Study of Metformin With Simvastatin for Men With Prostate Carcinoma

Men who participate in this study will take both metformin and simvastatin every day. Both
drugs are pills and can be taken at home.

Subjects will be asked to take metformin and simvastatin until metastasis from their
prostate cancer appears or until their PSA has doubled from what it was before they started
the study.

Primary Objective:

To define the efficacy, as measured by an improvement in PSA doubling time (PSADT) at 6
months, of the combination of metformin plus simvastatin in patients with recurrent prostate
cancer following definitive treatment.

Secondary Objectives:

1. To define the time to protocol-specified event for men treated with the combination of
metformin plus simvastatin.

2. To describe the pattern of change in log PSA levels and PSA velocity over time during
treatment with metformin plus simvastatin.

3. To describe the associations between changes in metabolic parameters (fasting
glucose/insulin/lipid panel/leptin/adiponectin and others) with the pattern of change
in log PSA levels.

Inclusion Criteria:

The study population will consist of subjects who have undergone primary therapy
(prostatectomy or primary radiation) for biopsy-proven adenocarcinoma of the prostate and
now have biochemical-only recurrence.

1. Ability to understand and the willingness to sign a written informed consent
document.

2. Male 18 years or older.

3. Histologically or cytologically confirmed diagnosis of prostate cancer.

4. Biochemical recurrence following prostatectomy or radiation to the prostate, defined
as at least 3 PSA rises, with each PSA determination at least 4 weeks apart, and each
PSA value greater than or equal to 0.2 ng/mL.

5. PSA must be less than 50 ng/mL at study entry.

6. Screening PSA greater than or equal to 0.5 ng/mL for men who had a prostatectomy.
Prior treatment with neoadjuvant, adjuvant, or salvage radiation therapy is allowed,
again, with screening PSA greater than or equal to 0.5 ng/mL required for
eligibility.

7. Screening PSA greater than or equal to 1.0 ng/mL above their postradiation nadir for
men who were treated with primary radiation therapy (external beam and/or
brachytherapy). Men who had primary radiation therapy followed by salvage
prostatectomy are eligible if screening PSA is greater than or equal to 0.5 ng/mL.

8. PSA doubling time between 3 and 36 months.

9. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
(Karnofsky greater than or equal to 60%).

10. Subjects must have normal organ and marrow function as defined below:

* Leukocytes greater than or equal to 3,000/mcL * Absolute neutrophil count greater
than or equal to 1,500/mcL * Hemoglobin greater than or equal to 10 g/dL * Platelets
greater than or equal to 100,000/mcL * Total bilirubin within normal institutional
limits * AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional upper limit of
normal * Creatinine within normal institutional limits OR creatinine clearance or
calculated greater than or equal to 60 mL/min/1.73 m2 for subjects with creatinine
clearance or estimated creatinine levels above institutional glomerular filtration
rate (eGFR) normal * Creatine phosphokinase (CPK) less than or equal to the
institutional upper limit of normal

11. Ability to swallow the study drugs.

12. Life expectancy of at least 12 months.

13. Subjects should agree to avoid grapefruit juice which is a major inhibitor of CYP3A4.

Exclusion Criteria:

1. Evidence of metastatic disease on imaging studies.

2. Need for treatment with any conventional modality for prostate cancer (surgery,
radiation therapy, and hormonal therapy).

3. 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).

4. Prior chemotherapy for prostate cancer.

5. Treatment within the last 30 days with any investigational drug.

6. Radiation therapy within prior 6 months.

7. Known hypersensitivity to metformin or statins.

8. Subjects who need to take CYP3A4 inhibitors, such as cyclosporin, sirolimus,
tacrolimus, verapamil,danazol, gemfibrozil, ketoconazole, or macrolide antibiotics
(e.g., azithromycin, clarithromycin, erythromycin)will be excluded. Prior use of
these agents is acceptable, as long as they are stopped at least a week prior to
study entry.

9. Subjects who need to take CYP3A4 inducers, such as phenobarbital, dexamethasone,
carbamazepine,phenytoin, rifampicin, or non-nucleoside reverse transcriptase
inhibitors (e.g., efavirenz, nevirapine,etravirine) will be excluded. Prior use of
these agents is acceptable, as long as they are stopped at least a week prior to
study entry.

10. Prior history of rhabdomyolysis.

11. Prior history of lactic acidosis.

12. Any history of myocardial infarction in the past 12 months.

13. HIV-positive status.

14. Subjects who consume more than 3 alcoholic beverages per day.

15. 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).

16. Subjects diagnosed with or treated for another malignancy within 2 years prior to
study enrollment or previously diagnosed with another malignancy and still having any
evidence of residual disease. Subjects with nonmelanoma skin cancer or carcinoma in
situ of any type are not excluded if they have undergone complete resection.

17. Subjects currently treated with metformin or a statin or who have been treated with
metformin or a statin in the past 6 months are ineligible for this study.

18. Subjects who have taken 5a-reductase inhibitors (finasteride or dutasteride), saw
palmetto, or PC-SPES within the last 6 weeks are ineligible for this study. Subjects
taking other herbal supplements, vitamins, or other alternative medications are
eligible for this study as long as they were started more than 2 months prior to
study entry, have remained on a stable regimen, and will remain on a stable regimen
for the duration of participation on this study.

Men of all races and ethnic groups are eligible for this trial.