Pediatrie Phase I Trial and Pharmacokinetic Study of Topotecan Administered as a 24-Hour Continuous Infusion1

Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatrie patients with refractory malignancies. A phase I and pharmacokinetic study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities, the incidence and severity of other toxicities, and the pharmacokinetics of topotecan in children. Twenty-nine patients received 42 courses of i.v. topotecan administered as a 24-h continuous infusion every 21 days at doses ranging from 2.0 to 7.5 mg/m2. Doserelated hematological toxicity was the dose-limiting toxicity. Leukopenia, neutropenia, and thrombocytopenia occurred sporadically at the 3.0to 5.5-mg/m2 dose levels, but at 7.5 mg/m2 4 of 5 patients experienced doselimiting thrombocytopenia (grade 4) and 2 of 5 had dose-limiting neutro penia (grade 4). No other dose-limiting toxicities were observed. Nausea and vomiting were mild and occurred in 20 and 10% of patients, re spectively. Grade 2 hematuria occurred in one patient. No objective re sponses were observed. Pharmacokinetic studies revealed a linear rela tionship between the steady-state topotecan concentration and dose. The mean steady-state concentration at the MTD was 18.2 ±3.7 nmol/liter and the total body clearance was 28.3 ±6.5 liters/h/m2. Elimination was biexponential with a t,a of 14.4 ±1.8 min and a I, ./i of 2.9 ±1.1 h. The recommended starting dose for phase II pediatrie trials is 5.5 mg/m2. Although this dose exceeds the MTD identified in heavily pretreated adult patients receiving topotecan on the same schedule, it is less than the MTD for minimally pretreated adult patients. Therefore, dose escalation to 7.5 mg/m2 in phase II pediatrie trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.