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

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 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.

• Authors: 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 Lowder, Mohammad Azab, Wolf H Fridman, Catherine Sautès-Fridman, Zlatko Trajanoski, Michele Maio
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 24 Pg. 7351-7362 (12 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31530631 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Ipilimumab
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• guadecitabine
• Azacitidine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Azacitidine (administration & dosage, analogs & derivatives)
• CD8-Positive T-Lymphocytes (immunology)
• DNA Methylation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Ipilimumab (administration & dosage)
• Male
• Maximum Tolerated Dose
• Melanoma (drug therapy, immunology, pathology)
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Staging
• Patient Safety
• Programmed Cell Death 1 Receptor (metabolism)
• Survival Rate
• Treatment Outcome