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

This will be a single arm, window of opportunity study in men with treatment-naïve prostate cancer who will proceed to prostatectomy. Men will be treated with carvedilol prior to undergoing prostatectomy.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Carvedilol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carvedilol; Carvedilol will be started at 6.25 mg by mouth twice daily. Patients will take carvedilol for 28 days prior to prostatectomy. They will be seen every 7 days and adjustments in the dose will be considered at those visits.	Drug: Carvedilol; Carvedilol will give twice daily until prostatectomy; Other Names: Coreg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Biomarkers in Prostate Biopsy Compared to Prostatectomy Tissues	BIomarker	28 days after beginning carvedilol

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum PSA	PSA	28 days after beginning carvedilol

Collaborators and Investigators

• Sponsor: Montefiore Medical Center
• Collaborators: Albert Einstein College of Medicine

Publications and helpful links

General Publications

• Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS. Autonomic nerve development contributes to prostate cancer progression. Science. 2013 Jul 12;341(6142):1236361. doi: 10.1126/science.1236361.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2017
• Primary Completion (Actual): December 31, 2020
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: October 21, 2016
• First Submitted That Met QC Criteria: October 21, 2016
• First Posted (Estimate): October 25, 2016

Study Record Updates

• Last Update Posted (Actual): February 21, 2021
• Last Update Submitted That Met QC Criteria: February 18, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: biomarkers; carvedilol; autonomic nerves
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Protective Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol
• Other Study ID Numbers: 2016-6632

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No