Phase I study of topotecan administered as a 21-day continuous infusion in children with recurrent solid tumors: A report from the children's cancer group

The purpose of this study was to determine the toxicity, maximum tolerated dose, and pharmacokinetics of a 21-day continuous infusion of topotecan in children with relapsed solid tumors. Fifteen patients received 40 courses of continuous ambulatory infusions of topotecan every 28 days or when there was resolution of hematological toxicity and any grade 2 or greater nonhematological toxicity. The starting dose was 0.4 mg/m²/day. Total topotecan levels were measured on days 1, 7, 14, and 21. Three of four patients who received a starting dose of 0.4 mg/m²/day experienced dose- limiting myelosuppression. At the reduced dose of 0.3 mg/m²/day, only two of the seven patients experienced dose-limiting myelosuppression. Subsequently, four patients with more limited prior therapy were treated with 0.4 mg/m²/day; three had dose-limiting myelosuppression. Two patients with a dose-limiting toxicity at 0.4 mg/m²/day tolerated additional courses at 0.3 mg/m²/day. An equal number of patients had grade 4 neutropenia or thrombocytopenia. Other adverse events were rare. Two patients with ependymoma, one with rhabdomyosarcoma, and one with retinoblastoma metastatic to the brain had objective responses. The steady state plasma concentration and clearance of topotecan (Css) was achieved by day 1. Css in six patients with complete data were 1.44 ± 0.50 and 2.13 ± 0.83 ng/ml at 0.3 and 0.4 mg/m²/day, respectively. Thus, a 21-day topotecan infusion was well- tolerated at 0.3 mg/m²/day. Myelosuppression was the dose-limiting toxicity at 0.4 mg/m²/day. The steady state and clearance of topotecan in this study are similar to those reported in adult patients.