Green Tea Extract in Treating Patients With Nonmetastatic Bladder Cancer

Study Overview
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Brief Summary
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Green tea extract contains ingredients that may slow the growth of certain cancers. It is not yet known whether green tea extract is more effective than a placebo when given before surgery in treating patients with bladder. This randomized phase II trial is studying green tea extract to see how well it works compared to a placebo when given before surgery in treating patients with nonmetastatic bladder cancer.

Detailed Description
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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.

Official Title
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A Phase II Randomized, Placebo-Controlled Trial of Polyphenon E to Evaluate Bladder Tissue Levels of EGCG

Conditions
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Stage I Bladder Cancer, Stage II Bladder Cancer, Stage III Bladder Cancer

Intervention / Treatment
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* Dietary Supplement: Defined Green Tea Catechin Extract
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Placebo
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm I (placebo)<br>Patients receive six oral placebo capsules once daily for 14-28 days. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Placebo<br>* Given orally<br>* Other names: sham therapy;|
| Experimental: Arm II (polyphenon E, placebo)<br>Patients receive four oral polyphenon E capsules and two oral placebo capsules once daily for 14-28 days in the absence of unacceptable toxicity. | Dietary Supplement: Defined Green Tea Catechin Extract<br>* Given orally<br>* Other names: Polyphenon E TM;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Placebo<br>* Given orally<br>* Other names: sham therapy;|
| Experimental: Arm III (polyphenon E, trans-urethral resection or cystectomy)<br>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. | Dietary Supplement: Defined Green Tea Catechin Extract<br>* Given orally<br>* Other names: Polyphenon E TM;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epigallocatechin Gallate (EGCG) Levels in Nonmalignant Bladder Tissue (e.g., Normal-appearing Urothelium, Inflammatory Lesions in the Bladder, Sessile Noninvasive Bladder Tumors, and Papillary Noninvasive Bladder Tumors) | Comparison of nonmalignant bladder tissue levels of EGCG between the placebo group and the EGCG groups combined using student t-test. | up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of EGCG in Malignant Bladder Tissue |  | up to 28 days | 
| Levels of Surrogate Intermediate Endpoint Biomarkers in Malignant and Nonmalignant Bladder Tissue Assessed by Immunohistochemistry |  | up to 28 days | 
| Serum Insulin Growth Factor-1 (IGF-1) Levels Assessed by ELISA |  | Baseline and up to day 28 | 
| Levels of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E Tumor Tissue Samples |  | up to 28 days | 
| Absolute Change for Baseline From EGCG in Serum Samples | The difference between the amount at the end of study (up to 28 days) from baseline. | Baseline and up to 28 days | 
| Metabolism of EGCG in Serum and Urine in Relation to Pharmacogenetic Polymorphisms in Catechol-O-Methyltransferase (COMT) |  | At Baseline | 
| Serum IGFBP-3 Levels Assessed by ELISA |  | Baseline and up to 28 days | 
| Levels of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E Normal Tissue Samples |  | up to 28 days | 
| Absolute Change From Baseline of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E in Urine Samples | The difference between the amount at the end of study (up to 28 days) from baseline. | Baseline and up to 28 days | 
| Absolute Change From Baseline of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E Plasma Samples | The difference between the amount at the end of study (up to 28 days) from baseline. | Baseline and up to 28 days | 
| Absolute Change for Baseline of EGCG in Urine Samples | The difference between the amount at the end of study (up to 28 days) from baseline. | Baseline and up to 28 days | 
| Metabolism of EGCG in Serum and Urine in Relation to Pharmacogenetic Polymorphisms in Uridinediphosphate- Glucuronosyltransferase (UGT) |  | At Baseline |