Phase I study of irinotecan in pediatric patients with malignant solid tumors.

Purpose: To determine the dose-limiting toxicity, maximum tolerated dose, and potential efficacy of irinotecan in children with refractory malignant solid tumors. Patients and Methods: In the present phase I clinical trial, 28 patients received irinotecan 50 to 200 mg/m 2 per day by intravenous 2-hour infusion over the course of 3 days, repeated once after an interval of 25 days. Fifty-one treatment courses were administered to these patients. Results: Dose-limiting toxicities were observed at the dose of 200 mg/m 2 per day for 3 days. Diarrhea and hematopoietic toxicities were the dose-limiting factors, and the former required support with intravenous fluid administration. The occurrence of vomiting was variable. Decreases in clinical tumor marker levels were observed in the majority of patients who received two cycles of irinotecan 80 mg/m 2 per day to 200 mg/m 2 per day over the course of 3 days, and partial response was attained in four patients who received irinotecan in two cycles of 140 mg/m 2 per day to 200 mg/m 2 per day over the course of 3 days. Pharmacokinetic studies showed that the plasma concentration of irinotecan and its active metabolite SN-38 ranged from 93 to 2,820 ng/mL and 5.2 to 34.8 ng/mL, respectively, during 3-day infusions of irinotecan 200 mg/m 2 per day. The mean clearance of irinotecan was 14.54 L/h per m 2 (range 8.45-20.83 L/h per m 2 ). Conclusion: The maximum tolerated dose was determined to be a dose of irinotecan between 160 mg/m 2 per day and 180 mg/m 2 per day administered over the course of 3 consecutive days on an inpatient basis, repeated once after 25 days off, and our results indicate that irinotecan is a promising anticancer agent that is worthy of phase II trials in pediatric solid tumors.