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

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.

Conditions

  • Cardiotoxicity
  • HER2/Neu Positive
  • Metastatic Malignant Neoplasm in the Brain
  • Recurrent Breast Carcinoma
  • Stage IV Breast Cancer AJCC v6 and v7

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Supportive Care
Masking
Single (Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
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.
  • Drug: Carvedilol
    Given PO
    Other names:
    • Coreg
  • Other: Laboratory Biomarker Analysis
    Correlative studies
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.
  • Other: Laboratory Biomarker Analysis
    Correlative studies
Active Comparator
Arm III (observation)
Patients undergo observation for up to 108 weeks.
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Patient Observation
    Undergo observation
    Other names:
    • Active Surveillance
    • deferred therapy
    • expectant management
    • observation
    • Watchful Waiting

Recruiting Locations

University of Kansas Cancer Center
Kansas City, Kansas 66160
Contact:
Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu

University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas 66205
Contact:
Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu

University of Kansas Cancer Center - North
Kansas City, Missouri 64154
Contact:
Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu

University of Kansas Cancer Center-West
Kansas City, Kansas 66112
Contact:
Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu

University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City, Missouri 64116
Contact:
Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu

University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas 66211
Contact:
Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu

University of Kansas Cancer Center-Overland Park
Overland Park, Kansas 66210
Contact:
Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu

University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri 64064
Contact:
Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu

University of Kansas Health System Saint Francis Campus
Topeka, Kansas 66606
Contact:
Site Public Contact
785-295-8000

More Details

Status
Recruiting
Sponsor
SWOG Cancer Research Network

Study Contact

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.