Phase 1 trial of O6-benzylguanine and BCNU in children with CNS tumors:: A children's oncology group study

Background. Efficacy of nitrosoureas is limited by host repair of drug-induced alkylation. O-6-benzylguanine (O-6-BG), an inhibitor of host alkylation repair, and BCNU were Studied in children with refractory/untreatable central nervous system tumors to determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of BCNU administered following O-6-BG. Procedure. O-6-BG (120 mg/m(2) IV over 1 hr) was followed by BCNU (IV over 1 hr). Cohorts of three to six patients were treated with escalating doses of BCNU. Courses were repeated every 6 weeks. Patients in Stage I were accrued irrespective of prior treatment. Once the MTD was exceeded, Stage II accrual was limited to less heavily pretreated patients (<= two prior chemotherapy regimens, no prior central axis radiation, no prior bone marrow transplant, and no bone marrow involvement). Results. Twelve patients in Stage I and 13 in Stage II (less heavily pretreated patients only) were evaluable for toxicity. The MTD of BCNU administered with O-6-BG (120 mg/m(2) IV) was 58 mg/m(2) in less-heavily pretreated patients. Myelosuppression, which was cumulative in some patients receiving multiple cycles of therapy, was the predominate DLT. Twenty-four patients were evaluable for response: after two Courses of therapy, 6 had stable disease, 17 had progressive disease, and 1 patient had a minor response but progressed after four Courses of therapy. Conclusions. Based on lack of activity of this combination in adult phase II studies, no further testing of O-6-BG plus BCNU in children is planned. Strategies to decrease hematopoeitic toxicity of BCNU Plus O-6-BG are required.