Sulindac in Preventing Lung Cancer in Current or Former Smokers With Bronchial Dysplasia

Study Overview
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Brief Summary
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This randomized phase II trial is studying sulindac to see how well it works compared to a placebo in preventing lung cancer in current or former smokers with bronchial dysplasia. Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of sulindac may prevent lung cancer from forming in patients with bronchial dysplasia. It is not yet known whether sulindac is more effective than a placebo in preventing lung cancer in patients with bronchial dysplasia.

Detailed Description
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PRIMARY OBJECTIVES: I. Compare the change in histologic grade of bronchial dysplasia, as determined from mucosal biopsy samples obtained during pre- and post-intervention autofluorescence bronchoscopy exams, in current or former smokers with bronchial dysplasia treated with sulindac vs placebo. SECONDARY OBJECTIVES: I. Compare the change in number of dysplastic lesions, as determined from mucosal biopsy samples obtained during pre- and post-intervention autofluorescence bronchoscopy exams, in patients treated with these regimens. II. Compare changes in tissue-based biomarkers (cyclooxygenase [COX]-2, 15-lipoxygenase [LOX]-1, PPAR γ, Ki-67, caspase-3, cyclin D1, cyclin E) in patients treated with these regimens. III. Determine the safety and adverse event profiles of these regimens in these patients. IV. Describe the frequency and patterns of bronchial dysplasia as well as biomarker characteristics in patients treated with this regimen. V. Establish a biospecimen repository archive for future correlative studies. OUTLINE: This is a multicenter, double-blind, randomized, placebo-controlled study. Patients are stratified according to smoking status (current vs former), prior lung cancer (yes vs no), and number of baseline dysplastic lesions (1-3 vs > 3). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral sulindac twice daily for 6 months. ARM II: Patients receive oral placebo twice daily for 6 months. Bronchoscopic examination and mucosal biopsy are performed at baseline and at completion of study treatment. Tissue samples are examined by immunohistochemistry for biological markers, including Ki-67, caspase-3, cyclooxygenase-2, cyclin D1, cyclin E, vascular endothelial growth factor, PPAR γ, and 15-lipoxygenase-1. Blood samples are collected for serum cotinine. After completion of study treatment, patients are followed for up to 30 days.

Official Title
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Randomized, Phase IIb Trial of Sulindac in Smokers With Bronchial Dysplasia

Conditions
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Precancerous Condition, Stage I Non-small Cell Lung Cancer, Tobacco Use Disorder

Intervention / Treatment
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* Drug: sulindac
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current or former smoker who has smoked at least 30 pack years AND meets 1 of the following criteria: No prior lung cancer Prior stage I non-small cell lung cancer(NSCLC) that was completely resected ≥ 1 year ago OR for which patient completed adjuvant chemotherapy ≥ 1 year ago Tissue blocks, blood, and sputum samples available for research purposes No carcinoma in situ ECOG performance status 0-1 Hemoglobin ≥ 12.0 g/dL (women) or hemoglobin ≥ 13.5 g/dL (men) WBC ≥ 3,000/mm³ Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT ≤ 1.5 times ULN Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥30 mL/min Room air oxygen saturation ≥ 90% Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Negative chest x-ray Negative electrocardiogram No other cancer within the past 3 years except nonmelanoma skin cancer, localized prostate, carcinoma in situ of the cervix cancer, or superficial bladder cancer Treatment must have been completed > 6 months ago No prior gastrointestinal ulceration, bleeding, or perforation No uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Myocardial infarction within the past 6 months Chronic renal disease Chronic liver disease Difficult to control hypertension Psychiatric illness or social situations that would limit study compliance No known HIV positivity No history of allergic reactions or hypersensitivity to sulindac or other NSAIDs, including aspirin-sensitive asthma or urticaria No known sensitivity to yellow dye FD&C Yellow #5 No continuous or intermittent supplemental oxygen At least 6 months since prior participation in another chemoprevention trial At least 6 months since prior regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids (may be eligible after washout period of 12 weeks for NSAIDs and 6 weeks for corticosteroids) No prior pneumonectomy No prior solid organ transplantation No other concurrent investigational agents No concurrent regular use of acetylsalicylic acid (aspirin) unless prescribed by a physician for prevention Maximum of 1 aspirin (81 mg) per day allowed No concurrent use of any of the following: Methotrexate Corticosteroids Antiplatelet agents: Warfarin Ticlopidine Clopidogrel bisulfate Aspirin Abciximab Dipyridamole Eptifibatide Tirofiban hydrochloride Lithium carbonate Cyclosporine Hydralazine Angiotensin-converting enzyme (ACE) inhibitors (ACE receptor antagonists are allowed) Angiotensin receptor blockers

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral sulindac twice daily for 6 months. | Drug: sulindac<br>* Given orally<br>* Other names: SULIN;|
| Placebo Comparator: Arm II<br>Patients receive oral placebo twice daily for 6 months. | Other: placebo<br>* Given orally<br>* Other names: PLCB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Definition of response: complete response = regression of all dysplastic lesions (DL) to normal, hyperplasia or metaplasia with no new DL identified; partial response = regression of one or more, but not all of the DL with no new DL identified and no lesions worsening; progression = worsening at one or more sites by at least 2 histologic grades or appearance of any new DL that were not previously biopsied; stable disease = participants not classified as having a complete response, partial response, or progressive disease | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Number of Dysplastic Lesions (DL) as Measured by Mucosal Biopsy Samples Before and After the Intervention | The number of dysplastic lesions was recorded pre-intervention and post-intervention for each participant in each group. Change in the number of lesions was compared between the two intervention groups. | Baseline and 6 months |