Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.

Carlos Rodriguez-Galindo, Kristine R. Crews, Clinton F. Stewart, Wayne Furman, J. Carl Panetta, Najat C. Daw, Alvida Cain, Ming Tan, Peter H. Houghton, Victor M. Santana

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

PURPOSE: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. METHODS: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. RESULTS: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n = 3) and 9 (level -2; n = 3) mg/m2/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n = 2). DLTs were neutropenia (n = 8), typhlitis (n = 5), and skin rash (n = 1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m2 and 27.6 (14.7-55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. CONCLUSION: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.

Original languageEnglish (US)
Pages (from-to)15-24
Number of pages10
JournalCancer chemotherapy and pharmacology
Volume57
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Rodriguez-Galindo, C., Crews, K. R., Stewart, C. F., Furman, W., Panetta, J. C., Daw, N. C., Cain, A., Tan, M., Houghton, P. H., & Santana, V. M. (2006). Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors. Cancer chemotherapy and pharmacology, 57(1), 15-24. https://doi.org/10.1007/s00280-005-0030-7