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Phase 1 study of 28-day, low-dose temozolomide
and BCNU in the treatment of malignant gliomas after radiation therapy
Jeffrey J. Raizer, Mark G. Malkin, Martin Kleber, Lauren E. Abrey
Neurology Department,
Northwestern Memorial Hospital, Chicago, IL 60611 (J.J.R.); Medical College of
Wisconsin, Milwaukee, WI 53226 (M.G.M), Memorial Sloan-Kettering Cancer Center,
New York, NY 10021 (M.K., L.E.A); USA
We conducted a study to determine the dose-limiting toxicity of an extended
dosing schedule of temozolomide (TMZ) when used with a fixed dose of BCNU, or
1,3bis(2-chloroethyl)-1-nitrosourea (carmustine), taking advantage of TMZ's
ability to deplete O6-alkylguanineDNA-alkyltransferase and the
synergistic activity of these two agents.
Patients with malignant gliomas who had undergone radiation therapy were
eligible.
Patients were treated with TMZ for 28 days, followed by a 28-day rest (1
cycle).
The TMZ was started at 50 mg/m2 and increased in 10-mg/m2
increments; a fixed dose of BCNU (150 mg/m2) was given within 72 h of
starting TMZ.
A standard phase 1 dose-escalation scheme was used with 3 patients per
cohort.
Fourteen glioblastoma patients and 10 anaplastic astrocytoma patients were
treated.
The dose-limiting toxicity was myelosuppression at 90 mg/m2 of
TMZ.
The total number of cycles given was 73 (median number was 2).
Six patients (25%) required a dose reduction in BCNU, and six were removed from
study for hematologic toxicity after cycle 1; three patients overlapped.
The median time to progression and overall survival were, respectively, 82 and
132 weeks for anaplastic astrocytomas and 14 and 69 weeks for
glioblastomas.
We conclude that the combination of BCNU and the extended dosing schedule of TMZ
is feasible and that the maximal tolerated dose of a 28-day course of TMZ is 80
mg/m2 when combined with a fixed dose of BCNU at 150 mg/m2.
This is the recommended dose for phase 2, but myelosuppression after cycle 1
suggests that long-term treatment may be difficult.
© 2004 Duke University Press
Source: http://ninetta.ingentaselect.com/vl=5034652/cl=43/nw=1/rpsv/cgi-bin/linker?ini=dup_no&reqidx=/cw/dup/15228517/v6n3/s8/p247
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