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Cardiac Outcomes With Near-Complete Estrogen Deprivation (CROWN)

Primary Purpose

Breast Cancer, Triple Negative Breast Cancer, Cardiovascular Complications

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Adenosine Stress Cardiac Magnetic Resonance Imaging
Electrocardiogram
Computed Tomography Angiogram
Laboratory Testing
Quality of Life Survey
Sponsored by
Wake Forest University Health Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer

Eligibility Criteria

18 Years - 55 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria

  • Women age ≤55 who were premenopausal at the time of breast cancer diagnosis; (Premenopausal is defined as per NCCN criteria).
  • Planned breast cancer treatment with NCED therapy that includes aromatase inhibitor therapy (or SERD) with medically or surgically induced menopause following completion of any planned chemotherapy, surgery and radiation therapy or within 3 months of initiating NCED (HR-positive tumor) or within three months of completing planned chemotherapy, surgery and radiation (HR-negative tumor). Treatment with a Gonadotropin Releasing Hormone (GnRH) agonist for fertility preservation during chemotherapy is allowed and is not considered part of the NCED antineoplastic therapy.
  • Women with human epidermal growth factor-2 (HER2) negative and women with human epidermal growth factor-2 (HER2) positive breast cancer are eligible.
  • Treatment with CDK-inhibitor, PARP inhibitor or other biologic (non-chemotherapy) agent as part of anti-neoplastic treatment plan is allowed.
  • Treatment with selective-estrogen receptor degrader (SERD) rather than aromatase inhibitor is allowed.
  • Diagnosed with Stage I-III breast cancer.
  • ECOG performance status of 0-2
  • Patients must have normal renal function and potassium as defined below:

    • eGFR >30 ml/min/1.73 m2;
    • Potassium 3.5-5.2 mmol/L
  • Patients with concurrent malignancies are eligible as long as therapies and disease course for these are reasonably expected to not impact cardiovascular function. (Examples of eligible malignancies include: papillary/follicular thyroid cancer, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in-situ and early stage cervical cancers, etc.).
  • Patients with prior COVID-19 are eligible if they have recovered from the illness and are free of COVID-related symptoms other than allowable persistent symptoms: loss of taste and smell and/or grade 1 fatigue.
  • Ability to understand and the willingness to sign an IRB-approved informed consent document (either directly or via a legally authorized representative).

Exclusion Criteria:

  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to adenosine
  • Active asthma or chronic obstructive pulmonary disease currently requiring medications or active wheezing.
  • Those with contraindications for MRI such as some breast expanders, ferromagnetic cerebral aneurysm clips or other intracranial metal, pacemakers, defibrillators, functioning neurostimulator devices or other implanted electronic devices.
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study. Because some methods of birth control are not 100% reliable, a pregnancy test is required, unless the patient has undergone either a bilateral oophorectomy, hysterectomy or both.
  • Coronary revascularization in the past 6 months or known severe multi-vessel coronary artery disease previously determined to be not amendable to mechanical intervention.
  • Ongoing, unrelieved symptoms thought to represent cardiac ischemia and requiring immediate cardiac catheterization
  • Allergy or prior sensitivity to gadolinium or other contrasting agents or their excipients.
  • Men with breast cancer

Sites / Locations

  • Duke Cancer Center
  • Wake Forest Baptist Comprehensive Cancer CenterRecruiting
  • Virginia Commonwealth University Massey Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Near-Complete Estrogen Deprivation Therapy Participants

Arm Description

Participants will receive cardiac imaging stress tests as well as study laboratory tests to monitor for changes in heart as well 30-day at the end of the study along with annual long-term follow up to 5 years from baseline imaging.

Outcomes

Primary Outcome Measures

Change in Myocardial Blood Flow - 24 months
Change in myocardial blood flow will be measured by adenosine CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment.

Secondary Outcome Measures

Change in Myocardial Blood Flow - 12 months
Change in myocardial blood flow will be measured by adenosine CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment
Change in Stiffness - Thoracic Pulse Wave Velocity
Stiffness will be assessed by thoracic pulse wave velocity (PWV) and distensibility using CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment
Change in Myocardial Perfusion Reserves
Myocardial perfusion reserve will be measured with adenosine CMR imaging. Myocardial perfusion reserve is calculated as the percent change in myocardial blood flow between stress and rest perfusion imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment
Number of Women at High Risk for Developing Deficits in Myocardial Blood Flow
The predictive models developed to identify premenopausal women treated with an aromatase inhibitor for high-risk hormone receptor-positive breast cancer at highest risk for developing deficits in myocardial blood flow will incorporate variables related to demographics, medical history, and additional clinical variables.
Overall Survival
Disease outcomes will be monitored, including invasive-breast cancer free survival, at the annual visits throughout the study. With any change in anti-cancer therapy the specific reason for the change will be requested.
Difference in Stress CMR Myocardial Blood Flow
Total coronary plaque burden from coronary computed tomography angiography will be measured to assess the difference in heart function, including cardiac volumes and mass and blood flow in both groups.

Full Information

First Posted
March 25, 2022
Last Updated
August 17, 2023
Sponsor
Wake Forest University Health Sciences
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT05309655
Brief Title
Cardiac Outcomes With Near-Complete Estrogen Deprivation
Acronym
CROWN
Official Title
The Cardiac Outcomes With Near-Complete Estrogen Deprivation (CROWN) Study
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 2, 2022 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Wake Forest University Health Sciences
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this research study is to understand what effect near complete estrogen deprivation (NCED) therapy has on the heart in breast cancer patients. Investigators want to understand if NCED changes how the heart works.
Detailed Description
Primary Objective: To determine the 24-month difference in stress myocardial blood flow during adenosine stress cardiovascular magnetic resonance imaging (CMR) in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone receptor-negative breast cancer. Secondary Objectives: To determine the 12-month difference in stress myocardial blood flow during adenosine stress cardiovascular magnetic resonance imaging (CMR) in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone receptor-negative breast cancer. To determine the 12-month and 24-month difference in aortic stiffness (thoracic pulse wave velocity and distensibility) with CMR in premenopausal women treated with an near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone-receptor-negative breast cancer. To determine the association of stress CMR myocardial blood flow with total coronary plaque burden from coronary computed tomography angiography (at baseline and 24 month difference) and difference in variability in these measures in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone receptor- negative breast cancer. To determine the 12-month and 24-month difference in myocardial perfusion reserve in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone-receptor-negative breast cancer. To develop predictive models to identify women at highest risk for developing deficits in myocardial blood flow in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer. To monitor disease outcomes, in particular invasive-breast cancer free survival and to assess if any changes in anti-neoplastic therapy occur on the basis cardiovascular diagnoses generally or specifically due to CROWN study results.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Triple Negative Breast Cancer, Cardiovascular Complications

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Investigators will recruit 90 women, 67 who will be in the near-complete estrogen deprivation (NCED) group and 23 in the triple-negative breast cancer (TNBC) group. This will allow for approximately a 10% loss-to-follow-up rate and will allow investigators to have 60 participants in the NCED group and 20 in the TNBC with 2-year of data. There are 2 primary types of statistical analyses to address the study questions. The first includes testing hypotheses concerning between group (NCED vs TNBC) and within group (i.e. longitudinal changes within the NCED group) comparisons (Aims 1 and 2). The second analyses involve developing predictive equations among the NCED patients to determine if patient demographics including age, race, ethnicity, social determinants of health, clinical parameters, serum biomarkers and/or markers of inflammation are associated with cardiovascular changes over time.
Masking
None (Open Label)
Allocation
N/A
Enrollment
90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Near-Complete Estrogen Deprivation Therapy Participants
Arm Type
Experimental
Arm Description
Participants will receive cardiac imaging stress tests as well as study laboratory tests to monitor for changes in heart as well 30-day at the end of the study along with annual long-term follow up to 5 years from baseline imaging.
Intervention Type
Drug
Intervention Name(s)
Adenosine Stress Cardiac Magnetic Resonance Imaging
Intervention Description
Adenosine stress CMR test with contrast to include cardiovascular structural and functional measures including myocardial blood flow through quantitative perfusion mapping. Participants will have 3 stress tests as a part of this research. These tests will happen when at the beginning of the study, and then every year for 2 years.
Intervention Type
Diagnostic Test
Intervention Name(s)
Electrocardiogram
Intervention Description
A 12-lead electrocardiogram will be done when at the start of the study and at the participant's 2 year stress test to look at the electrical signals of your heart.
Intervention Type
Diagnostic Test
Intervention Name(s)
Computed Tomography Angiogram
Intervention Description
Contrasted coronary CT angiography will be performed for visual and quantitative analysis of coronary artery plaque burdens.
Intervention Type
Other
Intervention Name(s)
Laboratory Testing
Intervention Description
10 teaspoons of blood will be withdrawn at every visit that participants receive a stress test. Participants may have up to six blood draws associated with each imaging visit.
Intervention Type
Behavioral
Intervention Name(s)
Quality of Life Survey
Intervention Description
A general health status survey with 10 questions and should take about 5-10 minutes to finish. This survey is related to research.
Primary Outcome Measure Information:
Title
Change in Myocardial Blood Flow - 24 months
Description
Change in myocardial blood flow will be measured by adenosine CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment.
Time Frame
At baseline and at 24 months
Secondary Outcome Measure Information:
Title
Change in Myocardial Blood Flow - 12 months
Description
Change in myocardial blood flow will be measured by adenosine CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment
Time Frame
At baseline and at 12 months
Title
Change in Stiffness - Thoracic Pulse Wave Velocity
Description
Stiffness will be assessed by thoracic pulse wave velocity (PWV) and distensibility using CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment
Time Frame
At 12 months and at 24 months
Title
Change in Myocardial Perfusion Reserves
Description
Myocardial perfusion reserve will be measured with adenosine CMR imaging. Myocardial perfusion reserve is calculated as the percent change in myocardial blood flow between stress and rest perfusion imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment
Time Frame
At 12 months and at 24 months
Title
Number of Women at High Risk for Developing Deficits in Myocardial Blood Flow
Description
The predictive models developed to identify premenopausal women treated with an aromatase inhibitor for high-risk hormone receptor-positive breast cancer at highest risk for developing deficits in myocardial blood flow will incorporate variables related to demographics, medical history, and additional clinical variables.
Time Frame
At 24 months
Title
Overall Survival
Description
Disease outcomes will be monitored, including invasive-breast cancer free survival, at the annual visits throughout the study. With any change in anti-cancer therapy the specific reason for the change will be requested.
Time Frame
Up to 5 years
Title
Difference in Stress CMR Myocardial Blood Flow
Description
Total coronary plaque burden from coronary computed tomography angiography will be measured to assess the difference in heart function, including cardiac volumes and mass and blood flow in both groups.
Time Frame
At baseline and at 24 months

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Premenopausal women that are receiving or have received therapy for breast cancer.
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Women age ≤55 who were premenopausal at the time of breast cancer diagnosis; (Premenopausal is defined as per NCCN criteria). Planned breast cancer treatment with NCED (near-complete estrogen deprivation) therapy that includes aromatase inhibitor therapy (or SERD) with medically or surgically induced menopause within three (3) months of initiating NCED (HR-positive tumor) or, for the cohorts not receiving NCED therapy, within three (3) months of planned chemotherapy, surgery or radiation. Index date for three months is defined as final date of treatment with chemotherapy, surgery or radiation which ever happens last (HR-negative tumor). Treatment with a Gonadotropin Releasing Hormone (GnRH) agonist for fertility preservation during chemotherapy is allowed and is not considered part of the NCED antineoplastic therapy. Women with human epidermal growth factor-2 (HER2) negative and women with human epidermal growth factor-2 (HER2) positive breast cancer are eligible. Treatment with CDK-inhibitor, PARP inhibitor immunotherapy or biologic (non-chemotherapy) agent as part of anti-neoplastic treatment plan is allowed. These agents are not considered chemotherapy. Treatment with selective-estrogen receptor degrader (SERD) rather than aromatase inhibitor is allowed. Diagnosed with Stage I-III breast cancer. ECOG performance status of 0-2 Patients with concurrent malignancies are eligible as long as therapies and disease course for these are reasonably expected to not impact cardiovascular function. (Examples of eligible malignancies include: papillary/follicular thyroid cancer, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in-situ and early stage cervical cancers, etc.). Patients with prior COVID-19 are eligible if they have recovered from the illness and are free of COVID-related symptoms other than allowable persistent symptoms: loss of taste and smell and/or grade 1 fatigue. Ability to understand and the willingness to sign an IRB-approved informed consent document (either directly or via a legally authorized representative). The study will allow up to 10% of patients with MRI non-compatible breast expanders recognizing that baseline CMR will be outside of imaging window. Note: Registration of these participants will require study PI approval (Dr. Jordan or Dr. Thomas). Exclusion Criteria: History of allergic reactions attributed to compounds of similar chemical or biologic composition to adenosine Active asthma or chronic obstructive pulmonary disease (COPD) currently requiring medications or active wheezing. Those with contraindications for MRI such as ferromagnetic cerebral aneurysm clips or other intracranial metal, pacemakers, defibrillators, functioning neurostimulator devices or other implanted electronic devices, or some breast expanders. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study. Because some methods of birth control are not 100% reliable, a pregnancy test is required, unless the patient has undergone either a bilateral oophorectomy, hysterectomy or both. Coronary revascularization in the past 6 months or known severe multi-vessel coronary artery disease previously determined to be not amendable to mechanical intervention. Ongoing, unrelieved symptoms thought to represent cardiac ischemia and requiring immediate cardiac catheterization Allergy or prior sensitivity to gadolinium or other contrasting agents or their excipients. Men with breast cancer. Known chronic renal insufficiency or chronic electrolyte abnormalities as determined by the treating physician.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Study Coordinator
Phone
336-713-5435
Email
jriley@wakehealth.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexandra Thomas, MD
Organizational Affiliation
Wake Forest Baptist Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke Cancer Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Study Coordinator
Email
jriley@wakehealth.edu
Facility Name
Wake Forest Baptist Comprehensive Cancer Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Study Coordinator
Email
jriley@wakehealth.edu
First Name & Middle Initial & Last Name & Degree
Alexandra Thomas, MD
Facility Name
Virginia Commonwealth University Massey Cancer Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Study Coordinator
Email
jriley@wakehealth.edu
First Name & Middle Initial & Last Name & Degree
Jennifer Jordan, Ph.D

12. IPD Sharing Statement

Plan to Share IPD
No

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Cardiac Outcomes With Near-Complete Estrogen Deprivation

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