Iloprost in Preventing Lung Cancer in Patients 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