Phase Ib Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Patients with Barrett's Esophagus

Abstract

This study was conducted to determine the safety and efficacy of the green-tea derived Polyphenon E (Poly E) in patients with Barrett’s Esophagus (BE). Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200 mg, 400 mg, or 600 mg). Endoscopic evaluation, including biopsies, was performed before and after treatment. The primary objective was to demonstrate safety; secondary objectives investigated catechin accumulation and effects in clinical specimens. Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached. The recommended phase 2 dose was 600 mg BID. The most common treatment-related adverse events (AEs) in Poly E-treated subjects were grade 1–2 nausea, grade 1 belching, and grade 1 LDH elevation. No treatment-related AEs were reported in placebo-treated subjects, aside from grade 1 laboratory abnormalities. Pill counts and subject diaries were not consistently collected, and compliance was difficult to determine. However, based on an intention-to-treat analysis there was a significant relationship between Poly E dose and esophageal EGCG level – mean changes (pmol/g) of 0.79 (placebo), 6.06 (200 mg), 35.67 (400 mg), and 34.95 (600 mg); p=0.005. There was a possible relationship between Poly E dose and urine PGE-M concentration. In conclusion, Poly E was well-tolerated, and 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.

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

“…Different nanoformulations, including EGCG, also showed great biocompatibility with no or very modest toxicity in animal models [105,106]. All these findings encourage the efforts to invest in biocompatible EGCG NPs to be used on humans, as interventional studies in pre-cancerous lesions, including prostate, breast, colon, and Barret's Esophagus [107][108][109][110] demonstrated EGCG efficacy despite the poor bioavailability and low plasma concentrations. Therefore, EGCG NPs are expected to improve the chemopreventive effects and to widen the applications in pre-neoplastic lesions, where the results were unclear or incomplete.…”

Inhibitory Effects of (−)-Epigallocatechin-3-gallate on Esophageal Cancer

“…Joe et al completed a prospective, phase I, placebo-controlled trial in patients with BE using a formula “Poly E” containing green tea EGCG. It showed that EGCG was significantly accumulated in the esophageal mucosa of the target organ after administration poly E (400 mg or 600 mg), which was clinically relevant and detectable, indicating that poly E has a measurable positive protective effect in esophageal tissue [ 87 ]. Acute radioactive esophagitis (ARIE) is one of the most frequent adverse effects of chest radiotherapy in the treatment of lung cancer complications, which seriously affects the life quality of patients and the effect of radiotherapy.…”

Cancer Preventive Activities of Tea Catechins

“…However, a recent trial in Florida with a similar design using PPE (containing 400 mg of EGCG) in 97 men with high-grade PIN and/or atypical small acinar proliferation (ASAP), supplementation for 6 to 12 months did not cause a reduction in the number of prostate cancer cases between the treatment and the placebo groups [37]. Some recent intervention studies on breast cancer and esophageal adenocarcinoma were mainly on the bioavailability and some biomarker [38,39]. At present, the earlier optimistic expectation of cancer preventive activity by tea polyphenols, based on laboratory results, has not materialized in RCTs.…”