Carvedilol for the Prevention of Anthracycline/Anti-HER2 Therapy Associated Cardiotoxicity Among Women With HER2-Positive Breast Cancer Using Myocardial Strain Imaging for Early Risk Stratification

Study Overview
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Brief Summary
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The purpose of this study is to find out the effects, good and/or bad, of a beta blocker (carvedilol) on heart function during treatment with anti-HER2 medication(s) including trastuzumab (Herceptin).

Detailed Description
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This phase II placebo-controlled study will evaluate the effect of carvedilol, compared to placebo, on anthracycline/anti-HER2 therapy induced left ventricular dysfunction in patients with HER2-positive breast cancer who are receiving adjuvant or neoadjuvant therapy. All patients will undergo routine cardiac surveillance with 2D echocardiograms per standard of care at multiple time points which will align as closely as possible to the following: pre-anthracycline (baseline), pre-anti-HER2 therapy, and 3, 6, 9, and 12 months (+/- 4 weeks) after initiation of anti-HER2 therapy. In the case that standard of care echocardiograms are not done at these time points, either due to a delay in anti-cancer therapy or due to the patient's medical condition, the principal investigator will determine if the standard of care echocardiogram may be used in lieu of one of the time points listed. Additional speckle tracking strain analysis will be performed on these echocardiograms, and blood specimens will be drawn at several time points for biomarker analysis. After completion of anthracycline treatment and prior to initiation of anti-HER2 therapy, 32 patients with abnormal myocardial strain, defined as global longitudinal strain < 19% or % change from baseline by > 11%, will be randomized in a 1:1 ratio to carvedilol versus placebo. Carvedilol will be administered twice daily for approximately 1 year OR until the end of anti-HER2 therapy, if it is discontinued prior to 1 year. Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.

Official Title
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Carvedilol for the Prevention of Anthracycline/Anti-HER2 Therapy Associated Cardiotoxicity Among Women With HER2-Positive Breast Cancer Using Myocardial Strain Imaging for Early Risk Stratification

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Carvedilol
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female Age ≥ 18 years Non-metastatic histologically confirmed primary invasive breast carcinoma Pathologically confirmed HER2-positive breast cancer Scheduled to receive anthracycline chemotherapy followed by anti-HER2 therapy at MSKCC Able and willing to provide informed consent Willing and able to comply with the requirements of the protocol Able to swallow capsules For Aim 2, all patients must meet the following criteria: Meet all inclusion criteria above LVEF > 50% Abnormal global longitudinal strain (<19%, or a % decrease of ≥ 11% from baseline) prior to initiation of planned anti-HER2 therapy Heart rate ≥ 50 beats per minute Sitting systolic blood pressure > 90 mmHg Exclusion Criteria: Patients are to be excluded from randomization for Aim 2 of this study if they meet any of the following criteria: Current treatment with ACE-inhibitors or beta blockers Allergies or inability to tolerate beta blockers previously due to bradycardia, hypotension, or AV block. Known history of NCI CTCAE (Version 4.0) Grade ≥ 2 symptomatic CHF, myocardial infarction within 12 months prior to randomization, significant symptoms (Grade ≥ 3) relating to left ventricular dysfunction, significant (moderate or severe) valvular disease, or significant cardiac arrhythmia (Grade ≥ 3) Pre-menopausal women without a negative serum or urine pregnancy test within 4 weeks of starting treatment Enrollment in a therapeutic intervention trial in the Breast Medicine service

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol<br>Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. | Drug: Carvedilol<br> <br> |
| Placebo Comparator: placebo<br>Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. | Other: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Change in LVEF at 3 Months | Value at 3 months minus value at baseline | 3 months | 
| Maximum Change in LVEF at 6 Months | Value at 6 months minus value at baseline | 6 months | 
| Maximum Change in LVEF at 9 Months | Value at 9 months minus value at baseline | 9 months | 
| Maximum Change in LVEF at 12 Months | Value at 12 months minus value at baseline | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Abnormal LVEF at 12 Months | The study is designed to detect an intergroup difference of absolute difference of 10 percentage points (simple difference) in the change in LVEF between the experimental and control group. Ten percent is the change in LVEF that is associated with differing degrees of left ventricular dysfunction, and long-term studies among non-cancer patients have shown that outcomes differ among groups of patients who have LVEF differing by 10%. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carvedilol, Anthracycline, HER2, 14-099