Bipolar Androgen-based Therapy for Prostate Cancer (BAT)

This is an open-label, single site, single arm pilot study designed to determine the
efficacy and safety of alternating androgen deprivation therapy (ADT) and parenteral
testosterone in men with recurrent or newly metastatic prostate cancer. Eligible patients
will initiate ADT with LHRH agonist (e.g. goserelin or leuprolide) if not surgically
castrated for a total of 6 months. After this initial 6 month lead-in phase, patients will
continue on ADT every three months but will also receive an intramuscular gluteal injection
with either testosterone cypionate or testosterone enanthanate(T) at a dose of 400 mg every
4 weeks for a total of 3 injections (i.e.12 weeks of therapy).Both formulations of T have
identical pharmacokinetics; exhibiting the same serum testosterone profile after
intramuscular injection into healthy volunteers. Patients will then cycle back to ADT only
for 12 weeks. This route and dose of T was selected based on data demonstrating that it
produces an initial supraphysiologic serum level of testosterone (i.e. > 3-8 times normal
level) with eugonadal levels achieved at the end of two weeks and return to low serum T
levels by the fourth week post-injection. The investigators have termed this rapid cycling
between supraphysiologic to low/castrate serum T Bipolar Androgen-based Therapy (BAT). One
BAT cycle will be defined as 24 weeks (i.e. 12 weeks on T; 12 weeks off T). Patients will
receive two cycles (i.e. 48 weeks) of BAT in total (see Study Scheme below). Upon completion
of the 18 month study period patients will be assessed for response and will then have the
option to continue on intermittent or continuous ADT at the discretion of their treating
physician.

Patients will have PSA and imaging studies during the screening period. A second set of
studies will be performed at the end of the 6-month LHRH agonist therapy lead-in period.
Based on prior studies the investigators expect >80% of patients to have a PSA <4 ng/ml and
without evidence of PSA progression after 6 months of ADT (Hussain et al. 2006; Crook et al.
2012). At the end of the lead-in phase only patients who either achieve a ≥50% reduction in
PSA from their screening baseline (i.e. a major PSA response) or have a PSA < 4 ng/ml and
are without signs of progression will be allowed to continue on the study. All others will
be removed from study and replaced. Those replaced individuals will be considered to have
not met the primary endpoint in our final analysis. PSA progression will be assessed at the
end of the 18 month study period. Standard PCWG2 criteria for PSA progression will be used
(Scher et al. 2008).

The primary endpoint for this trial will be the percent subjects with a PSA <4 ng/ml and
without PSA progression at the end of the 18 month treatment period. Secondary endpoints
will include: the rate of progression based on imaging and clinical assessments, percent of
patient who have a complete PSA response (PSA < 0.2 ng/ml), metabolic changes, changes in
quality of life as assessed through standard questionnaires, and safety.

CT and bone scans will be performed at the end of the second full cycle of BAT (i.e. at the
end of the 18 month study period) and be used to assess for radiographic progression. Soft
tissue metastasis will be evaluated by RECIST criteria (v1.1). Bone metastasis will be
evaluated per the standard PCWG2 criteria. This requires the appearance of at least 2 new
lesions with a confirmatory bone scan. For patients demonstrating radiographic progression
the investigators will require a confirmatory scan after an additional 8 weeks so as not to
misconstrue a tumor flare with true disease progression. A subject will be considered to
have clinically progressed if he develops pain that, in the opinion of the investigator, is
secondary to his cancer; he develops a pathologic fracture or other skeletal event. If there
is uncertainty regarding whether a symptom is due to a patient's cancer, the subsequent
workup will be at the investigator's discretion. Of the endpoints, only clinical progression
will result in early study termination.

To evaluate the effect BAT has on the metabolic syndrome associated with ADT the
investigators will monitor a number of parameters at baseline prior to initiation of ADT,
after 6 month "Lead-in" phase of ADT and after the 2nd cycle of T. Studies will include
measurements of bone density,estradiol, sex hormone binding globulins, fasting lipids,
metabolic parameters (insulin, fasting glucose, hemoglobin A1c, leptin, TSH, T3, fibrinogen,
C-reactive protein, serum C-telopeptide, blood pressure, Body Mass Index (BMI), body
weight). Quality of life (QOL) will be recorded through a series of questionnaires. These
surveys include the RAND-SF36 Quality of Life Survey, the FACT-P, the International Index of
Erectile Function (IIEF), the International Prostate Symptom Score (IPSS) and a visual pain
scale. Each of these instruments has been previously validated and is used extensively in
clinical trials to assess the effects of treatment intervention on quality of life. QOL will
be assessed at screening, after Lead-In Phase and at the end of each cycle of T or ADT.

Additional plasma and serum samples will be drawn and banked at -80°C at baseline prior to
initiation of ADT, prior to initiating a cycle of T or ADT and upon completion of the study.
These samples will be used for biologic and immunologic correlates. Examples of studies that
may be performed include, but are not limited to: quantitative immunoglobulins,TREC levels
and circulating DNA studies.

Inclusion Criteria:

1. Age ≥ 18 years

2. Performance status ≤2.

3. Documented histologically confirmed adenocarcinoma of the prostate.

4. No prior AD therapy (i.e. surgical castration LHRH agonist, LHRH antagonist) as
treatment for recurrent or metastatic disease (may have received neoadjuvant,
concurrent and/or adjuvant AD therapy in the context of definitive local therapy if
it was administered ≥ 1 year prior to recurrence).

5. No prior treatment with second line hormonal therapies (flutamide, bicalutamide,
nilutamide, ketoconazole, abiraterone acetate or MDV3100) is permitted.

6. Prior treatment with 5-alpha reductase inhibitors (e.g. finasteride or dutasteride)
for treatment of benign prostatic hyperplasia (BPH) is permitted, but patients must
be off therapy for ≥ 6 months prior to enrolling on study

7. No prior treatment with chemotherapeutic regimens allowed.

8. Prior treatment with non-hormonal investigational agents is permitted.

9. Evidence of rising PSA on two successive dates > 2 weeks apart. There is no maximum
or minimum PSA requirement to come on study.

10. Patients must have ≤ 10 total sites of bone metastases and no evidence for lung or
liver or other parenchymal metastases documented within 28 days of enrollment on
trial

11. Patient may have lymph node metastases with no single lymph node >5 cm short axis
diameter

12. Patients must be asymptomatic with no sites of pain due to prostate cancer.

Exclusion Criteria:

1. Evidence of serious and/or unstable pre-existing medical, psychiatric or other
condition (including laboratory abnormalities) that could interfere with patient
safety or provision of informed consent to participate in this study.

2. Any psychological, familial, sociological, or geographical condition that could
potentially interfere with compliance with the study protocol and follow-up schedule.

3. Evidence of disease that, in the opinion of the investigator, would put the patient
at risk from testosterone therapy (e.g. femoral metastases with concern over fracture
risk, spinal metastases with concern over spinal cord compression, lymph node disease
with concern for ureteral obstruction).

4. Requires urinary catheterization for voiding as a result of tumor obstructing the
urinary outflow tract; catheterization is permitted if due to a non-oncologic cause
(e.g urethral stricture or atonic bladder).

5. No prior history of deep venous thrombosis or pulmonary embolism within 5 years prior
to enrollment in the study

6. Abnormal liver function (bilirubin, AST, ALT ≥ 3 x upper limit of normal)

7. Abnormal kidney function (serum creatinine ≥ 2 x upper limit of normal)

8. Abnormal cardiac function as manifested by NYHA (New York Heart Association) class
III or IV heart failure or history of a prior myocardial infarction (MI) within 5
years prior to enrollment in the study

9. Inability to provide informed consent.