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

Brief Summary

Detailed Description

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.

Primary Outcomes

Secondary Outcomes

• 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)