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| ID | Type | Description | Link |
|---|---|---|---|
| P30CA138292 | U.S. NIH Grant/Contract | View source | |
| NCI-2024-07761 | Registry Identifier | CTRP (Clinical Trial Reporting Program) | |
| STUDY00007557 | Other Identifier | Emory University Hospital | |
| RAD6197-24 | Other Identifier | Emory University Hospital |
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| Name | Class |
|---|---|
| Pfizer | INDUSTRY |
| Sumitomo Pharma America, Inc. | INDUSTRY |
| National Comprehensive Cancer Network | NETWORK |
| National Cancer Institute (NCI) |
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This phase III/IV trial compares the impact of leuprolide and abiraterone acetate (AA) versus relugolix and AA on the heart in hormone-naive patients with advanced prostate cancer receiving pelvic radiation therapy. Leuprolide is in a class of medications called gonadotropin-releasing hormone agonists (GNRHa). It prevents the body from making luteinizing hormone-releasing hormone (LHRH) and luteinizing hormone (LH). This causes the testicles to stop making testosterone (a male hormone) in men and may stop the growth of prostate tumor cells that need testosterone to grow. Abiraterone acetate, an androgen biosynthesis inhibitor, works by decreasing the amount of certain hormones in the body. Relugolix, a GNRH antagonist, works by decreasing the amount of testosterone produced by the body. This may slow or stop the spread of prostate tumor cells that need testosterone to grow. The use of hormone therapy with radiation therapy has been shown to improve survival, however, studies have suggested that the addition of hormone therapy may worsen heart (cardiac) disease and high blood pressure. In fact, studies have shown that the most common cause of death in prostate cancer patients is due to heart disease or heart attacks. Computed tomography (CT) scans create a series of detailed pictures of areas inside the body; the pictures are created by a computer linked to an x-ray machine. In this study, sophisticated cardiac CT images are used to take pictures of patients' heart and coronary arteries to help assess damage to the heart. Using cardiac CT and blood tests, this trial may help doctors determine which patients are at risk of cardiac disease when treated with combination hormone therapy, as well as the differential risk of leuprolide versus relugolix in combination with abiraterone acetate.
PRIMARY OBJECTIVE:
I. Measure cardiovascular outcomes between combination gonadotropin releasing hormone agonist (GNRHa, i.e. leuprolide) plus abiraterone acetate (AA) versus gonadotropin releasing hormone antagonist (GNRH-antagonist, i.e. relugolix) plus AA in men with advanced prostate cancer receiving definitive radiation therapy.
SECONDARY OBJECTIVES:
I. Identify genomic alterations that predispose an individual to enhanced cardiovascular (CV) toxicity following hormone therapy with leuprolide or relugolix in combination with abiraterone acetate.
II. Evaluate serum testosterone kinetics during and after treatment with combination leuprolide+AA versus relugolix+AA.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive leuprolide intramuscularly (IM) or subcutaneously (SC) injection every 3 to 6 months plus oral AA with prednisone daily for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo standard of care radiation therapy. Patients may also receive bicalutamide orally (PO) once daily (QD) on days 21-30 with first injection of leuprolide at the discretion of the treating provider. All patients undergo pre-treatment and 12-month coronary computed tomography angiography (CCTA) and blood sample collection.
ARM II: Patients receive oral relugolix PO daily plus oral AA with prednisone daily for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo standard of care radiation therapy. All patients undergo pre-treatment and 12-month CCTA and blood sample collection.
After completion of study treatment, patients are followed up at 30 and 60 days for serum testosterone measurement.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm I (leuprolide plus abiraterone acetate/prednisone) | Experimental | Patients receive leuprolide IM or SC injections every 3 to 6 months plus oral abiraterone acetate (AA) with prednisone daily for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo standard of care radiation therapy. |
|
| Arm II (relugolix + abiraterone acetate/prednisone) | Experimental | Patients receive oral relugolix daily plus oral abiraterone acetate (AA) with prednisone daily for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo standard of care radiation therapy. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Abiraterone Acetate | Drug | Given abiraterone acetate |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of ambulatory systolic blood pressure (BP) > 140 or diastolic > 90 (measurement on 2 separate days) | The change will be estimated and tested using paired tests (Wilcoxon signed rank test or McNemar test). The difference at each interval for the two groups will be tested using Fisher's exact test for binary endpoints or Wilcoxon rank-sum test for continuous. Data transformation to fit statistical assumptions will be done as needed. Multivariable models that control for potential confounders will be implemented using general linear and logistic regression. | At baseline and up to 12 months |
| Need for new or escalated anti-hypertensive medication | The change will be estimated and tested using paired tests (Wilcoxon signed rank test or McNemar test). The difference at each interval for the two groups will be tested using Fisher's exact test for binary endpoints or Wilcoxon rank-sum test for continuous. Data transformation to fit statistical assumptions will be done as needed. Multivariable models that control for potential confounders will be implemented using general linear and logistic regression. | At baseline and up to 12 months |
| Incidence of moderate-to-severe atherosclerosis of major coronary vessels | Defined as > 50% luminal stenosis per the Society of Cardiac Computed Tomography. Change will be tested using paired tests (Wilcoxon signed rank test or McNemar test). Luminal stenosis will be measured on a per-vessel basis. Proportion of patients achieving > 50% luminal stenosis of a major coronary vessel between each arm will be compared using Fisher's exact test. The percent change of maximal stenosis between the two arms will be tested using Wilcoxon signed rank test. | From month 0 to month 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Total plaque volume | Total plaque volume (per-patient and per-vessel basis, respectively) will be measured. Adjusted mean difference will be calculated from baseline to month 12 between arms. Multivariable adjustment will be utilized that control age and statin using logistic regression. | From month 0 to month 12 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Bill Zheng, BS | Contact | 404-686-6856 | bill.zheng@emory.edu |
| Name | Affiliation | Role |
|---|---|---|
| Sagar A Patel, MD | Emory University Hospital/Winship Cancer Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Emory Proton Therapy Center | Recruiting | Atlanta | Georgia | 30308 | United States |
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| NIH |
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All principal investigators and co-investigators will be blinded to randomization block. All cardiac computed tomography images will be analyzed by a blinded level 3 boarded cardiac imaging expert.
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| Bicalutamide | Drug | Given PO |
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| Biospecimen Collection | Procedure | Undergo blood sample collection |
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| Computed Tomography Angiography | Procedure | Undergo CCTA |
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| Leuprolide | Drug | Given IM or SC |
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| Prednisone | Drug | Given prednisone |
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| Radiation Therapy | Radiation | Undergo standard of care radiation therapy |
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| Relugolix | Drug | Given PO |
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| Pre-existing genomic alterations promoting inflammatory immunity and associated with cardiovascular disease |
Pre-treatment samples will be subjected to whole exome sequencing to determine alterations to the protein-coding regions of the genome, specifically those associated with clonal hematopoiesis of indeterminate potential (CHIP). The association of CHIP mutations with development of cardiovascular toxicity following therapy will be measured. |
| At baseline |
| Castration rate | The cumulative probability of testosterone suppression to ≤ 50 ng/dL will be summarized using the Kaplan-Meier method. Confidence intervals will be calculated using the exponential Greenwood formulation via log-log transformation of the survival function | At study days 7, 30 and 90 |
| Sustained castration | The probability of testosterone suppression ≤ 50 ng/mL will be summarized using Kaplan-Meier. Confidence intervals will be calculated using the exponential Greenwood formulation via log-log transformation of the survival function | At months 6 and 12 |
| Testosterone recovery | The probability of testosterone recovery > 50 ng/mL and 200 ng/mL will be summarized using the Kaplan-Meier method. Confidence intervals will be calculated using the exponential Greenwood formulation via log-log transformation of the survival function | At day 30 and/or day 90 following completion of androgen deprivation therapy |
| Winship at Emory Midtown | Recruiting | Atlanta | Georgia | 30308 | United States |
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| Emory University Hospital/Winship Cancer Institute | Recruiting | Atlanta | Georgia | 30322 | United States |
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| Emory Saint Joseph's Hospital | Recruiting | Atlanta | Georgia | 30342 | United States |
|
| ID | Term |
|---|---|
| D011471 | Prostatic Neoplasms |
| ID | Term |
|---|---|
| D005834 | Genital Neoplasms, Male |
| D014565 | Urogenital Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D005832 | Genital Diseases, Male |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D011469 | Prostatic Diseases |
| D052801 | Male Urogenital Diseases |
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| ID | Term |
|---|---|
| D000069501 | Abiraterone Acetate |
| C053541 | bicalutamide |
| D013048 | Specimen Handling |
| D016729 | Leuprolide |
| D011241 | Prednisone |
| C407664 | deltacortene |
| C036266 | prednylidene |
| D011878 | Radiotherapy |
| D011827 | Radiation |
| C561634 | relugolix |
| ID | Term |
|---|---|
| D000736 | Androstenes |
| D000731 | Androstanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D008919 | Investigative Techniques |
| D007987 | Gonadotropin-Releasing Hormone |
| D010906 | Pituitary Hormone-Releasing Hormones |
| D007028 | Hypothalamic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D011244 | Pregnadienediols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013812 | Therapeutics |
| D055585 | Physical Phenomena |
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