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Patients with Barrett's Esophagus (BE) have an increased risk of developing esophageal adenocarcinoma. Preclinical models of BE and esophageal cancer have demonstrated the antitumor activity of the green-tea derived Polyphenon E (Poly E) and identified potential biomarkers for following its activity in clinical specimens. We conducted a multicenter trial of Poly E in patients with BE with or without low-grade dysplasia. Subjects were randomized to a 6-month, twice daily (BID) treatment of either placebo or Poly E (200 mg, 400 mg, 600 mg dose cohorts). Endoscopic evaluation, including multiple biopsies, was performed at baseline and after treatment. The primary objective of this study was to demonstrate safety (i.e., determine the maximum tolerated dose (MTD). Secondary objectives investigated accumulation of Poly E catechin constituents (e.g., EGCG) in esophageal tissue and biologic effects of Poly E in clinical specimens, including high throughput effects on mucosal protein expression using functional proteomics. Of the 44 randomized subjects, 11 received placebo, and 33 received Poly E (200 mg (6), 400 mg (7), 600 mg (20)). No dose-limiting toxicities were encountered, and the MTD was 600 mg BID. The most common treatment-related adverse events (AEs) reported in Poly E-treated subjects were grade 1-2 nausea (12%), grade 1 burping (6%), and grade 1 elevated serum LDH (6%). No treatment-related AEs were reported in placebo-treated subjects, aside from grade 1 laboratory abnormalities. Pill counts and daily patient diaries were not consistently collected, and compliance was difficult to determine for the majority of subjects. However, based on an intention-to-treat analysis there was a dose-exposure relationship (p=0.01, Spearman correlation test) between the dose of Poly E and EGCG levels in esophageal mucosa – mean changes (pmol/g) with treatment were 1.68 (placebo; n=9), 6.06 (200 mg; n=5), 31.66 (400 mg; n=6), and 30.86 (600 mg, n=10). There was a possible relationship between the dose of Poly E and urine PGEM concentration – mean urine PGEM concentrations (ng/mg creatinine) with treatment were 4.86 (placebo; n=9), 6.78 (200 mg; n=3), 9.02 (400 mg; n=5), and 7.89 (600 mg; n=11); however, this was not statistically significant. Treatment with Poly E or placebo did not reduce the length of Barrett's epithelium and did not lead to any statistically significant changes in mucosal protein expression. However, Poly E treatment may have affected the expression of stearoyl-CoA desaturase (SD1), PI3Kinase-alpha, and acetyl Coenzyme A Carboxylase (ACC); p-values ≥ 0.05, although false discovery rates were 0.93. In conclusion, Poly E was well-tolerated in all dose cohorts, with only grade 1 AEs seen more commonly in Poly E-treated subjects. There were no apparent significant effects of treatment on either tissue histology or mucosal biomarker expression. However, treatment with Poly E (400 mg and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa. Clinical development of this compound may include a phase 2 trial of Poly E administered at the 600 mg BID dose for a longer duration. Supported by NCI, DCP Contract N01-CN-035159 to the UT MD Anderson Early Phase Chemoprevention Consortium Citation Format: Andrew K. Joe, Felice Schnoll-Sussman, Robert S. Bresalier, Julian A. Abrams, Hanina H. Hibshoosh, Kenneth Cheung, Richard A. Friedman, Chung S. Yang, Ginger Milne, Diane D. Liu, Kazeem Abdul, Michelle Bigg, Jessica Foreman, Shing Lee, Tao Su, Aqeel Ahmed, Alfred I. Neugut, Esther Akpa, Scott Lippman, Marjorie Perloff, Powel H. Brown, Charles J. Lightdale. Phase Ib randomized, double-blinded, placebo-controlled, dose escalation study of Polyphenon E in patients with Barrett's esophagus. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C48.