Phase I Study of Oral Cyclophosphamide and Oral Topotecan for Children with Recurrent or Refractory Solid Tumors

Background. To determine the maximum-tolerated duration and dose-limiting toxicity of a daily schedule of orally administered cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. Methods. Patients received oral cyclophosphamide (50 mg/m ²/dose) in the morning followed by topotecan (0.8 mg/m ²/dose) 8-12 hr later for an escalating number of consecutive days (10, 14, and 17 days). Results. Seventeen pediatric patients were treated with oral cyclophosphamide and topotecan for durations of 10-17 days for a total of 58 treatment courses. Reversible hematologic toxicity (neutropenia and thrombocytopenia) was the dose-limiting toxicity. Nonhematologic toxicities of greater than grade 3 were not observed. A partial response (neuroblastoma following myeloablative chemotherapy and stem cell rescue) and prolonged stable disease (medulloblastoma) were each observed in one patient. Conclusions. The recommended duration of therapy with a daily schedule of both oral cyclophosphamide (50 mg/m²/day) and topotecan (0.8 mg/m ²/day) for previously treated pediatric patients with recurrent or refractory solid tumors is 14 consecutive days. The observed dose limiting toxicity (DLT) was reversible neutropenia. This regimen was well tolerated in heavily pretreated patients and demonstrated activity against recurrent pediatric solid tumors.