Trial Information

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

PRIMARY OBJECTIVES:

I. The primary objective of this study is to demonstrate the safety (i.e., determine the
maximum tolerated dose (MTD)) of using Polyphenon E (Poly E) over a six-month period in the
management of patients with Barrett's Esophagus (BE) with or without low-grade dysplasia
(LGD).

SECONDARY OBJECTIVES:

I. To investigate the dose-related biologic effects and pharmacodynamic properties of Poly E
(in order of decreasing priority):

II. Determine the efficacy of Poly E in inhibiting phosphorylation of EGFR or Her-2 or akt
in esophageal mucosa.

III. Determine the pharmacodynamic profile of Poly E constituents (EGCG, EGC, EC) in
esophageal tissue during and after 6 months of therapy using HPLC and GC-MS.

IV. Evaluate the efficacy of Poly E in reducing or stabilizing metaplasia and dysplasia of
esophageal Barrett's mucosa using visual endoscopic measurements and histological analysis.

V. Determine the efficacy of Poly E in modulating surrogate biomarkers in esophageal mucosa
- degrees of tetraploidy and aneuploidy; expression of cyclin D1, COX-2, EGFR, Her-2, akt,
and Ki-67; LOH at 9p (p16) and 17p (p53); apoptotic index.

VI. Determine the efficacy of Poly E in inhibiting methylation of p16. VII. Determine the
efficacy of Poly E in modulating eicosanoid levels (including PGE2) and lipoxygenase
profiles in esophageal mucosa.

The esophagus is the tube used for swallowing that connects the mouth to the stomach.
Barrett's esophagus is a condition in which the tissue lining of the esophagus is abnormal.
It develops in some people who have heartburn, reflux disease (acid in the esophagus), or
esophagitis (inflammation of the esophagus). Patients with this condition have a higher risk
of developing a type of cancer of the esophagus called adenocarcinoma.

Polyphenon E (Poly E [defined green tea catechin extract]) is a low-caffeinated polyphenol
mixture that is made from green tea. Poly E contains a chemical called Epigallocatechin-3
(EGCG) and other chemicals called "catechins." Research has shown that green tea, Poly E,
and EGCG may be effective in preventing cancer. Poly E, as used in this study, does not
contain green tea, but is made from products of green tea.

Before you can start treatment on this study, you will have what are called "screening
tests." These tests will help the doctor decide if you are eligible to take part in the
study. These procedures are part of regular care for someone at increased risk of esophagus
cancer. If you have had some of them recently, they may not need to be repeated. This will
be up to your study doctor. You will have a complete physical exam, and your medical history
will be reviewed. You will also have routine blood tests (about 2-3 tablespoons), as well as
an electrocardiogram (ECG--a test to measure the electrical activity of the heart).

If you are eligible to take part in the study, and you choose to take part, you will have to
complete a 1-month "wash-out period." The "wash-out period" is a period in which you must
not take medications, herbs, vitamins or mineral supplements that contain tea compounds. The
"wash-out" is a 30-day period before the baseline endoscopy. Because caffeine and tea may
affect the results of this trial, you will be asked to not drink any tea-containing
products. You will also be asked to record the amount of caffeine-containing foods and
medications that you consume. You will be given a list of caffeine-containing foods and
medications.

After the "wash-out" period, you will need to have a complete endoscopy and biopsy of your
esophagus. This is part of regular care for someone at increased risk for esophagus cancer.
This procedure will be performed in the outpatient setting. An endoscopy is an exam used by
your doctor to look at your esophagus (the tube that connects your mouth and stomach) and
stomach. Your doctor will place a thin scope into your mouth and carefully move the scope
down the esophagus and into the stomach. During the endoscopy, you will have a standard
biopsy, and a small area of abnormal tissue will be "snipped" off. The sample will be sent
to the lab to look at the chemical and structural make-up of the cells of the esophageal
lining. This test will be used to find out the extent of the Barrett's Esophagus.

Women who are able to have children must have a negative blood pregnancy test within 2 weeks
of being assigned to a treatment group.

You will then be randomly assigned (as in a roll of the dice) by computer into one of 4
study groups. You have an equal chance of being placed in each group. Neither you nor your
doctor can choose the group you will be in. Neither you, the research staff, nor your doctor
will know if you are taking Poly E or placebo capsules. In this study, you will get either
defined green tea catechin extract (at 1 of 3 different doses) or the placebo (a harmless
drug that looks like the study drug but has no medical benefit).

If you are assigned to Group 1 ("Arm I"), you will begin taking 1 capsule of defined green
tea catechin extract orally (PO) twice daily (BID) for the next 6 months.

If you are assigned to Group 2 ("Arm II"), you will begin taking 2 capsules of defined green
tea catechin extract PO BID for the next 6 months.

If you are assigned to Group 3 ("Arm III"), you will begin taking 3 capsules of defined
green tea catechin extract PO BID for the next 6 months.

If you are assigned to Group 4 ("Arm IV"), you will begin taking 1-3 capsules of placebo PO
BID for the next 6 months. The numbers you take in this group will depend on the amount of
EGCG you are assigned to receive. Each 200 mg Poly E capsule contains 200 mg of EGCG. The
dosage of Poly E is based on the EGCG content. The study capsules do not contain green tea.

You will be asked to keep a study diary during your entire participation in this study. In
this diary, you will record exactly when you take each dose of study drug, and how much you
took each time. You will also be asked to record the amount of caffeine-containing foods and
medications that you consume.

You may continue your histamine antagonist (for example, Zantac or Tagamet) or proton pump
inhibitor (for example, Nexium or Prilosec) for any symptoms you may have.

Certain tests and procedures will be performed during the study, to see how the treatment is
affecting your body. These tests will be done every 2 weeks for the first month, then once a
month until the completion of 6 months of treatment. You will have 20-minute follow-up
visits, that will including checking for any side effects and counting and writing down how
much medication you have taken. You will have blood drawn (about 2-3 tablespoons) for
routine tests, and you will also have urine tests (1 sample is less than 1 tablespoon).

Patients with Barrett's esophagus usually have an endoscopy every 1-3 years. For this study,
it will be performed twice (at the first visit and at the 6-month visit). You will have to
sign a separate consent form for each endoscopy. You cannot take aspirin, aspirin-containing
substances, coumadin (warfarin), heparin, or iron supplements for 5 days before each
endoscopy.

You may be taken off study if intolerable side effects occur, if the study doctor believes
it is in your best interest, if you do not follow the study rules, or if the sponsor decides
to stop the study for any reason.

When you have finished taking 6 months of "treatment" (either the Poly E or the placebo),
you will have a follow-up endoscopy and biopsy. You will have follow-up visits scheduled for
3 months and 6 months after completing treatment. During these visits, you will be checked
for side effects, blood (about 2-3 tablespoons) will be drawn for routine tests, and you
will also have urine tests (1 sample is less than 1 tablespoon) performed. You will be
contacted by telephone monthly after completing treatment, to check for side effects that
you may be experiencing.

This is an investigational study. Poly E has been authorized for use in research only. Up to
55 participants will take part in this multicenter study. About 12 will be enrolled at M. D.
Anderson.