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

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.

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