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

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.

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