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.