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Phase I Clinical and Pharmacokinetic Study of Flavopiridol in Children With Refractory Solid Tumors: A Children's Oncology Group Study

From the Vanderbilt Children's Hospital, Nashville, TN; University of Southern California Keck School of Medicine, Los Angeles; Children's Oncology Group, Arcadia, CA; Mayo Clinic and Foundation, Rochester, MN; Children's Hospital–King's Daughters, Norfolk, VA; Children's National Medical Center, Washington, DC

Address reprint requests to James Whitlock, MD, Vanderbilt Children's Hospital, Pediatric Hematology/Oncology, 2220 Pierce Ave, Room 397 PRB, Nashville TN 37232-6310; e-mail: jim.whitlock{at}vanderbilt.edu; CC: pubs{at}childrensoncologygroup.org

PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors.

PATIENTS AND METHODS: Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m²/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3.

RESULTS: Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m²/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m²/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 µmol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m² to 80 mg/m², respectively. The median flavopiridol plasma clearance was 8.0 L/h/m² (range, 2.6 to 17.1 L/h/m²).

CONCLUSION: The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m²/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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