Breast Cancer, Cardiac Toxicity
Conditions
Keywords
cardiac toxicity, HER2-positive breast cancer, recurrent breast cancer, stage IA 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
Brief summary
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
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.
Interventions
DRUGCoreg CR®
Given orally
DRUGlisinopril
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
University of South Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Trastuzumab-Induced Cardiotoxicity After 52 Weeks of Treatment | 2 years | 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. |
| Number of Participants With LVEF Decrease to <50% | 2 years | Number of Participants with Left Ventricular Ejection Fraction (LVEF) drop to \<50% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Trastuzumab Course Interruption | 2 years | Measure indicates the number of patients who had an interruption of trastuzumab for any reason |
| Quality-of-life Changes Between Baseline and 52-weeks | 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. |
| Number of Participants With Cardiotoxicity-free Survival at 750 Days From Baseline | 2 years | Number of Participants with cardiotoxicity-free survival at 750 days from baseline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I Lisinopril Patients receive oral lisinopril once daily.
lisinopril: Given orally | 158 |
| Arm II Coreg CR® Patients receive oral Coreg CR® once daily.
Coreg CR®: Given orally | 156 |
| Arm III Placebo Patients receive oral placebo once daily.
placebo: Given orally | 154 |
| Total | 468 |
Baseline characteristics
| Characteristic | Arm I Lisinopril | Arm II Coreg CR® | Arm III Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 50.58 Years STANDARD_DEVIATION 10.91 | 51.58 Years STANDARD_DEVIATION 10.93 | 51.11 Years STANDARD_DEVIATION 10.32 | 51.09 Years STANDARD_DEVIATION 10.71 |
| Body Mass Index (BMI) | 28.01 kg/m^2 STANDARD_DEVIATION 6.86 | 28.26 kg/m^2 STANDARD_DEVIATION 6.17 | 29.03 kg/m^2 STANDARD_DEVIATION 5.92 | 28.43 kg/m^2 STANDARD_DEVIATION 6.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 10 Participants | 16 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 141 Participants | 145 Participants | 137 Participants | 423 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 6 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 5 Participants | 15 Participants | 34 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) White | 137 Participants | 137 Participants | 130 Participants | 404 Participants |
| Sex: Female, Male Female | 158 Participants | 156 Participants | 154 Participants | 468 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 158 | 2 / 156 | 2 / 154 |
| other Total, other adverse events | 104 / 158 | 89 / 156 | 82 / 154 |
| serious Total, serious adverse events | 5 / 158 | 4 / 156 | 6 / 154 |
Outcome results
Primary
Number of Participants With LVEF Decrease to <50%
Number of Participants with Left Ventricular Ejection Fraction (LVEF) drop to \<50%
Time frame: 2 years
Population: LVEF drop to \<50%
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I Lisinopril | Number of Participants With LVEF Decrease to <50% | 5 Participants |
| Arm II Coreg CR® | Number of Participants With LVEF Decrease to <50% | 9 Participants |
| Arm III Placebo | Number of Participants With LVEF Decrease to <50% | 15 Participants |
Primary
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.
Time frame: 2 years
Population: Number of participants who experienced cardiotoxicity
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I Lisinopril | Number of Participants With Trastuzumab-Induced Cardiotoxicity After 52 Weeks of Treatment | 45 Participants |
| Arm II Coreg CR® | Number of Participants With Trastuzumab-Induced Cardiotoxicity After 52 Weeks of Treatment | 43 Participants |
| Arm III Placebo | Number of Participants With Trastuzumab-Induced Cardiotoxicity After 52 Weeks of Treatment | 46 Participants |
Secondary
Number of Participants With Cardiotoxicity-free Survival at 750 Days From Baseline
Number of Participants with cardiotoxicity-free survival at 750 days from baseline
Time frame: 2 years
Population: Number of Participants with cardiotoxicity-free survival at 750 days from baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I Lisinopril | Number of Participants With Cardiotoxicity-free Survival at 750 Days From Baseline | 15 Participants |
| Arm II Coreg CR® | Number of Participants With Cardiotoxicity-free Survival at 750 Days From Baseline | 24 Participants |
| Arm III Placebo | Number of Participants With Cardiotoxicity-free Survival at 750 Days From Baseline | 17 Participants |
Secondary
Number of Patients With Trastuzumab Course Interruption
Measure indicates the number of patients who had an interruption of trastuzumab for any reason
Time frame: 2 years
Population: Number of patients who had an interruption of trastuzumab for any reason
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I Lisinopril | Number of Patients With Trastuzumab Course Interruption | 27 Participants |
| Arm II Coreg CR® | Number of Patients With Trastuzumab Course Interruption | 24 Participants |
| Arm III Placebo | Number of Patients With Trastuzumab Course Interruption | 40 Participants |
Secondary
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.
Time frame: 52 weeks
Population: Mean change from baseline to 52-week endpoint
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I Lisinopril | Quality-of-life Changes Between Baseline and 52-weeks | 1 Scores on a scale | Standard Deviation 23 |
| Arm II Coreg CR® | Quality-of-life Changes Between Baseline and 52-weeks | 2 Scores on a scale | Standard Deviation 17 |
| Arm III Placebo | Quality-of-life Changes Between Baseline and 52-weeks | 5 Scores on a scale | Standard Deviation 21 |