A Phase 2 interventional study of sulindac and placebo in Precancerous Condition, Stage I Non-small Cell Lung Cancer and Tobacco Use Disorder, sponsored by National Cancer Institute (NCI). Completed at 6 sites in 2 countries. Open to participants aged 40 Years to 79 Years. Per ClinicalTrials.gov, last updated 2014-05-23.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Prevention
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.
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.
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This study's enrollment of 61 is close to the median of 60 across 5,295 interventional studies indexed under Lung Neoplasms.
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Inclusion Criteria:
Current or former smoker who has smoked at least 30 pack years AND meets 1 of the following criteria:
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
No uncontrolled illness including, but not limited to, any of the following:
No concurrent regular use of acetylsalicylic acid (aspirin) unless prescribed by a physician for prevention
No concurrent use of any of the following:
Antiplatelet agents:
Patients receive oral sulindac twice daily for 6 months.
Drug: sulindac
Patients receive oral placebo twice daily for 6 months.
Other: placebo
Given orally
Also known as: Aflodac, Algocetil, Clinoril, SULIN
Given orally
Also known as: PLCB
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
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
409 subjects were pre-registered through 6 Cancer Prevention Network (CPN) member organizations from 2006 to 2009.
| Milestone | Arm A (Sulindac) | Arm B (Placebo) |
|---|---|---|
| Started | 31 | 30 |
| Completed | 26 | 27 |
| Not completed | 5 | 3 |
| Withdrew: Lost to follow-up | 2 | 0 |
| Withdrew: Adverse event | 1 | 1 |
| Withdrew: Withdrawal by subject | 1 | 2 |
| Withdrew: Physician decision | 1 | 0 |
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
| percentage of participants | Arm A (Sulindac) | Arm B (Placebo) |
|---|---|---|
| Complete response | 38.5 | 48.2 |
| Partial response | 19.2 | 7.4 |
| Stable | 11.5 | 7.4 |
| Progression | 30.8 | 37.0 |
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.
| Percent change in number of DL | Arm A (Sulindac) | Arm B (Placebo) |
|---|---|---|
| Percent Change in Number of Dysplastic Lesions (DL) as Measured by Mucosal Biopsy Samples Before and After the Intervention | -55 (-100 to 100) | -100 (-100 to 200) |
Collected over Month 1 to ≤30 days after the end of intervention. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm A (Sulindac) | — | 2/31 (6.5%) | 25/31 (80.6%) |
| Arm B (Placebo) | — | 0/30 (0%) | 24/30 (80%) |
| Event | Arm A (Sulindac) | Arm B (Placebo) |
|---|---|---|
| Muscle weakness lower limbMusculoskeletal and connective tissue disorders | 1/31 | 0/30 |
| DepressionPsychiatric disorders | 1/31 | 0/30 |
| Event | Arm A (Sulindac) | Arm B (Placebo) |
|---|---|---|
| CoughRespiratory, thoracic and mediastinal disorders | 3/31 | 8/30 |
| HeadacheNervous system disorders | 1/31 | 6/30 |
| FatigueGeneral disorders | 6/31 | 4/30 |
| Back painMusculoskeletal and connective tissue disorders | 2/31 | 5/30 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 0/31 | 5/30 |
| Pharyngolaryngeal painRespiratory, thoracic and mediastinal disorders | 1/31 | 5/30 |
| Respiratory disorderRespiratory, thoracic and mediastinal disorders | 1/31 | 4/30 |
| Peripheral sensory neuropathyNervous system disorders | 4/31 | 0/30 |
| FeverGeneral disorders | 0/31 | 3/30 |
| PainGeneral disorders | 1/31 | 3/30 |
Two randomized participants (one in each arm) did not initiate their assigned study intervention, leaving 61 participants evaluable for all analyses.
| Age, Continuous(years) | Arm A (Sulindac) | Arm B (Placebo) | Total |
|---|---|---|---|
| Median | 59 (45 to 77) | 60 (44 to 77) | 59 (44 to 77) |
| Sex: Female, Male(Participants) | Arm A (Sulindac) | Arm B (Placebo) | Total |
|---|---|---|---|
| Female | 7 | 8 | 15 |
| Male | 24 | 22 | 46 |
| Region of Enrollment(participants) | Arm A (Sulindac) | Arm B (Placebo) | Total |
|---|---|---|---|
| United States | 19 | 16 | 35 |
| Canada | 12 | 14 | 26 |
| Body mass index(kg/m^2) | Arm A (Sulindac) | Arm B (Placebo) | Total |
|---|---|---|---|
| Median | 27.5 (19.1 to 38.9) | 28.8 (19.5 to 42.5) | 27.9 (19.1 to 42.5) |
| Smoking status(Participants) | Arm A (Sulindac) | Arm B (Placebo) | Total |
|---|---|---|---|
| Current | 20 | 20 | 40 |
| Former | 11 | 10 | 21 |
| Prior lung cancer(Participants) | Arm A (Sulindac) | Arm B (Placebo) | Total |
|---|---|---|---|
| Yes | 1 | 0 | 1 |
| No | 30 | 30 | 60 |
| Number of baseline dysplastic lesions(Participants) | Arm A (Sulindac) | Arm B (Placebo) | Total |
|---|---|---|---|
| 1 to 3 | 28 | 26 | 54 |
| > 3 | 3 | 4 | 7 |
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