Clinical trial NCT05679193: Perioperative Propranolol During Prostatectomy to Decrease Cancer Recurrence
Official title: Perioperative Propranolol in Robotic Assisted Laparoscopic Prostatectomy- A Feasibility Study of Propranolol to Target Perioperative Stress Induced Cancer Progression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Cancer
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: Ivar, Ragna og Morten Holes legat til fremme av kreftforskningen i Norge
name: Fondsstiftelsen ved Oslo Universitetssykehus
First posted: 2023-01-10
Enrollment: 40
Sex: MALE
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: parallel-group, phase 2, double-blind, 2-arm study
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: The feasibility of conducting a formal larger RCT to compare the efficacy of propranolol vs placebo to decrease PCa recurrence following RALP.
timeFrame: 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 outcomes:
measure: Safety and tolerability of PeP-RALP intervention
timeFrame: 9 weeks
measure: Determine the effect of RALP on catecholamine levels
timeFrame: Up to 5 weeks
measure: Determine the bioavailability of propranolol
timeFrame: Up to 5 weeks
measure: Determine the effect of preoperative propranolol treatment on the serum level of PSA
timeFrame: 7-14 days
measure: To determine the effect of propranolol on post-operative biochemical failure
timeFrame: Up to 9 weeks
measure: Intraoperative anesthesiological and surgical challenges Surgical complications in PeP RALP patients
timeFrame: 1 day
measure: Surgical complications
timeFrame: Up to 9 weeks
Other outcomes:
measure: Change in perceived distress during the study.
timeFrame: Up to 9 weeks
measure: 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.
timeFrame: Up to 9 weeks
measure: 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)
timeFrame: up to 1 year
measure: Differences between intervention arms with regard to intraoperative alterations in cerebral autoregulation and intracranial pressure, measured by transcranial doppler (TCD) floe velocity.
timeFrame: up to 1 year
Locations:
city: Oslo
country: Norway
facility: Oslo University Hospital The Norwegian Radium Hospital
Study officials:
affiliation: Oslo University Hospital
name: Shivanthe Sivanesan, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
citation: 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.