Clinical trial NCT02177175
Conditions: Breast Cancer
Keywords: Carvedilol Anthracycline HER2 14-099
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-06-24; Completion date: 2021-06-24
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to find out the effects, good and/or bad, of a beta blocker (carvedilol) on heart function during treatment with anti-HER2 medication(s) including trastuzumab (Herceptin).

Detailed description:
This phase II placebo-controlled study will evaluate the effect of carvedilol, compared to placebo, on anthracycline/anti-HER2 therapy induced left ventricular dysfunction in patients with HER2-positive breast cancer who are receiving adjuvant or neoadjuvant therapy. All patients will undergo routine cardiac surveillance with 2D echocardiograms per standard of care at multiple time points which will align as closely as possible to the following: pre-anthracycline (baseline), pre-anti-HER2 therapy, and 3, 6, 9, and 12 months (+/- 4 weeks) after initiation of anti-HER2 therapy. In the case that standard of care echocardiograms are not done at these time points, either due to a delay in anti-cancer therapy or due to the patient's medical condition, the principal investigator will determine if the standard of care echocardiogram may be used in lieu of one of the time points listed. Additional speckle tracking strain analysis will be performed on these echocardiograms, and blood specimens will be drawn at several time points for biomarker analysis.

After completion of anthracycline treatment and prior to initiation of anti-HER2 therapy, 32 patients with abnormal myocardial strain, defined as global longitudinal strain \< 19% or % change from baseline by \> 11%, will be randomized in a 1:1 ratio to carvedilol versus placebo. Carvedilol will be administered twice daily for approximately 1 year OR until the end of anti-HER2 therapy, if it is discontinued prior to 1 year. Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.

Arms: arm 1: Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. arm 2: Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.
Interventions: intervention 1: Carvedilol intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
1 
 
 
Approval date: 07-May-2020 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC   PROTOCO 
Principal Investigator/Department: 
Anthony F. Yu, MD 
L 
Medicine 
Co-Principal 
Chau Dang, MD 
Investigator(s)/Department: 
Jennifer Liu, MD 
Lakshmi V. Ramanathan, PhD 
Medicine  /Manhattan, 
West Harrison 
Medicine 
Laboratory Medicine 
Investigator(s)/Department: 
Richard M. Steingart, MD 
Michael S. Baum, MD 
Carol L. Chen, MD 
Dipti Gupta, MD 
Lee W. Jones, PhD 
Eileen P. McAleer, MD 
Nancy Roistacher, MD 
Wendy L. Schaffer, MD 
Vijai Joseph, MD 
Chaya S. Moskowitz, PhD 
Adam Schmitt, MD, PhD 
Annemarie Shepherd, MD 
Diana Lake, MD 
Karen Cadoo, MD 
Elizabeth Won, MD 
Medicine 
MedicineMedicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Epidemiology & 
Biostatistics 
Radiation Oncology 
Radiation Oncology 
West Harrison 
West Harrison 
West Harrison 
Consenting 
Anthony Yu, MD 
Professional(s)/Department: 
Jennifer Liu, MD 
Richard M. Steingart, MD 
Michael S. Baum, MD 
Carol L. Chen, MD 
Dipti Gupta, MD 
Eileen P. McAleer, MD 
Nancy Roistacher, MD 
Wendy L. Schaffer, MD 
Mary Coogan, RN (only part 1) 
Chau Dang, MD 
Diana Lake, MD 
Karen Cadoo, MD 
Elizabeth Won, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Medicine/  Manhattan, 
West Harrison 
West Harrison 
West Harrison 
West Harrison 
 


2 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 4 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................... 8 
4.1 Design .................................................................................................................................. 8 
4.2 Intervention .................................................................................................................................9 
4.3 
Future  use of  samples………………………………………………………………………….10 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 10 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 10 
6.1 Subject Inclusion Criteria .................................................................................................... 10 
6.2 Subject Exclusion Criteria ................................................................................................... 10 
7.0 
RECRUITMENT PLAN ................................................................................................................... 11 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 11 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 12 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION.................................................... 16 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 19 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 19 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 21 
14.0 
BIOSTATISTICS ............................................................................................................... 21 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES22 
15.1 Research Participant Registration ......................................................................................... 22 
15.2 
Randomization ................................................................................................................... 23 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 23 
16.1 
Quality Assurance ........................................................................................................ 23 
16.2 
Data and Safety Monitoring .............................................................................................. 23 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 24 
17.1 
Privacy .......................................................................................................................... 25 
17.2 
Serious Adverse Event (SAE) Reporting ......................................................................... 26 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 27 
19.0 
REFERENCES ...................................................................................................................... 28 
20.0 
APPENDICES ................................................................................................................... 29 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This phase II placebo-controlled study will evaluate the effect of carvedilol, compared to placebo, on 
anthracycline/anti-HER2 therapy induced left ventricular dysfunction in patients with HER2-positive 
breast cancer who are receiving adjuvant or neoadjuvant therapy.  Upon enrollment and after 
providing informed consent, a saliva sample will be obtained by use of protocol 06-107, and banked 
for future correlative gene analysis.  All patients (minimum 80 patients to maximum 100 patients) will 
undergo routine cardiac surveillance with 2D echocardiograms per standard of care at multiple time 
points, which will align as closely as possible to the following: pre-anthracycline (baseline), pre-anti- 
HER2 therapy, and 3, 6, 9, and 12 months (+/-  4 weeks) after initiation of anti-HER2 therapy. In the 
case that standard of care echocardiograms are not done at these time points, either due to a delay 
in anti-cancer therapy or due to the patient’s medical condition, the principal investigator will 
determine if the standard of care echocardiogram may be used in lieu of one of the time points  
listed. Additional  speckle tracking strain analysis will be performed on these echocardiograms, and 
blood specimens will be drawn at several time points for biomarker analysis. 
After completion of anthracycline treatment and prior to initiation of anti-HER2 therapy, 32 patients 
with abnormal myocardial strain, defined as global longitudinal strain < 19% or % change from 
baseline by > 11%, will be randomized in a 1:1 ratio to carvedilol versus placebo.  Carvedilol will be 
administered twice daily for approximately 1 year OR until the end of anti-HER2 therapy, if it is 
discontinued prior to 1 year.  Treatment in both carvedilol and placebo groups will be systematically 
up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. 
The primary and secondary outcome measures will be evaluated at months 3, 6, 9, and 12 (+/- 4 
weeks).   In addition, the prevalence of subclinical LV dysfunction after completion of anthracycline 
and anti-HER2 therapy will be estimated. 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
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2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Aims: 
 
Aim 1: To estimate the prevalence of subclinical LV dysfunction by completion of anthracycline and 
anti-HER2 therapy among consecutive women scheduled to receive anthracycline chemotherapy  
and anti-HER2 therapy for HER2-positive early breast cancer, as defined by abnormal global 
longitudinal strain (< 19% or % change from baseline > 11%).  Study participants will be followed  
with serial echocardiograms, ordered as per standard of care, with speckle tracking imaging as close 
as possible to the following time points: pre-anthracycline, pre-anti-HER2 therapy, and 3, 6, 9, and  
12 months (+/- 4 weeks) after the start of anti-HER2 therapy. 
Aim 2:  To generate preliminary evidence of the effect of prophylactic treatment with carvedilol on 
anthracycline-anti-HER2 induced changes in LV systolic function.  Patients with abnormal 
myocardial strain at pre-anti-HER2 therapy imaging will be randomized to carvedilol vs placebo 
starting at a dose of 3.125mg twice a day and up titrated to a maximal dose of 25mg twice a day. 
Hypothesis:  Prophylactic treatment with carvedilol can prevent the development of anthracycline- 
anti-HER2 associated LV systolic dysfunction. 
Secondary Aims: 
 
Aim 3:  To explore the effect of prophylactic carvedilol on  indices of LV function and the incidence 
of anti-HER2 therapy interruption. 
Exploratory Aims: 
1. To collect and bank specimens for future use in evaluating the association between 
echocardiographic markers of systolic function, specifically myocardial strain imaging, 
with cardiac biomarkers of cardiac injury and remodeling (troponin-I) and inflammation 
and candidate single nucleotide polymorphisms. 
2. To explore the effect of prophylactic carvedilol treatment on local or distant breast cancer 
recurrence, development of second primary cancers, and all-cause death. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1. Overview of HER2-positive Breast Cancer: 
 
Breast cancer is the most commonly diagnosed cancer in women, and the 2nd  leading cause of 
cancer death in women—an estimated 232,340 new cases of invasive breast cancer will be 
diagnosed this year.[1]  However, earlier detection and improved treatment have resulted in steadily 
decreasing rates of breast cancer related death.  Women surviving breast cancer represent 22% of 
all cancer survivors U.S.,[2, 3] with more than 2.9 million breast cancer survivors estimated in the 
U.S. today.[4]  The human epidermal growth factor receptor 2 (HER2) oncogene encodes a 
transmembrane tyrosine kinase receptor that is critical for cell growth and survival.  HER2 is over- 
expressed or amplified in 20-30% of invasive breast cancers and is associated with poor 
prognosis.[5, 6]  Trastuzumab (Herceptin) is a humanized monoclonal antibody against the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
 
 
 
extracellular domain of HER2 and was shown to reduce the risk of breast cancer recurrence by 40- 
50% in several landmark clinical trials.[7-9]  Since that time, trastuzumab therapy has become the 
standard of care among patients with HER2-positive breast cancer and is used mostly in 
combination with adjuvant  chemotherapy. 
 
3.2. Treatment Associated Cardiotoxicity: 
 
The benefit of trastuzumab therapy is substantial although there is a small risk of trastuzumab 
associated cardiotoxicity.  The concern over cardiac safety of trastuzumab was first raised during 
early clinical trials of patients with metastatic disease, in which increased rates of cardiac 
dysfunction were unexpectedly observed in 27% of patients receiving anthracycline based 
chemotherapy plus trastuzumab compared to 3-8% among patients receiving trastuzumab or 
anthracyclines alone.[10]  Subsequent trials of trastuzumab therapy in the adjuvant setting have 
shown fewer cardiac events.  In the joint analysis of the National Surgical Adjuvant Breast and 
Bowel (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials, the 
cardiac event rate (defined by cardiac related death or symptomatic CHF) was < 4% among the 
trastuzumab treated group.[11] 
Although the risk of symptomatic CHF is low in the adjuvant setting, milder forms of cardiac 
dysfunction are more common.  In the HERA trial 9.8% of patients treated with trastuzumab 
compared to 2.9% in the control group had at least one significant decline in LVEF (defined as a 
decrease of >10% from baseline to below 50%).[12]  Asymptomatic declines in LVEF led to 
discontinuation of trastuzumab in 14% of patients in NSABP B-31.[13]  However, in clinical practice, 
the incidence of significant asymptomatic LVEF decline is higher (17%-23%).[14-16]  As a result of 
these studies, an intensive cardiac surveillance program was mandated in order to detect signs of 
treatment associated cardiotoxicity.  LVEF assessment is performed most commonly by 
echocardiogram at baseline and every 3 months during trastuzumab therapy.  However, 
abnormalities of LV systolic function as determined by LVEF are a late manifestation of cardiotoxicity 
and may indicate the presence of irreversible myocardial damage. 
3.3. Mechanism of Treatment Associated Cardiotoxicity- 
 
Trastuzumab associated cardiotoxicity, in contrast to anthracycline mediated cardiotoxicity, is 
generally considered to be reversible after discontinuation of trastuzumab.  It occurs in a minority of 
patients, is not dose related, and shows no identifiable abnormalities on endomyocardial biopsy.[17] 
An early study by Ewer et al demonstrated that, among 38 patients with trastuzumab-associated 
cardiotoxicity, LVEF improved in 37 patients with no evidence of ultrastructural changes on 
myocardial biopsy in 9 of these patients.[18]  However, this concept of reversibility has recently been 
challenged in the 7 year follow-up from the NSABP B-31 study, in which 36 of 147 patients who 
discontinued trastuzumab for cardiac-related reasons had a LVEF < 50%.[11]  The irreversibility in 
these patients is likely due to the anthracycline chemotherapy, but it is unclear on the contribution 
from trastuzumab.  The exact mechanism of trastuzumab-induced cardiotoxicity has yet to be 
elucidated; however several hypotheses have been proposed.  HER2/neu (also known as ERBB2) is 
known to be required for cardiac development and is a critical component of the stress response of 
the heart.  In mice, inactivation of ERBB2 was shown to result in failure of ventricular trabeculation 
during midgestation.[19]  A study by Grazette et al demonstrated that inhibition of ERBB2 leads to 
mitochondrial dysfunction and activates the mitochondrial apoptosis pathway.[20]  Ventricle restricted 
ERBB2 knockout mice displayed features of dilated cardiomyopathy and were more 
 
6 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
7 
 
 
 
 
sensitive to biomechanical stress of volume overload and anthracycline therapy.[21]  In clinical 
practice, the risk of trastuzumab cardiotoxicity is most relevant among patients with prior treatment 
with anthracycline based chemotherapy.  This may suggest a two-hit model in which anthracycline 
exposure first induces cellular injury through free radical production.  When faced with the loss of 
HER2/neu signaling during trastuzumab therapy, cardiomyocytes are more susceptible to the 
adverse effects of cardiac stressors and at increased risk for further cardiac injury. 
 
3.4. Oncologic and Cardiac Implications of Trastuzumab Cardiotoxicity: 
 
Although trastuzumab therapy is commonly interrupted or discontinued in 15-25% of patients when 
there is evidence of changes in cardiac function, the impact of this practice on breast cancer 
outcomes is unknown.  Asymptomatic LV dysfunction is a significantly more common adverse event 
than symptomatic heart failure, and LV dysfunction can persist in some patients despite withdrawal 
of trastuzumab exposure.  Currently, no data is available on the association between treatment- 
induced asymptomatic LVEF decline and subsequent development of cardiac events (i.e. CHF or 
cardiac death), and longer prospective follow-up is needed to further investigate this.  Based on long 
term follow-up from the Framingham Heart Study, it has been shown that patients with  
asymptomatic LV dysfunction (ALVD) are at high risk of CHF and death, even when only mild 
impairment of EF is present.[22]  Rates of CHF among subjects with normal LV function and ALVD 
were 0.7 and 5.8 per 100 person years, respectively.   Mild ALVD (EF 40% to 50%) was associated 
with a hazards ratio for CHF of 3.3 compared to individuals with normal LV function. 
 
3.5. Interruption of anti-HER2 therapy and Breast Cancer Outcome 
 
Trastuzumab therapy can be interrupted or permanently discontinued for a significant decrease in  
left ventricular function; however the impact of this practice on breast cancer outcomes has never 
been studied prospectively.  To investigate this question further, we conducted a retrospective  
cohort study to assess the incidence of trastuzumab interruption in clinical practice and evaluate the 
effect of trastuzumab cardiotoxicity and subsequent trastuzumab interruption on breast cancer 
outcomes.  Among 585 patients with early HER2-positive breast cancer, 85 patients (14.9%) had 
trastuzumab treatment interrupted, and treatment associated cardiotoxicity was the most common 
reason for interruption. Patients in the interrupted group had a higher BMI (28.5 vs 26.8, p =0.027) 
and more had estrogen receptor-negative (49.4% vs 31.7%, p=0.001) and progesterone receptor- 
negative (59.8% vs 45.8%, p=0.016) disease. In terms of disease-free survival, the hazard ratio for a 
first event in the interrupted group, compared to the continuous group, was 2.58 (95 percent 
confidence interval, 1.848 to 7.059; p<0.001).  Among patients with trastuzumab interruption due to 
trastuzumab cardiotoxicity, the hazard ratio for a disease free survival event was 2.37 (95 percent 
confidence interval, 1.45-7.56, p=0.004).[23]  Patients in the interrupted group had poorer prognostic 
features and this could have accounted for more DFS events. However, as this was a retrospective 
study, no definitive conclusion can be made on the association between trastuzumab interruption  
and breast cancer outcomes.  Additional prospective data are needed. 
 
3.6. ACE-inhibitors and Beta Blockers May Reduce Trastuzumab Associated Cardiotoxicity: 
Cardinale et al performed a prospective randomized trial to study the effect of enalapril treatment on 
the prevention of cardiotoxicity among high risk patients receiving high dose chemotherapy, and 
showed that 43% of control and 0% in the enalapril group had >10% drop in LVEF.[24]  In a study of 
patients receiving anthracycline based chemotherapy, patients randomized to carvedilol 12.5mg 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
8 
 
 
 
 
daily showed no change in LVEF after chemotherapy compared to the placebo group, in which there 
was an absolute reduction in LVEF by 17%.[25]  Seicean et al retrospectively analyzed data of 
patients receiving anthracycline and/or trastuzumab for breast cancer and observed that use of BBs 
was associated with a lower incidence of heart failure.[26]  These studies suggest that ACE-I and 
BBs may effectively reduce the risk of trastuzumab-associated cardiotoxicity. 
3.7. Speckle Tracking Strain Echocardiography for Early Detection of Cardiotoxicity 
Speckle tracking strain imaging is a new echocardiographic modality that measures myocardial 
deformation and provides a more sensitive and quantitative assessment of cardiac contractile 
function than conventional 2D echocardiographic indices.[27, 28]  Strain is a highly reproducible and 
objective measurement that is superior to EF or fractional shortening in the detection of early 
subclinical myocardial dysfunction and has been shown to be useful in the early diagnosis of 
trastuzumab associated cardiotoxicity.[29, 30]  In a prospective multicenter study by Sawaya et al, 
global longitudinal strain < 19% was predictive of subsequent development of cardiotoxicity and 
present in all patients who later developed symptoms of heart failure.[30]  A study by Negishi et al 
also showed that an 11% reduction in global longitudinal strain was predictive of subsequent 
trastuzumab associated cardiotoxicity.[31] 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
A prospective observational cohort study design will be used to determine the prevalence of 
subclinical LV dysfunction by 1 year from the start of anti-HER2 therapy, as defined by global 
longitudinal strain < 19% or % reduction in global longitudinal strain by > 11% from baseline.  All 
patients with HER2-positive early breast cancer and treated with anthracycline plus anti-HER2 
therapy will be eligible for this study, and serial echocardiograms will be performed with additional 
speckle tracking strain analysis throughout the duration of therapy.   The minimum planned accrual 
for this study is 80 patients, and enrollment will continue to a maximum of 100 patients to allow for 
randomization of 32 patients in the treatment arm. 
After completion of anthracycline based chemotherapy and prior to initiation of anti-HER2 therapy, 
study participants will undergo a repeat routine transthoracic echocardiogram.  Thirty-two patients 
with abnormal global longitudinal strain (< 19% or a relative decrease in global longitudinal strain by 
> 11% from baseline) and who do not meet any exclusion criteria (outlined in section 9.0) will be 
randomized in a 1:1 ratio to receive carvedilol versus placebo prior to initiation of anti-HER2 therapy. 
Study drug will be started on the first day of anti-HER2 therapy (+/- 1 week), and administered twice 
daily for the duration of the study period (approximately 1 year, or sooner if anti-HER2 therapy is 
discontinued prematurely).  Routine serial echocardiograms with speckle tracking strain analysis will 
be performed for the duration of therapy.  Patients with normal global longitudinal strain at the end of 
anthracycline chemotherapy will be followed observationally and undergo routine serial 
echocardiograms with speckle tracking strain analysis until 1 year after anti-HER2 therapy is  
initiated. 
All patients will undergo biomarker testing as outlined in the study calendar in section 10.0, and all 
patients not previously registered to protocol 06-107 will be approached with the consent and option 
for banking of an Oragene sputum specimen for future DNA analysis at the time of enrollment. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
9 
 
 
 
 
4.3 
Intervention 
 
The minimum planned accrual for this study is 80 patients.  These patients will undergo routine  
serial LVEF assessments by 2D echocardiography at standard of care time points, as previously 
described.  We will perform additional speckle tracking strain analysis on all echocardiograms using 
these clinically indicated echocardiograms.  A sputum specimen will be collected and banked from  
all  study participants for future correlative studies. In addition, blood specimens will be collected for 
biomarker testing in tandem with anti-HER2 therapy administration and as close as possible to the 
following time points: baseline, pre-anti-HER2 therapy, and at 3 and 6 months (+/- 4 weeks). If anti- 
HER2 therapy is interrupted or delayed for any reason, blood specimens for biomarker testing will be 
collected once treatment resumes. Should anti-HER2 therapy be interrupted for a significant length  
of time, it will be at the principal investigator’s discretion whether to “skip” any given time point (for 
example, if there is a shorter window of time between the 3 month and 6 month time points due to a 
treatment delay.) All echocardiograms will be read by a core lab with readers blinded to treatment 
allocation.  For strain analysis, a non-sequential test ID will be assigned for each examination, 
identifiers and clinical information removed, and all will be interpreted by a single echocardiographer 
masked to treatment allocation, 2D echocardiogram results, and prior strain analyses.  The clinical 
treatment team will have access to results of routine 2D-echocardiogram measurements only (per 
standard of care). 
A total of 32 patients eligible for Aim 2 will be randomized in a 1:1 fashion to carvedilol versus 
placebo as follows.  After completion of anthracycline based chemotherapy and prior to initiation of 
anti-HER2 therapy, study participants will undergo a repeat routine transthoracic echocardiogram. 
Patients with abnormal global longitudinal strain (< 19% or a relative decrease in global longitudinal 
strain by > 11% from baseline) who do not meet any exclusion criteria (outlined in section 9.0) will be 
randomized in a 1:1 ratio to receive carvedilol versus placebo prior to initiation of anti-HER2 therapy. 
Study drug will be started on the first day (+/- 1 week) of anti-HER2 therapy, and administered twice 
daily for the duration of the study period (approximately 1 year, or sooner if anti-HER2 therapy is 
discontinued prematurely). 
The following parameters for carvedilol dosing will serve as a guide for the protocol. The investigator 
may opt for different carvedilol management at his or her discretion.  Carvedilol will be started at an 
initial dose of 3.125mg twice a day to a target dose of 25mg twice a day, and treatment in both the 
carvedilol and control groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after 
clinical assessment by a cardiology investigator.  Criteria for up-titration are described in section 9.0. 
All dosages will be labeled by dose level (1, 2, 3, or 4) and will be otherwise identical in appearance. 
 
Dose level 1 
3.125mg oral twice daily 
Dose level 2 
6.25mg oral twice daily 
Dose level 3 
12.5mg oral twice daily 
Dose level 4 
25mg oral twice daily 
 
 
Treatment will be continued until the completion of the 1 year course of anti-HER2 therapy or earlier 
if anti-HER2 therapy is prematurely discontinued.  2D echocardiograms with strain analysis will be 
performed as described in Aim 1.  In addition, follow-up visits will be scheduled with the Cardiology 
PI at 0, 3, 6, and 12 months (+/- 4 weeks) for patients who are randomized to study drug or placebo, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
10 
 
 
 
 
to assess for adverse medication effects and symptoms of congestive heart failure.  Patients will 
continue with all preplanned cardiac evaluations irrespective of anti-HER2 interruption. 
4.4 
Future Use of Samples 
 
Sputum samples (Oragene-DNA kit, DNA Genotek, Kanata, Ontario, Canada) will be collected and 
banked at room temperature and stored at the Breast and Imaging Center for future correlative 
studies to evaluate the association between anthracycline-anti-HER2 associated changes in 
myocardial function and candidate single nucleotide polymorphisms (i.e. HER2 polymorphisms 
IIe655Val and Ala1170Pro and polymorphisms of carbonyl reductase CBPR1 and CBPR3).  This 
biospecimen collection will be performed under protocol #06-107.  Any projects outside of the scope 
of this protocol will need to be approved by the IRB/PB. An Biospecimen Research Protocoldetailing 
the proposed project will need to be approved by the IRB/PB prior to the start of the project. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Commercially available carvedilol/placebo is provided by the study and will be administered by the 
MSKCC pharmacy.  The medication will be dispensed at the beginning of each treatment cycle and 
a pill diary will be used to track adherence.  Carvedilol and placebo will be supplied in bottles 
containing a 4 week (for titration) or 12 week (maintenance) supply.  Carvedilol and placebo should 
be stored at room temperature, not above 25°C (77°F).  Both carvedilol and placebo will be 
dispensed in capsules of uniform shape and color, and the packaging will be identical. 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
All patients must meet the following criteria: 
1. Female 
2. Age ≥ 18 years 
3. Non-metastatic histologically confirmed primary invasive breast carcinoma 
4. Pathologically confirmed HER2-positive breast cancer 
5. Scheduled to receive anthracycline chemotherapy followed by anti-HER2 therapy at 
MSKCC 
6. Able and willing to provide informed consent 
7. Willing and able to comply with the requirements of the protocol 
8. Able to swallow capsules 
 
For Aim 2, all patients must meet the following criteria: 
1. Meet all inclusion criteria above 
2. LVEF > 50% 
3. Abnormal global longitudinal strain (<19%, or a % decrease of > 11% from baseline) prior 
to initiation of planned anti-HER2 therapy 
4. Heart rate > 50 beats per minute 
5. Sitting systolic blood pressure > 90 mmHg 
 
6.3 
Subject Exclusion Criteria 
 
Patients are to be excluded from randomization for Aim 2 of this study if they meet any of the 
following criteria: 
1. Current treatment with ACE-inhibitors or beta blockers 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
11 
 
 
 
 
 
2. Allergies or inability to tolerate beta blockers previously due to bradycardia, hypotension, 
or AV block. 
3. Known history of NCI CTCAE (Version 4.0) Grade > 2 symptomatic CHF, myocardial 
infarction within 12 months prior to randomization, significant symptoms (Grade > 3) relating 
to left ventricular dysfunction, significant (moderate or severe) valvular disease, or significant 
cardiac arrhythmia (Grade > 3) 
4. Pre-menopausal women without a negative serum or urine pregnancy test within 4 weeks 
of starting treatment 
5. Enrollment in a therapeutic intervention trial in the Breast Medicine service 
 
 
7.0 
RECRUITMENT PLAN 
 
A member of the Breast Cancer Medicine Service will identify a patient before starting her on 
adjuvant/neoadjuvant  therapy.  The patient will be seen by Dr. Yu or Dr. Liu (or other members of  
the Cardiology Service) timely for eligibility and will discuss the study and the possibility of  
enrollment in the research study with the patient. Minorities and women are well represented in the 
breast cancer medicine clinics, and we expect that they will be well represented in the trial accrual. 
The principal investigator, Dr. Yu, will be available to all patients for further questions and  
information through a contact number which is provided on the consent form.  Given the annual 
estimate of ~125 patients seen at MSKCC with newly diagnosed HER2 positive early breast cancer, 
and a high historical participation rate in clinical protocols, this recruitment goal will be feasible within 
the prespecified study period. We expect study accrual will be completed in 18 months. 
The research investigators may also screen the medical records of patients with whom they do not 
have a treatment relationship for the limited purpose of identifying patients who would be eligible to 
enroll in the study and to record appropriate contact information in order to approach these patients 
regarding the possibility of enrolling in the study. Such patients are already contained in institutional 
databases and are part of the sampling frame.  During the initial conversation between the 
investigator/research staff and the patient, the patient may be asked to provide certain health 
information that is necessary for the recruitment and enrollment process. The investigator/research 
staff may also review portions of their medical records at MSKCC in order to further assess 
eligibility. They will use the information provided by the patient and/or medical record to confirm that 
the patient is eligible and to contact the patient regarding study enrollment. If the patient turns out to 
be ineligible for the research study, the research staff will destroy all information collected on the 
patient during the initial conversation and medical records review, except for any information that 
must be maintained for screening log purposes. 
8.1 
PRETREATMENT EVALUATION 
 
All aspects of the screening evaluation should be completed within four weeks of starting treatment 
unless otherwise noted. 
• 
Documentation of HER2-positive status 
• 
Full medical history (to be performed by primary oncologist) 
• 
Physical examination, complete vital signs, height, and weight (by breast cancer medicine 
service) at baseline 
• 
12-lead electrocardiogram within 3 months 
• 
Serum or urine pregnancy test 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
12 
 
 
 
 
 
• 
Baseline 2D echocardiogram with strain imaging 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
There are two components of this study.  For Aim 1, a prospective cohort study design will be used 
to determine the prevalence of subclinical LV dysfunction, as defined by global longitudinal strain 
<19% or % reduction by >11% from baseline, among all patients diagnosed with HER2-positive 
early breast cancer and treated with anthracycline based chemotherapy plus anti-HER2 therapy. 
These patients will undergo routine serial LVEF assessments by 2D echocardiography, per standard 
of care, as previously described.. 
Conventional 2-dimensional and Doppler echocardiography will be performed using a commercially 
available standard ultrasound scanner (E9, GE Medical Systems, Horten, Norway).  All 
echocardiograms will be performed by a registered diagnostic cardiac sonographer according to a 
standardized protocol.  Chamber quantification and other standard hemodynamic variables will be 
obtained according to the American Society of Echocardiography (ASE) guidelines.[32]   Diastolic 
function will be assessed using pulsed wave Doppler and tissue Doppler imaging. 
During the standard 2D echocardiogram, three apical views will be acquired at an increased frame 
rate (at least 80 frames per second) to allow for offline speckle tracking strain analysis (Echopac, GE 
Medical Systems).  This analysis will be performed independent of the clinical interpretation of the  
2D echocardiogram.  The methods of image acquisition and strain measurements with speckle 
tracking have been previously described.[33]  Briefly, after initial automated tracking of the 
endocardial border and software processing, manual correction will be performed to ensure  
adequate tissue tracking as needed.  Each view will be divided into 6 segments, and the entire 
myocardium will be represented by a 17 segment model.  In the case of unsatisfactory tracking due 
to inadequate image quality, that segment will be eliminated from analysis.  After longitudinal strain 
and strain rate curves are generated for each segment, peak global longitudinal strain will be 
calculated as the average value of the peak systolic strain values for all the segments within the 3 
standard apical views. 
All echocardiograms will be read by a core lab blinded to treatment allocation.  For strain analysis, a 
non-sequential test ID will be assigned for each examination, identifiers and clinical information 
removed, and all will be interpreted by a single echocardiographer masked to treatment allocation, 
2D echocardiogram results, and prior strain analyses.  The clinical treatment team will have access 
to results of routine 2D-echocardiogram measurements only (per standard of care). 
If the patient had an echocardiogram or multi-gated acquisition scan done locally before enrolling 
onto the study, the patient will be asked to have another baseline echocardiogram with strain 
imaging, which will not be charged to the patient. This will be covered by with internal funding. 
A double blind randomized placebo controlled study design will be used to accomplish the goals of 
Aim 2 (Fig 1).  After completion of anthracycline based chemotherapy and prior to initiation of anti- 
HER2 therapy, study participants from Aim 1 with abnormal global longitudinal strain (< 19% or a 
relative decrease in global longitudinal strain by > 11% from baseline) will be eligible for this study. 
Patients in the observational group who develop abnormal strain after initiation of anti-HER2 therapy 
will not be eligibile for randomization. 
 
Treatment Arms: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
13 
 
 
 
 
Prior to initiation of anti-HER2 therapy, patients will be randomized in a 1:1 ratio to receive carvedilol 
versus placebo through the MSKCC Protocol Participant Registration (PPR) system (see section 
15.2).  Study drug will be started on the first day of anti-HER2 therapy (+/- 1 week), and 
administered twice daily for the duration of the study period (approximately 1 year, or sooner if anti- 
HER2 therapy is discontinued prematurely). 
Commercially available carvedilol and placebo will be provided by the study at no cost to the study 
participants.  Study drug will be prepared by the research pharmacy staff at SKI (Core Manager: 
Mark G. Klang, MS, RPh, BCNSP, PhD). 
Dosing: 
 
Carvedilol will be started at an initial dose of 3.125mg twice a day to a target dose of 25mg twice a 
day, and treatment in both the carvedilol and control groups will be systematically up-titrated at 
weeks 3, 6, and 9 (+/- 1 week) by the PI or other member of the research team. Criteria for up- 
titration will include the following: heart rate > 50 beats per minute, systolic blood pressure > 90 
mmHg, and absence of dose-limiting symptoms suggestive of medication intolerance including 
dizziness, fatigue, or weakness.  Toxicity will be graded according to NCI CTCAE, version 4.0.  All 
capsules will be labeled by dose level (1, 2, 3, or 4) and will be otherwise identical in appearance. If 
a DLT is observed at dose level 1, patients will come off study. 
 
Dose level 1 
3.125mg oral twice daily 
Dose level 2 
6.25mg oral twice daily 
Dose level 3 
12.5mg oral twice daily 
Dose level 4 
25mg oral twice daily 
 
 
Treatment will be continued until the completion of the 1 year course of anti-HER2 therapy or earlier 
if anti-HER2 therapy is prematurely discontinued. 2D echocardiograms with strain analysis will be 
performed in all enrolled patients for the duration of the study period as described in Aim 1, 
irrespective of treatment interruption. 
 
 


Memorial Sloan Kettering Cancer Center 
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14 
 
 
 
 
Figure 1 – Study Design 
 
For the exploratory aim, blood specimens will be collected for biomarker analysis at baseline prior to 
anthracycline treatment as well as pre- and post- anti-HER2 infusion at approximately month 0, 3, 
and 6, per the study design outlined in Fig. 1. ). If anti-HER2 therapy is interrupted or delayed for  
any reason, blood specimens for biomarker testing will be collected once treatment resumes. 
Leftover blood samples will be stored for additional biomarker analysis (to be determined), including 
but not limited to ultrasensitive troponin-I which we anticipate will be FDA approved and available for 
clinical use in the next year and circulating markers of cardiac inflammation.  Study participants will 
also be asked to provide an optional saliva sample for DNA extraction and future study under 
protocol #06-107.  Specimens will be assigned a unique identification code that is independent of  
the patient’s medical record number to protect the confidentiality of the patient, while still facilitating 
subsequent correlation with clinical data. DNA extraction kits ((Oragene-DNA kit, DNA Genotek, 
Kanata, Ontario, Canada) will be stored at room temperature for future correlative studies to  
evaluate the association between anthracycline-anti-HER2 associated changes in myocardial 
function and candidate single nucleotide polymorphisms (i.e. HER2 polymorphisms IIe655Val and 
Ala1170Pro and polymorphisms of carbonyl reductase CBPR1 and CBPR3). 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Study drug administration: 
 
Investigators and patients will be blinded and study agents will be indistinguishable from each other. 
Patients who cannot swallow pills should not be enrolled, as capsules may not be opened.  Study 
agent will begin on the same day as anti-HER2 therapy (+/- 1 week).  Each study participant will self- 
administer 1 capsule by mouth twice daily.  Participants will document the number of capsules taken 
and any side effects on the study medicine daily log (Appendix A) 
Carvedilol and placebo will be started at an initial dose of 3.125mg twice a day.  Treatment in both 
the carvedilol and control group will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week). 
All capsules will be labeled by dose level (1, 2, 3, 4) and will otherwise be identical in appearance. 
The plan outlined in Section 11.0 “Toxicities/Side Effects” will be utilized to inform the patient about 
adverse events. Study drug will be made by the research pharmacy staff at SKI (Core Manager: 
Mark G. Klang, MS, RPh, BCNSP, PhD).  Upon completion of the study period, the principal 
investigator, treating cardiologist, and study staff will be unblinded to the patient’s randomization 
arm, so as to appropriately plan ongoing cardiology care for the patient. The decision to continue 
carvedilol therapy as standard cardiac treatment can be made at the discretion of the treating 
cardiologist after the patient is removed from the study. 
Cardiac Assessment: 
 
Routine evaluations will occur at each breast cancer medicine visit per standard of care. In addition, 
among patients in the randomized arm, follow-up visits will be scheduled with the Cardiology PI prior 
to initiation of anti-HER2 therapy and at 3, 6, and 12 months (+/- 4 weeks) after randomization to 
assess for adverse medication effects and symptoms of congestive heart failure.  Additional 
cardiology visits will be scheduled on an as needed basis if further dose adjustments are deemed 
necessary by the breast medicine oncologists or investigators.  The PI will be available throughout 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
15 
 
 
 
 
the study period to address any clinical concerns or evaluate patients as needed.  The evaluations 
are further defined in the study calendar. 
 
At any point during this study, study participants and their oncologists will be notified of a significant 
decline in LVEF (defined as an absolute decrease from baseline LVEF of 10-15% to below 50%, or 
decrease of > 16%), and referral to cardiology will be recommended. 
 
Biomarker evaluation: 
 
From each patient at 7 prespecified timepoints, and in tandem with anti-HER2 therapy as per 
standard of care, approximately ten mL of peripheral blood will be collected (1 green top tube, 1 
lavender top tube) for the measurement of TnI and high sensitivity TnI. For the troponin assays, 
plasma will be separated from peripheral blood and samples will be frozen for analysis and will not 
be known to the investigator until the completion of the study. The TnI samples will be evaluated by 
the Clinical Laboratory at MSKCC.   At all MSKCC sites, blood samples should be clearly labeled 
before transfer to Main campus. This labeling should include the study identifier (IRB-assigned 
protocol number), MSKCC-assigned patient identifier (once available), test ("troponin") and the time 
point of sample measurement.  TnI concentrations will be determined by a fluorometric enzyme 
immunoassay analyzer (Tosoh Bioscience, Inc., San Francisco, CA) with a low end sensitivity of 
1.6 ng/ml. Results will be blinded to the investigators until study is complete.  Any leftover plasma 
will be stored at -80oC by Dr. Ramanathan in Laboratory Medicine to allow for additional biomarker 
analysis (to be determined), including but not limited to ultrasensitive troponin-I which we anticipate 
will be FDA approved within the next 12 months or circulating markers of cardiac inflammation. 
Additional biomarker testing will be performed either by the Clinical Laboratory at MSKCC, the 
Schmitt Lab at MSKCC, or Singulex (Alameda, CA). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
16 
 
 
 
 
Study Calendar (for observational cohort): 
 
 
Study 
Baseline 
Pre-Anti- 
Follow up 
Follow-up 
Follow-up 
Study week 52, or time 
Assessments 
HER2 
month 3 
month 6 
month 9 
of anti-HER2  therapy 
therapy 
(+/- 4 weeks) 
(+/- 4 weeks) 
(+/- 4 weeks) 
discontinuation  (if 
before study  week 52) 
(+/- 4 weeks) 
Informed  consent 
X 
Medical history 
X 
Physical exam 
X 
Vital Signs 
X 
12-lead  EKG 
(within 3 months 
of study entry) 
X 
2D 
echocardiogram 
with strain 
X 
X 
X 
X 
X 
X 
Laboratory 
Assessments 
X 
X1 
X1 
X1 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
17 
 
 
 
 
 
Study Calendar (for randomized subjects): 
 
Study 
Assessments 
Baseline 
Pre-Anti- 
HER2 
therapy 
Follow up 
weeks 3, 6, 
9 
Follow up 
month 3 
(+/- 4 weeks) 
Follow-up 
month 6 
(+/- 4 weeks) 
Follow-up 
month 9 
(+/- 4 weeks) 
Study week 52, or time 
of anti-HER2  therapy 
discontinuation  (if 
before study  week 52) 
(+/- 4 weeks) 
Informed  consent 
X 
Medical history 
X 
Physical exam 
X 
Vital Signs 
X 
X3 
X3 
X3 
X3 
X3 
X3 
12-lead  EKG 
(within 3 months 
of study entry) 
X 
Pregnancy  Test* 
X 
2D- 
echocardiogram 
with strain 
X 
X 
X 
X 
X 
X 
Laboratory 
Assessments 
X 
X1 
X1 
X1 
Informed  Consent 
for randomization 
X 
Randomization 
X 
Dispense study 
agent 
X 
X 
X 
X 
X 
Cardiology   Visit 
X 
X2 
X 
X 
X 
Adverse  Events 
Form 
As needed 
As needed 
As needed 
As needed 
As needed 
As needed 
 
Whenever possible, all imaging studies and lab assessments will be completed within the protocol window of +/- 28 days. However, investigator 
discretion may determine the alignment of protocol time points with standard of care imaging studies and lab assessments, if needed. 
Initiation of study agent and titration assessments have a window of +/- 7 days. 
1Biomarkers will be drawn pre- and post- anti-HER2 infusion, and in tandem with the patient’s anti-HER2 treatment schedule 
2Focused visits for study drug titration. 
3Heart rate and blood pressure only. 
*Pregnancy test in pre-menopausal women only. 


Memorial Sloan Kettering Cancer Center 
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Approval date: 07-May-2020 
18 
 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0. If toxicities are 
encountered, adjustments will be made to the study drug dose, based on the treated physician’s 
discretion. Only severe or life-threatening events (Grade 3 or 4) will be recorded. For safety and 
adverse event reporting, see section 17.0 
Toxicities with carvedilol that are likely (>20%) include: 
• 
Dizziness 
• 
Fatigue 
 
Toxicities with carvedilol that are less likely (<20%) include: 
• 
Bradycardia 
• 
Hypotension 
• 
Headache 
• 
Syncope 
• 
Weakness 
• 
Cough 
• 
Diarrhea 
• 
Nausea and vomiting 
• 
Weight Gain 
• 
Hyperglycemia 
• 
Chest pain 
• 
Edema 
• 
Arthralgias 
• 
Abnormal vision 
• 
High cholesterol 
• 
Abnormal LFTs 
 
Side effects that are rare, but serious include: 
• 
Stevens-Johnson syndrome 
• 
Bronchospasm 
 
• 
Hypersensitivity  reaction 
• 
Pneumonitis 
• 
Angioedema 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
19 
 
 
 
 
 
 
 
11.1  Management of carvedilol related toxicities 
Carvedilol dose modifications will be made according to the criteria outlined in Table 11.1. 
 
 
Table 11.1:  Carvedilol dose modification criteria 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypotension 
Continue at 
same dose level 
Reduce by 1 
dose level 
Withhold therapy 
dose until toxicity 
is grade < 1, then 
resume treatment 
at dose level -1 
Withhold therapy 
dose until toxicity 
is grade < 1. 
 
Retreatment at 
dose level -1 at 
the discretion of 
the investigator 
Bradycardia 
Continue at 
same dose level 
Reduce by 1 
dose level 
Withhold therapy 
dose until toxicity 
is grade < 1, then 
resume treatment 
at dose level -1 
Withhold therapy 
dose until toxicity 
is grade < 1. 
Retreatment at 
dose level -1 at 
the discretion of 
the investigator 
Non- 
cardiovascular, 
general 
Continue at 
same dose level 
Continue at same 
dose level 
Withhold dose 
until toxicity is 
grade < 1, then 
resume treatment 
at same dose 
level, or dose 
level -1, at the 
discretion of the 
investigator 
Withhold dose 
until toxicity is 
grade < 1, then 
resume treatment 
at same dose 
level, or dose 
level -1, at the 
discretion of the 
investigator 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1. 2D Echocardiography and Speckle Strain 
 
For Aim 1, the primary outcome variable will be the prevalence of subclinical left ventricular 
dysfunction during anthracycline and anti-HER2 therapy as defined by an abnormal global 
longitudinal strain of < 19% or a change from baseline of > 11%.  For Aim 2, the maximum change in 
global LVEF (continuous variable) from beginning to end of anti-HER2 therapy (approximately 1 year 
or time of anti-HER2 therapy discontinuation) will serve as the primary outcome variable.  Markers of 
LV systolic function by myocardial strain imaging will be followed throughout the study, and 
secondary outcome variables will include 1) incidence of abnormal LVEF (< 50%) and 2)maximum 
% change from baseline in global longitudinal strain. 
 
12.2. Breast Cancer Specific Outcomes 
 
Patients will be followed for incidence of anti-HER2 therapy interruption (secondary outcome), 
defined as > 1 cycle of therapy missed (equal to or greater than 6 week gap between consecutive 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
20 
 
 
 
 
anti-HER2 therapy treatments). As per the exploratory aim, patients will be followed for breast 
cancer recurrence, development of second primary cancer, or all-cause death. 
12.3. Cardiac Bioimarkers, DNA analysis 
 
Blood samples will be drawn at prespecified timepoints as outlined in previous sections of this 
protocol.  From each patient at 7 prespecified timepoints approximately ten mL of peripheral blood 
will be collected (1 green top tube, 1 lavender top tube) for the measurement of TnI (exploratory 
outcome). For the troponin assay, plasma will be separated from peripheral blood and samples will 
be frozen for analysis and will not be known to the investigator until the patient has completed the 
study. The TnI samples will be evaluated by Clinical Laboratory at MSKCC.   At all MSKCC sites, 
blood samples should be clearly labeled before transfer to Main campus. This labeling should  
include the study identifier (IRB-assigned protocol number), MSKCC-assigned patient identifier (once 
available), test ("troponin") and the time point of sample measurement.  TnI concentrations will       
be determined by a fluorometric enzyme immunoassay analyzer (Tosoh Bioscience, Inc., San 
Francisco, CA) with a low end sensitivity of 0.06 ng/ml.  Leftover plasma will be stored at -80oC by 
Dr. Ramanathan in Laboratory Medicine to allow for additional biomarker analysis (to be  
determined), including but not limited to ultrasensitive troponin-I which we anticipate will be FDA 
approved within the next 12 months or circulating markers of cardiac inflammation.  Additional 
biomarker testing will be performed either by the Clinical Laboratory at MSKCC, the Schmitt Lab at 
MSKCC, or by Singulex (Alameda, CA) 
Saliva samples will be collected under protocol #06-107, using the Oragene-Discover kit (DNA 
GEnotek, Ontario, Canada) at the time of enrollment, and banked at the Breast and Imaging Center 
for future analysis to assess the association between candidate polymorphisms (i.e. HER2 
polymorphisms IIe655Val and Ala1170Pro and polymorphisms of carbonyl reductase CBPR1 and 
CBPR3) (exploratory outcome) and changes in myocardial strain . 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time. 
13.1. Criteria for discontinuation of study agent 
 
Patients randomized to carvedilol versus placebo will be discontinued from study agent should they 
experience any of the following: 
• 
Severe, unexpected toxicities or side effects, i.e. symptomatic bradycardia or hypotension, 
that is not responsive to dose modification per section 11.1. 
• 
If their treatment with anti-HER2 therapy is discontinued. 
• 
A significant decline in LVEF, defined by an absolute decrease in LVEF from baseline of 10- 
15% to below 50%, or absolute decrease in LVEF of  > 16%. 
 
After discontinuation, every effort will be made to continue with routine cardiac surveillance and 
cardiology follow-up per protocol.  Participants will be followed clinically until adverse events resolve, 
if applicable. 
 
Other reasons for study discontinuation at the discretion of the investigator include, but are not 
limited to: 
• 
Change in patient eligibility 


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Approval date: 07-May-2020 
21 
 
 
 
 
 
• 
Non-compliance with the defined treatment plan 
• 
Protocol violation 
• 
Investigator’s decision based on patient’s best interest 
• 
Withdrawal of consent 
• 
Lost to follow-up 
• 
Death 
 
14.0 
BIOSTATISTICS 
 
14.1. Statistical Analysis: 
 
Aim 1: The proportion of patients with abnormal global longitudinal strain values by the planned end 
of anthracycline + antiHER2 therapy (approximately 14 months after initiating treatment with 
anthracycline chemotherapy and 1 year after initiating anti-HER2 therapy) will be estimated together 
with the corresponding 95% confidence interval using all women enrolled to this study. All women 
eligible for the randomized study will be counted as having abnormal global longitudinal strain for 
this analysis. This number will be added to the remaining women who do not have abnormal global 
longitudinal strain by the end of anthracycline therapy but develop abnormal strain at a later 
timepoint to form the numerator of the estimated proportion. The denominator will consist of all 
women enrolled to the study. 
Aim 2:  The primary endpoint of the randomized study is the maximum change in global LVEF from 
the start of anti-HER2 therapy until 1 year later.  The difference in the maximum global LVEF 
therapy will be compared between the two arms using a two-sided 0.05 level Wilcoxon rank-sum 
test. Although every effort will be made to continue imaging patients who discontinue treatment, it is 
possible that dropout will occur. To make use of the longitudinal nature of these data taking into 
account potential dropout, in a secondary analysis we will also explore analyzing the data using a 
linear mixed effects model with robust standard errors and an exchangeable covariance structure 
using global LVEF at each time point as the outcome modeled as a function of time, randomization 
arm, age, presence of hypertension, and the interaction between time and randomization arm.  The 
mixed effects model produces valid estimates of the treatment effect as long as data are missing at 
random (missingness is independent of unobserved measurements conditional on the observed 
data), allows participants with incomplete data to contribute information to the estimated treatment 
effect, and is consistent with the intent-to-treat principle.[34, 35] 
Secondary aims: Secondary endpoints for the randomized study that will be described in an 
exploratory manner include changes in global longitudinal strain and the proportion of patients who 
discontinue anti-HER2 therapy. Proportions will be estimated with 95% confidence intervals 
separately in the two arms.  Although formal testing for differences between the arms for these 
secondary endpoints is not a primary goal of this study, depending upon the data we may further 
explore differences between the arms using a Wilcoxon rank-sum test or linear mixed models with 
an indicator for treatment arm in the model to explore differences in changes in global longitudinal 
strain 
Exploratory aims:   The proportion of patients with local or distant breast cancer recurrence, 
second primary cancer, and death will be described in an exploratory manner.  We expect the 
number of women who develop a recurrence, a second primary cancer or die within the time frame 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
22 
 
 
 
 
of this study to be too small to do any type of analysis. However, if the data permit we may estimate 
the cumulative incidence of these events using methods for competing risks as appropriate. 
General analysis: In the observational cohort, we will descriptively estimate the proportion of 
patients with abnormal LVEF (< 55%) at each time point and the proportion who discontinue anti- 
HER2 therapy. 
14.2. Sample Size: 
 
Aim 1:  With a minimum of 80 patients, we will be able to estimate the proportion of patients with 
abnormal global longitudinal strain to within + 0.11. 
Aim 2:  The study is designed to detect an intergroup difference of absolute difference of 10 
percentage points (simple difference) in the change in LVEF between the experimental and control 
group.  Ten percent is the change in LVEF that is associated with differing degrees of left ventricular 
dysfunction, and long-term studies among non-cancer patients have shown that outcomes differ 
among groups of patients who have LVEF differing by 10%.[22]   Assuming a standard deviation of 8 
(based on our preliminary data), at least 28 patients (14 patients per arm) will be needed to 
demonstrate this aim with 90% statistical power if the data were normally distributed and we were to 
use a t-test  a two-sided Type I error probability of 0.05.  To account for the possibility that the 
maximum change in LVEF measurements may not be normally distributed, we have planned to use 
a Wilcoxon rank-sum test for the analysis. The relative efficiency of the rank-sum test compared with 
the t-test is approximately 95%if the data are normally distributed and is greater if the data are 
skewed indicating that we should maintain greater than 80% power for this analysis. [36]  To allow  
for approximately 10% of the patients to drop out, we plan to enroll a total of 32 patients to the 
randomized study.  Based on preliminary data,[30] we estimate that 41% of patients with early 
HER2-positive breast cancer treated with anthracyclines followed by taxanes and trastuzumab (or 
other anti-HER2 regimens) will develop abnormal global longitudinal strain (<19%) at the completion 
of anthracycline treatment.  To achieve our target sample size of 32 patients in Aim 2, a minimum  of 
80 patients will be enrolled for Aim 1. To account for the possibility that some patients enrolled in  
Aim 1 may already be taking ACE-inhibitors or beta blockers (expected to be no more than 10-15%) 
and not be eligible for Aim 2 we may enroll an additional 20 patients as needed in order to reach our 
randomization target.  The maximum accrual for this study is 100 patients. Given the annual  
estimate of ~115-125 patients seen at MSKCC with newly diagnosed HER2 positive early breast 
cancer, and a high historical participation rate in clinical protocols, this recruitment goal will be 
feasible within the prespecified study period. We expect study accrual will be completed in 18 
months. With 14 months of follow-up on all patients, the total duration of this study is expected to be 
approximately 32 months. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 


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Approval date: 07-May-2020 
23 
 
 
 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
Of note, patients who are eligible for Aim 2 will be re-registered through PPR, using a 
separate (Part 2) Eligibility Checklist, before beginning this arm, in order to minimize risks for 
protocol violations  regarding eligibility. 
15.3 
Randomization 
 
After completion of anthracycline based chemotherapy and prior to initiation of anti-HER2 therapy, 
study participants from Aim 1 will undergo a repeat routine transthoracic echocardiogram.  Patients 
with abnormal global longitudinal strain (< 19% or a relative decrease in global longitudinal strain by 
> 11% from baseline) and who do not meet any exclusion criteria (outlined in section 9.0) will be 
randomized in a 1:1 ratio to receive carvedilol vs placebo prior to initiation of anti-HER2 therapy. 
After eligibility is established and immediately after consent is obtained, patients will be registered 
with PPR. Randomization will be accomplished by the method of random permuted block. 
16.1 
DATA MANAGEMENT ISSUES 
 
A Clinical Research Coordinator (CRC) will be assigned to the study. The responsibilities of the CRC 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. The data collected for this study will be entered into a secure database (Clinical Research 
Database (CRDB). Source documentation will be available to support the computerized patient 
record. The principal investigator will maintain ultimate responsibility for the clinical trial. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action.  Random-sample data quality and protocol 
compliance audits will be conducted by the study team, at a minimum of two times per year, more 
frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
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Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/patientsafety/dsm -guidelines /page1 
 
The DSM Plans at MSKCC were established and are monitored by the Office of Clinical Research. 
The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Quality%20A  
ssurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the 
Data and Safety Monitoring Board (DSMB) for Phase III  clinical trials, report to the Center’s 
Research Council and Institutional  Review Board. 
During the protocol development and review process, each protocol will be assessed for its level or 
risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industry sponsored, NCI cooperative group, etc.) will be addressed and the monitoring 
procedures will be established at the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be reviewed 
with the participant, including a discussion of the possible toxicities and side effects. Alternative, 
non-protocol, treatment options will be discussed with the patient. It will be reviewed that 
participation in this clinical trial is voluntary and that the patient may withdraw consent at any time. 
The study is designed with careful safety monitoring for toxicity including physician visits and serial 
cardiac monitoring. Specific guidelines for symptom management are in place to protect the study 
participant. 
Consent process: All patients at MSKCC who meet the inclusion criteria will be eligible. Participation 
in the trial is voluntary.  All patients will be required to sign a statement of informed consent, which 
must conform to IRB guidelines. The informed consent procedure is described in Section 18.0. 
Possible Toxicities/Side-Effects:  There are risks associated with treatment as described in Section 
11.0; however, patients screened for enrollment will be deemed appropriate for treatment 
independent of this study. 
Risks of research participation:  The greatest risk is release of information from health or research 
records in a way that violates privacy rights.  MSKCC will protect records so that name, address, 
phone number, and any other information that identifies the participant will be kept private.  It will be 
stated to the participant that the chance that this information will be given to an unauthorized 
individual without the participant’s permission is very small. 
 
Benefits:  A preventive treatment strategy with beta blockers among patients who are at increased 
risk for cardiotoxicity due to abnormal myocardial strain may lower the risk for developing treatment 


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IRB Number: 14-099 A(9) 
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25 
 
 
 
 
associated cardiotoxicity.  Treatment with beta blockers may also increase the likelihood of receiving 
anti-HER2 therapy without interruption, which has the potential to decrease breast cancer events. 
It is unlikely that the research using collected biospecimens will be of any medical benefit to 
participants.  Neither the patient nor the treating physician will be told of the specific results of any 
research tests on the samples; except in the case of an uncovered incidental finding which may be 
critical to the preventive care of the participant or their family.  Research using blood or tissues in 
this study could lead to medical and scientific products that could improve prevention, diagnosis and 
treatment of disease. 
 
Costs/compensation:  Patients will be charged for physician visits, routine laboratory tests and 
radiologic studies required for monitoring their condition. The patients will not be billed for the study 
drug, carvedilol/placebo.  The participant is informed that there are no plans to provide financial 
compensation for use of their human biologic specimens, nor are there plans for the participant to 
receive money for any new products, tests, and discoveries that might come from this research. 
Alternatives:  The alternative to this trial would be not to participate in the study and receive routine 
standard of care. 
Confidentiality:  Every effort will be made to maintain patient confidentiality. Research and hospital 
records are confidential. Patients’ names and any other identifying information will not be used in 
reports or publications resulting from this study. Other authorized agencies and appropriate  internal 
personnel (e.g. qualified monitors from MSKCC) and external personnel, its authorized agents, the 
FDA, and/or other governmental agencies) may review patient records as required. 
Patient safety:  Patients are monitored by physicians and oncology nurses who are very familiar with 
clinical trials. In the case of an adverse reaction, immediate medical attention is available. In the 
evenings and weekends, we have a 24-hour urgent care facility for outpatients. The PI will also be 
available at all times to organize any necessary intervention. 
Monitoring of data to ensure safety:  This study is to be monitored by the institutional IRB. This 
incorporates an independent data and safety monitoring board established by arrangement with the 
National Cancer Institute. The analysis of safety will include all patients. Adverse events, including   
all toxic effects of treatment, will be tabulated individually,  and summarized by severity and causality. 
 
Voluntariness of research participation:  It is stated that taking part in this study is voluntary and 
patients have the right to withdraw at any time. Participation in the study will not impact on the 
clinical care patients receive. 
 
17.2 
Privacy 
 
Medical information is confidential.  The participant’s personal identity will not be used in reports that 
are written about the research.  The MSKCC IRB/PB will review all requests for research performed 
involving biospecimens ascertained through this protocol.  Blood and tissue samples will be stored 
with a code linked to the patient’s medical record. With the permission of the IRB/PB, research 
studies on cellular, genetic, immunologic, or other features of tumor or normal samples may be 
performed with no names attached to the samples but linked by codes to personal identifiers. The 
results of any research using blood or tissues will not be placed in the medical record. 


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IRB Number: 14-099 A(9) 
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26 
 
 
 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A 
Research Authorization form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board (IRB/PB). 
 
The consent indicates that samples and genetic information collected may be shared with other 
qualified researchers. Such information will not include identifying information such as name. It is 
also stated in the consent and Research Authorization that research data (e.g. genomic sequence) 
may be placed into databases monitored by the National Institutes of Health, and may be made 
accessible to investigators approved by the U.S. government. 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 


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27 
 
 
 
 
 
Fields populated from CRDB: 
 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
17.2.1 
 
Not applicable. 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
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28 
 
 
 
 
signing the IRB Informed Consent, all patients must agree to the Research Authorization component 
of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
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Cancer survivors--United States, 2007. MMWR Morb Mortal Wkly Rep, 2011. 60(9): p. 269- 
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Ganz, P.A. and E.E. Hahn, Implementing a survivorship care plan for patients with breast 
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Slamon, D., et al., Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med, 
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Romond, E.H., et al., Seven-year follow-up  assessment of cardiac function in NSABP B-31, a 
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Procter, M., et al., Longer-term assessment of trastuzumab-related cardiac adverse events in 
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Tan-Chiu, E., et al., Assessment of cardiac dysfunction in a randomized trial comparing 
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Tarantini, L., et al., Trastuzumab adjuvant chemotherapy and cardiotoxicity in real-world 
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Piotrowski, G., et al., Cardiac complications associated with trastuzumab in the setting of 
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Murray, L.J., et al., Adjuvant trastuzumab in routine clinical practice and the impact of cardiac 
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Ewer, M.S. and S.M. Lippman, Type II chemotherapy-related cardiac dysfunction: time to 
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Ewer, M.S., et al., Reversibility of trastuzumab-related cardiotoxicity: new insights based on 
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Lee, K.F., et al., Requirement for neuregulin receptor erbB2 in neural and cardiac 
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29 
 
 
 
 
 
20. 
Grazette, L.P., et al., Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: 
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Crone, S.A., et al., ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med, 
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Wang, T.J., et al., Natural history of asymptomatic left ventricular systolic dysfunction in the 
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Yu AF, Y.N., Manrique CR, Thaler HT, Hudis CA, Dang CT, Steingart RM.  (2013, 
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Cardinale, D., et al., Prevention of high-dose chemotherapy-induced cardiotoxicity in high- 
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Kalay, N., et al., Protective effects of carvedilol against anthracycline-induced 
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20.0 
APPENDICES 
 
Appendix A: Maintenance Period Pill Diary 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-099 A(9) 
Approval date: 07-May-2020 
30 
 
 
 
 
Appedix B: Dose Titration Period Pill Diary