Phase I clinical and pharmacokinetic study of flavopiridol in children with refractory solid tumors: a Children's Oncology Group Study.
OBJECTIVE
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.


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 micromol/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).


CONCLUSIONS
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.
Whitlock
James A
JA
Vanderbilt Children's Hospital, Pediatric Hematology/Oncology, Nashville TN 37232-6310, USA. jim.whitlock@vanderbilt.edu
Krailo
Mark
M
Reid
Joel M
JM
Ruben
Stacie L
SL
Ames
Matthew M
MM
Owen
William
W
Reaman
Gregory
G
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005419:Flavonoids / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D010880:Piperidines / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib