Nivolumab and ipilimumab +/-UV1 vaccine as 1st line treatment in patients with malignant melanoma (INITIUM-trial)

Abstract

Nivolumab and ipilimumab +/- UV1 vaccine as 1st line treatment in patients with malignant melanoma (INITIUM-trial)Malignant melanomas (MM) are tumors originating from the melanocytes in the skin or mucosal surfaces. Even if the prognosis has improved considerably with the introduction of checkpoint inhibitors (CPIs) and BRAF/MEK inhibitors, half of the patients with metastatic MM dies within 5 years. Patients indicated for CPI as first line treatment will either receive a PD-1 antibody as monotherapy or a combination of CTLA-4 and PD-1 targeting antibodies. Patients are selected for monotherapy or combination therapy based on tumor staging, clinical- and biochemical status. The combination treatment has shown improved overall survival as compared to monotherapy, but also increased toxicity. The UV1 vaccine comprises 3 long peptides covering the active site of the tumor-associated antigen telomerase. Through UV1 vaccinations, patients induce telomerase-specific T cells with the potential of providing the necessary inflammatory tumor microenvironment for optimal immune-mediated tumor control. The UV1 vaccine is shown to induce immune responses in HLA-unselected patients across 3 completed phase I trials, covering MM, NSCLC, and prostate cancer. Accumulating evidence suggests that CPI efficacy is reliant on spontaneous anti-tumor immune responses. UV1 vaccination thus serves to increase CPI efficacy by providing the necessary anti-tumor immune responses, while the CPIs may reciprocally provide increased expansion and effector capacity of vaccine-induced T cells by blocking CTLA-4 and PD-l, respectively. The combination proposed in this trial may therefore lead to synergistic immunological activity translating to improved clinical outcome for MM patients.The INITIUM study (EudraCT no: 2019‐002026‐75) is an ongoing Ultimovacs sponsored, randomized, open-label, multi-center study comparing the efficacy and safety of nivolumab and ipilimumab with or without UV1 vaccination in 1st line metastatic MM patients.A total of 154 patients are randomized 1:1 to either arm A: 4 cycles of nivolumab (1 mg/kg q3w) + 4 cycles of ipilimumab (3 mg/kg q3w) + 8 injections with 300 μg UV1 and 75 μg GM-CSF as adjuvant (UV1 vaccination) during the first 13 weeks, or arm B: 4 cycles of nivolumab (1 mg/kg q3w) + 4 cycles of ipilimumab (3 mg/kg q3w). Patients randomized to treatment arm A will receive three UV1 vaccinations in week 1 and one in week 2, followed by 4 UV1 vaccinations throughout the following 11weeks, totaling to 8 UV1 vaccinations.Patients will continue with nivolumab maintenance treatment (480 mg q4w) according to the label. The primary endpoint is progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumours (RECIST 1.1) as determined by blinded independent central review (BICR).Samples of blood, feces, and tumor tissue are collected in a subset of patients for translational research purposes.Legal entity Ultimovacs ASA, Oslo, NorwayFundingUltimovacs ASA, Oslo, Norway