Phase III Study Investigating the Safety and Efficacy of TM5614 in Combination With Nivolumab for the Treatment of Unresectable Malignant Melanoma: Protocol.

TM5614, a plasminogen activator inhibitor-1 (PAI-1) inhibitor, has demonstrated potential in overcoming nivolumab resistance in patients with unresectable, anti-PD-1 antibody-refractory malignant melanoma. Previous Phase II trials have shown promising response rates, warranting further investigation through a randomised, placebo-controlled Phase III trial. This Phase III, randomised, double-blind, placebo-controlled, investigator-initiated clinical trial aims to evaluate the efficacy and safety of TM5614 in combination with nivolumab for treating patients with unresectable, anti-PD-1 antibody-refractory malignant melanoma. The study will enrol 124 participants across 18 medical institutions in Japan. Patients will receive either TM5614 plus nivolumab or placebo plus nivolumab for 48 weeks. The primary endpoint is overall survival (OS), while secondary endpoints include objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), and the incidence of treatment-related adverse events. This study is designed to compare OS between the TM5614 plus nivolumab group and the placebo plus nivolumab group. Statistical analyses will be conducted using the Kaplan-Meier method and Cox proportional hazards models. This Phase III trial will provide critical insights into the efficacy of TM5614 in combination with nivolumab as a novel treatment strategy for unresectable, anti-PD-1 antibody-refractory malignant melanoma. The results may offer new therapeutic options to improve patient outcomes and overcome resistance to immune checkpoint inhibitors. TRIAL REGISTRATION: jRCT2021240049 (https://jrct.niph.go.jp/en-latest-detail/jRCT2021240049). Protocol version: Ver.1.2 (3rd February, 2025).