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

Anne Marie Langevin, Daniel T. Casto, Paul J. Thomas, Steven D. Weitman, Cynthia Kretschmar, Holcombe Grier, Charles Pratt, Ronald Dubowy, Mark Bernstein, Susan Blaney, Teresa Vietti

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2494-2499
Number of pages6
JournalJournal of Clinical Oncology
Volume16
Issue number7
DOIs
Publication statusPublished - Jul 1998

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Langevin, A. M., Casto, D. T., Thomas, P. J., Weitman, S. D., Kretschmar, C., Grier, H., ... Vietti, T. (1998). Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: A pediatric oncology group study. Journal of Clinical Oncology, 16(7), 2494-2499. https://doi.org/10.1200/JCO.1998.16.7.2494