Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors

Purpose: We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd x 5 x 2) in pediatric patients with refractory solid tumors. Patients and Methods: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m²/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only. Results: Dose-limiting toxicity occurred at 2.3 mg/m²/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m²/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m²/d; the mean (± standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 ± 8.4 ng/mL·h. The population mean (± standard error) oral bioavailability of the injectable formulation was 0.27 ± 0.03; that of capsules was 0.36 ± 0.06 (P = .16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months. Conclusion: Oral topotecan (1.8 mg/m²/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.