HER2HEART-US: Prevention of Cardiotoxicity in Breast Cancer Patients Receiving HER2-directed Therapy

HER2HEART-US: Primary Prevention of Cardiotoxicity in Breast Cancer Patients Receiving HER2-directed Therapy: a Pilot 2x2 Factorial Randomized Controlled Trial

Ten to 15% of patients with breast cancer are HER2 positive, with treatment focused on targeting the HER2 receptor. Although these treatments are generally well tolerated, they are associated with an increased risk of cardiomyopathy. There are currently no treatments proven to prevent the cardiotoxicities associated with HER2-targeted therapy, but there is convincing preclinical data demonstrating that prophylactic treatment with a beta blocker (BB) and/or an SGLT2 inhibitor (SGLT2i) may each independently prevent cardiotoxicity and HER-targeted treatment interruptions.

The proposed pilot study will assess the feasibility and preliminary efficacy and safety of therapy with both a beta blocker (carvedilol) and an SGLT2 inhibitor (empagliflozin), alone and in combination, in a population initiating HER2-directed therapy for HER2+ breast cancer.

The hypotheses being tested in this study are:

1. It is feasible to recruit 20-40 patients over 6 months
2. There are no differences in tolerability and safety between participants taking carvedilol and/or empagliflozin and those receiving usual care.

Study Overview

• Status: Terminated
• Conditions: HER2-positive Breast Cancer; HER2+ Breast Cancer
• Intervention / Treatment: Drug: Carvedilol; Drug: Empagliflozin

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed HER2+ breast cancer by ASCO/CAP guidelines of any clinical or pathologic stage.
• Planning to commence standard of care HER2-directed therapy or started HER2-directed therapy within 6 months prior to randomization
• At least 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• For patients newly commencing HER2-directed therapy, left ventricular ejection fraction (LVEF) ≥ 50% up to 30 days prior to enrollment detected by echocardiogram. For patients already receiving HER2-directed therapy, LVEF ≥ 50% after the last cycle of therapy prior to enrollment. (Patient will be enrolled at the time of their next cycle after the echocardiogram.)
• Systolic blood pressure ≥ 100 mmHg and resting heart rate ≥ 60 bpm.
• eGFR > 30 mL/min/1.73m^2.
• Women of childbearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Patients with an acceptable support system (as determined by the treating medical team).
• Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior exposure to mantle cell lymphoma field radiation.
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen as determined by the treating physician. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
• Currently receiving treatment with SGLT2i or BB that cannot be stopped during the duration of study participation. Currently receiving non-dihydropyridine calcium channel blocker that cannot be transitioned to or used in combination with carvedilol.
• Patients with untreated brain metastases requiring central nervous system directed therapy and interruption of systemic HER2 directed therapy (as determined by the treating medical team.
• A known history of allergic reactions attributed to compounds of similar chemical or biologic composition to carvedilol, empagliflozin, or other agents used in the study.

• Contraindication to carvedilol or empagliflozin at the discretion of the investigator such as:

  • Bronchial asthma or related bronchospastic conditions where BB would be contraindicated
  • Second- or third-degree atrioventricular (AV) block
  • Sick sinus syndrome
  • Severe bradycardia (unless permanent pacemaker in place)
  • In cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy
  • Severe hepatic impairment in setting of cirrhosis that prevents use of carvedilol
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection or uncontrolled cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Carvedilol BID; Carvedilol by mouth twice per day (BID) for 12 weeks.	Drug: Carvedilol; 6.25 mg with food; Other Names: Coreg
Experimental: Arm 2: Empagliflozin QD; Empagliflozin by mouth daily (QD) for 12 weeks.	Drug: Empagliflozin; 10 mg in the morning with or without food; Other Names: Jardiance
Experimental: Arm 3: Carvedilol BID + Empagliflozin QD; Carvedilol by mouth twice per day (BID) for 12 weeks and empagliflozin by mouth daily (QD) for 12 weeks.	Drug: Carvedilol; 6.25 mg with food; Other Names: Coreg; Drug: Empagliflozin; 10 mg in the morning with or without food; Other Names: Jardiance
No Intervention: Arm 4: Usual Care; No medications.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of HER2HEART as measured by the number of patients enrolled over a 10-month period	Feasibility is defined as enrollment of 20-40 patients (5-10 per am) over a 10-month recruitment period.	10 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability as measured by treatment adherence via self-report		From start of treatment through last day of study treatment (estimated to be 3 months)
Tolerability as measured by incidence of serious adverse events		From start of treatment through last day of study treatment (estimated to be 3 months)
Tolerability as measured by incidence of adverse events of special interest	Symptomatic hypotension (systolic blood pressure <90 mmHg); Symptomatic bradycardia (heart rate <50 bpm); Acute renal dysfunction (eGFR decrease >30% from baseline); Syncope; Symptomatic hypoglycemia (blood glucose <70 mg/dL); Perineal infection; Urinary tract infection; Diabetic ketoacidosis (commonly accepted criteria are blood glucose > 250 mg/dL, arterial pH < 7.3, serum bicarbonate < 15 mEq/L, and the presence of ketonemia or ketonuria).; Euglycemic diabetic ketoacidosis (diabetic ketoacidosis in the absence of hyperglycemia)	From start of treatment through last day of study treatment (estimated to be 3 months)
Tolerability as measured by number of participants who withdraw from the study due to adverse events		From start of treatment through last day of study treatment (estimated to be 3 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Joshua Mitchell, M.D., MSCI, FAC, FICOS, Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2025
• Primary Completion (Actual): February 16, 2026
• Study Completion (Actual): May 7, 2026

Study Registration Dates

• First Submitted: February 17, 2025
• First Submitted That Met QC Criteria: February 21, 2025
• First Posted (Actual): February 25, 2025

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Heart failure; Breast cancer; Cardiotoxicity; Cardio-oncology
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Wounds and Injuries; Pathologic Processes; Neoplasms by Site; Neoplasms; Heart Diseases; Chemically-Induced Disorders; Skin Diseases; Breast Diseases; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Heart Failure; Breast Neoplasms; Cardiotoxicity; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amines; Indoles; Alcohols; Propanolamines; Amino Alcohols; Propanols; Heterocyclic Compounds, 3-Ring; Carbazoles; Carvedilol; empagliflozin
• Other Study ID Numbers: 202502113

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial will be shared after deidentification. These requests are reviewed and will be approved by study investigators on the basis of scientific merit.
• IPD Sharing Time Frame: Immediately following publication.
• IPD Sharing Access Criteria: These requests are reviewed and will be approved by study investigators on the basis of scientific merit.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No