Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.
OBJECTIVE
We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG.


METHODS
For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined.


RESULTS
The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression.


CONCLUSIONS
This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.
Quinn
Jennifer A
JA
Department of Surgery, Duke University Medical Center, Durham, NC, USA. quinn008@mc.duke.edu
Desjardins
Annick
A
Weingart
Jon
J
Brem
Henry
H
Dolan
M Eileen
ME
Delaney
Shannon M
SM
Vredenburgh
James
J
Rich
Jeremy
J
Friedman
Allan H
AH
Reardon
David A
DA
Sampson
John H
JH
Pegg
Anthony E
AE
Moschel
Robert C
RC
Birch
Robert
R
McLendon
Roger E
RE
Provenzale
James M
JM
Gururangan
Sridharan
S
Dancey
Janet E
JE
Maxwell
Jill
J
Tourt-Uhlig
Sandra
S
Herndon
James E
JE
Bigner
Darell D
DD
Friedman
Henry S
HS
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D018450:Disease Progression; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000077204:Temozolomide
C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D000077204:Temozolomide