Phase 1 trial of O6-benzylguanine and BCNU in children with CNS tumors: a Children's Oncology Group study

Pediatr Blood Cancer. 2008 Mar;50(3):549-53. doi: 10.1002/pbc.21362.


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 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).

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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / adverse effects
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bone Marrow Diseases / chemically induced
  • Carmustine / administration & dosage
  • Carmustine / adverse effects
  • Carmustine / pharmacology*
  • Central Nervous System Neoplasms / drug therapy*
  • Central Nervous System Neoplasms / therapy
  • Child
  • Child, Preschool
  • Cohort Studies
  • Combined Modality Therapy
  • DNA Repair / drug effects
  • DNA, Neoplasm / drug effects
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Guanine / administration & dosage
  • Guanine / adverse effects
  • Guanine / analogs & derivatives*
  • Guanine / pharmacology
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Neoplasm Proteins / antagonists & inhibitors*
  • O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors*
  • Salvage Therapy


  • Antineoplastic Agents, Alkylating
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • O(6)-benzylguanine
  • Guanine
  • O(6)-Methylguanine-DNA Methyltransferase
  • Carmustine