Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children

Wayne L. Furman, Clinton F. Stewart, Catherine A. Poquette, Charles B. Pratt, Victor M. Santana, William C. Zamboni, Laura C. Bowman, Margaret K. Ma, Fredrick A. Hoffer, William H. Meyer, Alberto S. Pappo, Andrew W. Walter, Peter J. Houghton

Research output: Contribution to journalArticlepeer-review

197 Scopus citations

Abstract

Purpose: 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. Patients and 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/m2 (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/m2, despite aggressive use of loperamide. The maximum- tolerated dose (MTD) on this schedule was 20 mg/m2/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). Conclusion: 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/m2. These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.

Original languageEnglish (US)
Pages (from-to)1815-1824
Number of pages10
JournalJournal of Clinical Oncology
Volume17
Issue number6
DOIs
StatePublished - Jun 1999
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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