Metformin for Rising PSA Remote Trial

Men with an isolated PSA recurrence after local therapy are an ideal population for the
evaluation of novel therapies given the minimal disease burden, generally indolent natural
history, and patients' preference to avoid the adverse effects of androgen deprivation
therapy. Metformin has shown anti-prostate cancer activity in preclinical models and cohort
studies. Metformin, a biguanide oral antihyperglycemic agent, abrogates hyperinsulinemia in
individuals with and without diabetes and has shown promising anti-prostate cancer activity
in preclinical models, epidemiologic studies, and retrospective cohorts. Several
epidemiologic/retrospective studies have shown that metformin has a positive impact on
overall survival among men with prostate cancer.

These nonclinical and clinical studies have led to calls for prospective studies of metformin
in patients with prostate cancer. This is a pilot telemedicine study of metformin in patients
with a rising PSA ("biochemical recurrence") after definitive local therapy for prostate
cancer.

The current study is supported by the following rationale:

- A large proportion of clinical trials close prematurely due to poor accrual.

- Geographic inaccessibility is a barrier to clinical trial participation.

- Metformin is a safe and inexpensive medication that has demonstrated anti-prostate
cancer activity in nonclinical and epidemiologic studies. Importantly, metformin has
been shown to be safe in non-diabetic patients (e.g., patients with polycystic ovary
disease) and does not cause hypoglycemia.

- Use of novel technologies may facilitate clinical trial accrual and minimize the burden
of participation for patients. Ultimately, these approaches may also decrease the cost
of drug development and increase the pace of progress.

In the absence of prohibitive toxicities or disease progression (defined in 4.4), patients
may continue treatment for the 6-month study period. This study will include a baseline visit
for study enrollment at Mount Sinai. The remainder of the visits will be telemedicine visits
conducted using secure video conferencing.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate. (*in situations where
pathology reports documenting prostate cancer are no longer available such as when the
initial biopsy or prostatectomy was performed in the remote past, a documented history
of prior prostate cancer and prostate cancer treatment in prior medical records will
be sufficient)

- Biochemical disease progression after radical prostatectomy and/or radiation therapy
(external-beam radiation therapy and/or brachytherapy), and no radiographic evidence
of metastases.

- Men with history of radical prostatectomy are required to have baseline PSA > 0.5
ng/mL (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).

- Men treated with primary radiation therapy are required to have baseline PSA ≥
1.0 ng/mL above their post radiation 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.

- Men with previous neoadjuvant adjuvant hormone therapy are eligible if
testosterone level at screening is non-castrate (≥ 50 ng/dl). Men previously
treated with intermittent hormonal therapy are also eligible if level of
testosterone at screening is non-castrate (≥ 50 ng/dl).

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

- Subjects must have normal organ as defined below:

- AST(SGOT)/ALT(SGPT) less than or equal to 1.8 X institutional upper limit of
normal

- Serum bilirubin ≤ ULN (except for subjects with Gilbert's Disease who are
eligible despite elevated serum bilirubin level)

- Creatinine ≤ 1.5 mg/dL and/or creatinine clearance > 60 ml/min

- English speaking

Exclusion Criteria:

- Concurrent use of other investigational agents or other prostate cancer therapies
(e.g., androgen deprivation therapy)

- Currently taking metformin, sulfonylureas, thiazolidinedione, insulin, or other
antidiabetic drugs for any reason.

- Known hypersensitivity or intolerance to metformin

- Condition associated with increased risk of metformin-associated lactic acidosis:

- New York Heart Association Class III or IV Heart Failure

- Intake of 3 or more alcoholic beverages per day

- Known history of lactic acidosis