Cefixime Allows Greater Dose Escalation of Oral Irinotecan: A Phase I Study in Pediatric Patients With Refractory Solid Tumors

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 ng×h/mL; standard deviation [SD], 6.8 ng × h/mL v 10.4 ng × h/mL; SD, 4.3 ng × 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.