Clinical trial NCT01904903
Conditions: HER2 Positive Breast Cancer Left Ventricular Function Systolic Dysfunction
Keywords: Breast Cancer HER2 Positive Cardiac Safety
Sponsor: Medstar Health Research Institute
Start date: 2013-10-01; Completion date: 2020-06-01
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
HER2 positive breast cancer cells have more HER2 receptor (a protein on the surface of cells) than normal breast cells. Approximately 30% of patients with breast cancer have HER2 positive breast cancer. Before HER2 targeted therapies (i.e. treatments that directly block the receptor HER2) were developed, patients with HER2 positive breast cancer had a very aggressive form of disease. With the use of trastuzumab, an anticancer drug that directly targets the receptor HER2, and more recently, pertuzumab and ado-trastuzumab emtansine, patients are able to live longer and have better control of their cancer.

Unfortunately the use of HER2 targeted therapies can increase the risk of heart problems and for this reason these treatments were only studied and approved for patients with normal heart function.

In this study we plan to give HER2 targeted therapies to patients with HER2 positive breast cancer and mildly decreased heart function along with concomitant evaluation by a heart doctor (called cardiologist) and appropriate medications to strengthen the heart. We will do frequent monitoring of the heart function with a test called echocardiogram that will give us a detailed "picture" of the heart. We will also draw blood along with routine blood tests to try to understand why some patients develop heart problems and others do not. The study will take a maximum of 12 months and patients will be monitored for 6 additional months.

We hypothesize that it is safe to administer HER2 targeted therapies to patients with breast cancer and mildly decreased heart function, i.e. LVEF between 40 and 50%, while on appropriate heart medications.

Detailed description:
Title: A pilot study evaluating the cardiac safety of HER2 targeted therapy (non-lapatinib) in patients with HER2 positive breast cancer and reduced left ventricular function Phase: Pilot study Study Duration: 4 years with up to 5 additional years of follow up Study Center(s): 3 centers will be participating: MedStar Washington Hospital Center (MWHC), MedStar Georgetown University Hospital (MGUH) and Memorial Sloan Kettering Cancer Center (MSKCC) Primary Objective: To evaluate the cardiac safety of HER2 targeted therapy (non-lapatinib) in patients with HER2 positive breast cancer and reduced left ventricular ejection fraction (LVEF) when given concomitantly with cardiac treatment.

Secondary Objectives:

* To evaluate time to development of cardiac event or asymptomatic worsening of cardiac function
* Absolute changes in LVEF
* Delays in HER2 therapy attributed to cardiac causes
* Correlations between echocardiographic myocardial strain
* cTnI and hs-cTnT at baseline and over time with cardiac events and asymptomatic worsening of cardiac function Sample size: 30 patients

Diagnosis and Main Inclusion Criteria:

* HER2 positive breast cancer, stage I-IV.
* Mildly decreased cardiac function (LVEF between 40 and 49%) prior to or while receiving non-lapatinib HER2 targeted therapy

Cardiac Intervention:

\- Beta-blockers and ACE-inhibitors titrated to the maximum tolerated doses

Oncology study Products, Doses, Routes, Regimens:

* Trastuzumab: loading dose of 8 mg/kg IV, followed by a maintenance dose of 6 mg/kg every 3 weeks, or a loading dose of 4 mg/kg followed by a maintenance dose of 2 mg/kg every week.
* Pertuzumab: loading dose of 840 mg IV, followed by 420 mg IV every 3 weeks, administered concomitantly with trastuzumab.
* Ado-trastuzumab emtansine: 3.6mg/kg IV every three weeks. Note: both trastuzumab and pertuzumab may be administered alone or in combination with other systemic or radiation therapy.

Duration of drug administration: Maximum of 12 months.

Arms: arm 1: Cardiac intervention - beta-blockers and ACE-inhibitors titrated to the maximum tolerated doses

Oncology intervention - patients will receive one of the three following HER2 targeted therapies at the discretion of the treating oncologist:

* Trastuzumab: loading dose of 8 mg/kg IV, followed by a maintenance dose of 6 mg/kg every 3 weeks, or a loading dose of 4 mg/kg followed by a maintenance dose of 2 mg/kg every week.
* Pertuzumab: loading dose of 840 mg IV, followed by 420 mg IV every 3 weeks, administered concomitantly with trastuzumab.
* Ado trastuzumab emtansine (TDM1): 3.6mg/kg IV every three weeks.
Interventions: intervention 1: Trastuzumab intervention 2: Pertuzumab intervention 3: Ado Trastuzumab Emtansine
Intervention descriptions: intervention 1: HER2 therapy intervention 2: HER2 therapy intervention 3: HER2 therapy

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
SAFE-HEaRt: A pilot study assessing the cardiac SAFEty of  
HER2 targeted therapy in patients with HER2 positive breast cancer and 
reduced left ventricular function 
 
Chair (Oncology):      
Sandra Swain, MD, FACP 
Georgetown University Medical Center 
4000 Reservoir Road NW 
120 Building D 
Washington, DC 20057 
(P) 202 687-8487 (F) 202 687-1110 
sandra.m.swain@georgetown.edu 
 
Co-chair (Oncology):  
Filipa Lynce, MD 
Assistant Professor of Medicine, Georgetown University  
Medical Oncologist, Lombardi Comprehensive Cancer Center, MedStar Georgetown University 
Hospital 
 
Co-chair (Cardiology):  
Ana Barac, MD, PhD 
Director, Cardio-oncology Program, Medstar Heart Institute 
Division of Cardiology, MedStar Washington Hospital Center 
Assistant Professor of Medicine, Georgetown University 
 
Study Statistician: 
Ming T. Tan, Ph.D. 
Dept. of Biostatistics, Bioinformatics & Biomathematics 
Georgetown University Medical Center 
 
Study Drugs:  
 
 
Trastuzumab (Herceptin) 
Pertuzumab (Perjeta) 
Ado-trastuzumab emtansine (Kadcyla)  
 
Funding Source: 
 
Institutional Funding, Genentech support 
 
 
 
Regulatory Affairs Coordinator: 
Kathryn Bailey 
Regulatory Affairs Coordinator, Washington Cancer Institute 
MedStar Health Research Institute 
(P) 202-877-8100        (F) 202-877-4072 
110 Irving Street, NW, Suite CG-111 
Washington, DC 20010 
Wci.regulatory@medstar.net 
 
 
CONFIDENTIAL 
 


 
 
 
Initial version: 4/8/2013 
 
Amended:  07/27/2017 Version 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Office 
Address 
6525 Belcrest Road, Suite 700   
Hyattsville, MD 20782 
CONFIDENTIAL 
 


 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and International Conference 
on Harmonization (ICH) guidelines. 
 
Principal Investigator (PI) Name:_______________________ 
 
PI Signature: ___________________ 
 
Date:______________
CONFIDENTIAL 
 


STUDY SCHEMA 
 
Figure 1: Flowchart of patient enrollment and management 
 
 
 
 
*Increasing shortness of breath, orthopnea, paroxysmal nocturnal dyspnea (PND), bilateral 
ankle swelling 
Hold criteria: 
LVEF decrease > 10% points from baseline or to < 35% 
 
Cardiac event criteria: 
1. Presence of symptoms attributable to Heart Failure (increasing shortness of breath, 
orthopnea, Paroxysmal Nocturnal Dyspnea, bilateral ankle swelling) as confirmed by a 
cardiologist 
2. Cardiac arrhythmia requiring pharmacological or electrical treatment 
3. Hospitalization due to a cardiovascular cause, e.g. myocardial infarction 
4. Sudden cardiac death or death due to myocardial infarction, arrhythmia or HF 
 
Asymptomatic worsening of cardiac function defined as: 
• 
Asymptomatic decline in LVEF > 10% points from baseline and/or EF < 
35% corroborated by a confirmatory echocardiogram in 2-4 weeks   
 
i 


 
 
 
 
TABLE OF CONTENTS 
 
STUDY SCHEMA ............................................................................................................ i 
TABLE OF CONTENTS ................................................................................................. 2 
LIST OF ABBREVIATIONS ............................................................................................ 3 
1.0   STUDY SUMMARY ................................................................................................ 5 
2.0 BACKGROUND AND RATIONALE ....................................................................... 7 
3.0 STUDY OBJECTIVES AND ENDPOINTS ........................................................... 13 
4.0 PATIENT ELIGIBILITY ........................................................................................ 14 
5.0 STUDY DESIGN ………………………………………………………………………….15 
6.0    INTERVENTION .................................................................................................. 16 
7.0 ASSESSMENT OF SAFETY…………………………………………........................ 28 
8.0 CORRELATIVES/SPECIAL STUDIES……………………………………………….. 33 
9.0    STATISTICAL CONSIDERATIONS ..................................................................... 34 
10.0 DATA SAFETY MONITORING COMMITTEE AND PLAN…………….…………. 37 
11.0  STUDY MANAGEMEN ...................................................................................... 38 
12.0    REFERENCES…………………………………………………………………….…….43 
13.0 APPENDICES .................................................................................................... 47 
 
 
1 


 
 
LIST OF ABBREVIATIONS 
 
ACE 
Angiotensin Converting Enzyme 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ARB 
Angiotensin II Receptor Blocker 
AST 
Aspartate Aminotransferase 
ASCO 
American Society of Clinical Oncology 
B-Blockers 
Beta-blockers 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CAD 
Coronary Artery Disease 
CBC 
Complete Blood Count 
CE 
Cardiac Event 
CI 
Confidence Intervals 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CRC 
Clinical Research Committee 
CRF 
Case Report Form 
cTns 
Cardiac Troponins 
cTnI 
Cardiac Troponin I 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
Disease Free Survival 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
EF 
Ejection Fraction 
EGFR 
Epidermal Growth Factor Receptor 
ERNA 
Equilibrium Radionuclide Angiocardiography 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HER2 
Human Epidermal Growth Factor Receptor 2 
HF 
Heart failure 
HR 
Heart Rate; Hazard Ratio 
HRPP 
Human Research Protections Program 
hs-cTnT 
Highly sensitive cardiac troponin T 
IAR 
Infusion Associated Reaction 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IV 
Intravenous 
LVEF 
Left Ventricular Ejection Fraction 
MGUH 
MedStar Georgetown University Hospital 
MI 
Myocardial Infarction 
2 


 
 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MUGA 
Multi Gated Acquisition Scan 
MWHC 
MedStar Washington Hospital Center 
NCCTG 
North Central Cancer Treatment Group 
NCI 
National Cancer Institute 
NRH 
Nodular Regenerative Hyperplasia  
NSABP 
National Surgical Adjuvant Breast and Bowel Project 
OS 
Overall Survival 
PD 
Progressive Disease 
PE 
Physical Exam 
PFS 
Progression Free Survival 
PND 
Paroxysmal Nocturnal Dyspnea 
PR 
Partial Response 
ROS 
Revision of Organs and Symptoms 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SNPs 
Single Nucleotide Polymorphisms 
T-DM1 
Ado-trastuzumab emtansine 
TTP 
Time to Progression 
WBC 
White Blood Cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 


 
 
 
1.0 STUDY SUMMARY 
 
 
Table 1: Synopsis 
 
Title 
A pilot study evaluating the cardiac safety of HER2 targeted 
therapy (non-lapatinib) in patients with HER2 positive breast 
cancer and reduced left ventricular function 
Protocol Number 
2013-0278 
Phase 
Pilot study 
Study Duration 
4 years with up to 5 additional years of follow up 
Study Center(s) 
3 centers will be participating initially: MedStar Washington 
Hospital Center (MWHC), MedStar Georgetown University 
Hospital (MGUH) and Memorial Sloan Kettering Cancer Center 
(MSKCC) 
Primary Objective 
To evaluate the cardiac safety of HER2 targeted therapy (non-
lapatinib) in patients with HER2 positive breast cancer and 
reduced left ventricular ejection fraction (LVEF) when given 
concomitantly with cardiac treatment. 
Secondary 
Objectives 
• To evaluate time to development of cardiac event or 
    asymptomatic worsening of cardiac function; 
• Absolute changes in LVEF; 
• Delays in HER2 therapy attributed to cardiac causes; 
•  Correlations between echocardiographic myocardial strain, 
    cTnI and hs-cTnT at baseline and over time with cardiac events   
    and asymptomatic worsening of cardiac function  
Sample size 
30 patients 
Diagnosis and Main 
Inclusion Criteria 
HER2 positive breast cancer, stage I-IV. 
Mildly decreased cardiac function (LVEF <50% and ≥40%) prior to 
or while receiving non-lapatinib HER2 targeted therapy 
Cardiac Intervention 
Beta-blockers and ACE-inhibitors titrated to the maximum 
tolerated doses  
Oncology study 
Products, Doses, 
Routes, Regimens 
• Trastuzumab: loading dose of 8 mg/kg IV, followed by a 
maintenance dose of 6 mg/kg every 3 weeks, or a loading dose 
of 4 mg/kg followed by a maintenance dose of 2 mg/kg every 
week.  
• Pertuzumab: loading dose of 840 mg IV, followed by 420 mg IV 
every 3 weeks, administered concomitantly with trastuzumab. 
• Ado-trastuzumab emtansine: 3.6mg/kg IV every three weeks. 
Note: both trastuzumab and pertuzumab may be administered 
alone or in combination with other systemic or radiation therapy. 
Duration of drug 
administration  
Maximum of 12 months.  
4 


 
 
Statistical 
Methodology 
 
Cardiac events are defined as any of the following:  
- 
Presence of symptoms and signs attributable 
to HF (increasing shortness of breath, 
orthopnea, PND, bilateral ankle swelling) as 
confirmed by a cardiologist 
- 
Cardiac arrhythmia requiring pharmacological 
or electrical treatment 
- 
Myocardial infarction 
- 
Sudden cardiac death or death due to 
myocardial infarct, arrhythmia or HF 
 
Asymptomatic worsening of cardiac function defined as: 
- 
Asymptomatic decline in LVEF > 10% points 
from baseline and/or EF < 35% corroborated 
by a confirmatory echocardiogram in 2-4 
weeks   
 
Planned oncologic therapy is defined as: 
- 
In the adjuvant setting: completion of 1 year 
total of HER2 targeted therapy. If a patient 
already received part of the planned HER2 
targeted therapy prior to enrollment in this trial, 
planned oncologic therapy will be achieved 
when a total of 1 year is completed.  
- 
In the metastatic setting: cessation of treating 
regimen due to progressive disease or non-
cardiac toxicity or non-cardiac death. 
 
The study is designed to assess the rate of completion of planned 
oncology therapy in the absence of a cardiac event or 
asymptomatic worsening of cardiac function. A completion rate of 
30% is considered of clinical relevance as to benefit breast cancer 
patients who would otherwise not be given HER2 targed therapy, 
where as a completion rate is of 10% is considered similar to the 
current practice. A two stage design with a total of 30 patients is 
used to test if the completion rate is at least 30% versus if it is 
below 10% with 80% power at a significance level of 5%.  
 
An exact confidence interval of the completion rate will be 
calculated. We estimate there will be no more than a 10% cardiac 
event rate. Due to the low expected cardiac event rate and small 
sample size, the analysis of secondary endpoints will be 
descriptive and will not include specific hypothesis testing. We will 
summarize the strain, troponins at each time point and graphically 
assess these measures over time in patients that do and not 
experience cardiac events.  
 
 
 
 
5 


 
 
1.0 
BACKGROUND AND RATIONALE 
 
Trastuzumab for HER2 Positive Breast Cancer 
 
Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 25% of 
breast cancers1. In the era preceding the development of HER2 targeted therapies, HER2 
positive breast cancer was associated with a poor prognosis2. However, the development of 
trastuzumab, a monoclonal antibody against the HER2 receptor, resulted in improvements in 
survival in both adjuvant and metastatic HER2 positive breast cancer3-7.  
 
 Efficacy 
The pivotal phase-III trial of trastuzumab plus chemotherapy in the first-line management of 
HER2-positive metastatic breast cancer (MBC) demonstrated robust improvements in response 
rates (RRs; 50% vs. 32%), median time to progression (TTP; 7.4 vs. 4.6 months) and median 
overall survival (OS; 25 vs. 20 months) with the addition of trastuzumab3. In the adjuvant setting, 
trastuzumab was also found to be associated with improved survival outcomes. In a review of 
eight trials that involved 11,991 women with HER2 positive operable breast cancer, trastuzumab 
significantly reduced recurrence and mortality: hazard ratio (HR) 0.66, 95% CI 0.57 to 0.77, p < 
0.00001 for OS, and HR 0.60, 95% CI 0.50 to 0.71, p<0.00001 for disease free survival (DFS) 
favoring the trastuzumab-containing regimens)8. 
 
 Cardiac toxicity 
HER2 targeted therapy has been associated with cardiac dysfunction. Although not expected in 
the initial trials of trastuzumab for metastatic breast cancer, retrospective analysis revealed 
rates of left ventricular (LV) dysfunction ranging from 3 to 27%. The incidence was greatest in 
patients receiving concomitant anthracyclines9, particularly if the cumulative dose of doxorubicin 
given concurrently with trastuzumab exceeded 300mg/m2. As a result, when the evaluation of 
trastuzumab moved into the adjuvant setting, most trials avoided co-administration of 
trastuzumab with anthracyclines and cumulative anthracyclines doses were limited. In addition, 
trials employed stringent cardiovascular eligibility criteria, cardiac monitoring schema, 
algorithms for holding trastuzumab in the setting of cardiac toxicity and early stopping rules 4-7.  
 
Although difficult to generalize due to differing definitions of cardiac endpoints across the trials, 
observed rates of severe trastuzumab-associated cardiac toxicity, (including various classes of 
symptomatic heart failure and cardiac death) in the adjuvant trastuzumab trials were low (0-
4.1%) and early stopping rules were not reached. For example, in the combined analysis of the 
NSABP B-31 and NCCTG N9831 trials of adjuvant trastuzumab, 14.2% of patients temporarily 
discontinued trastuzumab due to confirmed asymptomatic declines in left ventricular ejection 
fraction (LVEF) and 4.7% due to symptomatic heart failure (HF) or other adverse cardiac 
events4. Similarly, in the BCIRG006 adjuvant trastuzumab trial, 9-18% of the trastuzumab 
treated patients experienced a sustained drop in LVEF7.  
 
Trastuzumab-associated cardiac toxicity often occurs early during the course of treatment 
(median time to presentation 7.8 months) and is most commonly manifested by an 
asymptomatic decrease in LVEF10. In contrast to anthracyclines-associated cardiac toxicity9,11-13, 
trastuzumab-associated cardiac toxicity is not dose-dependent and is reversible within six 
months of discontinuing trastuzumab therapy for the majority of patients14. Recent data on long-
term follow up of cardiac function in NSABP B-31 reveals that the 7-year cumulative incidence 
of protocol defined cardiac events (CEs) was 4.0% in patients who received trastuzumab and 
1.3% in patients who did not resulting in an absolute difference in events of 2.7%. CEs were 
6 


 
 
defined as a definite or probable cardiac death or congestive heart failure (CHF) manifested by 
dyspnea with normal activity or at rest and associated with an absolute decrease in LVEF of 
greater than 10 percentage points from baseline to a value less than 55% or a decrease of more 
than 5% to a value below the lower limit of normal. Only two CEs occurred more than 2 years 
after initiation of trastuzumab15. Reported predictors of trastuzumab-associated cardiac toxicity 
have not been consistent across trials, although older age, hypertension, anthracycline 
exposure and lower baseline LVEF have been reported in several trials14,16.  
 
Cardiotoxicity induced by trastuzumab is though to occur at least in part due to the inhibition of  
cellular repair mechanisms that result from downstream HER2 inhibition. If trastuzumab inhibits 
this repair during a vulnerable period after anthracycline injury, the anthracycline damage could 
be augmented, resulting in increased myocyte death. This hypothesis could explain why some 
patients do not fully recover from the damage that, at least temporally, seems related to the 
administration of trastuzumab. Furthermore, such a mechanism would predict that the sooner 
trastuzumab is given following doxorubicin administration, the greater the extent of 
cardiotoxicity17. Indeed, in the combined analysis of NSABP B31 and NCCTG N9831, of 3497 
patients who had an evaluation of LVEF after doxorubicin and cyclophosphamide therapy, 233 
(6.7 percent) had an LVEF that declined at least 16 percentage points from baseline or that 
declined below the lower limit of normal or had cardiac symptoms during such treatment that 
would preclude the initiation of trastuzumab therapy4.  
 
 
 Current clinical recommendations 
According to the current Food and Drug Administration (FDA) approved package insert, patients 
should have LVEF evaluation prior to initiation of trastuzumab and at regular intervals during 
treatment. Patients should not receive it if there is evidence of cardiomyopathy. During 
treatment, if patients are found to have an absolute decrease in LVEF ≥16% from pre-treatment 
values or LVEF ≤50% and ≥10% absolute decrease from baseline, trastuzumab should be held 
until repeated echocardiogram confirms LVEF recovery.  
 
 
Newer HER2 targeted therapies 
 
More recently, the development of newer HER2 targeted therapies, such as lapatinib, 
pertuzumab and ado-trastuzumab emtansine (also known as T-DM1), have led to continued 
improvements in outcomes for HER2 positive breast cancer 18-20. 
 
 Efficacy 
Lapatinib with capecitabine has been shown to be superior to capecitabine alone in women with 
HER2 positive advanced breast cancer that had progressive disease after exposure to 
trastuzumab18. Lapatinib received approval by the FDA in 2007 for use in combination with 
capecitabine, and in 2010 for use in combination with letrozole for women with advanced or 
metastatic HER2 positive breast cancer.  
 
Like trastuzumab, pertuzumab targets the HER2 extracellular domain but at a different epitope, 
resulting in inhibited dimerization of HER2 with other HER family receptors (EGFR/HER1, HER3 
and HER4). Recently published results of the Cleopatra trial showed an increase in progression 
free survival (PFS) of 6.1 months (p<0.001) with the addition of pertuzumab to trastuzumab with 
docetaxel in first line treatment of metastatic HER2 positive breast cancer, as well as a strong 
trend towards improved OS in the pertuzumab group19. The FDA recently approved pertuzumab 
7 


 
 
in combination with trastuzumab and docetaxel for first line treatment of patients with HER2 
positive metastatic breast cancer and LVEF of 50% or more. 
 
Ado-trastuzumab emtansine is a novel anti-HER2 antibody-drug conjugate that comprises 
trastuzumab and the cytotoxic agent mertansine (DM1), a highly potent derivate of the 
antimicrotubule agent maytansine. Results from the EMILIA study, a phase III trial of ado-
trastuzumab emtansine compared with capecitabine plus lapatinib in metastatic HER2 positive 
patients who had progressed after taxane/trastuzumab therapy, revealed a significant 
improvement in PFS favoring ado-trastuzumab emtansine (9.6 vs. 6.4 months)20. Median OS at 
the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 
months; HR for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The FDA recently 
approved ado-trastuzumab emtansine for use in patients with metastatic breast cancer. 
 
 
 Cardiac toxicity 
In the cardiac safety evaluation, lapatinib infrequently affected the LVEF, with only 1.6% of 
patients experiencing a decrease in LVEF and most of them asymptomatic (1.4%). In a pooled 
analysis of 3689 patients enrolled in 44 clinical studies, of the total of 7 patients with 
symptomatic LVEF decrease, cardiotoxicity resolved in all but one, which suggests that cardiac 
effects of lapatinib are mild and mostly reversible21. 
 
Since trastuzumab and pertuzumab both target the HER2 receptor and are structurally similar, 
additive cardiac toxicity could be anticipated when the two drugs are administered concurrently. 
However the addition of pertuzumab did not increase rates of symptomatic or asymptomatic 
cardiac dysfunction in the Cleopatra trial. The rate of LV systolic dysfunction of any grade was 
8.3% in the placebo group and 4.4% in the pertuzumab group. Similarly, the rate of grade 3 or 
higher cardiac toxicity was 2.8% in the placebo group and 1.2% in the pertuzumab group. 
Notably, only patients with LVEF of 50% or more were enrolled in this trial19. 
 
Regarding ado-trastuzumab emtansine, cardiac toxicity was not increased in the cohort of 
patients treated with the experimental drug, compared to the lapatinib arm (1.7% vs.1.6%)20. 
However, the data on cardiac safety with novel anti-HER2 agents need to be interpreted with 
caution because the trials are conducted in carefully selected populations. 
 
 
 Current clinical recommendations 
Current FDA prescribing information recommends the confirmation of a normal LVEF prior to 
starting lapatinib. While on treatment, patients who develop an asymptomatic drop in LVEF 
below 50%, defined as grade 2 or greater by National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0, or drop in LVEF below the 
institution’s lower limit of normal, should have lapatinib discontinued. It may be restarted at a 
reduced dose (1,000 mg/day) after a minimum of 2 weeks if the LVEF recovers to normal and 
the patient is asymptomatic. 
 
Regarding pertuzumab and ado-trastuzumab emtansine, the package insert recommends to 
acess LVEF prior to initiation of these agents and at regular intervals (e.g., every three months). 
In addition it should only be administered to patients with LVEF within normal limits and held if 
there is a drop in LVEF to less than 40% or LVEF of 40% - 45% with ≥10% absolute decrease 
below pretreatment values.  
 
 
8 


 
 
Detection of cardiac toxicity 
 
 Echocardiogram with Strain analysis 
Traditionally, trastuzumab-associated cardiac toxicity has been identified through assessment of 
LVEF by equilibrium radionuclide angiocardiography (ERNA), more commonly known as multi-
gated acquisition (MUGA), or by 2D echocardiography. Clinical trials used different LVEF criteria 
for enrollment (most commonly LVEF >50% or institution’s lower limit of normal) as well as 
holding and stopping criteria based on LVEF results. However, both standard echocardiography 
and MUGA scanning have limitations and neither is able to detect cardiac dysfunction prior to the 
reduction in LVEF, which represents a late stage of drug-related cardiac toxicity.  
 
Myocardial strain is a new echocardiographic measure of cardiac contractility that offers the 
potential to detect subtle, early signs of cardiac dysfunction22. Among trastuzumab-treated 
patients, early decline in myocardial strain has been shown to predict subsequent decline in 
LVEF23-25. Sawaya et al prospectively evaluated 43 breast cancer patients receiving adjuvant 
trastuzumab and found that a decrease in global longitudinal strain after 3 months of therapy 
was an independent predictor of cardiac toxicity after 6 months of therapy23. This was confirmed 
in the follow-up multicenter study by the same group that included 81 women treated with 
anthracyclines followed by taxanes and trastuzumab and followed throughout the course of the 
treatment24.  
 
 
 Troponins 
Cardiac troponins (cTns) are structural proteins unique to the heart and their detection in 
peripheral blood indicates cardiac damage. cTnI is an established clinical marker for the 
diagnosis of acute myocardial infarction. cTnI has also been used in patients with cancer 
undergoing high-dose chemotherapy where it predicted subsequent development of cardiac 
dysfunction26. Recently developed, “highly-sensitive cTn assays” (hs-cTnT) differ from 
“standard” clinically-used cTn assays in their ability to detect positive levels in the majority of 
healthy patients and in their acceptable imprecision (coefficient of variation <10%) at the 99th 
percentile of a normal reference population27. The Roche Diagnostics hs-cTnT has been tested 
in several large cardiovascular cohorts where it predicted future cardiovascular events including 
heart failure events as well as overall mortality28,29. The results of these studies suggest that hs-
cTnT assays may have a role in detecting subclinical cardiac dysfunction and assessing the 
cardiovascular risk in the general population.  
 
 
 Stages of development of HF and recommended therapy by stage  
 HF is a complex clinical syndrome that can result from any structural or functional cardiac 
disorder that impairs the ability of the ventricle to fill with or eject blood. The cardinal 
manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance, and fluid 
retention, which may lead to pulmonary congestion and peripheral edema. Clinical guidelines 
recommend using classified stages of development of HF that can guide appropriate therapy for 
each stage30. Patients at high risk for HF but without structural heart disease or symptoms of HF 
are classified as stage A. Patients receiving chemotherapy agents that are known to affect the 
heart function, such as anthracyclines or trastuzumab, fall into this category. Stage B includes 
patients with structural heart disease but without signs or symptoms of HF, such as patients with 
asymptomatic LV dysfunction or patients with valvular heart disease. Stage C includes patients 
with current or past symptoms of HF and stage D designates patients with refractory HF who 
might be eligible for advanced treatment strategies31.  
 
9 


 
 
The goal of therapy for patients in stage A is to treat hypertension, encourage smoking 
cessation, treat lipid disorders, encourage regular exercise, discourage alcohol intake or illicit 
drug use, as well as control of metabolic syndrome if present. Patients in stage B, in addition to 
all the above measures, are recommended to receive ACE inhibitors or angiotensin-receptor 
blockers (ARB), and beta-blockers (B-Blockers), if no contraindications31. Treatment with ACE 
inhibitors is supported by large randomized studies in which ACE inhibitors have been shown to 
delay the onset of HF symptoms and decrease the risk of death and hospitalization for HF in 
asymptomatic patients with reduced LVEF, whether due to a remote ischemic injury or to a 
nonischemic cardiomyopathy32,33. Importantly, in a randomized trial that included patients at 
high-risk for HF but without LV dysfunction, defined as LVEF<40%, ramipril reduced the risk of 
HF hospitalization and HF death34. There are no studies that specifically address the use of 
ARBs in asymptomatic patients with reduced LVEF but the results of studies in symptomatic 
patients with low EF suggest that ARBs may be an appropriate alternative, particularly in 
patients who cannot tolerate ACE inhibitors 35,36.  
 
The use of different B-Blockers in patients with low EF has been supported by large randomized 
trials in symptomatic HF patients, as well as in asymptomatic patients with LV dysfunction 
following myocardial infarction37-40. Studies that compared different BB strategies suggest that 
carvedilol may be superior to metoprolol in patients in producing greater beneficial effects on left 
ventricular ejection fraction when given in similar doses that were used in clinical trials40,41.  
 
 
 Cardiac therapy in prevention and treatment of cardiotoxicity associated with trastuzumab 
Both ACE inhibitors and B-Blockers have been successfully used in the treatment and 
prevention of anthracycline-induced cardiotoxicity42-44. Two retrospective studies provide insight 
on LV dysfunction and response to cardiac treatment in the setting of trastuzumab therapy. A 
single institution report from MD Anderson Cancer Center describes experience with 38 patients 
referred for evaluation of trastuzumab-related cardiotoxicity because of either symptomatic or 
asymptomatic LV dysfunction. Trastuzumab was stopped in all but one patient, and the majority 
of patients received standard HF treatment with an ACE inhibitor and B-Blocker that were given 
at the discretion of the treating physician. Important findings of this study included an increase in 
LVEF in the majority of patients following the discontinuation of trastuzumab, as well as the 
feasibility of trastuzumab-rechallenge in a significant number of patients (66%) who had had 
prior favorable oncological response to trastuzumab and who experienced a period of stability of 
LV function and absence of symptoms45. The second study from the same institution 
retrospectively looked at 173 patients who received trastuzumab over a period of 5 years and 
reported cardiac events (including symptoms of HF and asymptomatic decreases in LVEF) in 44 
(28%) patients, HF symptoms in 15 (8%) and one cardiac death. That investigation also 
reported recovery of LVEF and resolution of symptoms with discontinuation of trastuzumab and 
start of cardiac treatment in the majority of patients46.  
There are no prospective trials that address the role of specific HF treatment choice, B-Blockers 
or ACE inhibitors, in trastuzumab-induced LV dysfunction. In addition, the majority of the 
patients in the trastuzumab trials had also received prior anthracycline treatment thus making it 
challenging to separate the effects of anthracyclines and trastuzumab and the cardiac treatment 
effects47,48. 
 
 
 
 
 
 
10 


 
 
Rationale 
Given the substantial oncologic benefit of these newer HER2 targeted therapies and their 
favorable cardiac toxicity profiles and the retrospective data demonstrating resolution of most 
trastuzumab induced cardiotoxicity with appropriate cardiac management, we seek to further 
evaluate the cardiac safety of non-lapatinib HER2 targeted therapy while on optimized cardiac 
therapy. We will not include lapatinib in our study given the low incidence of cardiac events 
associated with its use.  
 
Cardiotoxicity induced by trastuzumab is thought to occur at least in part due to the inhibition of  
cellular repair mechanisms that result from downstream HER2 inhibition. If trastuzumab inhibits 
this repair during a vulnerable period after anthracycline injury, the anthracycline damage could 
be augmented, resulting in increased myocyte death. This hypothesis could explain why some 
patients do not fully recover from the damage that, at least temporally, seems related to the 
administration of trastuzumab. Furthermore, such a mechanism would predict that the sooner 
trastuzumab is given following doxorubicin administration, the greater the extent of 
cardiotoxicity17. Based on this hypothesis, we will hold trastuzumab for at least 60 days after the 
last dose of anthracyclines. In this situation if a patient is planned to receive taxanes and 
trastuzumab after antracycline containing regimen as part of adjuvant treatment, we will proceed 
with the taxanes and postpone trastuzumab for 60 days. 
 
In this study we will also evaluate specific markers that may help predict earlier patients more 
likely to develop cardiac events or asymptomatic further worsening of cardiac function induced 
by HER2 targeted therapy: 1) myocardial strain analysis 2) cTnI and hs-cTnT. Earlier detection 
of these patients may allow consideration of alternative oncological treatments and/or different 
cardiac prevention strategies in these patients to prevent progressive LV dysfunction. 
 
With the results of this pilot study, we plan to proceed to a phase II trial that would support a 
change in the current recommendations regarding the initial recommendations regarding 
cardiac function and stopping rules for HER2 targeted therapies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 


 
 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
 
3.1 
Objectives 
2.1.1 Primary Objective 
 
To evaluate the cardiac safety of HER2 targeted therapy (non-lapatinib) in 
patients with HER2 positive breast cancer and reduced LVEF when given 
concomitantly with cardiac treatment. 
 
2.1.2 Secondary Objectives 
 
1) To evaluate time to development of cardiac events or asymptomatic 
worsening of cardiac function (secondary endpoint #1) 
2) To evaluate absolute changes in LVEF (endpoint #2) 
3) To evaluate delays in HER2 therapy attributed to cardiac causes 
(endpoint #3) 
4) To evaluate correlations between echocardiographic myocardial 
strain, cTnI and hs-cTnT at baseline and over time with cardiac events 
and asymptomatic worsening of cardiac function (endpoints #4,5) 
 
 
3.2     Endpoints 
 
3.2.1      Primary Endpoint 
 
Proportion of patients who complete planned oncologic therapy without the 
development of a cardiac event or asymptomatic worsening of cardiac function.  
 
 
 
 
CEs are defined as any of the following:  
- 
Presence of symptoms and signs attributable to HF (increasing shortness of 
breath, orthopnea, PND, bilateral ankle swelling) as confirmed by a 
cardiologist 
- 
Cardiac arrhythmia requiring pharmacological or electrical treatment 
- 
Myocardial infarction 
- 
Sudden cardiac death or death due to myocardial infarct, arrhythmia or HF 
 
 
 
Asymptomatic worsening of cardiac function defined as: 
- 
Asymptomatic decline in LVEF > 10% points from baseline and/or EF < 35% 
corroborated by a confirmatory echocardiogram in 2-4 weeks   
 
 
 
Planned oncologic therapy is defined as: 
- 
In the adjuvant setting: completion of 1 year total of HER2 targeted therapy. 
If a patient already received part of the planned HER2 targeted therapy prior 
to enrollment in this trial, planned oncologic therapy will be achieved when a 
total of 1 year is completed.  
12 


 
 
- 
In the metastatic setting: cessation of treating regimen due to progressive 
disease or non-cardiac toxicity or non-cardiac death. 
 
 
 
 
 
3.2.2     Secondary Endpoints 
   
 
1) Median time to development of an event defined as CE or asymptomatic 
worsening of LV dysfunction, among patients who developed one event. 
 
2) Absolute changes in LVEF during HER2 targeted therapy 
 
3) HER2 therapy holds attributed to proportion of patients with symptomatic or 
asymptomatic cardiotoxicity. 
o Hold is defined as any delay or discontinuation of HER2 targeted therapy 
due to cardiac toxicity. One cycle of HER2 targeted therapy will be 
considered 3 weeks. One therapy hold will be defined as any 3-week 
HER2 targeted therapy missed dose or 1/3 if one weekly trastuzumab 
dose. For patients who had a hold and resumed HER2 targeted therapy, 
duration of treatment hold will be described.  
 
4) Correlation of global longitudinal myocardial strain with CEs and 
asymptomatic worsening of cardiac function 
 
5) Correlation of standard cTnI and hs-cTnT with CEs and asymptomatic 
worsening of cardiac function     
 
 
3.0 
PATIENT ELIGIBILITY 
 
 
4.1. Inclusion Criteria 
 
1) Female or male patient diagnosed with stage I-IV breast cancer 
 
2) HER2 positive breast cancer, defined by immunohistochemical staining for HER2 protein 
of 3+ intensity and/or amplification of the HER2 gene on fluorescence in situ 
hybridization (FISH) ≥ 2.0 on breast specimen or biopsy of a metastatic site 
 
3) LVEF < 50% and ≥ 40% documented in echocardiogram done within the last 30 days 
 
4) HER2 therapy naïve or currently receiving non-lapatinib HER2 targeted therapy 
 
5) Patient receiving or planning to receive trastuzumab, trastuzumab with pertuzumab or 
ado-trastuzumab emtansine, for at least 3 months, alone or in combination with other 
systemic treatment or radiation 
 
6) Age ≥ 18 years 
 
7) Patient is willing and able to comply with protocol required assessments and procedures 
13 


 
 
 
4.2. Exclusion Criteria 
 
1) Previous hospitalization due to documented heart failure in the last 12 months 
 
2) Current signs or symptoms of HF or ischemia 
 
3) History of arrhythmia requiring pharmacological or electrical treatment 
 
4) Concomitant use of anthracyclines or use of anthracyclines in the last 50 days 
 
5) History of significant neurologic or psychiatric disorders including psychotic disorders or 
dementia that would prohibit the understanding and giving of informed consent 
 
6) Pregnant or lactating patients. Patients of childbearing potential must implement 
contraceptive measures during study treatment and for 7 months after the last dose of the 
study drug. 
 
4.0 
STUDY DESIGN 
 
Pilot study 
This will be a pilot study evaluating the cardiac safety of physician’s choice HER2 targeted 
therapy (non-lapatinib) in 30 patients with HER2 positive invasive breast cancer and mildly 
decreased LV function (LVEF ≥40% and <50%) while on concomitant cardiac treatment with B-
Blockers and ACE inhibitors.  
 
Sample size 
We will use a sample size of 30 patients determined based on the primary endpoint of therapy 
completion (see Section 9.0). In addition, we will estimate the rate of cardiac events and 
asymptomatic worsening of LV function with a 90% confidence interval. To achieve this goal we 
will add 10% of patients to our sample size to account for potential drop out before starting 
HER2 targeted therapy. Therefore we will plan to enroll 33 patients. In terms of patients 
screened, given the fact that patients will already have been "pre-screened" by the oncologists 
who will refer them to the study based on LVEF between 40 and 49%, we dont expect that we 
will have a very high screening failure. We anticipate that we may screen 4 to get 3 patients. So 
the anticipated number of patients to be screened would be around 44. 
 
Summary of our intervention 
The study will include patients in the adjuvant or metastatic setting, expected to receive at least 
3 months of HER2 targeted therapy (non-lapatinib). Patients will be candidates for trastuzumab, 
pertuzumab/trastuzumab or ado-trastuzumab emtansine at the discretion of their treating 
oncologist, alone or in combination with other systemic treatment or radiation. 
 
Patients included will either be found to have mildly decreased LVEF at the initial 
echocardiogram prior to HER2 targeted therapy or will have developed mildly reduced EF while 
receiving HER2 targeted therapy. This will classify the majority of the participants as stage B in 
the stages of development of HF31 (appendix B). Patients who have a remote history of 
symptomatic HF, i.e. more than one year prior to study enrollment, will be considered for the 
study and based on the HF guidelines they would be classified as stage C HF. While this 
14 


 
 
staging system recognizes that HF has established risk factors and structural prerequisites, it 
also emphasizes that HF is not equivalent to cardiomyopathy or to LV dysfunction, but is rather 
a clinical syndrome characterized by specific signs and symptoms.  
 
While on study, patients will be followed by an investigator cardiologist for evaluation of 
symptoms and signs of heart failure and for initiation and/or titration of cardiac medications (B-
blockers and ACE inhibitors).  
 
A schema will be followed to determine when HER2 targeted therapy should be held, when it 
may be rechallenged and when it must be stopped (figure 1). If at any time the patient develops 
symptomatic heart failure confirmed by the cardiologist, the patient will go off study.  
 
A blood specimen will be collected at baseline and stored for potential analysis of targets 
identified in the future. 
 
 
5.0 
INTERVENTION 
 
Figure 2. Study Phases 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1 
Subject Selection and Screening 
 
Patients who meet eligibility criteria (page 14) and sign informed consent will be registered for 
screening and assigned an ID number. All protocol-specific screening procedures must be 
performed within 30 days after signing informed consent. The decision about the need to 
Patient meets eligibility 
criteria for screening 
Screening/Preenrollment 
Procedures 
Treatment Phase 
Screen Failures 
Informed Consent 
Study Enrollment 
30 Days 
Maximum 12 months 
15 


 
 
perform an exercise stress echocardiogram or other test to exclude myocardial ischemia will be 
made at the discretion of the treating study cardiologist. 
 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for screening or other study 
purposes so long as they are done within 30 days prior to signing the consent. Screening 
and enrollment case report forms (CRFs) should be filled at this point (appendices K-L). 
 
 
5.1.1 Screening Procedures: 
 
• 
Screening study echocardiogram confirmation by the Core lab (appendix I) 
• 
Cardiac questionnaire (appendix E) 
• 
EKG 
• 
Six minute walk test 
• 
Laboratory work: 
o Troponin I (Tn-I) 
o Pregnancy test 
• 
Additional laboratory work if clinically indicated: 
o BNP or NT proBNP 
o Comprehensive metabolic panel (CMP) including albumin, alkaline phosphatase, 
ALT/sGPT, AST/sGOT, BUN, creatinine, sodium, potassium, calcium, chloride, 
bicarbonate, glucose, and total bilirubin;  
o Fasting lipid profile (total cholesterol, triglycerides, LDL and HDL cholesterol) for 
those who are on lipid-lowering agents 
o Hemoglobin A1c  
o Thyroid stimulating hormone (TSH) and free T4 
o Serum free ferritin 
• 
Exercise stress echocardiogram (if considered appropriate by the treating study cardiologist) 
• 
Summary of initial cardiac assessment (appendix G) 
• 
Oncology Visit 
• 
Cardiology Visit 
 
After signing the consent patient will undergo additional protocol-specific screening procedures 
to exclude presence of coronary ischemia or other treatable causes of cardiomyopathy. If 
ischemia is suspected patients will not be enrolled in the study unless the results of further, 
more specific ischemia work-up, excludes presence of ischemia. The results of the tests and 
procedures, such as lab tests or cardiac imaging, performed for clinical indications prior to 
signing of the consent may be used at the discretion of study investigators.  
 
Coronary artery disease is believed to be the underlying cause in approximately two thirds of 
patients with HF and low EF and also contributes to the progression of HF through mechanisms 
that include endothelial dysfunction, ischemia and infarction. The decision about the need to 
perform an exercise stress echocardiogram or other test to exclude myocardial ischemia will be 
made at the discretion of the treating study cardiologist. Patients who undergo a stress test and 
are found to have positive test, i.e. wall motion abnormality with stress consistent with ischemia, 
will be excluded from the study and will pursue further clinically-indicated work-up and treatment 
16 


 
 
that may include cardiac catheterization and revascularization. If findings of the further work-up 
are negative and no ischemia is found, or the patient is revascularized, she/he may be re-
considered for the study if anti-HER2 treatment is still indicated in the opinion of treating 
oncologist. For patients who had a prior stress test or other ischemia evaluation the results of 
these tests will be reviewed by a study cardiologist who will make a decision about whether 
repeat stress echocardiogram or other cardiac ischemia evaluation is needed. 
 
If a patient cannot complete exercise stress test, for example, because of the inability to walk on 
the treadmill, the need for further ischemia work-up will be decided by the study cardiologist 
taking into consideration cardiac risk factors, presence of symptoms, as well as the results of 
EKG, troponin, and presence of wall motion abnormalities on 2D echocardiogram. This work-up 
may include pharmacological stress testing (for example, dobutamine stress echocardiogram  or 
regadenoson perfusion study by cardiac MR), cardiac CT or coronary angiogram. Patient may 
be enrolled in the study if: a) further stress testing is considered not necessary given low risk for 
ischemia or b) the results of the performed functional or anatomical test are negative for 
significant ischemia or significant coronary disease.  
Thyroid function and serum free ferritin will be performed for clinical indications according to the 
American College of Cardiologists (ACC)/ American Heart Association (AHA) Practice Guideline 
recommendations to exclude possible treatable causes of LV dysfunction. Work-up for other 
systemic conditions such as hemochromatosis, rheumatologic disease, sleep-disturbed 
breathing or human-immunodeficiency virus infection will be assessed as clinically indicated. 
 
Standard cTnI will be collected as a screening procedure for each patient. If the results of the 
standard cTnI assay are > 1ng/ml, the results of the stress test will be reviewed and the patient 
will be scheduled for a clinical visit and appropriate clinical work-up will be initiated. Until further 
work up is completed and troponin ≤ 1ng/ml, the patient will not participate in the study. If 
exercise stress echocardiogram result is normal, patients may be allowed to participate in the 
study. This decision will be made by the study cardiologist. 
 
5.1.2 Screen Failure: 
 
The following instances will be considered a screen failure: 
 
• 
Study echocardiogram doesn’t confirm LVEF reported in initial echocardiogram (LVEF<50% 
and >40%) 
• 
Presence of treatable and reversible HF cause as assessed by study cardiologist (for 
example, hyperthyroidism) 
• 
Presence of ischemia (as assessed by study cardiologist) 
• 
Positive pregnancy test. Patients of childbearing potential must have negative urine or 
serum pregnancy test within 21 days after signing initial consent. 
 
After completion of all screening procedures, patients unable to continue will be considered 
screen failures. Patients able to continue the study, i.e., did not meet any screen failure criteria, 
will enroll and move to the treatment phase.   
 
 
17 


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pressure and other clinical characteristics. For patients with bradycardia  (heart rate < 60) beta-
blocker will not be started and ACE-inhibitor will be considered as the first choice. Carvedilol will 
be initiated with the starting dose of 3.125 mg twice a day with dose increases as tolerated. In 
patients who already take different beta-blockers for the treatment of blood pressure or other 
reasons their beta-blockers will be substituted for a corresponding dose of carvedilol. In the 
absence of hypotension (symptoms of lightheadedness or BP < 100/60 mmHg), or bradycardia 
(heart rate <60 bpm) the dose of carvedilol will be increased at weekly intervals up to 25 mg 
twice daily (Figure 3). If the titration is not possible due to hypotension or bradycardia the patient 
will be kept on the same dose and re-evaluated in two weeks for titration. Carvedilol will be our 
beta-blocker of choice because it has been showed to have beneficial effects in patients with 
chronic HF as well as benefit over metoprolol tartarate49. 
 
 
Once a patient reaches the maximum tolerated dose of carvedilol twice daily, ramipril will 
be added at 1.25mg daily dose. Ramipril dose will be doubled approximately every 3 weeks to 
coincide with infusion center visits for HER2 targeted therapy, assuming a 3 week treatment 
schedule. It will be uptitrated to the maximum tolerated dose, up to a maximum dose of 10mg.  
Patients who are on different ACE inhibitors, including lisinopril and enalapril, for the treatment 
of blood pressure or other causes, will be continued.  Figure 3 is representative of events in 
patients not on beta-blocker, ACE inhibitor or ARB at the time of study entry and who are able to 
tolerate increases in beta-blockers and addition ACE inhibitor without low blood pressure, 
bradycardia and/or other side effects. 
 
 
In patients who have a history of allergy or intolerance to ACE inhibitors, angiotensin 
receptor blockers (ARBs) will be started instead of ACE inhibitors. Candesartan will be 
considered as the first ARB of choice. Other approved ARBs can be used depending on clinical 
circumstances or insurance coverage at the discretion of study cardiologist. If the patients are 
already on valsartan or other approved ARBs, their dose will be continued and up titrated as 
tolerated. 
 
 
Patients will not receive ACE inhibitors, B-blockers or ARBs if they have known allergy to 
any of these classes of drugs, history of bronchial asthma or related bronchospastic conditions, 
hereditary or idiopathic angioedema or history of severe hypersensitivity reactions to drugs or 
other causes, i.e. bee stings.  If a patient can’t receive any of the cardiac medications due to 
any contraindication, patient can still participate in the study. If for any reason a patient is unable 
to receive the choice ACE-inhibitor or/and B-blocker, appropriate substitutions will be made 
according to study cardiologist. 
 
 
Patients with baseline creatinine of equal or more than 1.5 mg/dl will not initiate ACE 
inhibitors or ARBs but they will be allowed to participate in the study. Serum creatinine level will 
be assessed after the first dose of either ACE inhibitor or ARB and following after every dose 
increase, until creatinine levels is stable defined as less than 10% change from baseline 
creatinine. If there is an increase of serum creatinine of more than 0.5mg/dL from baseline, the 
medication will not be increased further and serum creatinine will be repeated.. If the creatinine 
continues to be elevated to more than 30% of baseline value the dose will be reduced or, if the 
patient is on the lowest dose, the medication will be stopped.  
 
Other Medications 
Patients’ medications will be reviewed during initial cardiac assessment and the following drugs 
that can exacerbate or provoke the syndrome of HF will be discontinued and/or replaced with 
alternative agents as possible. These drugs include calcium channel blockers (all with the 
19 


 
 
exception of amlodipine and felodipine), antiarrhythmic agents and nonsteroidal anti-
inflammatory drugs (all with the exception of aspirin).  
 
If patient does not meet his/her LDL goal based on standard NCEP/ATP (National Cholesterol 
Education Program/ Adult Treatment Panel) guidelines and is not on statin therapy, atorvastatin 
will be initiated according to the standard clinical practice. In patient who require either new 
initiation of statin therapy or dose escalation, lipid profile will be repeated in 3 months and statin 
dose will be further increased as clinically indicated. In patients intolerant of statins other lipid-
lowering medications can be used at the discretion of study cardiologist.  
 
 
Blood pressure log  
 
 
Patients will be instructed to take their blood pressure (BP) every day during the first 
month or until maximum tolerated cardiac medication dose is achieved. Patients will be provided 
with a BP monitor cuff and taught how to use it. After that, patients will be instructed to take their 
BP weekly while participating in the study. BP results will be documented on a BP Daily Log 
(appendix T). In case the patient cannot adequately learn how to monitor his BP at home, 
she/he will come once a week to the hospital and he will have BP registered, for the first month 
or until maximum tolerated dose of cardiac medications has been achieved. After that blood 
pressure will be checked at routine study visits. 
 
 
The titration of the medications will be pursued based on the results of the BP daily log. 
As an example, if there are no values of systolic blood pressure of less than 100 mmHg and the 
median weekly systolic BP is >110mmHg the medication will be up titrated according to the 
schema in figure 3. Otherwise patients will be continued on the current dose of medication. In 
case of symptoms of lightheadedness or 2 or more values of systolic blood pressure of less 
than 100 mmHg, the dose of medication will be reduced or stopped if the patient is one the 
minimal dose. If a patient cannot check the blood pressure at home she/he will come for the BP 
appointment. 
 
 
On Study Cardiac Visits 
 
After receiving the first dose of HER2 targeted therapy while on study,  patients will come for 
cardiology follow up assessments (appendix I) every six weeks (+/- 10 days) for a total of 2 
visits and then every twelve weeks (+/- 10 days). Medical history and physical exam will be 
performed at each follow up cardiac assessment visit. Echocardiogram and laboratory testing 
including other serum chemistries and BNP may be performed at cardiologist‘s discretion if 
there is a concern for HF signs and symptoms based on the review of systems and physical 
exam during the follow-up assessment visit. 
The treating physicians will have access to the LVEF assessed by the Core lab that will be used 
for clinical decision making. (see 6.1.3.2) 
Criteria for withholding HER2 targeted therapy will be followed according to Figure 1. If a patient 
has an asymptomatic absolute decline in LVEF of >10% points from baseline or to equal or less 
than 35%, HER2 targeted therapy will be temporarily held. At any time that HER2 targeted 
therapy is withheld, the patient will undergo follow up cardiology assessment to evaluate for the 
presence of HF signs and symptoms. Further testing including chest X-ray, echocardiogram and 
laboratory testing will be done at the discretion of the cardiologist.  
20 


 
 
Confirmatory study echocardiogram will be performed within 2-4 weeks (Figure 1). If repeated 
study echocardiogram confirms the change in LVEF that meets holding criteria, patient will 
come off the study. This will be named asymptomatic worsening of cardiac function and 
considered a primary endpoint. However, if repeated echocardiogram shows improvement in 
LVEF and holding criteria are not further met, HER2 targeted therapy will be resumed and 
patient will undergo regular cardiac assessments and study echocardiograms every 6 weeks for 
two times and then every 12 weeks. Dose reduction will not be considered for any of the HER2 
targeted therapies in the case of cardiac toxicity. 
 
If a patient develops symptoms suggestive of HF, he/she will undergo follow-up cardiac 
assessment. If patient presents with symptoms mandating urgent medical evaluation (worsening 
dyspnea, hemodynamic compromise), he/she will be directed to the nearest emergency room or 
a tertiary acute care center. HER2 targeted therapy will be temporarily held in any patient who 
develops clinical signs and symptoms suggestive of HF until cardiology assessment. If 
symptoms are confirmed to be due to HF, the patient will be taken off the study. At the time of 
any cardiac event, any grade 3 or 4 adverse event will be collected (Appendix S). 
 
Adverse events related to cardiac medications (B-Blockers, ACE inhibitors and/or ARBs) will be 
treated at the discretion of the treating cardiologist. 
 
 
 
6.2.1.2 Study Echocardiograms 
 
Screening Echocardiogram: 
 
Patients will be initially identified based on LVEF (< 50% and ≥ 40%) detected in a routine 
clinical echocardiogram. If LVEF was assessed using different cardiac imaging modality 
(cardiac MR or radionuclide imaging (MUGA)) the same LVEF criteria will apply for 
determination of eligibility (< 50% and ≥ 40%). Patients will sign consent and will undergo 
screening procedures.  
LVEF value will be confirmed through the MedStar Health Research Institute Cardiovascular 
Ultrasound Core Laboratory (Core Lab) LVEF assessment. Clinical echocardiogram that was 
used to obtain eligibility will be sent to the Core Lab labeled with the subject’s Study ID, Date of 
Study and Time Interval. If the images of the clinical echocardiogram used to determine 
eligibility are not available, or LVEF was obtained using different cardiac imaging technique, the 
patient will undergo a new study echocardiogram in this period. 
 
Baseline and Subsequent Study Echocardiogram:  
 
“Screening” echocardiogram may be used as a baseline study echocardiogram if the study is 
available and fulfills the following: it was completed within 30 days prior to study enrollment, it 
includes raw frequency data (for strain assessment) and all the measurements listed in the 
Echocardiography protocol (Appendix H) are included and are evaluable as determined by the 
Core lab.  
21 


 
 
Study echocardiograms will be performed at clinical echocardiography laboratories following the 
Echocardiography protocol (Appendix H) and will include transthoracic echocardiograms with 
strain analysis, 2D and 3D measurements. The echocardiograms will be sent for interpretation, 
electronically or using a DVD copy, to the MHRI’s Cardiovascular Core lab.  
 
The echocardiograms will be performed at baseline and after starting HER2 therapy every 6 
weeks for 2 assessments and then every 3 months while on study. Additional echocardiograms 
may be performed at the discretion of study investigators to evaluate changes in cardiac 
function while patients is on study. These echocardiograms will be paid by the study if indicated 
for study reasons, for example, suspected symptoms of HF.  
 
All echocardiograms need to be scheduled with enough time prior to the next dose of 
HER2 targeted therapy to allow image transfer, processing and reporting from the Core 
Lab. 
The echocardiograms will be labeled as: 
 
- Study ID, Date of Study and Time interval: 
-Screening 
-Baseline (as above, screening echo may qualify for baseline) 
-6 weeks 
-12 weeks (3 months) 
-24 weeks  (6 months) 
-36 weeks (9 months) 
-48 weeks (12 months) 
-Off Study  
-6 months post Off Study 
-Other: Clinical (for additional echocardiograms ordered at discretion of study 
investigators due to change in clinical status),  
-Other: Safety Check 1 etc (additional echocardiograms ordered for subjects whose EF 
has dropped as per protocol parameters) 
 
In the case of treatment delay, both weeks and cycles follow the infusion of HER2 therapy. 
Therefore, 3 weeks corresponds to cycle 1 etc.  
 
 
 
6.2.1.3 Transfering and Core Lab Reporting of Study 
Echocardiograms 
 
Echocardiographic images will be transferred digitally or recorded on a DVD and 
brought/shipped to the Core Lab.  Core Lab personnel will be notified of image transfer and will 
be provided with the Study label including Study ID, Date of Study and Time Interval as above. 
 
Case report form (CRF, Appendix I) will be sent back to the research coordinator within 72 
business hours from the time the Core Lab receives the study images and the notification with 
Study label. Scheduling of echocardiograms will be done in accordance to this timing. 
 
LVEF reported in the CRF will be used for decision making in the study in the following fashion: 
-  If 3D measurement LVEF is available it will be used as LVEF of record for that study, 
-  if 3D measurement is not available, 2D LVEF will be used, 
22 


 
 
-  if neither 3D or 2D measurements are available, visual EF will be used. 
 
Other measures, including measures of diastolic function and strain measures will be collected 
in the CRF but will not be provided to the treating physicians and will not influence management 
of the patients. 
Screening echocardiograms will have only LVEF measured and reported, and Baseline 
echocardiograms will have all the fields reported..  
 
 
 
5.2.2 Oncology Assessments on Study 
 
Initial oncological assessment must include: 
 
• 
TNM staging 
• 
ER, PR, HER2 status 
• 
Previous treatments received for breast cancer: radiation, surgery, chemotherapy, 
endocrine or targeted therapies  
• 
Performance status (appendix C) 
 
CRF on previous hormonal and chemotherapy agents received, radiation therapy and previous 
breast surgery will be filled by the investigator during initial oncological assessment (Appendices 
N-Q). In this initial oncological assessment, the planned oncologic therapy will be defined by the 
investigator and fill the appropriate form (appendix N). 
 
Patients will receive one of the three following HER2 targeted therapies at the discretion of their 
oncologist: trastuzumab, trastuzumab/pertuzumab or ado-trastuzumab emtansine. These will be 
administered on an outpatient basis. The first dose of HER2 targeted therapy will be initiated 
after BB +/- ACE inhibitor doses have been optimized at the discretion of one of the study 
cardiologists. Supportive care medications such as anti-emetics, growth factors and medications 
to prevent infusion reactions may be given at the treating oncologist’s discretion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2. Treatment dosage and administration 
23 


 
 
 
Agents 
Indication, dosage, route of administration, cycle length 
Trastuzumab 
For intravenous (IV) infusion only. Do not administer as an IV push or 
bolus. Administer at either: Initial dose of 4 mg/kg over 90 minute IV 
infusion, then 2 mg/kg over 30 minute IV infusion weekly for 52 weeks, 
or initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 
30−90 minutes IV infusion every three weeks for 52 weeks. There is no 
need for a loading dose if the patient has been on trastuzumab and the 
last dose was given less than 6 weeks prior, or less than 2 weeks prior 
if on weekly infusions. If given in the metastatic setting, continue 
trastuzumab beyond 52 weeks if considered appropriate by the treating 
oncologist. No need for premedications. 
Pertuzumab 
For intravenous infusion only. Do not administer as an IV push or bolus. 
The initial dose is 840 mg administered as a 60-minute IV infusion, 
followed every 3 weeks thereafter by 420 mg administered as a 30 to 
60 minute IV infusion. There is no need for a loading dose if the patient 
has been on pertuzumab and the last dose was given less than 6 
weeks prior. 
Ado-trastuzumab 
emtansine 
3.6mg/kg IV every three weeks. The first infusion will be administered 
over 90 minutes (± 10 minutes). Following the first dose, patients will be 
observed for at least 60 minutes for fever, chills, or other infusion-
associated symptoms. If prior infusions were well tolerated, subsequent 
doses of ado-trastuzumab emtansine may be administered over 30 
minutes (± 10 minutes), with a minimum 30-minute observation period 
after infusion. 
 
 
Screening and Off Study evaluations are required. Other oncology visits will be at the discretion 
of the treating oncologist. Routine laboratory studies required to evaluate oncologic therapy-
related, non-cardiac toxicity are at the discretion of the treating oncologist and, therefore, have 
not been specified in the protocol. Restaging scans will be performed as needed at the 
discretion of the treating oncologist. Appropriate form with information from each patient 
regarding ongoing HER2 targeted therapy, dose and days of treatment, concomitant 
chemotherapy, endocrine therapy and/or radiation therapy will be filled by the investigator 
(appendix AA). 
 
Dose reductions for trastuzumab and pertuzumab will not be allowed. Ado-trastuzumab 
emtansine dose can be reduced to 3.0 mg/kg and 2.4 mg/kg, in case of thrombocytopenia, 
hepatotoxicity, neurotoxicity or other toxicities, and will be at discretion of the treating oncologist. 
 
For delayed or missed doses, if the time between 2 sequential infusions is less than 6 weeks, 
the 420 mg IV dose of pertuzumab will be administered without waiting until the next planned 
dose. If the time between 2 sequential infusions is 6 weeks or more, the initial dose of 840 mg 
pertuzumab will be re-administered as a 60 minute IV infusion followed every 3 weeks thereafter 
by a dose of 420 mg IV administered over 30-60minutes. 
 
HER2 targeted therapies have been associated with both cardiac (see section 6.3.1) and non-
cardiac toxicities. Among non-cardiac toxicities, infusion-associated symptoms, hematologic 
toxicity, neutropenic infections, respiratory events, diarrhea, rash, liver toxicity and peripheral 
24 


 
 
neuropathy have been associated with HER2 targeted therapy. Assessment and treatment of 
non-cardiac toxicities will be done at the discretion of the treating oncologist. 
 
For oncological treatment other than HER2 targeted therapies, management of adverse events 
will be at the discretion of the treating oncology. Delays of chemotherapy based on side effects 
from non-HER2 targeted therapy will be up to the treating oncologist. If HER2 targeted therapy 
is held for non-cardiac reasons for more than 9 weeks (more than 3 cycles of HER2 targeted 
therapy), patient will go off study. 
 
 
 
 
 
6.4  
Treatment delays 
 
 
Cardiac assessments (echocardiogram, cardiology visit and blood samples) are done in 
accordance with administration of HER2 targeted therapy. Treatment delays will be 
documented. If HER2 therapy is on hold for more than 9 weeks for any reason patient will be 
removed from protocol. 
 
5.5 
Schedule of Events 
 
The schedule of events table present in appendix Z will be followed for patients who do not have 
significant drops in the LVEF that mandate to hold treatment. If patient develops a significant 
drop in the LVEF and/or symptoms and signs suggestive of heart failure, follow up will be done 
according to Figure 1. 
 
 
5.6 
Removal of patients from protocol therapy 
 
Patients can be taken off the study at any time at their own request, or they may be withdrawn 
at the discretion of the investigator for safety, behavioral or administrative reasons. The 
reason(s) for discontinuation will be documented and may include: 
6.6.1 Patient voluntarily withdraws from treatment (follow-up permitted); 
6.6.2 Patient withdraws consent (termination of treatment and follow-up); 
6.6.3 Patient is unable to comply with protocol requirements; 
6.6.4 Treating physician judges continuation on the study would not be in the 
patient’s best interest; 
6.6.5 Patient becomes pregnant (pregnancy to be reported along same 
timelines as a serious adverse event); 
6.6.6 Lost to follow-up; 
6.6.7    Completion of planned course of HER2 targeted therapy; 
6.6.8 Cardiac event or asymptomatic worsening of cardiac function as defined 
in protocol that preclude continuation of patient participation in the study; 
6.6.9   HER2 therapy on hold for more than 9 weeks due to non-cardiac reasons. 
6.6.10 Disease progression with change in treatment regimen. 
25 


 
 
5.7 
Duration of study  
 
Patients will be followed for up to 12 months on study. For patients with metastatic breast 
cancer who may be appropriate to continue on HER2 therapy beyond the 12 month study 
period, this will be allowed off-study at the discretion of the treating oncologist. Patients who 
complete their current HER2 targeted therapy regimen will be taken off the study prior to 12 
months of follow-up. For the normal course of the study, completion of planned course of HER2 
targeted therapy will mark the end of treatment. However, if patients experience a Cardiac event 
or asymptomatic worsening of cardiac function (as defined in protocol) that precludes 
continuation of patient participation in the study, then this event will mark the end of treatment. 
 
 
 
5.8 
Off Study Procedures  
 
• 
Complete medical history and physical exam 
• 
Troponin I, hs troponin 
• 
Study echocardiogram 
 
Off Study procedures will be performed within 30 days after the patients’ end of treatment 
determination. 
 
 
5.9 
Duration of follow up after being off study 
 
At the time of going off study, patients will have completed HER2 targeted therapy if they were 
being treated in the adjuvant setting. If they are being treated in the metastatic setting they may 
continue to receive HER2 targeted therapy after the study is finished. All patients will be 
followed for 6 months after being off study. Cardiac medications will be continued at the 
discretion of the treating physicians. Cardiac events occurring during this period of 6 months will 
be recorded and considered as possibly related to HER2 targeted therapy, independently of 
whether HER2 targeted therapy is continued off study. All the patients will be reevaluated in a 
single visit at 6 months (+/- 10 days) with:  
 
• Complete history and physical exam  
• Study echocardiogram (6 months post Off Study) 
• Lipid profile for patients who were started on a lipid lowering agent while on the study 
• Troponin I, hs troponin 
 
5.9.1 Optional extended follow up after being off study 
 
• Patients will be provided with an optional consent where they are asked to allow for 
extended follow up up to 5 years after being off study. For patients who continue to be 
followed in the participating institutions this would mean to agree to have records 
reviewed periodically up to 5 years. For patients no longer being followed in the clinic 
this would mean to be contacted periodically by a member of the research staff 
regarding any new symptoms or events since coming off study, as well as authorization 
to request records during this period of time.  
26 


 
 
 
 
5.10 
Compliance with laws and regulations  
 
This study will be conducted in accordance with FDA regulations, the International Conference 
on Harmonization (ICH) E6 Guideline for Good Clinical Practice (GCP), the Declaration of 
Helsinki (October 1996), and applicable local, state, and federal laws. 
 
 
 
6.0 
ASSESSMENT OF SAFETY 
 
Safety assessments will consist of monitoring and recording protocol-defined AEs and serious 
adverse events (SAEs); measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study drugs. 
 
The Sponsors or their designee are responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in accordance 
with ICH guidelines, FDA regulations, European Clinical Trials Directive (Directive 2001/20/EC), 
and/or local regulatory requirements. 
 
All cardiac AE occurring on or after the date of the first study treatment administered will be 
summarized by mapped term, appropriate thesaurus levels, and NCI CTCAE version 4.0 toxicity 
grades. 
 
6.1 
Adverse event 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution.  
This includes the following:  
- AEs not previously observed in the patient that emerge during the protocol-specified AE      
   reporting period.  
 
- Complications that occur as a result of protocol-mandated interventions. 
- AEs that occur prior to assignment of study treatment that are related to a protocol     
  mandated intervention. 
 
- Preexisting medical conditions judged by the investigator to have worsened in severity or  
           frequency or changed in character during the protocol-specified AE reporting period. 
 
AEs attributed to ACE inhibitors and B-blockers will be documented but not reported: 
- 
Renal insufficiency 
- 
Cough 
- 
Anaphylaxis 
- 
Hypotension 
- 
Dizziness 
- 
Weight gain 
27 


 
 
- 
Depression 
- 
Weakness 
- 
Impotence 
- 
Nausea/vomiting/diarrhea 
 
Very common non-cardiac AEs attributed to T-DM1 will be documented but not reported: 
- 
fatigue, weight loss, decrease in appetite 
- 
nose bleed 
- 
upper respiratory tract infection, cough 
- 
fever, chills 
- 
urinary tract infection 
- 
depression 
- 
nausea, vomiting, constipation, diarrhea 
- 
low numbers of white blood cells (cells that fight infection, all types) or red 
blood cells (may make you feel tired) 
- 
rash 
- 
dry mouth 
- 
edema (swelling due to a buildup of fluid under skin) in arms and legs 
- 
neuropathy in arms and legs (tingling, pain, numbness, itching, pins and     
needles) 
- 
muscle spasms 
- 
low potassium in blood (caused by the loss of fluids due to vomiting, diarrhea 
or sweating a lot) 
- 
pain in joints, muscles, back, arms and legs, headaches 
 
Very common non-cardiac AEs attributed to Trastuzumab and Pertuzumab: 
- 
Weakness 
- 
Diarrhea  
- 
Skin rashes 
- 
Chest pain, abdominal pain, joint pain, muscle pain 
- 
Febrile neutropenia (infection due to low white blood cell count) 
- 
Mucosal inflammation (inflammation of the mucosal surfaces throughout the 
body 
 
 
6.2 
Serious adverse event (Immediately reportable to the sponsor) 
 
An SAE is any AE that result in the following outcomes or require medical intervention to 
prevent any of these outcomes:  
- 
Fatal (i.e., the AE actually causes or leads to death, sudden cardiac death or 
death due to myocardial infarct, arrhythmia or heart failure).  If death results 
from progression of the disease, it should be reported as a SAE. 
- 
Life threatening (i.e., the AE, in the view of the investigator, places the patient 
at immediate risk of death at the time of the event) 
- 
Requires or prolongs inpatient hospitalization. 
- 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
- 
A congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product(s). 
28 


 
 
- 
Considered a significant medical event by the investigator (e.g., may 
jeopardize the patient or require medical/surgical intervention to prevent one 
of the outcomes listed above) 
- 
Pregnancies 
 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(as in mild, moderate, or severe pain); the event itself may be of relatively minor medical 
significance (such as severe headache). “Serious” is a regulatory definition and is based on 
patient or event outcome or action criteria usually associated with events that pose a threat to a 
patient’s life or vital functions. Seriousness (not severity) serves as the guide for defining 
regulatory reporting obligations. Severity and seriousness should be independently assessed 
when recording AEs and SAEs on the eCRF.  Grading will be based on CTCAE v. 4.0. The 
CTCAE v4.0 is available at: http://ctep.cancer.gov/reporting/ctc.html. 
 
7.3  
Non serious adverse events of special interest (Immediately reportable to 
the sponsor) 
 
Non-serious AEs of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event); AEs of special 
interest for this study include the following: 
 
-     any cardiac event (CE) defined as any of the following:  
- 
Presence of symptoms attributable to HF (increasing shortness of breath, 
orthopnea, PND, bilateral ankle swelling) as confirmed by a cardiologist 
- 
Cardiac arrhythmia requiring pharmacological or electrical treatment 
- 
Myocardial infarction 
 
Heart failure should be graded according to NCI CTCAE v4.0 for “heart failure” (Grade 2, 3, 4, 
or 5) and in addition according to the NYHA classification. 
Any CE should be reported to the Cardiac Review Panel within three weeks after learning of the 
CE. 
Asymptomatic declines in LVEF will  not be reported.   Exceptions to this rule are as follows: 
• 
An asymptomatic decline in LVEF ≥ 10 percentage-points from baseline to an LVEF ≤35% 
must be reported as an AE with the term of “ejection fraction decreased” as per NCI 
CTCAE v4.0, and, in addition, a comment in the AE comments field should confirm that this 
was asymptomatic. 
 
7.4 Reporting Requirements for Pregnancies 
 
7.4.1 Pregnancies in Female Patients 
 
Female patients of childbearing potential will be instructed to immediately inform the investigator 
if they become pregnant during the study or within 7 months after the last dose of study drug. A 
Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no more 
than 24 hours after learning of the pregnancy).The investigator should counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring of the 
29 


 
 
patient should continue until conclusion of the pregnancy. Any SAEs associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the pregnancy, or a 
congenital anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  
 
 
7.4.2 Pregnancies in Female Partners of Male Patients  
 
Male patients will be instructed to immediately inform the investigator if their partner becomes 
pregnant during the study or within 7 months after the last dose of study drug. Male patients 
whose partners are pregnant must use condoms for the duration of the pregnancy. A Pregnancy 
Report eCRF should be completed by the investigator immediately (i.e., no more than 24 hours 
after learning of the pregnancy). Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study drug. 
The pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy 
Health Information to allow for follow-up on her pregnancy. Once the authorization has been 
signed, the investigator will update the Pregnancy Report eCRF with additional information on 
the course and outcome of the pregnancy. An investigator who is contacted by the male patient 
or his pregnant partner may provide information on the risks of the pregnancy and the possible 
effects on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician.  
 
6.5 
Methods and timing for assessing and recording safety variables  
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, 
Inc. in accordance with CFR 312.32 (IND Safety Reports).   
6.5.1 Adverse Event Reporting Period 
 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends when the patient comes off study. 
During the 6 month follow up period only SAEs and AE of special interest will be reported. 
 
7.5.2. Assessment of Adverse Events 
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the HER2 
targeted therapies and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
• 
Yes: There is a plausible temporal relationship between the onset of the AE and 
administration of the HER2 targeted therapies, and the AE cannot be readily explained by 
the subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the HER2 targeted therapies; and/or the AE abates 
30 


 
 
or resolves upon discontinuation of the HER2 targeted therapies or dose reduction and, if 
applicable, reappears upon re-challenge. 
• 
No: Evidence exists that the AE has an etiology other than the HER2 targeted therapies 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to HER2 targeted 
therapies administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For example, under 
this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated 
hepatic enzymes or hepatitis. 
 
6.6 
Expedited Reporting Requirements for Adverse Events of Special Interest 
The Sponsors or their designee will notify the, DSMC, Genentech and the FDA within 7 
business days of learning of any unexpected adverse event of special interest that is thought to 
be related to the study intervention. These adverse events of special interest will be reported to 
the IRB at annual renewal along with all other adverse events. DSMC and IPRC reports of these 
events will be submitted to the IRB as an amendment. 
 
6.7 
Expedited Reporting Requirements for Serious Adverse Events 
The Sponsors or their designee will notify the FDA  within 7 business days of learning of any 
unexpected fatal or life-threatening adverse event with possible relationship to study drugIn 
addition, the cause of death will be summarized (e.g., disease related, treatment related, other, 
unknown). The Sponsor or their designee will notify the IRB, DSMC and Genentech of relevant 
SAEs (i.e., death, a life-threatening experience, inpatient hospitalization, prolonged 
hospitalization or significant disability/incapacity) by a written safety report within 24 hours of 
learning of the serious adverse event. 
 
SAEs must be reported whether or not considered related to the treatment under investigation.  
An early report can then be followed up by a more detailed report.  The clinical course of the 
serious adverse evenrt, regardless of its relationship to the study intervention, should be 
managed according to accepted standards of medical practice.  Patients will be monitored until 
the SAE resolves or the symptoms or signs that constitute the event return to baseline; or a 
satisfactory explanation is found or the investigator considers it medically justified to terminate 
follow-up of the event; or death (a full pathology report shold be supplied if possible). 
 
Reports should include the following information: 
 Protocol number  
 Disease information 
 Date event occurred 
 Event grade  
 To what degree the event is related to the study intervention 
 If the event was expected 
31 


 
 
 Severity of the event 
 Intervention   
 Event Detail - Detailed text that includes the following information: 
 
Event description and how it was handled  
 
Current condition of participant 
 
Indication if participant remains on the study 
 Indicate if an amendment to protocol and/or consent is necessary 
 Indicate if the report is a follow-up to a previously submitted event report 
 
6.8 
MedWatch 3500A reporting guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
- Protocol description (and number, if assigned) 
- Description of event, severity, treatment, and outcome if known 
- Supportive laboratory results and diagnostics 
- Investigator’s assessment of the relationship of the AE to each investigational product and 
suspect medication 
 
6.8.1 Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
- Adding to the original MedWatch 3500A report and submitting it as follow-up 
- Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
- Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B. initial, patient number), protocol description and number, if assigned, brief AE 
description, and notation that additional or follow-up information is being submitted (The patient 
identifiers are important so that the new information is added to the correct initial report) 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 
 
 
7.0 
CORRELATIVES/SPECIAL STUDIES 
7.1 
Cardiac troponins 
Cardiac troponin I will be performed in the clinical laboratories at MWHC, MGUH and MSKCC 
collected in accordance with institutional protocol and using standard cTnI assay. These results 
will be available to the treating physician but will not be used to make clinical decisions unless it 
is is more than 1ng/ml. Based on the published data50, mild elevation of troponin in patients 
receiving chemotheray is common and its prognostic significance is being investigated in this 
study. However, higher elevations of troponin which we arbitrarily set as troponin higher than 
1ng/ml are not expected in this patient population and may indicate presence of cardiac 
ischemia or an inflammatory process such as myocarditis. Therefore, if the results of the 
standard cTnI assay are higher than 1ng/ml patient will come for a clinical visit and appropriate 
clinical work-up will be initiated.  
32 


 
 
 
Hs-cTnT assay will be measured offsite by Roche Diagnostics. These results will not be 
available to the treating physician, will only be used for research purposes and no clinical 
decisions will be made based on Hs-cTnT measurements. 
Standard cTnI and Hs-cTnT will be performed at enrollment, every 6 weeks after starting HER2 
therapy for 2 assessments and thereafter every 12 weeks. 
 
7.2 
Optional Sample Collection Guidelines for future analysis 
We will collect a specimen of blood at enrollment from each participant and then at 6 weeks, 12 
weeks, 6 months, 9 months and 12 months after starting HER2 therapy.  Blood specimens will 
be obtained at the same time with the samples for cardiac troponin and/or clinical laboratory. 
Whole blood will be collected and processed within 24h to separate the buffy coat from the 
plasma and RBCs. Buffy coat and plasma will be frozen at -80°C and processed for DNA or 
biomarkers at a later date. Serum samples will be processed, aliquoted and frozen at --80°C for 
analysis at a later day.  
 
After enrollment, and if patient accepts to have collected blood for future analysis, approximately 
16 ml of blood will be collected for research (storage for future analysis and troponins) and 
approximately 15ml for clinical labs. At week 6, 12, 24, 36 and 48 after initiating HER2 therapy, 
approximately 11 ml will be collected for research.  
 
Patient samples collected for this study will be kept at Georgetown University, at Medstar 
Washington Center Campus or at MHRI headquarters in Hyattsville. Specimens will be stored 
indefinitely or until they are used up. If future use is denied or withdrawn by the patient, best 
efforts will be made to stop any additional studies and to destroy the blood samples.  
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value.  The Informed Consent form contains this information. 
 
The collection of blood for future analysis is optional and patients that declined to have their 
blood collected and stored for future analysis can still participate in the study. 
 
 
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Two-stage design, Sample Size, Accrual and Study Duration 
 
The study is designed to assess the rate of completion of planned oncology therapy in the 
absence of cardiac event and asymptomatic worsening of cardiac function. The primary 
endpoint is the proportion of patients who completed planned oncologic therapy without 
developing a cardiac event or asymptomatic worsening of cardiac function.  
 
There is no data about the current proportion of patients with low LVEF who are being treated 
with HER2 targeted therapy but we estimate to be fewer than 10% based on current clinical 
recommendations. We consider that if 30% or more of patients will be able to safely receive 
HER2 targeted therapy despite low LVEF it will be clinically meaningful allowing additional 
patients to receive this beneficial treatment. Therefore we defined a completion rate of 30% as 
considered of clinical relevance, where as a completion rate is of 10% is considered similar to 
the current practice.  
33 


 
 
 
A two stage design with a total of 30 patients is used to test if the completion rate is at least 
30% versus it is below 10% with 80% power at a significance level of 5%51,52. This multistage 
design has operating properties similar to that of the Simon’s two-stage designs but this two 
stage design offers flexibility in monitoring and interim analysis should the planned schedule be 
variated. Morevoer it allows an early assessment of statistical evidence for both efficacy and 
futility, and provides a discordance probability that early trend could be reversed should the trial 
continue to to enroll all 30 patients. At the first stage, 15 patients will be entered. If one or more 
patient complete therapy in the absence of cardiac event, then an additional 15 patients will be 
enrolled in the second stage; If none of the 15 patients in the first stage complete the therapy, 
we will conclude that the therapy is not feasible in this patient population. The protocol will be 
amended. The chance for a reversal of the conclusion either for efficacy or for futility based on 
this decision rule is less than 2% (the discordance probability). At the completion of the second 
stage, if more than 6 among the 30 patients complete the therapy, we conclude that the therapy 
is feasible in this patient population, and otherwise it is not.  
 
This statistical design would have 80% probability to consider the therapy as beneficial to this 
patient population with reduced LVEF if the true completion rate is indeed 30% and 5% 
probability to consider this therapy as beneficial if the completetion rate is indeed only 10% or 
below.  Exact binomial calculations were used. The intention-to-treat (ITT) population of this trial 
will be composed of patients who are actually enrolled and received at least one dose of HER2 
targeted therapy since they are on study. 
 
CE is defined as any of the following:  
- 
Presence of symptoms attributable to HF (increasing shortness of breath, 
orthopnea, PND, bilateral ankle swelling) as confirmed by a cardiologist 
- 
Cardiac arrhythmia requiring pharmacological or electrical treatment 
- 
Hospitalization due to a cardiovascular cause, e.g. myocardial infarction 
- 
Sudden cardiac death or death due to myocardial infarct, arrhythmia or HF 
 
 
We estimate there will be no more than 10% cardiac events by month 6 based on Tarantini et 
al53. With 30 patients we will be able to estimate the cardiac event rate within 13% accuracy at a 
confidence level of 95%, or estimate it within 11% accuracy at a confidence level of 90%. We 
will plan to enroll additional 10% of our sample size (N=3) to account for patients that will drop 
out after enrollment and before receiving any HER2 targeted therapy.   
 
We anticipate to accrue 1 patient per month based on our historical data. If we do not have 
enough accrual among the two institutions (MWHC and MGUH), we plan to expand the study to 
other institutions that have the capability of performing echocardiograms with strain analysis. 
The accrual period is expected to be approximately 30 months. All patients will be followed for a 
maximum of 12 months. Study duration will be approximately 4 years with additional extended 
follow up up to 9years.  
 
8.2 
Statistical Analysis Plan 
 
The two-stage analysis will follow the design described in 9.1. An exact confidence interval of 
the completion rate based on binomial calculation will be obtained. We estimate there will be no 
more than 10% cardiac events.  
 
34 


 
 
The outliers and data errors will be checked. Descriptive statistics will be used to characterize 
the demographic profile of the subjects. Frequency and percentages will be used to summarize 
categorical variables. Mean (SD) or median (interquartile range) based on the normalization of 
the data will be used to summarize continuous variables.  
 
The incidence of CEs and asymptomatic worsening of cardiac function during study treatment 
will be calculated, as well as time to CEs and asymptomatic worsening of cardiac function. Due 
to the expected small number of subjects with incident CE, descriptive statistics and graphical 
analyses will be used to assess the difference between those with and without cardiac 
dysfunction. We will  calculate the mean (SD) of the strain, cTn I and hs-cTn T at each time 
point and graphically assess these measures over time in patients that had an event and that 
did not have an event. Difference (95% CI) in mean of the strain, cTn I and hs-cTn T between 
those with and without incident CE event at each time point will be calculated. The mean 
change in strain, cTn I and hs-cTn T from baseline to each follow-up point will be calculated in 
those with and without incident CE. Generalized linear model will be utilized for the correlative 
analysis of completion rate and cardiac events. The longitudinal generalized linear model will be 
used to assess the serial strain, cTn I and hs-cTn T measures with the clinical outcomes 
(completion rate and cardiac events). These analyses will most likely be in a pairwise fashion 
given the moderate sample size. 
 
8.2.1 Interim Analysis:  
The study has a two-stage design. There will be an interim analysis after enrollment of 50% of 
the patients. The interim analysis plan is contained in 9.1 two stage design description.  
 
 
8.2.2 Safety Analysis:   
All subjects who have received treatment will be in the safety analysis. All adverse events will 
be summarized in terms of frequency, severity and relatedness to the study treatment. At the 
end of the study, the cumulative incidences of adverse events will be calculated.  
 
8.3 
Safety Stopping Rules 
 
Early stopping rules will be incorporated for safety based on cardiac death and symptomatic HF 
separately. If one cardiac death related to treatment is observed the trial will be terminated. With 
30 patients enrolled, if 0 cardiac deaths are observed, the exact binomial 90% CI would be 0 to 
9.48%. Thus we feel confident that the true cardiac death rate in this population is less than 
10%. The probability of observing at least one cardiac death, for a range of true underlying 
rates, is summarized in Table 4, indicating for example, that if the true cardiac death rate is as 
high as 10% then the study has a 0.96 probability of observing one or more when 30 patients 
are treated, and even if as high as 5% there is a 0.79 probability of having observed one or 
more. 
 
If we don’t observe any cardiac death, then the likelihood that the true rate is 10%, is extremely 
low.  
 
 
35 


 
 
Table 4. Probability of observing at least one cardiac death, for a range of true underlying event 
rates, with n=30 patients. 
 
 
True Probability of Cardiac Death 
 
.01 
.05 
.1 
.2 
.3 
.4 
.5 
Probability 
0.26 
0.79 
0.96 
1 
1 
1 
1 
 
 
If 3 patients experience symptoms of HF (increasing shortness of breath, orthopnea, PND, 
bilateral ankle swelling) and confirmed by the cardiologist, then the trial will be terminated. 
Adjuvant phase III clinical trials reported an incidence of HF that ranged from 2.1% (BCIRG0067, 
only grade 3/4 reported) to 4% (NSABP at 7y15). In a retrospective study with patients at a 
higher cardiovascular risk, a rate of 9% of symptomatic HF was reported54. Based on these 
reports, we will accept a rate of less than 10% for events of symptomatic HF, which represents 
less than 3 events. With 30 patients enrolled, if 3 symptomatic HF events are observed, the 
exact binomial 90% CI would be (2.78% to 23.85%). The probability of observing 3 or more 
symptomatic HF events, for a range of true underlying rates, is summarized in Table 5, 
indicating for example, that if the true rate is as high as 10% then the study has a 0.59 
probability of observing three or more when 30 patients are treated, and if as high as 15% there 
is a 0.85 probability of having observed three or more. 
 
If the rate of symptomatic HF events in a sample of 30 patients is higher than what was 
expected from the adjuvant and metastatic setting observed in randomized trials, the likelihood 
of detecting it is high.  
 
 
Table 5. Probability of observing at least three symptomatic HF events, for a range of true 
underlying event rats, with n=30 patients. 
 
 
True Probability of Symptomatic HF event  
 
.03 
.04 
.05 
.06 
.07 
.10 
.15 
Probability 
.06 
.12 
.19 
.27 
.35 
.59 
.85 
 
 
9.0 
DATA SAFETY MONITORING COMMITTEE AND  CARDIAC REVIEW 
PANEL 
9.1 
Data and Safety Monitoring Committee (DSMC) 
 
As this study is an investigator initiated study utilizing FDA approved agents it is considered a 
moderate risk study which requires real-time monitoring by the PI and study team and semi-
annual reviews by the LCCC Data and Safety Monitoring Committee (DSMC). 
The Principal Investigator and the Co-Investigators will review the data including safety 
monitoring at weekly disease group meetings and on monthly network disease group 
teleconferences.  The investigators shall meet regularly to review toxicities and follow up on 
results of patients enrolled on the study. 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and 
Safety Monitoring Committee every 6 months from the time the first patient is enrolled on the 
36 


 
 
study. Results of the DSMC meetings will be forwarded to the IRB. E-mail notification from the 
PI will be sent to the DSMC Chair any time there is a major event or issue with the trial affecting 
patient safety or conduct of the trial. The DSMC Chair has the discretion to have the study 
reviewed by the DSMC sooner more frequently than every 6 months based on information 
received.  
All Severe Adverse Events (SAEs) are required to be reported to the IRB. In addition, all SAEs 
will be submitted to the DSMC at time of submission to IRB and/or Sponsor.  Based on SAEs, 
the IRB retains the authority to close the study to further accrual pending more detailed 
reporting and/or modifications to further reduce risk and maximize the safety of participating 
patients. 
DSMC recommendations should be based not only on results for the trial being monitored as 
well as on data available to the DSMC from other studies.  It is the responsibility of the PI to 
ensure that the DSMC is kept apprised of non-confidential results from related studies that 
become available.  It is the responsibility of the DSMC to determine the extent to which this 
information is relevant to its decisions related to the specific trial being monitored. 
 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the 
DSMC recommends a study change for patient safety or efficacy reasons the trial PI must act to 
implement the change as expeditiously as possible.  In the unlikely event that the trial PI does 
not concur with the DSMC, then the Lombardi Cancer Center Associate Director of Clinical 
Research must be informed of the reason for the disagreement.  The trial PI, DSMC Chair, and 
the Lombardi Cancer Center ADCR will be responsible for reaching a mutually acceptable 
decision about the study. Confidentiality must be preserved during these discussions. However, 
in some cases, relevant data may be shared with other selected trial investigators and staff to 
seek advice to assist in reaching a mutually acceptable decision. 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy 
the DSMC will provide an adequate rationale for its decision. 
An external cardiologist expert will be added to the DSMC particularly for this study given its 
nature.  
 
9.2 
Cardiac Review Panel 
 
A cardiac review panel will be formed and quarterly review data on clinical and 
echocardiographic data. Cardiac data will be reviewed by the cardiac review panel within three 
weeks in case of any CE. 
 
 
 
10.0 
STUDY MANAGEMENT 
 
10.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by Medstar Health Research Institute. All investigators will follow the University conflict 
of interest policy. 
 
37 


 
 
 
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
 
All oncology clinical research protocols must be submitted to the Clinical Research Committee 
(CRC) for scientific review before submission to and final approval by the IRB. The initial review 
includes an assessment of the specific plans for data and safety monitoring, which vary 
depending on the study type, phase, size, and sponsorship.  
For Investigator Initiated studies, the PI will write the data and safety monitoring plan for 
approval by the CRC. The PI will also perform ongoing monitoring with oversight by the DSMC, 
which conducts a formal review at established increments. This type of study is considered to 
have moderate level of risk (investigator initiated study with commercially available agents 
investigated or use in an unapproved indication). As such, requirements include real-time 
monitoring by the PI and study team; quarterly reviews by the DSMC and reviews by an 
independent DSMC every 6 months.  
 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
 
10.3 
Required Documentation 
 
Before the study can be initiated at any site, the following documentation must be provided to 
the Research Office. 
 
A copy of the official IRB approval letter for the protocol and informed consent 
38 


 
 
• 
IRB membership list  
• 
CVs and medical licensure for the principal investigator and any associate investigators who 
will be involved in the study 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation  
• 
A copy of the IRB-approved consent form 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Executed clinical research contract 
 
Before the start of this study, the following documents must be on file with Genentech or a 
Genentech representative: 
• 
Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any sub-investigators must appear on this form.  Investigators must also 
complete all regulatory documentation as required by local and national regulations. 
• 
Current curriculum vitae of the Principal Investigator 
• 
Written documentation of IRB approval of protocol and informed consent document 
• 
A copy of the IRB-approved informed consent document 
• 
A signed Clinical Research Agreement 
 
 
10.4 
Registration and Enrollment Procedures 
 
All participants must be registered and enrolled through the Oncology Research office at the 
Washington Cancer Institute. Participating sites should fax or email (redacted if from entity 
outside MedStar Georgetown Cancer Network) completed enrollment case report forms (CRFs), 
together with all source documentation used to support eligibility, ordered per the CRF. Please 
send these during business hours Monday - Friday between 8am and 4:30pm (EST), the latest 
at the moment that patient is signing informed consent. In the event that there is a time 
constraint, please notify the research office at (202)877-8839 to discuss possibility of expediting 
the process. 
 
 
10.5 
Data Management and Monitoring 
 
Data management and monitoring will be performed by MHRI. 
 
 
 
10.6 
Adherence to the Protocol 
 
39 


 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.   
 
10.6.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior 
IRB approval. For any such emergency modification implemented, an IRB 
modification form must be completed within five (5) business days of 
making the change.   
 
10.6.2 Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility 
criteria of this study requires the approval of the Principal Investigator and 
the IRB.  
 
10.6.3 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by 
the Principal Investigator and the IRB.  According to the IRB, a protocol 
deviation is any unplanned variance from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research 
plan or the value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the 
investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring 
committee in accordance with their policies. Minor deviations should be summarized and 
reported to the IRB at the time of continuing review. Major deviations should be 
summarized and reported to the Regulatory Affairs Coordinator who will submit to the 
IRB as soon as possible, but not more than 10 calendar days after acquiring information 
reasonably suggesting that a reportable (major) deviation has occurred. 
  
40 


 
 
 
Protocol Violations: Violations should be reported by study personnel within one (1) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.   
 
10.7 
Amendments to the Protocol 
 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an amendment to 
the protocol substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.   
 
The written amendment, and if required the amended consent form, must be sent to the IRB for 
approval prior to implementation.   
 
10.8 
Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator.  In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
 
10.9 
Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 
41 


 
 
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
10.10 Study Medication Accountability  
 
HER2 targeted therapies will be provided by Genentech. The recipient (MHWC, MGUH or 
MSKCC) will acknowledge receipt of the drug by returning the INDRR-1 form indicating 
shipment content and condition.  Damaged supplies will be replaced. All study drug will be 
stored at 2-8°C (36-46°F) upon receipt. Vials should not be used beyond the expiration date 
provided by Genentech. 
Accurate records of all study drug receipt, disposition and return should be maintained by using 
the institution’s drug inventory log or the NCI drug accountability log. 
• 
Separate logs will be maintained at each site for each of the three study drugs provided. 
• 
Study drug supplies are not patient specific. 
• 
Pertuzumab and ado-trastuzumab vials are for single use only with unused portions 
discarded immediately.  Dose preparation is per institutional standard. 
• 
Trastuzumab, when reconstituted according to package instructions with supplied diluent 
(bacteriostatic water for injection), will be used as a multi-dose vial and may be used to 
prepare doses for more than one patient.  Upon reconstitution, the solution will be stored 
at 2-8°C (36-46°F) and used within 28 days.  Any reconstituted solution remaining after 
28 days will be discarded immediately.  If trastuzumab must be reconstituted with sterile 
water for injection (no preservative), the vials will be considered single use only with 
unused portions discarded immediately. Dose preparation is per institutional standard.  
To maintain accurate drug accountability of partial vials, the study site will record 
trastuzumab inventory in milligrams. 
All partially used or empty containers should be disposed of at the study site according to 
institutional standard operating procedure.  Return unopened, expired, or unused study drug 
with the Inventory of Returned Clinical Material form as directed by Genentech. 
 
10.11 Study Close-Out 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study. 
  
 
12. 
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randomized controlled trial. Lancet 2003;362:7-13.  
50 Cardinale D, et al. Trastuzumab-induced cardiotoxicity: Clinical and prognostic implications of 
troponin I evaluation. J Clin Oncol 2010;28:3910–3916. 
51 Tan M and Xiong X. Continuous and group sequential conditional probability ratio tests for 
Phase II clinical trials.  Statistics in Medicine, 15:2037-2051, 1996. 
52 Tan M, and Xiong X. A Flexible Multi-Stage Design for Phase II Oncology Trials. Pharm Stat. 
2011;10:369-73 
53 Tarantini L, Cioffi G, Gori S, Tuccia F, Boccardi L, Bovelli D, Lestuzzi C, Maurea N, Oliva S, 
Russo G, Faggiano P. Trastuzumab adjuvant chemotherapy and cardiotoxicity in real-world 
women with breast cancer J Card Fail. 2012;18:113-119. 
54 Serrano C, et al. Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular 
risk factors. Ann Oncol 2012;4:897-902.  
 
45 


 
 
 
13.  
LIST OF APPENDICES 
 
A – New York Heart Association Classification 
B - Stages of Development of HF and recommended therapy by stage  
C – ECOG Performance Status 
D – Framingham criteria for the definition of Congestive Heart Failure (CHF) 
E – Cardiac Questionnaire – Initial Visit (to be filled by the patient) 
F – Cardiac visits CRF (to be filled by the investigator) 
G – Summary of initial cardiac assessment CRF (to be filled by the investigator) 
H – Echocardiographic Acquisition Protocol 
I – EchoCore lab CRF 
J – Eligibility criteria for screening 
K – Eligibility criteria for enrollment 
L – Study Requirements (to be filled by the research coordinator) 
M – Enrollment information (to be filled by the investigator) 
N – Prior hormonal therapy and chemotherapy (to be filled by the investigator)  
O – Prior radiation therapy (to be filled by the investigator) 
P – Prior Breast Surgical History (to be filled by the investigator) 
Q – Laboratorial data CRF (to be filled by the research coordinator) 
R – Adverse events  
S – Blood Pressure Daily Log (to be filled by the patient) 
T – Off Study Summary (to be filled by the investigator) 
U – Death summary 
V – Exercise and chronic disease (info for patients) 
W – Exercise: Finding Activities that Work for You (info for patients) 
X – Low salt diet (info for patients) 
Y - Schedule of Events 
Z – Oncological therapy while on study (to be filled by investigator) 
AA- Specimen Form 
BB- Flow sheet for Patient Recruitment  
 
 
 
 
46 


 
 
Appendix A:  New York Health Association Classification 
 
Functional Capacity 
Class I.  
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
 
Class II.  
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
 
Class III.  
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain. 
 
Class IV.  
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is increased. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
47 


 
 
Appendix B:Stages of Development of HF and recommended therapy 
by stage 
Figure 4. Recommended therapy for patients with heart failure, by disease stage. (ACE = 
angiotensin-converting enzyme; ARB = angiotensin receptor blocker)  
 
Adapted from Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. 
ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in 
the adult—summary article: a report of the American College of Cardiology/American Heart 
Association Task Force on Practice Guidelines. Circulation 2005;112:1830 
 
 
 
 
 
 
 
 
 
48 


 
 
Appendix C.: ECOG (Eastern Cooperative Oncology Group) PERFORMANCE 
STATUS* 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
49 


 
 
Appendix D.: Framingham criteria for the definition of Congestive Heart Failure 
(CHF) 
Diagnosis of CHF requires the simultaneous presence of at least 2 major criteria or 1 major 
criterion in conjunction with 2 minor criteria. 
Major criteria: 
·        Paroxysmal nocturnal dyspnea 
·        Neck vein distention 
·        Rales 
·        Radiographic cardiomegaly (increasing heart size on chest radiography) 
·        Acute pulmonary edema 
·        S3 gallop 
·        Increased central venous pressure (>16 cm H2O at right atrium) 
·        Hepatojugular reflux 
·        Weight loss >4.5 kg in 5 days in response to treatment 
  
Minor criteria: 
·        Bilateral ankle edema 
·        Nocturnal cough 
·        Dyspnea on ordinary exertion 
·        Hepatomegaly 
·        Pleural effusion 
·        Decrease in vital capacity by one third from maximum recorded 
·        Tachycardia (heart rate>120 beats/min.) 
 
Minor criteria are acceptable only if they can not be attributed to another medical condition 
(such as pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or the nephrotic 
syndrome). 
The Framingham Heart Study criteria are 100% sensitive and 78% specific for identifying 
persons with definite congestive heart failure.  
 
McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart 
failure: the Framingham study. N Engl J Med 1971 Dec 23;285(26):1441-6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
50 


 
 
 
 
 
 
 
 
 
 
 
Appendix E: Cardiac Questionnaire (Initial Visit) 
 
Medical History: 
1. Have you been diagnosed with diabetes?    
 
 
 
No    Yes 
 
a. If yes, are you taking insulin?            
 
 
 
 
No    Yes 
 
2. Have you been diagnosed with high blood pressure?    
 
 
No    Yes 
 
3. Have you been diagnosed with high cholesterol or other lipid problem?      No    Yes     
 
4. Have you ever had any of the following:   
a. Heart attack 
 
 
               
 
No      Yes   Year         _ 
b. Angioplasty (balloon angioplasty, stent procedure)  
No      Yes    Year_____ 
c. Coronary artery bypass grafting (CABG)  
 
No      Yes    Year_____ 
d. Heart surgery for another reason  
 
 
No      Yes    Year_____ 
e. Angina (chest pain) 
 
                
 
No      Yes    Year____ 
f. Heart Murmur 
 
 
                
 
No      Yes    Year____ 
g. Heart failure                                            
 
No      Yes    Year____ 
h. Needed a pacemaker or defibrillator (ICD) 
 
No      Yes    Year____ 
i. 
Peripheral arterial disease                      
 
No      Yes    Year____ 
j. 
Surgery for circulation problem in the legs 
 
No      Yes    Year____ 
k. Carotid artery disease                             
 
No      Yes    Year____ 
l. 
Transient ischemic attack (TIA)        
    
 
No      Yes    Year____ 
m. Stroke 
 
 
 
                
 
No      Yes    Year____ 
n. Rheumatic fever    
 
    
 
 
No      Yes    Year____ 
o. Rheumatologic disease such as systemic lupus erythematosus,  
 
 
     
scleroderma or rheumatoid arthritis 
 
 
No      Yes    Year____ 
p. Thyroid disease 
 
 
   
 
 
No      Yes    Year____ 
q. Pheochromocytoma 
 
 
   
 
No      Yes    Year____ 
 
5. Do you have congenital heart disease?  
 
 
 
No      Yes          
a. If known, what congenital heart disease do you have? 
 
 
Page:  
1 of 3 
Investigator’s Signature: 
Date 
          
 
 
Date form completed: 
 
Institution Code: 
Patient ID: 
Patient Initials/Name:    
 
Case Report Form 
Washington Cancer Institute 
Clinical Research 
51 


 
 
Appendix E: Cardiac Questionnaire (pg2) 
6. Do you have history of weak muscles *myopathy”?  
 
No      Yes          
 
7. Do you have history of sleep-disordered breathing (sleep apnea)? No      Yes          
a. If yes, are you using CPAP (continuous positive pressure treatment) at night?  
No      Yes          
8. Other than your ongoing cancer treatment, do you have prior history of receiving 
chemotherapy? 
 
 
 
 
 
No      Yes       Year ___ 
 
9.  Other than your ongoing cancer treatment, do you have prior history of receiving 
radiation therapy? 
 
 
 
 
 
No      Yes       Year___   
 
10. Are you HIV positive?  
 
 
 
 
 
No      Yes        
 
 
Family History  
1. Has anyone in your immediate family (your blood-related parent, brother, sister or child) 
been diagnosed with any of the following: 
 
a. Premature cardiovascular disease, either heart attack, coronary artery bypass 
surgery or stroke before age 55 (male relatives) or before age 65 (female relatives)? 
No      Yes  
 
b. Heart failure? 
 
 
 
 
 
 
No      Yes  
 
c. Unexplained heart muscle weakness?  
 
 
No      Yes 
  
d. Sudden cardiac death?  
 
 
 
 
No      Yes 
  
e. Need for pacemaker? 
 
 
 
 
 
No      Yes  
 
Please write down who from your relatives had the event and his/her/their age at the 
time of the event, if known: 
______________________________________________________________________
______________________________________________________________________ 
______________________________________________________________________
______________________________________________________________________ 
______________________________________________________________________
______________________________________________________________________ 
 
Habits 
1. Are you a current smoker?      
 
          
 
 No    Yes  
(Answer “Yes” if you have smoked cigarettes within the past month) 
2. Have you ever smoked?                                          
 
 No      Yes 
a. If Yes, how many years ago did you stop smoking?  __________   
          
Page:  
2 of 3 
Investigator’s Signature: 
Date 
52 


 
 
Appendix E: Cardiac Questionnaire (pg3) 
b. How many packs per day? __________ 
c. For how many years?  __________ 
3. Have you ever used any of the following substances: cocaine, amphetamines or fen-
phen (fenfluramine, phentermine, dexfenfluramine)? 
 
 No   Yes                        
a. If  Yes, which substances?   ________________________________________                            
b. How many years ago did you stop using them? _________________________ 
c. For how many years did you use these substances? _____________________      
4. Do you drink more than one drink a day?                             
No Yes    
 (One drink is equivalent of 5 fluid ounces of wine, 12 fluid ounces of beer, or 1.5 fluid 
ounces of 80-proof spirits such as whisky or vodka)  
5. Have you ever drunk more than one drink a day over a period of week or longer?                                     
No Yes 
a. If  Yes, how many years ago have you stopped drinking?  _________________ 
b. For how many years were you drinking more than a drink per day? __________                           
 
Please list your medications: 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
Allergies: 
 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
Page:  
3 of 3 
Investigator’s Signature: 
Date 
53 


 
 
 
 
 
 
 
 
 
 
Appendix F: Cardiac Visit CRF (to be filled by investigator)  
 
Cardiology Visit #:___________           Date: _______________ 
 
Medications: 
Carvedilol   Y N   Dose________  Side effects Y N   Describe______________ 
Ramipril     Y  N   Dose________  Side effects YN    Describe______________ 
Statin         Y  N    Dose ________Side effects YN    Describe______________ 
Other Medications: 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
Presence of HF symptoms 
Paroxysmal nocturnal dyspnea  YES    NO  
Orthopnea 
YES    NO      If yes, how many pillows does the patient sleep on  ___ 
Nocturnal cough 
YES    NO  
Shortness of breath with exertion  
YES    NO  
Shortness of breath when going up one flight of stairs without stopping? (ordinary 
exertion) YES    NO               
Shortness of breath with walking around your home and activities of daily living? YES 
  NO  
Shortness of breath at rest   YES   NO  
Page:  
1 of 3 
Investigator’s Signature: 
Date 
           
 
Date form completed: 
 
Institution Code: 
Patient ID: 
Patient Initials/Name:    
 
Case Report Form 
Washington Cancer Institute 
Clinical Research 
54 


 
 
Appendix F: Cardiac Visit CRF (pg2) 
Indicate NYHA class   _______________________ 
 
Class I. Patients with cardiac disease but without resulting limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal 
pain. 
Class II. Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
Class III. Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
Class IV. Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest. If any physical activity is undertaken, discomfort is increased. 
 
Physical Exam 
Height: 
Weight (measured): 
Blood pressure (sitting): 
Heart rate: 
Oxygen saturation: 
Jugular venous distention:  
 
 
 
 
 
YES  
NO  
If yes, estimated JVP (cm H2O) above the right atrium:___________    
Crackles or rales on lung auscultation:  
 
 
 
YES     
NO  
Pleural effusion: 
 
 
 
 
 
 
 
YES    
NO  
Hepatojugular reflux: 
 
 
 
 
 
 
YES   
NO  
Pulmonary edema:  
 
 
 
 
 
 
YES       
NO  
Presence of S3 gallop: 
 
 
 
 
 
 
YES   
NO  
Hepatomegaly: 
 
 
 
 
 
 
 
YES     
NO  
Bilateral ankle edema:  
 
 
 
 
 
 
YES  
NO  
(If Yes, describe extent using the scale: 1+ minimal edema, 2+ mild edema, 3+ 
moderate edema, 4+ significant edema)  ____________________ 
 
Additional tests ordered based on findings: 
- Chest X Ray:  Ordered   Not-ordered           Result:________________________ 
- EKG: Ordered    Not-ordered        Result:_________ 
- BNP: Ordered    Not-ordered        Result:_________        (baseline BNP)_______ 
- CMP: Ordered   Not ordered         Result:_________      (baseline creatinine) ____ 
 
Page:  
2 of 3 
Investigator’s Signature: 
Date 
55 


 
 
Appendix F: Cardiac Visit CRF (pg3) 
Other tests ordered (please specify): 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page:  
3 of 3 
Investigator’s Signature: 
Date 
56 


 
 
 
 
 
 
 
 
 
 
Appendix G: Summary of Initial Cardiac Assessment CRF (to be filled 
by investigator) 
2D echocardiogram baseline LVEF result:  __________                 
Presence of symptoms and signs of HF:        YES    NO  
ECG result:        
 
 Normal ECG 
 ECG suggestive of ischemia    
 ECG with evidence of atrial fibrillation 
 Other:   ___________________________ 
 
Stress Echocardiogram done:                         YES    NO  
If Yes, Stress Echocardiogram Result:    
ECG evidence of ischemia: Yes/ No/ Equivocal 
Wall motion abnormalities suggestive of ischemia: Yes/No/ Equivocal 
 
Laboratory test results: 
 
Troponin I   ______ 
BNP           ______ 
Creatinine  ______ 
 
Based on the initial evaluation ischemia is suspected. Patient needs further testing.  
YES    NO  
Test of choice ordered: 
Date of test: 
Result 
Ischemia and other reversible causes of cardiomyopathy still suspected:  YES    
NO  
 
6 minute walk test:   
 
Meters walked   ___________ 
 
 
 
BP, HR and O2 sats at the start and at the end   ________ 
Presence of symptoms   __________ 
 
Lipid profile result: TC _____ HDL _____ TG _____ LDL_____ 
LDL goal:   __________________ 
Patient meets LDL goal. YES    NO  
Start or increase dose of statin is needed to meet goal    YES    NO  
 
Page:  
1 of 2 
Investigator’s Signature: 
Date 
           
 
Date form completed: 
 
Institution Code: 
Patient ID: 
Patient Initials/Name:    
 
Case Report Form 
Washington Cancer Institute 
Clinical Research 
57 


 
 
Appendix G: Summary of Initial Cardiac Assessment CRF (pg2) 
 
If, yes, indicate statin and the dose prescribed:    _____________ 
 
Patient has contraindications to start or increase the dose of beta-blocker: YES  NO 
 
Patient has contraindications to start or increase the dose of ACE-inhibitor: YESNO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page:  
2 of 2 
Investigator’s Signature: 
Date 
58 


 
 
 
Appendix H: Echocardiographic Acquisition Protocol 
 
 
Echocardiography will be used to make assessments of left ventricular (LV) and left atrial 
dimensions and volumes, LV wall thickness and LV mass, LV ejection fraction (LVEF), as well 
as LV myocardial strain measured by speckle-tracking echocardiography. All study 
echocardiograms will be performed at clinical echocardiographic laboratories and sent to the 
MHRI Core lab for the study analysis and interpretation.  
 
 
Equipment   
Contemporary echocardiographic equipment (Philips, Andover MA, iE33 or newer) with strain 
assessment capacity will be used in this protocol.  All images will be transferred (digitally or on a 
DVD) to the Core lab and securely stored.  
 
The acquisition Transthoracic Echo (TTE) protocol listed below may be further modified to be 
compatible with different echocardiographic machines and operating systems. 
 
 
Transthoracic Echo (TTE) Protocol: 
• 
Long Axis 
o Parasternal Long Axis View 
o 2-D measurements 
 
LVIDd 
 
LVIDs 
o ‘Zoom’ in on the LVOT for diameter measurement 
o Color Flow of Mitral and Aortic Valves 
 
• 
Right ventricular inflow view 
o 2D of RV inflow  
o Color and spectral Doppler of the tricuspid regurgitation 
 
• 
Short Axis – Aortic Level 
o 2-D imaging of the aortic valve 
 
‘Zoom’ in on the aortic valve 
 
Color Doppler of aortic valve 
o 2-D imaging of the tricuspid valve 
 
Color Doppler of valve 
 
Spectral Doppler of TR 
o 2-D imaging of the pulmonic valve 
 
Color Doppler of pulmonic valve 
 
• 
Short Axis – Mitral level  
o 2-D imaging of the Mitral Valve 
o Color Doppler of the Mitral Valve 
 
• 
Short Axis – Papillary and LV apex level 
o 2-D imaging of the mid-papillary level, acquiring images at both the papillary level 
and the apical level 
59 


 
 
Appendix H.: Echocardiographic Acquisition Protocol (pg2) 
 
• 
Apical 4 Chamber 
o 2-D image of the LV for LVEF measurements (assure that all LV walls remain within 
the field during all part of the cardiac cycle). Optimize picture to visualize the 
endocardial border.  
  
o Mitral Valve 
 
2D image of valve 
 
Color imaging of valve 
 
Pulsed Doppler at the leaflet tips 
 
o Tricuspid Valve 
 
2D image of tricuspid valve 
 
Color Flow Imaging 
 
CW of tricuspid regurgitation 
 
• 
Apical 5 Chamber 
o 2-D image of aortic valve 
 
Color Doppler of aortic valve 
 
Pulsed Doppler of LVOT (just proximal to the aortic valve) 
o Continuous wave Doppler through the aortic valve 
 
• 
Apical 2 Chamber 
o 2-D image of the entire LV for LVEF measurements 
o 2-D imaging of the mitral valve 
o Color Doppler of mitral valve 
 
• 
Apical 3 Chamber (Apical Long Axis) 
o 2-D imaging of LV and valves 
o Color Doppler of mitral valve 
o Color Doppler of aortic valve 
 
• 
Subcostal View 
o 2D image of LV and RV 
o 2D image of IVC  
 
• 
3D 4 beat Full Volume view of the LV 
 
Strain Protocol  
o Obtain the Apical 4 Chamber (AP4) View  
o Adjust Depth so that the LV fills the screen (with the MV annulus visible) and 
center the LV in the sector 
o Obtain the Apical 4 chamber (AP4) with focus on the RV  
o Center RV in the middle of the screen 
o Obtain the Aortic Valve Closure Time (AVC time)  
o Obtain the Apical 2 Chamber (AP2) View 
o Obtain the Apical 3 Chamber (AP3) View 
o Obtain the Parasternal Short Axis View at the mid papillary level (SAX M) 
 
60 


 
 
 
Appendix H.: Echocardiographic Acquisition Protocol (pg3) 
 
 
Contrast Use Protocol (for technically difficult Echocardiograms) 
Contrast use for enhancing endocardial borders in patients with technically difficult images will 
be indicated if endocardial border cannot be visualized in two consecutive segments.  Contrast 
will be used only after the strain protocol is completed as speckle tracking cannot be reliably 
performed post administration of echocardiographic contrast. Intravenous access will be 
obtained and contrast (Definity, Bristol Myers Squibs or Optison, GE Healthcare) will be 
administered according to manufacturer’s protocol. Two chamber and four-chamber apical 
views (AP2 and AP4) will be obtained following the administration of the contrast for the 
calculation of LV volumes and EF. 
 
 
61 


 
 
 
 
 
 
 
 
 
 
 
Appendix I. : Core Lab Case Report Form  
 
 
 
Page:  
1 of 1 
Investigator’s Signature: 
Date 
           
 
Date form 
completed: 
Institution Code: 
Patient ID: 
Patient Initials/Name:    
 
Case Report Form 
Washington Cancer Institute 
Clinical Research 
62 


 
 
 
 
 
 
 
 
 
Appendix J: Eligibility Checklist - Inclusion Criteria (prior to screening 
procedures) 
 
 
Yes 
No 
Female or male patient diagnosed with stage I-IV breast 
cancer 
Source Document + Date: ________________ 
 
 
HER2 positive breast cancer, defined by IHC 
immunohistochemical staining for HER2 protein of 3+ 
intensity and/or amplification of the HER2 gene on 
fluorescence in situ hybridization (FISH) ≥ 2.0 on breast 
specimen or biopsy of a metastatic site 
IHC and FISH report date: ______________  Score 
IHC/FISH:____________ 
 
 
LVEF < 50% and ≥ 40% (initial clinical report) documented in 
cardiac imaging done within the last 30 days 
Date of Last Echocardiogram:__________________ 
 
 
HER2 therapy naïve or currently receiving non-lapatinib 
HER2 targeted therapy 
Source Document + Date last treatment: 
_____________________ 
 
 
Patient receiving or planning to receive trastuzumab, 
trastuzumab with pertuzumab or T-DM1- ado-trastuzumab 
emtansine, for at least 3 months, alone or in combination with 
other systemic treatment or radiation 
HER2 treatment plan (drug): ____________________ 
 
 
Age ≥ 18 years 
DOB: ____________ 
 
 
 
Patient is willing and able to comply with protocol required 
assessments and procedures 
 
 
 
 
 
 
Page:  
1 of 2 
Investigator’s Signature: 
Date 
           
 
Date form completed: 
 
Institution Code: 
Patient ID: 
Patient Initials/Name:    
 
Case Report Form 
Washington Cancer Institute 
Clinical Research 
63 


 
 
Appendix J: Eligibility Checklist (pg2) 
Eligibility Checklist: Exclusion Criteria (prior to screening 
procedures) 
 
 
 
Yes 
No 
Previous hospitalization due to documented heart failure in the 
last 12 months 
Source document + Date: ____________________ 
 
 
Current signs or symptoms of HF or ischemia 
Source Document + Date: _____________________ 
 
 
 
History of arrhythmia requiring pharmacological or electrical 
treatment 
Source Document + Date: ______________________ 
 
 
Concomitant use of anthracyclines or use of anthracyclines in 
the last 50 days 
Last date of anthracycline use: _________________  
 
 
History of significant neurologic or psychiatric disorders 
including psychotic disorders or dementia that would prohibit 
the understanding and giving of informed consent.  
 
 
 
 
ELIGIBILITY DETERMINATION: 
 
Is patient eligible based on above inclusion and exclusion criteria to sign informed 
consent? 
Yes □       No □ 
 
_________________________________________ 
 
 
______________________ 
     (Physician Verification) 
 
 
 
 
 
 
(Date)  
 
 
_________________________________________ 
 
 
______________________ 
     (Enrolling Coordinator Signature) 
 
 
 
 
 
(Date)  
 
Note: Final eligibility will be determined after screening procedures are performed. 
Participants who do not meet screening criteria will be screen failures and will not be 
enrolled 
 
 
 
 
 
 
 
Page:  
2 of 2 
Investigator’s Signature: 
Date 
64 


 
 
 
 
 
 
 
 
 
 
 
Appendix K: Eligibility Procedures for Enrollment 
Inclusion Criteria 
 
Yes 
No 
Confirmed baseline LVEF < 50% and ≥ 40% (by Core 
Lab) 
 
 
 
 
Exclusion Criteria 
 
Yes 
No 
Presence of treatable and reversible HF cause as 
assessed by study cardiologist 
 
 
Presence of ischemia (as assessed by study 
cardiologist) 
 
 
Pregnant or lactating patients. (Patients of childbearing 
potential must implement contraceptive measures 
during study treatment and for 7 months after the last 
dose of the study drug and must have negative urine or 
serum pregnancy test within 21 days after signing initial 
consent). 
Urine/Serum pregnancy test date: _______ 
Result: Positive or negative 
 
 
 
FINAL ELIGIBILITY DETERMINATION: 
 
Is patient eligible based on above screening criteria for study enrollment? 
Yes □       No □ 
 
 
_________________________________________ 
 
 
______________________ 
     (Cardiologist Verification) 
 
 
 
 
 
 
(Date)  
 
 
_________________________________________ 
 
 
______________________ 
     (Enrolling Coordinator Signature)  
 
 
 
 
(Date)  
Page:  
1 of 1 
Investigator’s Signature: 
Date 
           
 
Date form completed: 
 
Institution Code: 
Patient ID: 
Patient Initials/Name:    
 
Case Report Form 
Washington Cancer Institute 
Clinical Research 
65 


 
 
 
 
 
 
 
 
 
 
Appendix L: Study Requirements (to be filled by research 
coordinator): 
 
Pre-enrollment Evaluation: 
 Informed Consent 
 Complete history and physical 
examination 
 Cardiac questionnaire 
 Study echocardiogram read by the Core 
lab 
 Pregnancy test 
 Exercise stress testing (if deemed 
appropriate by study cardiologist) 
 EKG 
Troponin I, hs-tropo, research sample 
 
 
 
Initial cardiac assessment: (Day 1 +/- 7 days) 
 hs-cTnT, research blood sample 
 6 minute walk test 
 Initiation of cardiac medications 
 Provide Blood pressure cuff and BP diary  
 Provide Education on exercise and low salt diet 
 
 
Follow up cardiac assessment #1: 
 
 Complete history and physical examination 
 
 Cardiac questionnaire 
 
 Troponin I, hs-cTnT, research blood sample 
 
 Study echocardiogram read by the Core lab 
 
 Review BP diary 
 
Follow up cardiac assessment #2: 
 
 Complete history and physical examination 
 
 Cardiac questionnaire 
 
 Troponin I, hs-cTnT, research blood sample 
 
 Study echocardiogram read by the Core lab 
 
 Review BP diary 
 
 
Page:  
1 of 2 
Investigator’s Signature: 
Date 
           
 
Date form completed: 
 
Institution Code: 
Patient ID: 
Patient Initials/Name:    
 
Case Report Form 
Washington Cancer Institute 
Clinical Research 
66 


 
 
Appendix L: Study Requirements (pg2) 
 
Follow up cardiac assessment #3: 
 
 Complete history and physical examination 
 
 Cardiac questionnaire 
 
 Troponin I, hs-cTnT, research blood sample 
 
 Study echocardiogram read by the Core lab 
 
 Review BP diary 
 
Follow up cardiac assessment #4: 
 
 Complete history and physical examination 
 
 Cardiac questionnaire 
 
 Troponin I, hs-cTnT, research blood sample 
 
 Study echocardiogram read by the Core lab 
 
 Review BP diary 
 
Follow up cardiac assessment #5: 
 
 Complete history and physical examination 
 
 Cardiac questionnaire 
 
 Troponin I, hs-cTnT, research blood sample 
 
 Study echocardiogram read by the Core lab 
 
 Review BP diary 
 
Follow up cardiac assessment #6: 
 
 Complete history and physical examination 
 
 Cardiac questionnaire 
 
 Troponin I, hs-cTnT, research blood sample 
 
 Study echocardiogram read by the Core lab 
 
 Review BP diary 
 
Off-Study/Post-Study evaluation (within 30 days of the patient’s end of treatment 
determination): 
 
 Complete history and physical examination 
 
 Troponin, hs-cTnT, research blood sample 
 
 Study echocardiogram read by the Core lab 
 
Follow up visit 6 months after being off study: 
 
 Complete history and physical examination 
 
 Study echocardiogram read by the Core lab 
Troponin I, hs-cTnT, research blood sample 
 
 
 
 
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Appendix N: Enrollment information  
Sex:
Male
Date of Birth:
Age:
Female
Enrollment date
       /       /       
Race:
White
Ethnicity:
Hispanic or Latino
Black or African American
Non-Hispanic
Asian
Unknown
Native Hawaiian/Pacific Islander
American Indian or Alaskan Native
Other
More than one
Registration Institution:
Zip Code: 
Demographics
     /      /            
(MM/DD/YYYY)
(MM/DD/YYYY)
 
Stage at diagnosis:
Stage I
Stage III
Date of Original Diagnosis:
Stage II
Stage IV
      /      /          
(MM/DD/ YYYY)
Indication for treatment:
Adjuvant
Locally advanced unresectable disease
Neoadjuvant
Metastatic
Planned oncologic therapy:
________ months (adjuvant or neoadjuvant setting)
until disease progression (locally advanced or metastatic disease)
ECOG Performance Status:
0
1
Date Informed Consent:       /       /             
(MM/DD/YYYY)
Informed Conset
Disease Information
 
 
 
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Clinical Research 
68 


 
 
 
  
 
Appendix N: Prior Hormonal Therapy & Chemotherapy 
 
Neoadj
    /     /        
    /     /        
Adj
(MM/DD/YYYY)
(MM/DD/YYYY)
Met
Completed Treatment
Progression
Toxicity/Side Effects/Complications
Complete Response
Maximum Benefit (for Neoadjuvant or adjuvant therapy)
Other: 
Neoadj
    /     /        
    /     /        
Adj
(MM/DD/YYYY)
(MM/DD/YYYY)
Met
Completed Treatment
Progression
Toxicity/Side Effects/Complications
Complete Response
Maximum Benefit (for Neoadjuvant or adjuvant therapy)
Other: 
Note: if patient received > 2 prior regimens, this form can be copied and filled out again.
Date of First 
Dose
Dose & 
Schedule
Agents
Date of Last 
Dose
Reason for Discontinuation:
Toxicities:
Cycle 
Length
Number 
of cycles
Reason for Discontinuation:
Toxicities:
Regimen 
Number
Date of First 
Dose
Date of Last 
Dose
Agents
Dose & 
Schedule
Change of Therapy (despite not meeting criteria for progressive 
disease nor experiencing unacceptable tox.)
Change of Therapy (despite not meeting criteria for progressive 
disease nor experiencing unacceptable tox.)
Cycle 
Length
Number 
of cycles
Regimen 
Number
 
 
  
 
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69 


 
 
 
 
 
 
Appendix O: Prior Radiation Treatment 
 
Has patient received prior radiation treatment:
Yes
No
 
Gy
 
Gy
Gy
Gy
Gy
    /    /       
5
    /    /       
4
    /    /       
3
    /    /       
Total dose
1
Last Dose
Site (Laterality, areas involved)
    /    /       
    /    /       
Prior Radiation
No.
First Dose
2
    /    /       
    /    /       
    /    /       
    /    /       
 
  
 
 
 
 
 
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70 


 
 
 
 
 
 
 
 
 
 
Appendix P: Prior Breast Surgical History: 
 
Has patient received prior surgical treatment: 
 Yes         
 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Institution Code: 
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71 


 
 
 
 
 
 
 
 
 
 
 
Appendix Q: Laboratory data (to be filled by research coordinator) 
 
 
 
Unit 
Initial 
Visit 
__/__/__ 
Cycle #1 
__/__/__ 
Cycle #2 
__/__/__ 
Cycle 
#3 
__/__/_ 
Cycle 
#4 
__/__/_ 
Cycle 
#5 
__/__/_ 
Cycle 
#6 
__/__/_ 
Off 
Study 
__/__/__ 
F/u at 
6m 
__/__/__ 
CMP 
Glucose 
mg/dL 
 
 
 
 
 
 
 
 
 
BUN 
mg/dL 
 
 
 
 
 
 
 
 
 
Creatinine 
mg/dL 
 
 
 
 
 
 
 
 
 
Sodium 
Mmol/l 
 
 
 
 
 
 
 
 
 
Potassium 
Mmol/l 
 
 
 
 
 
 
 
 
 
Chloride 
Mmol/l 
 
 
 
 
 
 
 
 
 
Calcium 
mg/dL 
 
 
 
 
 
 
 
 
 
Magnesium 
mg/dL 
 
 
 
 
 
 
 
 
 
Phosphorus 
mg/dL 
 
 
 
 
 
 
 
 
 
CO2 
Mmol/l 
 
 
 
 
 
 
 
 
 
Alk. Phos 
Lu/l 
 
 
 
 
 
 
 
 
 
AST 
Lu/l 
 
 
 
 
 
 
 
 
 
ALT 
Lu/l 
 
 
 
 
 
 
 
 
 
Protein Ttl 
Gm/dL 
 
 
 
 
 
 
 
 
 
Albumin 
Gm/dL 
 
 
 
 
 
 
 
 
 
Total Bili 
Gm/dL 
 
 
 
 
 
 
 
 
 
Cardiac work-up 
Troponin I 
Ng/mL 
 
 
 
 
 
 
 
 
 
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72 


 
 
Appendix Q: Laboratory data (pg 2) 
BNP 
ng/L 
 
 
 
 
 
 
 
 
 
TSH/fT4 
mU/l/ng/dL 
 
 
 
 
 
 
 
 
 
Hemoglobin 
A1c 
% 
 
 
 
 
 
 
 
 
 
Serum free 
ferritin 
ng/mL 
 
 
 
 
 
 
 
 
 
Total 
Cholesterol 
Mg/dL 
 
 
 
 
 
 
 
 
 
LDL/HDL 
Cholesterol 
Mg/dL 
 
 
 
 
 
 
 
 
 
Triglycerides 
Mg/dL 
 
 
 
 
 
 
 
 
 
CBC 
BWC 
K/uL 
 
 
 
 
 
 
 
 
 
RBC 
M/uL 
 
 
 
 
 
 
 
 
 
HGB 
Gm/dL 
 
 
 
 
 
 
 
 
 
HCT 
% 
 
 
 
 
 
 
 
 
 
Platelet 
count 
K/mm3 
 
 
 
 
 
 
 
 
 
Neutrophils 
Abs 
K/uL 
 
 
 
 
 
 
 
 
 
Lymphocyte 
Abs 
K/uL 
 
 
 
 
 
 
 
 
 
Monocyte 
Abs 
K/uL 
 
 
 
 
 
 
 
 
 
Eosinophil 
K/uL 
 
 
 
 
 
 
 
 
 
Basophil Abs 
K/uL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Date 
           
 
Date form completed: 
 
Institution Code: 
Patient ID: 
Patient Initials/Name:    
 
Case Report Form 
Washington Cancer Institute 
Clinical Research 
R
74 


 
 
 
 
 
 
 
 
 
 
Appendix S: Blood Pressure Daily Log  
 
Date 
(MM/DD/YY) 
Did you 
take your 
medicine 
Blood 
pressure 
Symptoms (List the number showing the severity of the 
symptoms)  0= None  1=Mild  2=Moderate  3=Severe 
None 
today 
Shortness 
of breath 
Tiredness 
Fainting 
Dizziness 
Any others 
(please 
specify) 
 
__/__/__ 
 
Y N 
 
___/___ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
Y N 
 
___/___ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
Y N 
 
___/___ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
Y N 
 
___/___ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
Y N 
 
___/__ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
 
Y N 
 
___/__ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
 
Y N 
 
___/__ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
 
Y N 
 
___/__ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
 
Y N 
 
___/__ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
 
__/__/__ 
 
 
Y N 
 
___/__ 
Y N 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
Y N 
___ (0-3) 
 
__________ 
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Clinical Research 
75 


 
 
 
 
 
 
 
 
 
 
Appendix T: Off Study Summary  
 
Date of Off Study: ___/___/_____ 
                              (MM/DD/YYYY) 
 
Off Study Summary: 
Reason for off Study: (Choose appropriate box) 
 
  Lost to Follow-up (Date last Known Alive: ___/___/_____ 
                                                                       (MM/DD/YYYY) 
  Completion of planned course of HER2 Targeted Therapy 
 
  Cardiac events that preclude further HER2 directed treatment 
 
  Patient voluntarily withdraws from treatment (follow-up permitted) 
 
  Patient is unable to comply with protocol requirements 
 
  Patient withdraws consent (termination of treatment and follow-up) 
 
  HER2 therapy on hold for > 9 weeks due to non-cardiac causes 
 
  Disease Progression with change in treatment regimen 
 
 
  End of Study 
 
  Treating physician 
decision 
  Patient becomes 
preganant 
 
  Protocol Violation 
 
During treatment, and documented: 
 
Dates 
(MM/DD/YYYY) 
  Cardiac event criteria 
 
___/___/____ 
 
  Asymptomatic worsening of cardiac function 
 
___/___/____ 
 
  Symptoms of HF 
 
___/___/____ 
 
  Cardiac arrhythmia requiring pharmacological or electrical treatment 
___/___/____ 
 
  Hospitalization due to a cardiac cause 
___/___/____ 
 
  Sudden cardiac death or death due to MI, arrhythmia or HF 
___/___/____ 
 
 
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Appendix U: Death Summary 
 
     Date of Last Follow up:
      /       /          
Date of death: 
(MM/DD/YYYY)
List any further treatments:
Has subject developed a new primary cancer? 
Yes
No
If Yes, Diagnosis:
Date:       /      /            
(MM/DD/YYYY)
Cause of Death: (Check appropriate box)
Malignant Disease
Toxicity from Protocol Treatment
Infection
Other:
Autopsy?
Yes
No
Cause of Death at Autopsy: (Check appropriate box)
Malignant Disease
Toxicity from Protocol Treatment
Infection
Other:
Site of Disease at Autopsy:
NOTE: If patient dies within 30 days of off-study, an SAE must be filed.
Assess for any unresolved toxicities at that time.
 
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Appendix V: Exercise and chronic disease (info for patients) 
 
78 


 
 
 
 
 
 
 
79 


 
 
Appendix W: Exercise: Finding Activities That Work for You 
 
 
 
 
 
 
 
 
 
80 


 
 
Appendix W: Exercise: Finding Activities That Work for You (pg 2) 
 
 
 
 
 
81 


 
 
Appendix X: Low salt diet (info for  patients) 
 
82 


 
 
83 


 
 
Appendix Y: Schedule of Events 
 
A. Protocol specific procedures should be completed within 30 days after signing informed consent. Clinical 
assessments used for meeting screening eligibility can be used if done w/in 30 days prior to signing informed 
consent 
B. Once enrollment has occurred, all visits/assessments should occur +/- 10 days  of scheduled date. 
C. Collection of hs Troponin for central laboratory. Refer to section 8.0 for shipping instructions. 
D. Provide patient with blood pressure cuff and provide instructions for blood pressure monitoring and recording 
throughout study treatment.  Please refer to section 6.2.1. 
E. Patient will initiate appropriate cardiac therapy as assigned by cardiologist. If a patient is already on a BB or 
ACE inhibitor they will be uptitrated to the maximum tolerated dose. Please refer to section 6.2.1. Please refer to 
page 18 fig 3 for more detailed instructions regarding titration of cardiac medications. 
F. Oncology visit is mandatory at screening and Off Study. All other visits should be scheduled according to 
standard of  care. These will not be research visits. 
G. HER2 targeted therapy should begin within 3 weeks of enrollment and continued on Q 1-3 weeks according to 
treating oncologist.  
H. Off Study  visit should occur within 30 days after last treatment or unacceptable toxicity, symptomatic cardiac 
disease, or ECHO has met hold criteria.  
I. 
Research will arrange for the visit/test and will cover the costs. Research will cover Week 1 drug, but not drug 
administration.  
J. 
All echocardiograms need to be completed at least 2 days prior to the next HER2 targeted therapy  
K. Treatment will be assessed starting with weeks.  In the event of treatment delays, time will be counted according 
to the administration of HER2 targeted therapy  so that cardiac assessments (echocardiogram, cardiology visit 
and blood samples) are done in accordance with this  administration. Echocardiograms sent to the Core lab need 
to be labeled according to the weeks on HER2 therapy. 
L. The exercise stress test will be performed only if deemed appropriate by the treating study cardiologist 
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Appendix Z: Oncological therapy while on study  
Cycle # 
Date 
(MM/DD/YY) 
HER2 targeted therapy 
Dose 
Endocrine 
therapy 
Chemotherapy 
Radiation 
(local, 
dose) 
Cycle #____ 
__/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
 
Cycle #____ 
__/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
 
Cycle #____ 
__/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
 
Cycle #___ 
___/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
Cycle #____ 
__/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
Cycle #____ 
__/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
 
Cycle #___ 
___/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
 
Cycle #___ 
___/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
Cycle #____ 
__/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
Cycle #____ 
__/__/__ 
Trastuzumab  
Tras/Pertuzumab  
Ado-trastuzumab emtansine  
 
 
 
 
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Appendix AA: Specimen Form 
 
Treating Institution: _____________________________           Date: ___ / ____ / ____ 
 
Shipping Institution to fill out (please copy for your records) 
Patient Study ID# ___________    Study Site ID: (circle)  WCI / GT 
Study Time point: ___________________  
Date/Time drawn: ___ /___ / ___ Time: ___ : ___ 
1. STORAGE SAMPLES:    
BL ONLY: (PRPL) PLASMA:                   Type of Tubes ______ # of Tubes ________ 
BL ONLY: (PRPL) BUFFY COAT            Type of Tubes ______ # of Tubes ________ 
ALL VISITS:(RED) SERUM                     Type of Tubes ______ # of Tubes ________ 
 2. HS-TROPONIN: Type of Tubes ______ # of Tubes ________ 
Form completed by: _________________________ Email/Phone Number: _______________ 
Signature: _________________________ 
 
FEDEX Tracking Number___________________________________ 
Date/Time Shipped: ___ /___ / ___ Time: ___ : ___ 
 
 
 
 
 
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Appendix AA: Specimen Form (pg2) 
 
Receiving Institution to fill out  
Date Received in Lab: ___ /____ / ____ 
Type of Tubes ______ # of Tubes ________   Study ID # __________________ 
Received in good condition   
   
Not received in good condition. Explain: 
____________________________________________________ 
Received by: _________________________  
PLEASE RETAIN A COPY OF THIS FORM IN THE PATIENT’S STUDY BINDER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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