A Phase I Dose-Escalation Study of Polyphenon E in Liver Cirrhosis: Evaluation of Safety and Effect on Liver γ-OHPdG Levels.

Accumulation of the DNA adduct γ-hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG) is associated with hepatocellular carcinoma development. Theaphenon E-a green tea polyphenol extract dosed according to mg of epigallocatechin gallate-suppresses the formation of γ-OHPdG and reduces hepatocellular carcinoma development in preclinical models. This study aimed to evaluate the safety of Polyphenon E (Theaphenon E equivalent) and its effect on liver γ-OHPdG levels in patients with cirrhosis. This phase I trial used a 3 + 3 dose-escalation design with five planned Polyphenon E (epigallocatechin gallate) dose levels: 400, 800, 1,200, 1,600, and 2,000 mg daily, administered orally for 24 weeks. Each dose cohort was monitored for "discontinue therapy" criteria for 4 weeks before additional participants were enrolled in the next cohort. Participant liver samples were assessed for γ-OHPdG levels using LC/MS-MS and vibration-controlled transient elastography; endogenous catechin pharmacokinetic data were analyzed. Grade 1 and 2 treatment-related adverse events were observed in 38% of the participants. Liver γ-OHPdG levels declined after treatment in most participants. There was a decrease in the vibration-controlled transient elastography-controlled attenuation parameter in some participants. After Polyphenon E dosing, catechin pharmacokinetic clearance patterns were equivalent for all doses except 1,600 mg. Polyphenon E was well tolerated in participants with cirrhosis at a dose up to and including 1,600 mg/day. Therefore, the recommended starting dose for a phase II trial in a cirrhotic population is 1,200 mg. We observed promising Polyphenon E suppression of liver γ-OHPdG levels.

Prevention relevance: In this phase I dose-escalation trial, Polyphenon E was well tolerated in participants with cirrhosis at a dose up to and including 1,600 mg/day. We observed promising Polyphenon E suppression of liver γ-OHPdG levels and recommend 1,200 mg dose for a future phase II trial in a cirrhotic population.