Precancerous Condition, Stage I Non-small Cell Lung Cancer, Tobacco Use Disorder
Conditions
Brief summary
This randomized phase II trial is studying sulindac to see how well it works compared to a placebo in preventing lung cancer in current or former smokers with bronchial dysplasia. Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of sulindac may prevent lung cancer from forming in patients with bronchial dysplasia. It is not yet known whether sulindac is more effective than a placebo in preventing lung cancer in patients with bronchial dysplasia.
Detailed description
PRIMARY OBJECTIVES: I. Compare the change in histologic grade of bronchial dysplasia, as determined from mucosal biopsy samples obtained during pre- and post-intervention autofluorescence bronchoscopy exams, in current or former smokers with bronchial dysplasia treated with sulindac vs placebo. SECONDARY OBJECTIVES: I. Compare the change in number of dysplastic lesions, as determined from mucosal biopsy samples obtained during pre- and post-intervention autofluorescence bronchoscopy exams, in patients treated with these regimens. II. Compare changes in tissue-based biomarkers (cyclooxygenase \[COX\]-2, 15-lipoxygenase \[LOX\]-1, PPAR γ, Ki-67, caspase-3, cyclin D1, cyclin E) in patients treated with these regimens. III. Determine the safety and adverse event profiles of these regimens in these patients. IV. Describe the frequency and patterns of bronchial dysplasia as well as biomarker characteristics in patients treated with this regimen. V. Establish a biospecimen repository archive for future correlative studies. OUTLINE: This is a multicenter, double-blind, randomized, placebo-controlled study. Patients are stratified according to smoking status (current vs former), prior lung cancer (yes vs no), and number of baseline dysplastic lesions (1-3 vs \> 3). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral sulindac twice daily for 6 months. ARM II: Patients receive oral placebo twice daily for 6 months. Bronchoscopic examination and mucosal biopsy are performed at baseline and at completion of study treatment. Tissue samples are examined by immunohistochemistry for biological markers, including Ki-67, caspase-3, cyclooxygenase-2, cyclin D1, cyclin E, vascular endothelial growth factor, PPAR γ, and 15-lipoxygenase-1. Blood samples are collected for serum cotinine. After completion of study treatment, patients are followed for up to 30 days.
Interventions
DRUGsulindac
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Current or former smoker who has smoked at least 30 pack years AND meets 1 of the following criteria: * No prior lung cancer * Prior stage I non-small cell lung cancer(NSCLC) that was completely resected ≥ 1 year ago OR for which patient completed adjuvant chemotherapy ≥ 1 year ago * Tissue blocks, blood, and sputum samples available for research purposes * No carcinoma in situ * ECOG performance status 0-1 * Hemoglobin ≥ 12.0 g/dL (women) or hemoglobin ≥ 13.5 g/dL (men) * WBC ≥ 3,000/mm³ * Absolute neutrophil count ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * ALT ≤ 1.5 times ULN * Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥30 mL/min * Room air oxygen saturation ≥ 90% * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Negative chest x-ray * Negative electrocardiogram * No other cancer within the past 3 years except nonmelanoma skin cancer, localized prostate, carcinoma in situ of the cervix cancer, or superficial bladder cancer * Treatment must have been completed \> 6 months ago * No prior gastrointestinal ulceration, bleeding, or perforation * No uncontrolled illness including, but not limited to, any of the following: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Myocardial infarction within the past 6 months * Chronic renal disease * Chronic liver disease * Difficult to control hypertension * Psychiatric illness or social situations that would limit study compliance * No known HIV positivity * No history of allergic reactions or hypersensitivity to sulindac or other NSAIDs, including aspirin-sensitive asthma or urticaria * No known sensitivity to yellow dye FD&C Yellow #5 * No continuous or intermittent supplemental oxygen * At least 6 months since prior participation in another chemoprevention trial * At least 6 months since prior regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids (may be eligible after washout period of 12 weeks for NSAIDs and 6 weeks for corticosteroids) * No prior pneumonectomy * No prior solid organ transplantation * No other concurrent investigational agents * No concurrent regular use of acetylsalicylic acid (aspirin) unless prescribed by a physician for prevention * Maximum of 1 aspirin (81 mg) per day allowed * No concurrent use of any of the following: * Methotrexate * Corticosteroids * Antiplatelet agents: * Warfarin * Ticlopidine * Clopidogrel bisulfate * Aspirin * Abciximab * Dipyridamole * Eptifibatide * Tirofiban hydrochloride * Lithium carbonate * Cyclosporine * Hydralazine * Angiotensin-converting enzyme (ACE) inhibitors (ACE receptor antagonists are allowed) * Angiotensin receptor blockers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Baseline and 6 months | Definition of response: complete response = regression of all dysplastic lesions (DL) to normal, hyperplasia or metaplasia with no new DL identified; partial response = regression of one or more, but not all of the DL with no new DL identified and no lesions worsening; progression = worsening at one or more sites by at least 2 histologic grades or appearance of any new DL that were not previously biopsied; stable disease = participants not classified as having a complete response, partial response, or progressive disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Number of Dysplastic Lesions (DL) as Measured by Mucosal Biopsy Samples Before and After the Intervention | Baseline and 6 months | The number of dysplastic lesions was recorded pre-intervention and post-intervention for each participant in each group. Change in the number of lesions was compared between the two intervention groups. |
Countries
Canada, United States
Participant flow
Recruitment details
409 subjects were pre-registered through 6 Cancer Prevention Network (CPN) member organizations from 2006 to 2009.
Pre-assignment details
346 subjects were excluded pre-assignment: 256 ineligible via sputum cytology/bronchoscopy, 37 patient/treating physician reasons, 12 comorbidities, 9 concomitant medications, 24 unable to adhere to the study timelines for tests/procedures, 8 other eligibility criteria. 2 subjects did not receive study intervention, were excluded from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Sulindac) Patients receive oral sulindac twice daily for 6 months. | 31 |
| Arm B (Placebo) Patients receive oral placebo twice daily for 6 months. | 30 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Arm A (Sulindac) | Arm B (Placebo) | Total |
|---|---|---|---|
| Age, Continuous | 59 years | 60 years | 59 years |
| Body mass index | 27.5 kg/m^2 | 28.8 kg/m^2 | 27.9 kg/m^2 |
| Number of baseline dysplastic lesions 1 to 3 | 28 Participants | 26 Participants | 54 Participants |
| Number of baseline dysplastic lesions > 3 | 3 Participants | 4 Participants | 7 Participants |
| Prior lung cancer No | 30 Participants | 30 Participants | 60 Participants |
| Prior lung cancer Yes | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Canada | 12 participants | 14 participants | 26 participants |
| Region of Enrollment United States | 19 participants | 16 participants | 35 participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Male | 24 Participants | 22 Participants | 46 Participants |
| Smoking status Current | 20 Participants | 20 Participants | 40 Participants |
| Smoking status Former | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 31 | 24 / 30 |
| serious Total, serious adverse events | 2 / 31 | 0 / 30 |
Outcome results
Primary
Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment
Definition of response: complete response = regression of all dysplastic lesions (DL) to normal, hyperplasia or metaplasia with no new DL identified; partial response = regression of one or more, but not all of the DL with no new DL identified and no lesions worsening; progression = worsening at one or more sites by at least 2 histologic grades or appearance of any new DL that were not previously biopsied; stable disease = participants not classified as having a complete response, partial response, or progressive disease
Time frame: Baseline and 6 months
Population: The population used for the analysis is patients completing both the pre- and post-intervention bronchoscopy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Sulindac) | Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Complete response | 38.5 percentage of participants |
| Arm A (Sulindac) | Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Stable | 11.5 percentage of participants |
| Arm A (Sulindac) | Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Partial response | 19.2 percentage of participants |
| Arm A (Sulindac) | Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Progression | 30.8 percentage of participants |
| Arm B (Placebo) | Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Progression | 37.0 percentage of participants |
| Arm B (Placebo) | Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Stable | 7.4 percentage of participants |
| Arm B (Placebo) | Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Complete response | 48.2 percentage of participants |
| Arm B (Placebo) | Percentage of Participants With Response Determined by Change in Histologic Grade of Bronchial Dysplasia as Measured by Mucosal Biopsy Samples Before and After Treatment | Partial response | 7.4 percentage of participants |
Comparison: With a sample size of 60 evaluable participants per intervention arm, we would have 90% power to detect a bronchial dysplasia response rate of 54% and 82% power to detect a bronchial dysplasia response rate of\> 51% among participants assigned to receive active sulindac (2-sided chi-square test with continuity correction; alpha=0.05).p-value: 0.85Fisher Exact
Secondary
Percent Change in Number of Dysplastic Lesions (DL) as Measured by Mucosal Biopsy Samples Before and After the Intervention
The number of dysplastic lesions was recorded pre-intervention and post-intervention for each participant in each group. Change in the number of lesions was compared between the two intervention groups.
Time frame: Baseline and 6 months
Population: The population used for the analysis is patients completing both the pre- and post- intervention bronchoscopy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Sulindac) | Percent Change in Number of Dysplastic Lesions (DL) as Measured by Mucosal Biopsy Samples Before and After the Intervention | -55 Percent change in number of DL |
| Arm B (Placebo) | Percent Change in Number of Dysplastic Lesions (DL) as Measured by Mucosal Biopsy Samples Before and After the Intervention | -100 Percent change in number of DL |
Comparison: A sample size of 60 participants per intervention arm would provide 90% power and 80% power to detect effect sizes of 60% and 52%, respectively, using a two-sample t-test(alpha=0.05).p-value: 0.63t-test, 2 sided