title: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children.
abstract: OBJECTIVE
  In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children.
  
  
  METHODS
  Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m(2) (qd x 5) x 2 every 21 days.
  
  
  RESULTS
  The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m(2), despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m(2)/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL).
  
  
  CONCLUSIONS
  This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m(2). These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.
authors.affiliation: Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA. wayne.furman@stjude.org
authors.forename: W L
authors.initials: WL
authors.lastname: Furman
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
authors.forename: C A
authors.initials: CA
authors.lastname: Poquette
authors.forename: C B
authors.initials: CB
authors.lastname: Pratt
authors.forename: V M
authors.initials: VM
authors.lastname: Santana
authors.forename: W C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: L C
authors.initials: LC
authors.lastname: Bowman
authors.forename: M K
authors.initials: MK
authors.lastname: Ma
authors.forename: F A
authors.initials: FA
authors.lastname: Hoffer
authors.forename: W H
authors.initials: WH
authors.lastname: Meyer
authors.forename: A S
authors.initials: AS
authors.lastname: Pappo
authors.forename: A W
authors.initials: AW
authors.lastname: Walter
authors.forename: P J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D009447:Neuroblastoma / Q000188:drug therapy*; D013370:Subrenal Capsule Assay; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin