PHASE-I STUDY OF TOPOTECAN IN COMBINATION WITH CYCLOPHOSPHAMIDE IN PEDIATRIC-PATIENTS WITH MALIGNANT SOLID TUMORS - A PEDIATRIC-ONCOLOGY-GROUP STUDY

Purpose: To determine the maximum-tolerated dose (MTD) and dose-limiti ng toxicity of topotecan when combined with cyclophosphamide in pediat ric patients with recurrent or refractory malignant solid tumors. Pati ents and Methods: A total of 33 patients received cyclophosphamide (25 0 mg/m(2)/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m(2)/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these p atients. Results: Neutropenia was the dose-limiting toxicity of the th erapy at both topotecan dose levels. The addition of filgrastim allowe d escalation of the topotecan dose to the 0.75-mg/m(2) level with acce ptable neutropenia. Other significant toxicities were anemia and throm bocytopenia. Nonhematopoietic toxicity of grades greater than or equal to 3 was not observed. Responses were reported in patients with Wilms ' tumor (one complete response [CR], one partial response [PR]), neuro blastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide admi nistered on the schedule used in this study did not alter topotecan di sposition on day 5. As with previous studies, a pharmacodynamic relati on between systemic exposure and myelosuppression was noted. Conclusio n: The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with accept able hematopoietic toxicity with the use of filgrastim support. We rec ommend that pediatric phase II trials use cyclophosphamide 250 mg/m(2) followed by topotecan 0.75 mg/m(2) daily for 5 days with filgrastim f or amelioration of neutropenia. (C) 1998 by American Society of Clinic al Oncology.