Potential subjects are screened by the research coordinator using an Eligibility Checklist. The study population will consist of men who meet the following eligibility criteria: (a) AA and Caucasian men between the ages of 30 (to be inclusive of AA men with earlier age diagnosis) and 80; (b) diagnosis of localized CaP, based on pathological assessment from biopsy specimens; (c) with no prior or current therapy for CaP or history of cancer except non-melanoma skin cancer; (d) scheduled for prostatectomy between 4–6 weeks (+/− 3) days after registration; (e) No known history of hepatic or renal disease (LFTs (SGOT/SGPT) < 2.5 x upper limit of normal, Actual creatinine clearance of >60 utilizing the Cockroft-Gault formula (1976), which employs creatinine measurements and a patient’s weight to predict the clearance. A modification of this formula, useful for the common units of measure is as follows: X=(140-age) x Weight in Kgs x Constant/Creatinine in μmol/L. The constant is 1.23 for men and 1.04 for women); (f) Omnivorous diet; (g) No evidence of prostatitis or urinary tract infection; (h) Able and willing to give written informed consent; (i) Currently not using nutritional supplements (other than the multivitamin/mineral provided for all study participants); (j) not allergic to study supplements; (k) not on antibiotics; (l) men who do not consume more than 3 oz – 4 oz of soy or soy products per week; (m) willing to comply with scheduled visits as proposed for 4–6 weeks; (n) not taking steroid hormones or medications which have known impact on PSA; (o) health status cleared by primary MD or urologist and (p) ECOG performance status of 0–1. Allowing a dropout rate of 20% as previously observed in chemoprevention trials, we plan to recruit 130 AA men and 130 Caucasian men (n=260; 65/arm) to total 260 men over the study period. Once eligibility is determined, subjects are then provided with information about the research study and informed of the experimental nature of therapy, alternatives, potential benefits, sideeffects, risks and discomforts. Interested subjects who appear eligible based on information available at this time are given the opportunity to sign an Informed Consent document.
All subjects who sign an Informed Consent document are assigned a registration number assigned by the clinic site. As subjects are registered, demographic information and registration information are entered into a computerized system for tracking purposes. Participating subjects have blood drawn for confirmation of eligibility, if not available from within the last fourteen days (e.g., to verify normal liver function). Subjects are provided with: (a) an information package regarding the study; (b) lists of foods, medications and nutritional supplements to avoid during the study period; (c) log for recording study agent intake (which includes assessment for AEs and concomitant medications); (d) two-day diet recall forms with instructions; (e) Godin-Leisure Time Exercise questionnaire.
There is no run-in period for this study. Only men meeting all inclusion and exclusion criteria are randomized to a treatment or placebo arm using the Moffitt SRARS program, a web delivered application that records subject registrations and provides blocked randomization assignments. A protocol is developed in the SRARS program using randomization lists, stratified by race (AA and other) and by site was developed by the Moffitt Statistics department, to ensure that for every site with subjects in the 2 racial groups, a corresponding placebo and treatment assignment is planned. Descriptive summary statistics will be reported on patient characteristics at baseline (epidemiological data including demographics, personal and physical characteristics, family history, history of environmental and personal exposures, alcohol intake, dietary and physical activity, cancer screening, medication use including nutritional supplements and dietary intake, and several plasma and serum biomarker levels) as well as outcome variables at 4–6 weeks post intervention, respectively, both by arm and race. An attempt will be made to discern any possible differences in the baseline patient characteristics between the two arms within each race group. This will hopefully identify any imbalances that may be large enough but have occurred at randomization by chance that will need to be controlled for in the statistical analyses in order not to confound the study results and their interpretations. All baseline group comparisons of demographic, anthropometrics, clinical, and dietary measures will be conducted empirically without using formal statistical tests.
As this is a double-blinded study, the treatment/randomization is hidden from all users except the pharmacist preparing and labeling the treatment drug. Once the randomization is complete, the study agent is mailed overnight via UPS. If lab results disqualify from participation, subjects are notified of results and taken off study. They are also given an opportunity to speak with the study physician, a copy of their labs made available to them and the samples collected during screening are destroyed.
At the end of the study, on the day of prostatectomy, participants undergo interviews and serum, plasma and tissue samples are obtained. Laboratory analysis is completed for safety (the determination of and the absence of toxicity caused by the study agent) and compliance, as well as evaluation of the biochemical and mechanistic molecular markers considered in this study (Scheme 1: Study Schema).
Phase II Clinical Trial of Purified Isoflavones in Prostate Cancer: Comparing Safety, Effectiveness and Mechanism of Action between African American and Caucasian Men.
African American (AA) and Caucasian men between the ages of 30 (to be inclusive of AA men with earlier age diagnosis) and 80 with a diagnosis of localized CaP, based on pathological assessment from biopsy specimens;
with no prior or current therapy for CaP or history of cancer except non-melanoma skin cancer;
scheduled for prostatectomy between 4–6 weeks (+/−3 days) after start of study agent (n=260)
Screening/Randomization: Informed consent; confirm diagnostic prostate biopsy pathology; Digital Rectal Exam (DRE); Prostate Specific Antigen (PSA); (DRE and PSA do not need to be repeated if results are available from pre-biopsy tests); Comprehensive Metabolic Panel (CMP) including LFTs; Complete Blood Count (CBC) (these do not need to be completed if results available from within 14 days prior to randomization); serum steroid hormones; collect plasma for baseline isoflavone measurements; collect buffy coat for banking; obtain anthropometric measurements (weight, height, BMI, waist and hip circumference); On-study Epidemiological Questionnaire; assess baseline Lower Urinary Tract Symptoms (LUTS) score; signs and symptoms assessment; concomitant medication assessment; distribute and collect Godin-Leisure Time Exercise Questionnaire; distribute instructions and forms for 2-day Diet Recall; obtain tissue from diagnostic biopsy for baseline measurements; randomize to active agent (40 mg purified isoflavones daily) or placebo (n=65/arm)
Intervention: Confirm eligibility based on screening tests; self administration of purified isoflavones (40 mg daily) or placebo for 4–6 weeks; weekly telephone contact to assess signs and symptoms and concomitant medications while on study
End of Intervention (Week 6 or time of Prostatectomy): Prostate Specific Antigen (PSA); Comprehensive Metabolic Panel (CMP) including LFTs; Complete Blood Count (CBC); serum steroid hormones; collect plasma for isoflavone measurements; collect buffy coat for banking; obtain anthropometric measurements (weight, height, BMI, waist and hip circumference); collect and review 2-day Diet Recall forms; signs and symptom assessment; concomitant medication assessment; review study agent intake log and check compliance (pill count); assess end of intervention Lower Urinary Tract Symptoms (LUTS); distribute and collect Godin-Leisure Time Exercise Questionnaire
Post-intervention Follow-up (7 days (+/−3 days) post-treatment): Telephone contact to assess signs and symptoms and concomitant medications occurring post-treatment
Efficacy (Primary): Change in percent Ki-67 evaluated in prostate cancer tissue specimens after 4–6 weeks of intervention with purified isoflavones (40 mg daily) vs. Placebo.
Safety (Primary): Incidence and severity of AEs occurring during intervention with either 20 mg purified isoflavones bid or placebo.
Secondary (When tissue available):
→ Drug effect measurements in tissue samples
→ To determine if purified isoflavones (40 mg daily) vs. placebo results in decreased expression of the androgen receptor and increased expression levels of FOXO1 and its target genes from baseline to prostatectomy in prostate cancer patients
→ Whether the treatment effect of the study agent in the AR-FOXO axis is more profound in AA patients as compared to the Caucasian group and correlates inversely with ERα/ERβ ratio