Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatric 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. Dose-related hematological toxicity was the dose-limiting toxicity. Leukopenia, neutropenia, and thrombocytopenia occurred sporadically at the 3.0- to 5.5-mg/m2 dose levels, but at 7.5 mg/m2 4 of 5 patients experienced dose-limiting thrombocytopenia (grade 4) and 2 of 5 had dose-limiting neutropenia (grade 4). No other dose-limiting toxicities were observed. Nausea and vomiting were mild and occurred in <20 and 10% of patients, respectively. Grade 2 hematuria occurred in one patient. No objective responses were observed. Pharmacokinetic studies revealed a linear relationship 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 t½α of 14.4 ± 1.8 min and a t½β of 2.9 ± 1.1 h. The recommended starting dose for phase II pediatric 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 pediatric trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.
↵1 Portions of the work reported here were supported by Grant CA13539 to The Childrens Cancer Group from the Cancer Therapeutics Evaluation Program-Division of Cancer Treatment/NCI, USPHS.
↵2 To whom requests for reprints should be addressed, at Pediatric Branch, National Cancer Institute, Building 10 Room 13N240, 9000 Rockville Pike, Bethesda, Maryland 20892.
- Received July 3, 1992.
- Accepted December 22, 1992.
- ©1993 American Association for Cancer Research.