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Phase
I trial of temozolomide plus O6-benzylguanine in the treatment of
patients with recurrent or progressive cerebral anaplastic gliomas
J.
A. Quinn, J. Weingart, H. Brem, J. Rich, D. Reardon, J. Sampson, A. Friedman, H.
S. Friedman, O. M. Colvin, E. Dolan
and
Brain Tumor Center at Duke Sub-Sites; Duke Univ Medical Center, Durham, NC;
Johns Hopkins Hospital, Baltimore, MD; University of Chicago, Chicago, IL
The
major mechanism of resistance to alkylnitrosourea therapy involves the DNA
repair protein O6-alkylguanine-DNA alkyltransferase (AGT) which
removes chlorethylation or methylation damage from the O6-position of
guanine.
O6-benzylguanine (O6-BG) is an AGT substrate which
inhibits AGT by suicide inactivation.
We are conducting a phase I trial of temozolomide (Temodar) (T) plus O6-BG
to define the maximal tolerated dose (MTD) of T along with the toxicity and
activity of this drug combination in the treatment of adults with progressive or
recurrent, World Health Organization (WHO) grade 3 or greater astrocytoma,
oligodendroglioma, or mixed glial tumor.
Patients are treated with IV O6-BG and a 48-hour infusion of O6-BG.
Following demonstration of the dose of O6-BG (120 mg/m2
over 1 hour followed by the 48 hour infusion of 30 mg/m2/day) that
depletes tumor AGT levels, we started T at a single dose of 100 mg/m2
given at the end of the IV push of O6-BG.
T doses are escalated in cohorts of 3 - 6 patients.
Treatment cycles are repeated at 28-day intervals.
Radiographic response criteria were utilized to evaluate activity using
T1-weighted, enhanced MRI images.
Fifty-two patients have been treated to date, 36 with glioblastoma multiforme (GBM),
14 with anaplastic astrocytoma (AA) and 2 with anaplastic oligodendroglioma
(AO).
Seven patients received T at 100 mg/m2, 7 patients received 200 mg/m2,
6 patients received 267 mg/m2, 6 patients received 355 mg/m2,
7 patients received 472 mg/m2, 5 patients received 628 mg/m2,
and 14 patients received 500 mg/m2.
Dose-limiting toxicities observed thus far have been limited to five episodes of
grade 4 thrombocytopenia, 6 episodes of grade 4 leukopenia, and 10 episodes of
grade 4 neutropenia.
Stable disease has been observed in 17 patients.
One patient with AA who previously failed T has shown a complete response while
completing 12 cycles of this drug combination.
Although no one achieved a partial response, 5 patients demonstrated a near
partial response.
The MTD of this drug combination was found to be 472 mg/m2.
© Copyright 2003
American Society of Clinical Oncology All rights
reserved worldwide
Source: http://www.asco.org/ac/1,1003,_12-002489-00_18-002003-00_19-00101742-00_29-00A,00.asp?cat=CNS+Tumors&parent=
Central+Nervous+System+Tumors&returnpid=2325&SubCat_ID=4
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