Cefixime allows greater dose escalation of oral irinotecan: A phase I study in pediatric patients with refractory solid tumors

Wayne L. Furman, Kristine R. Crews, Catherine Billups, Jianrong Wu, Amar J. Gajjar, Najat C. Daw, Christian C. Patrick, Carlos Rodriguez-Galindo, Clinton F. Stewart, Jeffrey S. Dome, John C. Panetta, Peter J. Houghton, Victor M. Santana

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Purpose: Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea. Patients and Methods: In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. Results: Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ngxh/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P= .030). Conclusion: Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

Original languageEnglish (US)
Pages (from-to)563-570
Number of pages8
JournalJournal of Clinical Oncology
Volume24
Issue number4
DOIs
StatePublished - Feb 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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