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


Phase 2
18 Years
N/A
Not Enrolling
Both
Stage I Bladder Cancer, Stage II Bladder Cancer, Stage III Bladder Cancer

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Trial Information

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


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., PCNA, MMP2, clusterin, 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 COMT and 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 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.

Inclusion 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

- WBC >= 3,000/mm^3

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

- Hemoglobin >= 10 g/dL

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

- Bilirubin =< ULN

- AST and 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Outcome Measure:

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)

Outcome Description:

Comparison of nonmalignant bladder tissue levels of EGCG between the placebo group and the EGCG groups combined using student t-test. In the case of violation of normality assumptions, an appropriate transformation of the data such as logarithm will be considered or a nonparametric test such as Wilcoxon rank-sum test will be used for comparison.

Outcome Time Frame:

End of surgery

Safety Issue:

No

Principal Investigator

Tracy Downs

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00906

NCT ID:

NCT00666562

Start Date:

July 2008

Completion Date:

Related Keywords:

  • Stage I Bladder Cancer
  • Stage II Bladder Cancer
  • Stage III Bladder Cancer
  • Urinary Bladder Neoplasms

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001