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

NCT04023110 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: UPCC12118R21HL150723849569
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Risk-Guided Intervention; Carvedilol; Cardiotoxicity of Chemotherapy; Cardio-Oncology; Cardiomyopathy

Outcome Measures

Primary Outcomes (3)

• Left Ventricular Ejection Fraction (LVEF)

  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.

  up to 24 months

• Treatment Adherence as Measured by Pill Count

  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.

  12 months

• Adverse Events

  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.

  Up to 12 months

Secondary Outcomes (7)

• Diastolic Function (E/e') by Echocardiogram

  up to 24 months

• Ventricular-arterial Coupling Measured by Echocardiogram

  up to 24 months

• Cardiac Strain Measurements by Echocardiogram

  up to 24 months

• Frequency of Individuals With Cardiac Dysfunction

  up to 24 months

• High-sensitivity Troponin (hsTnT) Level

  up to 24 months

Study Arms (2)

Carvedilol

EXPERIMENTAL

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

Usual Care

NO INTERVENTION

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

Carvedilol DRUG

Individually dosed carvedilol

Also known as: Coreg

Carvedilol

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Abramson Cancer Center at Penn Medicine: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• American Heart Association: collaborator

Study Sites (1)

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• Jung W, Hubbard RA, Smith AM, Ko K, Huang A, Wang J, Isaacs JM, Zhang L, Liu PP, Chen Z, Shah PD, Mintzer D, Bhattacharya S, Knollman HM, Clark AS, Koropeckyj-Cox D, Messinger M, Wilcox NS, Xia C, Narayan V, Upshaw JN, Armenian SH, Ky B. Risk-guided cardioprotection with carvedilol in patients with breast cancer (CCT guide): a phase 1 randomized clinical trial. Breast Cancer Res Treat. 2025 Jun;211(2):293-305. doi: 10.1007/s10549-025-07636-3. Epub 2025 Apr 2.

  PMID: 40172740 DERIVED

MeSH Terms

Conditions

Cardiotoxicity; Breast Neoplasms; Cardiomyopathies; Heart Failure

Interventions

Carvedilol

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Limitations and Caveats

The limitations include small sample size and the fact that concomitant use of cardiac medications was not controlled. The study was executed during the COVID-19 pandemic which may have impacted patient recruitment and adherence. Hypothesis testing was not conducted due to the limited sample size and exploratory nature of the study. Descriptive summary statistics were used to characterize the study population, outcome measures, and adverse events.

Results Point of Contact

• Title: Bonnie Ky, MD, MSCE
• Organization: University of Pennsylvania

bonnie.ky@pennmedicine.upenn.edu

215-573-6606

Study Officials

• Bonnie Ky, MD, MSCE

  Perelman School of Medicine at the University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 22, 2019
• First Posted: July 17, 2019
• Study Start: August 9, 2019
• Primary Completion: August 31, 2024
• Study Completion: January 14, 2025
• Last Updated: October 9, 2025
• Results First Posted: October 9, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)