S1501 Dual Observational and Randomized Cohort Study of Patients With Metastatic HER-2+ Breast Cancer at Risk of Cardiac Toxicity

Phase 3

Recruiting

• Conditions: Stage IV Breast Cancer AJCC v6 and v7; Recurrent Breast Carcinoma; HER2/Neu Positive; Metastatic Malignant Neoplasm in the Brain; Cardiotoxicity
• Interventions: Other: Laboratory Biomarker Analysis; Drug: Carvedilol; Other: Patient Observation

• Registration Number: NCT03418961
• Lead Sponsor: SWOG Cancer Research Network

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.

Study Timeline

• Study Start: 2017-11-01
• Study First Submitted: 2018-01-02
• Study First Submitted QC: 2018-01-31
• Study First Posted: 2018-02-01
• Status Verified: 2025-10
• Last Update Submitted: 2025-10-03
• Last Update Posted: 2025-10-08
• Primary Completion: 2027-09-15
• Study Completion: 2027-09-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 491

Inclusion Criteria

• STEP 1 REGISTRATION

Patients must:

1. Have metastatic breast cancer, AND
2. Be initiating within 11 calendar days of Step 1 Registration OR be continuing trastuzumab-based HER-2 targeted therapy without concurrent anthracyclines, AND
3. 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.

  • Patients must be at increased risk for cardiotoxicity defined by at least one of the following:

    1. Previous anthracycline exposure OR

    2. 1 or more of the following risk factors for heart disease:

       • LVEF 50-54% by local ECHO read*
       • Age ≥ 65
       • BMI ≥ 30 kg/m2
       • Current or prior anti-hypertensive therapy
       • Diagnosis of coronary artery disease (CAD)
       • Diagnosis of diabetes mellitus
       • Diagnosis of atrial fibrillation/flutter Note: ECHO can be performed at any time prior to registration with the most recent being sent.

  • 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 enrolling in the observational cohort (Arm 3) must be currently taking a beta blocker, ARB, or ACE inhibitor at the time of Step 1 Registration.

• 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% echocardiogram (2D or 3D) 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.

If a 3D echocardiogram is performed at baseline, sites must ensure that standard 2D images, including 40chamber and 2-chamber views, are also obtained and submitted at subsequent timepoints.

All follow-up echocardiograms (every 12 weeks) must be performed using 2D imaging to allow for standardized assessments. Follow-up scans must be completed at a site that can provide 2D images per protocol requirements. The echocardiograms cannot be submitted for central read until after Step 1 registration is complete.

• Patients must have adequate hepatic function as evidenced by all of the following within 28 days prior to registration:

  • 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 not be dialysis dependent

• 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

• For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and CIRB regulations.

• 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 confirming via RAVE EDC that the patient's LVEF by echocardiogram was >= 50% by central review. Patients must be registered within 21 calendar days of submission of the ECHO study/

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm III (observation)	Laboratory Biomarker Analysis	Patients undergo observation for up to 108 weeks.
Arm II (no intervention)	Laboratory Biomarker Analysis	Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive no study intervention for up to 108 weeks.
Arm III (observation)	Patient Observation	Patients undergo observation for up to 108 weeks.
Arm I (carvedilol)	Laboratory Biomarker Analysis	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.
Arm I (carvedilol)	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.

Primary Outcome Measures

Name	Time	Method
Time to the first identification of cardiac dysfunction	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 Outcome Measures

Name	Time	Method
Incidence of adverse events associated with beta blocker treatment	Up to 108 weeks	Adverse events associated with beta blocker treatment will be assessed.
Drug adherence	Up to 108 weeks	Patients on the active arm will be asked to record study drug consumption on a monthly intake calendar. Amount of study drug taken among patients randomized to the active arm and study drug adoption among patients randomized to the no intervention arm (i.e., contamination) will be recorded by study site staff on a case report form at each follow-up visit to assess the sensitivity of the primary treatment effect to observed conditions.
Rate of first interruption of trastuzumab	Up to 108 weeks	The distributions of time to interruption of trastuzumab-based therapy 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 to the primary endpoint to assess whether the results are sensitive to different model assumptions.
Rate of death	Up to 108 weeks	Will compare rate of death from competing causes between treatment arms via Cox regression to evaluate whether those rates impact the primary analysis comparison.
Time to first occurrence of cardiac event	Up to 108 weeks	any of the following treating physician documented events requiring hospitalization or medical treatment, and subsequent temporary or permanent discontinuation of trastuzumab- based HER-2 targeted therapy: arrhythmia, unstable angina, non-ST segment elevated myocardial infarction, myocardial infarction, or congestive heart failure.

Trial Locations

Locations (590)

Anchorage Associates in Radiation Medicine; 🇺🇸 Anchorage, Alaska, United States

Alaska Breast Care and Surgery LLC; 🇺🇸 Anchorage, Alaska, United States

Alaska Oncology and Hematology LLC; 🇺🇸 Anchorage, Alaska, United States

Alaska Women's Cancer Care; 🇺🇸 Anchorage, Alaska, United States

Anchorage Oncology Centre; 🇺🇸 Anchorage, Alaska, United States

Katmai Oncology Group; 🇺🇸 Anchorage, Alaska, United States

Providence Alaska Medical Center; 🇺🇸 Anchorage, Alaska, United States

Fairbanks Memorial Hospital; 🇺🇸 Fairbanks, Alaska, United States

CHI Saint Vincent Cancer Center Hot Springs; 🇺🇸 Hot Springs, Arkansas, United States

Kaiser Permanente-Deer Valley Medical Center; 🇺🇸 Antioch, California, United States

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