title: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors.
abstract: OBJECTIVE
  The DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine) induces DNA demethylation and re-expression of epigenetically silenced genes, and increases carboplatin sensitivity of tumor xenograft models. We designed a clinical study to determine the feasibility of delivering a dose of decitabine, combined with carboplatin, that would be capable of producing equivalent biologic effects in patients with solid tumors.
  
  
  METHODS
  In a two-stage design, 33 patients received escalating doses of decitabine administered as a 6-hour infusion on day 1 followed by carboplatin, area under the concentration-time curve (AUC) 5 (cohort 1) and AUC 6 (cohort 2), on day 8 of a 28-day cycle. Pharmacodynamic analyses included 5-methyl-2'-deoxycytidine levels, MAGE1A CpG island methylation, and fetal hemoglobin (HbF) expression.
  
  
  RESULTS
  The major toxicity was myelosuppression. Dose limiting toxicities, prolonged grade 4 neutropenia (one patient), and sepsis and grade 3 anorexia/fatigue (one patient), were seen in two of four patients treated with decitabine 135 mg/m2 and carboplatin AUC 5. Dose limiting toxicity comprising neutropenic sepsis (one patient) and grade 3 fatigue (one patient) was seen in two of 10 patients treated at decitabine 90 mg/m2 and carboplatin AUC 6. Decitabine induced dose-dependent, reversible demethylation in peripheral-blood cells (PBCs) maximally at day 10. Furthermore, decitabine 90 mg/m2 induced demethylation of the MAGE1A CpG island in PBCs, buccal cells, and tumor biopsies, as well as elevation of HbF expression.
  
  
  CONCLUSIONS
  Decitabine can be combined safely with carboplatin at a dose and schedule that causes epigenetic changes equivalent to or greater than that observed in mice with carboplatin-sensitized xenografts. The recommended dose/schedule for phase II trials is decitabine 90 mg/m2 (day 1) followed by carboplatin AUC 6 (day 8) every 28 days.
authors.affiliation: Centre for Oncology and Applied Pharmacology, Glasgow University, Cancer Research UK Beatson Laboratories, Glasgow, United Kingdom.
authors.forename: Kim
authors.initials: K
authors.lastname: Appleton
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mackay
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.forename: Jane A
authors.initials: JA
authors.lastname: Plumb
authors.forename: Carol
authors.initials: C
authors.lastname: McCormick
authors.forename: Gordon
authors.initials: G
authors.lastname: Strathdee
authors.forename: Chooi
authors.initials: C
authors.lastname: Lee
authors.forename: Sophie
authors.initials: S
authors.lastname: Barrett
authors.forename: Sarah
authors.initials: S
authors.lastname: Reade
authors.forename: Dalal
authors.initials: D
authors.lastname: Jadayel
authors.forename: Adrian
authors.initials: A
authors.lastname: Tang
authors.forename: Katharine
authors.initials: K
authors.lastname: Bellenger
authors.forename: Lynsay
authors.initials: L
authors.lastname: Mackay
authors.forename: Albert
authors.initials: A
authors.lastname: Setanoians
authors.forename: Andreas
authors.initials: A
authors.lastname: Schätzlein
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Kaye
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000077209:Decitabine; D016190:Carboplatin; D015254:DNA Modification Methylases; D001374:Azacitidine