Clinical trial NCT01009918
Conditions: Breast Cancer Cardiac Toxicity
Keywords: cardiac toxicity HER2-positive breast cancer recurrent breast cancer stage IA breast cancer stage IB breast cancer stage II breast cancer stage IIIA breast cancer stage IIIB breast cancer stage IIIC breast cancer male breast cancer
Sponsor: University of South Florida
Start date: 2010-03-01; Completion date: 2018-11-01
Enrollment: 468 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Lisinopril or Coreg CR®, may help reduce side effects caused by trastuzumab. It is not yet known whether lisinopril or Coreg CR® are more effective than a placebo in reducing side effects caused by trastuzumab.

PURPOSE: This phase II trial is studying lisinopril and Coreg CR® to see how well they work compared with a placebo in reducing side effects in patients with HER2-positive breast cancer receiving trastuzumab.

Detailed description:
OBJECTIVES:

Primary

* The primary objective of this study is to determine if administration of lisinopril or Coreg CR®, compared to placebo, will reduce the incidence of trastuzumab-induced cardiotoxicity, as measured by LVEF, in patients receiving adjuvant, or neoadjuvant,therapy for HER2 positive breast cancer.

Secondary

* To determine whether subjects randomized to active agent have fewer interruptions in trastuzumab therapy due to cardiomyopathy.
* To determine whether the treatment effect is consistent in anthracycline and nonanthracycline patient cohorts
* To compare changes in HRQL among the treatment groups during the study intervention
* To evaluate the long term effects on the prevention of cardiomyopathy and impact on HRQL for either or both study agents
* To compare the predictive value of troponin I and BNP in the identification of trastuzumab-induced cardiotoxicity

OUTLINE: This is a multicenter study. Patients are stratified according to chemotherapy comprising an anthracycline (yes vs no). Patients are randomized to 1 of 3 treatment arms.

* Arm I: Patients receive oral lisinopril once daily.
* Arm II: Patients receive oral Coreg CR® once daily.
* Arm III: Patients receive oral placebo once daily.

In all arms, study treatment begins with the first dose of trastuzumab and continues for up to 52 weeks or until the end of trastuzumab therapy.

Quality of life is assessed using the EORTC QLQ-C30 questionnaire at baseline, at 52 weeks (or at the end of trastuzumab therapy), and at 18 and 24 months (or 6 and 12 months after the completion of trastuzumab).

After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months.

Arms: arm 1: Patients receive oral lisinopril once daily. arm 2: Patients receive oral Coreg CR® once daily. arm 3: Patients receive oral placebo once daily.
Interventions: intervention 1: Coreg CR® intervention 2: lisinopril intervention 3: placebo
Intervention descriptions: intervention 1: Given orally intervention 2: Given orally intervention 3: Given orally

Protocol documents:
Prot_SAP_000.pdf: 
SCUSF 0806  
Protocol Act V6.0 August 31, 2012 
(Amendment #5) 
 
 
 
 
Telephone: 
800-909-1242  
Fax: 
813-910-5998 
Email: 
ccop@epi.usf.edu  
Website: 
http://www.SunCoastccop.org  
 
 
 
SCUSF 0806 “Phase II placebo-controlled trial of lisinopril and Coreg CR® to 
reduce cardiotoxicity in patients with breast cancer receiving (neo)adjuvant 
chemotherapy with trastuzumab (Herceptin®)”   
 
 
NCT #: 01009918 
 
Cancer Control Credit:  1.0 
 
 
Study Chair (Cardiology):     
           Maya Guglin, M.D., Ph.D. 
 
Associate Professor of Medicine 
 
Director - Heart Failure Program 
 
University of South Florida 
 
4 Columbia Dr., Suite 725 
 
Tampa, FL 33606  
 
Phone: 813-259-0600 
 
Fax: 813-259-0640 
 
Email: mguglin@health.usf.edu 
 
 
Study Co-Chair (Medical Oncology): 
Pamela Munster, M.D. 
Associate Professor of Medicine 
Associate Director of Investigational 
Therapeutics 
Helen Diller Family Comprehensive Cancer 
Center 
University of California San Francisco 
1600 Divisadero, Room 722 
San Francisco, CA 94143 
Phone: 415-476-1000 
 
 Email: Pmunster@medicine.ucsf.edu 
 
 
 
Participating Institutions: 
 
All CCOP/MBCCOPs may participate 
 
SunCoast CCOP Research Base Affiliates 
 
CTSU Affiliated Institutions 
 
 
 
 
Activation Date:  March 01, 2010 
 
 
Amendment #1: September 24, 2010 
 
 
Amendment #2: October 08, 2010 
 
 
Amendment #3: November 19, 2010 
 
 
Amendment #4: June 3, 2011 
 
 
Amendment #5: August 31, 2012 
 
 
 
(See next page)
09/24/2010 
11/19/2010 
08/31/2012 


SCUSF 0806  
Protocol Act V6.0 August 31, 2012 
(Amendment #5) 
 
 
 
 
Amendment #1:  September 24, 2010 
Name changed from Moffitt CCOP Research  
 
Base to SunCoast CCOP Research Base,  Added 
 
logo and toll free number.  All changes made 
 
throughout protocol. 
 
Amendment #2:  October 08, 2010  
Standardize title, pt schedule to 13 weeks +/- 
 
(3 months) [protocol, App I ICF, App III Data Forms], 
 
new co-investigator, added Refill study agent 
 
directions (4.15), added Medication Order Form – Site 
 
Stock  (table of contents, 4.6.8, 6.5.2.4, Appendix 
 
III), added LVEF Reimbursement Form (App III Data 
 
Collection Forms), added Refill Worksheet & sample 
 
email App II IVR), added FDA IND Exemption letter & 
 
Herceptin® prescribing information (Appendix IV), 
 
CTCAE V4.0 (8.7, 8.9, App III),  administrative 
 
clarifications & formatting (4.6.2, 4.6.3, 4.6.10, 4.7.2, 
 
4.8.1, 4.10.3, 5.65, 5.68.1, 6.1, 6.5.2, 9.1, 9.2, all 
 
appendices  
  
Amendment #3:  November 19, 2010 
Added participation through CTSU: cover, TOC., 
 
CTSU support page, , §,4.0, 6.5.1, 6.5.4.2, App 1-ICF, 
 
App II-IVR, App III-Data forms, updated LVEF 6.5.1. 
 
administrative 4.8.2. 
 
 
Amendment #4:  June 3, 2011 
Added troponin I (biomarker) [schema, §,2.10, 3.2.4, 
6.1,  6.5.4, 10.8, and App III-Data forms]; Clarified 
patient schedule of events [protocol, App I ICF, App III 
Data Forms]; requesting de-identified ECHO results 
submitted for central review [§ 6.1, 6.5.7, 9.2, App III 
Data Forms]
 
Amendment #5:  August 31, 2012 
Includes males (§2.12.1, §4.8.8); Stratified based 
on chemotherapy regimen - with/without an 
anthracycline (schema, §2.9.8, §3.2.2); 
Pertuzumab allowed in chemo regimen (§4.8.2); 
Use of ARBs, such as losartan, now allowed 
(§4.9.4); No metastatic disease (§4.9.1); 
Chemistry profile is a non-fasting sample (schema, 
§2.10, §6.8.4); Expanded study plan tables (§6.1-
6.4); Examples of MUGA scan/ECHO calculations 
for study failure (§7.1, §7.2); Revised reportable 
adverse events (§8.0); Process of payment for 
LVEF testing not considered standard of care 
(§12.9). Revised ICF (Appendix I). 


 
 
SCUSF 0806  
Protocol Act V6.0 August 31, 2012 
(Amendment #5) 
 
 
 
 
CONTACTS 
 
Co-Investigator(s):   
 
 
Rebecca Sutphen, MD 
 
 
Scientific Director 
 
 
SunCoast CCOP Research Base 
 
 
at the University of South Florida 
 
 
Pediatrics Epidemiology Center 
 
 
3650 Spectrum Boulevard, Suite 100 
 
 
Tampa, FL  33612 
 
 
Email: 
ccop@epi.usf.edu  
 
 
Phone: 
800-909-1242 
 
 
Fax: 
813-910-5998 
 
 
Biostatistician:  
 
Roy Tamura, Ph.D. 
Associate Professor, University of South Florida  
SunCoast CCOP Research Base  
At the University of South Florida  
3650 Spectrum Blvd  
Suite 100  
Tampa, Florida 33612  
Phone: (813)-396-9548  
Fax: (813) 910-5998  
Email: roy.tamura@epi.usf.edu  
 
 
  
Protocol Coordinator: 
 
Viki Huegel, BA, CCRP 
Research Base Coordinator 
SunCoast CCOP Research Base 
At the University of South Florida 
Pediatrics Epidemiology Center 
3650 Spectrum Boulevard 
Suite 100 
Tampa, FL  33612 
Email:  
Viki.Huegel@epi.usf.edu   
Phone:  
813-396-9503 
Fax:  
813-910-5998 
 
SunCoast CCOP Research Base Operations Center: 
Email: 
CCOP@epi.usf.edu 
Phone: 
800-909-1242 
Cell:  
813-476-9518 
Fax: 
813-910-5998 
 
10/08/2010 
08/31/2012 


 
 SCUSF 0806  
Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
 
 
 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Institutions not aligned with the SunCoast (SCUSF) CCOP Research Base will 
participate through the CTSU mechanism as outlined below and detailed in the 
CTSU logistical appendix (Appendix VIII). 
 
• 
The study protocol and all related forms and documents must be downloaded from the 
protocol-specific Web page of the members’ section of the CTSU Web site located at 
www.ctsu.org. 
 
• 
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU 
logistical appendix for specific instructions and documents to be submitted.  
 
• 
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for 
specific instructions and forms to be submitted. 
 
• 
Data management will be performed by the SCUSF CCOP Research Base Data Management 
Center (DMC). Case report forms (with the exception of patient enrollment forms), signed 
consents, clinical reports, symptom/ medication diaries, quality of life questionnaires, and 
transmittals must be sent via mail or fax to the SCUSF CCOP Research Base DMC unless 
otherwise directed by the protocol. Your institution’s standard fax transmittal cover sheet should 
accompany all data submissions. Do not send study data or case report forms to CTSU Data 
Operations.  
 
• 
Data query and delinquency reports will be sent directly to the enrolling site by SCUSF CCOP 
Research Base DMC. Please send query responses and delinquent data to SCUSF CCOP 
Research Base DMC and do not copy the CTSU Data Operations. Each site should have a 
designated CTSU Administrator and Data Administrator and must keep their CTEP IAM account 
contact information current. This will ensure timely communication between the clinical site and 
the SCUSF CCOP Research Base DMC. 
  
11/19/2010 


 
 SCUSF 0806  
Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
 
 
11/19/2010 
 
CANCER TRIALS SUPPORT UNIT (CTSU)  
CONTACT INFORMATION FOR SCUSF-0806 
 
 
 
 
To submit site registration 
documents: 
For patient enrollments:  
 
Submit study data  directly to 
SunCoast CCOP Research Base 
unless otherwise specified in the 
protocol:  
CTSU Regulatory Office 
1818 Market Street,  
Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email:  
CTSURegulatory@ctsu.coccg.org 
 
CTSU Patient Registration 
Voice Mail – 1-888-462-3009 
Fax – 1-888-691-8039  
Hours: 9:00 AM – 5:30 PM 
Eastern Time, Monday – Friday 
(excluding holidays) 
 
[Registrations received after 5:00 
PM ET will be handled the next 
business day. For CTSU patient 
enrollments that must be 
completed within approximately 
one hour, or other extenuating 
circumstances, call 301-704-2376 
between 9:00 am and 5:30 pm.] 
SCUSF CCOP Research Base 
Operations Center: 
 
FAX: 813-910-5998 
 
Do not submit study data or forms 
to CTSU Data Operations. Do not 
copy the CTSU on data 
submissions.   
For patient eligibility or treatment-related questions contact Viki Huegel by phone or by email: 
1-813-396-9503, or Viki.Huegel@epi.usf.edu. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at: www.ctsu.org.  
CTSU logistical information is located in Appendix VIII. 
 


 
 SCUSF 0806  
Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
 
 
Appendix VIII 
CTSU Logistics
 
TABLE OF CONTENTS 
 
Schema 
 
 
1.0 
Introduction 
 
 
2.0 
Background and Significance 
 
 
3.0 
Objectives    
 
 
4.0 
Regulatory / Subject Selection  
 
 
5.0 
Study Agent Information  
 
 
6.0 
Study Plan 
 
 
7.0 
Treatment Response Assessment 
 
 
8.0 
Toxicity Assessment and Adverse Event Reporting 
 
 
9.0 
Records to be Kept / Data Collection Forms Submission Guidelines  
 
 
10.0 
Statistical Considerations 
 
 
11.0 
Data Safety and Monitoring 
 
 
12.0 
Study Feasibility 
 
 
13.0 
References 
 
 
Appendix I 
Sample Informed Consent 
 
 
Appendix II 
Registration & Randomization 
 
 
Appendix III 
Data Collection Forms: 
 
 
Intent to Participate Form 
 
 
Eligibility Form 
 
 
On-Study Form 
 
Patient Assessment Form 
 
Follow-up Form 
 
 
 
Medication Order Form 
 
Medication Order Form – Site Stock 
 
 
Concomitant Medications Form 
 
European Organization for Research and Treatment for Cancer’s Quality of Life 
Questionnaire (EORTC QLQ-C30)  
 
 
Study Medicine Daily Log 
 
 
Off Study Form 
 
 
Study Agent Accountability Record  
 
Adverse Events Form 
 
 
MedWatch Adverse Event Report 
 
LVEF Reimbursement Form 
 
 
Appendix IV 
Drug Information 
 
FDA IND 102825 Exemption Letter for Study Agents 
 
 
Study Agent:  Lisinopril 
 
 
Study Agent:  Coreg CR®  
 
Herceptin® 
 
 
Appendix V 
Reportable Concomitant Medications 
 
 
Appendix VI  
Laboratory Submission Guidelines 
 
Appendix VII 
Recruitment Materials 
10/08/2010 
10/08/2010 


 
 SCUSF 0806  
Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
 
 
Schema 
This Phase II placebo-controlled study will enroll 468 subjects to evaluate the effect of lisinopril or Coreg 
CR®, compared to placebo, on trastuzumab-induced cardiotoxicity in patients with breast cancer who are 
receiving adjuvant or neoadjuvant therapy.   The study will enroll to 2 separate cohorts; patients who 
received an anthracycline-containing regimen and patients whose treatment regimen did not contain an 
anthracycline. Should accrual to a cohort reach 281, that cohort will be closed to new accrual and the 
study will be completed with accrual to the remaining cohort.  Study agent will be administered daily for 
52 weeks OR until the end of trastuzumab therapy, if it is discontinued prior to week 52.  Primary 
response, change in LVEF, will be evaluated at baseline, every 3 months X 4 while on trastuzumab 
therapy, then at study months18 and 24 (or 6 and 12 months after last dose of trastuzumab).  Study 
failure is defined as an absolute decrease ≥ 10% in LVEF at study follow-up OR an absolute decrease ≥ 
5% in LVEF if it is < 50% at study follow-up. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completes 52 weeks of 
randomized study agent  
while receiving trastuzumab 
Informed Consent, Eligibility Screening and Registration (Call 1-866-835-6793) 
Conduct Baseline Assessments: 
• 
Measure ejection fraction (measurements within 6 weeks of study entry can be used) 
• 
Collect demographic data  
• 
Obtain medical history & perform physical exam (including height and weight) 
• 
Collect and send blood samples to LabCorp (non-fasting CMP, BNP and troponin I)  
• 
Administer EORTC Quality of Life Questionnaire  
lisinopril 10mg 
Coreg CR® 10 mg 
Placebo 
Does not complete 52 weeks (e.g. 
study failure or trastuzumab D/C 
before study week 52)  
Follow-up at study months 15 and 21  
 Disease status and review of concomitant medications only 
Follow-up 6 and 12 months after ending trastuzumab 
• 
Measure ejection fraction 
• 
Physical exam, including height and weight 
• 
Blood samples to LabCorp (non-fasting CMP, BNP 
troponin I) 
• 
Symptom assessment  
• 
EORTC Quality of Life Questionnaire 
Study Week 52  
• 
Discontinue study agent 
• 
Measure ejection fraction 
• 
Physical exam, including height and weight 
• 
Blood samples to LabCorp (non-fasting CMP, BNP, 
troponin I)  
• 
Symptom assessment 
• 
EORTC Quality of Life Questionnaire 
Follow-up at study months 18 and 24  
• 
Measure ejection fraction 
• 
Physical exam, including height and weight 
• 
Blood samples to LabCorp (non-fasting CP,BNP, 
troponin I)  
• 
Symptom assessment 
• 
EORTC Quality of Life Questionnaire 
Follow-up approximately every 3 months  
X 4 (+/- 2 weeks) 
• Measure Ejection Fraction 
• PE, including height and weight 
• Blood samples to LabCorp (non-fasting CMP, BNP, 
troponin I) 
• Symptom Assessment 
End of treatment with trastuzumab 
• 
Discontinue study agent 
• 
Measure ejection fraction 
• 
Physical exam, including height and weight 
• 
Blood samples to LabCorp (non-fasting CMP, BNP, 
troponin I)  
• 
Symptom assessment 
• 
EORTC Quality of Life Questionnaire 
Follow-up 3 and 9 months after ending trastuzumab  
 Disease status and review of concomitant medications only 
  Patients will be randomized to: 
Off Study (after completing Study Month 24) 
Off Study (12 months after ending trastuzumab)  
10/08/2010 
10/08/2010 
6/3/2011 
08/31/2012 
08/31/2012 


 
 
SCUSF 0806  
Protocol Act V6.0 August 31, 2012 
(Amendment #5) 
 
 
 
 
 
Glossary of Terms: 
Angiotensin-Converting Enzyme Inhibitor 
 
 
ACE Inhibitor 
B-Type Natriuretic Peptide 
 
 
 
BNP 
Beta Blocker 
 
 
 
 
β-Blocker 
Cancer Therapy Evaluation Program 
 
 
CTEP 
Carvedilol phosphate extended-release 
 
 
Coreg CR® 
Clinical Trials Support Unit 
 
 
 
CTSU 
Common Terminology Criteria and Adverse Events  
 
CTCAE 
Community Clinical Oncology Program 
 
 
CCOP 
Comprehensive Metabolic Panel 
 
 
CMP 
Confidence Intervals 
 
 
 
CI 
Continuous Release 
 
 
 
CR 
Ejection Fraction 
 
 
 
EF 
European Organization for Research and Treatment of Cancer’s Quality of Life  EORTC QLQ-C30  
Extended Release  
 
 
 
ER 
Food and Drug Administration  
 
 
FDA 
Health Insurance Portability and Accountability Act 
 
HIPAA 
Heart Failure   
 
 
 
HF  
Heart Outcomes Prevention Evaluation  
 
 
HOPE 
Human Epidermal Growth Factor -2  
 
 
HER2 
Institutional Review Board 
 
 
 
IRB 
Interactive Voice Response system 
 
 
IVR system 
Investigational New Drug 
 
 
 
IND 
Left Ventricular  
 
 
 
LV 
Left Ventricular Ejection Fraction  
 
 
LVEF  
Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure  
MERIT-HF 
National Cancer Institute 
 
 
 
NCI 
New York Heart Association  
 
 
 
NYHA 
Power 
 
 
 
 
p= 
Private Health Information  
 
 
 
PHI 
Quality of Life  
 
 
 
QOL 
Randomized Evaluation of Strategies for Left Ventricular Dysfunction pilot trial 
RESOLVD 
Relative Risk 
 
 
 
 
RR 
Studies of Left Ventricular Dysfunction  
 
 
SOLVD 
Survival and Ventricular Enlargement  
 
 
SAVE 
Trastuzumab   
 
 
 
Herceptin® 
Troponin I 
 
 
 
 
TnI 
 
 
 
11/19/2010 
6/3/2011 


 
 SCUSF 0806  
Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 1 of 32 
 
1.0 
 Introduction  
1.1 
Chemotherapy-induced cardiotoxicity is a well-established treatment side effect, most 
notably of anthracycline-based treatment regimens. It is also a side effect of trastuzumab 
(Herceptin®), which is now standard in adjuvant treatment regimens for women with 
human epidermal growth factor -2 (HER2) positive breast  cancers.  The projected number 
of women who will have HER2-positive disease and who can benefit from trastuzumab 
therapy, well exceeds 50,000 per year 
1.2 
A decrease in left ventricular ejection fraction (LVEF) has been reported in as many as 28-
34% of women when trastuzumab is combined with standard chemotherapy.1-3  As new 
agents are introduced into clinical practice and treatment outcomes improve, there will be 
more long-term survivors of breast cancer.  As the number of survivors increases, it is 
likely that treatment-induced cardiotoxicity will be more prevalent.  
1.3 
One of the new challenges in oncology and cardiology is safe and effective short and long-
term use of trastuzumab.  In addition to improving progression-free survival in women with                           
metastatic breast cancer that overexpresses HER2, trastuzumab also has been shown to 
reduce the risk of recurrence in the adjuvant setting for early stage breast cancers that are 
HER2-positive.4    
1.4 
Trastuzumab is the prototype of novel targeted molecular chemotherapeutic agents. HER2 
is amplified or overexpressed in up to 30% of breast cancers5 and is also expressed in 
myocardial cells.6  Inhibition of signaling through the myocardial receptor may cause 
cardiotoxicity secondary to disrupted cardiac contractile function and structure6, especially 
in the previously stressed heart; however, the exact mechanism of cardiotoxicity is under 
intense investigation. 
1.5 
While studies have demonstrated improved disease-specific and overall survival in                                       
patients with HER2 overexpressing disease, treated with trastuzumab,5, 7 oncologists 
commonly interrupt or discontinue trastuzumab therapy when there is evidence of 
cardiotoxic changes.  Cardiotoxicity is commonly manifested by an asymptomatic 
decrease in the left ventricular ejection fraction (LVEF) and less commonly by clinical 
heart failure.3  Unlike anthracycline-induced cardiotoxicity, trastuzumab-induced changes 
are not dose-dependent,3 and may be substantially reversible,3,8 despite continuation of 
trastuzumab in the face of cardiotoxic changes or a subsequent drug rechallenge.9  
Endomyocardial biopsies from patients with trastuzumab-induced cardiac dysfunction also 
do not have the typical anthracycline-related ultrastructural changes.10, 11  Evidence has 
suggested that LVEF recovery is evident within six months of discontinuing trastuzumab 
therapy for the majority of patients who demonstrate a decrease in LVEF.12  However, the 
data on long-term sequelae of these changes are still being gathered.   
1.6 
Cardiac side effects of trastuzumab have, like anthracycline therapy, prompted mandatory 
screening practices before and during treatment with trastuzumab.  Evaluation of LVEF is 
the most common screening procedure conducted.                                                                                          
1.7 
Due to the recognition of increased cardiac toxicity observed with anthracyclines and 
trastuzumab combinations, there has been much emphasis on finding alternative 
treatments that will reduce the incidence of cardiotoxicity.  Even with changes in breast 
cancer treatment regimens that may reduce its prevalence, cardiotoxicity will remain a 
concern for oncologists.      
1.8 
Recent studies have demonstrated the effectiveness of angiotensin-converting enzyme 
(ACE) inhibitors and beta blockers (β-blockers) in preventing anthracycline-induced 
cardiotoxicity.13, 14  The majority of patients who develop trastuzumab-induced 
cardiotoxicity respond to standard treatment for chronic heart failure, which usually 
consists of diuretics, ACE inhibitors, β-blockers, cardiac glycosides and other inotropic 
agents.2, 3  Optimal treatment of these patients includes identification of individuals at risk 
for and the prevention of cardiotoxicity, as well as early diagnosis and effective treatment 
of cardiotoxic changes.   


 
 SCUSF 0806  
Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 2 of 32 
 
1.9 
This is a randomized, phase II placebo-controlled trial evaluating the effects of an ACE 
inhibitor (lisinopril) and a β-blocker Coreg CR® on cardiotoxicity in patients with breast 
cancer who are receiving adjuvant trastuzumab. If we can demonstrate that the use of an 
ACE inhibitor or a β-blocker can reduce the degree of trastuzumab-induced cardiotoxicity, 
it is hoped that patients will receive complete and uninterrupted therapy for breast cancer.   
 
2.0 
Background and Significance   
2.1 
The clinical significance of cardiotoxicity associated with trastuzumab is acknowledged as 
a serious concern within the oncology community.  While a recent review reported the 
incidence of trastuzumab-induced cardiotoxicity to range from 6.5% to 34%,2 large 
adjuvant trastuzumab trials (NSABP B-31, BCIRG 006, HERA, NCCTG N9831. FinHER) 
report the incidence to range from 0-17%.15  The variation in incidence within studies is a 
result of inconsistent definitions and measurements of cardiotoxicity.  It also depends on 
whether trastuzumab was used in a treatment or adjuvant setting; with higher incidence in 
patients receiving concurrent anthracycline and cyclophosphamide (AC).  Based on these 
past studies and anecdotal clinical experience, a conservative incidence estimate of 
cardiotoxicity in our study population is approximately 15%.   
2.2 
To further assess trastuzumab-induced cardiotoxicities, the study co-chair (Dr. Guglin, 
Cardiologist) conducted a retrospective study at the H. Lee SunCoast Cancer Center in 
Tampa, Florida in patients receiving trastuzumab therapy for breast cancer in two settings 
(adjuvant n = 118; metastatic n = 38).2  Patients in the adjuvant group receiving 
concomitant cardiac medications, including ACE inhibitors, angiotensin receptor blockers, 
statins, and β-blockers, were more likely to receive uninterrupted trastuzumab therapy (p = 
0.0335), had less change in ejection fraction (p = .0083), and had fewer symptoms of 
heart failure (p = 0.0083).  Adjuvant patients who were receiving these medications for 
hypertension alone had significantly less cardiotoxicity (p = .0063), less change in ejection 
fraction (p = 0.0466), and fewer symptoms of heart failure (p= .0466).  This was less 
evident in patients with one or more co-morbidities aside from hypertension alone (p = 
0.0915).  In the adjuvant group, cardiotoxicity was observed in one-third of patients (n=39) 
evaluated.   Seventeen patients (14.4%) demonstrated a decrease in ejection fraction to < 
50%.  Of these, only seven patients exhibited signs and symptoms of heart 
failure.  Nineteen patients (16.1%) exhibited a decline in ejection fraction by ≥ 10% during 
trastuzumab therapy; however, none of these patients were symptomatic. Three patients 
had signs and symptoms heart failure in the presence of normal systolic function.  Data 
from the metastatic group were less consistent.  Of the 38 patients, 34.2% developed 
cardiotoxicities.  Two of the patients initiated trastuzumab with a baseline EF of 48% and 
30%.   
2.3 
The exact mechanism of trastuzumab-induced cardiotoxicity has yet to be elucidated.  
Several hypotheses have been proposed, including; inhibition of HER2 signaling in cardiac 
tissues, drug-drug interactions, an induction of immune mediated destruction of 
cardiomyocytes, and indirect consequences of trastuzumab-induced affects outside of the 
heart.16-18  In a recent study by Grazette et. al., cultures of neonatal rat ventricular 
myocytes were exposed to anti-erbB2 (HER2) antibody.19  There was a time-dependent 
increase in mitochondrial translocation and oligomerization of Bcl-associated protein, as 
indicated by 1,6-bismaleimidohexane cross linking.  This process was associated with 
cytochrome C release and caspase activation.  These alterations induced mitochondrial 
dysfunction, a loss of mitochondrial membrane potential, a 35% decline in adenosine 
triphosphate levels, and a loss of redox capacity.  Anti-erbB2 activates the mitochondrial 
apoptosis pathway through a modulation of Bcl-xL and -xS, which was previously not 
described, causing impairment of mitochondrial function and integrity, and disruption of 
cellular energetics.  Evidence also supports a direct cardiotoxic effect of HER2 blockade.  
Mice were generated with ventricular-restricted knockout of the HER2 gene.17  These mice 
developed signs of a dilated cardiomyopathy, and their cardiomyocytes showed enhanced 
susceptibility to anthracycline-induced cell death.  Thereby concluding that the signaling 


 
 SCUSF 0806  
Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 3 of 32 
 
cascade associated with HER2 in cardiomyocytes is essential for the prevention of dilated 
cardiomyopathy.  This data provides evidence that the cardiotoxicity induced from 
exposure to trastuzumab is presumably due to its direct effects on the HER2 receptor. 
2.4 
There are strong indicators from existing literature and in related topics that suggests how 
ACE inhibitors and β-blockers might effectively reduce trastuzumab-induced cardiotoxicity.  
2.5 
Angiotensin Converting Enzyme (ACE) Inhibitors: 
2.5.1 
Angiotensin converting enzyme (ACE) inhibitors are a standard therapy for heart 
failure (HF) and asymptomatic left ventricular (LV) systolic dysfunction, 
regardless of etiology.20  Multiple, large, prospective, randomized trials have 
consistently demonstrated a significant reduction in mortality and morbidity after 
therapy with ACE inhibitors.21, 22   Further, the use of ACE inhibitors in the 
treatment of trastuzumab-induced cardiotoxicity was observed in the 
retrospective data collected by the study co-chair with promising results.2  The 
exact mechanism of action in this treatment setting is not clearly understood, but 
several explanations have been suggested.  The primary effect includes the 
limiting of oxidative stress, largely mediated through angiotensin II 
suppression.23  In addition to interrupting the renin-angiotensin system, ACE 
inhibitors also enhance the action of kinins and augments kinin-mediated 
prostaglandin production.24    
2.5.2 
ACE inhibitors are an important class of agents that have multiple benefits in the 
treatment, as well as prevention, of heart failure in susceptible populations.  The 
benefits are a class effect, as the same benefits have been demonstrated in 
many agents of this class.  We chose lisinopril for this study because it has been 
shown to be superior to alternative ACE inhibitors in this regard.25, 26   
2.5.3 
The efficacy of ACE inhibitors in patients with asymptomatic LV dysfunction was 
demonstrated in the SOLVD27 prevention and the SAVE22 trials.  The Studies of 
Left Ventricular Dysfunction (SOLVD) prevention trial included 4,228 patients 
with asymptomatic LV dysfunction with an LVEF ≤ 35%.  The combined 
incidence of symptomatic HF or cardiovascular death was reduced by enalapril 
(30% versus 39% for placebo) and the risk reduction of 29% (95% CI 21% to 36 
%, p < 0.001) was demonstrated with a mean follow-up of just over three years.  
In the XSOLVD, extension of the SOLVD prevention trial, there were significant 
reductions in all-cause mortality (51% versus 56% for placebo, p = 0.001) and 
cardiovascular mortality (37% versus 42% for placebo, p = 0.0008) at 11 years.21 
2.5.4 
The Survival and Ventricular Enlargement (SAVE) trial demonstrated that when 
administered 3 to 16 days after acute myocardial infarction in select patients, 
captopril (an ACE inhibitor) led to a reduction in risk of 21% for death from 
cardiovascular causes (95% confidence interval, 5% to 35%; p = 0.014).  It also 
led to a 37% risk reduction for the development of severe HF (95% confidence 
interval, 20% to 50%; p < 0.001).22  
2.5.5 
The analysis of the Heart Outcomes Prevention Evaluation (HOPE) trial 
suggests that 10 mg daily ramipril therapy may reduce the risk of developing HF 
in high-risk patients without LV dysfunction.28  Two prospectively defined 
endpoints (HF death and HF hospitalization) were combined with two post hoc 
endpoints (HF leading to open label ACE inhibitor use or development of signs 
and symptoms of HF).  Ramipril significantly reduced the event rate from 11.5% 
to 9.0% (RR 0.77, 95% CI 0.68 to 0.87, p < 0.0001).  
2.5.6 
Studies have evaluated the effect of ACE inhibitors in anthracycline induced-
cardiotoxicity.  The value of treatment with ACE inhibitors was demonstrated in a 
prospective series of patients who were being monitored for evidence of LV 
dysfunction while on epirubicin for metastatic breast cancer.29  In contrast, there 
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plus a diuretic.  Seven of eight (88%) patients treated with an ACE inhibitor had 
a sustained increase in LVEF of ≥ 15% as compared to one of 33 (8%) in those 
who were not treated with an ACE inhibitor (p < 0.001).  The patients with 
decreased cardiac function did not spontaneously recover during the observation 
period.  Cardiac function could only be reversed by treatment with ACE inhibitors 
for several months.  Three patients in this study stopped ACE inhibition therapy 
after years of stabilized cardiac function, after which all three experienced a 
deterioration of cardiac function.  Sixty additional patients with severe HF from 
anthracyclines have since been successfully treated with ACE inhibition, with a 
remarkably long-lasting recovery evaluated clinically and by LVEF 
determination.29   
2.5.7 
The potential protective effect of ACE inhibitors for preventing the development 
of left ventricular dysfunction in response to chemotherapy has since been 
evaluated.  Cardinale, et. al., report a randomized trial of patients after high-dose 
chemotherapy.13  One hundred fourteen adult patients who had elevated 
troponin-I soon after high-dose chemotherapy were randomized to enalapril 
(target of 20 mg/day) or open-label control, with treatment initiation delayed until 
one month after chemotherapy and continued for one year.  The results were 
impressive; 43% of the control and 0% in the enalapril group had a more than 
10% drop in LVEF (p < 0.001), and clinical cardiac events were likewise nearly 
eliminated with enalapril, from 30 events in the control population to one event in 
the enalapril group (p < 0.001).  This was primarily attributable to reductions in 
heart failure and arrhythmias.  There were some weaknesses in the trial such as 
the trial was a single-center, open-label trial, the diversity of cancer diagnoses 
and chemotherapy regimens included in the study, and possible bias because of 
the lack of pre-specified and clearly defined clinical endpoints.  
2.5.8 
A study conducted by Silber et. al., evaluated the use of enalapril in 135 pediatric 
cases who already had one anthracycline-induced cardiac abnormality.30  
Treatment with enalapril demonstrated that during the first year of treatment, the 
rate of reduction in LV end-systolic wall stress was greater in the enalapril group 
than in the placebo group (-8.59 versus 1.85 g/cm2; p = 0.033).  This difference 
was maintained over the study period, resulting in a 9% reduction in estimated 
LV end-systolic wall stress by year five in the enalapril group.  There was no 
change in the functional capacity. 
2.5.9 
An animal study conducted by Boucek et. al., demonstrated that treatment with 
an ACE inhibitor, lisinopril, reduces the time-dependent effects of an 
anthracycline on cardiac gene expression and myocellular apoptosis.31  Rabbits 
were randomized to one of four treatment groups; saline (control) +/- lisinopril or 
anthracycline +/- lisinopril.  After a 10-week intervention, histopathology 
demonstrated a reduced number of cardiomyocytes relative to interstitial cells in 
the LV of the anthracycline treated group compared to the control and the 
anthracycline + lisinopril groups.  Gene expression of the pro-atrial naturetic 
peptide (ANP) increased approximately 12-fold (n = 10; p < 0.05) in the LV of the 
anthracycline treated group compared to the control and anthracycline + lisinopril 
groups. 
2.6 
Beta Blockers (β-Blockers): 
2.6.1 
The increase of sympathetic activity in HF may have deleterious effects.  A 
number of trials have shown that blockade of β-adrenergic receptors leads to 
symptomatic improvement and enhanced survival in many patients with HF.32  
The use of β-blockers has consistently been associated with a 30% reduction in 
mortality and a 40% reduction in hospitalization in patients with HF.33-37  As a 
result of this compelling evidence, β-blockers are now considered an important 
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adverse effects of the sympathetic nervous systems in patients with HF.24  β-
Blockers also reduce cardiotoxicities by preventing free radical mediated lipid 
oxidation and intracellular calcium overload.     
2.6.2 
The MERIT-HF trial38 and the RESOLVD pilot study39 demonstrated that the use 
of sustained release metoprolol has a mortality benefit.  In the Metoprolol CR/XL 
Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), 3,991 
patients with class II to IV HF and an LVEF ≤ 40% who were receiving any 
combination of diuretic and ACE inhibitor, were randomly assigned to therapy 
with extended-release metoprolol, beginning with 12.5 or 25 mg daily and titrated 
up to 200 mg/day, or placebo.  The study was terminated early when it showed a 
34% relative risk reduction in all-cause mortality at 12 months (7.2% versus 11% 
for placebo, p = 0.0062).  There was also a reduction in cardiovascular deaths in 
the metoprolol group, (6.4% versus 10.1%; RR 0.62, 95% CI 0.50-0.78, p = 
0.00003) and deaths from aggravated HF (1.5% versus 2.9%; RR 0.51, 95% CI 
0.33-0.79, p = 0.0023).  The total risk reduction of deaths related to 
cardiovascular and aggravated HF was 38% and 49%, respectively.  While the 
proportion of sudden cardiac deaths decreased, when grouped by the New York 
Heart Association (NYHA) functional class, a greater proportion of deaths were 
observed in subjects who exhibited increasing severity of HF.  The study agent 
was well tolerated. 
2.6.3 
In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction pilot 
trial (RESOLVD) study metoprolol CR showed a significant improvement in 
measures of LV function with an attenuation in the increase in LV end-diastolic 
volume (+6±61 mL versus +23±65 mL, p = 0.01) and LV end-systolic volume (-
2±51 mL versus +19±55 mL, p < 0.001) after 24 weeks of therapy.39  LVEF was 
unchanged (-0.05%) in the placebo group but increased by 2.4% in the 
metoprolol CR–treated patients (p = 0.001).  There were fewer deaths in the 
group receiving β-blockers (3.4% versus 8.1%, not significant). 
2.6.4 
Animal studies have suggested that the β-blocker, Coreg CR®, may protect 
against the cardiotoxicity of anthracyclines.40  Further support for this possibility 
comes from a small randomized trial of 50 patients undergoing anthracycline 
chemotherapy for a variety of malignancies.14  Patients were randomly assigned 
to carvedilol, 12.5 mg daily, or placebo.  All patients underwent 
echocardiography prior to and six months after chemotherapy.  Among the 
patients assigned to carvedilol, there was no change in the mean LVEF after 
chemotherapy (70% before and after therapy).  In contrast, patients assigned to 
placebo had a statistically significant absolute reduction in LVEF by 17% (69 to 
52%, p < 0.001).  The incidence of cardiotoxicity observed was unusually large 
(20%) in the control group as compared to 4% in the treatment group, which may 
be from the high doses of anthracycline used in the study for both groups.  
However the standard deviation of the doses was not reported and it could 
greatly affect the significance of the study.   
2.6.5 
Several studies have been completed comparing the efficacy of various β-
blockers.41-47  Use of carvedilol is associated with a greater improvement of 
LVEF, longer estimated median survival, a reduction in the total number of 
hospitalizations, and hospitalizations for cardiovascular reasons and those for 
HF.   
2.6.6 
Coreg CR® is a nonselective beta-adrenergic blocking agent approved to treat 
essential hypertension, impaired left ventricular function related to acute 
myocardial infarction, and heart failure.  Coreg CR® is indicated for the 
treatment of mild-to-severe congestive heart failure of ischemic or 
cardiomyopathic origin.  It has been shown to reduce symptoms and clinical 
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mechanism by which Coreg CR® produces a beneficial effect in patients with 
congestive heart failure and left ventricular dysfunction following an acute 
myocardial infarction is not known (Prod Info Coreg CR® (carvedilol phosphate, 
extended-release) oral capsules, 2006).   
2.6.7 
In a retrospective study, M. Guglin et al. demonstrated that being on cardiac 
medications thought to prevent cardiac remodeling (ACE-inhibitors, angiotensin 
receptor blockers, statins, beta-blockers) was possibly associated with less 
cardiomyopathy (RR=0.69; p 0.092) and less HF symptoms (RR=0.38; p 0.086) 
in adjuvant patients with one or more cardiovascular comorbidities. The use of 
these medications was significantly associated with less cardiomyopathy 
(RR=0.35; p = 0.0063), less EF drop < 50% (RR=0.13; p 0.0083), less heart 
failure symptoms (RR=0.13; p = 0.0083), and less trastuzumab discontinuation 
(RR=0.25; p = 0.034) in adjuvant patients with hypertension alone.2 
2.7 
Using the same strategies that have demonstrated promising results in anthracycline-
induced cardiotoxicity, this study will evaluate and compare the effect of an ACE inhibitor, 
lisinopril, and a β-blocker, Coreg CR®, on trastuzumab-induced cardiotoxicity in women 
with breast cancer.  Participants will start study agent at the same time as they start 
trastuzumab treatment and continue on study agent for 52 weeks (or end of trastuzumab if 
it is discontinued prior to week 52). The efficacy of ACE inhibitors and β-blockers in the 
treatment of chemotherapy-induced cardiotoxicity, specifically LVEF, are equivalent.  
Therefore, a study to compare the efficacy of these agents is warranted.  Should either 
intervention prove effective, fewer patients will experience the deleterious effects of 
cardiotoxicity; and, more patients will be able to complete optimal therapy for breast cancer 
treatment.   
2.8 
Measurement of Left Ventricular Ejection Fraction (LVEF): 
2.8.1 
Multiple Gated Acquisition (MUGA) scans and echocardiograms (ECHO) are 
routinely used to monitor and assess cardiac function and LVEF of patients with 
cancer who are treated with cardiotoxic-inducing chemotherapeutic agents.  
LVEF provides an overall assessment of cardiac function, and is a measure of 
the proportion of blood that is expelled from the ventricle with each heartbeat. 
2.8.2 
A MUGA is a noninvasive assessment that produces a moving image of the 
heart, which can accurately assess the activity of the left ventricle and provides a 
reproducible measure of LVEF.  The MUGA scan involves the introduction of a 
radioactive marker into the bloodstream, which can be scanned to determine the 
circulation dynamics of the marker and blood flow. 
2.8.3 
An ECHO is a noninvasive ultrasound assessment of sound waves to examine 
the structure and motion of the heart.  It provides a real-time image of the heart 
and can produce accurate assessments of the velocity of the blood and cardiac 
tissues, as well as calculate cardiac output and EF.   
2.8.4 
Ejection fraction will be assessed at baseline, every 3 months (+/- 2 weeks) 
through study week 52, (or until the end of trastuzumab, if discontinued prior to 
week 52) and at study month 18 and 24 (or 6 and 12 months after the last dose 
of trastuzumab, if it was discontinued prior to study week 52).   
 
2.9 
Biomarkers of cardiotoxicity will be evaluated in an effort to identify patients at risk for 
cardiomyopathy prior to development of cardiac symptoms and before the drop of ejection 
fraction (EF) can be appreciated by echocardiography or MUGA.  
 
Brain natriuretic peptide (BNP) 
2.9.1 
Brain natriuretic peptide (BNP) concentration is a measurement of the amount of 
BNP hormone in the blood and is an indicator of heart function.  Normal levels of 
BNP are low (0-99 pg/mL) and the concentration increases as a consequence of 
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HF severity (≥ 100 pg/mL).  The concentration of BNP is also used to measure 
the response to treatment for HF.  Monitoring BNP has been demonstrated to 
measure changes of heart function during and after trastuzumab treatment.50, 51  
The concentration of BNP will be assessed at baseline and compared every 3 
months (+/- 2 weeks) through study week 52 throughout the duration of the 
study.  An additional BNP assessment will be completed at the six and 12 month 
post treatment visit and compared to previous concentrations.  
2.9.2 
Biomarkers like natriuretic peptides have been widely used for monitoring of 
heart failure of any etiology. Natriuretic peptides levels are more sensitive than 
symptoms and become elevated even in asymptomatic left ventricular 
dysfunction.  Specifically, brain natriuretic peptide (BNP) is produced primarily in 
cardiac atria and ventricles. Its levels rise in response to stretch of ventricular 
myocytes or increases in wall tension and reflect the severity of heart failure. 52, 53 
2.9.3 
In the setting of chemotherapy-induced cardiomyopathy, early detection of these 
markers may identify “high-risk” group which can benefit from close 
observation.54 During the evolution of doxorubicin-induced left ventricular 
dysfunction the secretion of natriuretic peptides is more closely associated with 
the impairment of left ventricular diastolic filling than with the deterioration of left 
ventricular systolic function.55 
2.9.4 
Brain natriuretic peptide and not NT-proBNP was chosen to be measured for this 
study because the difference between the two is subtle, and the use of BNP is 
more common.56  The objective for measuring BNP is to allow for early detection 
of LVEF in subjects receiving trastuzumab therapy.   
Troponin I (TnI) 
 
2.9.5 
Cardiac troponin I is a well established early marker of myocardial injury, 
including injury related to high-dose chemotherapy.57 Even minimal elevations of 
TnI  is predictive of late changes in ejection fraction;58 and, increases soon after 
high-dose chemotherapy is considered a strong predictor of poor cardiac 
outcome.13  Most recently the utility of TnI as a predictor of unforeseeable and 
refractory cardiotoxicity in patients treated with trastuzumab for breast cancer 
has been reported.59   
2.9.6 
In a single center study by Cardinale et al.59  evaluated TnI before and after each 
course of trastuzumab as adjuvant therapy or treatment of metastatic breast 
cancer.  Only 5% of patients without TnI elevation in the course of treatment 
developed cardiomyopathy.  On the other hand, 62% of those with elevated TnI 
later demonstrated reduced left ventricular ejection fractions.  Moreover, there 
was less recovery of cardiac function in those patients who had elevated TnI, the 
strongest predictor of cardiotoxicity reported in this study. 
2.9.7 
We believe this prospective randomized controlled clinical trial presents an ideal 
opportunity to compare the specificity, sensitivity, positive and negative predictive 
value of both BNP and TnI in patients with breast cancer who are receiving 
trastuzumab.  If TnI is a more sensitive marker of trastuzumab-induced 
cardiomyopathy, the practice of screening with cumbersome and costly cardiac 
imaging every three months could change to selectively imaging only those 
patients in whom a screening TnI was abnormal.   
2.9.8 
Given the large difference in cardiac toxicity between anthracycline- and non-
anthracycline-containing regimens,60 the protocol seeks to approximate the 
sample size of each regimen to ensure that the power of the study wlll be 
sufficient. 
 
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2.10 
Non-fasting comprehensive metabolic panel (CMP)  
2.10.1 
For safety monitoring purposes, a comprehensive metabolic panel (CMP) will be 
collected at each follow-up visit during active therapy monitor renal and liver 
function for potential adverse reactions 
2.11 
Quality of Life: 
2.11.1 
Cardiotoxicity is often associated with adverse symptoms, including fatigue, 
coughing spells, and shortness of breath.   Therefore, an assessment of health 
related quality of life (HRQL) will be measured as a secondary objective to 
determine whether the hypothesized reduction of cardiotoxicity in patients 
randomized to lisinopril or Coreg CR® correlates with HRQL. An improvement in 
HRQL or at least stable HRQL should accompany prevention of 
cardiotoxicity.  Measurement of HRQL can also be correlated to the possible 
onset of LVEF changes measured by ECHO or MUGA and/or the change in 
troponin I and/or BNP.  
 
2.11.2 
The European Organization for Research and Treatment of Cancer Core Quality 
of Life Questionnaire (EORTC QLQ-30) will be used to assess quality of life at 
baseline, at study week 52 (or at the end of trastuzumab therapy, if it is given for 
less than one year), and at study months 18 and 24 (or 6 and 12 months after the 
last dose of trastuzumab, if given for less than one year). The EORTC QLQ-C30 
is a validated, multidimensional, self-administered questionnaire developed to 
assess the quality of life in cancer patients across a range of cultural settings.60-62  
It will be used to assess quality of life as a secondary endpoint.  The 
questionnaire consists of 30 questions that pertain to the patient and their health.  
Questions are answered using a scale of 1 to 4, with 1 being “not at all” and 4 
being “very much”, except for questions 29 and 30, which are answered using a 
7 point scale ranging from 1 “very poor” to 7 “excellent”.  Approximately 10 to 15 
minutes are required to complete the questionnaire.  
2.12 
Gender and Ethnicity: 
2.12.1 
Entry into this study is open to males and females of all ethnic backgrounds.  
SunCoast CCOP Research Base members estimate that approximately 20% of 
accrual to CCOP Research Base studies in general will be patients with minority 
backgrounds.  A similar distribution is anticipated for this protocol. 
 
3.0 
Objectives: 
3.1 
The primary objective of this study is to determine if administration of lisinopril or Coreg 
CR®, compared to placebo, will reduce the incidence of trastuzumab-induced 
cardiotoxicity, as measured by LVEF, in patients receiving adjuvant, or neoadjuvant, 
therapy for HER2 positive breast cancer. 
3.2 
The secondary objectives of this study are to determine: 
3.2.1 
determine whether subjects randomized to active agent have fewer interruptions 
in trastuzumab therapy due to cardiomyopathy   
3.2.2 
determine whether the treatment effect is consistent in anthracycline and non-
anthracycline patient cohorts 
3.2.3 
compare changes in HRQL among the treatment groups during the study 
intervention 
3.2.4 
evaluate the long term effects on the prevention of cardiomyopathy and impact 
on HRQL for either or both study agents  
3.2.5 
compare the predictive value of troponin I and BNP in the identification of 
trastuzumab-induced cardiotoxicity 
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4.0 
Regulatory,  Subject Selection (§4.7), Registration & Randomization  
4.1 
CTSU sites should refer to Appendix VIII, CTSU Logistics, for CTSU registration and 
randomization procedures. 
Regulatory: 
4.2 
Send the Intent to Participate form (available on the SunCoast CCOP Research Base 
website (http://www.SunCoastccop.org) by fax [813-910-5998] or email (ccop@epi.usf.edu) 
to the SunCoast CCOP Research Base Operations Center at the time of submission to IRB 
to begin site set-up needed to activate each institution.   
4.3 
Forms will be available through the SunCoast CCOP Research Base website 
(http://www.SunCoastccop.org) via PDF to download and printout as a Master forms packet 
4.4 
The sample informed consent contains all of the NCI required elements and is available on 
the SunCoast CCOP Research Base website (http://www.SunCoastccop.org ) as a Word 
document to download and add the local IRB language.  
4.5 
When preparing the consent for local IRB review, be sure all information in the sample 
informed consent is included.  Additional information may be added, but information may 
not be deleted or changed significantly.  Contact the SunCoast CCOP Research Base 
Operations Center for questions (email ccop@epi.usf.edu or telephone 1-800-909-1242). 
4.6 
Modifications and inclusion to site-specific language made to the informed consent must be 
approved by the SunCoast CCOP Research Base Operations Center.  The Word version of 
the site-specific informed consent should be emailed to ccop@epi.usf.edu at the time of 
IRB submission.   
4.7 
Prior to enrollment of patients, Affiliation regulatory paperwork for each institution must be 
on file with the SunCoast CCOP Research Base Operations Center, which include: 
4.7.1 
A signed letter of collaboration or affiliation agreement. 
4.7.2 
HHS Form 1572 and CV for Responsible Investigator. 
4.7.3 
HHS Form 1572 for all participating physicians who will receive drug shipment, 
noting the address for drug shipment 
4.7.4 
SCUSF CCOP Research Base Financial Disclosure / Conflict of Interest Form  
for Responsible Investigator 
4.7.5 
The SunCoast CCOP Research Base Operations Center requires evidence of 
training on the Protection of Human Research Subjects. 
4.7.6 
List of all enrolling centers covered under the IRB review process with shipping 
address, Responsible Investigator and Primary contact telephone, fax and email 
information for each enrolling center 
4.7.7 
FWA and IRB numbers for all enrolling centers 
4.7.8 
Medication Order Form – Site Stock; have the investigator responsible for this 
study sign the form and return to the SunCoast CCOP Research Base 
Operations Center by fax (813-910-5998) or email (ccop@epi.usf.edu).  The 
Operations Center will release to the investigational pharmacy at the time of 
activation so site stock can be shipped at the time each institution enrolls their 
first patient.  
4.7.9 
Send the current IRB approval (HHS Form 310 or IRB approval letter) by email 
(ccop@epi.usf.edu) or fax (813-910-5998) to begin site activation. 
4.7.10 
At receipt of the IRB approval and activation processes completed, the SunCoast 
CCOP Research Base Operations Center will release a “Welcome Letter” 
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providing site identification code, any study-specific materials and/or study agent 
at this time. 
 
Subject Selection: 
4.8 
Inclusion Criteria: 
4.8.1 
Males and Females ≥ 18 years old diagnosed with HER2 positive breast cancer  
4.8.2 
Scheduled to receive neoadjuvant or adjuvant trastuzumab (Herceptin®) therapy 
(anthracycline-containing regimens are permitted).  Patients receiving 
Herceptin® with their chemotherapy are permitted for eligibility work-up.  
Taxanes are permitted.  Trastuzumab (Herceptin®) therapy may be given with or 
after primary chemotherapy. Pertuzumab may be used in conjunction with 
trastuzumab. 
4.8.3 
Left Ventricular Ejection Fraction (LVEF) ≥ 50% by MUGA scan or 
echocardiogram  
4.8.4 
Adequate renal function for administration of trastuzumab-containing 
chemotherapy regimen.    
4.8.5 
Sitting systolic blood pressure of > 90 mm Hg  
4.8.6 
Pulse ≥ 60 beats/minute  
4.8.7 
Not pregnant or breastfeeding  
4.8.7.1 
Female patients of childbearing potential, who are sexually active, 
must have a negative pregnancy test before starting the study 
4.8.8 
Both men and women must be willing to use effective contraception during the 
study.  Teratogenicity  is documented for both active study agents 
4.8.9 
Able to swallow capsules 
4.8.10 
Able and willing to give informed consent 
4.8.11 
Signed HIPAA compliant research authorization (or equivalent for international 
sites) to release Personal Health Information to the SunCoast CCOP Research 
Base.   
 
4.9 
Exclusion criteria: 
4.9.1 
Patients with metastatic disease  
4.9.2 
Prior treatment with trastuzumab or anthracyclines prior to this chemotherapy 
regimen 
4.9.3 
Current treatment with angiotensin converting enzyme (ACE) inhibitors, 
angiotensin receptor blockers (ARBs), such as losartan, β-blockers or digoxin 
4.9.4 
Known cardiac history: heart failure, myocardial infarction, radiation-induced 
cardiac dysfunction 
4.9.5 
Known allergy to either ACE inhibitors or β-blockers 
4.9.6 
History of bronchial asthma or related bronchospastic conditions 
4.9.7 
Hereditary or idiopathic angioedema 
4.9.8 
History of severe hypersensitivity reactions to drugs or other causes, i.e. bee 
stings 
4.9.9 
This protocol does not exclude patients who are participating on other 
investigational studies. Refer to the local IRB guidelines.   
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Registration and Randomization: 
4.10 
Patients must not start protocol treatment prior to registration. 
4.11 
Treatment should start within ten (10) working days after registration; however, there may 
be unanticipated and justifiable delays.   
4.11.1 
For unanticipated delays contact the SunCoast CCOP Research Base 
Operations Center (by email ccop@epi.usf.edu or telephone 1-800-909-1242) 
and document the reason for delay in the participant’s research chart for audit 
purposes.  Each unanticipated delay will be evaluated for study continuation.   
4.11.2 
If a participant does not receive any assigned protocol treatment, the baseline 
(On Study   Form – see Appendix III) and off-study data (Off Study Form – see 
Appendix III) will still be collected and must be submitted according to the 
Records to be Kept section (see Section 9.0).  Document the reason for not 
starting protocol treatment on the Off Study Form. 
4.11.3 
Screening workup can  be completed within 14 days before registration  
4.11.3.1 
Except LVEF which can be done ≤  6 weeks before enrollment 
 
Eligibility Verification: 
4.12 
Study candidates must meet all of the eligibility requirements listed in Section 4.0.  
4.13 
After obtaining informed consent, patients will be registered and randomized. CTSU sites 
must refer to the CTSU Logistical Appendix VIII for patient enrollment instructions. 
All other site will register by calling the SunCoast CCOP Research Base Interactive Voice 
Response (IVR) system at (1-866-835-6793) (Appendix II).  The following information will 
be requested: 
4.13.1 
SunCoast CCOP Research Base study number 0806 
4.13.2 
Site identification/institution code (unique to each institution) 
4.13.3 
First letter of the subject's first name (see numeric code Appendix II) 
4.13.4 
First letter of the subject's last name (see numeric code Appendix II) 
4.13.5 
Subject date of birth (MM/DD/YYYY) 
4.13.6 
Does the subject live in the United States? 
4.13.7 
(if yes) Subject five-digit Zip Code (XXXXX).  
4.13.8 
(if no) Country Code __ __ (see CTEP Country Code Appendix II)  
4.13.9 
Does the subject meet all eligibility requirements? 
4.13.10 Has the patient signed a HIPAA compliant authorization to release of private 
health information (PHI), or equivalent for international sites, to the SunCoast 
CCOP Research Base Operations Center? 
4.13.11 Did the subject sign the informed consent? 
4.14 
The SunCoast CCOP Research Base Operations Center Interactive Voice Response (IVR) 
telephone system will assign a unique study identification number (sequence number) and 
treatment randomization for each patient entered on study.  
  
4.15 
When the first patient is being enrolled by an institution:  Fax the Medication Order 
Form (Appendix III) to the investigational pharmacy at 1-866-992-9966. Order forms will be 
processed within one week for shipping via express courier to the site. 
 
Calling for Study Agent Refills or Stop Study Agent: 
10/08/2010 
10/08/2010 
09/24/2010 
08/31/2012 
08/31/2012 


 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 12 of 32 
 
4.15.1 
Patients must complete the LVEF cardiac monitoring criteria prior to requesting 
refill study agent 
4.15.2 
Call through the IVR system 1-866-835-6793 
4.15.3 
Use the REFILL REQUEST IVR worksheet (see Appendix II) 
You will be asked: 
4.15.4 
Study Number:   0806 
4.15.5 
Site identification/institution code (unique to each institution) 
4.15.6 
Has the subject previously been enrolled?  If Yes: 
4.15.7 
Subject Sequence Number: 
IVR system will confirm:  
4.15.8 
First letter of the subject's first name (see numeric code Appendix II) 
4.15.9 
First letter of the subject's last name (see numeric code Appendix II) 
4.15.10 Subject date of birth (MM/DD/YYYY) 
You will need to answer: 
4.15.11 For which study visit are you requesting a refill or stop study agent? 
4.15.11.1 Press “1” for 3-month study agent follow-up 
4.15.11.2 Press “2” for 6-month study agent follow-up 
4.15.11.3 Press “3” for 9-month study agent follow-up 
4.15.12 Date of LVEF (MUGA / echocardiogram) assessment: MM/DD/YYYY 
4.15.13 Is the patient eligible to continue on study per protocol section 7.0? 
IVR system will respond:  
4.15.14 The patient should continue taking study agent 
OR: IVR system will respond  
4.15.15 The patient should stop taking study agent 
4.15.16 Discontinue Study Agent  
4.15.17 Complete assessments per the study plan table 
4.15.18 Patient moves into Follow-up for 12 months 
 
5.0 
Study Agent Information (FDA IND 102825 exemption granted) 
Lisinopril:  
Product Description 
5.1 
Lisinopril is an oral long acting angiotensin converting enzyme inhibitor, which inhibits the 
conversion of angiotensin I to angiotensin II. 
Manufacturer:  
5.2 
Lupin Limited 
Supplier:  
5.3 
Carter’s Park and King Pharmacy, Inc.  
Clinical Pharmacology:   
5.4 
A copy of the package insert is included in Appendix IV for reference.  
Dose selection:  
5.5 
Lisinopril10 mg will be administered once daily.  This dosage was based on the commonly 
used dose for asymptomatic left ventricular systolic dysfunction. 
Pharmacokinetics: 
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5.6 
Following oral administration, the concentration of lisinopril peaks within 7 hours.  
Absorption of lisinopril is approximately 25% (6-60%), of which the consumption of food is 
not affected.   
5.7 
Lisinopril is not metabolized and is excreted in the feces (69%) and urine (29%) 
unchanged.   
5.8 
The effective half-life of accumulation of lisinopril is 12 hours after multiple dosing. 
Storage and Stability: 
5.9 
Store at controlled room temperature 20-25°C (68-77°F).  Protect from moisture, freezing 
and excessive heat.   
5.10 
Dispense in a tight, light resistant container. 
Specifications: 
5.11 
Lisinopril is FDA approved for the treatment of adult acute myocardial infarction, heart 
failure and hypertension. 
5.12 
See product information (Appendix IV). 
Known toxicity/dose limiting toxicity: 
5.13 
Cardiovascular effects:  Angina, chest pain, orthostatic effects, palpitations, peripheral 
edema, tachycardia, arrhythmias, vasculitis. 
5.14 
Dermatologic effects:  Angioedema, rash, flushing, urticaria, diaphoresis, pruritis, toxic 
epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), photosensitivity, psoriasis. 
5.15 
Endocrine/metabolic effects:  Acute intermittent prophyria, body temperature above normal, 
gynecomastia, hyperglycemia, hyperkalemia, hyperuricemia,     hypoglycemia, 
hyponatremia, abnormal lipids. 
5.16 
Gastrointestinal effects:  Drug-induced acute pancreatitis, diarrhea, nausea, vomiting, 
dyspepsia, abdominal pain, anorexia, constipation, dry mouth, taste disturbances, 
flatulence, gastrointestinal ulcer, intestinal angioedema. 
5.17 
Hematologic effects:     Pancytopenia, eosinophilia, thrombocytopenia, reduced hemoglobin 
and hematocrit, hemolytic anemia, Schonlein-Henoch Purpura. 
5.18 
Hepatic effects:  Hepatoxicity, abnormal liver enzymes. 
5.19 
Immunologic effects:  Drug-induced neutropenia, immune hypersensitivity reaction, 
sarcoma, systemic lupus erythematosus (SLE) 
5.20 
Musculoskeletal effects:  Arthralgia, articular gout, muscle cramps, back pain, joint pain, 
shoulder pain. 
5.21 
Neurologic effects:  Dizziness, headache, asthenia, vertigo, lassitude, fatigue, insomnia, 
paraesthesias, stroke, nervousness, confusion, depression, somnolence. Ophthalmic 
effects:  Blurred vision, diplopia, photophobia. 
5.22 
Otic effects:  Tinnitus 
5.23 
Renal effects:  Nephrotoxicity, urinary tract infections 
5.24 
Reproductive effects:  Impotence in males, decreased libido 
5.25 
Respiratory effects:  Cough, upper respiratory infections 
5.26 
Other:  Angioedema of the head and neck, withdrawal signs/symptoms 
5.27 
Teratogenicity:  Category C (1st trimester); Category D (2nd trimester); Category D (3rd 
trimester)  


 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
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Contraindications, Drug Interactions and Precautions: 
5.28 
See package insert – Appendix IV. 
 
Coreg CR® (carvedilol phosphate, extended-release): 
Product Description: 
5.29 
Coreg CR® is a non-selective β-adrenergic blocking agent with α1-blocking activity. 
Manufacturer:  
5.30 
GlaxoSmithKline 
Supplier:  
5.31 
Carter’s Park and King Pharmacy, Inc.  
Clinical Pharmacology:   
5.32 
A copy of the package insert is included in Appendix IV for reference. 
Dose selection:  
5.33 
Coreg CR® 10 mg will be administered once daily.  This dosage was based on the 
commonly used dose for asymptomatic left ventricular systolic dysfunction. 
Pharmacokinetics: 
5.34 
Coreg CR® is readily absorbed following oral administration.  Approximately 25-35% of the 
compound is absorbed, the concentration of which peaks after five hours.  Consumption 
with food significantly improves absorption.   
5.35 
Less than two percent of Coreg CR® is excreted through the urine unchanged.  
Approximately 60% of Coreg CR® is excreted through feces.   
5.36 
The effective half-life of Coreg CR® is seven to ten hours. 
Storage and Stability: 
5.37 
Store Coreg CR® at 25°C (77°F).   
5.38 
Dispense in a tight, light resistant container. 
Specifications: 
5.39 
Coreg CR® is FDA approved for the treatment of adult acute myocardial infarction, heart 
failure and hypertension. 
5.40 
See product information (Appendix IV). 
Known toxicity/ dose limiting toxicity: 
5.41 
Cardiovascular effects:  Angina, atrioventricular block, bradyarrhythmnia, edema, 
hypotension, palpitations, peripheral edema, rebound hypertension, shock, syncope. 
5.42 
Dermatologic effects:  Rash, pruritis, edema, photosensitivity, Stevens-Johnson Syndrome 
(SJS) 
5.43 
Endocrine/metabolic effects:  Diabetes mellitus, disorder of glucose regulation, insulin 
resistance, hyperinsulinemia, hyperglycemia, abnormal lipids, hyperkalemia, weight gain. 
5.44 
Gastrointestinal effects:  Diarrhea, nausea, vomiting 
5.45 
Hematologic effects:  Reduced hemoglobin and hematocrit, thrombocytopenia 
5.46 
Hepatic effects:  Hepatoxicity, abnormal liver enzymes  
5.47 
Immunologic effects:  Immune hypersensitivity reaction 


 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 15 of 32 
 
5.48 
Musculoskeletal effects:  Arthralgia 
5.49 
Neurologic effects:  Cerebrovascular accident, dizziness, headache, insomnia,  
somnolence 
5.50 
Ophthalmic effects:  Abnormal vision, blurred vision 
5.51 
Psychiatric effects:  Fatigue 
5.52 
Renal effects:  Kidney disease, microalbuminuria 
5.53 
Reproductive effects:  Erectile dysfunction, impotence and Peyronie's disease in males, 
sexual dysfunction  
5.54 
Respiratory effects:  Asthma with status asthmaticus, bronchospasm, dyspnea 
5.55 
Other:  Withdrawal signs/symptoms 
5.56 
Teratogenicity:  Category C (All trimesters) 
Contraindications, Drug Interactions and Precautions: 
5.57 
See package insert – Appendix IV 
 
Placebo: 
Product Description: 
5.58 
The placebo capsule contains potato starch as filler.  It will appear identical to lisinopril and 
Coreg CR®.   
Supplier: 
5.59 
Carter’s Park and King Pharmacy, Inc. 
Storage and Stability: 
5.60 
Store at 25°C (77°F).   
5.61 
Dispense in a tight, light resistant container. 
Specifications: 
5.62 
The supplier has certified that the placebo contains no active agent.  The weight of the 
capsule, with contents, is equivalent to the active agent capsules. 
 
Study Agent Procurement: 
5.63 
Study agents will be provided by the SunCoast CCOP Research Base Operations Center 
to enrolling centers at no cost to the patient or clinical center. 
5.64 
Patient-specific drug supply will be filled by Carter’s Park and King Pharmacies with 
prescriptions from enrolling center using the Medication Order Form included in Appendix 
III Data Collection Forms. 
 
5.65 
Disposition of Study Agent 
 
5.65.1 
Any study agent remaining after the participant completes active study agent (up 
to week #52) may be disposed on site according to local institutional guidelines. 
Dosing and Administration:   
5.66 
Study agents will be blinded and indistinguishable by locking, over-encapsulation with 
potato starch as filler for weight equivalency.  Patients who cannot swallow pills should not 
be enrolled, as capsules may not be opened.  
5.67 
Begin study agent starting on the same day as trastuzumab therapy  
10/08/2010 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
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5.67.1 
Preventative agents (SCUSF 0806 Study agent) should be administered before 
the offending agent (Herceptin®) is introduced. 
5.68 
Administer 1 capsule by mouth once daily, instructing patient to take study agent around 
the same time each day, and to take it with food 
5.69 
The plan outlined in Section 8.0. “Toxicity Assessment and Adverse Event Reporting” will 
be utilized to inform the patient about adverse events and limit the exposure to lisinopril 
should a patient present with a serious adverse event 
5.70 
Participants will document the number of capsules taken, the time of administration and 
any side effects on the Study Medicine Daily Log (see Appendix III) 
 
 
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Protocol Act V6.0 August  31, 2012 
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6.0 
Study Plan Tables 
6.1 
Study Requirements WHILE RECEIVING STUDY AGENT and ADJUVANT TRASTUZUMAB (See table 6.3 if neoadjuvant)  
 
Study Requirements 
Screen 
 
Pre-
Treatment 
 
Tx follow up 
every 3  
months X 3 
(+/- 2 weeks) 
Trastuzumab or  
study agent D/Cd  
before study week 52  
(≤ 1 month since last LVEF) 
Trastuzumab or  
study agent D/Cd  
before study week 52  
 (> 1 month since last LVEF) 
Study 
Week 52 
Signed informed consent/HIPAA form 
X 
 
 
 
 
 
Measurement of left ventricular ejection 
fraction (LVEF)1  
X1, 2 
 
X2 
 
X2 
X2 
History & physical (height and weight) 
X 
 
X 
 
X 
X 
Eligibility form 
X 
 
 
 
 
 
Registration / randomization  
X 
 
 
 
 
 
On-study form 
 
X 
 
 
 
 
Patient assessment form 
 
X 
X 
 
X 
X 
Blood samples to LabCorp: 
• 
Non-fasting CMP 
• 
Troponin I 
• 
BNP 
 
 
X3  
X3  
X3, 4 
 
X 
X 
X4 
 
 
X  
X  
X4 
 
X 
X 
X4 
QOL questionnaire (EORTC QLQ C-30)  
 
X 
 
X 
X 
X 
**Order study agent refills, using IVR**  
 
 
X 
 
 
 
Follow-up Form 
 
 
X 
X 
X 
X 
Concomitant Medication Form  
 
X 
X 
X 
X 
X 
Study Medicine Daily Log  
 
X5 
X5 
X 
X 
X 
Adverse Events Form 
 
 
X 
X 
X 
X 
 1    May be done within 6 weeks of study entry, using a MUGA scan (CMPT code 78472] or an ECHO [CMPT code 93306 without contrast].  The method of 
assessing LVEF must be same for the study duration, and be performed at the same institution as screening.   
2    Send de-identified copies of ECHO reports to the SunCoast CCOP Research Base.  
3    Draw and send pretreatment labs to LabCorp AFTER study registration and BEFORE starting study agent and Herceptin®  
4 Contrast material used for MUGA Scan may alter BNP results.  Draw samples as long as possible after the MUGA scan (or before the MUGA if for a follow-up 
visit).  If labs are drawn within 1 week after the MUGA, please list “contrast for MUGA” on the concomitant medication form.  
5   Distribute and instruct patients to start a new log each week. Logs are to be returned and reviewed at least every 3 months (if logs are returned more frequently, 
review and submit at that time).  Review Study Medicine Daily Logs with patients and document any side effects on the Adverse Events Form.  Study Medicine 
Daily Logs will be used as a measure of compliance.   
** A patient-specific medication order form and a site stock medication order form must be submitted ONLY when the first patient at an institution is being enrolled.  
Study agent for all subsequent participants and all study refills will be dispensed from institution’s site stock, which is replenished automatically**   
10/08/2010 
11/19/2010 
6/3/2011 
08/31/2012 


 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 18 of 32 
 
 
6.2 
Study requirements WHILE IN 12-MONTH FOLLOW-UP AFTER ADJUVANT TRASTUZUMAB: 
 
Study Requirements 
 
Follow up every 3  months X 3 (+/- 2 weeks) 
 
Completed 12-month FU 
(Off Study) 
Month 3 
(phone) 
Month 6 
(clinic) 
Month 9 
(phone) 
Measurement of left ventricular ejection fraction (LVEF)1  
 
X2 
 
X2 
History & physical (height and weight) 
 
X 
 
X 
Blood samples to LabCorp: 
• 
Non-fasting CMP 
• 
Troponin I 
• 
BNP 
 
 
X 
X 
X3 
 
 
X 
X 
X3 
QOL questionnaire (EORTC QLQ C-30)  
 
X 
 
X 
Patient assessment form 
X 
X 
X 
X 
Follow-up Form 
X 
X 
X 
X 
Concomitant Medication Form  
X 
X 
X 
X 
Adverse Events Form 
As Needed 
 
 
 
Off-Study Form 
 
 
 
X 
 
1    A MUGA scan (CMPT code 78472] or an ECHO [CMPT code 93306 without contrast] may be used.  The method of assessing LVEF must be 
same for the study duration, and be performed at the same institution as screening. 
2    Send de-identified copies of ECHO reports to the SunCoast CCOP Research Base.  
3 Contrast material used for MUGA Scan may alter BNP results.  Draw samples before the MUGA scan if possible.   If labs are drawn within 1 week after 
the MUGA, please list “contrast for MUGA” on the concomitant medication form. 
 
 
 
 
08/31/2012 


 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 19 of 32 
 
6.3 
Study Requirements WHILE RECEIVING STUDY AGENT and NEOADJUVANT TRASTUZUMAB  
 
 
Study Requirements 
Screen 
 
Pre-
Treatment 
 
Prior to 
surgery 
When 
resuming 
trastuzumab 
Tx follow up 
every 3  mo X 3 
(+/- 2 weeks) 
Study agent or 
trastuzumab 
D/Cd before 52nd 
dose of TZB 
(≤ 1 month since 
last LVEF) 
Study agent or 
trastuzumab 
D/Cd before 52nd 
dose of TZB 
(≤ 1 month since 
last LVEF) 
Post  
dose 52 
of TZB  
Signed informed consent/HIPAA 
form 
X 
 
 
 
 
 
 
 
Measurement of left ventricular 
ejection fraction (LVEF)1  
X1, 2 
 
X2 
 
X2 
 
X2 
X2 
History & physical (ht and wt) 
X 
 
X 
 
X 
 
X 
X 
Eligibility form 
X 
 
 
 
 
 
 
 
Registration / randomization  
X 
 
 
 
 
 
 
 
On-study form 
 
X 
 
 
 
 
 
 
Patient assessment form 
 
X 
X 
 
X 
 
X 
X 
Blood samples to LabCorp: 
• 
Non-fasting CMP 
• 
Troponin I 
• 
BNP 
 
 
X3  
X3  
X3, 4 
 
X 
X 
X4 
 
 
X 
X 
X4 
 
 
X  
X  
X4 
 
X 
X 
X4 
EORTC QLQ C-30  
 
X 
 
 
 
X 
X 
X 
**Order study agent refills, using 
IVR**  
 
 
X 
X 
X 
 
 
 
Follow-up Form 
 
 
X 
 
X 
X 
X 
X 
Concomitant Medication Form  
 
X 
X 
X 
X 
X 
X 
X 
Study Medicine Daily Log  
 
X5 
X5 & 6 
X 
X5 
X 
X 
X 
Adverse Events Form 
 
 
X 
X 
X 
X 
X 
X 
1 May be done within 6 weeks of study entry, using a MUGA scan (CMPT code 78472] or an ECHO [CMPT code 93306 without contrast].  The method of 
assessing LVEF must be same for the study duration, and be performed at the same institution as screening.   
2    Send de-identified copies of ECHO reports to the SunCoast CCOP Research Base.  
3    Draw and send pretreatment labs to LabCorp AFTER study registration and BEFORE starting study agent and Herceptin®  
4 Contrast material used for MUGA Scan may alter BNP results.  Draw samples as long as possible after the MUGA scan (or before the MUGA if for a follow-up 
visit).  If labs are drawn within 1 week after the MUGA, please list “contrast for MUGA” on the concomitant medication form.  
5   Distribute and instruct patients to start a new log each week. Logs are to be returned and reviewed at least every 3 months (if logs are returned more frequently, 
review and submit at that time).  Review Study Medicine Daily Logs with patients and document any side effects on the Adverse Events Form.  Study Medicine 
Daily Logs will be used as a measure of compliance.  6  Continue to give study agent during the surgical recovery period. 
** A patient-specific medication order form and a site stock medication order form must be submitted ONLY when the first patient at an institution is being enrolled.  
Study agent for all subsequent participants and all study refills will be dispensed from institution’s site stock, which is replenished automatically**  
11/19/2010 
6/3/2011 
08/31/2012 


 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 20 of 32 
 
 
6.4 
Study requirements WHILE IN 12-MONTH FOLLOW-UP AFTER NEOADJUVANT TRASTUZUMAB: 
 
Study Requirements 
 
Follow up every 3 months X 3 (+/- 2 weeks) after 
resuming trastuzumab post-operatively 
 
Completed 12-month FU 
(Off Study) 
Month 3 
(phone) 
Month 6 
(clinic) 
Month 9 
(phone) 
Measurement of left ventricular ejection fraction (LVEF)1  
 
X2 
 
X2 
History & physical (height and weight) 
 
X 
 
X 
Blood samples to LabCorp: 
• 
Non-fasting CMP 
• 
Troponin I 
• 
BNP 
 
 
X 
X 
X3 
 
 
X 
X 
X3 
QOL questionnaire (EORTC QLQ C-30)  
 
X 
 
X 
Patient assessment form 
X 
X 
X 
X 
Follow-up Form 
X 
X 
X 
X 
Concomitant Medication Form  
X 
X 
X 
X 
Adverse Events Form 
As Needed 
 
 
 
Off-Study Form 
 
 
 
X 
 
1    A MUGA scan (CMPT code 78472] or an ECHO [CMPT code 93306 without contrast] may be used.  The method of assessing LVEF must be 
same for the study duration, and be performed at the same institution as screening. 
2    Send de-identified copies of ECHO reports to the SunCoast CCOP Research Base.  
3 Contrast material used for MUGA Scan may alter BNP results.  Draw samples before the MUGA scan if possible.   If labs are drawn within 1 week after 
the MUGA, please list “contrast for MUGA” on the concomitant medication form. 
08/31/2012 


 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 21 of 32 
 
 
 
6.5 
Discontinuation of study agent criteria 
Completion of study week 52  
6.5.1 
Follow-up with LVEF at study month 18 and 24. 
6.5.2 
Report disease status and concomitant medications every 3 months X 4 (study 
months 15, 18, 21 and 24) 
6.5.3 
Discontinuation of trastuzumab prior to study week 52  
6.5.4 
Follow-up with LVEF in 6 and 12 months after the last dose of trastuzumab.   
6.5.5 
Report disease status and concomitant medications every 3 months X 4 (3, 6, 9, 
and 12 months after last dose of trastuzumab) 
Treatment (study agent) failure (section 7.0) 
6.5.6 
Follow-up with LVEF in 6 and 12 months after determination of treatment (study 
agent) failure 
6.5.7 
Report disease status and concomitant medications every 3 months X 4 (3, 6, 9 
and 12 months after treatment failure)  
6.5.8 
Patients may be rechallenged with trastuzumab per ASCO guidelines; however 
they will be considered study failures and discontinue study agent 
Other: (e.g. symptomatic bradycardia or hypotension attributable to study agent) 
6.5.9 
Do not rechallenge study agent 
6.5.10 
Follow-up with LVEF in 6 and 12 months after discontinuing study agent  
6.5.11 
Report disease status and concomitant medications every 3 months X 4 (3, 6, 9 
and 12 months after discontinuing study agent)   
6.6 
Forms are due to the SunCoast CCOP Research Base Operations Center within 14 days 
of protocol visit (see Records to be Kept section 9.0).   Forms can be faxed to 813-910-
5998. 
6.7 
To prevent biasing the outcome of the study, this is a double-blind study design, where 
both the clinical staff and the participants are blinded to the specific nature of the product 
(study agent and placebo).  
6.8 
After consenting to participate in the study, the following steps will occur: 
6.8.1 
Subjects will be registered and randomized by calling the automated Interactive 
Voice Response (IVR) telephone System at 1-866-835-6793, which is available 
24 hours/day and 7 days/week. (Note:  CTSU sites should contact the CTSU 
registration to perform the enrollment, per Appendix VIII). 
6.8.2 
For the first patient enrolled at each site: 
6.8.2.1 
Research staff will complete the Medication Order Form for treating 
physician’s signature, and then fax the form to the investigational 
pharmacy at 1-866-992-9966.   
6.8.2.2 
If the form is received for processing by 12:00pm noon, study agent 
will be released to the site the same day for courier two-day  delivery.   
6.8.2.3 
If the form is received after 12:00pm, the study agent will be 
processed within 1 business day for shipment by courier two-day 
delivery. 
10/08/2010 
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Protocol Act V6.0 August  31, 2012 
(Amendment #5) 
Page 22 of 32 
 
6.8.2.4 
With the first patient registration, “site stock” study agent will be 
released to the site for future patients and for patient refills.  Patient-
Specific Medication Order Forms need to be faxed to the 
investigational pharmacy at 1-866-992-9966 for the first patient only. 
6.8.3 
Research staff will complete the On-Study Form (See Appendix III) at baseline, 
collecting demographic information, personal and medical history.  
6.8.4 
Laboratory assessments CMP (non-fasting comprehensive metabolic panel) 
(CMPT code 80053),Troponin I (CMPT code 84484) and BNP [B-Type Natriuretic 
Peptide] (CMPT code 83880) will be submitted to LabCorp using pre-printed 
forms supplied by the SCUSF CCOP Research Base Operations Center at no 
charge. CMP,  Troponin I and BNP will be collected at baseline, every 3 months 
X 4 (+/- 2 weeks), study week 52 (or end of trastuzumab therapy if discontinued 
before week 52 or if study agent is stopped before week #52), study month 18 (or 
6 months after the last dose of trastuzumab or stopped study agent) and Study 
month 24 (or 12 months after the last dose of trastuzumab or stopped study 
agent).  
6.8.4.1 
BNP and Troponin I should be drawn AFTER registration and 
BEFORE patient receives study agent and trastuzumab 
6.8.4.2 
Laboratory specimens should be drawn BEFORE contrast material is 
administered for a MUGA Scan, as test results may be altered. 
6.8.4.3 
Laboratory specimens will be submitted to the local LabCorps.  
Preliminary and final results will be sent directly to the site as 
indicated on the Intent to Participate Form (or, for CTSU sites, the 
Site Contact Form).  LabCorp will submit Final results directly to the 
SunCoast CCOP Research Base Operations Center.  LabCorp will 
invoice the SunCoast CCOP Research Base Operations Center for 
the tests. 
6.8.5 
MUGA scan [CMPT code 78472] or ECHO [CMPT code 93306 without contrast] 
LVEF will be used to measure cardiac function at baseline, every 3 months X 4 (+/- 
2 weeks), Study week 52 (or end of trastuzumab therapy if discontinued before 
week 52 or study agent is stopped before week #52), study month 18 (or 6 
months after the last dose of trastuzumab or stopped study agent) and Study 
month 24 (or 12 months after the last dose of trastuzumab or stopped study 
agent).  
6.8.5.1 
Baseline LVEF within 6 weeks of study entry is acceptable.  The 
same measurement test (MUGA or ECHO) must be used throughout 
the study.   
6.8.6 
For sites using ECHO,de-identified copies of the ECHO report will be submitted 
with the Patient Assessment form for a central review by the study’s Principle 
Investigator of the mitral regurgitation, tricuspid regurgitation and velocity, mitral 
inflow E’ & A’ velocities, tissue Doppler E’ and A’ velocities, mitral annulus E’ & A’ 
velocities, and septal side E’ & A’ velocities. 
6.8.7 
Participants will complete the European Organization for Research and 
Treatment of Cancer’s Quality of Life Questionnaire (EORTC QLQ-C30), 
supplied by the Research Base (see Appendix III).  The EORTC QLQ-C30 will be 
completed at pre-treatment visit, study week 52 (or end of  trastuzumab therapy if 
discontinued before week 52 or study agent is stopped before week #52) and 
study months 18 and 24 (or 6 and 12 months after the last dose of  trastuzumab 
or stopped study agent.  EORTC QLQ-C30 should be completed AFTER 
registration and BEFORE patient receives study agent and trastuzumab 
 
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6.8.8 
Physical examination, including height and weight will be performed at baseline, 
every 3 months X 4 (+/- 2 weeks), study week 52 (or end of  trastuzumab therapy if 
discontinued before week 52) and study months 18 and 24 (or 6 and 12 months 
after the last dose of trastuzumab. Reports of disease status will be requested 
every 3 months until the study ends (3, 6, 9 and 12 months after discontinuation 
of study agent). 
6.8.9 
Research Staff will complete a baseline Concomitant Medication Form (see 
Appendix III) at baseline and every 3 months X 4 (+/- 2 weeks), study week 52 (or 
end of trastuzumab therapy if discontinued before week 52), and every 3 months 
following discontinuation of study agent at each subsequent study visit.  Reports 
of disease status will be requested and concomitant medications will be 
submitted every 3 months until the study ends (3, 6, 9, and 12 months after 
discontinuation of study agent). Concomitant Medications should include 
chemotherapy agents and any medications listed in Appendix V. 
6.8.10 
Research staff will instruct participants to begin taking their study medicine on 
the morning of the day they are scheduled to begin trastuzumab treatment.  
Participants will be instructed to take study agent once daily with food at about 
the same time each day.   
6.8.11 
For monitoring of compliance, patients will complete Study Medicine Daily Logs.  
Instructions for completing the forms will be given each time study agent is 
dispensed.  Research staff will collect and review Study Medicine Daily Logs at 
all follow-up visits and the off-treatment visit (see Appendix III) for compliance, 
documentation of blood pressure monitoring and adverse event reporting.     
6.8.12 
Discrepancies noted on the Study Medicine Daily Logs will be addressed and 
documented.  If a discrepancy is evident, research staff will clarify with the 
patient, and instruct on how to prevent future discrepancies.   
6.8.13 
Study Medicine Daily Logs are to be submitted to the Research Base Operations 
Center at least every 3 months.  If the logs are being collected more frequently, 
they may be submitted at any time. 
6.8.14 
Adverse events will be documented, using the Adverse Event (AE) Form 
(Appendix III), graded using the Common Terminology Criteria for Adverse 
Events(CTCAE) version 4.0, and reported per guidelines in section 8.11. 
6.8.15 
Patients will be instructed to take their blood pressure every day during the first 
week of study medicine, three times a week the second week of the study, and 
then weekly while taking the study medicine.  Blood pressure results will be 
documented on the Study Medicine Daily Log.   
6.8.15.1 
Blood pressure cuffs will be provided to the patient by the SunCoast 
CCOP Research Base at no charge. 
6.8.16 
Follow-up visits will be scheduled every 3 months X 4 (+/- 2 weeks) through Study 
week 52 (or when trastuzumab therapy ends, if it is discontinued before week 
52).  Follow-up visits should occur within +/- 10 working days of the expected visit 
schedule.  
6.8.17 
Patients who fail treatment or discontinue study agent prematurely, will continue 
in study follow-up for 12 months, having LVEF measurements 6 and 12 months 
after study agent was discontinued.  An additional report of concomitant 
medications and disease status will be requested every 3 months X 4 after 
discontinuing study agent. 
6.8.17.1 
Patients may be re-challenged with trastuzumab per ASCO 
guidelines; however they will be considered study failures and 
discontinue study agent. 
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7.0 
Treatment Response Assessment: 
 
Study failure is defined as:  
7.1 
An absolute decrease in LVEF from baseline of  ≥ 10% at follow-up (for example– if MUGA 
is 80% at baseline, then 70% is a 10% decrease in LVEF and study failure; if ECHO is 60 – 
65%, then 50 – 55% is a 10% decrease in LVEF and study failure). 
7.2 
An absolute decrease of ≥ 5% in LVEF from baseline for individuals with < 50% LVEF at 
follow-up  (for example– if MUGA is 52% at baseline, then 47% is a 5% decrease in LVEF 
and study failure). 
 
Criteria for discontinuing study agent: 
7.3 
Treatment failure 
7.4 
Treatment with trastuzumab discontinued 
7.5 
Symptomatic bradycardia or hypotension 
7.6 
Withdrawal of consent to participate in study 
7.7 
All data acquired prior to discontinuation will be included in the primary analysis.  Every 
effort will be made to conduct a final study visit with the participant.  Participants will be 
followed clinically until adverse events resolve, if applicable. 
 
8.0 
Toxicity Assessment, Adverse Event Reporting and Unblinding Procedures 
Toxicity Assessment: 
8.1 
CTCAE version 4.0 will be used to evaluate all toxicities. All appropriate treatment areas 
should have access to a copy of the CTCAE. To access the CTCAE version 4.0 click 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40.      
8.2 
For help in determining AE categories, you may access Safety Profiler at:  
http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx.  
8.3 
Definitions: 
8.4 
An adverse event is defined as:  “…an unfavorable and unintended sign, symptom or 
disease associated with a participant’s participation in this research study.”   
8.5 
Serious adverse events include those events that:  “result in death; are life-threatening; 
require inpatient hospitalization or prolongation of existing hospitalization; create 
persistent or significant disability/incapacity, or a congenital anomaly/birth defects.”   
8.6 
An unexpected adverse event is defined as “any adverse experience…the specificity or 
severity of which is not consistent with the risks of information described in the literature 
(protocol and package inserts).”  
8.7 
Expected adverse events are those that are “identified in the research protocol as having 
been previously associated with or having the potential to arise as a consequence of 
participation in the study.”   
Adverse Event (AE) Reporting Requirements (FDA IND Exemption #102,825): 
8.8 
This study utilizes drugs that are commercially available 
8.9 
Adverse events will be reported using FDA Guidelines  
8.10 
Serious and unexpected adverse events: 
8.10.1 
Events that are both serious and unexpected with possible, probable or definite 
attribution to study agent:  
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8.10.1.1 
Notify the Research Base Operations Center within 24 hours of 
learning about the event by telephone (800-909-1242), fax (813-910-
5998) or email (ccop@epi.usf.edu). 
8.10.1.2 
Report known details of event to the Research Base using the FDA 
MedWatch Adverse Reaction (ADR) Form FDA 3500A (see Appendix 
III), which must be signed by the treating Investigator.  Update the 
form as more information becomes available and submit to the 
Research Base Operations Center. 
8.10.1.2.1 
All follow-up information referencing a reported 
adverse event will go through the SunCoast CCOP 
Research Base Operations Center. 
8.10.1.2.2 
The SunCoast CCOP Research Base Operations 
Center ensures that the FDA is notified according to 
the Code of Federal Regulations. 
8.10.1.3 
Supply written documentation of the event to the Research Base 
within 10 days (include the event on the Adverse Event Reporting 
Form, which provides information on grading and attribution). 
8.10.1.3.1 
Notify the local IRB within 10 days or per IRB 
institutional guidelines. 
8.11 
Reportable adverse events: 
8.11.1 
An adverse event is defined as:  “…an unfavorable and unintended sign, 
symptom or disease associated with a participant’s participation in this research 
study.”  As such: 
8.11.1.1 
Adverse events, such as hospitalization with febrile neutropenia, are 
not reportable events on this study.  In this example, the event is 
associated with administration of cytotoxic chemotherapy, which 
would be administered regardless of participation in this study.   
8.11.1.2 
In this same example, if the severity of neutropenia is higher than 
expected, and if a clinician determines that it is possibly, probably or 
definitely related to administration of a study agent, the event would 
be reportable.  
8.11.2 
Review the patient’s Study Medicine Log regularly for patient reported AEs that 
may be related to administration of study agent.  In particular, document the 
incidence of: 
8.11.2.1 
Shortness of breath 
8.11.2.2 
Diarrhea 
8.11.2.3 
Tiredness 
8.11.2.4 
Fainting/Dizziness  
8.11.3 
Document toxicity grade using CTCAE V4.0 
8.11.3.1 
The Adverse Event Reporting Form captures both toxicity grade and 
attribution, which is determined by the treating clinician. 
Submit the Adverse Event Reporting Form to the Research Base Operations 
Center within the timeframes addressed in Section 9.2. 
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Unblinding procedure: 
8.12 
A patient’s treatment may be unblinded if an event requires knowledge of the assigned 
treatment in order to deliver appropriate medical care.  An investigator, who feels this is 
the case, should contact the SunCoast CCOP Research Base Operations Center.  If the 
biostatistician is in agreement, treatment will be unblinded and the investigator will be 
informed.  This action will be reported to the Data Monitoring Committee. 
8.13 
At the conclusion of the study, all investigators will be unblinded with respect to their 
patient’s treatments.  They should inform their patients of their actual treatment.   
 
9.0 
Records to be Kept / Data Collection Forms Submission Guidelines 
 
9.1 
Fax (813-910-5998) or email (ccop@epi.usf.edu ) forms to the SunCoast CCOP Research 
Base Operations Center within 14 days of each protocol visit:  
 
9.2 
Records to be Kept Table  
 
Type of form 
Time due 
Study Agent Accountability Record 
Do not submit – This form is to be updated 
each time study agent is received and 
dispensed. 
Intent to Participate Form 
At IRB submission 
Eligibility Form 
Within 14 days of registration 
Registration & Randomization Worksheet 
Within 14 days of registration 
Demographics Form 
Within 14 days of registration 
Patient Assessment Form 
Within 14 days of protocol visit 
Follow-up Form 
Within 14 days of protocol visit 
Medication Order Forms (to Carter King 
Pharmacy) 
At first patient registration to Carter King 
dispensing pharmacy 
Concomitant Medications Form 
Within 14 days of protocol visit 
EORTC QLQ C-30 Quality of Life Form  
Within 14 days of protocol visit 
Study Medicine Daily Log 
Within 14 days of protocol visit 
Off Study Form 
Within 14 days of protocol visit 
Adverse Events Form 
Within 14 days of protocol visit 
MedWatch Adverse Events Report copy 
Within 5 days of completion if required 
 
10.0 Statistical considerations 
 
Primary Outcome Variables: 
10.1 
The primary aim of this study is to determine if treatment with lisinopril or Coreg CR® can 
reduce the incidence of trastuzumab-induced cardiotoxicity in patients with HER2-positive 
breast cancer after 52 weeks of treatment as measured by the preservation of left 
ventricular ejection fraction (LVEF).  Patients who demonstrate an LVEF < 50% at follow-
up and a ≥ 5% absolute decrease in EF from baseline, or a  ≥ 10% absolute decrease in 
LVEF after initiating trastuzumab therapy will be considered failures. 
 
10.2 
We will compare the LVEF of each treatment group with the placebo arm. In addition, a 
comparison of the two study agents will be completed, recognizing that we do not have 
sufficient power for this secondary analysis.  Linear regression with treatment and 
anthracycline regimen (yes/no) as independent factors will be used to compare the 
changes of LVEF, a continuous measure between the two arms (treatment arms with 
placebo).  Logistic regression with treatment and anthracycline regimen (yes/no) will be 
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used to compare the proportions of cardiac failures in each arm. For comparisons of each 
treatment with placebo, we will consider one-sided 0.025 significant levels to adjust for the 
multiple testing.  A mixed linear model will be utilized to analyze the pattern of LVEF 
change during the course of this study using the data from all follow-up visits. 
Furthermore, a multiple regression model will be used to control for potential confounders 
such as use of other agents (i.e. pertuzumab). 
Sample Size:   
10.3 
The sample size calculation is based on the comparisons of each treatment with placebo.  
Using a conservative incidence estimate, we hypothesize that 15% of women treated for 
breast cancer with adjuvant or neoadjuvant trastuzumab will have decreased LVEF in the 
placebo arm as compared to 5% of the women on the treatment arms.  To detect a 10% 
difference in women who exhibit a decrease in LVEF in response to study agent, lisinopril 
or Coreg CR®, a sample size of 141 participants for each of the three arms is required to 
achieve 80% power for a one-sided Pearson’s chi-square test at the 0.025 significance 
level.  Assuming a 10% drop-out rate, 468 subjects will be randomized to one of the three 
arms.   
 
10.4 
Given the large difference in cardiac toxicity between the regimens,60 the protocol seeks to 
approximately balance the regimens by enrollment to 2 separate cohorts; patients who 
received an anthracycline-containing regimen and patients whose treatment regimen did 
not contain an anthracycline. A minimum of 187 subjects will be enrolled to each cohort.  
As such, should accrual to a cohort reach 281, that cohort will be closed to new accrual 
and the study will be completed with accrual to the remaining cohort.   
 
Intent-to-Treat Principle: 
 
10.5 
As possible, all statistical analyses will be based on the intent-to-treat principle. Subjects 
will be analyzed according to their randomized assignment. 
 
Secondary Outcome Variables 
10.6 
Interruptions of trastuzumab therapy caused by a decrease of LVEF will be evaluated by 
comparing the number of trastuzumab cycles completed without interruption by patients 
within each treatment group.  Poisson regression will be utilized to compare the number of 
trastuzumab cycles completed.  Furthermore, the proportion of patients completing 
uninterrupted trastuzumab therapy will be compared.  Logistic regression will be utilized to 
compare the proportion of patients completing trastuzumab therapy between treatment 
arms.  The frequency of all trastuzumab interruptions categorized by the criteria for study 
agent discontinuation (Section 7.0) and 95% confidence interval will be reported and 
compared by treatment group.  A Fisher’s exact test or chi-square test, depending on cell 
size, will be utilized to compare the frequency of categorized trastuzumab interruptions 
between the treatment arms.  
 
10.7 
Quality of life changes will be evaluated using the EORTC QLQ-C30 V 3.0 at baseline and 
at the end of treatment (end of trastuzumab therapy or week 52).  The analysis plan will 
follow a linear regression model to consider the treatment effects on these measurements 
(dependent variables) adjusted for baseline age and potentially other covariates to 
compare the treatment arms.  The observed data will be evaluated for normality and 
appropriate transformation introduced prior to conducting the analysis.  
 
10.8 
To assess the long term effect of the study agents, follow-up measurements will be 
collected at study months 18 and 24 (or 6 and 12 months after the last dose of 
trastuzumab, if it was discontinued before week 52). This exploratory analysis will be 
completed to determine the long term effects on the prevention of cardiomyopathy and 
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impact on QOL for either or both study agents. The treatment groups will be compared to 
using appropriate two sample tests.  
 
10.9 
Receiver operating characteristic (ROC) curves will be used to determine the predictive 
value of two most common biomarkers in predicting trastuzumab-induced cardiotoxicity: 
Brain natriuretic peptide (BNP) vs. Cardiac troponin I. The null hypothesis is that areas 
under ROC (AUCROC) for the two biomarkers regarding identification of trastuzumab-
induced cardiotoxicity (primary endpoint) are equal. Areas under the ROC curves will be 
tested using Delong’s nonparametric approach, applying generalized U-statistics to 
generate an estimated covariance matrix for correlated ROC curves 63. Due to the 
uncertainty about the treatment effect of the active drugs, this analysis will be limited to the 
placebo group only. With approximate 15% incidence rate in the placebo group, the 
proposed sample size will achieve a power greater than 80% to reject the null if the true 
difference between two ROCAUCs is 20% or more, assuming the correlation between 
BNP and Troponin I is 0.60.  
 
Adverse Events 
10.10 
Adverse Events and side effects will be tabulated and compared for all patients.  Adverse 
Events experienced will be compared with respect to frequency using the Fisher’s exact 
test or chi square test if the cell size is sufficient between arms.  Estimates of the AE rates 
as well as exact 95% confidence intervals for AEs will also be reported by treatment arm.  
All available AE data will be summarized and reviewed by the SCUSF CCOP Research 
Base Data Monitoring Committee at least every six months.  
 
11.0 Data Safety Monitoring Plan 
 
11.1 
This protocol will be monitored in accordance with the SunCoast CCOP Research Base 
Data Safety Monitoring plan on file with the NCI last updated June 09, 2009. 
 
11.2 
The Data Monitoring Committee will review this project at least every six months. 
 
12.0 Study Feasibility: Role of participating CCOPs 
12.1 
Member CCOPs and SunCoast affiliates will be responsible for enrolling 468 subjects 
during this study, which is expected to accrue for 3 years. 
 
12.2 
This study will be conducted in the community setting where this patient population is 
seen. 
 
12.3 
Study forms are available via the SunCoast CCOP Research Base website 
(http://www.SunCoastccop.org) 
 
12.4 
An automated registration/randomization system is available 24/7. 
 
12.5 
Study agent will be provided at no cost to the patient or clinical center by the SunCoast 
CCOP Research Base. 
 
12.6 
Laboratory testing will be provided at no cost to the patient or clinical center by the 
SunCoast CCOP Research Base.  Specimens will be submitted to the local LabCorp for 
processing.  Preliminary and final reports will be submitted directly to the site by LabCorp 
and final results will be submitted directly to the SunCoast CCOP Research Base 
Operations Center by LabCorp. 
 
12.7 
Blood pressure cuffs will be provided at no cost to the patient or clinical center. 
12.8 
EORTC QLQ-C30 Quality of Life Forms will be provided at no cost to the patient or clinical 
center by the SunCoast CCOP Research Base. 
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12.9 
Funds are available to reimburse clinical centers in the event payment of follow-up LVEF 
testing is not covered as standard of care.  Using Medicare reimbursable rates, a clinical 
center may invoice the Research Base, using the Reimbursement Request From in 
Appendix III, for $300 if other payment is denied.   
12.10 
Evidence of training in Responsible Conduct of Research shall be on file at the SunCoast 
Research Base Operations Center prior to study start-up. 
12.11 
Informed consent will be obtained and documented prior to initiation of any study related 
procedures. 
12.12 
Basic guidelines for confidentiality and medical ethics will be closely adhered to during the 
study. 
12.13 
Data submission guidelines addressed in Section 9.0 will be followed.  Queries will be 
generated by the SunCoast Research Base Operations Center for missing or unclear data 
elements. 
12.14 
CCOPs and enrolling SunCoast affiliates will be audited within 18 months of the first 
accrual and at least once every three years thereafter. 
12.15 
Subjects may be enrolled on other research studies if the studies do not impact eligibility 
criteria or protocol treatment for this study and is permitted by the local site Institutional 
Review Board.   
12.16 
This trial is feasible to conduct in the community setting.  To determine the feasibility of 
completing this trial under the CCOP mechanism, we surveyed our adult CCOP members 
for interest and estimated annual accrual.  We received an enthusiastic response to this 
study.  Of the 17 members surveyed, 11 members plan to participate in this study.  Based 
on the feedback we received from our adult CCOP members, and allowing for a 
reasonable start up period, we estimate that the protocol will accrue at a rate of 12 
patients per month.  We anticipate that recruiting for this study will take approximately 39 
months to reach the accrual goal of 468.  
12.17 
We are aware of 6 treatment trials in patients with HER-2 positive breast cancer that 
employ trastuzumab in the treatment regimen.  While the cardiotoxic effects of study 
therapy will be evaluated, only 2 studies will include this in their primary objectives.  
Furthermore, these trials do not include the use of supportive care agents such as those 
listed in this study.  SCUSF 0806 differs from the BETH trial (NSABP B-44-1) in that 
SCUSF 0806 allows neoadjuvant chemotherapy (including anthracycline-containing 
regimens) the pathology requirements are not as stringent, no tissue samples are required 
and the LVEF entry criterion is lower for SCUSF 0806 (≥ 50% vs. ≥ 55%).  As such, we do 
not anticipate any effect on our accrual potential. 
 
13.0 References: 
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trastuzumab? 12th Annual Scientific Meeting of the Heart Failure Society of America. Vol 
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3. 
Perez EA, Rodeheffer R. Clinical cardiac tolerability of trastuzumab. J Clin Oncol. Jan 15 
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4. 
Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med. Jul 5 
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Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human 
breast and ovarian cancer. Science. May 12 1989;244(4905):707-712. PMID:2470152. 
6. 
Negro A, Brar BK, Lee KF. Essential roles of Her2/erbB2 in cardiac development and function. 
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7. 
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in 
first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. Feb 1 
2002;20(3):719-726. PMID:11821453. 
8. 
Rastogi P, Jeong J, Geyer C, et al. Five year update of cardiac dysfunction on NSABP B-31, a 
randomized trial of sequential doxorubicin/cyclophosphamide (AC)paclitaxel (T) vs. ACT with 
trastuzumab (H). J Clin Oncol. 2007;25(18S (June 20 Supplement)):LBA513.  
9. 
Kelly H, Kimmick G, Dees EC, et al. Response and cardiac toxicity of trastuzumab given in 
conjunction with weekly paclitaxel after doxorubicin/cyclophosphamide. Clin Breast Cancer. Aug 
2006;7(3):237-243. PMID:16942640. 
10. 
Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new 
insights based on clinical course and response to medical treatment. J Clin Oncol. Nov 1 
2005;23(31):7820-7826. PMID:16258084. 
11. 
Valero V, Gill E, Paton V, et al. Normal cardiac biopsy results following co-administration of 
doxorubicin (A), Cyclophosphamide (C) and trastuzumab (H) to women with HER2 positive 
metastatic breast cancer J Clin Oncol (Meeting Abstracts). 2004;22:572.  
12. 
Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial 
comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab 
as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing 
breast cancer: NSABP B-31. J Clin Oncol. Nov 1 2005;23(31):7811-7819. PMID:16258083. 
13. 
Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced 
cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. Dec 5 
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14. 
Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced 
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15. 
Telli ML, Hunt SA, Carlson RW, Guardino AE. Trastuzumab-related cardiotoxicity: calling into 
question the concept of reversibility. J Clin Oncol. Aug 10 2007;25(23):3525-3533. 
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16. 
Chien KR. Stress pathways and heart failure. Cell. Sep 3 1999;98(5):555-558. PMID:10490095. 
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Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. 
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18. 
Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C. Requirement for neuregulin receptor 
erbB2 in neural and cardiac development. Nature. Nov 23 1995;378(6555):394-398. 
PMID:7477377. 
19. 
Grazette LP, Boecker W, Matsui T, et al. Inhibition of ErbB2 causes mitochondrial dysfunction in 
cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol. Dec 7 
2004;44(11):2231-2238. PMID:15582322. 
20. 
Crozier I, Ikram H. Angiotensin converting enzyme inhibitors versus digoxin for the treatment of 
congestive heart failure. Drugs. May 1992;43(5):637-650. PMID:1379144. 
21. 
Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Effect of enalapril on 12-year survival 
and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet. 
May 31 2003;361(9372):1843-1848. PMID:12788569. 
22. 
Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients 
with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular 
enlargement trial. The SAVE Investigators. N Engl J Med. Sep 3 1992;327(10):669-677. 
PMID:1386652. 
23. 
Thomas WG, Brandenburger Y, Autelitano DJ, Pham T, Qian H, Hannan RD. Adenoviral-directed 
expression of the type 1A angiotensin receptor promotes cardiomyocyte hypertrophy via 
transactivation of the epidermal growth factor receptor. Circ Res. Feb 8 2002;90(2):135-142. 
PMID:11834705. 
24. 
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and 
Management of Chronic Heart Failure in the Adult: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to 
Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in 
collaboration with the American College of Chest Physicians and the International Society for 
Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. Sep 20 
2005;112(12):e154-235. PMID:16160202. 


 
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25. 
Davis BR, Piller LB, Cutler JA, et al. Role of diuretics in the prevention of heart failure: the 
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. May 9 
2006;113(18):2201-2210. PMID:16651474. 
26. 
Giles TD, Fisher MB, Rush JE. Lisinopril and captopril in the treatment of heart failure in older 
patients. Comparison of a long- and short-acting angiotensin-converting enzyme inhibitor. Am J 
Med. Sep 23 1988;85(3B):44-47. PMID:2844087. 
27. 
Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with 
reduced left ventricular ejection fractions. The SOLVD Investigattors. N Engl J Med. Sep 3 
1992;327(10):685-691. PMID:PMID:1463530. 
28. 
Arnold JM, Yusuf S, Young J, et al. Prevention of Heart Failure in Patients in the Heart Outcomes 
Prevention Evaluation (HOPE) Study. Circulation. Mar 11 2003;107(9):1284-1290. 
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