Clinical trial NCT00666562: Green Tea Extract in Treating Patients With Nonmetastatic Bladder Cancer
Official title: A Phase II Randomized, Placebo-Controlled Trial of Polyphenon E to Evaluate Bladder Tissue Levels of EGCG
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Stage I Bladder Cancer
Stage II Bladder Cancer
Stage III Bladder Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-04-25
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: up to 28 days
Secondary outcomes:
measure: Levels of EGCG in Malignant Bladder Tissue
timeFrame: up to 28 days
measure: Levels of Surrogate Intermediate Endpoint Biomarkers in Malignant and Nonmalignant Bladder Tissue Assessed by Immunohistochemistry
timeFrame: up to 28 days
measure: Serum Insulin Growth Factor-1 (IGF-1) Levels Assessed by ELISA
timeFrame: Baseline and up to day 28
measure: Levels of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E Tumor Tissue Samples
timeFrame: up to 28 days
measure: Absolute Change for Baseline From EGCG in Serum Samples
timeFrame: Baseline and up to 28 days
measure: Metabolism of EGCG in Serum and Urine in Relation to Pharmacogenetic Polymorphisms in Catechol-O-Methyltransferase (COMT)
timeFrame: At Baseline
measure: Serum IGFBP-3 Levels Assessed by ELISA
timeFrame: Baseline and up to 28 days
measure: Levels of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E Normal Tissue Samples
timeFrame: up to 28 days
measure: Absolute Change From Baseline of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E in Urine Samples
timeFrame: Baseline and up to 28 days
measure: Absolute Change From Baseline of Other Catechins (Epicatechin Gallate, Epicatechin, and Epigallocatechin) Found in Polyphenon E Plasma Samples
timeFrame: Baseline and up to 28 days
measure: Absolute Change for Baseline of EGCG in Urine Samples
timeFrame: Baseline and up to 28 days
measure: Metabolism of EGCG in Serum and Urine in Relation to Pharmacogenetic Polymorphisms in Uridinediphosphate- Glucuronosyltransferase (UGT)
timeFrame: At Baseline
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Burlington
country: United States
facility: Lahey Hospital and Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: Minneapolis Veterans Medical Center
state: Minnesota
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: San Antonio
country: United States
facility: Urology San Antonio Research PA
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Tracy Downs
role: PRINCIPAL_INVESTIGATOR
References: