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.


METHODS
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.
Adams
Denise M
DM
Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. Denise.Adams@cchmc.org
Zhou
Tianni
T
Berg
Stacey L
SL
Bernstein
Mark
M
Neville
Kathleen
K
Blaney
Susan M
SM
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D016879:Salvage Therapy
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine