Lung Carcinoma, Tobacco Use Disorder
Conditions
Brief summary
This randomized phase II trial studies the safety and effects of acetylsalicylic acid (aspirin) taken continuously or intermittently on gene expression in the nasal tissue of current smokers. Smokers are at increased risk of developing lung cancer. Acetylsalicylic acid may be useful in preventing lung cancer.
Detailed description
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.
Interventions
DRUGAspirin
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPlacebo
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Smoking-related Gene Expression Signature Score in Nasal Epithelium | Baseline to 12 weeks (End-of-Intervention) | Change in 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 Urine Prostaglandin E2 Metabolite (PGE-M) Levels | Baseline to 12 weeks (End-of-Intervention) | Urinary PGE-M was used as a biomarker of cyclooxygenase (COX) mediated arachidonic acid metabolism. Decreased PGE-M implicated inhibition of COX mediated pathway. |
| Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events | Up to 2 weeks post-treatment | — |
| Gender Effect on Smoking-related Gene Expression Signature Score | Baseline to 12 weeks (End-of-Intervention) | Change in nasal smoking-related gene expression signature score was compared between male and female participants. The gender comparison was not stratified by arm because of the small sample size. 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 Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium | Baseline to 12 weeks (End-of-Intervention) | Change in lung cancer-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that the score was higher in lung cancer cases than healthy controls. A decreased score implicated a more favorable intervention effect. There is no minimum or maximum score. |
| Changes in Urine Leukotriene E4 (LTE(4)) Levels | Baseline to 12 weeks (End-of-Intervention) | Urinary LTE(4) was used as a biomarker 5-lipoxygenase (5-LOX) mediated arachidonic acid metabolism. Decreased LTE4 implicated inhibition of the 5-LOX mediated pathway. |
| Persistence of the Change in the Smoking-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention | Baseline to 1 week post-intervention | Change in nasal smoking-related gene expression signature score from baseline to 1 week post-intervention 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. |
| Whole-genome Gene Expression - Number of Canonical Pathways Differentially Expressed | Baseline to 12 weeks | Gene set enrichment analysis was performed on the MSigDB canonical pathways with the intent to discover differentially expressed genes after aspirin intervention. |
| Change in Buccal Cells Via Karyometric Analysis | Baseline to up to one week post-intervention | — |
| Persistence of the Change in the Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention | Baseline to 1 week post-intervention | Change in the lung cancer-related gene expression signature score from baseline to one week off agent intervention was compared between the two study arms. Prior research showed that higher scores were observed in lung cancer cases than healthy controls. A decreased score implicated a favorable intervention effect. There is no minimum or maximum score. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Continuous Aspirin) Participants receive aspirin PO QD for 12 weeks.
Aspirin: Given PO
Laboratory Biomarker Analysis: Correlative studies | 27 |
| Arm II (Intermittent Aspirin) 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.
Aspirin: Given PO
Laboratory Biomarker Analysis: Correlative studies
Placebo: Given PO | 27 |
| Total | 54 |
Baseline characteristics
| Characteristic | Arm II (Intermittent Aspirin) | Total | Arm I (Continuous Aspirin) |
|---|---|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 8 | 52 years STANDARD_DEVIATION 8 | 52 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 10 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 44 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 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 | 21 Participants | 45 Participants | 24 Participants |
| Sex: Female, Male Female | 12 Participants | 24 Participants | 12 Participants |
| Sex: Female, Male Male | 15 Participants | 30 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 27 |
| other Total, other adverse events | 14 / 27 | 21 / 27 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 |
Outcome results
Primary
Changes in Smoking-related Gene Expression Signature Score in Nasal Epithelium
Change in 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 (Continuous Aspirin) | Changes in Smoking-related Gene Expression Signature Score in Nasal Epithelium | -1.11 gene expression signature score | Standard Deviation 4.05 |
| Arm II (Intermittent Aspirin) | Changes in Smoking-related Gene Expression Signature Score in Nasal Epithelium | 1.39 gene expression signature score | Standard Deviation 4.41 |
p-value: 0.04t-test, 1 sided
Secondary
Change in Buccal Cells Via Karyometric Analysis
Time frame: Baseline to up to one week post-intervention
Population: Data were not collected
Secondary
Changes in Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium
Change in lung cancer-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that the score was higher in lung cancer cases than healthy controls. A decreased 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 (Continuous Aspirin) | Changes in Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium | -0.03 gene expression signature score | Standard Deviation 0.12 |
| Arm II (Intermittent Aspirin) | Changes in Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium | 0.04 gene expression signature score | Standard Deviation 0.11 |
p-value: 0.97t-test, 1 sided
Secondary
Changes in Urine Leukotriene E4 (LTE(4)) Levels
Urinary LTE(4) was used as a biomarker 5-lipoxygenase (5-LOX) mediated arachidonic acid metabolism. Decreased LTE4 implicated inhibition of the 5-LOX mediated pathway.
Time frame: Baseline to 12 weeks (End-of-Intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Continuous Aspirin) | Changes in Urine Leukotriene E4 (LTE(4)) Levels | -6.89 pg/mg creatinine | Standard Deviation 95.16 |
| Arm II (Intermittent Aspirin) | Changes in Urine Leukotriene E4 (LTE(4)) Levels | -21.90 pg/mg creatinine | Standard Deviation 309.8 |
p-value: 0.84t-test, 2 sided
Secondary
Changes in Urine Prostaglandin E2 Metabolite (PGE-M) Levels
Urinary PGE-M was used as a biomarker of cyclooxygenase (COX) mediated arachidonic acid metabolism. Decreased PGE-M implicated inhibition of COX mediated pathway.
Time frame: Baseline to 12 weeks (End-of-Intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Continuous Aspirin) | Changes in Urine Prostaglandin E2 Metabolite (PGE-M) Levels | -3.73 ng/mg creatinine | Standard Deviation 9.69 |
| Arm II (Intermittent Aspirin) | Changes in Urine Prostaglandin E2 Metabolite (PGE-M) Levels | -5.59 ng/mg creatinine | Standard Deviation 13.74 |
p-value: 0.61t-test, 2 sided
Secondary
Gender Effect on Smoking-related Gene Expression Signature Score
Change in nasal smoking-related gene expression signature score was compared between male and female participants. The gender comparison was not stratified by arm because of the small sample size. 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 (Continuous Aspirin) | Gender Effect on Smoking-related Gene Expression Signature Score | 0.45 gene expression signature score | Standard Deviation 5.04 |
| Arm II (Intermittent Aspirin) | Gender Effect on Smoking-related Gene Expression Signature Score | -0.72 gene expression signature score | Standard Deviation 3.48 |
p-value: 0.42t-test, 2 sided
Secondary
Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events
Time frame: Up to 2 weeks post-treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Continuous Aspirin) | Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events | 3 Participants |
| Arm II (Intermittent Aspirin) | Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events | 4 Participants |
p-value: 1Fisher Exact
Secondary
Persistence of the Change in the Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention
Change in the lung cancer-related gene expression signature score from baseline to one week off agent intervention was compared between the two study arms. Prior research showed that higher scores were observed in lung cancer cases than healthy controls. A decreased score implicated a favorable intervention effect. There is no minimum or maximum score.
Time frame: Baseline to 1 week 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 (Continuous Aspirin) | Persistence of the Change in the Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention | -0.04 gene expression signature score | Standard Deviation 0.09 |
| Arm II (Intermittent Aspirin) | Persistence of the Change in the Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention | 0.02 gene expression signature score | Standard Deviation 0.1 |
p-value: 0.97t-test, 1 sided
Secondary
Persistence of the Change in the Smoking-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention
Change in nasal smoking-related gene expression signature score from baseline to 1 week post-intervention 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 1 week 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 (Continuous Aspirin) | Persistence of the Change in the Smoking-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention | -1.95 gene expression signature score | Standard Deviation 3.42 |
| Arm II (Intermittent Aspirin) | Persistence of the Change in the Smoking-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention | -0.1 gene expression signature score | Standard Deviation 3.38 |
p-value: 0.06t-test, 1 sided
Secondary
Whole-genome Gene Expression - Number of Canonical Pathways Differentially Expressed
Gene set enrichment analysis was performed on the MSigDB canonical pathways with the intent to discover differentially expressed genes after aspirin intervention.
Time frame: Baseline to 12 weeks
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 (NUMBER) |
|---|---|---|
| Arm I (Continuous Aspirin) | Whole-genome Gene Expression - Number of Canonical Pathways Differentially Expressed | 301 canonical pathway |
| Arm II (Intermittent Aspirin) | Whole-genome Gene Expression - Number of Canonical Pathways Differentially Expressed | 120 canonical pathway |