title: 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: OBJECTIVE
  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).
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA. gollo001@mc.duke.edi
authors.forename: Jared A
authors.initials: JA
authors.lastname: Gollob
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Sciambi
authors.forename: Bercedis L
authors.initials: BL
authors.lastname: Peterson
authors.forename: Tina
authors.initials: T
authors.lastname: Richmond
authors.forename: Monica
authors.initials: M
authors.lastname: Thoreson
authors.forename: Kelly
authors.initials: K
authors.lastname: Moran
authors.forename: Holly K
authors.initials: HK
authors.lastname: Dressman
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005319:Fetal Hemoglobin / Q000187:drug effects; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D011237:Predictive Value of Tests; D016896:Treatment Outcome
chemical_list: D007376:Interleukin-2; D000077209:Decitabine; D005319:Fetal Hemoglobin; D001374:Azacitidine