Prospective Evaluation of Carvedilol in Prevention of Cardiac Toxicity in Patients With Metastatic HER-2+ Breast Cancer, Phase III (S1501)
This phase III trial studies how well carvedilol works in preventing cardiac toxicity in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer that has spread to other places in the body. A beta-blocker, such as carvedilol, is used to treat heart failure and high blood pressure, and it may prevent the heart from side effects of chemotherapy.
PRIMARY OBJECTIVES:
I. To assess whether prophylactic beta blocker therapy with carvedilol compared with no intervention reduces the risk of subsequent cardiac dysfunction in patients with metastatic breast cancer receiving trastuzumab?based HER-2 targeted therapy.
SECONDARY OBJECTIVES:
I. To assess whether prophylactic beta blocker therapy with carvedilol compared with no intervention reduces the risk of predefined subsequent cardiac events in patients with metastatic breast cancer receiving trastuzumab?based HER-2 targeted therapy.
II. To evaluate if prophylactic carvedilol compared with no intervention results in a longer time to first interruption of trastuzumab?based HER-2 targeted therapy due to either cardiac dysfunction or events.
III. To assess whether prophylactic beta blocker therapy with carvedilol compared with no intervention reduces the risk of subsequent cardiac dysfunction OR events in this population.
IV. To establish and prospectively collect a predefined panel of baseline core cardiovascular measures and develop a predictive model of cardiac dysfunction.
V. To evaluate the rate of cardiac dysfunction in an observational arm consisting of individuals otherwise eligible for the study except for use of beta blockers, angiotensin receptor blocker (ARB), or angiotensin converting enzyme (ACE) inhibitors for other medical reasons.
TERTIARY OBJECTIVES:
I. To evaluate the isoleucine (lle) 655 valine (Val) and and alanine (Ala)ll70 proline (Pro) single nucleotide polymorphisms (SNPs) of the HER-2 gene as a predictive biomarker of study-defined cardiac dysfunction.
II. To evaluate plasma neuregulin-1 at baseline and over study time as a predictive biomarker of study-defined cardiac dysfunction.
III. To evaluate the feasibility of performing serial left ventricular strain in a National Clinical Trials Network (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.
After completion of study, patients are followed up for up to 108 weeks.
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Patients must have a Zubrod Performance status of 0-2;
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Patients must have a complete physical examination and medical history within 28 days prior to registration;
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Patients must have LVEF >= 50% by 2-dimensional (D) echocardiogram within 28 days prior to registration. The echocardiogram must be obtained from a S1501 validated ECHO laboratory (lab) and submitted for central review by the S1501 ECHO core lab. ECHO should not be submitted for central read until patient has been otherwise deemed eligible;
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Serum bilirubin < 3.0 x institutional upper limit of normal (IULN);
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Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) < 5.0 x IULN;
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Patients must have electrocardiogram with corrected QT (QTc) with correction within 28 days prior to registration;
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Patients must have a systolic blood pressure >= 80 mm Hg within 14 days prior to registration;
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Patients must be able to swallow tablets;
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Patients must not co-enroll on other treatment trials;
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Please contact study personnel for more eligibility criteria;
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Patients must not have taken within 21 days prior to step 1 registration, be currently taking at the time of step 1 registration, or planning to take once registered to step 1 a beta blocker, ARB, or ACE inhibitor in order to be randomized (Arms 1 and 2);
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Patients currently taking a beta blocker, ARB, or ACE inhibitor at the time of step 1 registration are eligible to register for the non-randomized observational cohort (Arm 3);
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Patients must not be currently taking or planning to take during study treatment the following medications: B2 agonists, Bosutinib, Ceritinib, Floctafenine, Methacholine, Pazopanib, Rivastigmine, Vincristine, Silodosin;
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Patients must not have uncontrolled asthma;
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Patients must not be dialysis dependent;
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No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer on active surveillance, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years;
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Please contact study personnel for more eligibility criteria;
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Adrenergic alpha-1 Receptor Antagonists
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Adrenergic alpha-Antagonists
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Adrenergic beta-Antagonists
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Calcium-Regulating Hormones and Agents
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Chemically-Induced Disorders
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Drug-Related Side Effects and Adverse Reactions
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Membrane Transport Modulators
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Molecular Mechanisms of Pharmacological Action
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Physiological Effects of Drugs
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