Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial

作者：Anna Maria Di Giacomo, Alessia Covre, Francesca Finotello, Dietmar Rieder, Riccardo Danielli, Luca Sigalotti, Diana Giannarelli, Florent Petitprez, Laetitia Lacroix, Monica Valente, Ornella Cutaia, Carolina Fazio, Giovanni Amato, Andrea Lazzeri, Santa Monterisi, Clelia Miracco, Sandra Coral, Andrea Anichini, Christoph Bock, Amelie Nemc, Aram Oganesian, James N. Lowder, Mohammad Azab, Wolf H. Fridman, Catherine Sautès‐Fridman, Zlatko Trajanoski, Michele Maio · 发表于：Clinical Cancer Research · 年份：2019 · DOI：10.1158/1078-0432.ccr-19-1335 · 被引用次数：86 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Epigenetics and DNA Methylation

Abstract Purpose: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. Patients and Methods: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and 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, and 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 < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P < 0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune ...