Perioperative Propranolol During Prostatectomy to Decrease Cancer Recurrence

Prostate Cancer Clinical Trial

— PeP-RALP  

Official title:

Perioperative Propranolol in Robotic Assisted Laparoscopic Prostatectomy- A Feasibility Study of Propranolol to Target Perioperative Stress Induced Cancer Progression

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05679193
• Other study ID #: 488466
• Status: Completed
• Phase: Phase 2
• Start date: January 2, 2023
• Est. completion date: January 27, 2024

Study information

• Verified date: May 2024
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the feasibility of conducting a larger randomized controlled trial to assess the efficacy of perioperative propranolol capsules compared with placebo capsules in decreasing recurrence of prostate cancer (PCa) after robotic assisted laparoscopic prostatectomy (RALP) in participants with intermediate to high-risk for prostate cancer recurrence.

Description:

PCa is the most commonly diagnosed cancer in Norway (2020) and RALP is the most frequent curative treatment offered to men with non-metastatic PCa. Biochemical recurrence (BCR) is estimated to occur to 40% of patients with EAU IR and HR PCa. Attempts to combat the high recurrence rates after RALP with neoadjuvant treatment, aiming to reduce the local tumor burden and treat possible micrometastasis, has of yet not proven beneficial.

The prostate is highly innervated and recent evidence has shown the importance of nerves in the development and progression of PCa. The action of particularly adrenergic nerves, in sum lead to a pro-cancerous and metastatic state by influencing key hallmarks of cancer like apoptosis resistance, angiogenesis, immune suppression, invasiveness and metastasis.

Perioperative stress caused by the cancer surgery, in this case RALP, has been found to promote cancer progression and recurrence both by enhancing growth of preexisting residual tumor/micrometastasis and facilitating formation of new metastasis. The surgical stress response cause a catecholamine-induced cancer progression where β2-adrenergic receptor (ADRB2) have a key role.

Our newly published pharma co-epidemiologic study indicate perioperative stress can be targeted by a non-selective ß-blocker (nsBB) like propranolol [1]. RCTs have found perioperative administration of propranolol alone, or in conjunction with COX-2 inhibition, to be safe and to reduce biomarkers associated with poor prognosis compared with the control group receiving placebo medication in patients undergoing radical surgery for breast-, ovarian- and colorectal cancer [2-7}.

The result of our register study, together with existing evidence of an effect of propranolol/nsBBs, provides foundation for PeP-RALP, a pilot study to establish the recruitment- and infrastructure feasibility of a double-blinded, placebo controlled RCT. The results of this pilot study will be used to investigate the feasibility of a formal larger RCT aiming to assess efficacy of perioperative propranolol to reduce PCa recurrence and progression after RALP.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: January 27, 2024
• Est. primary completion date: November 28, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

• European Association of Urology Intermediate- and High Risk for Biochemical recurrence and planned for curative RALP

• ECOG Performance Status 0-1

Exclusion Criteria:

Medical Conditions

1. Sick sinus syndrome

2. Atrioventricular (AV) block grade 2 and 3

3. Recent (3 months) myocardial infarction

4. Known unstable- or vasospastic- angina

5. Heart failure (New York Heart Association [NYHA] > 2)

6. Symptomatic peripheral vascular disease (e.g. intermittent claudication)

7. Known pulmonary hypertension

8. Known carotid artery stenosis or recent (3 months) stroke

9. Bronchial asthma or other chronic obstructive pulmonary disease (COPD)

10. Kidney failure (estimated Glomerular filtration rate [eGFR]<50)

11. Liver failure (cirrhosis, jaundice, signs of hepatic decompression)

12. Unregulated diabetes mellitus

13. Untreated thyroid disorder

14. Depressive episode within last 6 months (within last 12 months if major depressive episode)

15. Known drug allergy against propranolol or excipients

16. Any medical conditions considered to prohibit Propranolol use as judged by the treating physician (including frailty).

17. Participants with known substance- or alcohol-abuse

Prior/Concomitant Therapy

18. Recent (<3 month) use of systemic beta-blockers prior to screening.

19. Patients receiving non-dihydropyridine calcium channel blocking agents (eg diltiazem, verapamil)

20. Patients receiving anti-arrhythmic agents (e.g. amiodarone, sotalol, digoxin, verapamil, flecainide)

21. Patients receiving digoxin, rizatriptan, hydralazine, fluvoksamin, or fluoksetin

22. Patients using daily anxiolytics (e.g. benzodiazepines), alpha-receptor adrenergic agonists (e.g. clonidine)

23. Recommendations in the Summary of Product Characteristics for propranolol regarding concomitant use of other medications will be adhered to.

Diagnostic assessments

24. Sinus bradycardia (<60 beats/minute)

25. Resting blood pressure <110/60mmHg OR hypertension BP >160/100

26. AV-block 2 or 3 on ECG

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Propranolol
Propranolol capsules 20mg taken orally. Day: 1-3: 20mg twice daily Day: 4-19 (25 , In cases of delayed RALP an extension of up to 6 days is allowed.in cases of delayed surgery). 2x 20mg twice daily Day 20-22 20mg twice daily

Locations

Country	Name	City	State
Norway	Oslo University Hospital The Norwegian Radium Hospital	Oslo

Sponsors (3)

Lead Sponsor	Collaborator
Oslo University Hospital	Fondsstiftelsen ved Oslo Universitetssykehus, Ivar, Ragna og Morten Holes legat til fremme av kreftforskningen i Norge

Country where clinical trial is conducted

Norway, 

References & Publications (7)

Haldar R, Ricon-Becker I, Radin A, Gutman M, Cole SW, Zmora O, Ben-Eliyahu S. Perioperative COX2 and beta-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial. Cancer. 2020 Sep 1;126(17):3991-4001. doi: 10.1002/cncr.32950. Epub 2020 Jun 13. — View Citation

Haldar R, Shaashua L, Lavon H, Lyons YA, Zmora O, Sharon E, Birnbaum Y, Allweis T, Sood AK, Barshack I, Cole S, Ben-Eliyahu S. Perioperative inhibition of beta-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome. Brain Behav Immun. 2018 Oct;73:294-309. doi: 10.1016/j.bbi.2018.05.014. Epub 2018 May 22. — View Citation

Hiller JG, Cole SW, Crone EM, Byrne DJ, Shackleford DM, Pang JB, Henderson MA, Nightingale SS, Ho KM, Myles PS, Fox S, Riedel B, Sloan EK. Preoperative beta-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase II Randomized Trial. Clin Cancer Res. 2020 Apr 15;26(8):1803-1811. doi: 10.1158/1078-0432.CCR-19-2641. Epub 2019 Nov 21. — View Citation

Jang HI, Lim SH, Lee YY, Kim TJ, Choi CH, Lee JW, Kim BG, Bae DS. Perioperative administration of propranolol to women undergoing ovarian cancer surgery: A pilot study. Obstet Gynecol Sci. 2017 Mar;60(2):170-177. doi: 10.5468/ogs.2017.60.2.170. Epub 2017 Mar 16. — View Citation

Shaashua L, Shabat-Simon M, Haldar R, Matzner P, Zmora O, Shabtai M, Sharon E, Allweis T, Barshack I, Hayman L, Arevalo J, Ma J, Horowitz M, Cole S, Ben-Eliyahu S. Perioperative COX-2 and beta-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial. Clin Cancer Res. 2017 Aug 15;23(16):4651-4661. doi: 10.1158/1078-0432.CCR-17-0152. Epub 2017 May 10. — View Citation

Sivanesan S, Tasken KA, Grytli HH. Association of beta-Blocker Use at Time of Radical Prostatectomy With Rate of Treatment for Prostate Cancer Recurrence. JAMA Netw Open. 2022 Jan 4;5(1):e2145230. doi: 10.1001/jamanetworkopen.2021.45230. — View Citation

Zhou L, Li Y, Li X, Chen G, Liang H, Wu Y, Tong J, Ouyang W. Propranolol Attenuates Surgical Stress-Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy. J Immunol. 2016 Apr 15;196(8):3460-9. doi: 10.4049/jimmunol.1501677. Epub 2016 Mar 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in perceived distress during the study.	Investigate alterations in perioperative perceived distress, assessed by Hospital Anxiety and Depression Scale (HADS)	Up to 9 weeks
Other	Immunohistochemistry and Image mass cytometry of tumor to assess for differences between treatment arms. Flow cytometry to assess of periferal blood to assess for differences between treatment arms.	Immunohistochemistry and image mass cytometry to assess for differences between treatment arms in intra-tumor immune cell infiltration.; Flow cytometry to assess differences between treament arms in systemic immune cell acitivity.	Up to 9 weeks
Other	Difference in prognostic markers (e.g. Decipher GRID transcriptome analysis) between treatment arms. Identify predictive biomarkers for propranolol responsiveness (e.g. Decipher GRID transcriptome analysis)	Determine the effect of pre-operative propranolol treatment on prognostic markers and assess for predictive biomarkers. Identify predictive biomarkers for propranolol responsiveness.	up to 1 year
Other	Differences between intervention arms with regard to intraoperative alterations in cerebral autoregulation and intracranial pressure, measured by transcranial doppler (TCD) floe velocity.	Intraoperative alterations in cerebral autoregulation and intracranial pressure by Transcranial Doppler flow velocity measurement of the middle cerebral artery.	up to 1 year
Primary	The feasibility of conducting a formal larger RCT to compare the efficacy of propranolol vs placebo to decrease PCa recurrence following RALP.	Numbers of eligible participants needed to screen to include 40 patients in the study, reported as % of eligible participants that subsequently were included in the study.; Compliance of study intervention (defined as >80% of doses taken). Reported as % of participants compliant to the study intervention before RALP and % of participants compliant to the study intervention after RALP.	The total duration of study participation from screening to end of follow-up is 50-102 days per participant. The primary outcome will be assessed when inclusion is completed, or if inclusion is not completed within 12 months.
Secondary	Safety and tolerability of PeP-RALP intervention	Safety: Proportion (%) of patients experiencing treatment related clinical significant hypotension and/or bradycardia.; Adverse events of PeP-RALP medication as assessed by CTCAE v5.0.; Tolerability: Proportion (%) of patients tolerating daily dose of 80mg propranolol.	9 weeks
Secondary	Determine the effect of RALP on catecholamine levels	Changes in catecholamine levels in the perioperative period.	Up to 5 weeks
Secondary	Determine the bioavailability of propranolol	Serum levels of propranolol pre-operatively and at end of PeP-RALP medication.	Up to 5 weeks
Secondary	Determine the effect of preoperative propranolol treatment on the serum level of PSA	Changes in PSA levels after 7-14 days of PeP-RALP medication.	7-14 days
Secondary	To determine the effect of propranolol on post-operative biochemical failure	Proportion of patients with serum PSA levels above 0.1 ng/ml at 6 weeks post-RALP.	Up to 9 weeks
Secondary	Intraoperative anesthesiological and surgical challenges Surgical complications in PeP RALP patients	Anesthesiological challenges are assed by: Proportion of patients (%) in each intervention group requiring vasopressors to maintain an acceptable mean arterial pressure (MAP >60mmhg). Amount of vasopressor needed.; Surgical challenges are assed by: The surgical procedure time (minutes) and estimated intraoperative blood loss (milliliters).	1 day
Secondary	Surgical complications	Frequence (n=) and severity of surgical complications as classified by the Clavian-Dindo classification.	Up to 9 weeks