Lisinopril or Coreg CR® in Reducing Side Effects in Women With Breast Cancer Receiving Trastuzumab

OBJECTIVES:

Primary

- The primary objective of this study is to determine if administration of lisinopril or
Coreg CR®, compared to placebo, will reduce the incidence of trastuzumab-induced
cardiotoxicity, as measured by LVEF, in patients receiving adjuvant, or
neoadjuvant,therapy for HER2 positive breast cancer.

Secondary

- To determine whether subjects randomized to active agent have fewer interruptions in
trastuzumab therapy due to cardiomyopathy.

- To determine whether the treatment effect is consistent in anthracycline and
nonanthracycline patient cohorts

- To compare changes in HRQL among the treatment groups during the study intervention

- To evaluate the long term effects on the prevention of cardiomyopathy and impact on HRQL
for either or both study agents

- To compare the predictive value of troponin I and BNP in the identification of
trastuzumab-induced cardiotoxicity

OUTLINE: This is a multicenter study. Patients are stratified according to chemotherapy
comprising an anthracycline (yes vs no). Patients are randomized to 1 of 3 treatment arms.

- Arm I: Patients receive oral lisinopril once daily.

- Arm II: Patients receive oral Coreg CR® once daily.

- Arm III: Patients receive oral placebo once daily.

In all arms, study treatment begins with the first dose of trastuzumab and continues for up
to 52 weeks or until the end of trastuzumab therapy.

Quality of life is assessed using the EORTC QLQ-C30 questionnaire at baseline, at 52 weeks
(or at the end of trastuzumab therapy), and at 18 and 24 months (or 6 and 12 months after the
completion of trastuzumab).

After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months.

INCLUSION CRITERIA

- Males and Females ≥ 18 years old diagnosed with HER2 positive breast cancer

- Scheduled to receive neoadjuvant or adjuvant trastuzumab (Herceptin®) therapy
(anthracycline-containing regimens are permitted). Patients receiving Herceptin® with
their chemotherapy are permitted for eligibility work-up. Taxanes are permitted.
Trastuzumab (Herceptin®) therapy may be given with or after primary chemotherapy.
Pertuzumab may be used in conjunction with trastuzumab.

- Left Ventricular Ejection Fraction (LVEF) ≥ 50% by MUGA scan or echocardiogram

- Adequate renal function for administration of trastuzumab-containing chemotherapy
regimen.

- Sitting systolic blood pressure of > 90 mm Hg

- Pulse ≥ 60 beats/minute

- Not pregnant or breastfeeding

- Female patients of childbearing potential, who are sexually active, must have a
negative pregnancy test before starting the study

- Both men and women must be willing to use effective contraception during the study.
Teratogenicity is documented for both active study agents

- Able to swallow capsules

EXCLUSION CRITERIA:

- Patients with metastatic disease

- Prior treatment with trastuzumab or anthracyclines prior to this chemotherapy regimen

- Current treatment with angiotensin converting enzyme (ACE) inhibitors, angiotensin
receptor blockers (ARBs), such as losartan, β-blockers or digoxin

- Known cardiac history: heart failure, myocardial infarction, radiation-induced cardiac
dysfunction

- Known allergy to either ACE inhibitors or β-blockers

- History of bronchial asthma or related bronchospastic conditions

- Hereditary or idiopathic angioedema

- History of severe hypersensitivity reactions to drugs or other causes, i.e. bee stings

- This protocol does not exclude patients who are participating on other investigational
studies. Refer to the local IRB guidelines.