Phase I Study of O6-Benzylguanine plus Carmustine for Advanced Melanoma, Breast Cancer,
Colorectal Cancer, Lymphoma, Gliomas, and Other Adult Solid Tumors
Protocol IDs: UCCRC-7341, NCI-T94-0082C
Protocol Type: treatment
Sponsorship: NCI-sponsored, NCI CTEP-approved
Status: Active
Age Range: 18 and over
PROJECTED ACCRUAL:
3-6 patients will be entered at each dose studied.
OBJECTIVES:
I. Define the maximum tolerated dose and associated acute and chronic toxic
effects of O6-benzylguanine (BG) administered alone and in combination with
carmustine (BCNU).
II. Define the maximum tolerated dose and associated acute and chronic toxic
effects of BCNU administered alone and in combination with BG.
III. Describe the distribution, metabolism, and elimination of BG in humans.
IV. Determine the dose of BG required to achieve at least a 90% depletion of
O6-alkylguanine-DNA alkyltransferase (AGT) activity in human lymphocytes and
tumor tissue.
V. Assess the time to recovery of AGT activity following administration of BG.
VI. Define the relationships between BG pharmacokinetics and the extent and
duration of depletion of AGT activity.
VII. Determine the frequency of GGA to AGA mutation at codon 160 in exon 5 of
the human AGT gene in cancer patients receiving BG and to correlate with in
vivo sensitivity to BG.
PROTOCOL ENTRY CRITERIA:
--Disease Characteristics--
Any histologically confirmed advanced cancer for which one of the following
applies:
Refractory to standard therapy
No standard therapy exists
Protocol treatment is an acceptable alternative to standard therapy
The following histologies are included:
Melanoma
Breast cancer
Colorectal cancer
Lymphoma
Malignant gliomas
Measurable or evaluable disease required
No bone marrow metastases
No CNS metastases requiring therapy
Brain CT required within 2 weeks of entry for melanoma patients
Previously treated, stable metastases eligible
--Prior/Concurrent Therapy--
Recovery from prior therapy required
Biologic therapy:
At least 4 weeks since immunotherapy
Chemotherapy:
At least 4 weeks since chemotherapy (6 weeks since mitomycin or
nitrosoureas)
Endocrine therapy:
Stable steroid dose for at least 2 weeks prior to entry required of brain
tumor patients
Radiotherapy:
At least 4 weeks since radiotherapy
Surgery:
Not specified
--Patient Characteristics--
Age:
18 and over
Performance status:
Karnofsky 60-100%
Life expectancy:
At least 8 weeks
Hematopoietic:
WBC at least 3,500/mm3
Platelet count at least 100,000/mm3
Hemoglobin at least 10 g/dL
Hepatic:
Bilirubin no more than 1.6 mg/dL
AST less than 2 times normal
Renal:
Creatinine no more than 1.6 mg/dL OR
Creatinine clearance at least 60 mL/min
Cardiovascular:
No significant cardiac disorder that would compromise treatment or obscure
results
Other:
No active infection
No significant neurologic, endocrine, gastrointestinal, rheumatologic,
dermatologic, or allergic disorder that would compromise treatment or
obscure results
No serious medical or psychiatric illness that would prevent informed
consent or treatment
No pregnant women
Adequate contraception required of fertile patients during and for 2 months
after completion of treatment
Laboratory studies required to determine eligibility within 1 week of entry;
pulmonary function studies, imaging for tumor assessment, and other
pretreatment studies required within 2 weeks of entry
PROTOCOL OUTLINE:
All patients receive O6-benzylguanine as a single dose. Two weeks later,
patients receive a second dose, followed 1 hour later by carmustine.
Groups of 2-6 patients are treated at increasing doses of O6-benzylguanine
until the optimum dose is determined; the dose of carmustine is then increased
in additional patient groups to determine its maximum tolerated dose.
Courses of O6-benzylguanine/carmustine then repeat every 6 weeks until disease
progression. Treatment continues until disease progression, at which time
patients may be eligible for further treatment at the next higher dose.
WARNING:
The purpose of most clinical trials listed in this database is to test new
cancer treatments, or new methods of diagnosing, screening for or preventing
cancer. Because all potentially harmful side effects are not known before
a trial is conducted, dose and schedule modifications may be required for
participants if they develop side effects from the treatment or test. The
therapy or test described in this clinical trial is intended for use by
clinical oncologists in carefully structured settings, and may not prove to
be more effective than standard treatment. A responsible investigator
associated with this clinical trial should be consulted before using this
protocol.
PARTICIPATING ORGANIZATIONS/INVESTIGATORS
Richard L. Schilsky, Chair, Ph: 773-702-6180
University of Chicago Cancer Research Center |
