Tobacco Use Disorder
Conditions
Brief summary
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
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.
Interventions
DRUGAspirin
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPlacebo Administration
Given aspirin placebo PO
DRUGZileuton
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers | Baseline to 12 weeks (End-of-intervention) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention | Baseline to 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. |
| 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 | Baseline to 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. |
| 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) | — |
| 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 | Baseline to 12 weeks (End of Intervention) | 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. |
| Gender Effect on Smoking-related Gene Expression Signature | Baseline to 12 weeks (End-of-intervention) | 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. |
| Changes in the Metabolomics Profile of the Arachidonic Acid Pathway | Baseline to 12 weeks (End-of-intervention) | 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. |
| Number of Genes Differentially Expressed After Aspirin and Zileuton Intervention Compared to Placebo | Baseline to 12 weeks (End-of-intervention) | Number of genes differentially expressed after aspirin and zileuton intervention compared to placebo using whole-genome gene expression data |
| Impact of ASA and Zileuton on Karyometric Analysis of Buccal Cells | Up to week 12 | — |
| Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events | Up to 2 weeks post-treatment | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Aspirin, Zileuton) Patients receive aspirin PO QD and zileuton PO BID for 12 weeks in the absence of unacceptable toxicity.
Aspirin: Given PO
Laboratory Biomarker Analysis: Correlative studies
Zileuton: Given PO | 31 |
| Arm II (Double Placebo) Patients receive aspirin placebo PO QD and zileuton placebo PO BID for 12 weeks.
Laboratory Biomarker Analysis: Correlative studies
Placebo Administration: Given aspirin placebo PO
Placebo Administration: Given zileuton placebo PO | 32 |
| Total | 63 |
Baseline characteristics
| Characteristic | Arm I (Aspirin, Zileuton) | Total | Arm II (Double Placebo) |
|---|---|---|---|
| Age, Continuous | 49.6 years STANDARD_DEVIATION 8.6 | 51.6 years STANDARD_DEVIATION 9.9 | 53.5 years STANDARD_DEVIATION 10.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 56 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 52 Participants | 24 Participants |
| Region of Enrollment United States | 31 participants | 63 participants | 32 participants |
| Sex: Female, Male Female | 13 Participants | 27 Participants | 14 Participants |
| Sex: Female, Male Male | 18 Participants | 36 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 32 |
| other Total, other adverse events | 25 / 31 | 17 / 32 |
| serious Total, serious adverse events | 0 / 31 | 0 / 32 |
Outcome results
Primary
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.
Time frame: Baseline to 12 weeks (End-of-intervention)
Population: The number of participants analyzed is different from the numbers provided in the Participant Flow Module because gene expression analysis was restricted to samples that met quality metrics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Aspirin, Zileuton) | Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers | -0.15 score on a scale | Standard Deviation 2.89 |
| Arm II (Double Placebo) | Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers | 0.26 score on a scale | Standard Deviation 2.26 |
Secondary
Change in Urinary LTE (4) Levels
Time frame: Baseline to 12 weeks (End-of-intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Aspirin, Zileuton) | Change in Urinary LTE (4) Levels | -57.6 pg/mg creatinine | Standard Deviation 65.6 |
| Arm II (Double Placebo) | Change in Urinary LTE (4) Levels | 35.2 pg/mg creatinine | Standard Deviation 92.7 |
Secondary
Change in Urinary PGE-M Levels
Time frame: Baseline to 12 weeks (End-of-intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Aspirin, Zileuton) | Change in Urinary PGE-M Levels | -5.9 ng/mg creatinine | Standard Deviation 13.9 |
| Arm II (Double Placebo) | Change in Urinary PGE-M Levels | 0.71 ng/mg creatinine | Standard Deviation 9.3 |
Secondary
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.
Time frame: Baseline to 14 days post intervention
Population: The number of participants analyzed is different from the numbers provided in the Participant Flow Module because gene expression analysis was restricted to samples that met quality metrics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Aspirin, Zileuton) | Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention | -0.24 score on a scale | Standard Deviation 3.04 |
| Arm II (Double Placebo) | Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention | -1.16 score on a scale | Standard Deviation 3.55 |
Secondary
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.
Time frame: Baseline to 12 weeks (End-of-intervention)
Population: Data were not collected.
Secondary
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.
Time frame: Baseline to 12 weeks (End of Intervention)
Population: The number of participants analyzed is different from the numbers provided in the Participant Flow Module because gene expression analysis was restricted to samples that met quality metrics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Aspirin, Zileuton) | 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 | bronchial smoking signature | -1.0 score on a scale | Standard Deviation 2.87 |
| Arm I (Aspirin, Zileuton) | 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 | PI3 pathway gene signature | -0.32 score on a scale | Standard Deviation 1.57 |
| Arm I (Aspirin, Zileuton) | 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 | nasal diagnostic gene signature | 1.82 score on a scale | Standard Deviation 8.63 |
| Arm II (Double Placebo) | 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 | nasal diagnostic gene signature | 2.17 score on a scale | Standard Deviation 11.21 |
| Arm II (Double Placebo) | 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 | bronchial smoking signature | -0.43 score on a scale | Standard Deviation 3.37 |
| Arm II (Double Placebo) | 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 | PI3 pathway gene signature | 0.42 score on a scale | Standard Deviation 1.68 |
Secondary
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.
Time frame: Baseline to 14 days post intervention
Population: The number of participants analyzed is different from the numbers provided in the Participant Flow Module because gene expression analysis was restricted to samples that met quality metrics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Aspirin, Zileuton) | 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 | bronchial signature | -1.37 score on a scale | Standard Deviation 2.69 |
| Arm I (Aspirin, Zileuton) | 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 | PI3K pathway gene signature | -0.16 score on a scale | Standard Deviation 1.63 |
| Arm I (Aspirin, Zileuton) | 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 | nasal diagnostic gene signature | 2.78 score on a scale | Standard Deviation 6.35 |
| Arm II (Double Placebo) | 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 | bronchial signature | 0.88 score on a scale | Standard Deviation 3.71 |
| Arm II (Double Placebo) | 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 | PI3K pathway gene signature | 0.71 score on a scale | Standard Deviation 2.35 |
| Arm II (Double Placebo) | 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 | nasal diagnostic gene signature | -1.98 score on a scale | Standard Deviation 11.58 |
Secondary
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.
Time frame: Baseline to 12 weeks (End-of-intervention)
Population: The number of participants analyzed is different from the numbers provided in the Participant Flow Module because gene expression analysis was restricted to samples that met quality metrics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Aspirin, Zileuton) | Gender Effect on Smoking-related Gene Expression Signature | Females | 0.01 score on a scale | Standard Deviation 2.93 |
| Arm I (Aspirin, Zileuton) | Gender Effect on Smoking-related Gene Expression Signature | Males | -0.27 score on a scale | Standard Deviation 2.99 |
| Arm II (Double Placebo) | Gender Effect on Smoking-related Gene Expression Signature | Females | -0.20 score on a scale | Standard Deviation 2.01 |
| Arm II (Double Placebo) | Gender Effect on Smoking-related Gene Expression Signature | Males | 0.76 score on a scale | Standard Deviation 2.51 |
Secondary
Impact of ASA and Zileuton on Karyometric Analysis of Buccal Cells
Time frame: Up to week 12
Population: Data were not collected.
Secondary
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
Time frame: Baseline to 12 weeks (End-of-intervention)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Aspirin, Zileuton) | Number of Genes Differentially Expressed After Aspirin and Zileuton Intervention Compared to Placebo | 83 gene |
| Arm II (Double Placebo) | Number of Genes Differentially Expressed After Aspirin and Zileuton Intervention Compared to Placebo | 0 gene |
Secondary
Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events
Time frame: Up to 2 weeks post-treatment
Population: All participants who have received at least one dose of the study agent.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Aspirin, Zileuton) | Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events | 9 Participants |
| Arm II (Double Placebo) | Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events | 8 Participants |