Phase I study of temozolomide in children and adolescents with recurrent solid tumors: A report from the children's cancer group

Purpose: The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). Patients and Methods: Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m² daily. Results: Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m² daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m² daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m² daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m² daily and in two of four patients (50%) at 215 mg/m² daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. Conclusion: The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m² daily and for those with prior CSI is 180 mg/m² daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.