Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia

Purpose: To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia. Patients and Methods: Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (C-ss). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan, A two-compartment model was fit to the data using a Bayesian algorithm, C-ss was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course. Results: Thirteen bays and five girls each received 23 courses of topotecan, Target C-ss ranged From 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m(2)/d), Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL, A significant relation between topotecan lactone C-ss and the severity of mucositis was observed, Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted. Conclusion: The MTSE for continuous infusion topotecan was 4.0 ng/ml. Responses were noted at C-ss comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model, Further studies of topotecan are warranted. (C) 1996 by American Society of Clinical Oncology.