Clinical trial NCT06844669: HER2HEART-US: Prevention of Cardiotoxicity in Breast Cancer Patients Receiving HER2-directed Therapy
Official title: HER2HEART-US: Primary Prevention of Cardiotoxicity in Breast Cancer Patients Receiving HER2-directed Therapy: a Pilot 2x2 Factorial Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: HER2-positive Breast Cancer
HER2+ Breast Cancer
Keywords: Breast cancer
Cardiotoxicity
Heart failure
Cardio-oncology
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2025-02-25
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: This is a 2x2 factorial, open-label, randomized pilot study. Patients will be randomized on a 1:1 basis to either carvedilol or no carvedilol, and again on a 1:1 basis to either empagliflozin or no empagliflozin, meaning that there are four arms:

* Arm 1: carvedilol
* Arm 2: empagliflozin
* Arm 3: carvedilol + empagliflozin
* Arm 4: usual care
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: 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. Plan for concurrent anthracycline with HER2-directed therapy is exclusionary.
* At least 18 years of age.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
* Left ventricular ejection fraction (LVEF) ≥ 50% up to 30 days prior to enrollment detected by 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
* Prior cancer treatment with anthracyclines.
* 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.

Primary outcomes:
measure: Feasibility of HER2HEART as measured by the number of patients enrolled over a 6-month period
timeFrame: 6 months
Secondary outcomes:
measure: Tolerability as measured by treatment adherence via self-report
timeFrame: From start of treatment through last day of study treatment (estimated to be 3 months)
measure: Tolerability as measured by incidence of serious adverse events
timeFrame: From start of treatment through last day of study treatment (estimated to be 3 months)
measure: Tolerability as measured by incidence of adverse events of special interest
timeFrame: From start of treatment through last day of study treatment (estimated to be 3 months)
measure: Tolerability as measured by number of participants who withdraw from the study due to adverse events
timeFrame: From start of treatment through last day of study treatment (estimated to be 3 months)
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Joshua Mitchell, M.D., MSCI, FAC, FICOS
role: PRINCIPAL_INVESTIGATOR
References: