Prospective Observational Cohort Study of Patients With Metastatic HER-2+ Breast Cancer at Risk of Cardiac Toxicity
Overview
- Phase
- Phase 3
- Intervention
- Carvedilol
- Conditions
- Cardiotoxicity
- Sponsor
- SWOG Cancer Research Network
- Enrollment
- 491
- Locations
- 590
- Primary Endpoint
- Time to the first identification of cardiac dysfunction
- Status
- Recruiting
- Last Updated
- 6 months ago
Overview
Brief Summary
This trial has two cohorts of patients with human epidermal growth factor receptor (HER)-2-positive breast cancer that has spread to other places in the body. All patients must be receiving trastuzumab-based treatment. Both cohorts are being observed for cardiac toxicity. The largest cohort (currently open to accrual) is observational, and contains patients who are taking a beta blocker, ACE inhibitor, or ARB as well as their trastuzumab-based treatment. The goal is to understand how common cardiac problems are in this group of patients at high risk. The smaller cohort (currently closed to accrual) is randomized. Patients in this second cohort are randomized to either carvedilol or no treatment, with the goal of seeing whether carvedilol (used to treat heart failure and high blood pressure) may prevent the heart from side effects of chemotherapy.
Detailed Description
PRIMARY OBJECTIVES: I. To estimate the 2-year cumulative incidence of cardiac dysfunction and/or predefined cardiac events in patients with metastatic breast cancer receiving trastuzumab-based HER-2 targeted therapy and beta blockers, angiotensin receptor blocker (ARB), or angiotensin converting enzyme (ACE) inhibitor. II. To develop a model including clinical factors and potential biomarkers to predict risk of cardiac dysfunction and/or predefined cardiac events in patients with metastatic breast cancer receiving trastuzumab-based HER-2 targeted therapy and beta blockers, angiotensin receptor blocker (ARB), or angiotensin converting enzyme (ACE) inhibitor. SECONDARY OBJECTIVES: I. To assess whether prophylactic beta blocker therapy with carvedilol compared with no prophylaxis reduces the risk of cardiac dysfunction and/or predefined cardiac events in patients with metastatic breast cancer receiving trastuzumab-based HER-2 targeted therapy. II. To evaluate if prophylactic carvedilol compared with no prophylaxis results in a longer time to first interruption of trastuzumab-based HER-2 targeted therapy due to either cardiac dysfunction or events. III. To compare the local and central reads of left ventricular ejection fraction (LVEF) and strain and assess if strain changes can predict drop in ejection fraction. IV. Assess if strain can be used in the community as a marker of cardiotoxicity. TERTIARY OBJECTIVES: I. To evaluate the lle655Val and Alall70Pro single nucleotide polymorphisms (SNPs) of the HER-2 gene as a predictive biomarker of study-defined cardiac dysfunction and/or predefined cardiac events. II. To evaluate plasma neuregulin-1 at baseline and over study time as a predictive biomarker of study-defined cardiac dysfunction and/or predefined cardiac events. III. To evaluate the feasibility of local labs performing serial left ventricular strain in an NCTN group setting, with the goal of 75% of patients contributing both a baseline and at least one follow-up strain measurement. IV. To bank blood for future translational medicine studies such as brain natriuretic peptide (BNP), additional SNPs, and high sensitivity troponin. OUTLINE: Patients are randomized to 1 of 2 arms. Patients taking beta blocker, ARB, or ACE inhibitor at registration are assigned to Arm III. ARM I: Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive carvedilol orally (PO) twice daily (BID). Courses repeat every 12 weeks for 108 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive no study intervention for up to 108 weeks. ARM III: Patients undergo observation for up to 108 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •STEP 1 REGISTRATION
- •Patients must:
- •Have metastatic breast cancer, AND
- •Be initiating within 11 calendar days of Step 1 Registration OR be continuing trastuzumab-based HER-2 targeted therapy without concurrent anthracyclines, AND
- •Be receiving the trastuzumab-based HER-2 targeted therapy for metastatic disease in first, second, third-, or fourth-line setting. Patients may have brain metastasis. There is no limit for number of doses of HER-2 targeted therapy prior to registration.
- •Examples of eligible HER-2 targeted therapy:
- •Trastuzumab or a trastuzumab biosimilar
- •Trastuzumab + chemotherapy or hormonal therapy
- •Trastuzumab + other HER-2 targeted agent with or without chemotherapy (such as pertuzumab, lapatinib, and tucatinib)
- •Ado-trastuzumab (Kadcyla®)
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I (carvedilol)
Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive carvedilol PO BID. Courses repeat every 12 weeks for 108 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Carvedilol
Arm I (carvedilol)
Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive carvedilol PO BID. Courses repeat every 12 weeks for 108 weeks in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm II (no intervention)
Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive no study intervention for up to 108 weeks.
Intervention: Laboratory Biomarker Analysis
Arm III (observation)
Patients undergo observation for up to 108 weeks.
Intervention: Laboratory Biomarker Analysis
Arm III (observation)
Patients undergo observation for up to 108 weeks.
Intervention: Patient Observation
Outcomes
Primary Outcomes
Time to the first identification of cardiac dysfunction
Time Frame: Up to 108 weeks
Real-time, blinded, central echocardiography (ECHO) read as a decrease in the left ventricular ejection fraction (LVEF) of \>= 10 percentage points from baseline to a value of \< 50% OR decrease of LVEF by \>= 5 percentage points from baseline to LVEF \< 50% in those baselines having a baseline LVEF of 50-54%. The distributions of time to cardiac dysfunction will be described using cumulative incidence estimates, with the statistical significance of treatment arm differences assessed by Cox and Fine-Gray regression models with adjustment for stratification factors. Gray's test will also be applied
Secondary Outcomes
- Incidence of adverse events associated with beta blocker treatment(Up to 108 weeks)
- Drug adherence(Up to 108 weeks)
- Rate of first interruption of trastuzumab(Up to 108 weeks)
- Rate of death(Up to 108 weeks)
- Time to first occurrence of cardiac event(Up to 108 weeks)