Study of Polyphenon E in Men With High-grade Prostatic Intraepithelial Neoplasia

Study Overview
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Brief Summary
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The purpose of this study was to determine whether the daily consumption of decaffeinated green tea catechins (Polyphenon E®) for 1 year reduces the rate of progression to prostate cancer (PCa) in men diagnosed with HGPIN or ASAP. The aim was to recruit and treat 240 (120 men/arm) men diagnosed with the prostate condition HGPIN or ASAP with a capsule form of standardized green tea extract called Polyphenon E or placebo for a 12-month period and see if it can prevent progression of the prostate condition to prostate cancer. Investigators wanted to see if Polyphenon E reduces lower urinary tract symptoms and if this can be taken safely over one year. Investigators wanted to study how Polyphenon E is able to slow the progression to prostate cancer, or the mechanism of action of Polyphenon E. If the safety and the effects of Polyphenon E on slowing down the progression of prostate cancer is shown in our study, this will be a safe way of treating men who are at high risk or men like you who have a prostate condition that increases your chances of getting prostate cancer, so that we can prevent prostate cancer in the future.

Detailed Description
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At the baseline/randomization visit, a QOL (Medical Outcomes Study Short Form-36) and lower urinary tract symptoms (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 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, lactate dehydrogenase (LDH) and prothrombin time/partial thromboplastin time (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 3 and 6 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 digital rectal exam (DRE) and prostate specific antigen (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 6-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 2-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.

Official Title
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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)

Conditions
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Prostatic Hyperplasia

Intervention / Treatment
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* Drug: Polyphenon E
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 participant to gastrointestinal bleeding (acute or chronic gastritis or colitis, or acute diverticulitis or hemorrhoids) 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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Polyphenon E Treatment<br>Polyphenon E, 200 mg epigallocatechin gallate (EGCG) twice a day (BID) | Drug: Polyphenon E<br>* Polyphenon E, at a dose of 400 mgs EGCG (200 mgs BID) for 1 year in men diagnosed with HGPIN and ASAP.<br>* Other names: PolyE;|
| Placebo Comparator: Placebo Administration<br>Matching placebo BID | Drug: Placebo<br>* Matching placebo BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Progression to Prostate Cancer (PCa) | Number of participants with diagnosis of high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) who progressed to prostate cancer (PCa) at one year. | 12 months | 
| Rate of Progression From HGPIN to ASAP or PCa | Analyses of participants reaching a definitive endpoint. Number of baseline HGPIN participants who progressed to ASAP or PCa. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Emergent Adverse Events (AEs) | Safety of Polyphenon E (200 mg EGCG bid for one year) in men with HGPIN or ASAP. Number of participants with AEs Possibly or Probably related to treatment. | 12 months | 
| Occurrence of Grade 3 or Higher Adverse Events (AEs) | Number of participants with AEs grade 3 or higher, per treatment arm. | 12 months | 
| Median Serum Total Prostatic Specific Antigen (tPSA) | Median ng/mL serum tPSA post treatment, per treatment arm. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, PIN, polyphenon E, EGCG