A protocol for phase II study investigating the safety and efficacy of TM5614 in combination with nivolumab in the treatment of unresectable malignant melanoma

Abstract

Abstract Introduction: Plasminogen activating inhibitor-1 (PAI-1) plays a significant role in the development of various cancers, including melanomas, and modulation of tumor-associated inflammation is one of the key anti-tumor functions of PAI-1. A recent report suggested that PAI-1 inhibitors suppress the expression of programmed cell death 1 ligand 1 (PD-L1) on tumor-associated macrophages (TAMs), suppressing the induction of regulatory T cells and promoting anti-melanoma immune responses. Methods and analysis: This is a single-arm, open-label, multi-institutional, phase 2 clinical trial to assess the efficacy and safety of nivolumab in combination with TM5614 (pPAI-1 inhibitor) in patients with advanced malignant melanoma. Nivolumab will be administered every 4 weeks, and TM5614 will be administered daily for 8 weeks. For the first-line cohort, assuming the null hypothesis of a response rate of 22.2% and an alternative hypothesis of 40%, a minimum of 22 patients are required to achieve a two-sided, type I error of 5% and power of 70% based on the exact binomial distribution. For the second-line and beyond cohorts, assuming the null hypothesis of a response rate of 5% and the alternative hypothesis of 22.2%, a minimum of 18 patients are required to achieve a two-sided, type I error of 5%, and power of 70% based on the exact binomial distribution. Discussion: This study will contribute to the development of novel combination therapy for anti- programmed cell death 1 antibodies-resistant advanced melanoma patients, which remains an unmet clinical need. Trial registration: Trial registration number: jRCT2021210029