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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

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

Conditions
-----------------
Lung Cancer, Precancerous Condition

Intervention / Treatment
-----------------
* Drug: iloprost
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral iloprost twice daily for 6 months in the absence of unacceptable toxicity. | Drug: iloprost<br>* Given orally<br>|
| Placebo Comparator: Arm II<br>Patients receive oral placebo twice daily for 6 months in the absence of unacceptable toxicity. | Other: placebo<br>* Given orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average (Follow-up - Baseline) From All Biopsies | This outcome measure is created for each subject as follows: From all biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From all biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated.Histology on bronchial biopsies pre-treatment and post-treatment will be compared. All biopsies will be graded according to the WHO classification for bronchial epithelium for this outcome, and all the following outcomes. WHO Classification Grade Normal 1.0 Reserve Cell Hyperplasia 2.0 Metaplasia 3.0 Mild Dysplasia 4.0 Moderate Dysplasia 5.0 Severe Dysplasia 6.0 Carcinoma in Situ 7.0 Carcinoma 8.0 The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject. | Nine years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Dysplasia Index (Follow-up - Baseline) Using All Biopsies | This outcome measure is created for each subject as follows: From all biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From all biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject. | 9 Years | 
| Change in Average (Follow-up - Baseline) Using Reference Sites | This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL (Right upper lobe: the superior region of the right lung), RML (Right middle lobe: an anatomic portion of the right lung), RB6 (The carina in the right lower lobe at the entrance to the superior segment), LUL (Left upper lobe: the superior portion of the lung), LUDB (Left upper division bronchus: the carina between the lingular orifice and the left upper lobe), and LB6 (The carina in the left lower lobe at the entrance to the superior segment). From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject. | 9 Years | 
| Change in Maximum (Follow-up - Baseline) Using Reference Sites | This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject. | 9 Years | 
| Change in Dysplasia Index (Follow-up - Baseline) Using Reference Sites | This outcome measure is created for each subject as follows: The biopsies used in this analysis are those from the following 6 anatomical sites pre-specified in the protocol to be biopsied: RUL, RML, RB6, LUL, LUDB, and LB6. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject. | 9 Years | 
| Change in Average (Follow-up - Baseline) Using Matched Sites | This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating pairs of biopsies. From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject. | 9 Years | 
| Change in Maximum (Follow-up - Baseline) Using Matched Sites | This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject. | 9 Years | 
| Change in Dysplasia Index (Follow-up - Baseline) Using Matched Sites | This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject. | 9 Years | 
| Change in Average (Follow-up - Baseline) Using Baseline Non-Normal Pairs | This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating pairs of biopsies. Any pair for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the mean WHO score is calculated. From these biopsies scored at the follow-up bronchoscopy, the mean WHO score is calculated. The difference (follow-up mean - baseline mean) is used as the outcome measure for each subject. | 9 Years | 
| Change in Maximum (Follow-up - Baseline) Using Baseline Non-Normal Pairs | This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating pairs of biopsies. Any pair for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the maximum WHO score is used. From these biopsies scored at the follow-up bronchoscopy, the maximum WHO score is used. The difference (follow-up maximum - baseline maximum) is used as the outcome measure for each subject. | 9 Years | 
| Change in Dysplasia Index (Follow-up - Baseline) Using Baseline Non-Normal Pairs | This outcome measure is created for each subject as follows: The biopsies used in this analysis are restricted to biopsies from anatomical sites that were biopsies during both the baseline and follow-up bronchoscopies, thus creating pairs of biopsies. Any pair for which the baseline WHO score was 1 (i.e. normal tissue) was excluded from the analysis. From these biopsies scored at the baseline bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated (this is the definition of Dysplasia Index (DI)). From these biopsies scored at the follow-up bronchoscopy, the percentage with a WHO score greater than or equal to 4 is calculated. The difference (follow-up DI - baseline DI) is used as the outcome measure for each subject. | 9 Years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
non-small cell lung cancer, squamous lung dysplasia