Guadecitabine plus ipilimumab in unresectable melanoma: the NIBIT-M4 clinical trial

Purpose: The immuno-modulatory activity of DNA hypomethylating agents (DHA) suggests they may improve the effectiveness of cancer immunotherapies. The phase 1b NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. Experimental Design: Unresectable Stage III/IV melanoma patients received escalating doses of guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on Days 1-5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on Day 1 every 3 weeks, starting 1 week after guadecitabine, for 4 cycles. Primary endpoints were safety, tolerability and maximum tolerated dose of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. Results: Nineteen patients were treated; 84% had grade 3/4 adverse events, neither dose limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n=8) at Week 4 (74.5%) and Week 12 (75.5%) was significantly (p 2 or