A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations
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Background Melanoma cell lines treated with decitabine show upregulation of cancer antigens, and interferon-α upregulates MHC Class I antigens in cancer cells, leading to enhanced T-cell recognition and T-cell mediated tumor apoptosis. We evaluated the synergy between the hypomethylating effects of decitabine and the immunomodulatory effects of interferon in a combination regimen administered to advanced melanoma patients in a phase 1 trial. Methods Patients with one prior systemic therapy were eligible. Using a modified 3 + 3 design, patients received escalating doses of decitabine and pegylated interferon α-2b (PEG-IFN) during every 28-day treatment cycle. Global DNA methylation was measured on days 1 and 5 of cycles 1 and 3. Cytokine profiling and quantification of T-cell subpopulations by FACS were performed at baseline and cycle 3. Results Seventeen patients were assigned to one of four dose levels. Decitabine 15 mg/m2/d + PEG-IFN 3 μg/kg was the maximum tolerated dose (MTD). Grade 3/4 cytopenias were seen across all dose levels: anemia (1), neutropenia (7), and thrombocytopenia (2). One patient remained progression-free for 37 weeks. The other 16 patients progressed at or before 12 weeks. Median overall survival was 39 weeks. Hypomethylation was seen at all dose levels. Due to treatment-induced lymphocytopenia, absolute changes in T-cell populations post-treatment were too small to be meaningfully interpreted. Conclusions The response to this combination regimen was characterized by significant myelosuppression, particularly neutropenia. Although disappointing efficacy and slow accrual led to early closure of the trial, hypomethylation showed pharmacodynamic evidence of a therapeutic effect of decitabine at all dose levels.
KeywordsMelanoma Immunotherapy Epigenetic therapy Decitabine Interferon
The authors would like to acknowledge the following sources of support for this study: ERP received funding from the University of Texas Center for Clinical and Translational Sciences KL2 RR024149. ERP and W-JH received support to conduct the study through the University of Texas Center for Clinical and Translational Sciences Pilot Project Award. ERP would like to acknowledge the support and guidance of the faculty at the 2007 Methods in Clinical Cancer Research Workshop for assistance with the design of this trial. This study was supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. The decitabine for this study was provided by Eisai, Inc.
Conflict of interest
Dr. Plimack has received research funding from Merck. Dr. Issa has received research funding from Merck and honoraria from Eisai. Dr. Hwu has received research funding from Merck and served as Advisory Board consultant for Merck. The other authors have no conflicts of interest to declare.
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