Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well metformin hydrochloride works compared to placebo in treating patients with prostate cancer undergoing surgery. Metformin hydrochloride may make some enzymes active. These enzymes may block other enzymes needed for cell growth and stop the growth of tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the effect of 4-12 weeks of metformin (metformin hydrochloride) intervention on cell proliferation in the prostatectomy tissue. SECONDARY OBJECTIVES: I. To determine the effect of metformin intervention on prostate tissue bioavailability of metformin. II. To determine the effect of metformin intervention on apoptosis and angiogenesis in the prostatectomy tissue. III. To determine the effect of metformin intervention on potential molecular targets of metformin including activated protein kinase (AMPK) activation, mammalian target of rapamycin (mTOR) regulation, and cell cycle regulation in the prostatectomy tissue. IV. To determine the effect of metformin intervention on changes in systemic hormones and growth factors that have been shown to be modulated by metformin in other patient populations including fasting glucose, fasting insulin, insulin-like growth factor axis, testosterone, and sex hormone binding globulin (SHBG). V. To determine the effect of metformin intervention on changes in prostate-specific antigen (PSA) levels. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive extended-release metformin hydrochloride orally (PO) once daily (QD) for 4-12 weeks. ARM II: Patients receive placebo PO QD for 4-12 weeks. Patients in both arms undergo surgery one day after completion of treatment. After completion of study treatment, patients are followed up within 30 days of surgery.

Official Title
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Phase II Study of Metformin in a Pre-prostatectomy Prostate Cancer Cohort

Conditions
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Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage I Prostate Cancer, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer

Intervention / Treatment
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* Drug: metformin hydrochloride
* Other: placebo
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men will be eligible to this study if they are diagnosed with a histologically confirmed organ-confined adenocarcinoma of the prostate (PCa) treatable by prostatectomy and have a current PSA less than 50 ng/ml Have not received chemotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) in the past 5 years Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 70%) Leukocytes >= 3,000/uL Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin =< 1.5 times institutional upper limits of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 times institutional ULN Creatinine within normal institutional limits Willing to use adequate contraception (barrier method, abstinence, subject has had a vasectomy or partner is using effective birth control or is postmenopausal) for the duration of study participation Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Type I or type II diabetic patients on treatment with any drug for diabetes or participants with fasting glucose >= 126 mg/dL History of impaired liver or kidney function Participants with a current history of high alcohol consumption (> 3 standard drinks/day) or binge drinking (5 or more drinks) in one session of 1-3 hours History of lactic acidosis or at increased risk for lactic acidosis such as patients with unstable or acute congestive heart failure who are at risk of hypoperfusion with hypoxemia Participants may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical composition to metformin Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements History of acute or chronic metabolic acidosis Concurrent use of cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) Concurrent use of non-study metformin or other biguanides

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (metformin hydrochloride)<br>Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks. | Drug: metformin hydrochloride<br>* Given PO<br>* Other names: Glucophage;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD for 4-12 weeks. | Other: placebo<br>* Given PO<br>* Other names: PLCB;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cell Proliferation in the Prostatectomy Tissue as Assessed by Ki67 Expression Using Immunohistochemistry (IHC) | Data between the two study groups will be compared using a two-group t-test at a two-sided 0.05 level of significance. If the data are not normally distributed, a non-parametric rank-sum test will be utilized. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate Tissue Metformin Concentration Levels as Assessed by Liquid Chromatography Tandem Mass Spectrometry |  | 12 weeks | 
| Apoptosis Levels in the Prostatectomy Tissue as Assessed by IHC of Cleaved Caspase 3 | Average number of positively stained cells that exhibited nuclear fragmentation from five randomly selected high-power fields (40x) in the tumor region was calculated for each participant | 12 weeks | 
| Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Cyclin D1 |  | 12 weeks | 
| mTOR Regulation in the Prostatectomy Tissue as Assessed by IHC of Phospho-p70 S6 Kinase (p-p70S6K) |  | 12 weeks | 
| Angiogenesis in the Prostatectomy Tissue as Assessed by IHC of CD34 |  | 12 weeks | 
| AMPK Activation in the Prostatectomy Tissue as Assessed by IHC of p-AMPK |  | 12 weeks | 
| Cell Cycle Regulation in the Prostatectomy Tissue as Assessed by IHC of Retinoblastoma Protein Phosphorylation (p-pRb) |  | 12 weeks | 
| Changes in Serum PSA |  | Baseline and 12 weeks | 
| Changes in Serum Fasting Insulin |  | Baseline and 12 weeks | 
| Changes in Serum IGF-1/IGFBP-3 |  | Baseline and 12 weeks | 
| Changes in Serum Testosterone |  | Baseline and 12 weeks | 
| Changes in Serum SHBG |  | Baseline and 12 weeks | 
| Changes in Serum Fasting Glucose |  | Baseline and 12 weeks |