RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. The use of zileuton may be an effective way to prevent lung cancer in patients who have bronchial dysplasia.

PURPOSE: Randomized phase II trial to study the effectiveness of zileuton in preventing lung cancer in patients who have bronchial dysplasia.

Condition	Treatment or Intervention	Phase
Hypopharyngeal Cancer Laryngeal Cancer lip and oral cavity cancer Lung Cancer Nasopharyngeal Cancer Oropharyngeal Cancer	Drug: zileuton  Procedure: cancer prevention intervention  Procedure: chemoprevention of cancer	Phase II

Further Study Details: 

OBJECTIVES:

• Determine the efficacy of zileuton, in terms of number of sites and grade of dysplastic lesions in the bronchial epithelium, in patients with documented bronchial dysplasia.
• Correlate the regression of bronchial dysplasia (number and grade) and improvement in sputum cytology with the modulation of molecular biomarkers in patients treated with this drug.
• Determine the overall toxicity of this drug in these patients.
• Determine the 6-month stability of the chemopreventive effect of zileuton in patients who are randomized to receive initial treatment with this drug.
• Determine the 6-month natural history of bronchial dysplasia in patients who are randomized to receive initial treatment with a placebo.

OUTLINE: This is a randomized, double-blind, placebo-controlled, crossover study. Patients are stratified according to smoking status (current vs recently quit smoker), and prior cancer (none vs lung or head and neck). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral zileuton 4 times daily for 6 months followed by oral placebo 4 times daily for an additional 6 months in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral placebo 4 times daily for 6 months followed by oral zileuton 4 times daily for an additional 6 months in the absence of disease progression or unacceptable toxicity. Patients are followed at 4 weeks.

PROJECTED ACCRUAL: A total of 134 patients (67 per treatment arm) will be accrued for this study within 3 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• At high risk for dysplasia, defined by 1 of the following criteria:
• Current or former smokers who have smoked at least 30 pack-years
• Former smokers must be enrolled within 20 years of complete smoking cessation
• Patients with curatively treated stage I non-small cell lung cancer*
• Patients with curatively treated stage I or II squamous cell carcinoma of the head and neck (limited to oral cavity, pharynx, or larynx)* NOTE: *At least 12 months post-curative therapy
• Histologic confirmation of mild to severe bronchial dysplasia on bronchoscopic biopsy required
• Moderate or severe atypia on sputum cytology required before bronchoscopy (not required for patients with prior lung or head and neck cancer)
• No evidence of malignancy by chest x-ray

PATIENT CHARACTERISTICS: Age

• 18 and over (for patients with prior lung or head and neck malignancy)
• 35 and over (for all other patients)

Performance status

• SWOG 0-1

Life expectancy

• Not specified

Hematopoietic

• WBC at least 3,000/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 10.0 g/dL
• No bleeding disorder

Hepatic

• Bilirubin no greater than upper limit of normal (ULN)
• Liver enzymes no greater than ULN
• PT/PTT no greater than ULN
• No active or chronic liver disease (even if transaminases have normalized)

Renal

• Creatinine no greater than ULN

Cardiovascular

• No unstable angina
• No uncontrolled heart failure

Pulmonary

• No significant asthma or chronic obstructive pulmonary disease requiring chronic or periodic (at least once per year) steroids for flares
• No acute or chronic respiratory failure

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Willing and able to undergo serial bronchoscopic examinations
• No ongoing alcohol use (i.e., at least 1 glass of wine, beer, or a mixed drink per day on a regular basis)
• No other medical condition that would preclude safety during study participation
• No other active or invasive malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix
• No hypersensitivity to study drug or any of its inactive ingredients

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• More than 3 months since prior corticosteroids*
• No concurrent corticosteroids*
• No concurrent anticancer hormonal agents NOTE: *Systemic or inhaled, including chronic administration

Radiotherapy

• No concurrent radiotherapy

Surgery

• Not specified

Other

• More than 3 months since prior lipoxygenase inhibitors*
• More than 3 months since prior investigational agents
• More than 3 months since prior nutritional supplements (except 1 daily multivitamin)
• No concurrent nutritional supplements (except 1 daily multivitamin)
• No other concurrent lipoxygenase inhibitors*
• No other concurrent investigational agents
• No concurrent warfarin, beta-blockers, or theophylline
• No other concurrent antineoplastic agents
• No concurrent or chronic daily use of non-steroidal anti-inflammatory agents (NSAIDS) (except cardioprotective doses of aspirin less than 100 mg/day)
• Periodic use of NSAIDS allowed
• Concurrent participation in a smoking cessation program (including use of bupropion or nicotine gum or patch) allowed NOTE: *Systemic or inhaled, including chronic administration

Michigan
      Barbara Ann Karmanos Cancer Institute, Detroit,  Michigan,  48201,  United States; Recruiting

Study chairs or principal investigators

Omer Kucuk, MD,  Study Chair,  Barbara Ann Karmanos Cancer Institute   

Study ID Numbers:  CDR0000271915; WSU-C-2405; WSU-093201MP4F; NCT00056004
Record last reviewed:  September 2004
Last Updated:  December 6, 2004
Record first received:  March 6, 2003
ClinicalTrials.gov Identifier:  NCT00056004
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08