A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: Impact on DNA methylation and lymphocyte populations

E. R. Plimack, J. R. Desai, J. P. Issa, J. Jelinek, P. Sharma, L. M. Vence, R. L. Bassett, J. L. Ilagan, N. E. Papadopoulos, W. J. Hwu

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Background Melanoma cell lines treated with decitabine show upregulation of cancer antigens, and interferon-α upregulatesMHC 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 (PEGIFN) 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.

Original languageEnglish (US)
Pages (from-to)969-975
Number of pages7
JournalInvestigational New Drugs
Volume32
Issue number5
DOIs
StatePublished - Oct 2014

Keywords

  • Decitabine
  • Epigenetic therapy
  • Immunotherapy
  • Interferon
  • Melanoma

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

MD Anderson CCSG core facilities

  • Biostatistics Resource Group

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