Bicalutamide With or Without Metformin for Biochemical Recurrence in Overweight or Obese Prostate Cancer Patients

Study Overview
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Brief Summary
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Obesity and metabolic syndrome are prevalent among prostate cancer patients. Having an elevated insulin level in the blood is associated with a shorter median time to cancer progression and median overall survival in patients with an elevated PSA after prior treatment. Androgen deprivation therapy (ADT) with drugs like bicalutamide is frequently used in this patient population,with no proven benefit, which may increase mortality and morbidity.This study evaluates how metformin in combination with bicalutamide affects prostate cancer.

Detailed Description
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1 Cycle = 28 days = 4 weeks. Treatment will be administered on an outpatient basis ӿ Metformin starting dose is 500 mg BID, will be gradually increased to target dose of 1000mg BID. Treatment ARM A Cycles 1 - 2: Observation without treatment Cycles 3 - 8: Bicalutamide 50 mg daily, orally, continuously to the end of study (week 32). Treatment ARM B Cycles 1 - 2: In order to minimize gastrointestinal discomfort, metformin dosing will be ramped up over a period of 2 weeks. Metformin treatment will be started at 500 mg BID (Dose Level -2) and increased by an increment of 500 mg daily every week +/- 2 days provided no grade 2 or higher gastrointestinal toxicity is noted. If grade 2 or greater gastrointestinal toxicity occurs during the first 4 weeks of treatment, the subject will be evaluated every 2 weeks until resolution of toxicity to grade 0 or 1 and, then, the metformin dose will be increased to the next dose level. The target dose of metformin is 1000 mg BID.

Official Title
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Bicalutamide With or Without Metformin for Biochemical Recurrence in Overweight or Obese Prostate Cancer Patients (BIMET-1)

Conditions
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Cancer of Prostate

Intervention / Treatment
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* Drug: Observation and Bicalutamide
* Drug: Metformin and Bicalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and the willingness to sign a written informed consent Male 18 years or older Histologically or cytologically confirmed diagnosis of prostate cancer Patient must have had previous treatment with definitive surgery or radiation therapy or cryoablation Patient may have prior salvage therapy (surgery, radiation or other local ablative procedures) within 6 months prior to randomization if the intent was for cure.Prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to randomization is allowed BMI > 25 at study entry Patient may have had prior neoadjuvant and/or adjuvant therapy (chemotherapy, vaccines or experimental agents) within 4 weeks prior to randomization, if the PSA rise and PSADT were documented after the testosterone level was > 150ng/dL. Patient must have hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150 ng/dL within 12 weeks prior to randomization. PSA must be < 30 ng/mL at study entry Patient may not have had therapy modulating testosterone levels (such as luteinizing hormone,releasing-hormone agonists/antagonists and antiandrogens) within 1 year prior to randomization, unless it was in the neoadjuvant and/or adjuvant setting Patient must have evidence of biochemical failure after primary therapy and subsequent progression. Biochemical failure is declared when the PSA reaches a threshold value after primary treatment and it differs for radical prostatectomy or radiation therapy. For radical prostatectomy the threshold for this study is PSA ≥ 0.2ng/mL For radiation therapy the threshold is a PSA rise of 2 ng/mL above the nadir PSA achieved post radiation with or without hormone therapy (2006 RTOG-ASTRO Consensus definition). PSA progression requires a PSA rise above the threshold measured at any time point since the threshold was reached. PSA doubling time between 3 and 9 months. PSA calculation requires two consecutive PSA rises (PSA2 and PSA3) above the threshold PSA (total 3 PSA values); PSA2 and PSA3 must be obtained within 12 months of study entry. All baseline PSAs should be obtained at the same reference lab. Patient's PSA doubling time must be calculated using the following formula (http://www.mskcc.org/nomograms/prostate/psa doubling-time): ECOG performance status less than or equal to 2 Ability to swallow the study drugs Subjects must have normal organ and marrow function as defined below: Absolute neutrophil count greater than or equal to 1,000/mL Hemoglobin greater than or equal to 10 g/dL Platelets greater than or equal to 100,000/mL Total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional ULN Creatinine clearance greater than or equal to 60 mL/min/1.73 m2 Hgb A1c ≤ 6.5 Exclusion Criteria: Evidence of metastatic disease on imaging studies (CT and/or bone scan) Diagnosis of diabetes mellitus defined as Fasting blood glucose > 126 mg/dl or, Random blood glucose > 200 mg/dl Hemoglobin A1C > 6.5% Need for treatment with any conventional modality for prostate cancer (surgery, radiation therapy, and hormonal therapy) Prior hormonal therapy for recurrent prostate cancer (hormonal therapy given in a neoadjuvant or adjuvant setting and greater than 6 months before entry is acceptable) Treatment within the last 30 days with any investigational drug Radiation therapy within prior 6 months (prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to randomization is allowed) Known hypersensitivity to metformin Prior history of lactic acidosis Any history of myocardial infarction in the past 12 months Subjects who consume more than 3 alcoholic beverages per day Subjects with serious intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or other nonmalignant medical or psychiatric illness that is uncontrolled or whose control may be jeopardized by the complications of this therapy or may limit compliance with the study requirements (at the discretion of the investigator) Patient with previous or concurrent malignancy. Exceptions are made for patients who meet any of the following conditions: Basal cell or squamous cell carcinoma of the skin or prior malignancy that has been adequately treated and patient has been continuously disease free for ≥ 2 years. Subjects currently treated with metformin and/or bicalutamide or who have been treated with metformin and/or bicalutamide in the past 6 months. Subjects who have taken 5a-reductase inhibitors (finasteride or dutasteride), saw palmetto, or PC-SPES within the last 6 weeks are ineligible. Subjects will be eligible for the study after the wash out period of 6 weeks.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Observation and Bicalutamide<br>Cycles 1-2: Observation without treatment Cycles 3-8: Bicalutamide 50 mg daily continuously to end of study | Drug: Observation and Bicalutamide<br>* Cycles 1 - 2: Observation without treatment Cycles 3 - 8: Bicalutamide 50 mg daily, orally, continuously to the end of study (week 32).<br>|
| Experimental: Metformin and Bicalutamide<br>Cycles 1-2: Metformin 1000mg BID Cycles 3-8: Bicalutamide 50 mg daily and Metformin 1000 mg BID | Drug: Metformin and Bicalutamide<br>* Cycles 1-2: Metformin 1000mg BID Cycles 3-8: Bicalutamide 50 mg daily and Metformin 1000 mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Response Rate Based on PSA | Participants with undetectable PSA after 32 weeks | 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Decline ≥ 85% at 32 Weeks | Number of patients with PSA decline ≥ 85% after 32 weeks | 32 Weeks | 
| PSA Decline | Number of patients with PSA decline after 8 weeks (observation vs metformin) | 8 Weeks | 
| Median PSA Decline | Median PSA decline after 8 weeks % (range) | 8 weeks | 
| BMI Decline After 32 Weeks | Number of patients with BMI decline after 32 weeks | 32 Weeks |