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

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Supportive Care
    • Masking: None (Open Label)
  • Study Primary Completion Date: February 2022

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.

Interventions

  • Drug: Carvedilol
    • Individually dosed carvedilol

Arms, Groups and Cohorts

  • Experimental: 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.
  • No Intervention: Usual Care
    • 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.

Clinical Trial Outcome Measures

Primary Measures

  • Left Ventricular Ejection Fraction (LVEF)
    • Time Frame: up to 24 months
    • LVEF derived from quantitative analyses of echocardiography-derived measurements of left ventricular volumes in diastole and systole.
  • Treatment adherence as measured by pill count
    • Time Frame: 12 months
    • Rate of compliance with prescribed dose of carvedilol by pill count
  • Adverse Events
    • Time Frame: Up to 24 months
    • 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.

Secondary Measures

  • Diastolic function (E/e’) by echocardiogram
    • Time Frame: up to 24 months
    • 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.
  • Ventricular-arterial coupling measured by echocardiogram
    • Time Frame: up to 24 months
    • Defined by echocardiography-derived measures of end systolic elastance divided by effective arterial elastance
  • Cardiac Strain measurements by echocardiogram
    • Time Frame: up to 24 months
    • Echocardiography-derived measures of longitudinal, circumferential, and radial strain.
  • Frequency of individuals with clinical heart failure
    • Time Frame: up to 24 months
    • Frequency of clinical heart failure diagnosis
  • High-sensitivity Troponin (hsTnT) level
    • Time Frame: up to 24 months
    • Change in the cardiac biomarker of injury hsTnT over time, defined as a continuous variable
  • N-terminal pro B-type natriuetic peptide (NTproBNP) level
    • Time Frame: up to 24 months
    • Change in the cardiac biomarker of neurohormonal stress NT-proBNP over time, defined as a continuous variable

Participating in This Clinical Trial

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

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Abramson Cancer Center of the University of Pennsylvania
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Bonnie Ky, MD, MSCE, Principal Investigator, Perelman School of Medicine at the University of Pennsylvania
  • Overall Contact(s)
    • Bonnie Ky, MD, MSCE, 215-573-6606, bonnie.ky@uphs.upenn.edu

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