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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Failure; Breast Cancer; Cardiomyopathies; Risk Factor, Cardiovascular; Cardiotoxicity; Toxicity Due to Chemotherapy
• Intervention / Treatment: Drug: Carvedilol

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.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Carvedilol; Individually dosed carvedilol; Other Names: Coreg
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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Abramson Cancer Center at Penn Medicine
• Investigators: Principal Investigator: Bonnie Ky, MD, MSCE, Perelman School of Medicine at the University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2019
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: March 22, 2019
• First Submitted That Met QC Criteria: July 16, 2019
• First Posted (Actual): July 17, 2019

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Cardiomyopathy; Carvedilol; Cardio-Oncology; Risk-Guided Intervention; Cardiotoxicity of Chemotherapy
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Wounds and Injuries; Breast Diseases; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Breast Neoplasms; Cardiomyopathies; Cardiotoxicity; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Protective Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol
• Other Study ID Numbers: UPCC12118

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Investigators do not plan to make the IPD, analytic methods, or study materials available to other researchers for purposes of reproducing our results or replicating the procedure given the pilot Phase 1 nature of this study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No