Aspirin and Zileuton and Biomarker Expression in Nasal Tissue of Current Smokers

Study Overview
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Brief Summary
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This randomized phase II trial studies the effects of aspirin and zileuton on genes related to tobacco use in current smokers. Aspirin and zileuton may interfere with genes related to tobacco use and may be useful in preventing lung cancer in current smokers.

Detailed Description
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PRIMARY OBJECTIVES: I. To analyze the impact of combined treatment of acetylsalicylic acid (ASA) (aspirin) and zileuton on smoking-related gene expression signature in the nasal epithelium in current smokers and to analyze any difference between the ASA and zileuton intervention and placebo control. SECONDARY OBJECTIVES: I. To assess the impact of ASA and zileuton on three lung cancer gene signatures (an 80-gene bronchial signature, a phosphatidylinositol 3-kinase [PI3K] pathway gene signature and a nasal diagnostic gene signature) and to compare this to placebo control. II. To determine whether the change in the smoking-related gene expression signature and the three lung cancer gene signatures of nasal epithelium persists 10-14 days off agent intervention. III. To measure urinary prostaglandin E metabolite (PGE-M) and leukotriene E(4) (LTE[4]) levels in current smokers after ASA and zileuton. IV. To assess the safety in current smokers of 12 week exposure to ASA and zileuton. V. To evaluate a gender effect in the modulatory effects of ASA and zileuton on smoking related-gene expression signature. VI. To explore the effect of ASA and zileuton on the metabolomics profile of the arachidonic acid pathway. VII. To explore, in a discovery-driven fashion, the effect of ASA and zileuton on whole-genome gene expression. VIII. To analyze the impact of ASA and zileuton on karyometric analysis of buccal cells. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive aspirin orally (PO) once daily (QD) and zileuton PO twice daily (BID) for 12 weeks in the absence of unacceptable toxicity. ARM II: Patients receive aspirin placebo PO QD and zileuton placebo PO BID for 12 weeks. After completion of study treatment, patients are followed up for 2 weeks.

Official Title
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Clinical Study of the Effect of Combined Treatment of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers

Conditions
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Tobacco Use Disorder

Intervention / Treatment
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* Drug: Aspirin
* Other: Laboratory Biomarker Analysis
* Other: Placebo Administration
* Other: Placebo Administration
* Drug: Zileuton


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current tobacco smokers with >= 20 pack years of self-reported smoking exposure and an average use of >= 10 cigarettes/day Karnofsky >= 70% Leukocytes >= 3,000/microliter Absolute neutrophil count >= 1,500/microliter Hematocrit >= the lower institutional limit Platelets >= the lower institutional limits Total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) within normal institutional limits Creatinine =< the upper institutional limits Prothrombin time (PT)/partial thromboplastin time (PTT) within normal institutional limits Fertile subjects must use adequate contraception (abstinence, barrier methods, or birth control pills) prior to study entry and for the duration of study participation; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Participants may have a history of indeterminate pulmonary nodule(s) by chest imaging if nodule follow-up has been completed or the study procedures would not interfere with nodule follow-up Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: History of allergic reaction to aspirin or attributed to compounds of similar chemical or biologic composition to aspirin, including other nonsteroidal anti-inflammatory drugs (NSAIDs) Gastric intolerance attributable to ASA or NSAIDs History of gastric ulcer within the past 5 years (with or without bleeding) Use of ASA or NSAIDs for more than 5 days per month within 3 months of enrollment Not willing or are unable to refrain from use of any non-study ASA, NSAIDs and leukotriene antagonists during the study period Adult asthma Chronic, current or recent (within the past three months) use of leukotriene antagonists Require chronic anticoagulation or anti-platelet therapy History of bleeding disorder or hemorrhagic stroke Chronic, current or recent (within the past three months) use of glucocorticoids (systemic, topical and/or nasal sprays or steroid topical creams to large body surface area); use of steroid topical creams for small body areas (=< 10% body surface) during study intervention is allowed History of chronic sinusitis or recent nasal polyps History of, or current, active or chronic liver disease even if transaminases have normalized History of allergic reaction to zileuton or attributed to compounds of similar chemical or biologic composition to zileuton Are taking drugs known to interact with zileuton, including theophylline, warfarin, and propranolol Not willing or are unable to limit alcohol consumption to =< 2 alcoholic beverages a day during the study period Pregnant or lactating women; breastfeeding should be discontinued if the mother is treated with aspirin; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Participants may not be receiving any other investigational agents Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Have a known history of inability to absorb an oral agent Invasive cancer within the past five years except non-melanoma skin cancer Urine cotinine level, if collected at screening, does not confirm active smoking status

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (aspirin, zileuton)<br>Patients receive aspirin PO QD and zileuton PO BID for 12 weeks in the absence of unacceptable toxicity. | Drug: Aspirin<br>* Given PO<br>* Other names: Measurin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Zileuton<br>* Given PO<br>* Other names: Zyflo;|
| Placebo Comparator: Arm II (double placebo)<br>Patients receive aspirin placebo PO QD and zileuton placebo PO BID for 12 weeks. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given aspirin placebo PO<br>Other: Placebo Administration<br>* Given zileuton placebo PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers | Change in a nasal smoking-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score. | Baseline to 12 weeks (End-of-intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Three Lung Cancer Gene Signatures (an 80-gene Bronchial Signature, a PI3K Pathway Gene Signature and a Nasal Diagnostic Gene Signature) in the Nasal Epithelium of Current Smokers | Change in three lung cancer gene signatures (an 80-gene bronchial signature, a PI3K pathway gene signature and a nasal diagnostic gene signature) derived from prior research was compared between the two study arms. A decreased signature score implicated a more favorable intervention effect. There is no minimum or maximum score. | Baseline to 12 weeks (End of Intervention) | 
| Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention | Change (from baseline to 10-14 days off intervention) in a nasal smoking-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score. | Baseline to 14 days post intervention | 
| Changes in Three Lung Cancer Gene Signatures (an 80-gene Bronchial Signature, a PI3K Pathway Gene Signature and a Nasal Diagnostic Gene Signature) in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention | Change (from baseline to 10-14 days off intervention) in three lung cancer gene signatures (an 80-gene bronchial signature, a PI3K pathway gene signature and a nasal diagnostic gene signature) derived from prior research was compared between the two study arms. A decreased signature score implicated a more favorable intervention effect. There is no minimum or maximum score. | Baseline to 14 days post intervention | 
| Change in Urinary PGE-M Levels |  | Baseline to 12 weeks (End-of-intervention) | 
| Change in Urinary LTE (4) Levels |  | Baseline to 12 weeks (End-of-intervention) | 
| Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events |  | Up to 2 weeks post-treatment | 
| Gender Effect on Smoking-related Gene Expression Signature | Change in a nasal smoking-related gene expression signature score derived from prior research was analyzed by gender. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score. | Baseline to 12 weeks (End-of-intervention) | 
| Changes in the Metabolomics Profile of the Arachidonic Acid Pathway | Two sample t tests will be performed to evaluate whether or not there are significant differences in changes in oxylipin metabolome between the treatment and placebo groups. In addition, system biology methods will also be used to analyze the oxylipin metabolome data. | Baseline to 12 weeks (End-of-intervention) | 
| Number of Genes Differentially Expressed After Aspirin and Zileuton Intervention Compared to Placebo | Number of genes differentially expressed after aspirin and zileuton intervention compared to placebo using whole-genome gene expression data | Baseline to 12 weeks (End-of-intervention) | 
| Impact of ASA and Zileuton on Karyometric Analysis of Buccal Cells |  | Up to week 12 |