Current Smoker, Former Smoker, Multiple Pulmonary Nodules, Tobacco Use Disorder
Conditions
Brief summary
This randomized phase II trial studies acetylsalicylic acid compared to placebo in treating high-risk patients with subsolid lung nodules. A nodule is a growth or lump that may be malignant (cancer) or benign (not cancer). Chemoprevention is the use of drugs to keep cancer from forming or coming back. The use of acetylsalicylic acid may keep cancer from forming in patients with subsolid lung nodules.
Detailed description
PRIMARY OBJECTIVES: I. The evaluation of the effect of aspirin (acetylsalicylic acid) as a chemopreventive agent for lung cancer. SECONDARY OBJECTIVES: I. The modulation of biological markers after treatment and the correlation of these findings with modification of lung nodules diameters. II. The per-lesion analysis including the evaluation of lung nodule density before and after treatment, the number and size of non target lesions including solid nodules and evaluation of response according to modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive acetylsalicylic acid orally (PO) once daily (QD) for 12 months. ARM II: Patients receive placebo PO QD for 12 months. After completion of study treatment, patients are followed up for 1 month.
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
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Asymptomatic current or former smokers (having stopped within the last 20 years) * Smoking history \>= 20 pack/years; subjects must be included in an ongoing annual screening with low dose CT scan or must have two consecutive CT outside the context of a screening program confirming subsolid nodules * Subjects must have subsolid (non solid or partially solid) nodules with size between 4 and 10 mm with any volume doubling time (VDT) not candidate to surgical excision and/or subsolid (non solid or partially solid) nodule larger than 10 mm with VDT higher than 400 days and not candidate to surgical excision * All nodules should be persistent at least after three months follow up with 1 dimension (1d)-CT; a reduction up to 15% of the diameter of the largest target nodule from the previous CT scan is allowed * All current smokers should accept to receive support for smoking cessation * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%) * Leukocytes \>= 3,000/microliter * Absolute neutrophil count \>= 1,500/microliter * Platelets \>= 100,000/microliter * Total bilirubin =\< 2 x institutional upper limit of normal (ULN) and/or history of Gilbert's syndrome * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 1.5 x institutional ULN * Serum creatinine =\< institutional ULN * Women of child-bearing potential (from first menstruation to 1 year after last menstruation) 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 * Ability to understand and the willingness to sign a written informed consent document * Signed informed consent
Exclusion criteria
* Subjects with chronic treatment (at least twice/week for more than 3 months) with aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) * History of allergic reactions attributed to compounds of similar chemical or biological composition to aspirin, NSAIDs, cyclooxygenase-2 (COX2) inhibitors * Invasive malignancy (with the exclusion of basal cell carcinoma or skin squamous cell carcinoma) diagnosed during the last 2 years before randomization; stage I-II invasive malignancies that were diagnosed more than 2 years prior to randomization and have been treated curatively are allowed as long as all treatment is finished at least 18 months prior to randomization * History of therapeutic doses of anticoagulants including warfarin and low molecular weight heparin (e.g. for prior deep venous thrombosis and pulmonary embolisms) in the preceding year * 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 women are excluded from this study; breastfeeding should be discontinued if the mother is treated with aspirin * Individual may not be receiving any other investigational agents, antiplatelet agents (e.g. aspirin, clopidogrel \[Plavix or others\]), anticoagulants (e.g. heparin or heparinoids, Coumadin, or others), methotrexate, lithium * Participants with bleeding diathesis, history of gastric/duodenal ulcers in the last 5 years, NSAID-precipitated bronchospasm, patients unwilling or unable to limit alcohol consumption to i.e. =\< 3 alcohol drinks a day * Participants who in the opinion of the principal investigator (PI) will be at higher risk of acetylsalicylic acid (ASA)-related complications * Participants with known inability to adequately absorb oral medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Sum of Longest Diameters of Baseline Target Nodules (Person-specific Analysis) | Twelve-month treatment | Difference (12 month-baseline) in the sum of longest diameters of baseline target nodules. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lesion Volume | Baseline to 1 year | Difference (12 month-baseline) in lesion volume |
| Change in Lesion Density | Baseline up to 1 year | Difference (12 month-baseline) in lesion density |
| Modulation of Thromboxane B2 | Baseline up to 1 year | Difference (12 month-baseline) in biomarker concentration |
| Change in the Sum of Baseline Target Nodules Diameters (Per Nodules Analysis) | Baseline up to 1 year | Difference (12 month-baseline) in the sum of baseline target nodules diameters |
| Modulation of Leukotriene E4 (Normalized to Urinary Creatinine Concentration) | Baseline up to 1 year | Difference (12 month-baseline) in biomarker concentration |
| Modulation of High Sensitive CRP | Baseline up to 1 year | Difference (12 month-baseline) in biomarker concentration |
| Modulation of miRNA Prediction Risk Score | Baseline up to 1 year | Difference (12 month-baseline) of the score on a scale (scale from -20 to +30 which measure the risk of lung cancer. Higher values indicate higher risk. A value\<0 is considered negative, a value ≥0 positive for lung cancer). |
| Modulation of Prostaglandin E Metabolites (Normalized to Urinary Creatinine Concentration) | Baseline up to 1 year | Difference (12 month-baseline) in biomarker concentration |
Countries
Italy, United States
Participant flow
Recruitment details
A total of 619 ld-CT scans, belonging to the lung screening programs, showed potentially eligible nodules. A total of 109 subjects signed a written informed consent and underwent baseline visit while 98 have been randomized.
Pre-assignment details
After enrollment, 11 participants were not randomized (baseline screening failures)
Participants by arm
| Arm | Count |
|---|---|
| Aspirin 1 tablet of aspirin 100 mg a day for one year | 49 |
| Placebo 1 tablet of placebo a day for one year | 49 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 2 |
Baseline characteristics
| Characteristic | Aspirin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 25 Participants | 49 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 24 Participants | 49 Participants |
| Age, Continuous | 64.6 years STANDARD_DEVIATION 4.1 | 64.6 years STANDARD_DEVIATION 4.7 | 64.6 years STANDARD_DEVIATION 4.4 |
| Baseline lesion density | -628 Hounsfield Unit STANDARD_DEVIATION 76 | -663 Hounsfield Unit STANDARD_DEVIATION 98 | -647 Hounsfield Unit STANDARD_DEVIATION 90 |
| Baseline lesion volume | 138 Millimeter^3 STANDARD_DEVIATION 139 | 151 Millimeter^3 STANDARD_DEVIATION 151 | 145 Millimeter^3 STANDARD_DEVIATION 145 |
| Circulating biomarkers and miRNA risk score | 10.4 Score on a scale STANDARD_DEVIATION 9.5 | 10 Score on a scale STANDARD_DEVIATION 10.6 | 10.2 Score on a scale STANDARD_DEVIATION 10 |
| Circulating High sensitive CRP | 0.47 mg/dL STANDARD_DEVIATION 1.01 | 0.29 mg/dL STANDARD_DEVIATION 0.52 | 0.38 mg/dL STANDARD_DEVIATION 0.8 |
| Circulating Leukotriene E4 normalized to uCr concentration | 1701 pg/mg creatinine STANDARD_DEVIATION 1670 | 1226 pg/mg creatinine STANDARD_DEVIATION 909 | 1463 pg/mg creatinine STANDARD_DEVIATION 1359 |
| Circulating Prostaglandin E metabolite (PGEM) normalized to uCr concentration | 385 pg/mg creatinine STANDARD_DEVIATION 218 | 334 pg/mg creatinine STANDARD_DEVIATION 213 | 359 pg/mg creatinine STANDARD_DEVIATION 216 |
| Circulating Thromboxane | 60.4 ng/mL STANDARD_DEVIATION 32.6 | 61.1 ng/mL STANDARD_DEVIATION 37.3 | 60.8 ng/mL STANDARD_DEVIATION 34.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 49 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Italy | 48 participants | 49 participants | 97 participants |
| Region of Enrollment United States | 1 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 28 Participants | 27 Participants | 55 Participants |
| Sex: Female, Male Male | 21 Participants | 22 Participants | 43 Participants |
| Sum of diameters of baseline target nodules | 6.8 millimeters STANDARD_DEVIATION 2.8 | 7.2 millimeters STANDARD_DEVIATION 2.7 | 7.0 millimeters STANDARD_DEVIATION 2.8 |
| Sum of longest diameters of baseline target nodules | 8.5 millimeters STANDARD_DEVIATION 4.3 | 11 millimeters STANDARD_DEVIATION 11.3 | 9.8 millimeters STANDARD_DEVIATION 8.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 0 / 49 |
| other Total, other adverse events | 43 / 49 | 41 / 49 |
| serious Total, serious adverse events | 8 / 49 | 4 / 49 |
Outcome results
Primary
Change in the Sum of Longest Diameters of Baseline Target Nodules (Person-specific Analysis)
Difference (12 month-baseline) in the sum of longest diameters of baseline target nodules.
Time frame: Twelve-month treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Change in the Sum of Longest Diameters of Baseline Target Nodules (Person-specific Analysis) | 0.3 millimeter (mm) | Standard Deviation 2.54 |
| Placebo | Change in the Sum of Longest Diameters of Baseline Target Nodules (Person-specific Analysis) | -0.12 millimeter (mm) | Standard Deviation 1.55 |
Secondary
Change in Lesion Density
Difference (12 month-baseline) in lesion density
Time frame: Baseline up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Change in Lesion Density | 24 Hounsfield unit (HU) | Standard Deviation 65 |
| Placebo | Change in Lesion Density | 28 Hounsfield unit (HU) | Standard Deviation 78 |
Secondary
Change in Lesion Volume
Difference (12 month-baseline) in lesion volume
Time frame: Baseline to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Change in Lesion Volume | -4.5 millimiter^3 (mm3) | Standard Deviation 78 |
| Placebo | Change in Lesion Volume | -4.8 millimiter^3 (mm3) | Standard Deviation 134 |
Secondary
Change in the Sum of Baseline Target Nodules Diameters (Per Nodules Analysis)
Difference (12 month-baseline) in the sum of baseline target nodules diameters
Time frame: Baseline up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Change in the Sum of Baseline Target Nodules Diameters (Per Nodules Analysis) | 0.1 millimeter (mm) | Standard Deviation 2.4 |
| Placebo | Change in the Sum of Baseline Target Nodules Diameters (Per Nodules Analysis) | -0.1 millimeter (mm) | Standard Deviation 1.1 |
Secondary
Modulation of High Sensitive CRP
Difference (12 month-baseline) in biomarker concentration
Time frame: Baseline up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Modulation of High Sensitive CRP | -0.12 mg/dL | Standard Deviation 0.88 |
| Placebo | Modulation of High Sensitive CRP | -0.08 mg/dL | Standard Deviation 0.5 |
Secondary
Modulation of Leukotriene E4 (Normalized to Urinary Creatinine Concentration)
Difference (12 month-baseline) in biomarker concentration
Time frame: Baseline up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Modulation of Leukotriene E4 (Normalized to Urinary Creatinine Concentration) | -235 pg/mg creatinine | Standard Deviation 1240 |
| Placebo | Modulation of Leukotriene E4 (Normalized to Urinary Creatinine Concentration) | -9 pg/mg creatinine | Standard Deviation 592 |
Secondary
Modulation of miRNA Prediction Risk Score
Difference (12 month-baseline) of the score on a scale (scale from -20 to +30 which measure the risk of lung cancer. Higher values indicate higher risk. A value\<0 is considered negative, a value ≥0 positive for lung cancer).
Time frame: Baseline up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Modulation of miRNA Prediction Risk Score | 0.14 Score on a scale | Standard Deviation 8.94 |
| Placebo | Modulation of miRNA Prediction Risk Score | 0.36 Score on a scale | Standard Deviation 7.36 |
Secondary
Modulation of Prostaglandin E Metabolites (Normalized to Urinary Creatinine Concentration)
Difference (12 month-baseline) in biomarker concentration
Time frame: Baseline up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Modulation of Prostaglandin E Metabolites (Normalized to Urinary Creatinine Concentration) | -60.7 pg/mg creatinine | Standard Deviation 210 |
| Placebo | Modulation of Prostaglandin E Metabolites (Normalized to Urinary Creatinine Concentration) | 29.8 pg/mg creatinine | Standard Deviation 215 |
Secondary
Modulation of Thromboxane B2
Difference (12 month-baseline) in biomarker concentration
Time frame: Baseline up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Modulation of Thromboxane B2 | -35.8 ng/mL | Standard Deviation 53.4 |
| Placebo | Modulation of Thromboxane B2 | 20.5 ng/mL | Standard Deviation 50.7 |