Green Tea Extract in Treating Current or Former Smokers With Bronchial Dysplasia

Study Overview
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Brief Summary
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RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming. The use of Polyphenon E, a substance found in green tea, may keep cancer from forming in current or former smokers with bronchial dysplasia. PURPOSE: This randomized phase II trial is studying the side effects and how well green tea extract works in treating current or former smokers with bronchial dysplasia.

Detailed Description
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OBJECTIVES: Primary To evaluate the efficacy and safety of Polyphenon E, a defined green tea catechin extract, in current or former smokers with bronchial dysplasia and increased inflammatory load as measured by C-reactive protein. Secondary To evaluate the ability of Polyphenon E to modulate other surrogate endpoint biomarkers of oxidation stress, inflammation, aberrant methylation, cell cycle regulation, apoptosis, oncogene/tumor suppressor gene expression, as well as phase I and II enzyme regulation in biological samples from these patients. To establish a library of optical coherent tomography (OCT) images of the bronchial epithelium with corresponding histopathology, nuclear morphometry, and other biomarker information. To assess the potential of OCT as a non-biopsy method for evaluating chemoprevention agents. OUTLINE: This is a multicenter study. Patients are stratified by gender. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral Polyphenon E twice daily for 3 months in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive a placebo twice daily for 3 months in the absence of disease progression or unacceptable toxicity. Patients undergo standard white-light bronchoscopy and fluorescence bronchoscopy with optical coherence tomography (OCT) at baseline and at 3 months. During these procedures, patients are evaluated using the Onco-LIFE clinical device, which digitally records OCT images of abnormal areas or areas suspicious for intraepithelial neoplasia or invasive carcinoma. Once these areas have been localized, patients are biopsied under fluorescence bronchoscopy guidance to obtain both dysplastic bronchial epithelial tissue and normal bronchial mucosa. Biopsy specimens are examined by immunostaining for tissue-based biomarkers (i.e., Ki-67, cleaved caspase-3, p53, and VEGF). Patients also undergo oral brushing, bronchial brushing, and bronchoalveolar lavage at baseline and at 3 months to obtain bronchial epithelial cells for differential gene expression and methylation biomarker studies (e.g., cDNA microarray analysis, polymerase chain reaction, and northern blotting). Cytokines and other molecular biomarkers (i.e., C-reactive protein, surfactant protein D, oxidized glutathione, interleukin [IL]-6, IL-13, and macrophage inflammatory protein-1 levels) are measured in blood and bronchoalveolar lavage fluid samples by enzyme-linked immunoassay. Plasma EGCG levels are assessed by high-performance liquid chromatography. Urine cotinine levels and exhaled carbon monoxide levels are also assessed. After completion of study therapy, patients are followed at 1 month.

Official Title
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Phase II Trial of Polyphenon E in Current and Former Smokers With Bronchial Dysplasia

Conditions
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Lung Cancer, Precancerous Condition, Tobacco Use Disorder

Intervention / Treatment
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* Drug: defined green tea catechin extract
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Current or former smoker who has smoked ≥ 30 pack-years (i.e., 1 pack per day for ≥ 30 years) A former smoker is defined as one who has stopped smoking for ≥ 1 year C-reactive protein level > 1.2 mg/L One or more areas of dysplasia with a surface diameter > 1.2 mm on autofluorescence bronchoscopy No carcinoma in situ or invasive cancer on bronchoscopy No abnormal spiral chest CT scan suspicious of lung cancer PATIENT CHARACTERISTICS: ECOG performance status 0-1 Willing to take Polyphenon E or placebo twice a day regularly Willing to undergo bronchoscopy and spiral chest CT scan Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Creatinine normal Bilirubin normal AST and ALT normal Alkaline phosphatase normal No chronic active hepatitis or liver cirrhosis No severe heart disease (e.g., unstable angina or chronic congestive heart failure) No ongoing gastric ulcer No acute bronchitis or pneumonia within the past month No known reaction to xylocaine, salbutamol, midazolam, or alfentanil No known allergy to green tea and/or corn starch, gelatin, or other nonmedicinal ingredients No medical condition, such as acute or chronic respiratory failure or bleeding disorder, that, in the opinion of the investigator, could jeopardize patient safety during study participation PRIOR CONCURRENT THERAPY: No concurrent consumption of > 7 cups of tea a week No other concurrent natural health products containing green tea compounds No concurrent antiarrhythmic agents No concurrent anticoagulants, such as warfarin or heparin

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral Polyphenon E twice daily for 3 months in the absence of disease progression or unacceptable toxicity. | Drug: defined green tea catechin extract<br>* Given orally<br>|
| Placebo Comparator: Arm II<br>Patients receive a placebo twice daily for 3 months in the absence of disease progression or unacceptable toxicity. | Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the severity of dysplasia (as defined by WHO criteria) in bronchial biopsy specimens as assessed at baseline and at 3 months |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the morphometric index in bronchial biopsy specimens as assessed at baseline and at 3 months |  | 3 months | 
| Change in the concentrations (or grades) of Ki-67, p53, cleaved caspase-3, and VEGF in bronchial biopsy specimens as assessed by immunostaining at baseline and at 3 months |  | 3 months | 
| Methylation biomarkers in bronchoalveolar lavage (BAL) cells as assessed at baseline and at 3 months |  | 3 months | 
| Oncogene/ tumor suppressor gene expression in bronchial brush cells as assessed by cDNA microarray analysis at baseline and at 3 months |  | 3 months | 
| Phase I and II enzyme regulation in bronchial brush cells as assessed by Affymetrix microarray analysis at baseline and at 3 months |  | 3 months | 
| Change in C-reactive protein levels in plasma as assessed by enzyme-linked immunoassay (ELISA) at baseline and then monthly for 3 months |  | 3 months | 
| Volumetric measurement of CT-detected lung nodules at baseline and then every 3-12 months for up to 24 months, depending on the size of the nodule |  | 24 months | 
| Change in the concentrations (or grades) of surfactant protein D, oxidized glutathione, interleukin (IL)-6, IL-13, and MPIF-1 in plasma and BAL cells as assessed by ELISA at baseline and at 3 months |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-small cell lung cancer, squamous lung dysplasia, tobacco use disorder