Guadecitabine plus ipilimumab in unresectable melanoma: the NIBIT-M4 clinical trial
Mené sur 19 patients atteints d'un mélanome non résécable, cet essai de phase IB évalue la dose maximale tolérée et l'efficacité, du point de vue du taux de contrôle de la maladie et du taux de réponse objective, de la guadécitabine en combinaison avec l'ipilimumab, et analyse les caractéristiques pharmacocinétiques de la combinaison
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<0.05) lower than at baseline (80.3%), with a median of 2454 (Week 4) and 4131 (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 contexture analysis (n=11) demonstrated up-regulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in post-treatment tumor cores. Conclusions: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma, and has promising immunomodulatory and anti-tumour activity.