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Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101.

Abstract：

PURPOSE:To determine the maximum tolerated dose and the toxicity profile of the PDGF receptor pathway inhibitor SU101 in pediatric patients with refractory solid tumors, and to define the plasma pharmacokinetics of SU101 and its active metabolite SU0020 in children. EXPERIMENTAL DESIGN:Patients between 3 and 21 years of age with CNS malignancy, neuroblastoma, or sarcoma refractory to standard therapy were eligible. The starting dose of SU101 was 230 mg/m(2) per day administered as a 96-h continuous infusion every 21 days. Blood for pharmacokinetic analysis was obtained during the first cycle. RESULTS:Entered into the trial were 27 patients, and 24 were fully evaluable for toxicity. Dose-limiting central nervous system toxicity was observed in two patients at the 440 mg/m(2) per day dose level. Non-dose-limiting toxicities included nausea, vomiting, headache, fatigue, abdominal discomfort, diarrhea, pruritus, anorexia, constipation, and paresthesias. There were no complete or partial responses. One patient with rapidly progressive desmoplastic small round-cell tumor experienced symptomatic improvement and prolonged stable disease. Steady-state concentrations of SU101 were rapidly achieved and proportional to dose. The concentration of SU0020 was 100- to 1000-fold greater than that of SU101. The median clearance of SU0020 was 0.19 l/day per m(2) and its terminal elimination half-life was 14 days. CONCLUSIONS:SU101 administered on this schedule was generally well tolerated. The maximum tolerated dose of SU101 is 390 mg/m(2) per day for 4 days repeated every 3 weeks. The neurotoxicity observed at the 440 mg/m(2) per day dose level suggests that patients receiving repetitive cycles must be monitored closely, as SU0020 may accumulate over time.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Adamson PC,Blaney SM,Widemann BC,Kitchen B,Murphy RF,Hannah AL,Cropp GF,Patel M,Gillespie AF,Whitcomb PG,Balis FM

doi

10.1007/s00280-004-0769-2

keywords:

subject

Has Abstract

pub_date

2004-06-01 00:00:00

pages

482-8

issue

eissn

0344-5704

issn

1432-0843

journal_volume

pub_type

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Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101.