Oltipraz in the Prevention of Lung Cancer in People Who Smoke

Clinical Phase I Multiple-Dose Safety Research Study of Oltipraz in Smokers

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development of cancer.

PURPOSE: Randomized phase I trial to study the effectiveness of oltipraz in preventing lung cancer in people who smoke.

OBJECTIVES:

• Determine the effect of oltipraz on the level of BP-7,8-diol-9,10-epoxide (BPDE) DNA adducts in the lung lining cells (macrophages and bronchial epithelial cells) of smokers.
• Determine the tolerability and toxicity of this treatment regimen in these patients.
• Determine the effect of this treatment regimen on the level of macromolecule adducts in the blood (e.g., BPDE DNA, BPDE hemoglobin, and 8-hydroxy-deoxyguanine), oral lining cells (BPDE DNA), bladder lining cells (4-aminobiphenyl DNA), and lung macrophages (8-hydroxy-deoxyguanine) in these patients.
• Determine the effect of this treatment regimen on the change (decrease) in activation of NNK as measured by change (increase) in urinary NNAL plus NNAL glucuronide in these patients.
• Determine the effect of this treatment regimen on the oxidative state, glutathione-S-transferase activity, and superoxide dismutase 3 and phase II enzymes in the lungs and blood of these patients.
• Compare the changes in oxidative state and phase II enzymes with changes in adduct levels in the lungs and blood of these patients.
• Determine the correlation between oltipraz-induced changes in phase II enzymes and adduct formation with genotypic variation in glutathione-S-transferase isozymes in these patients.
• Compare the response to this treatment regimen in terms of oxidative state, phase II enzymes, and adduct formation in the lungs vs the blood in these patients.

OUTLINE: This is a randomized, double-blind, multicenter study. Patients are stratified according to participating center. Patients are randomized to one of three treatment arms.

• Arm I: Patients receive an oral placebo weekly.
• Arm II: Patients receive low-dose oral oltipraz weekly.
• Arm III: Patients receive high-dose oral oltipraz weekly. Treatment continues for 12 weeks in the absence of unacceptable toxicity.

Patients are followed at 4 weeks.

PROJECTED ACCRUAL: A total of 66 patients (22 per treatment arm) will be accrued for this study within 21 months.

DISEASE CHARACTERISTICS:

• Current cigarette smokers

  • At least 20 cigarettes a day
  • No variation of more than 10 in the number of cigarettes smoked per day within the past 3 months
  • At least 10 years of smoking any amount
  • Failed to stop smoking after at least one attempt to quit within the last 3 years

• Prior stage I non-small cell lung cancer allowed if surgically resected with at least a lobectomy

• No concurrent evidence of lung cancer

• Willing to undergo 2 bronchoscopies

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0

Life expectancy:

• Not specified

Hematopoietic:

• CBC normal
• Hemostasis normal

Hepatic:

• PT and PTT normal

Renal:

• Blood chemistries normal
• Nonfasting glucose no greater than 200 mg/dL
• No active renal disease
• No urinary tract infection by urinalysis (trace protein allowed)

Cardiovascular:

• EKG normal
• No coronary artery disease requiring continuous medication

Pulmonary:

• Chest radiograph normal (postsurgical changes allowed)
• No acute or significant chronic abnormality
• FEV1 greater than 1.8 L or 75% predicted
• No chronic obstructive pulmonary disease requiring continuous medication

Other:

• No known hypersensitivity or prior adverse reaction to oltipraz
• No inmates or prisoners
• No medical or psychological condition that would preclude study (e.g., acute psychosis)
• No prior malignancy except nonmelanomatous skin cancer, cervical dysplasia, or curatively treated stage I or II cancer of the head and neck
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• At least 3 months since prior potential chemoprevention agent (e.g., oltipraz, retinoids, or acetylcysteine)

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• See Disease Characteristics