title: A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study.
abstract: To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide(®) (TMZ). Patients received O6BG 120 mg/m(2)/d IV followed by TMZ 75 mg/m(2)/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed. Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas. The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA. warrenk@mail.nih.gov
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Warren
authors.forename: Sri
authors.initials: S
authors.lastname: Gururangan
authors.forename: J Russell
authors.initials: JR
authors.lastname: Geyer
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Tina Young
authors.initials: TY
authors.lastname: Poussaint
authors.forename: Dana
authors.initials: D
authors.lastname: Wallace
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Berg
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Jane E
authors.initials: JE
authors.lastname: Minturn
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.forename: Larry E
authors.initials: LE
authors.lastname: Kun
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D025521:Tumor Suppressor Proteins; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide