Perlmutter Cancer Center

This is an open-label, randomized, Phase 2 study. Approximately 150 eligible patients will be randomly assigned in a 2:1 ratio to the combination arm (approximately 100 patients who receive mRNA-4157 and pembrolizumab) and the control arm (approximately 50 patients who receive pembrolizumab alone). Patients with completely resected cutaneous melanoma at one of the following stages: ? Stage IIIB, only if relapsed within 3 months of initial surgery of curative intent. That is, the patient must have relapsed within 3 months of their first surgery of curative intent and subsequently had a second surgery of curative intent before entering this study (as such, newly diagnosed Stage IIIB patients are not eligible). ? Stage IIIC. ? Stage IIID. ? Stage IV. Patients must have had complete resection (surgery of curative intent) within 13 weeks before study enrollment, and must be disease free at study entry (screening). Once a patient is enrolled, they will be randomized and should commence pembrolizumab treatment as soon as possible (ideally within 13 weeks of their surgery of curative intent). For patients randomly assigned to the mRNA-4157 plus pembrolizumab combination arm: ? A pembrolizumab run-in period, typically 2 pembrolizumab cycles, will occur while mRNA-4157 is being manufactured. ? Once a patient’s mRNA-4157 is available, the combination treatment period will commence. The first dose of mRNA-4157 will be administered with the next dose of pembrolizumab in order to achieve synchronous combination dosing in 21-day cycles. All patients on both arms of the study may continue on pembrolizumab until disease recurrence, unacceptable toxicity, or they undergo 18 total cycles (approximately 1 year of treatment), whichever is sooner. Crossover to the mRNA-4157 and pembrolizumab combination arm is not permitted for patients who relapse following pembrolizumab monotherapy. Recurrence-free survival (RFS) is the primary endpoint of the trial and is defined as the time between the first dose of pembrolizumab and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma or death (from any cause), whichever occurs first. Patients will be assessed for recurrence by radiological imaging.