Pomegranate-Extract Pill in Preventing Tumor Growth in Patients With Localized Prostate Cancer Undergoing Active Surveillance

Study Overview
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Brief Summary
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This randomized phase II trial studies pomegranate-extract pill in preventing tumor growth in patients with prostate cancer that is limited to a certain part of the body (localized), who have chosen observation as their treatment plan. The use of pomegranate-extract pill may slow disease progression in patients with localized prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the effect of pomegranate fruit extract (PFE) 1000 mg, taken daily for 1 year, on the plasma levels of insulin-like growth factor (IGF-1) from baseline to end of study (52 weeks) in participants undergoing active surveillance (AS) for early stage prostate cancer. SECONDARY OBJECTIVES: I. To assess compliance with a once daily oral administration of PFE versus placebo over a 52-week period of time. II. To assess the toxicity of PFE vs. placebo when taken daily for 52 weeks (+/- 1 week). III. To compare and correlate the effect of 52 weeks of daily dosing with PFE vs placebo on the end of study biopsy results including the presence or absence of tumor, the extent of tumor and Gleason scores. IV. To compare and correlate the modulation of the following biomarkers with response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core, tumor tissue from a positive core, and normal tissue adjacent to tumor from a positive core; plasma: insulin-like growth factor 1/IGF binding protein 3 ratio (IGF-1/IGFBP-3 ratio); prostate tissue (normal and abnormal): apoptosis (CASPASE 3), Ki-67, 8OHdG, IGF-1R, androgen receptor, IGF-1, IGFBP-3, prostate specific antigen (PSA). V. Measure PFE constituents/metabolites in plasma and urine for evidence of accumulation (trough levels): ellagic acid, dimethyl ellagic acid, dimethyl ellagic acid glucuronide (DMEAG), urolithin A, urolithin A-glucuronide, urolithin B and urolithin B-glucuronide. VI. Measure PSA doubling time (PSA DT) in serum, using the calculation provided on the Memorial Sloan Kettering Cancer Center website. VII. To assess the feasibility of cancer chemoprevention trials in a population of men undergoing active surveillance for prostate cancer. VIII. Measurement of serum testosterone. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive pomegranate-extract pill orally (PO) once daily (QD) for 52 weeks (+/- 1 week). GROUP II: Patients receive placebo PO QD for 52 weeks (+/- 1 week).

Official Title
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A Phase IIA Exploratory, Randomized, Placebo-Controlled Trial of Pomegranate Fruit Extract/Pomx™ in Subjects With Clinically Localized Prostate Cancer Undergoing Active Surveillance

Conditions
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PSA Level Less Than or Equal to Fifteen, PSA Level Less Than Ten, Stage I Prostate Cancer AJCC v7, Stage II Prostate Cancer AJCC v7, Stage IIA Prostate Cancer AJCC v7, Stage IIB Prostate Cancer AJCC v7

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Placebo
* Drug: Pomegranate-Extract Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have had a standard-of-care biopsy within 13 months of the baseline study visit and must have been diagnosed with low-grade, clinically localized prostate cancer (Gleason score =< 3+3 with a PSA at baseline < 10 ng/ml in participants < 70 years of age, OR Gleason score =< 3+4 with a PSA at baseline =< 15 ng/ml in participants >= 70 years of age); eligible participants will be those men who are able and willing to undergo AS with PSA monitoring and a scheduled biopsy performed at the end of the study No concurrent treatment (hormonal, radiation or systemic chemotherapy) for prostate cancer during study enrollment is planned (unless participants demonstrate clinical evidence of prostate cancer progression such as symptoms, physical exam findings, a rapidly increasing PSA, or radiologic findings which confirm disease progression) Eastern Cooperative Oncology Group (ECOG) performance status =< 1 White blood cells (WBC) >= 3000/mm^3 Platelets >= 100,000 mm^3 Hemoglobin >= 10 g/dL Total bilirubin =< 1.5 x upper limit of institutional normal Alkaline phosphatase =< 1.5 x upper limit of institutional normal Aspartate aminotransferase (AST) =< 1.5 x upper limit of institutional normal Alanine aminotransferase (ALT) =< 1.5 x upper limit of institutional normal Serum creatinine within 1.5 x upper limit of institutional normal Sodium 135-144 mmol/L (inclusive) Potassium 3.2-4.8 mmol/L (inclusive) Participants will be required to use a medically-approved method of birth control or abstinence if their sexual partner is of child-bearing potential Participants must be willing to forego foods, beverages and supplements containing pomegranate for the duration of the study Ability to understand, and the willingness to sign, a written informed consent document Exclusion Criteria: Any prior surgery to the prostate within 30 days of baseline procedures; NOTE: Biopsies are not considered surgeries Evidence of other cancer(s) (excluding non-melanoma skin cancer) within last 5 years Prior pelvic radiation for any reason Participants cannot be taking 5-alpha-reductase inhibitors while on study or within 6 months of the baseline study visit Participants may not be taking carbamazepine (tegretol) Participants may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to PFE Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements Any significant cardiac event(s) within the 12 months prior to registration, such as episode(s) of symptomatic congestive heart failure, myocardial infarction, unstable angina pectoris or persistent, stable angina pectoris, or cardiac arrhythmia requiring medication

Ages Eligible for Study
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Minimum Age: 21 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (pomegranate-extract pill)<br>Patients receive pomegranate-extract pill PO QD for 52 weeks (+/- 1 week). | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Pomegranate-Extract Pill<br>* Given PO<br>* Other names: POMx;|
| Placebo Comparator: Group II (placebo)<br>Patients receive placebo PO QD for 52 weeks (+/- 1 week). | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma IGF-1 From Baseline to Post-Treatment | The primary endpoint for modulation of intermediate endpoint biomarkers will be the change in the plasma levels of IGF-1 by a quantitative assay (ELISA) from pre-study to post-treatment. The difference between these time points for the placebo group and the pomegranate fruit extract (PFE) group will be tested using a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test. | Baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance: Number of Participants Who Took Study Drug Per Protocol | Summarized by treatment arm with descriptive statistics, and tested for imbalance using Wilcoxon rank-sum test. Reported for each visit per protocol at Week 13, Week 26, Week 39, and Week 52 (end of study). | Up to 1 year | 
| Incidence of Adverse Events Graded Per Common Terminology Criteria for Adverse Events (CTCAE) | Patient toxicity throughout the study will be summarized in several ways; the presence or absence of any toxicity, worst CTCAE grade, and strongest investigator-defined relationship will all be examined and characterized by treatment arm, and analyzed appropriately (Wilcoxon rank-sum for ordinal data, Fisher's exact test for dichotomous data, and log rank test for time to event data). | Up to 1 year | 
| Change in Plasma Biomarker Levels From Baseline: IGFBP-3 | Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Week 13, Week 26, Week 39, Week 52 | 
| Change in Plasma Biomarker Levels From Baseline: IGF-1/GFBP-3 | Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Week 13, Week 26, Week 39, Week 52 | 
| Change in Total Serum Prostate Specific Antigen (PSA) From Baseline |  | Up to 1 year | 
| Change in Serum Testosterone |  | up to 1 year | 
| Prostate Specific Antigen Doubling Time (PSA DT) | PSA DT will be determined from PSA values obtained during study participation (baseline and weeks 13, 26, 39 and 52). The secondary endpoint of PSA DT is based on the value at study completion (week 52 or at point of early termination). However, PSA DT will be determined starting at week 26 (the earliest time point with 3 values) and week 39 and recorded. PSA doubling time is a measure based on the slope of the PSA at multiple time points. If the slope is relatively flat, the predicted doubling time could be far beyond the length of the actual study. As such, the value is not limited to the time frame over which data is collected from the participant. | up to 52 Weeks | 
| Change in Tissue Biomarker Levels: PSA | Compare and correlate biomarker modulation in response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core (benign in results), tumor tissue from a positive core (tumor in results), and normal tissue adjacent to tumor from a positive core (adjacent in results). Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Baseline to Week 52 | 
| Change in Tissue Biomarker Levels: IGF-1 | Compare and correlate biomarker modulation in response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core (benign in results), tumor tissue from a positive core (tumor in results), and normal tissue adjacent to tumor from a positive core (adjacent in results). Measurements for each are per nuclear (Nuc in results), cytoplasmic (Cyt in results), and cellular (Cell in results) basis. Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Baseline to Week 52 | 
| Change in Tissue Biomarker Levels: IGFBP-3 | Compare and correlate biomarker modulation in response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core (benign in results), tumor tissue from a positive core (tumor in results), and normal tissue adjacent to tumor from a positive core (adjacent in results). Measurements for each are per nuclear (Nuc in results), cytoplasmic (Cyt in results), and cellular (Cell in results) basis. Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Baseline to Week 52 | 
| Change in Tissue Biomarker Levels: CASP3 | Compare and correlate biomarker modulation in response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core (benign in results), tumor tissue from a positive core (tumor in results), and normal tissue adjacent to tumor from a positive core (adjacent in results). Measurements for each are per nuclear (Nuc in results), cytoplasmic (Cyt in results), and cellular (Cell in results) basis. Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Baseline to Week 52 | 
| Change in Tissue Biomarker Levels: Ki-67 | Compare and correlate biomarker modulation in response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core (benign in results), tumor tissue from a positive core (tumor in results), and normal tissue adjacent to tumor from a positive core (adjacent in results). Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Baseline to Week 52 | 
| Change in Tissue Biomarker Levels: IGF-Rb | Compare and correlate biomarker modulation in response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core (benign in results), tumor tissue from a positive core (tumor in results), and normal tissue adjacent to tumor from a positive core (adjacent in results). Measurements for each are per nuclear (Nuc in results), cytoplasmic (Cyt in results), and cellular (Cell in results) basis. Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Baseline to Week 52 | 
| Change in Tissue Biomarker Levels: 8OHdG | Compare and correlate biomarker modulation in response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core (benign in results), tumor tissue from a positive core (tumor in results), and normal tissue adjacent to tumor from a positive core (adjacent in results). Measurements for each are per nuclear (Nuc in results), cytoplasmic (Cyt in results), and cellular (Cell in results) basis. Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Baseline to Week 52 | 
| Change in Tissue Biomarker Levels: AR | Compare and correlate biomarker modulation in response to PFE versus placebo in three areas of interest: tissue from a completely benign biopsy core (benign in results), tumor tissue from a positive core (tumor in results), and normal tissue adjacent to tumor from a positive core (adjacent in results). Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Baseline to Week 52 | 
| Change in Levels of Pomegranate Fruit Extract (PFE) Constituents/Metabolites: Urolithin A | Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Change from Baseline at Week 13, Week 26, Week 39, and Week 52 | 
| Change in Levels of PFE Constituents/Metabolites: Urolithin B | Differences between the groups will be examined for the change from baseline with the appropriate tests; for dichotomous data Fisher's exact test will be used, for ordinal data Wilcoxon rank-sum test will be used, and for continuous data, and a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | Change from Baseline at Week 13, Week 26, Week 39, and Week 52 | 
| Change in Gleason Score | The Gleason Score is a grading system used to determine the aggressiveness of prostate cancer, scored 1-5 with 1 being healthy tissue and 5 being abnormal. Prostate cancers are assigned 2 scores to define the 2 most prevalent tissue types. They are added together (total range of 2-10). Typical scores fall between 6-10, the higher the overall score, the more likely the cancer will spread. | Baseline to 1 year | 
| Change in Biopsy Tumor Involvement on Prostate Biopsy | Change in the length of biopsy cores that contained cancerous tissue from Baseline to end of study. | Baseline to 1 year |