Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03418961
Recruitment Status : Recruiting
First Posted : February 1, 2018
Last Update Posted : September 16, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Southwest Oncology Group

Tracking Information
First Submitted Date  ICMJE January 2, 2018
First Posted Date  ICMJE February 1, 2018
Last Update Posted Date September 16, 2020
Actual Study Start Date  ICMJE September 15, 2017
Estimated Primary Completion Date February 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 20, 2018)
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
Original Primary Outcome Measures  ICMJE
 (submitted: January 31, 2018)
  • Drug adherence [ Time Frame: 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 cardiac event [ Time Frame: Up to 108 weeks ]
    Real-time, blinded, central ECHO read as a decrease in the 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 events 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 se
  • Rate of death [ Time Frame: 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.
  • Rate of first interruption of trastuzumab [ Time Frame: 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.
  • 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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2018)
  • Incidence of adverse events associated with beta blocker treatment [ Time Frame: Up to 108 weeks ]
    Adverse events associated with beta blocker treatment will be assessed.
  • Rate of first interruption of trastuzumab [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Drug adherence [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 31, 2018)
Incidence of adverse events associated with beta blocker treatment [ Time Frame: Up to 108 weeks ]
Adverse events associated with beta blocker treatment will be assessed.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE S1501 Carvedilol in Preventing Cardiac Toxicity in Patients With Metastatic HER-2-Positive Breast Cancer
Official Title  ICMJE Prospective Evaluation of Carvedilol in Prevention of Cardiac Toxicity in Patients With Metastatic HER-2+ Breast Cancer, Phase III
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Supportive Care
Condition  ICMJE
  • Cardiotoxicity
  • HER2/Neu Positive
  • Metastatic Malignant Neoplasm in the Brain
  • Recurrent Breast Carcinoma
  • Stage IV Breast Cancer AJCC v6 and v7
Intervention  ICMJE
  • Drug: Carvedilol
    Given PO
    Other Name: Coreg
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Patient Observation
    Undergo observation
    Other Names:
    • Active Surveillance
    • deferred therapy
    • expectant management
    • observation
    • Watchful Waiting
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Carvedilol
    • Other: Laboratory Biomarker Analysis
  • 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.
    Intervention: Other: Laboratory Biomarker Analysis
  • Active Comparator: Arm III (observation)
    Patients undergo observation for up to 108 weeks.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Patient Observation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 31, 2018)
817
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2023
Estimated Primary Completion Date February 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Puerto Rico,   Saudi Arabia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03418961
Other Study ID Numbers  ICMJE S1501
NCI-2016-01047 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1501 ( Other Identifier: SWOG )
SWOG-S1501 ( Other Identifier: DCP )
UG1CA189974 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Southwest Oncology Group
Study Sponsor  ICMJE Southwest Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Justin Floyd Southwest Oncology Group
PRS Account Southwest Oncology Group
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP