Iloprost in Preventing Lung Cancer in Patients at High Risk for This Disease

A Randomized Phase II Chemoprevention Study of Iloprost Versus Placebo in Patients at High Risk for Lung Cancer

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Iloprost may be effective in preventing lung cancer.

PURPOSE: This randomized phase II trial is studying how well iloprost works in preventing lung cancer in patients who are at high risk for this disease.

OBJECTIVES:

Primary

• Compare the reversal of premalignant histological changes in the bronchial epithelium of patients at high risk for lung cancer (defined by > 20 pack years of smoking and sputum atypia) treated with iloprost vs placebo.
• Determine whether this drug modulates Ki-67 proliferation index (Antigen Ki-67) in these patients.
• Determine whether this drug affects prostaglandin metabolism in these patients.
• Determine the toxicity profile of this drug in these patients.

Secondary

• Determine whether this drug modulates a panel of biomarkers, including MCM-2(Minichromosome maintenance protein: forms DNA helicase), EGFR (Epidermal growth factor receptor: cell surface receptor for the epidermal growth factor family of proteins. Mutations in EGFR expression or activity can result in cancer.) , HER2/neu (Human epidermal growth factor receptor 2 HER2 is a member of the EGFR family), RARβ (Retinoic Acic Receptor Beta is a nuclear transcription regulator and a member of the thyroid-steroid hormone receptor superfamily), p53, FHIT (Fragile histidine triad protein is an enzyme involved in purine metabolism and had been demonstrated to be a tumor suppressor), apoptotic index, and microvessel density, in these patients.
• Determine the genes whose expression is altered by this drug in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to smoking status (current vs former) and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral iloprost twice daily.
• Arm II: Patients receive oral placebo twice daily. In both arms, treatment continues for 6 months in the absence of unacceptable toxicity.

Patients are followed at 1 month and then annually thereafter.

PROJECTED ACCRUAL: A total of 152 patients (76 [38 current smokers and 38 former smokers] per treatment arm) will be accrued for this study within 2 years.

Inclusion Criteria:

• Current or former smoker with ≥ 20 pack-year history of smoking with no tobacco use within the past 6 months
• Mild atypia or worse on sputum cytology, or
• Bronchial biopsy with mild or worse dysplasia within the past 12 months
• Age 18 and over
• SWOG (Southwest Oncology Group)0-2
• Life expectancy at least 6 months
• Granulocyte count > 1,500/mm^3
• Platelet count > 100,000/mm^3
• Alkaline phosphatase ≤ 2.5 times upper limit of normal (ULN)
• Transaminases ≤ 2.5 times ULN
• Bilirubin ≤ 2.0 mg/dL
• Albumin ≥ 2.5 g/dL
• Creatinine ≤ 1.5 mg/dL
• Well-controlled atrial fibrillation OR rare (< 2 minutes) premature ventricular contractions allowed
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able and willing to undergo bronchoscopy

Exclusion Criteria

• Clinically apparent bleeding diathesis
• Ventricular tachycardia
• Multifocal premature ventricular contractions or supraventricular tachycardias with rapid ventricular response
• Pneumonia or acute bronchitis within the past 2 weeks
• Hypoxemia (< 90% saturation with supplemental oxygen)
• Pregnant or nursing
• Malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• Serious medical condition that would preclude bronchoscopy or study participation
• Clinically active coronary artery disease
• Myocardial infarction within the past 6 weeks
• Chest pain
• Congestive heart failure
• Cardiac dysrhythmia that is potentially life-threatening

Exclusion for PRIOR CONCURRENT THERAPY:

• Biologic therapy (Not specified)
• More than 5 years since prior chemotherapy
• More than 6 weeks since prior inhaled steroids
• More than 5 years since prior thoracic radiotherapy
• Surgery (Not specified)
• No prior prostacyclin