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Phase I Trial of Sequential Low-Dose 5-Aza-2'-Deoxycytidine Plus High-Dose Intravenous Bolus Interleukin-2 in Patients with Melanoma or Renal Cell Carcinoma

Authors' Affiliations: ¹ Division of Medical Oncology, Department of Medicine, ² Departments of Biostatistics and Bioinformatics, and ³ Center for Genome Technology, Department of Molecular Genetics and Microbiology, and Duke Institute for Genome Sciences and Policy, Duke University Medical Center; ⁴ Division of Hematology and Oncology, Geriatrics Research, Education, and Clinical Center, Department of Medicine, Durham VA Medical Center, Durham, North Carolina; and ⁵ Department of Leukemia and Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Jared A. Gollob, Hematology/Oncology, Duke University Medical Center, DUMC 3441, Durham, NC 27710. Phone: 919-668-3979; Fax: 919-668-2163; E-mail: gollo001{at}mc.duke.edu.

Purpose: The silencing of gene expression through DNA methylation contributes to defects in antigen presentation and apoptosis in melanoma and renal cell cancer. To determine how a hypomethylating agent would modulate the toxicity and antitumor activity of immunotherapy, we initiated a phase I trial of 5-aza-2'-deoxycytidine (decitabine) plus high-dose interleukin 2 (IL-2).

Experimental Design: Patients received s.c. decitabine daily x 5 days on weeks 1 and 2 of a 12-week cycle. High-dose IL-2, consisting of two cycles of IL-2 600,000 IU/kg i.v. q8 hours x 14 doses separated by a 2-week break, was administered starting on week 3. Decitabine was escalated from 0.1 to 0.25 mg/kg. The hypomethylating activity of decitabine was assessed during cycle 1 by measuring hemoglobin F levels and changes in DNA methylation in peripheral blood mononuclear cells.

Results: Twenty-one patients with melanoma or renal cell cancer were enrolled. Decitabine did not alter the tolerability of IL-2 but caused grade 4 neutropenia in most patients. Grade 4 neutropenia lasting more than 7 days was the only dose-limiting toxicity, with a trend toward a higher incidence with increasing decitabine doses. Infection occurred in only one patient despite the high incidence of neutropenia, and granulocyte colony-stimulating factor use in several patients expedited neutrophil recovery. Decitabine augmented hemoglobin F levels and altered DNA methylation and gene expression in peripheral blood mononuclear cells in a dose-independent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients.

Conclusions: Decitabine can be safely administered with high-dose IL-2 and may enhance the activity of IL-2 in melanoma.

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