Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid tumors

Purpose: To determine the maximum tolerated dose, toxicity, and pharmacokinetics of gemcitabine in children with refractory solid tumors. Patients and Methods: Gemcitabine was given as a 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks, to 42 patients aged 1 to 21 years. Doses of 1,000, 1,200 and 1,500 mg/m² were administered for 3 weeks. Subsequently, gemcitabine was given for only 2 consecutive weeks at 1,500, 1,800, and 2,100 mg/m². Plasma concentrations of gemcitabine and its metabolite, 2′2′-difluorodeoxyuridine, were measured in 28 patients. Results: Forty patients who received 132 courses of gemcitabine were assessable for toxicity. The maximum tolerated dose of gemcitabine given weekly for 3 weeks was 1,200 mg/m². Dose-limiting toxicity was not seen in one-third of children treated at any doses given for 2 weeks. The major toxicity was myelosuppression in three of five patients at 1,500 mg/m² for 3 weeks, and one of seven patients at 1,800 mg/m² for 2 weeks. Other serious adverse events were somnolence, fever and hypotension, and rash in three patients. Gemcitabine plasma concentration-time data were fit to a one- (n = 5) or two-compartment (n = 23) open model. Mean gemcitabine clearance and half-life values were 2,140 mL/min/m² and 13.7 minutes, respectively. One patient with pancreatic cancer had a partial response. Seven patients had stable disease for 2 to 17 months. Conclusion: Gemcitabine given by 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks was tolerated well by children at doses of 2,100 mg/m² and 1,200 mg/m², respectively.