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

Phase 1

Completed

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

Interventions: Drug: Carvedilol

Registration Number: NCT04023110

Lead Sponsor: Abramson Cancer Center at Penn Medicine

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 68

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Carvedilol	Carvedilol	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.

Primary Outcome Measures

Name	Time	Method
Left Ventricular Ejection Fraction (LVEF)	up to 24 months	LVEF by echocardiogram. Left ventricular ejection fraction (LVEF) is defined as the left ventricular stroke volume (left ventricular end diastolic volume minus the left ventricular end systolic volume) divided by the left ventricular end diastolic volume. This fraction is multiplied by 100 to yield the LVEF, and is defined as a % (the unit of measure) (J Am Soc Echocardiogr 2015;28:1-39.). 2D left ventricular volumes are estimated according to the biplane method of disks (modified Simpson's rule), as recommended by societal guidelines. Higher values are generally considered more favorable.
Treatment Adherence as Measured by Pill Count	12 months	Rate of compliance with prescribed dose of carvedilol assessed based on pill count. Patients in the elevated-risk carvedilol group were asked to bring their study medications to all study visits and remaining pills were counted by the study coordinator to determine how many pills had been taken. Treatment adherence was calculated as the ratio of number of pills taken to expected number of pills taken, and is reported as a percentage. An adherence rate closer to 100 is better. Treatment adherence is reported only for those patients who were assigned to the elevated risk/carvedilol group, and therefore expected to take study medication.
Adverse Events	Up to 12 months	Targeted Adverse Events were prospectively assessed according to the CTCAE v5.0. The number of patients experiencing any adverse event (Grade 2-5) was tabulated by risk group and by treatment arm during carvedilol intervention (baseline - 12 months). In the CTCAE, grade refers to the severity of the event. Grade 2 events are moderate, or have non-urgent/non-invasive intervention indicated, or limit age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 events are severe/medically significant but not immediately life-threatening, or have hospitalization or prolongation of hospitalization indicated, or limit self-care ADLs. Grade 4 events have life-threatening consequences or have urgent intervention indicated. Grade 5 indicates a death related to the adverse event.

Secondary Outcome Measures

Name	Time	Method
Diastolic Function (E/e') by Echocardiogram	up to 24 months	E/e' is a measure of diastolic function derived from the ratio of the pulse wave Doppler interrogations of the mitral inflow at the mitral valve leaflet tips and at the lateral and septal mitral annulus via tissue Doppler imaging. This measure provided insight into myocardial relaxation, preload, and left ventricular filling pressures, with values \> 14 indicative of elevated filling pressure. This is core-lab quantified, blinded to patient and treatment characteristics.
Ventricular-arterial Coupling Measured by Echocardiogram	up to 24 months	Ventricular-arterial (VA) coupling, the ratio between effective arterial elastance (Ea), indicative of load, and end-systolic elastance (Ees), indicative of LV contractility, was also quantified. Ea/Ees is a measure of cardiac efficiency, with normal values of 0.8-1.0, and lower numbers typically indicative of greater efficiency and higher values reflective of worse function. This is core-lab quantified, blinded to patient and treatment characteristics.
Cardiac Strain Measurements by Echocardiogram	up to 24 months	Global longitudinal strain (GLS, %) averaged from 3 apical views (left ventricular apical 4-chamber, 2-chamber, and 3-chamber) was obtained using speckle-tracking technology using Tomtec Imaging Systems. GLS is a more sensitive measure of cardiac function, with values greater than -16% (e.g., -15%) for GLS associated with worse outcomes. Circumferential strain (GCS, %) from the short axis view (mid left ventricle) was obtained using speckle-tracking technology using Tomtec Imaging Systems. Circumferential strain is a more sensitive measure of cardiac function, with values or greater than -20% (e.g., -19%) associated with worse outcomes. GLS and GCS are core-lab quantified, blinded to patient and treatment characteristics.
Frequency of Individuals With Cardiac Dysfunction	up to 24 months	Frequency of individuals with cardiac dysfunction, as defined by reduction in LVEF of \>/= 10% to \< 50%.
High-sensitivity Troponin (hsTnT) Level	up to 24 months	Change in the cardiac biomarker of injury hsTnT over time, defined as a continuous variable. hsTnT is a biomarker that is indicative of cardiac injury, with higher values associated with more severe injury. This is core-lab quantified, blinded to patient and treatment characteristics.
N-terminal Pro B-type Natriuetic Peptide (NTproBNP) Level	up to 24 months	Change in the cardiac biomarker, NT-proBNP over time, defined as a continuous variable. NTproBNP is a biomarker that is indicative of neurohormonal stress, with higher levels associated with more neurohormonal stress. This is core-lab quantified, blinded to patient and treatment characteristics.
Left Ventricular Mass	up to 24 Months	LV mass by echocardiogram. Measurements of left ventricular mass (g) provided insight into cardiac structure, size, and remodeling. LV mass was calculated by the area-length method, as recommended by societal guidelines. This is core-lab quantified, blinded to patient and treatment characteristics.

Trial Locations

Locations (1): Abramson Cancer Center of the University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Abramson Cancer Center of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States