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
Abstract
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 5 days on weeks 1and 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 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 1by 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 doseindependent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients.
Authors
Jared A. Gollob, CatherineJ. Sciambi, Bercedis L. Peterson,Tina Richmond, Monica Thoreson, KellyMoran, Holly K. Dressman, Jaroslav Jelinek, and Jean-Pierre J. Issa
Contact
- Jared A Gollob, MD (gollo001@mc.duke.edu)