumab versus placebo plus pembrolizumab in terms of recurrence-free survival (RFS).

The clinical trial is designed as a **randomized**, **double-blind**, placebo- and active-comparator-controlled study to evaluate the efficacy and safety of V940 (mRNA-4157) plus **pembrolizumab** versus placebo plus pembrolizumab in participants with high-risk stage II-IV **melanoma**. The trial aims to assess the primary endpoint of Recurrence-Free Survival (RFS) and secondary endpoints including Distant Metastasis Free Survival (DMFS), Overall Survival, and various quality of life measures. The study is expected to run until September 2030, with recruitment having commenced in July 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having resected cutaneous melanoma with histologically confirmed stage IIB to IV, being disease-free post-surgery, and having adequate organ function. Following successful screening, participants will be randomized to receive either the investigational treatment or placebo. The treatment phase will involve 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 final outcomes and any long-term effects of the treatment.

The expected length of participant involvement is up to 54 weeks for those receiving pembrolizumab and up to 27 weeks for those receiving mRNA-4157, with conditions for early termination including significant adverse events or disease progression. Participants will be closely monitored throughout the trial to ensure adherence to the protocol and to address any safety concerns promptly. The trial's rigorous design and comprehensive monitoring aim to provide robust data on the potential benefits and risks of the investigational treatment in this patient population.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is administered via **intravenous infusion**. The maximum daily dose is 400 mg, with a total maximum dose of 3600 mg over a treatment period of up to 54 weeks. Pembrolizumab is a biological product, specifically a protein of other origin, and is not formulated for pediatric use. The product is manufactured by Merck Sharp & Dohme BV and is identified by the sponsor product code MK-3475.

The trial also includes the investigational product **mRNA-4157**, which is a **dispersion for injection**. This product is administered through **intramuscular injection**. The maximum daily dose is 1 mg, with a total maximum dose of 9 mg over a treatment period of up to 27 weeks. mRNA-4157 is classified as an Advanced Therapy Medicinal Product (ATMP) and is composed of synthetic, non-heritable mRNA encapsulated in a synthetic lipid nanoparticle. It is designed to deliver a patient-specific mRNA sequence without integrating into the host genome. This product is developed by MODERNATX, INC.

A **placebo** is also utilized in the study, specifically as a comparator to mRNA-4157. The placebo is referred to as "Placebo to V940 (mRNA-4157)" and does not contain any active substance. It serves as a control to evaluate the efficacy and safety of the experimental treatments. The placebo is not associated with any specific pharmaceutical form or route of administration as per the trial documentation.

Efficacy in this clinical trial will be assessed primarily through **Recurrence-Free Survival (RFS)**, which serves as the primary endpoint. Secondary endpoints include **Distant Metastasis Free Survival (DMFS)**, **Overall Survival**, and various patient-reported outcomes such as changes in Global Health Status/Quality of Life (QoL) scores, Physical Functioning scores, and Role Functioning scores, as evaluated by the QLQ-C30 questionnaire. Additionally, the number of participants experiencing adverse events (AEs) and those discontinuing study treatment due to AEs will be monitored.

The trial is designed to compare the efficacy of V940 (mRNA-4157) plus pembrolizumab against a placebo plus pembrolizumab in participants with high-risk Stage II-IV melanoma. The efficacy parameters will be collected and analyzed at specified intervals throughout the study duration, which is estimated to conclude by September 2030. The trial will employ validated scales and instruments to ensure the accuracy and reliability of the data collected. The study will follow a randomized, double-blind, placebo- and active-comparator-controlled design to maintain objectivity and minimize bias in the assessment of treatment efficacy.