Beta Adrenergic Receptor Blockade as a Novel Therapy for Patients With Adenocarcinoma of the Prostate

Preclinical research has demonstrated that autonomic nerve fibers in the prostate gland
regulate prostate cancer development and dissemination. Studies in human prostate cancer
specimens indicate that higher densities of autonomic nerve fibers are associated with poor
clinical outcomes.

In this clinical trial the beta-blocker carvedilol will be given to men diagnosed with
prostate cancer. Men will begin carvedilol following their diagnostic prostate biopsy and
will continue carvedilol until prostatectomy. The primary outcome measure is the change in
Ki-67 and TUNEL assay biomarkers in prostate biopsy and prostatectomy tissues.

Inclusion Criteria:

1. The patient must be able to provide study-specific informed consent prior to study
entry.

2. Age ≥ 18

3. ECOG Performance Status 0-1

4. Pathologically proven diagnosis of prostate adenocarcinoma diagnosed by prostate
biopsy with archival biopsy tissue available for analysis. The amount of cancer tissue
present must be sufficient for analysis.

5. Prostate adenocarcinoma classified as intermediate or high-risk as defined by one or
more of the following criteria: PSA >10 ng/ml, Gleason score ≥7, or tumor stage ≥T2b

6. Patients must have no evidence of metastatic disease (including clinically negative
pelvic lymph nodes) as established by imaging (CT or MRI of the pelvis and a bone
scan) within 60 days prior to registration. Equivocal bone scan findings are allowed
if plain film x-rays are negative for metastasis.

7. The patient and the attending urologist have decided to proceed with prostatectomy

8. Lab values meeting the following criteria

1. Total bilirubin < 2.0 X Upper Limit of Normal (ULN)

2. Aspartate aminotransferase (AST) ≤ 2.5 X ULN.

3. Alanine aminotransferase (ALT ) ≤ 2.5 X ULN

4. Absolute Neutrophil Count (ANC) > 1.5 K/mm3

5. Platelets > 100 K/mm3

6. Hemoglobin ≥9.0 g/dL

7. calculated creatinine clearance ≥ 40 mL/min

Exclusion Criteria:

9. Patients with low risk prostate adenocarcinoma as defined by meeting all three of the
following criteria: Gleason score ≤6, PSA <10 and tumor stage ≤T2b

10. The presence of metastatic disease including to pelvic lymph nodes

11. Use of any beta-blocker at the time of diagnostic biopsy for prostate cancer or use of
any beta-blocker at the time of screening. If the investigator does not believe that
carvedilol can be safely added to the patients existing antihypertensive regimen, then
the patient is not eligible for this study.

12. Prior therapy for prostate cancer including radiation therapy (external beam or
brachytherapy), surgery, high-intensity focused ultrasound (HIFU), cryotherapy,
previous hormonal therapy with androgen deprivation therapy by bilateral orchiectomy
or LHRH analogues (e.g. leuprolide, goserelin, triptorelin, degarelix), antiandrogens,
ketoconazole, abiraterone or chemotherapy (for prostate cancer, chemotherapy in the
past for other indications is allowed).

13. Treatment with any investigational agent within 30 days prior to being registered for
protocol therapy.

14. No prior malignancy is allowed except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, or other cancer for which the patient has
been disease-free for at least 5 years.

15. Inability to take oral medication

16. Hypotension (systolic blood pressure <100 mm Hg or diastolic blood pressure <50 mm Hg)
or bradycardia (pulse <55 beats/min) at screening. For patients with a functioning
pacemaker, bradycardia is not an exclusion.

17. Bronchial asthma or related bronchospastic conditions such as chronic obstructive
pulmonary disease.

18. Patients must not have New York Heart Association Class III or IV heart failure at the
time of screening. Patients must not have any unstable angina, myocardial infarction,
or serious uncontrolled cardiac arrhythmia within 6 months prior to registration.

19. Prolonged QTc interval on pre-entry 12-lead ECG (> 460 msec), obtained within 28 days
prior to being registered on study. No second- or third-degree atrioventricular block
on screening 12-lead ECG.

20. Any other serious illness or medical condition that the principal investigator feels
would make the patient a poor candidate for this study