title: Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.
abstract: BACKGROUND
  Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ.
  
  
  METHODS
  In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR).
  
  
  RESULTS
  The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients.
  
  
  CONCLUSIONS
  The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.
authors.affiliation: Department of Medicine/Division of Hematology/Oncology, School of Medicine, University of Pittsburgh, Pittsburgh 15232, USA. tawbih@upmc.edu
authors.forename: H A
authors.initials: HA
authors.lastname: Tawbi
authors.forename: J H
authors.initials: JH
authors.lastname: Beumer
authors.forename: A A
authors.initials: AA
authors.lastname: Tarhini
authors.forename: S
authors.initials: S
authors.lastname: Moschos
authors.forename: S C
authors.initials: SC
authors.lastname: Buch
authors.forename: M J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: S
authors.initials: S
authors.lastname: Christner
authors.forename: J M
authors.initials: JM
authors.lastname: Kirkwood
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077209:Decitabine; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D000077209:Decitabine; D003606:Dacarbazine; D001374:Azacitidine; D000077204:Temozolomide