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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase II Placebo-controlled Trial of Lisinopril and Coreg CR® to Reduce Cardiotoxicity in Patients With Breast Cancer Receiving (Neo)Adjuvant Chemotherapy With Trastuzumab (Herceptin®)

Conditions
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Breast Cancer, Cardiac Toxicity

Intervention / Treatment
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* Drug: Coreg CR®
* Drug: lisinopril
* Other: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I lisinopril<br>Patients receive oral lisinopril once daily. | Drug: lisinopril<br>* Given orally<br>* Other names: Registered Trade names: Prinivil, Tensopril, Zestril, Hipril;|
| Experimental: Arm II Coreg CR®<br>Patients receive oral Coreg CR® once daily. | Drug: Coreg CR®<br>* Given orally<br>* Other names: carvedilol phosphate extended-release;|
| Placebo Comparator: Arm III placebo<br>Patients receive oral placebo once daily. | Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Trastuzumab-Induced Cardiotoxicity After 52 Weeks of Treatment | Reduction in incidence of trastuzumab-induced cardiotoxicity after 52 weeks of treatment as measured by preservation of Left Ventricular Ejection Fraction (LVEF). Number of Patients who experienced a cardiotoxicity. | 2 years | 
| Number of Participants With LVEF Decrease to <50% | Number of Participants with Left Ventricular Ejection Fraction (LVEF) drop to <50% | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Trastuzumab Course Interruption | Measure indicates the number of patients who had an interruption of trastuzumab for any reason | 2 years | 
| Quality-of-life Changes Between Baseline and 52-weeks | Quality-of-life changes as assessed by North European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30), which measures the quality of life of cancer patients. Higher score indicates higher quality of life. Score range is 0-100. The questionnaire was administered at baseline and at 52 weeks. | 52 weeks | 
| Number of Participants With Cardiotoxicity-free Survival at 750 Days From Baseline | Number of Participants with cardiotoxicity-free survival at 750 days from baseline | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IA breast cancer, cardiac toxicity, HER2-positive breast cancer, recurrent breast cancer, stage IB breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, male breast cancer