Intermittent or Continuous Acetylsalicylic Acid and Gene Expression in the Nasal Tissue of Current Smokers

PRIMARY OBJECTIVES:

I. To analyze the impact of a 12-week intervention of intermittent and continuous
acetylsalicylic acid (ASA) on a smoking-related gene expression signature in the nasal
epithelium of current smokers and to analyze any difference between the intermittent and
continuous ASA interventions.

SECONDARY OBJECTIVES:

I. To determine whether the change in the smoking-related gene expression signature of nasal
epithelium persists one week off agent intervention.

II. To compare the change in urinary prostaglandin E metabolite (PGE-M) and leukotriene E (4)
(LTE [4]) between the continuous and intermittent dosing arms and to determine whether the
change persists one week off agent intervention.

III. To analyze the impact of intermittent and continuous ASA on a three lung cancer-related
gene signatures (an 80-gene signature, a phosphoinositide 3-kinase [PI3K] gene signature, and
a nasal epithelium cancer signature) in the nasal epithelium and to analyze any difference
between the intermittent and continuous ASA interventions.

IV. To determine whether the change, if any, in the lung cancer-related gene expression
signatures of nasal epithelium persists one week off agent intervention.

V. To compare the safety in current smokers of 12 week exposure to continuous versus
intermittent ASA.

VI. To evaluate a gender effect in the modulatory effects of intermittent and continuous ASA
on smoking-related gene expression signature.

VII. To explore in a discovery-driven fashion the effect of ASA intervention on whole-genome
gene expression.

VIII. To analyze the impact of intermittent and continuous ASA on karyometric analysis of
buccal cells and to analyze any difference between intermittent and continuous ASA
interventions.

OUTLINE: Participants are randomized to 1 of 2 treatment arms.

ARM I (CONTINUOUS): Participants receive aspirin orally (PO) once daily (QD) for 12 weeks.

ARM II (INTERMITTENT): Participants receive placebo PO QD during weeks 1, 3, 5, 7, 9, and 11
and aspirin PO QD during weeks 2, 4, 6, 8, 10, and 12.

After completion of study treatment, participants are followed up for 2 weeks.

Inclusion Criteria:

- Male or female 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 within normal institutional limits

- Platelets within normal institutional limits

- Total bilirubin =< 1.5 × institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 1.5 × institutional ULN

- 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

- 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 or NSAIDs 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)

- History of chronic sinusitis or recent nasal polyps

- 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