Green Tea Extract in Treating Patients With Nonmetastatic Bladder Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Stage III Bladder Cancer; Stage I Bladder Cancer; Stage II Bladder Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery; Drug: Placebo; Dietary supplement: Defined Green Tea Catechin Extract

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Cancer Center
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Minneapolis Veterans Medical Center
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Texas
    • San Antonio, Texas, United States, 78229
      • Urology San Antonio Research PA
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Tracy Downs, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2008
• Primary Completion (Actual): April 26, 2012
• Study Completion (Actual): June 9, 2017

Study Registration Dates

• First Submitted: April 24, 2008
• First Submitted That Met QC Criteria: April 24, 2008
• First Posted (Estimate): April 25, 2008

Study Record Updates

• Last Update Posted (Actual): November 17, 2017
• Last Update Submitted That Met QC Criteria: October 17, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Neuroprotective Agents; Protective Agents; Antioxidants; Anticarcinogenic Agents; Antimutagenic Agents; Epigallocatechin gallate
• Other Study ID Numbers: NCI-2009-00906 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA014520 (U.S. NIH Grant/Contract); N01CN35153 (U.S. NIH Grant/Contract); CO06810; CDR0000594276; H-2007-0250; UWI06-8-01 (Other Identifier: DCP)