Phase I trial of paclitaxel in children with refractory solid tumors: a Pediatric Oncology Group Study.
OBJECTIVE
A phase I study was performed to describe the principal toxicities and identify the maximum-tolerated dose (MTD) of Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in children with therapy-resistant solid tumors. Additionally, the pharmacokinetic disposition of Taxol in children was studied, and preliminary evidence of the activity of Taxol against pediatric solid tumors was assessed.


METHODS
Twenty-four-hour continuous infusions of Taxol were administered every 21 days to children (median age, 12 years; range, 2 to 22) with refractory solid tumors. Doses ranged from 200 to 420 mg/m2, there was no intrapatient dose escalation.


RESULTS
A total of 62 courses of Taxol were administered to 31 patients. Two patients developed acute anaphylaxis during their second infusion of taxol at doses of 200 mg/m2 and 350 mg/m2, respectively. No other allergic reactions were documented. Myelosuppression occurred at all dose levels, but was of short duration (< or = 7 days) and did not appear to increase with consecutive courses or at higher dosage levels. A stocking-and-glove peripheral neuropathy became evident at doses > or = 290 mg/m2. Dose-limiting neurotoxicity occurred at 420 mg/m2 and comprised a significant fine-motor and peripheral neuropathy in one patient, and a tonic-clonic seizure in another. End-of-infusion plasma concentrations ranged from 0.40 to 6.4 mumol/L, and were not found to be dose-dependent over the range of doses studied. A complete response was documented in one patient, partial response in two, and minimal response in one for an overall response rate of 13%.


CONCLUSIONS
Neurotoxicity was dose-limiting when Taxol was administered by 24-hour continuous infusion to pediatric patients with relapsed solid tumors. In this population, the recommended dose for phase II trials is 350 mg/m2/d.
Hurwitz
C A
CA
Department of Hematology/Oncology, St Jude Children's Research Hospital, Memphis, TN.
Relling
M V
MV
Weitman
S D
SD
Ravindranath
Y
Y
Vietti
T J
TJ
Strother
D R
DR
Ragab
A H
AH
Pratt
C B
CB
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D017239:Paclitaxel