title: A phase I and pharmacokinetic study of ixabepilone in combination with Carboplatin in patients with advanced solid malignancies.
abstract: OBJECTIVE
  To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B).
  
  
  RESULTS
  Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B).
  
  
  CONCLUSIONS
  Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.
authors.affiliation: Northern Centre for Cancer Treatment, Newcastle upon Tyne, United Kingdom. ruth.plummer@ncl.ac.uk
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.forename: Penella
authors.initials: P
authors.lastname: Woll
authors.forename: David
authors.initials: D
authors.lastname: Fyfe
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
authors.forename: Melanie
authors.initials: M
authors.lastname: Griffin
authors.forename: Paula
authors.initials: P
authors.lastname: Hewitt
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
authors.forename: Fouad
authors.initials: F
authors.lastname: Namouni
authors.forename: Marvin
authors.initials: M
authors.lastname: Cohen
authors.forename: Mark
authors.initials: M
authors.lastname: Verrill
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D034261:Epothilones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D016190:Carboplatin; C430592:ixabepilone