Sulindac in Preventing Lung Cancer in Current or Former Smokers With Bronchial Dysplasia

Randomized, Phase IIb Trial of Sulindac in Smokers With Bronchial Dysplasia

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.

Study Overview

• Status: Completed
• Conditions: Tobacco Use Disorder; Precancerous Condition; Stage I Non-small Cell Lung Cancer
• Intervention / Treatment: Other: placebo; Drug: sulindac

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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1L3
      • British Columbia
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral sulindac twice daily for 6 months.	Drug: sulindac; Given orally; Other Names: Aflodac; Algocetil; Clinoril; SULIN
Placebo Comparator: Arm II; Patients receive oral placebo twice daily for 6 months.	Other: placebo; Given orally; Other Names: PLCB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and 6 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: James Jett, Mayo Clinic

Publications and helpful links

General Publications

• Limburg PJ, Mandrekar SJ, Aubry MC, Ziegler KL, Zhang J, Yi JE, Henry M, Tazelaar HD, Lam S, McWilliams A, Midthun DE, Edell ES, Rickman OB, Mazzone P, Tockman M, Beamis JF, Lamb C, Simoff M, Loprinzi C, Szabo E, Jett J; Cancer Prevention Network. Randomized phase II trial of sulindac for lung cancer chemoprevention. Lung Cancer. 2013 Mar;79(3):254-61. doi: 10.1016/j.lungcan.2012.11.011. Epub 2012 Dec 20.

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: August 24, 2006
• First Submitted That Met QC Criteria: August 24, 2006
• First Posted (Estimate): August 29, 2006

Study Record Updates

• Last Update Posted (Estimate): May 23, 2014
• Last Update Submitted That Met QC Criteria: May 7, 2014
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Tobacco Use Disorder; Precancerous Conditions; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Sulindac
• Other Study ID Numbers: NCI-2009-00836 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA015083 (U.S. NIH Grant/Contract); CDR0000496457; MAY03-1-02 (Other Identifier: DCP); MAYO-03-1-02 (Other Identifier: Mayo Clinic); N01CN35000 (U.S. NIH Grant/Contract)