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

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.

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