Phase I study of topotecan administered as a 21-day continuous infusion inchildren 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 o f continuous ambulatory infusions of topotecan every 28 days or when there was resolution of hematological toxicity and any grade 2 or greater nonhema tological toxicity, The starting dose was 0.4 mg/m(2)/day. Total topotecan levels were measured on days 1, 7, 14, and 21, Three of four patients who r eceived a starting dose of 0.4 mg/m(2)/day experienced dose-limiting myelos uppression. At the reduced dose of 0.3 mg/m(2)/day, only two of the seven p atients experienced dose-limiting myelosuppression. Subsequently, four pati ents with more limited prior therapy were treated with 0.4 mg/m(2)/day; thr ee had dose-limiting myelosuppression, Two patients with a dose-limiting to xicity at 0.4 mg/m(2)/day tolerated additional courses at 0.3 mg/m(2)/day. An equal number of patients had grade 4 neutropenia or thrombocytopenia, Ot her adverse events were rare, Two patients with ependymoma, one with rhabdo myosarcoma, and one with retinoblastoma metastatic to the brain had objecti ve responses. The steady state plasma concentration and clearance of topote can (Css) was achieved by day 1, Css in six patients dth complete data were 1.44 +/- 0.50 and 2.13 +/- 0.83 ng/ml at 0.3 and 0.4 mg/m(2)/day, respecti vely. Thus, a 21-day topotecan infusion was well-tolerated at 0.3 mg/m(2)/d ay. Myelosuppression was the dose-limiting toxicity at 0.4 mg/m(2)/day. The steady state and clearance of topotecan in this study are similar to those reported in adult patients.