Phase I study of O6-benzylguanine and temozolomide administered daily for 5 days to pediatric patients with solid tumors.
OBJECTIVE
This pediatric phase I trial of O6-benzylguanine (O6BG) and temozolomide (TMZ) on a daily schedule for 5 days, every 28 days was performed to determine the maximum-tolerated dose of TMZ when given with a biologically active dose of O6BG and to define the toxicity profile of the combination in children with solid tumors.


METHODS
Patients < or = 21 years old with refractory solid tumors were eligible. O6BG was administered intravenously over 60 minutes daily for 5 days. TMZ was administered orally 30 minutes after completion of each O6BG infusion. Starting doses of O6BG and TMZ were 60 mg/m2/d and 28 mg/m2/d, respectively. O6BG was escalated to 90 and 120 mg/m2/d; TMZ was subsequently escalated to 40, 55, 75, and 100 mg/m2/d. Cycles were repeated every 28 days.


RESULTS
Forty-one patients were enrolled; 32 patients were assessable for toxicity. The combination of O6BG and TMZ was tolerable at TMZ doses less than half of the conventional dose of 200 mg/m2/d. Myelosuppression occurred sporadically at all dose levels and was the dose-limiting toxicity (DLT) at 100 mg/m2/d of TMZ combined with 120 mg/m2/d O6BG. Nonhematologic toxicities were generally mild. Evidence of antitumor activity was observed at 120 mg/m2/d O6BG combined with TMZ doses of 55 mg/m2/d and above.


CONCLUSIONS
The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.
Warren
Katherine E
KE
National Cancer Institute Neuro-Oncology Branch, Building 82, Room 219, 9030 Old Georgetown Rd, Bethesda, MD 20892-8200, USA. warrenk@mail.nih.gov
Aikin
Alberta A
AA
Libucha
Madeleine
M
Widemann
Brigitte C
BC
Fox
Elizabeth
E
Packer
Roger J
RJ
Balis
Frank M
FM
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D000077204:Temozolomide
C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D000077204:Temozolomide