Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information

Alternate Title

Combination Chemotherapy in Treating Patients With Advanced Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	18 and over	NCI	UCCRC-7341 NCI-T94-0082C, T94-0082

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.

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

Expected Enrollment

3-6 patients will be entered at each dose studied.

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.

Schilsky RL, Dolan ME, Bertucci D, et al.: Phase I clinical and pharmacological study of O6-benzylguanine followed by carmustine in patients with advanced cancer. Clin Cancer Res 6 (8): 3025-31, 2000.[PUBMED Abstract]

Dolan ME, Roy SK, Fasanmade AA, et al.: O6-benzylguanine in humans: metabolic, pharmacokinetic, and pharmacodynamic findings. J Clin Oncol 16 (5): 1803-10, 1998.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

University of Chicago Cancer Research Center

Richard Schilsky, MD, Protocol chair		Ph: 773-834-3914; 888-824-0200 Email: rschilsk@medicine.bsd.uchicago.edu