Defined Green Tea Catechin Extract in Preventing Liver Cancer in Patients With Cirrhosis

PRIMARY OBJECTIVES:

I. To establish maximum tolerated dose (MTD) and to collect safety data of defined green tea
catechin extract (Polyphenon E/epigallocatechin gallate [EGCG]) treatment in patients with
cirrhosis.

II. To determine the effects of Polyphenon E/EGCG treatment on the suppression of
gamma-hydroxy-1,N(2)-propanodeoxyguanosine (gamma-OHPdG) levels in cirrhotic liver.

SECONDARY OBJECTIVES:

I. To collect Polyphenon E/EGCG pharmacokinetic data in patients with cirrhosis.

II. To study the correlation between gamma-OHPdG levels and mutation frequency and
deoxyribonucleic acid (DNA) damage spectrum in the p53 and beta-catenin genes in cirrhotic
liver tissue.

III. To estimate the fraction of patients with liver cirrhosis that have high levels of
gamma-OHPdG.

EXPLORATORY OBJECTIVES:

I. To assess the effects of Polyphenon E/EGCG on the grade of cirrhosis as measured by
FibroScan and Fibrosis-4 (FIB-4) score.

II. To develop a liquid chromatography-mass spectrometry (LC-MS) and/or enzyme-linked
immunosorbent assay (ELISA)-based method for detecting urinary and blood gamma-OHPdG, to
correlate with liver gamma-OHPdG levels.

OUTLINE: This is a dose-escalation study.

Patients receive defined green tea catechin extract orally (PO) once daily (QD) or twice
daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study intervention, patients are followed up at 28 days.

Inclusion Criteria:

- Participants with a clinical diagnosis of cirrhosis based on the investigator's
evaluation, confirmed by any one of following methods to define cirrhosis:

- Established cirrhosis on liver biopsy (Meta-analysis of Histological Data in
Viral Hepatitis [METAVIR] F4);

- Computed tomography (CT) or magnetic resonance imaging (MRI) findings consistent
with cirrhosis; nodular appearing liver with or without evidence of portal
hypertension

- Transient elastography (FibroScan) with a result > 12.5 kPa

- FibroScan score > 0.75 and aspartate aminotransferase (AST) to platelet ratio
index (APRI) > 2

- Etiology of cirrhosis will not be considered in determining inclusion in the
study

- Participant is able and willing to comply with study procedures, and signed and dated
informed consent is obtained

- Participant agrees to consume no more than 2 cups of green tea per day and refrain
from taking supplements or foods labeled as containing green tea

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Platelets >= 75,000 / uL (obtained within 4 weeks [unless noted otherwise] prior to
beginning polyphenon E)

- Hemoglobin >= 8 g/dL (obtained within 4 weeks [unless noted otherwise] prior to
beginning polyphenon E)

- Serum creatinine OR measured or calculated creatinine clearance within normal
institutional limits; glomerular filtration rate (GFR) can also be used in place of
creatinine or creatinine clearance (CrCl) within normal institutional limits as
adjusted for age and sex (obtained within 4 weeks [unless noted otherwise] prior to
beginning polyphenon E)

- Serum total bilirubin within normal institutional limits (obtained within 4 weeks
[unless noted otherwise] prior to beginning polyphenon E)

- AST (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase
(ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X upper normal level (UNL)
(obtained within 4 weeks [unless noted otherwise] prior to beginning polyphenon E)

- Albumin >= 3.5 mg/dL (obtained within 4 weeks [unless noted otherwise] prior to
beginning polyphenon E)

- International normalized ratio (INR) or prothrombin time (PT) within normal
institutional limits (obtained within 4 weeks [unless noted otherwise] prior to
beginning polyphenon E)

- Activated partial thromboplastin time (aPTT) within normal institutional limits
(obtained within 4 weeks [unless noted otherwise] prior to beginning polyphenon E)

- Ascites absent (obtained within 4 weeks [unless noted otherwise] prior to beginning
polyphenon E)

- Encephalopathy absent (obtained within 4 weeks [unless noted otherwise] prior to
beginning polyphenon E)

- Only participants found to express high levels (immunohistochemistry [IHC] score 3 and
above) of gamma-OHPdG (gamma-OHPdG-high hepatocellular carcinoma [HCC]) in baseline
liver biopsy will be enrolled to receive Polyphenon E treatment

- Screening visit 2 must occur within 8 weeks prior to administration of the first dose
of Polyphenon E

- Participant is able to undergo radiographic evaluation with CT or MRI

- The effects of Polyphenon E on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason,women of child-bearing potential and men
must agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence); contraception must be used prior to study entry and for the duration of
study participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her study physician immediately; female
participants of childbearing potential should have a negative urine or serum pregnancy
test within 72 hours prior to receiving the first dose of study medication (if a urine
test is positive or cannot be confirmed as negative, a serum pregnancy test will be
required)

Exclusion Criteria:

- Participant has confirmed HCC by CT/MRI; participants who have previously had HCC but
have been treated and have been recurrence free for 5 years are eligible

- Participant has or has had other cancer(s) within 3 years of study; however, in situ
breast, in situ cervical, and basal cell/squamous cell skin cancers are allowed;
participant with active, other cancer that requires systemic therapy will be excluded
from this study; participant with early stage cancer that requires local therapy, such
as cervical ablation for early stage cervical cancer, are allowed to be enrolled in
the study and are allowed to receive local therapy

- Inability to swallow capsules

- Participant has a known diagnosis of mental incapacitation that may affect their
ability to consent and be compliant with the protocol

- Participant has ever experienced one or more hepatic decompensation events or a
history of decompensated liver disease as listed below:

- Clinical ascites

- Variceal bleeding documented by endoscopy

- Spontaneous bacterial peritonitis documented by positive culture

- Hepatic encephalopathy

- Hepatorenal syndrome (type 1 or 2)

- Porto-pulmonary hypertension

- Hepato-pulmonary hypertension

- Any liver-related event which led to a hospitalization or a grade 4 event

- Participant has an underlying predisposition to gastrointestinal (GI) or rectal
bleeding are considered ineligible for study participation

- History of allergic reactions attributed to compounds of similar chemical composition
to Polyphenon E (or green tea), or intravenous contrast that is required for CT scan

- Participant is receiving any other investigational agents

- Participants have taken supplements or foods that are labelled as containing green tea
for 8 weeks before start of treatment

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements; hepatitis b virus (HBV) and hepatitis C virus (HCV) infections are
allowed

- Green tea has been consumed by humans for thousands of years and teratogenic or
abortifacient effects have not been reported; however, subjects in this study will
take high doses of Polyphenon E; the teratogenic or abortifacient effects of high dose
Polyphenon E is unknown; therefore pregnant women are excluded from this study;
because there is an unknown but potential risk for adverse events (AEs) in nursing
infants secondary to treatment of the mother with Polyphenon E, breastfeeding should
be discontinued if the mother is treated with this study agent