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Phase II, Randomized, Double-blind, Multi-centered Study of Polyphenon E in Men With High-grade Prostatic Intraepithelial Neoplasia (HGPIN) or Atypical Small Acinar Proliferation (ASAP)

Phase 2
30 Years
80 Years
Open (Enrolling)
Prostatic Hyperplasia

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Trial Information

Phase II, Randomized, Double-blind, Multi-centered Study of Polyphenon E in Men With High-grade Prostatic Intraepithelial Neoplasia (HGPIN) or Atypical Small Acinar Proliferation (ASAP)

This clinical study is a Phase II, randomized, double-blinded, placebo-controlled trial in
men 30-80 years of age with biopsy proven HGPIN and no evidence of prostate cancer,
prostatitis or urinary tract infection. A total of 272 men will be randomized to the study,
with the goal of completing 240 evaluable participants. Presence of HGPIN and absence of
prostate cancer will be confirmed from a diagnostic biopsy with a minimum of 12 core
biopsies. When possible, samples from the diagnostic biopsy will be used for baseline
endpoint measurements (proteasome inhibition, Ki-67, apoptotic index, exploratory
mechanistic studies) and for tissue banking (if a participant consents). Screening tests
will also include a Demographic Questionnaire, physical exam, DRE, blood chemistry and
hematology, prothrombin time/partial thromboplastin time (PT/PTT), lactose dehydrogenase
(LDH), hepatic function panel and serum PSA. Participants who consent to the study and meet
initial eligibility criteria will be provided with a seven-day multivitamin/mineral
supplement, and will undergo a one-week run-in period during which they will be asked to
self-administer the supplement daily as well as complete study logs and two-day diet recall
forms. Participants must meet all inclusion criteria and remain compliant during the run-in
period to be randomized to a treatment arm. At the baseline/randomization visit, a Medical
Outcomes Study Short Form-36 (QOL)and LUTS score assessment will be completed; urine and
serum will be collected for measurement of diagnostic markers; plasma will be collected for
measurement of baseline catechin levels; serum will be collected for banking; and diet
recall forms will be collected. Participants will be equally randomized (n=136 per arm) to
blinded treatment with either Polyphenon E 200 mg EGCG bid or matching placebo, and an
initial supply of study drug will be dispensed. All participants will also be provided with
a standard multivitamin/mineral supplement to assure consistent, appropriate nutrient intake
among study participants. The planned intervention period is 12 months; participants will
return for monthly clinic visits during the intervention period. At each monthly clinic
visit, blood will be drawn for repeat hepatic function panel, LDH and PT/PTT, and
participants will be interviewed to review and capture information from study agent intake
log (pill count), assess signs and symptoms and concomitant medications; additional study
medication will be dispensed as needed. After three and six months of intervention, blood
will be drawn for serum chemistry and hematology, and LUTS and QOL assessments will be
performed. In addition, at the 6 month visit, two-day diet recall forms will be collected,
blood will be drawn for plasma catechin measurements and serum banking, serum and urine will
be collected for diagnostic marker measurement, and repeat DRE and PSA will be performed. If
there is a palpable prostate nodule or confirmed PSA increase (>0.75 ng/ml) at 6 months, a
repeat biopsy will be performed. If the six-month biopsy shows evidence of disease
progression, participants will stop intervention and proceed to the post-intervention
assessment; otherwise, intervention will continue through month 12. At the end of
intervention (maximum of 12 months), a repeat prostate biopsy will be performed for
post-intervention endpoint measurements. In addition, the physical exam and DRE, LUTS and
QOL will be repeated, and two-day diet recall forms will be collected. Blood will be drawn
for serum chemistry and hematology, PSA, hepatic function panel, LDH, PT/PTT; serum and
urine will be collected for diagnostic marker measurement; plasma will be collected for
catechin measurements; and serum will be collected for banking. Participants will be
interviewed to review and capture information from study agent intake log (pill count),
assess signs and symptoms and concomitant medications. The primary endpoint of the study is
a comparison of the incidence of prostate cancer between participants in the treatment vs.
placebo arm; in addition, the prevalence of HGPIN in pre-treatment and post-treatment
biopsies in participants treated with Polyphenon E vs. placebo will be compared. If
participants develop prostate cancer during the course of the study, the extent and grade of
cancer will be assessed and compared between treatment groups. Other endpoints include:
assessing the safety of Polyphenon E under the proposed dosing regimen; investigating the
effect of Polyphenon E treatment on proteasome activity (chymotrypsin-like activity, IκBα
protein expression, accumulation of p27 proteins, NFκB binding activity), cell proliferation
(Ki-67) and apoptosis (TUNEL) in prostate tissue biopsy samples; correlating changes in
proteasome activity with proliferation and apoptosis; evaluating the potential of ABCA5
level in urine and PCADM-1 level in serum as markers of HGPIN and prostate cancer,
respectively; and evaluating effects of Polyphenon E on these putative diagnostic markers.
Additional exploratory endpoints include treatment-related stabilization and accumulation of
tumor suppressor p53 and pro-apoptotic protein Bax, inhibition of vascular endothelial
growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9
(MMP-9). It is anticipated that approximately 40 months will be required to enroll all
participants; the entire study is expected to take 60 months to complete.

Inclusion Criteria:

- Men with a diagnosis of HGPIN or ASAP in a minimum of 1 of 8 cores from a biopsy
performed within six months of study entry. Diagnosis of HGPIN or ASAP (which
includes men with ASAP and HGPIN) via trans-rectal ultrasound (TRUS biopsy) is also
considered acceptable for inclusion.

- Prostate biopsy with a minimum of 8 cores performed within 6 months of study entry
that shows no evidence of cancer.

- 30−80 years of age at the time of registration

- PSA ≤10 ng/ml

- Omnivorous diet

- Eastern Cooperative Oncology Group (ECOG) performance status 0−2

- Participants must have normal organ and marrow function as demonstrated by the
following parameters being within normal institutional limits: complete blood count
(CBC); liver function tests (LFTs); albumin, total and direct bilirubin, alkaline
phosphatase, aspartic transaminase (AST), alanine transaminase (ALT), and total
protein), PT/PTT, and LDH; serum creatinine <1.5 mg/dl or measured creatinine
clearance 60 cc/min

- Absence of consumption of toremifene citrate, finasteride, testosterone,
dehydroepiandrosterone (DHEA) or other testosterone-like supplements or medications
which have known impact on PSA within 30 days of informed consent, or dutasteride
within 90 days of informed consent

- Absence of consumption of any nutritional or herbal supplements containing green tea
or green tea polyphenols

- No or low regular tea consumption (no more than 3 servings of hot tea or 6 servings
of iced tea per week)

- Willing to discontinue current vitamin/mineral supplement use and substitute with a
standard multivitamin supplement provided for the study

- Willing to use an effective method of contraception, if the partner is of
child-bearing age, while on study

- Willing to comply with proposed visit and treatment schedule

- Able to understand and willing to sign a written informed consent document

Exclusion Criteria:

- Evidence of acute prostatitis or urinary tract infection at the time of PSA
measurement; men may be enrolled 30 days after completion of treatment, provided all
other eligibility criteria are met

- Current or prior history of prostate cancer or other malignancies (exceptions include
non-melanoma skin cancer or other cancer with no evidence of tumor recurrence 5 years
after definitive treatment)

- History of renal or hepatic disease, including history of hepatitis B, C or delta

- Participation in any other investigational study or use of any other investigational
agents within 30 days of study entry

- History of allergic reactions attributed to tea or other compounds of similar
chemical or biologic composition to Polyphenon E or the inactive components present
in Polyphenon E and placebo capsules.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or any psychological, familial, sociological or other concomitant
condition that would not allow adequate compliance with the study protocol

- History of medical conditions that may predispose the subject to gastrointestinal
bleeding (acute or chronic gastritis or colitis, or acute diverticulitis or

- Members of all races and ethnic groups are eligible for this trial. Since this is an
investigation targeting men with HGPIN or ASAP, women are not eligible for the study.

Type of Study:


Study Design:

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

Outcome Measure:

Rate of Progression

Outcome Description:

Rate of progression to prostate cancer at one year in men treated with Polyphenon E (200 mg EGCG twice a day [bid]) following diagnosis of HGPIN or ASAP

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

Nagi Kumar, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

December 2007

Completion Date:

April 2014

Related Keywords:

  • Prostatic Hyperplasia
  • PIN
  • polyphenon E
  • EGCG
  • Prostatic Hyperplasia
  • Neoplasms
  • Hyperplasia
  • Prostatic Intraepithelial Neoplasia
  • Carcinoma in Situ



Minneapolis VA Medical Center Minneapolis, Minnesota  55417
H Lee Moffitt Cancer Center Tampa, Florida  33612
Overton Brooks VA Medical Center Shreveport, Louisiana  71101-4295
LSU Health Sciences Center, Feist-Weiller Cancer Center Shreveport, Louisiana  71130
University of Florida/Shands-Department of Urology Gainesville, Florida  32610
University of Florida - Jacksonville Jacksonville, Florida  32209
Watson Clinic Center for Research, Inc. Lakeland, Florida  33805
James A Haley VA Tampa, Florida  33612
University of Chicago - Department of Surgery Chicago, Illinois  60637
Jefferson Medical College - Department of Urology Philadelphia, Pennsylvania  19107