A phase I study was performed to determine the maximum tolerated dose and the recommended dose of continuous intravenous infusion of topotecan in combination with radiotherapy (RT) in patients with previously untreated glioblastoma multiforme (GBM). Twenty patients with histologically proven GBM and 1 with rhabdoid tumor were enrolled. After surgery or stereotactic biopsy, patients received cranial RT (60 Gy/30 fractions/40 days) and 3 cycles of topotecan as continuous infusion (CIV) from day 1 to 5 on weeks 1, 3, and 5 during RT. The dose of topotecan was escalated from 0.6 to 1.0 mg/m2/day. Four dose levels were tested. One grade 4 thrombocytopenia was seen at level 1 (topotecan dose 0.6 mg/m2/day; 6 patients). No dose-limiting toxicity was seen at level 2 (0.8 mg/m2/day; 3 patients) or an intermediate level of 2 bis (0.9 mg/m2/day; 6 patients). Six patients were included at level 3 (1.0 mg/m2/day), 4 of whom experienced dose-limiting toxicities, including 3 episodes of grade 4 thrombocytopenia, 1 platelet transfusion, 1 febrile neutropenia, and 1 grade 4 neutropenia of more than 7 days. Eighty percent of patients with GBM were alive at 12 months. The dose-limiting toxicity of topotecan administered as CIV for 5 days every 2 weeks is hematological. The maximum tolerated dose is 1.0 mg/m2/day and the recommended dose is 0.9 mg/m2/day. A phase II trial using the recommended dose of topotecan is ongoing.