title: Phase I trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors.
abstract: OBJECTIVE
  The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.
  
  
  METHODS
  Patients >or= 2 and <or= 18 years with relapsed or refractory solid tumors were enrolled onto sequential cohorts to the following five dose levels: 3.0 (n = 3), 4.5 (n = 4), 6.0 (n = 3), 8.0 (n = 6), and 10 (n = 3) mg/m(2)/d. Eligibility criteria, dose levels, definitions of DLT and MTD, and pharmacokinetic sampling times were designed to be as similar as possible to the adult phase I trial of ixabepilone on the same schedule.
  
  
  RESULTS
  Nineteen children (median age, 10 years; range, 2 to 18 years) were enrolled, and 18 (12 with sarcomas) were assessable for toxicity. DLTs (grade 4 neutropenia for > 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m(2)/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m(2)/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 +/- 247 mL/min/m(2), volume of distribution at steady-state was 12.2 +/- 5.4 L/kg, and half-life was 14 hours.
  
  
  CONCLUSIONS
  The recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m(2)/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.
authors.affiliation: Pediatric and Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. widemanb@mail.nih.gov
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Wendy
authors.initials: W
authors.lastname: Goodspeed
authors.forename: Anne
authors.initials: A
authors.lastname: Goodwin
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D034261:Epothilones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D018197:Hepatoblastoma / Q000188:drug therapy; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D008452:Maximum Allowable Concentration; D009447:Neuroblastoma; D012509:Sarcoma / Q000188:drug therapy*; D009396:Wilms Tumor / Q000188:drug therapy
chemical_list: D034261:Epothilones; C430592:ixabepilone