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Testing the Addition of a Blood Pressure Medication, Carvedilol, to HER-2 Targeted Therapy for Metastatic Breast Cancer to Prevent Cardiac Toxicity

Cancer Type
Breast Cancer
Trial Phase
Phase III
18 Years and older, Male and Female
Study Type
Supportive care
Protocol IDs
S1501 (primary)
Study Sponsor


This phase III trial studies compares prophylactic beta blocker therapy with carvedilol versus no prophylaxis 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 (metastatic). A beta-blocker, such as carvedilol, is used to treat heart failure and high blood pressure, and it may protect the heart from the side effects of chemotherapy.


I. To assess whether prophylactic beta blocker therapy with carvedilol compared with no prophylaxis reduces the risk of subsequent cardiac dysfunction in patients with metastatic breast cancer receiving trastuzumab–based HER-2 targeted therapy.

I. To assess whether prophylactic beta blocker therapy with carvedilol compared with no prophylaxis 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 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 assess whether prophylactic beta blocker therapy with carvedilol compared with no prophylaxis 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.
VI. 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.
VII. Assess if strain can be used in the community as a marker of cardiotoxicity.

I. To evaluate the isoleucine (lle) 655 valine (Val) 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 local labs 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). Cycles 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 (CLOSED TO ACCRUAL 7/7/21): Patients undergo observation for up to 108 weeks.

After completion of study, patients are followed up every 12 weeks for up to 108 weeks.


  2. 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) * Fam-trastuzumab deruxtecan (Enhertu) ** NOTE: Patients on lapatinib without trastuzumab are not eligible; planned treatment with concurrent HER-2 targeted therapy and anthracyclines is not permitted
  3. 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) ** Diagnosis of diabetes mellitus ** Diagnosis of atrial fibrillation/flutter *** ECHO can be performed at any time prior to registration. If the participant has multiple ECHOs prior to registration, they may be eligible as long as any one of those ECHOS shows an LVEF reading within the allowable range
  4. 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) ** Arm 3 is permanently closed to accrual; therefore, participants who previously would have been eligible based on beta blocker, ARB, or ACE inhibitor usage will not be eligible for enrollment after the closure of Arm 3. Participants enrolled prior to that closure remain eligible and may continue study participation
  5. Patients must not be currently taking or planning to take the following medications during study treatment or observation: * B2 agonists (except rescue inhalers) * Bosutinib * Ceritinib * Floctafenine * Methacholine * Pazopanib * Rivastigmine * Vincristine * Silodosin
  6. Patients must have a Zubrod performance status of 0-2
  7. Patients must be at >= 18 years of age
  8. Patients must have a complete physical examination and medical history within 28 days prior to registration
  9. Patients must have LVEF >= 50% by 2-dimensional (D) echocardiogram within 28 days prior to registration; the echocardiogram must be obtained from the site's approved S1501 validated ECHO laboratory (lab) and submitted for central review by the S1501 ECHO core lab; an ECHO should not be submitted for central read until patient has been registered; Participants must be planning on having ECHO’s completed and submitted every 12 weeks
  10. Serum bilirubin < 3.0 x institutional upper limit of normal (IULN) (within 28 days prior to registration)
  11. Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) < 5.0 x IULN (within 28 days prior to registration)
  12. Patients must have a systolic blood pressure >= 80 mm Hg within 14 days prior to registration * NOTE: Patients enrolled at sites in Korea must have a systolic blood pressure >= 90 mm Hg within 14 days prior to registration
  13. Patients must not be dialysis dependent
  14. Patients must be able to swallow tablets
  15. Patients must not have uncontrolled asthma; patients may use a steroid inhaler or other treatment, but patients must not require use of B2 agonists more than once weekly
  16. 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
  17. 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
  18. Patients must be willing to submit blood specimens
  19. Sites must seek additional patient consent for the future use of specimens
  20. 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
  21. As a part of the Oncology Patient Enrollment Network (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
  22. STEP 2 REGISTRATION (Randomization)
  23. Patients must not be registered to step 2 until confirming via RAVE electronic data capture (EDC) that the patient’s LVEF by echocardiogram was >= 50% by central review; patients must be registered within 11 calendar days of submission of the ECHO study
  24. Site must verify that there is no known change in the step 1 eligibility since initial registration

Treatment Sites in Georgia

Atlanta Cancer Care - Conyers

1498 Klondike Road
Suite 106
Conyers, GA 30094

Atlanta Cancer Care - Decatur

2545 Lawrenceville Highway
Suite 300
Decatur, GA 30033


Lijo Simpson MD

Atlanta Cancer Care - Stockbridge

7813 Spivey Station Boulevard
Suite 210
Jonesboro, GA 30236
678 466-2069


Gurinderjit K. Sidhu MD
Lijo Simpson MD

Emory Saint Joseph's Hospital

5665 Peachtree Dunwoody Road NE
Atlanta, GA 30342

Emory University Hospital - Midtown

550 Peachtree Street NE
Atlanta, GA 30308

Georgia Cancer Specialists - CenterPointe

1100 Johnson Ferry Road
Suite 600
Sandy Springs, GA 30342
404-256-4777 ext 9242


Rodolfo E. Bordoni MD
Nishan H. Fernando MD
Pradeep C. Jolly MD

Georgia Cancer Specialists - Macon-Coliseum

308 Coliseum Drive
Suite 120
Macon, GA 31217
478-745-6130 x8152


Cheryl F. Jones MD
Premila Malhotra MD

Winship Cancer Institute of Emory University

1365 Clifton Road NE
Building C
Atlanta, GA 30322

**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts... Click here to learn more about clinical trials.
Georgia CORE


Advancing Cancer Care through Partnerships and Innovation

Georgia CORE is a statewide nonprofit that leverages partnerships and innovation to attract more clinical trials, increase research, and promote education and early detection to improve cancer care for Georgians in rural, urban, and suburban communities across the state.