Zileuton With or Without Celecoxib As Chemopreventive Agents in Smokers

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn how zileuton alone or the combination of zileuton and celecoxib may affect certain chemicals in the body that may be linked with a risk for smoking-related lung disease. These effects will be measured by a urine test

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether short-term administration of zileuton, a 5-lipoxygenase (5-LO) inhibitor, in current smokers will suppress the formation of urinary leukotriene E4 (LTE4) and shunt arachidonic acid into the cyclooxygenase (COX) pathway, resulting in elevated urinary prostaglandin E-metabolite (PGE-M). SECONDARY OBJECTIVES: I. To determine whether short-term co-administration of celecoxib, a selective COX-2 inhibitor, and zileuton suppresses levels of both urinary LTE4 and PGE-M in current smokers. II. To evaluate the association between baseline levels of urinary LTE4 and magnitude of the arachidonic acid shunt induced by zileuton. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive zileuton orally (PO) twice daily (BID) on days 1-6. ARM II: Patients receive zileuton as in Arm I and celecoxib PO BID on days 1-6.

Official Title
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Modulation of Arachidonic Acid Metabolism by Chemopreventive Agents in Smokers

Conditions
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Tobacco Use Disorder

Intervention / Treatment
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* Drug: Zileuton
* Drug: Celecoxib
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female current tobacco smokers with more or equal to 10 pack years of self-reported smoking exposure and an average of more or equal to 10 cigarettes/day Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky 70-100%) Total bilirubin less or equal to 2 * upper limit of normal (ULN) Direct bilirubin less or equal to 2 * ULN aspartate aminotransferase (AST)/(SGOT) less or equal to 2 * ULN alanine aminotransferase (ALT)/(SGPT) less or equal to 2 * ULN Alkaline phosphatase less or equal to 2 * ULN If the participant is female, of childbearing potential and not lactating, she has a documented negative serum pregnancy test within 14 days prior to randomization Exclusion Criteria: The participant has active cancer (excluding non-melanoma skin cancer) The participant has a history of curatively treated cancer with surgical therapy finished within 6 months prior to the Screening visit; or has had chemotherapy, cancer-related immunotherapy, hormonal therapy (other than Hormone replacement therapy (HRT) for menopause), or radiation therapy within 12 months of the screening visit The participant has a chronic inflammatory condition, including but not limited to, ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, gout and pancreatitis The participant has an ongoing or active infection, including but not limited to HIV, pneumonia, urinary tract infection The participant has a history of nonsteroidal anti-inflammatory drugs (NSAIDs) use, including aspirin (low-dose aspirin also prohibited) and selective COX-2 inhibitors within the previous 4 weeks The participant has used zileuton or a leukotriene receptor antagonist within the previous 4 weeks The participant has a history of corticosteroid use (excluding topical nasal sprays and dermal application) within the last 6 weeks The participant has an acute or chronic kidney disorder The participant exhibits clinical evidence of active liver disease or history of chronic liver disease The participant has active cardiac disease, or a history of myocardial infarction, angina or coronary artery disease within the past 6 months The participant has a history of a cerebrovascular accident (CVA) or transient ischemic attack (TIA) The participant has a bleeding history The participant is taking drugs known to interact with zileuton or celecoxib, including theophylline, warfarin, propranolol, fluconazole or lithium The participant has received any investigational medication within 30 days of the screening visit or is scheduled to receive an investigational agent during the study The participant is pregnant or nursing; women must not be pregnant or lactating The participant is a female of child-bearing potential (women are considered not of childbearing potential if they are at least two years postmenopausal and/or surgically sterile) who has not used adequate contraception (abstinence; barrier methods such as intrauterine device (IUD), diaphragm with spermicidal gel, condom, or others; and hormonal methods such as birth control pills or others) since her last menses prior to study entry The participant is a female of child-bearing potential or male who does not agree to use adequate contraception 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 The participant has participated in the study previously and was withdrawn 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 Pregnant or nursing participants or those who are HIV-positive will be excluded from the study

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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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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: Zileuton<br>Zileuton 1200 mg twice orally twice a day on days 1-6. | Drug: Zileuton<br>* 1200 mg twice daily given orally (PO) for 6 days<br>* Other names: Zyflo CR;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II: Zileuton and Celecoxib<br>Combined Zileuton 1200 mg twice daily plus Celecoxib 200 mg twice daily on days 1-6. | Drug: Zileuton<br>* 1200 mg twice daily given orally (PO) for 6 days<br>* Other names: Zyflo CR;Drug: Celecoxib<br>* 200 mg twice daily given orally for 6 days<br>* Other names: Celebrex;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Urinary PGE-M Levels (Pre and Post Treatment) | Pre and Post treatment differences in urinary PGE-M levels measured in each treatment arm. PGE-M levels reported as median with full range (ng/mg creatinine) for Pre treatment versus Post treatment PGE-M levels among study participants compliant to treatment with evaluable urine samples at both time points (baseline and Day 6 +/- 1 day). | Baseline and Day 6 | 
| Median Urinary LTE4 Levels (Pre and Post Treatment) | Pre and Post treatment differences in urinary LTE4 levels measured in each treatment arm compared using paired t-test should the data conform to the normality assumption or one-sample Wilcoxon rank-sum test. LTE4 levels reported as median with full range (pg/mg creatinine) for Pre treatment versus Post treatment LTE4 levels among study participants compliant to treatment with evaluable urine samples at both time points (baseline and Day 6 +/- 1 day). | Baseline and day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Cases With a Post-treatment Increase in Urinary PGE-M Levels | Proportion of cases with a post-treatment increase in urinary PGE-M levels by comparing those treated with Zileuton and Celecoxib combined therapy compared to those treated with Zileuton alone. Pre/postchange in levels (Increase) derived from baseline level to Day 6 +/- 1 day. Differences in baseline levels between 2 treatment arms were examined using the Wilcoxon rank-sum test. | Baseline to Day 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer Prevention, Smoking-related lung disease, Smoking, Celecoxib, Celebrex, Zileuton, Zyflo CR, Prevention