TrAstuzumab Cardiomyopathy Therapeutic Intervention With Carvedilol

The objective of the current application is to evaluate different strategies of
cardiovascular therapy with carvedilol, aiming to reduce the incidence of LVEF decline and HF
in patients undergoing curative intent trastuzumab-based HER2-directed therapy for breast
cancer. It will compare: a) a pre-emptive preventive approach, i.e. cardiovascular therapy
with the beta-blocker carvedilol started before trastuzumab-based HER2-directed therapy and
b) a reactive preventive approach, i.e. cardiovascular therapy started in response to early
subclinical signs of cardiac dysfunction/injury (either cardiac troponin elevation or
abnormal global longitudinal strain), with the current standard approach of initiation
cardiovascular therapy once cardiotoxicity has occurred, addressing the question if and at
which point in time carvedilol therapy would be efficacious. It will furthermore compare
outcome measures between a limited carvedilol therapy duration, confined to the time of the
active trastuzumab-based HER2-directed treatment and cardiac function recovery versus an
extended carvedilol therapy duration continuing one year after completion of
trastuzumab-based HER2-directed therapy, addressing how long carvedilol needs to be given in
this unique patient population. The above will be combined with pharmacogenomic measures to
identify those at highest risk of irreversible LVEF decline and lack of response to therapy.
The investigator's central hypothesis is that a pre-emptive or a reactive preventive approach
will reduce the incidence of cardiotoxicity in breast cancer patients undergoing treatment
with trastuzumab, and that extension of carvedilol therapy beyond the active
trastuzumab-based HER2-directed therapy treatment will prove superior for preservation of
cardiac function.

Three specific aims will be pursued:

Aim 1: to compare the incidence of a) HF or asymptomatic decline in LVEF by >10% in patients
whose LVEF is ≥50% or LVEF drop ≥5% in those with a decrease to <50%. (primary aim #1), and
b) reversible LVEF decline to within 5% of baseline (secondary aim #1) with a pre-emptive and
reactive preventive approach with carvedilol versus a "wait-and-see strategy" of carvedilol
initiation in response to HF or LVEF declines in breast cancer patients over the course of
trastuzumab therapy. It is to address the question if and when to start cardioprotective
efforts for patients undergoing trastuzumab therapy.

Aim 2: To compare the delta change in LVEF from completion to one year after completion of
trastuzumab therapy between cardioprotective approach with carvedilol confined the duration
of trastuzumab therapy or extended for one year thereafter. This aim is to address the
question of duration of cardioprotective efforts for patients undergoing trastuzumab therapy.

Aim 3: To identify genetic variants that predict trastuzumab cardiotoxicity in general as
well as lack of response (primary prevention of drop in LVEF or secondary improvement of
LVEF) to carvedilol.

Inclusion Criteria:

- ≥18 years of age,

- new diagnosis of HER2+ breast cancer that will be treated with curative intent (can be
recurrent disease)

- planned HER2-directed therapy for one year total (can be dual-HER-2 directed therapy)

Exclusion Criteria:

- history of HF of any class and type, or diagnosis of cardiomyopathy in the past,

- LVEF <50% at screening,

- intolerance to beta-blocker,

- baseline use of any beta-blocker for coronary artery disease including myocardial
infarction,

- current ACE inhibitor or ARB therapy for hypertension in the presence of diabetes
and/or for chronic kidney disease/proteinuria,

- on active therapy with amiodarone, sotalol, or any other antiarrhythmic

- history of bronchial asthma or related bronchospastic conditions,

- heart rate < 50 BPM at screening,

- history of or current sick sinus syndrome,

- AV block grade II or higher (unless patient has a permanent pacemaker) at screening,

- systolic blood pressure < 90 mmHg at screening,

- severe hepatic dysfunction, as defined by NCI ODWG (total bilirubin >3x ULN, any AST
elevation) or Child Pugh C class

- pregnancy