S1501 Carvedilol in Preventing Cardiac Toxicity in Patients With Metastatic HER-2-Positive Breast Cancer

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- STEP 1 REGISTRATION.

- Patients must have metastatic breast cancer and be initiating within 7 days of step 1 registration or continuing trastuzumab?based HER-2 targeted therapy without concurrent anthracyclines in first or second 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.

- Trastuzumab + chemotherapy or hormonal therapy.

- Trastuzumab + other HER-2 targeted agent with or without chemotherapy (such as pertuzumab) - Ado-trastuzumab (Kadcyla) - NOTE: Patients on lapatinib without trastuzumab are not eligible; planned treatment with concurrent HER-2 targeted therapy and anthracyclines is not permitted.

- Patients must be at increased risk for cardiotoxicity defined by at least one of the following: - Previous anthracycline exposure, OR.

- 1 or more of the following risk factors for heart disease: - Left ventricular ejection fraction (LVEF) 50-54% by local echocardiography (ECHO) read.

- Age >= 65.

- Body mass index (BMI) >= 30 kg/m^2.

- Current or prior anti-hypertensive therapy.

- Diagnosis of coronary artery disease (CAD) - Diabetes mellitus.

- Atrial fibrillation/flutter.

- 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) - 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) - 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.

- Patients must have a Zubrod Performance status of 0-2.

- Patients must have a complete physical examination and medical history within 28 days prior to registration.

- 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.

- Serum bilirubin < 3.0 x institutional upper limit of normal (IULN) - Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) < 5.0 x IULN.

- Patients must have electrocardiogram with corrected QT (QTc) with correction within 28 days prior to registration.

- Patients must have a systolic blood pressure >= 80 mm Hg within 14 days prior to registration.

- Patients must not be dialysis dependent.

- Patients must be able to swallow tablets.

- Patients must not have uncontrolled asthma.

- Patients must not co-enroll on other treatment trials.

- 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.

- Patients must not be pregnant or nursing due to potential fetal or nursing infant harm; women/men of reproductive potential must have agreed to use an effective contraceptive method, a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.

- Patients must be willing to submit blood specimens.

- Sites must seek additional patient consent for the future use of specimens.

- Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

- As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.

- STEP 2 REGISTRATION (Randomization) - Patients must not be registered to step 2 until receiving confirmation from the ECHO Core Lab that the patient?s LVEF by echocardiogram was >= 50% by central review; patients must be registered within 5 calendar days of receiving the e-mail notification.

- Site must verify that there is no known change in the step 1 eligibility since initial registration

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03418961
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	SWOG Cancer Research Network
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Justin Floyd
Principal Investigator Affiliation	SWOG Cancer Research Network
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other, NIH
Overall Status	Recruiting
Countries	Puerto Rico, Saudi Arabia, South Korea, United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Cardiotoxicity, HER2/Neu Positive, Metastatic Malignant Neoplasm in the Brain, Recurrent Breast Carcinoma, Stage IV Breast Cancer AJCC v6 and v7

Additional Details

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.

Arms & Interventions

Arms

Experimental: 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.

Active Comparator: Arm II (no intervention)

Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive no study intervention for up to 108 weeks.

Active Comparator: Arm III (observation)

Patients undergo observation for up to 108 weeks.

Interventions

Drug: - Carvedilol

Given PO

Other: - Laboratory Biomarker Analysis

Correlative studies

Other: - Patient Observation

Undergo observation

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Anchorage 5879400, Alaska 5879092

Status

Suspended

Address

Anchorage Associates in Radiation Medicine

Anchorage 5879400, Alaska 5879092, 98508

Alaska Breast Care and Surgery LLC, Anchorage 5879400, Alaska 5879092

Status

Suspended

Address

Alaska Breast Care and Surgery LLC