Phase I trial of rebeccamycin analog (NSC #655649) in children with refractory solid tumors: A Pediatric Oncology Group study

Anne Marie Langevin, Steven D. Weitman, John G. Kuhn, Susan T. Weintraub, Sylvain Baruchel, Wayne Furman, Mark Bernstein, Susan Blaney, Teresa Vietti

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Purpose: To conduct a phase 1 trial of rebeccamycin analog (NSC #655649) in children with solid tumors to establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); to establish the pharmacokinetic profile in children, and to document any evidence of antitumor activity. Methods: A 1-hour infusion of NSC #655649 was administered every 21 days to 17 patients younger than 21 years who had malignant tumors refractory to conventional therapy. Doses ranged from 450 mg/m2 to 760 mg/m2. Pharmacokinetics were done in at least three patients per dose level. The first course was used to determine DLT and MTD. Results: Sixteen patients on three dose levels were assessable for toxicities. At 760 mg/m2, four patients had dose-limiting neutropenia and thrombocytopenia. Pharmacokinetics were assessable in 13 patients. Plasma concentrations declined triexponentially and concentrations above the range of in vitro antitumor activity were maintained for 3 days. Analysis of urine extracts revealed the presence of an N-de-ethylated metabolite and probable involvement of cytochrome P450 isoenzyme(s) in the metabolism of NSC #655649. Pharmacodynamic studies showed a relationship between the area under the curve and percentage change in absolute neutrophil count in the Emax model (r2 = 0.56, P = 0.001). Conclusions: The recommended phase 2 dose of NSC #655649 administered as a 1-hour infusion every 21 days to children with solid tumors is 585 mg/m2. Both neutropenia and thrombocytopenia were found to be dose-limiting toxicities.

Original languageEnglish (US)
Pages (from-to)526-533
Number of pages8
JournalJournal of Pediatric Hematology/Oncology
Volume25
Issue number7
DOIs
StatePublished - Jul 1 2003

Keywords

  • Pediatric
  • Phase I trial
  • Rebeccamycin analog

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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