Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: A pediatric oncology group study

Purpose: A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. Patients and Methods: A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 μg/m² per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. Results: Nineteen patients on four dose levels were assessable for toxicities. At 62 μg/m² per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% ± 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 ± 3.8 and 7.1 ± 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 ± 13.3 L/m² and 135.3 ± 52.5 L/m², respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. Conclusion: The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 μg/m² per hour. Neutropenia and thrombocytopenia were dose limiting.