Published in:
01-06-2004 | Original Article
Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101
Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2004
Login to get accessAbstract
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/m2 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/m2 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 m2 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/m2 per day for 4 days repeated every 3 weeks. The neurotoxicity observed at the 440 mg/m2 per day dose level suggests that patients receiving repetitive cycles must be monitored closely, as SU0020 may accumulate over time.