Efficacy of nitrosoureas is limited by host repair of drug‐induced alkylation. O⁶‐benzylguanine (O⁶‐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 O⁶‐BG.

O⁶‐BG (120 mg/m² 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 1 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).

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 O⁶‐BG (120 mg/m² IV) was 58 mg/m² 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.

Based on lack of activity of this combination in adult phase II studies, no further testing of O⁶‐BG plus BCNU in children is planned. Strategies to decrease hematopoeitic toxicity of BCNU plus O⁶‐BG are required. Pediatr Blood Cancer 2008;50:549–553. © 2007 Wiley‐Liss, Inc.