Phase I study of temozolomide combined with oral etoposide in children with malignant glial tumors

The treatment of children with malignant glioma remains challenging. The aim of this multicenter phase I study is to establish the recommended dose (RD) of the combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with relapsed or refractory malignant glioma and brainstem glioma at diagnosis. A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by a classical 3 + 3 design. Cohorts of patients were enrolled at 4 different levels: (1) TMZ 120 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (2) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (3) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–10; (4) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–12. Therapy was administered in 28-day courses. A total of 118 courses were administered to 18 patients with a median age of 11.2 years. At dose level 1, none displayed toxicity. Of the 6 patients at dose level 2, 1 patient had dose limiting toxicity (DLT). None of the 3 patients at dose level 3 had DLT. At dose level 4, grade III/IV thrombocytopenia and neutropenia were observed in 2 out of the 6 patients enrolled. Therefore, the MTD was established at dose level 3. The RD for phase II trial in children with malignant glial is TMZ 150 mg/m² for 5 days and VP-16 50 mg/m² for 10 days every 28 days.