Green Tea Extract in Treating Patients With Nonmetastatic Bladder Cancer

Phase 2

Completed

• Conditions: Stage I Bladder Cancer; Stage II Bladder Cancer; Stage III Bladder Cancer
• Interventions: Other: Laboratory Biomarker Analysis; Dietary Supplement: Defined Green Tea Catechin Extract; Other: Pharmacological Study; Drug: Placebo; Procedure: Therapeutic Conventional Surgery

• Registration Number: NCT00666562
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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

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 Timeline

• Study First Submitted: 2008-04-24
• Study First Submitted QC: 2008-04-24
• Study First Posted: 2008-04-25
• Study Start: 2008-07-02
• Primary Completion: 2012-04-26
• Results First Submitted: 2016-01-20
• Results First Submitted QC: 2016-02-24
• Results First Posted: 2016-03-28
• Study Completion: 2017-06-09
• Status Verified: 2017-10
• Last Update Submitted: 2017-10-17
• Last Update Posted: 2017-11-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 31

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm III (polyphenon E, trans-urethral resection or cystectomy)	Pharmacological Study	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.
Arm I (placebo)	Laboratory Biomarker Analysis	Patients receive six oral placebo capsules once daily for 14-28 days.
Arm II (polyphenon E, placebo)	Defined Green Tea Catechin Extract	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 II (polyphenon E, placebo)	Laboratory Biomarker Analysis	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 I (placebo)	Pharmacological Study	Patients receive six oral placebo capsules once daily for 14-28 days.
Arm I (placebo)	Placebo	Patients receive six oral placebo capsules once daily for 14-28 days.
Arm II (polyphenon E, placebo)	Pharmacological Study	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 (polyphenon E, trans-urethral resection or cystectomy)	Therapeutic Conventional Surgery	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.
Arm III (polyphenon E, trans-urethral resection or cystectomy)	Defined Green Tea Catechin Extract	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.
Arm II (polyphenon E, placebo)	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.
Arm III (polyphenon E, trans-urethral resection or cystectomy)	Laboratory Biomarker Analysis	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.

Primary Outcome Measures

Name	Time	Method
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)	up to 28 days	Comparison of nonmalignant bladder tissue levels of EGCG between the placebo group and the EGCG groups combined using student t-test.

Secondary Outcome Measures

Name	Time	Method
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	Baseline and up to 28 days	The difference between the amount at the end of study (up to 28 days) from baseline.
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	Baseline and up to 28 days	The difference between the amount at the end of study (up to 28 days) from baseline.
Absolute Change From Baseline of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E Plasma Samples	Baseline and up to 28 days	The difference between the amount at the end of study (up to 28 days) from baseline.
Absolute Change for Baseline of EGCG in Urine Samples	Baseline and up to 28 days	The difference between the amount at the end of study (up to 28 days) from baseline.
Metabolism of EGCG in Serum and Urine in Relation to Pharmacogenetic Polymorphisms in Uridinediphosphate- Glucuronosyltransferase (UGT)	At Baseline

Trial Locations

Locations (6)

Lahey Hospital and Medical Center; 🇺🇸 Burlington, Massachusetts, United States

University of Wisconsin Hospital and Clinics; 🇺🇸 Madison, Wisconsin, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

University of Alabama at Birmingham Cancer Center; 🇺🇸 Birmingham, Alabama, United States

Minneapolis Veterans Medical Center; 🇺🇸 Minneapolis, Minnesota, United States

Urology San Antonio Research PA; 🇺🇸 San Antonio, Texas, United States