Metformin Hydrochloride in Treating Patients With Prostate Cancer Undergoing Surgery

• Prostate tissue metformin concentration levels as assessed by liquid chromatography tandem mass spectrometry [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Comparison of apoptosis (cleaved caspase 3), angiogenesis (CD34), AMPK activation (p-AMPK), mTOR regulation (p-p70S6K), cell cycle regulation (cyclin D1and p-pRb) in the prostatectomy tissue between study groups as assessed by IHC [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Comparison of changes in serum PSA, fasting glucose, fasting insulin, IGF-1/IGFBP-3, testosterone, and SHBG between study groups as assessed by liquid chromatography-tandem mass spectrometry assay [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]

• metformin concentration in prostate tissue removed at surgery [ Time Frame: after 4-12 weeks of agent intervention ] [ Designated as safety issue: No ]
• molecular changes in prostate tissue removed at surgery [ Time Frame: after 4-12 weeks of agent intervention ] [ Designated as safety issue: No ]
• Blood hormones/proteins related to prostate cancer risk [ Time Frame: after 4-12 weeks of agent intervention ] [ Designated as safety issue: No ]

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

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 prostate tissue bioavailability of metformin. II. To determine apoptosis and angiogenesis in the prostatectomy tissue. III. To determine potential molecular targets of metformin including AMPK activation, mTOR regulation, and cell cycle regulation in the prostatectomy tissue.

IV. To determine 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 changes in prostate-specific antigen (PSA) levels.

OUTLINE: Patients are stratified by whether or not the institution will provide fresh frozen tissue for measurement of tissue metformin hydrochloride concentrations. 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. Paraffin-embedded blocks or slides from diagnostic biopsy and tumor tissue samples from prostatectomy are collected for cell proliferation and biomarker studies by sensitive liquid chromatography-tandem mass spectrometric, and immunohistochemistry. Patients also undergo serum sample collection at baseline and after completion of study treatment for PSA, fasting glucose, fasting insulin, insulin-like growth factor (IGF-1, IGFBP3, and SHBG), testosterone, and SHBG by ELISA and liquid chromatography-tandem mass spectrometry assay.

After completion of study treatment, patients are followed up within 30 days of surgery.

• Adenocarcinoma of the Prostate
• Stage I Prostate Cancer
• Stage IIA Prostate Cancer
• Stage IIB Prostate Cancer

• Drug: metformin hydrochloride
  Given PO
  Other Name: Glucophage
• Other: placebo
  Given PO
  Other Name: PLCB

• Experimental: Arm I
  Patients receive extended-release metformin hydrochloride PO QD for 4-12 weeks.
  Intervention: Drug: metformin hydrochloride
• Placebo Comparator: Arm II (placebo)
  Patients receive placebo PO QD for 4-12 weeks.
  Intervention: Other: placebo

Inclusion Criteria:

Men will be eligible to this study if they are diagnosed with a biopsy-proven 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/μL Absolute neutrophil count ≥ 1,500/μL Platelets ≥ 100,000/μL Total bilirubin ≤ 1.5 times institutional upper limits of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic 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 No type I or type II diabetic patients on treatment with any drug for diabetes or participants with fasting glucose ≥ 126 mg/dL No history of impaired liver or kidney function No 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 No 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 No history of allergic reactions attributed to compounds of similar chemical composition to metformin No 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 No history of acute or chronic metabolic acidosis Participants may not be receiving any other investigational agents No plan to undergo radiologic studies involving intravascular administration of iodinated contrast materials No concurrent use of cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) No concurrent use of non-study metformin or other biguanides