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

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.

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.

1. For radical prostatectomy the threshold for this study is PSA ≥ 0.2ng/mL

2. 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).

3. 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:

1. Absolute neutrophil count greater than or equal to 1,000/mL

2. Hemoglobin greater than or equal to 10 g/dL

3. Platelets greater than or equal to 100,000/mL

4. Total bilirubin within normal institutional limits

5. AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional ULN

6. Creatinine clearance greater than or equal to 60 mL/min/1.73 m2

7. Hgb A1c ≤ 6.5

Exclusion Criteria:

Evidence of metastatic disease on imaging studies (CT and/or bone scan)

Diagnosis of diabetes mellitus defined as

1. Fasting blood glucose > 126 mg/dl or,

2. Random blood glucose > 200 mg/dl

3. 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.