Green Tea Extract in Treating Patients With Nonmetastatic Bladder Cancer

PRIMARY OBJECTIVES I. To compare the levels of epigallocatechin-3-gallate (EGCG) in
nonmalignant bladder tissue from patients with bladder cancer treated with oral polyphenon E
800 mg EGCG or polyphenon E 1200 mg EGCG once daily for 14-28 days.

SECONDARY OBJECTIVES:

I. To compare the levels of EGCG in nonmalignant versus malignant bladder tissue samples from
these patients.

II. To examine the dose-response modulation of surrogate intermediate endpoint biomarkers
(e.g., Proliferating Cell Nuclear Antigen [PCNA], Matrix Metallopeptidase 2 [MMP2],
clusterin, Vascular endothelial Growth Factor [VEGF], p27, and ODC) in malignant and
nonmalignant samples of bladder tissue from these patients after administration of polyphenon
E.

III. To correlate EGCG levels in samples of serum, urine, and tissue from these patients.

IV. To examine the levels of other catechins (i.e., epicatechin, epicatechin gallate, and
epigallocatechin) found in polyphenon E in samples of serum, urine, and tissue from these
patients.

V. To compare the metabolism of EGCG by Catechol-O-Methyltransferase (COMT) and
Uridinediphosphate-Glucuronosyltransferase (UGT) in relation to pharmacogenetic polymorphisms
in COMT and UGT in samples of serum, urine, and tissue from these patients.

VI. To examine the changes in serum Insulin Growth Factor 1 (IGF-1) and IGFBP-3 levels after
administration of polyphenon E in these patients.

OUTLINE:

This is a multicenter study. Patients are stratified according to tumor site and disease
invasiveness (invasive vs noninvasive). Patients are randomized to 1 of 3 treatment arms.

Arm I: Patients receive six oral placebo capsules once daily for 14-28 days in the absence of
unacceptable toxicity.

Arm II: Patients receive four oral polyphenon E capsules and two oral placebo capsules once
daily for 14-28 days in the absence of unacceptable toxicity.

Arm III: Patients receive six oral polyphenon E capsules once daily for 14-28 days in the
absence of unacceptable toxicity.

After completion of study treatment, patients undergo trans-urethral resection of bladder
tumor or cystectomy.

Blood, urine, and tissue samples are obtained at baseline and at the end of study treatment
for correlative laboratory studies. Samples are evaluated for pharmacokinetics of polyphenon
E using high performance liquid chromatography. Levels of epigallocatechin-3-gallate [EGCG]
and other catechins found in polyphenon E are assessed for correlation in serum, urine, and
tissue. Intermediate endpoint biomarkers are evaluated for dose-response modulation in serum
(i.e., IGF-1 and IGFBP-3) via ELISA and in bladder tissue obtained at the time of bladder
surgery (i.e., PCNA, MMP2, clusterin, VEGF, p27, and ODS) via IHC. Patients at the University
of Wisconsin undergo additional biopsy of bladder tissue for matrix-assisted laser desorption
quadrupole time-of-flight (O-MALDI-qTOF) analysis of EGCG pharmacokinetics. Tissue samples
are examined for intracellular concentration and distribution of EGCG. Genotyping studies for
pyrosequencing of UGT and COMT polymorphisms are also performed.

Criteria:

- Diagnosis of bladder cancer

- Bladder tumor discovered on cystoscopy within the past 60 days

- Invasive or non-invasive tumor

- Primary tumor may represent either an initial diagnosis or recurrent disease of any
clinical stage

- No metastatic disease

- Must be an eligible candidate for a partial cystectomy, radical cystectomy, or
trans-urethral resection of bladder tumor (TURBT)

- Has not undergone any treatment for superficial or invasive bladder cancer since the
diagnostic cystoscopy

- TURBT or radical cystectomy is the planned curative surgical treatment

- ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%

- More than 30 days since any prior intravesical therapy or adjuvant chemotherapy

- More than 30 days since prior bladder surgery

- Biopsies are not considered surgeries

- No prior pelvic radiotherapy

- No concurrent systemic chemotherapy for any other cancer, except nonmelanoma skin
cancer

- No concurrent NSAIDs (e.g., ibuprofen, naproxen, or cyclooxygenase-2 inhibitors)
except =< 81 mg aspirin per day

- Concurrent acetaminophen (Tylenol) or prescription opioids combined with acetaminophen
(i.e., Percocet, Darvocet, Vicodin, Tylenol #3) allowed for pain

- No other concurrent investigational agents

- White Blood Cell (WBC) >= 3,000/mm^3

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 10 g/dL

- Alkaline phosphatase =< upper limit of normal (ULN)

- Bilirubin =< ULN

- Asparate Aminotransferase (AST) and Alanine Transaminase (ALT) =< ULN

- Sodium 135-144 mmol/L (inclusive)

- Potassium 3.2-4.8 mmol/L (inclusive)

- Chloride 85-114 mmol/L (inclusive)

- Bicarbonate >11 mEQ/dL

- Negative pregnancy test

- Fertile patients must use effective contraception

- Willing to avoid green tea beverages and green tea-containing products during study
participation

- No evidence of other cancers, except nonmelanoma skin cancer

- No history of allergic reactions attributed to tea or to any of the compounds of
similar chemical or biologic composition to Polyphenon E or any of the inactive
ingredients in Polyphenon E capsules

- No uncontrolled intercurrent illness including, but not limited to, any of the
following: Ongoing or active infection, Symptomatic congestive heart failure, Unstable
angina pectoris, Cardiac arrhythmia, Psychiatric illness/social situations that would
limit study compliance

- More than 24 hours since prior and no concurrent consumption of any other green tea
supplements or more than 2 cups (16 oz) of green tea either through dietary sources or
through nutritional supplementation

- Topical cosmetics (i.e., lotions, shampoos, makeup) that contain green tea are allowed

- Creatinine normal

- Not pregnant or nursing