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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 4x, every 6 weeks. The initial dose level was 125 mg/m(2)/day, with subsequent escalations to 160 and 200 mg/m(2)/day. A MTD was defined in heavily-pretreated and less-heavily-pretreated (< or =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/m(2)/day. Neutropenia was the DLT in less-heavily pretreated; the MTD was 160 mg/m(2)/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 4x, every 6 weeks in children with solid tumors is 125 mg/m(2)/dose for heavily pretreated patients and 160 mg/m(2)/dose for less heavily pretreated patients.

Purpose: Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer., Methods: PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m2. Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection., Results: PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55+/-18 min at the 1.8 g/m2 dose and 77+/-22 min at the 2.5 g/m2 dose. The half-life of PAG was 112+/-53 min at the 1.8 g/m2 dose and 135+/-75 min at the 2.5 g/m2 dose. The clearance of PAA was 66+/-33 ml/min per m2 at the 1.8 g/m2 dose and 60+/-24 ml/min per m2 at the 2.5 g/m2 dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (Vm and Km) were (means+/-SD) 18.4+/-13.8 mg/m2 per min and 152+/-155 microg/ml, respectively. The volumes of distribution for PAA and PAG (V(d-PAA) and V(d-PAG)) were 7.9+/-3.4 l/m2 and 34.4+/-16.1 l/m2, respectively. The first-order elimination rate constant for PAG (k(e-PAG)) was 0.0091+/-0.0039 min(-1)., Conclusions: The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.