A phase I study of irinotecan administered on a weekly schedule in pediatric patients

Abstract

Background The objectives of this study were to determine the maximum tolerated dose (MTD), dose‐limiting toxicities (DLTs), pharmacokinetics, and anti‐tumor effect of irinotecan in pediatric patients with recurrent or refractory malignancies. Procedure Twenty‐three patients between 1 and 21 years of age, with a solid tumor refractory to standard therapy or for which there was no standard therapy were enrolled. Irinotecan was administered over 90 min weekly 4×, every 6 weeks. The initial dose level was 125 mg/m²/day, with subsequent escalations to 160 and 200 mg/m²/day. A MTD was defined in heavily‐pretreated and less‐heavily‐pretreated (≤2 prior chemotherapy regimens, no prior bone marrow transplantation, and no central axis radiation) patients. Pharmacokinetic studies were also performed. Results Neutropenia and diarrhea were the DLTs in heavily pretreated patients; the MTD was 125 mg/m²/day. Neutropenia was the DLT in less‐heavily pretreated; the MTD was 160 mg/m²/day. Five patients had stable disease for two to four cycles including one patient each with rhabdomyosarcoma, Ewing sarcoma, neuroblastoma, and two patients with ependymoma. Irinotecan clearance was greater that that previously reported for children receiving high dose irinotecan. Conclusions The recommended phase II dose of irinotecan administered weekly 4×, every 6 weeks in children with solid tumors is 125 mg/m²/dose for heavily pretreated patients and 160 mg/m²/dose for less heavily pretreated patients.