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

• Reduction in incidence of trastuzumab-induced cardiotoxicity after 52 weeks of treatment as measured by preservation of LVEF [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Comparison of the LVEF of each treatment group with the placebo arm [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• Number of trastuzumab courses completed without interruption [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Quality-of-life changes as assessed by EORTC-QLQ-C30 questionnaire at baseline and at the end of treatment [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Long-term effects of study drugs as assessed at 18 and 24 months (or 6 and 12 months after completion of trastuzumab therapy) [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• Number of trastuzumab courses completed without interruption [ Designated as safety issue: No ]
• Quality-of-life changes as assessed by EORTC-QLQ-C30 questionnaire at baseline and at the end of treatment [ Designated as safety issue: No ]
• Long-term effects of study drugs as assessed at 18 and 24 months (or 6 and 12 months after completion of trastuzumab therapy) [ Designated as safety issue: No ]

RATIONALE: Lisinopril or Coreg CR®, may help reduce side effects caused by trastuzumab. It is not yet known whether lisinopril or Coreg CR® are more effective than a placebo in reducing side effects caused by trastuzumab.

PURPOSE: This phase II trial is studying lisinopril and Coreg CR® to see how well they work compared with a placebo in reducing side effects in patients with HER2-positive 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.

• Breast Cancer
• Cardiac Toxicity

• Drug: Coreg CR®
  Given orally
  Other Name: carvedilol phosphate extended-release
• Drug: lisinopril
  Given orally
  Other Name: Registered Trade names: Prinivil, Tensopril, Zestril, Hipril
• Other: placebo
  Given orally

• Experimental: Arm I lisinopril
  Patients receive oral lisinopril once daily.
  Intervention: Drug: lisinopril
• Experimental: Arm II Coreg CR®
  Patients receive oral Coreg CR® once daily.
  Intervention: Drug: Coreg CR®
• Placebo Comparator: Arm III placebo
  Patients receive oral placebo once daily.
  Intervention: Other: placebo

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.