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

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 NemcAram Oganesian, James Lowder, Mohammad Azab, Wolf H. Fridman, Catherine Sautes-Fridman, Zlatko Trajanoski, Michele Maio

Research output: Contribution to journalArticlepeer-review


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 contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in posttreatment tumor cores. Conclusions: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.

Original languageEnglish
Pages (from-to)7351-7362
Number of pages12
JournalClinical Cancer Research
Issue number24
Publication statusPublished - Dec 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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