Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab

Study Overview
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Brief Summary
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Investigators will evaluate the safety, tolerability, and feasibility of a risk-guided cardioprotective treatment strategy with carvedilol, as compared to usual care, in breast cancer patients undergoing treatment with doxorubicin, trastuzumab, or the combination.

Detailed Description
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This is a single-center, randomized clinical trial that seeks to determine if a risk guided treatment strategy that initiates carvedilol in high risk breast cancer patients prior to doxorubicin and/or trastuzumab is safe, tolerable, and feasible. Subjects who are identified as having elevated CTX Risk by an internally validated clinical risk score (exceeding a pre-specified risk threshold) will be randomized to individually-dosed, open-label carvedilol or usual care. Investigators will use a stratified randomization according to trastuzumab therapy (yes/no) to ensure balance across treatment regimen. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months.

Official Title
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A Pilot Study of Risk-Guided Cardioprotection With Carvedilol in Breast Cancer Patients Treated With Doxorubicin and/or Trastuzumab

Conditions
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Cardiotoxicity, Risk Factor, Cardiovascular, Toxicity Due to Chemotherapy, Breast Cancer, Cardiomyopathies, Heart Failure

Intervention / Treatment
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* Drug: Carvedilol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females At least 18 years old Diagnosed with Stage I-III breast cancer with treatment plan to include therapy with anthracyclines and/or trastuzumab in the adjuvant or neo-adjuvant setting Study team is able to obtain all necessary information for calculating Cardiotoxicity Risk Score (including echocardiographic measurement of left ventricular ejection fraction) Exclusion Criteria: Pregnant or breast feeding. Due to unknown risks and potential harm to the unborn fetus a negative pregnancy test within 10 days prior to enrollment is required in women with child-bearing potential. Due to the potential nursing infant harm, women who are currently breast feeding are not eligible for this study. Contraindication to carvedilol Baseline systolic blood pressure < 90mmHg (if multiple blood pressures are available in the medical record within 1 month prior to screening, the average SBP will be considered) Baseline heart rate < 55 bpm consistent with severe bradycardia (if multiple resting heart rates are available in the medical record within 1 month prior to screening, the average heart rate will be considered) Allergy to carvedilol History of bronchial asthma or related bronchospastic conditions Known history of sick sinus syndrome Severe hepatic impairment, defined as serum bilirubin > 3.0x ULN, AST or ALT > 5.0 ULN within 28 days of enrollment Second- or third-degree AV block, as determined by electrocardiogram Severe bradycardia (unless permanent pacemaker is in place) Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy Current use of: Bupropion (Wellbutrin), Fluoxetine (Prozac), Paroxetine (Paxil), Quinidine (Quinidex), Duloxetine (Cymbalta), Digoxin Current treatment with beta blocker Unable to provide consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An internally validated CV risk score will be used to determine an individual patient's risk. Low risk patients will be observed and managed according to usual care. Elevated risk patients will be randomized to open label, individually dosed carvedilol for 1 year or usual care.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol<br>Carvedilol will be initiated at 3.125mg twice daily and uptitrated as tolerated in a stepwise fashion to a maximum dose of 25mg twice daily or to a systolic blood pressure (SBP) of 110-120mmHg or heart rate (HR) of 50-55 beats per minute (bpm). Patients will start carvedilol in the evening after first dose of chemotherapy and will continue on medication for 12 months. Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months. | Drug: Carvedilol<br>* Individually dosed carvedilol<br>* Other names: Coreg;|
| No Intervention: Usual Care<br>Clinical, echocardiographic, and biomarker data will be collected on all patients at baseline and standardized time intervals during and after therapy at approximately 3, 6, 9, 12, and 24 months. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left Ventricular Ejection Fraction (LVEF) | LVEF derived from quantitative analyses of echocardiography-derived measurements of left ventricular volumes in diastole and systole. | up to 24 months | 
| Treatment adherence as measured by pill count | Rate of compliance with prescribed dose of carvedilol by pill count | 12 months | 
| Adverse Events | Adverse Events will be assessed using the CTCAE v5.0. The number of Grade 2-5 toxicities observed will be tabulated by risk group and by treatment arm. Differences will be evaluated using Fisher exact tests. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diastolic function (E/e') by echocardiogram | The mitral valve inflow velocity divided by the average early diastolic tissue velocities of the mitral valve annulus (septal, lateral) measured by tissue Doppler echocardiography. | up to 24 months | 
| Ventricular-arterial coupling measured by echocardiogram | Defined by echocardiography-derived measures of end systolic elastance divided by effective arterial elastance | up to 24 months | 
| Cardiac Strain measurements by echocardiogram | Echocardiography-derived measures of longitudinal, circumferential, and radial strain. | up to 24 months | 
| Frequency of individuals with clinical heart failure | Frequency of clinical heart failure diagnosis | up to 24 months | 
| High-sensitivity Troponin (hsTnT) level | Change in the cardiac biomarker of injury hsTnT over time, defined as a continuous variable | up to 24 months | 
| N-terminal pro B-type natriuetic peptide (NTproBNP) level | Change in the cardiac biomarker of neurohormonal stress NT-proBNP over time, defined as a continuous variable | up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Risk-Guided Intervention, Carvedilol, Cardiotoxicity of Chemotherapy, Cardio-Oncology, Cardiomyopathy