Phase I trial and pharmacological study of a 3-hour paclitaxel infusion inchildren with refractory solid tumours: a SFOP study

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antit umour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and th e pharmacokinetics of paclitaxel in children when administered in 3-h infus ion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied stand ard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmaco kinetic analysis and solvent assays (ethanol, cremophor) were performed dur ing the first course. 20 courses were studied in 17 patients; 4 dosage leve ls were investigated (240 to 420 mg/m(2)). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion a t the highest dosage, Delayed peripheral neurotoxicity and moderate allergi c reactions were also encountered. Pharmacokinetic analysis showed dose-dep endent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurol ogical toxicity. (C) 2001 Cancer Research Campaign.