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.
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
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.
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.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention
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. 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.
End of surgery
University of Wisconsin Hospital and Clinics
United States: Food and Drug Administration
|University of Wisconsin Hospital and Clinics||Madison, Wisconsin 53792-0001|