RElugolix VErsus LeUprolide Cardiac Trial

Stage III Prostate Cancer AJCC v8 Clinical Trial

— REVELUTION  

Official title:

Mechanism and Predictors of Cardiotoxicity After Prostate Cancer Treatment: A Parallel Cohort and Randomized Trial Comparing Radiation Alone, Radiation Plus Leuprolide, and Radiation Plus Relugolix

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05320406
• Other study ID #: STUDY00003654
• Secondary ID: NCI-2022-00117ST
• Status: Recruiting
• Phase: Phase 4
• Start date: June 6, 2022
• Est. completion date: April 29, 2025

Study information

• Verified date: June 2023
• Source: Emory University
• Contact: Sagar A. Patel, MD
• Phone: 404-778-3473
• Email: sagar.patel[@]emory.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase IV clinical trial investigates the impact of prostate cancer treatment, specifically androgen deprivation therapy (ADT), on the heart and coronary vessels among men with localized, non-metastatic prostate cancer undergoing definitive radiation therapy and concomitant ADT. Recently, cardiovascular toxicity from hormone therapy that is routinely used for prostate cancer (e.g. leuprolide) has emerged as a concern, yet studies identifying who is at risk and the mechanism of cardiac damage are lacking. Additionally, a new hormone therapy drug, relugolix, has recently been Food and Drug Administration (FDA)-approved and may reduce toxicity to the heart. This trial intends to investigate the mechanism of cardiovascular toxicity from ADT, investigate the mechanism by which relugolix reduces cardiovascular toxicity, and identify predictive biomarkers to improve individualized risk-assessment for cardiovascular toxicity from ADT.

Description:

PRIMARY OBJECTIVES: I. Identify and compare the association of gonadotrophin releasing hormone (GNRH)-agonist leuprolide versus GNRH-antagonist relugolix with coronary atherosclerosis and progression in men with prostate cancer. II. Determine the relationship between leuprolide versus relugolix with downstream immune effector response that is implicated in atherosclerosis. II. Determine how pre-existing genomic alterations associated with proinflammatory immunity impact development of CV toxicity following GNRH-agonist (GNRHa) versus relugolix. III. Identify imaging biomarkers associated with increased risk of CV toxicity from ADT OUTLINE: Patients undergoing radiation therapy alone as part of their standard treatment are assigned to Arm I. Patients undergoing radiation therapy and ADT as part of their standard treatment are randomized to Arm II or Arm III. ARM I: Patients undergo definitive radiation therapy in the absence of disease progression or unacceptable toxicity. ARM II: Patients undergo radiation therapy as in Arm I and receive leuprolide subcutaneously (SC) or intramuscularly (IM) every 3 or 6 months. Treatment continues for 6 to 24 months (depending on cancer risk) in the absence of disease progression or unacceptable toxicity. ARM III: Patients undergo radiation therapy as in Arm I and receive relugolix orally (PO) once daily (QD) for 6 to 24 months (depending on risk) in the absence of disease progression or unacceptable toxicity.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 94
• Est. completion date: April 29, 2025
• Est. primary completion date: April 29, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Men >= 18 years old
• Non-metastatic prostate cancer
• Non-metastatic, biochemically recurrent prostate cancer
• Plan to undergo curative-intent pelvic radiation therapy with or without ADT

Exclusion Criteria:

• Metastatic prostate cancer requiring > 24 months of ADT
• Prior exposure to androgen deprivation therapy
• Prior exposure to chemotherapy or immunotherapy

Related Conditions & MeSH terms

• Biochemically Recurrent Prostate Carcinoma
• Carcinoma
• Prostatic Neoplasms
• Stage I Prostate Cancer AJCC v8
• Stage II Prostate Cancer AJCC v8
• Stage IIA Prostate Cancer AJCC v8
• Stage IIB Prostate Cancer AJCC v8
• Stage IIC Prostate Cancer AJCC v8
• Stage III Prostate Cancer AJCC v8
• Stage IIIA Prostate Cancer AJCC v8
• Stage IIIB Prostate Cancer AJCC v8
• Stage IIIC Prostate Cancer AJCC v8

Intervention

Radiation:
• Radiation therapy
Undergo radiation therapy

Drug:
• Leuprolide
Given IM or SC
• Relugolix
Given PO

Locations

Country	Name	City	State
United States	Emory Proton Therapy Center	Atlanta	Georgia
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University/Winship Cancer Institute	Atlanta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Emory University	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Coronary plaque volume in major coronary arteries (i.e. left anterior descending, left circumflex, right major coronary arteries)	Using cardiac computed tomography angiography (CCTA), coronary plaque volume will be determined by measuring extent of coronary vessel luminal stenosis on an ordinal scale 0-100% as defined by the Society of Cardiac Computed Tomography. Change in luminal stenosis from baseline to month 12 will be tested using paired tests (Wilcoxon signed rank test or McNemar test). The incidence of moderate-to-severe atherosclerosis (defined as >50% luminal stenosis of a major coronary vessel) at month 12 will be compared between the three treatment groups using Fisher's exact test. Finally, the percent change of maximal stenosis from baseline to month 12 between the three treatment arms will be compared using Kruskal-Wallist test followed by pairwise Wilcoxon signed rank test (P-value adjusted for multiple testing using Holm-Bonferroni method). Multivariable adjustment will be utilized that control for anti-platelet/coagulation and statin use using general logistic regression.	From baseline to 12 months post-treatment initiation
Primary	Incidence of high-risk coronary plaque features at month 12 after treatment initiation	Using CCTA, high-risk plaque features, categorized as positive remodeling, low attenuation plaque, and spotty calcium, will be measured at month 0 and month 12 for each treatment arm. Differences in incidence of high-risk plaque features amongst the three treatment arms will be compared using Fisher's exact test. Multivariable adjustment will be utilized that control for anti-platelet/coagulation and statin use using general logistic regression.	From baseline to 12 months post-treatment initiation
Primary	Major adverse cardiovascular events	Incidence of myocardial infarction, need for coronary revascularization, and/or sudden cardiac death will be measured for up to 2 years following enrollment. Incidence curves will be estimated by the Kaplan-Meier method and compared between the three treatment arms using a two-sided log-rank test followed by pairwise comparisons with Bonferonni correction.	From baseline to at least 2 years post-treatment initiation
Secondary	Acute and late patient-reported morbidity	Adverse events will be assess using patient-reported outcomes (PRO) questionnaires including EPIC-26, IPSS, and SHIM scoring. Assessment will be collected before and at the end of radiotherapy treatment and in follow-up. For each symptom and each domain (i.e. frequency, severity, and interference), counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores >=1 and >=3 will be compared between groups using a chi-square test (or Fisher's exact test if cell frequencies are <5).	Baseline and month 0, 3, 6, 12, 18, 24
Secondary	Testosterone kinetics	Change in total and free testosterone levels will be measured at baseline and month 0, 3, 6, and 12 between treatment arms. Testosterone change over time will be summarized and plotted over time for each treatment arm. Testosterone levels over time will be assessed using mixed effects regression modeling.	Baseline and month 0, 3, 6, 12