RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing
so they stop growing or die. Combining more than one drug may kill more tumor cells.
PURPOSE: Phase I trial to study the effectiveness of combining temozolomide and
O6-benzylguanine in treating patients who have newly diagnosed, recurrent, or progressive
- Determine the dose of O6-benzylguanine (O6-BG) effective in producing complete
suppression of tumor O6-alkylguanine-DNA alkyltransferase activity in patients with
newly diagnosed (closed to accrual 12/19/2000) or recurrent or progressive cerebral
- Determine the maximum tolerated dose of temozolomide administered after O6-BG in these
- Determine the toxicity of this regimen in these patients.
- Determine the anti-tumor response in patients treated with this regimen.
OUTLINE: This is a dose-escalation, multicenter study.
- Part I: Patients receive escalating doses of O6-benzylguanine (O6-BG) IV continuously
for 49 hours until the dose that produces the target depletion of tumor
O6-alkylguanine-DNA alkyltransferase (AGT) is determined. Patients undergo a craniotomy
after completion of the O6-BG infusion. (closed to accrual 12/19/2000)
- Part II: After determination of the O6-BG dose in Part I, patients with recurrent
malignant gliomas receive O6-BG IV continuously for 49 hours beginning on day 1.
Patients also receive oral temozolomide on day 1. Treatment repeats every 28 days in
the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of temozolomide until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose at which no more than 1 of 6
patients experiences dose-limiting toxicity.
PROJECTED ACCRUAL: Approximately 20-30 patients (with 14 patients participating in Part II)
will be accrued for this study.
- Part I:
- Histologically confirmed, newly diagnosed glioblastoma multiforme or anaplastic
astrocytoma (closed to accrual 12/19/2000)
- Parts I and II:
- Histologically confirmed astrocytic, oligodendroglial, or mixed glial tumor
- Grade III or higher
- Recurrent or progressive after radiotherapy
- Evaluable residual disease by contrast-enhanced MRI or CT scan
- 18 and over
- Karnofsky 60-100%
- Not specified
- Granulocyte count at least 1,500/mm3
- Platelet count at least 100,000/mm3
- SGOT no greater than 2.5 times upper limit of normal
- Bilirubin normal
- Creatinine no greater than 1.5 mg/dL OR
- Creatinine clearance greater than 60 mL/min
- BUN no greater than 25 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 2 months after study
PRIOR CONCURRENT THERAPY:
- At least 6 weeks since prior biologic therapy and recovered
- At least 2 weeks since prior chemotherapy (including but not limited to topotecan)
- Patients in trials with one of the following treatment combinations are allowed
to enroll 6 weeks after receiving carmustine (BCNU):
- BCNU on day 1
- BCNU on day 1 and topotecan on days 1, 8, 15, 22, 29, and 36
- BCNU on day 1 and irinotecan on days 1, 8, 15, and 22
- Patients on corticosteroids must be on a stable dose for at least 2 weeks before
- At least 6 weeks since other prior endocrine therapy and recovered
- See Disease Characteristics
- At least 6 weeks since prior radiotherapy and recovered
- Not specified