Zileuton With or Without Celecoxib As Chemopreventive Agents in Smokers

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.

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