Safety and Efficacy of Single Agent Adjuvant Trastuzumab (Herceptin®) in Older Women With Early-Stage and Locally Advanced Breast Cancer: A Phase II Trial
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Cynthia Owusu, MD

 
CASE 10107 12/28/2018 
Page 1 of 85 
 
 
 
CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
 
STUDY NUMBER:  CASE 10107 
 
 
STUDY TITLE:  
Safety and Efficacy of Single Agent Adjuvant Trastuzumab (Herceptin®) in 
Older Women with Early-Stage and Locally Advanced Breast Cancer: A 
Phase II Trial 
 
  
 
PRINCIPAL INVESTIGATOR: 
Cynthia Owusu, M.D., M.Sc. 
 
 
 
 
Assistant Professor of Medicine 
Division of Hematology/Oncology  
 
Case Western Reserve University 
Seidman Cancer Center 
 
 
 
11100 Euclid Avenue Lakeside 1232 
 
 
 
Cleveland, OH   44106 
 
 
 
 
(216) 844-7670  
 
 
 
 
 
 
CO- INVESTIGATORS: 
              Adam Brufsky, MD, PhD 
 
 
 
              University of Pittsburgh 
 
 
 
               300 Halket Street, Suite 4628 
 
 
 
 
Pittsburgh, PA 15213 
 
 
 
 
              Heidi Klepin, MD 
                                                                Wake Forest University Health Sciences 
 
 
 
 
Medical Center Boulevard 
 
 
 
 
Winston-Salem, NC 27157 
 
 
 
 
 
 
 
 
 
Charles Vogel, MD 
 
 
 
 
       Sylvester at Deerfield Beach 
 
 
 
 
1192 East Newport Center Drive, Suite # 100 
 
 
 
 
 
 
Deerfield Beach, FL 33442 
 
 
 
 
 
 
STATISTICIAN: 
 
              Pingfu Fu, PhD 
 
 
 
              Assistant Professor of Biostatistics 
 
 
 
              Dept of Epidemiology & Biostatistics 
 
 
 
              Case Western Reserve University   
 
CLINICAL FACILITY: 
              University Hospitals Cleveland Medical Center 
 
 
 
 
 
 
APPROVALS: 
 
 
              Protocol Review and Monitoring Committee: 11/20/2007 
 
 
                             CASE Cancer IRB: 04/10/2008 
 
STUDY COORDINATOR 
 
Lauren Hricik 
                                                                 Clinical Trials Unit 
 
 
 
 
University Hospitals Cleveland Medical Center 
 
 
 
 
Case Western Reserve University 
 
 
 
 
11100 Euclid Avenue 
 
 
 
 
Cleveland, OH 44106-5065 
 
 
 
 

 
CASE 10107 12/28/2018 
Page 2 of 85 
 
 
 
TABLE OF CONTENTS                                       
                                                                                                                                       Page 
1. 
INTRODUCTION ............................................................................................      7 
1.1 
Background ...........................................................................................      7 
1.2 
Significance...........................................................................................      9 
1.3 
HER2 Overexpression and Breast Cancer ............................................      9 
1.4 
Herceptin Clinical Experience in the Adjuvant Setting ........................      10 
1.5 
Herceptin Clinical Experience in the Metastatic Setting ......................      12 
1.6 
Safety ....................................................................................................      13 
1.7       Clinical Pharmacokinetics of Trastuzumab ..........................................      14 
1.8       Physiologic Cardiac Markers Background  
            and Rationale ........................................................................................      15 
1.9       Comprehensive Geriatric Assessment Background and 
            Rationale ...............................................................................................      16  
 
2. 
OBJECTIVES ...................................................................................................      19 
2.1 
Primary Objective .................................................................................      19 
2.2 
Secondary Objectives............................................................................      19  
 
3. 
STUDY DESIGN..............................................................................................      19  
 
3.1 
Description of the Study .......................................................................      19 
3.2 
Rationale for Study Design ...................................................................      20 
3.3       Assessments ..........................................................................................      22  
3.4 
Outcome Measures................................................................................      24  
3.4.1 
Primary Outcome Measure ....................................................      24  
3.4.2 
Secondary Outcome Measures ...............................................      25  
 
3.5 
Safety Plan ............................................................................................      29 
3.6       Compliance With Laws and Regulations ..............................................      33 
 
4.    STUDY PARAMETERS AND CALENDER ....................................................      34 
 
5. 
MATERIALS AND METHODS ......................................................................      35  
5.1 
Subjects .................................................................................................      35  
5.1.1 
Inclusion Criteria ...................................................................      35 
5.1.2 
Exclusion Criteria ..................................................................      36  
5.1.3 
Inclusion of women and minorities........................................      36 
5.2       Registration Procedures ........................................................................      37 
5.3 
Treatment Plan ......................................................................................      37 
5.4       Study Treatment ....................................................................................      38 
5.4.1 
Herceptin Formulation ...........................................................      38 
5.4.2 
Dosage, Preparation, Administration, and Storage ................      38  
5.4.3 
Dosage Modification ..............................................................      40 
5.4.4       Toxicities................................................................................      41  
5.4.5       Herceptin Overdosage ............................................................      46 
5.5      Ancillary Therapy ..................................................................................      45 
5.6      Concomitant and Excluded Therapy ......................................................      46  

 
CASE 10107 12/28/2018 
Page 3 of 85 
 
 
 
 
 
TABLE OF CONTENTS (cont'd) 
 
Page 
5.7      Study Assessments .................................................................................      46 
5.8      Discontinuation of Protocol-Specifies Therapy .....................................      46 
5.9      Subject Discontinuation .........................................................................      47 
         5.10    Study Discontinuation ............................................................................      47 
5.11    Statistical Methods .................................................................................      47 
5.11.1 
Study design ...........................................................................      47 
5.11.2 
End points ..............................................................................      47  
5.11.3 
Sample Size Justification .......................................................      48 
5.11.4     Accrual Estimates and Rate ...................................................      49 
5.11.5 
Statistical Analysis .................................................................      50  
5.11.6 
Missing Data ..........................................................................      50  
 
5.12 
Data Quality Assurance ........................................................................      51  
5.13     Data Safety and Monitoring Plan ..........................................................      51 
 
 
6. 
REPORTING OF ADVERSE EVENTS ..........................................................      51  
6.1 
Adverse Event and Reporting Definitions ............................................      52  
6.2 
Reporting of Serious Adverse Events Associated With the 
Herceptin ...............................................................................................      53  
 
 
 
 
7. 
INVESTIGATOR REQUIREMENTS .............................................................      55 
7.1 
Study Initiation......................................................................................      55 
7.2 
Study Completion .................................................................................      55  
7.3 
Informed Consent..................................................................................      55  
7.4       Institutional Review Board or Ethics Committee Approval .................      56  
7.5 
Study Monitoring Requirements ...........................................................      56  
7.6 
Data Collection .....................................................................................      56  
7.7 
Study Medication Accountability .........................................................      56  
7.8 
Disclosure of Data.................................................................................      57 
7.9 
Retention of Records.............................................................................      57  
 
8. 
PROTECTION OF HUMAN SUBJECTS .......................................................      57  
8.1 
Ethics.....................................................................................................      57 
8.2 
Privacy and Confidentiality ..................................................................      57  
 
 
9.     REFERENCES ..................................................................................................      58  
 
 
 
 
 
 
 

 
CASE 10107 12/28/2018 
Page 4 of 85 
 
 
 
 
 
 
TABLES AND FIGURES 
 
Table 1: 
Incidence of Cardiac Dysfunction in Adjuvant and Metastatic 
Trials of Trastuzumab ........................................................................         8 
Table 2: 
Validated Comprehensive Geriatric Assessment Instruments and 
Corresponding Domain ......................................................................       18 
Table 3: 
Asymptomatic Decrease in LVEF: Percentage Points from 
Baseline ..............................................................................................       32 
 
Table 4: 
Study Parameters and Calendar .........................................................       34 
 
Table 5: 
Herceptin Infusion Time and Post-Infusion Observation Period .......       40 
 
Figure 1:          Study Schema………………………………………… ....................         6   
 
 
 
APPENDICES 
Appendix A: NCI Common Toxicity Criteria 
Appendix B: HFSA Guidelines for CHF Treatment 
Appendix C: FDA Medwatch 3500 Form  
Appendix D: Instructions for Handling and Shipping Serum to Case Comprehensive  
                        Cancer Center  
Appendix E: Self-administered Geriatric and Quality of Life Instruments   
Appendix F: Staff-administered Geriatric Instruments 
 

 
CASE 10107 12/28/2018 
Page 5 of 85 
 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trastuzumab 
Loading dose= 8mg/kg 
Maintenance dose= 6mg/kg 
q3 weekly 
 
Unable or unwilling to 
receive chemotherapy 
Women 60 years with 
Her2+ breast cancer 
≥T1b, any N, M0 
 
Mastectomy or lumpectomy  
 
52 weeks** 
 
**Adjuvant radiation therapy and endocrine therapy may be given as per institutional 
  standard during this period  

 
CASE 10107 12/28/2018 
Page 6 of 85 
 
 
 
 
1. 
INTRODUCTION  
1.1      BACKGROUND   
Persons 65 years and older are the fastest growing segment of the population in America 
and by 2030 will account for 20% of the US population.1,2 They however bear a 
disproportionate burden of the incidence and mortality of cancer and account for more 
than 50% of all new cancers that occur in the US including breast cancer.2,3 Because the 
most important risk factor for breast cancer is age and because of recent gains in life 
expectancy, these proportions are expected to increase. Unfortunately older cancer 
patients are more likely to receive sub-optimal cancer treatment4-6, and are consistently 
under-represented in clinical trials of new cancer therapies.7,8 With the dramatic shift in 
the demographics of the aging population it is imperative that treatment strategies tailored 
to the needs of the older cancer patients are developed.  
 
Evaluation of the biology of breast cancer by age has suggested that estrogen–receptor 
positive, low S phase, low tumor grade and Her-2 negative tumors are more common 
among older than younger women.9-11  Inspite of this favorable tumor profile and recent 
advances in breast cancer therapy this has not translated into any major survival 
advantage for older women with breast cancer as compared with their younger 
counterparts.12 There is evidence that receipt of sub-optimal treatment by older women 
may be contributing to this poor outcome.4  In addition there is a reluctance among 
clinicians to include older women in breast cancer clinical trials.8 Under-representation 
has been found to be particularly striking in Southwest Oncology Group (SWOG)` breast 
cancer trials, with the percentage of elderly patients participating in SWOG trials and the 
general population being nine percent and 49%, respectively.13This has led to a paucity of 
efficacy data and a lack of definitive recommendations for the use of adjuvant 
chemotherapy in women 70 yrs and older with breast cancer.14   
 
Trastuzumab (herceptin; Genentech, South San Francisco, CA) is a humanized mono-
clonal antibody targeting the extracellular domain of the human epidermal growth factor 
receptor 2 (HER2) protein. Amplification or overexpression of Her2 is seen in 
approximately 25-30%  of invasive breast cancers and is associated with an unfavorable 
prognosis.15 Trastuzumab as a single agent and also in combination with chemotherapy 
has proven to be efficacious in the treatment of Her2-positive breast cancer in the 
metastatic setting resulting in response rates of 34% and 50%, respectively.16,17 The 
benefit of this approach and the poor prognosis associated with this disease has recently 
led to a number of pivotal phase III trials in the adjuvant setting which have all 
demonstrated statistically significant increases in disease-free survival when trastuzumab 
is used either concurrently with or sequential to docetaxel, after anthracycline-based 
chemotherapy.18,19 The role of single agent trastuzumab in the adjuvant setting, however, 
has not been explored. 
 
The main adverse effect associated with trastuzumab is cardiotoxicity. Concurrent use of 
anthracycline-based chemotherapy with trastuzumab in the metastatic setting was 
associated with an overall cardiac dysfunction rate of 27%16. Furthermore trastuzumab 
use in the adjuvant setting in combination with  paclitaxel was associated with a 4.1% 
cardiac event rate and an asymptomatic decline in left ventricular ejection fraction of 

 
CASE 10107 12/28/2018 
Page 7 of 85 
 
 
 
14%, resulting in an overall cardiac dysfunction rate of 18%19,20. In contrast use of single 
agent trastuzumab as a first line agent in the metastatic setting  was associated with a 
cardiac event rate of only 2% 17  and an overall cardiac dysfunction rate of up to 7%.21,22 
.There is no data of single agent use of trastuzumab in the adjuvant setting. However, the 
existing data does suggest that use of trastuzumab concurrently with or sequentially after 
chemotherapy is associated with a much increased risk of cardiotoxicity.  
 
 
 
Consistent with the under-representation of older women in breast cancer clinical trials of 
chemotherapy8,13, trastuzumab was administered to only 257 patients (6%) who were 65 
years and older (124 (adjuvant) and 133 (metastatic)) out of 4443 women who 
participated in clinical trials of trastuzumab that led to FDA-approval.23 Besides cardiac 
dysfunction, limitations in data collection and differences in study design of the two 
studies of trastuzumab in the adjuvant setting precluded a determination of whether the 
toxicity profile of trastuzumab in older patients was different from younger patients. The 
reported clinical experience was also not adequate to determine whether the efficacy 
improvements (ORR, TTP, OS, DFS) of trastuzumab treatment in older patients was 
different from that observed in patients <65 years of age. 
 
Since older women bear a disproportionate burden of the incidence and mortality 
associated with breast cancer it is paramount that they receive optimal treatment just like 
their younger counterparts. However based on the existing literature several questions 
remain unanswered as these results cannot be generalized to the older population. Is 
trastuzumab safe and effective in older breast cancer patients considering age-related 
changes in physiology and an increased incidence of comorbidities? Will single agent 
adjuvant trastuzumab be less cardiotoxic but yet still effective? The risk-benefit profile in 
older patients remains poorly understood and this study is designed to address these 
questions. 
Table 1: Incidence of Cardiac Dysfunction in Adjuvant and Metastatic Trials of 
Trastuzumab 
 
Study 
           % NYHA Class III-IV CHF 
Control arm 
Trastuzumab arm 
Adjuvant Studies 
NSABP B-31 
0.8 
  4.1 
N9831 
0 
  2.9 
HERA 
0 
  0.6* 
BCIRG 006** 
.95† 
  1.33‡ - 2.34§ 
FinHer¶ 
0 
  0 
Metastatic Studies 
Vogel (JCO 1999) 
No control arm 
  2 (Trastuzumab alone) 
Cobleigh (JCO, 1999) 
No control arm 
  5 (Trastuzumab) 
 
Slamon (NEJM, 2001)  
3 (AC alone)  
1 (Paclitaxel )          
16 (AC + Trastuzumab)              
  2 (Paclitaxel + trastuzumab) 
*1-yr trastuzumab arm; **Includes: Grade 3 or 4 arrhythmias, Grade 3 or 4 cardiac ischemia / infarction; 
†ACT; ‡TCH; §ACTH; ¶Small sample size. 

 
CASE 10107 12/28/2018 
Page 8 of 85 
 
 
 
1.2      SIGNIFICANCE 
This study is significant because it seeks to address an important question in a subset of 
the population that has been consistently under-represented in clinical trials. Our long-
term goal is to develop effective and tolerable therapeutic interventions for the treatment 
of breast cancer in older women. The objective for this particular study is to determine 
the tolerability and efficacy of adjuvant trastuzumab in older women. Trastuzumab is 
particularly attractive because except for cardiotoxicity it has a favorable safety profile, 
and has been proven to be very effective in the adjuvant setting for younger patients with 
Her2 positive breast cancer.18,19 These attributes suggest that with careful patient 
selection this biological agent may play a significant role in the management of breast 
cancer in older women and therefore this option should be explored. Currently there are 
no published data from phase II or III trials on the safety of trastuzumab in older breast 
cancer patients nor is there efficacy data on use of single agent adjuvant trastuzumab in 
the management of breast cancer. Contrary to what was previously believed a recent 
review of trastuzumab cardiotoxicity data appears to suggest that declines in LVEF are 
more sustained.24 The long-term implications of trastuzumab cardiotoxicity therefore 
remain unclear. Long-term cardiac monitoring data, which will be collected in this study, 
will be particularly useful since increasing age is a risk factor for trastuzumab related 
cardiactoxicity,20 and cardiac diseases generally. It is our expectation that at the 
completion of this study when the safety and efficacy of single agent trastuzumab in the 
adjuvant setting has been demonstrated, physicians will be more inclined to enroll older 
patients in trials that address the safety of trastuzumab in combination with chemotherapy 
and or with other biologic agents. It is in the light of this missing safety and efficacy data 
that we propose to conduct this study, to answer critical safety and efficacy questions 
related to the care of older women with early stage breast cancer. Findings from this 
study will afford the opportunity to inform the debate on the role of systemic therapy in 
older women with breast cancer. 
 
1.3      HER2 OVEREXPRESSION AND BREAST CANCER 
Growth factors and their receptors play critical roles in development, cell growth, 
differentiation, and apoptosis.25 Such receptors span the cell membrane, with the 
extracellular domain binding specific growth factors and the intracellular domain 
transmitting growth signals. Interaction of the extracellular domain with its cognate 
ligand often results in intracellular activation of tyrosine kinase activity. Overexpression 
of human epidermal growth factor receptor 2 (HER2, also known as erbB2, neu, and 
p185HER2) is observed in approximately 25-30% of human breast cancers.15 HER2 
overexpression has been reported to only rarely occur in the absence of gene 
amplification. 26,27 High level of HER2 expression has been correlated with poor clinical 
outcome.15  
 
Several lines of evidence support a direct role for HER2 overexpression in the 
pathogenesis and poor clinical course of human tumors.28 When the mutated gene is 
transfected into murine fibroblast (NIH 3T3) cells, it causes transformation, and the 
resulting cells are tumorigenic in the nude mice.29,30 Additionally, transgenic mice that 
overexpress the rodent homolog of the human HER2 gene develop breast cancer.31 
Finally, specific antibodies to the extracellular domain of HER2 inhibit the experimental 
growth of tumors that overexpress the gene.32-34 These data suggest a direct role for 
HER2 in both malignant transformation and enhanced tumorigenicity. Therefore a 

 
CASE 10107 12/28/2018 
Page 9 of 85 
 
 
 
strategy to antagonize the abnormal function of overexpressed HER2 was developed to 
improve the course of patients with HER2-overexpressing tumors. Monoclonal antibodies 
directed against the HER2 protein were developed and humanized to minimize the 
likelihood of immunogenicity. One of these antibodies (trastuzumab) was very effective 
in inhibiting both in vitro and in vivo proliferation of human breast cancer tumor cells 
overexpressing the HER2 protein and in mediating antibody-dependent cellular 
cytotoxicity in the presence of human effector cells.35 
 
There is substantial preclinical evidence that inhibition of signal transduction pathways 
can potentiate the cytotoxic activity of chemotherapeutic drugs. Indeed, trastuzumab has 
been shown to have synergy, in vitro and in vivo, with several chemotherapeutic drugs 
including cisplatin, doxorubicin, thiotepa, etoposide, vinorelbine, and taxanes.36-41 Given 
this promising preclinical data, Trastuzumab was tested in the clinic both as a single 
agent and in combination with chemotherapy. 
 
Amplification or overexpression of Her1 is also seen in approximately 15-50% of women 
with invasive breast cancers, and is also associated with an unfavorable prognosis.42 
Inhibition of both her1 and Her2 receptor types should therefore improve optimal 
inhibition 
of 
tumor 
growth 
and 
survival. 
Recently, 
Lapatinib 
ditosylate 
(GW572016/Tykerb®; Glaxo-SmithKline, Research Triangle Park, NC) has been 
developed as an oral dual TK inhibitor targeting both the ErbB-1 and ErbB-2 receptors 
and has shown promising activity in preclinical investigations43-45 and clinical trials 
mainly in the advanced breast cancer46.Geyer, et al,46 in their pivotal randomized 
controlled trial of lapatanib plus capecitabine versus capecitabine alone among locally 
advanced and metastatic her2+ breast cancer patients, heavily pretreated with 
combination chemotherapy demonstrated a 51% proportional reduction in time to 
progression in the combination-therapy arm in comparison with the capecitabine alone 
without increase in serious toxic effects or symptomatic cardiac events. It is unclear how 
many women enrolled in this trial were 65 years and older. However the median age of 
participants in the combination arm was 54 years and in the capecitabine alone arm was 
51 years.  
 
1.4      HERCEPTIN CLINICAL EXPERIENCE IN THE ADJUVANT SETTING  
In November 2006 the FDA approved trastuzumab for use as part of a treatment regimen 
containing doxrubicin, cyclophosphamide and paclitaxel for the treatment of patients 
with HER2 overexpressing, node positive breast cancer based on the results of two 
pivotal randomized, open-label, clinical trials with a total of 3752 patients who were 
randomized in the studies prior to a pre-specified interim analysis.19 The data from both 
arms in NSABP-31 and two of the three study arms in N-9831 were pooled for efficacy 
analyses. Breast tumor specimens were required to show HER2 overexpression (3+ by 
IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory 
prior to randomization (N-9831) or was required to be performed at a reference 
laboratory (NSABP-31). Patients with a history of active cardiac disease based on 
symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction 
findings or uncontrolled hypertension (diastolic >100 mmHg or systolic >200 mmHg) 
were not eligible. Patients were randomized (1:1) to receive doxorubicin and 
cyclophosphamide followed by paclitaxel alone or paclitaxel plus trastuzumab. In both 
trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and 

 
CASE 10107 12/28/2018 
Page 10 of 85 
 
 
 
cyclophosphamide 600 mg/m2. Paclitaxel was administered either weekly (80 mg/m2) or 
every 3 weeks (175 mg/m2) for a total of 12 weeks in NSABP-31; paclitaxel was 
administered only by the weekly schedule in the N9831. Trastuzumab was administered 
at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for 
a total of 52weeks. Radiation therapy, if administered, was initiated after the completion 
of chemotherapy. Disease-free survival (DFS), defined as the time from randomization to 
recurrence, occurrence of contralateral breast cancer, other second primary cancer, or 
death, was the primary endpoint of the combined efficacy analysis. A total of 3752 
patients were included in the efficacy analyses. Overall, there were 1,736 patients in the 
B-31 trial and 1,615 patients in N-9831, and at the time of the combined analysis, the 
median follow-up was 2.0 years.  Compared with the control arm, the trastuzumab arm 
showed a statistically signficant increase in 3-year disease-free survival (DFS), 75.4% vs 
87.1% respectively, p<0.0001;HR=0.48, 95% CI (0.39-0.59). The cumulative incidence 
of class III or IV heart failure was 0.8% in the control group and 4.1% in the trastuzumab 
group.   
 
Three other important trials in addition to the two pivotal trials described above validate 
the use of trastuzumab in the adjuvant treatment of breast cancer. The HERA (Herceptin 
Adjuvant) trial focused on determining the optimal duration of trastuzumab for early-
stage breast cancer.18 Patients were randomized to one of three arms: observation, 
trastuzumab every 3 weeks for 1 year, or trastuzumab every 3 weeks for 2 years. 
Trastuzumab was dosed with 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks 
thereafter.  Patients had either node-negative disease if tumor size >1cm (32.1%) or node-
positive disease, and all patients had HER2-positive tumors.  At a median follow-up of 2 
years, the addition of trastuzumab to neoadjuvant and adjuvant chemotherapy resulted in 
a statistically signficant improvement in DFS (86.1% vs 78%) and overall survival 
(96.9% vs 93.6%).  Further analysis is expected to determine if 2 years is superior to a 
year of treatment.   
 
The BCIRG 006 trial aimed at maximizing the efficacy of trastuzumab while minimizing 
cardiac toxicity.47 The trial enrolled 3,222 patients with node-positive or high-risk lymph 
node-negative HER2-positive tumors to 1 of 3 arms: doxorubicin-cyclophosphamide 
every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (ACT); or 
the same regimen plus 52 weeks of trastuzumab,weekly during chemotherapy then every 
3 weeks during follow-up (ACTH); or docetaxel-carboplatin every 3 weeks for 6 cycles 
plus 52 weeks of trastuzumab with the same schedule as given in arm 2 (TCH). At a 36 
month follow-up, presented at the 2006 San Antonio Breast Conference, the 2 
trastuzumab arms showed a statistically significant improvement in DFS compared with 
the control arm. Symptomatic cardiac events and an LVEF decline >15% were 
statistically significantly greater in the ACTH group compared with the ACT. There was 
no statistically significant difference between the ACT and TCH groups in terms of 
cardiac side-effects. This trial shows that fewer cardiac events are observed when 
trastuzumab is administered without prior anthracycline-based therapy. There was no 
statistically significant difference in terms of disease free survival across the two 
trastuzumab-containing arms.   
 
The FinHer trial involved 1,010 patients randomized to docetaxel every 3 weeks for three 
doses versus 9 weeks of vinorelbine followed, in both groups, by three weeks of 

 
CASE 10107 12/28/2018 
Page 11 of 85 
 
 
 
cyclophosphamide, epirubicin, and fluoruracil (CEF).48   The 232 patients found to be 
HER2 positive were randomized to receive weekly trastuzumab for 9 weeks with 
docetaxel or vinorelbine.  This trial enrolled women with axillary node-positive disease 
or women with node-negative breast cancer with tumors >2cm and progesterone-receptor 
negative. After a median follow-up of 3 years, they found that recurrence was less 
frequent amongst women receiving docetaxel/CEF with 42/502 recurrences compared 
with 71/507 recurrences in the vinorelbine/CEF arm at 3 years.  They also found that 
trastuzumab for 9 weeks was effective in preventing breast cancer recurrence, with 
12/115 events in the trastuzumab arm compared with 27/116 events in the arm without 
trastuzumab (p=  0.01).   
 
1.5     HERCEPTIN CLINICAL EXPERIENCE IN METASTATIC BREAST  
CANCER 
The clinical benefit of trastuzumab in women with metastatic breast cancer has been 
demonstrated in two pivotal studies.  
 
A large Phase II trial (H0649g) assessed the activity of trastuzumab as a single agent in 
222 women with HER2 overexpressing metastatic breast cancer with progressive disease 
after one or more chemotherapy regimens.49 A blinded, independent response evaluation 
committee identified 8 complete and 26 partial responses, for an objective response rate 
of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The 
median duration of response was 9.1 months, and the median duration of survival was 13 
months. The most common adverse events, which occurred in approximately 40% of 
patients, were mild to moderate infusion-associated fever and/or chills. These symptoms 
usually occurred only during the first infusion. The most clinically significant event was 
cardiac dysfunction, which occurred in 4.7% of patients. 
 
A large, open-label, randomized Phase III study (H0648g) in 469 patients with HER2-
positive metastatic breast cancer was conducted to evaluate the efficacy of trastuzumab in 
combination with chemotherapy as first-line treatment. Patients who were anthracycline-
naïve were randomized to receive either anthracycline plus cyclophosphamide (AC) or 
trastuzumab plus AC. Patients who had received prior anthracyclines in the adjuvant 
setting were randomized to receive either paclitaxel or trastuzumab plus paclitaxel. 
Patients randomized to trastuzumab and chemotherapy measurably benefited in 
comparison to patients treated with chemotherapy alone in terms of time to disease 
progression, overall response rate, median duration of response, and survival. As 
determined by an independent Response Evaluation Committee (REC), trastuzumab 
prolonged median time to disease progression from 4.6 months to 7.4 months (p<0.001), 
improved the overall response rate (complete and partial responses) from 32% to 50% 
(p<0.001), and increased median duration of response from 6.1 to 9.1 months (p<0.001). 
Compared to chemotherapy alone, the addition of trastuzumab significantly lowered the 
incidence of death at one year from 33% to 22% (p=0.008) and increased median overall 
survival 24% from 20.3 months to 25.1 months (p=0.046). The observed survival 
advantage remained despite crossover of 66% of patients initially randomized to 
chemotherapy alone who elected to receive trastuzumab upon disease progression.50 
Fever/chills were observed with the initial trastuzumab infusion in approximately 25% of 
patients. Class III or IV cardiac dysfunction was observed in 16% of the Trastuzumab + 

 
CASE 10107 12/28/2018 
Page 12 of 85 
 
 
 
AC subgroup; increasing age was an associated risk factor for the development of 
cardiotoxicity in this treatment cohort.  
 
Based on these data, trastuzumab was approved by the U.S. Food and Drug 
Administration (FDA) for use in HER2-overexpressing metastatic breast cancer in 
combination with paclitaxel for first-line treatment and as a single agent for patients 
failing prior chemotherapy for metastatic disease. However, current usage patterns of 
trastuzumab indicate that the drug is now being used in a broader array of circumstances 
than in the pivotal clinical trials. Since initiation of the pivotal clinical trials, docetaxel 
has become a commonly used taxane in the treatment of metastatic breast cancer 51 and 
new data have emerged on the weekly use of paclitaxel52. Trastuzumab has been studied 
in combination with paclitaxel and docetaxel using a variety of doses and schedules with 
promising results.53-55 In addition, the combination of trastuzumab with vinorelbine has 
recently been studied.56 In this study, 30 of 40 women treated with trastuzumab (4 mg/kg 
x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted 
each week for neutrophil count) responded to therapy, for an overall response rate of 75% 
(95% confidence interval 57% to 89%). Neutropenia was the only grade IV toxicity. No 
patients had symptomatic heart failure. Grade 2 cardiotoxicity was observed in 3 patients; 
prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing 
cardiac function were associated with this toxicity. 
 
1.6 
SAFETY 
Experience with trastuzumab administration has shown that the drug is relatively safe. 
The most significant safety signal observed during clinical trials was cardiac dysfunction 
(principally clinically significant heart failure [CHF]), particularly when Herceptin was 
given in combination with an anthracycline-containing regimen. Much of the cardiac 
dysfunction was reversible on discontinuation of trastuzumab.  
 
In addition, during the first infusion with trastuzumab, a symptom complex most 
commonly consisting of fever and/or chills was observed in approximately 40% of 
patients. The symptoms were usually mild to moderate in severity and controlled with 
acetaminophen, diphenhydramine, or meperidine. These symptoms were uncommon with 
subsequent infusions. However, in the post approval setting, more severe adverse 
reactions to trastuzumab have been reported. These have been categorized as 
hypersensitivity reactions (including anaphylaxis), infusion reactions, and pulmonary 
events. Rarely, these severe reactions culminated in a fatal outcome. 
 
There are no adequate or well-controlled studies in pregnant women, and animal 
reproduction studies are not always predictive of human response.  Therefore, 
trastuzumab should be used during pregnancy only if the potential benefit to the mother 
outweighs the potential risk to the fetus. In the post marketing setting, oligohydramnios 
(decreased amniotic fluid) has been reported in women who received trastuzumab during 
pregnancy, either in combination with chemotherapy or as a single agent.  Given the 
limited number of reported cases, the high background rate of occurrence of 
oligohydramnios, the lack of clear temporal relationships between drug use and clinical 
findings, and the lack of supportive findings in animal studies, an association between 
trastuzumab and oligohydramnios has not been established.   
 

 
CASE 10107 12/28/2018 
Page 13 of 85 
 
 
 
Trastuzumab appears to be relatively nonimmunogenic. Only 1 of 903 patients evaluated 
developed neutralizing antibodies to trastuzumab. The development of anti-Herceptin 
antibodies in this patient was not associated with clinical signs or symptoms.  
 
1.7 
CLINICAL PHARMACOKINETICS OF TRASTUZUMAB 
A Phase I single dose study (H0407g) of intravenous trastuzumab infusions ranging from 
10-500 mg resulted in dose-dependent pharmacokinetics (PK) with serum clearance of 
trastuzumab decreasing with an increasing dose at doses <250 mg.  PK modeling of 
trastuzumab concentration-time data from 7 patients that were administered doses of 250 
mg and 500 mg had a mean half-life of 5.8 days (range 1-32 days).  Additionally, PK 
modeling showed that weekly trastuzumab doses ≥250 mg resulted in serum trough levels 
of >20 
that was above the minimum effective concentration observed in 
preclinical xenograft studies in tumor-bearing mice. The Phase I data supported the 
weekly dosing schedule that was implemented in all subsequent Phase II and Phase III 
clinical trials. A weight-based dose schedule was adopted after two Phase II trials 
(H0551g and H0552g) suggested that inter-subject variability in trastuzumab PK was 
related to body weight.  These findings resulted in a trastuzumab dose schedule of a 
4 mg/kg loading dose followed by a weekly 2 mg/kg maintenance dose utilized in the two 
pivotal Phase III trials (H0648g and H0649g) that were the basis of the BLA filing  and 
subsequent FDA approval of trastuzumab for HER2+ metastatic breast cancer.  
 
The trastuzumab PK data from studies H0407g (Phase I), H0551g (Phase II), and H0649 
(pivotal) have been subsequently reanalyzed by a population PK approach using 
nonlinear mixed effect modeling (NONMEM).57 A linear two-compartment model best 
described the concentration-time data, and accounted for the accumulation of 
trastuzumab serum concentrations seen in the Phase II and Phase III clinical studies. A 
covariate analysis was conducted using the subjects from these single agent studies to 
evaluate the effect of pathophysiologic covariates (e.g.  age, weight, shed antigen) on the 
PK parameter estimates.  The covariates, that significantly influenced clearance, were the 
level of shed antigen and the number of metastatic sites. Volume of distribution was 
significantly influenced by weight and shed antigen level.  Additionally, data from the 
Phase III study, H0648g, were added to assess the influence of concomitant 
chemotherapy on trastuzumab PK.  Importantly, chemotherapy (AC or paclitaxel) did not 
significantly alter trastuzumab PK. The estimated half-life of trastuzumab based on the 
final model was 28.5 days. 
 
Analysis of data obtained from two Phase II studies which utilized a loading dose of 
8 mg/kg trastuzumab followed by a 6 mg/kg maintenance dose administered every 3 
weeks (q3 week) as a single-agent40, and in combination with paclitaxel (175 mg/m2)58, 
confirmed that a two-compartment model best describes the PK of trastuzumab. Model-
independent analysis of the data obtained in these studies gives comparable PK parameter 
estimates to those obtained by the population PK model, thus confirming the validity of 
the population PK model.   In addition, the population PK model adequately predicted 
trastuzumab serum concentrations obtained independently in these studies.  After two 
treatment cycles, trastuzumab exposure were similar to those measured in the once 
weekly dosing regimen used in the pivotal trials. Trough levels were in excess of the 
targeted serum concentrations established from preclinical xenograft models, and as 
expected, peak levels were greater than those observed upon weekly administration. The 

 
CASE 10107 12/28/2018 
Page 14 of 85 
 
 
 
apparent half-life of trastuzumab in these studies was determined to be approximately 21 
days, and the PK was supportive of a q3 week dosing schedule. 
 
The efficacy and safety results from these Phase II studies with q3 week dosing do not 
appear to be different from those with weekly dose-schedules16,49,59.  In the trastuzumab 
q3 weekly monotherapy study40, 105 patients with HER2+ metastatic breast cancer were 
treated, with an objective response rate of 19% (23% in patients with measurable 
centrally confirmed HER2+ disease).  The median baseline LVEF was 63%, which did 
not significantly change during the course of the study.  One patient experienced 
symptomatic CHF, which resolved with medical treatment for CHF and discontinuation 
of trastuzumab.  In the study of q3 weekly trastuzumab and paclitaxel58, 32 patients were 
treated with an investigator-assessed response rate of 59%.  Ten patients had a decrease 
in LVEF of 15% or greater.  One patient experienced symptomatic CHF, which improved 
symptomatically after medical therapy for CHF and discontinuation of trastuzumab. 
 
1.8    PHYSIOLOGIC CARDIAC MARKER STUDIES BACKGROUND AND 
         RATIONALE 
The pathophysiology of trastuzumab-related cardiac dysfunction remains undefined with 
several hypotheses being proposed. These include drug-drug interactions, the induction of 
immune-mediated destruction of cardiomyocytes, and defects in HER2 signaling required 
for maintenance of cardiac contractility.60 HER2 may also play a role in myocyte 
survival, which may then be impaired during treatment with trastuzumab61,62. What is 
definitely known about trastuzumab-related cardiotoxicity is that it is different from that 
induced by anthracyclines. Cardiac biopsy specimens have revealed no anthracycline-like 
morphologic abnormalities and unlike anthracycline-induced cardiotoxicity it is largely 
reversible.63 
 
Currently, existing literature suggest that detection of trastuzumab related cardiac toxicity 
is best accomplished by serial measurements of left ventricular ejection fractions by 
either multiple-gated acquisition scans or echocardiography techniques20 These 
measurements do not, however, provide early detection of abnormalities. A plausible 
explanation for the lack of early detection of cardiac abnormalities may be attributable to 
physiologic compensations for significant damage, with abnormalities only becoming 
evident when physiologic compensations are no longer possible. The need for a screening 
tool that could reveal trastuzumab related cardiac toxicity in a more sensitive and 
immediate manner cannot be over emphasized and hence the rationale for measuring 
plasma physiologic cardiac markers in this study and to determine it’s correlation with 
trastuzumab-related cardiac dysfunction.   
 
Cardiac troponin, a component of the myocardial contractile apparatus, is released after 
just one cycle of chemotherapy and is more frequently abnormal with each cycle in 
patients who ultimately develop left ventricular dysfuction64. Pretreatment levels of N-
terminal brain natriuretic protein (NT-proBNP) has also shown promise regarding the 
prediction of trastuzumab-related cardiac toxicity and requires further exploration65 
Lastly, inflammatory immune activation is an important feature of chronic heart failure 
and therefore physiologic markers such as interleukin-6 (IL-6) and tumor necrosis factor 
alpha (TNF-) levels maybe useful as early predictors of trastuzumab-related cardiac 
dysfunction.66-68 

 
CASE 10107 12/28/2018 
Page 15 of 85 
 
 
 
1.9    COMPREHENSIVE GERIATRIC ASSESSMENT BACKGROUND AND 
         RATIONALE 
Comprehensive Geriatric Assessment (CGA) is a multidisciplinary evaluation which 
assesses function, comorbidity, nutrition, cognition, emotional, psychological and social 
support, and a review of medication list for polypharmacy and drug interactions. It is a 
key tool currently recommended as an integral part of the treatment and follow-up of the 
older patient with cancer.69 The rationale for integrating the principles of geriatrics 
evaluation into oncology care for older cancer patients is to use this assessment to 
determine an estimation of life expectancy and treatment tolerance, allowing a common 
language beyond that provided by chronological age. The expectations are that this 
approach will result in improved treatment outcomes in older patients with cancer.  
 
Domains of the Comprehensive Geriatric Assessment 
 
Functional status 
Functional status refers to a patient's ability to perform routine daily tasks and is an 
independent predictor for mortality in both the geriatric70 and geriatric-oncology71 
population. Impaired functional status also increases the risk of toxicity due to 
chemotherapy.72 An accurate assessment of functional status will therefore increase 
identification of those at risk for non-adherence to chemotherapy and those at increased 
risk of dying from cancer. The commonly used performance status scores (eg, Karnofsky 
or Eastern Cooperative Oncology Group (ECOG) scales tend to under-represent the 
degree of functional impairment in the older patient.73  Functional state is better reflected 
by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living 
(IADL) scales. ADLs are the skills that are necessary for basic living, and include 
feeding, grooming, transferring, and toileting. IADLs are required to live independently 
in the community and include activities such as shopping, managing finances, preparing 
meals, housekeeping, and taking medications.  
 
Co-morbidity 
Co-morbidity is an important factor to consider in determining the prognosis of patients 
with a cancer diagnosis. As an individual ages, the number of comorbid medical 
conditions increases making comorbidity an important domain of a CGA.1 Co-morbidity 
adversely impacts survival74, and tolerance to chemotherapy75. The impact of 
comorbidity on survival was well illustrated by a longitudinal observational study of 936 
women with breast cancer ages 40 to 84. Patients who had three or more comorbid 
medical conditions had a 20-fold higher rate of mortality from causes other than breast 
cancer and a fourfold higher all-cause mortality rate compared to those who had no 
comorbid medical conditions.74 The adverse impact of comorbidity on chemotherapy 
tolerance was illustrated in a study of patients age 70 years with advanced non–small 
cell lung cancer.75 In this study patients with a Charlson Comorbidity Index of 2 were 
more likely to discontinue chemotherapy earlier than patients with a comorbidity score 
<2. Because comorbidity has been shown to be independent of functional status is it is 
important that both domains are assessed when evaluating an older patient with cancer.76 
 
Cognitive function 
Cognitive function plays an important role in the outcome of the older patient with cancer 
and therefore is an important domain that needs to be assessed. In the geriatric oncology 

 
CASE 10107 12/28/2018 
Page 16 of 85 
 
 
 
population dementia is associated with a lack of diagnosis of cancer until discovery at 
death77, advanced stage at diagnosis78, receipt of suboptimal therapy78, and survival79. 
Additionally, an assessment of cognitive status is important prior to treatment in order to 
ensure the process of informed consent, that the patient can comply with instructions 
regarding supportive medications or oral agents, and in order to understand and 
remember to seek medical attention if side effects develop. 
 
Nutrition 
The adverse impact of weight loss and low Body Mass Index (BMI) have been 
demonstrated in all older patients including those with cancer.80,81 In a study among older 
cancer patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative 
Oncology Group (ECOG) weight loss was associated with a lower performance status, a 
decrease in chemotherapy response rates in women with breast cancer, and was found to 
be an independent prognostic factor for survival.82 The importance of a thorough 
nutritional assessment and the development of interventions to improve nutritional status 
among malnourished older cancer patients cannot be overemphasized. 
 
Social support and psychological state  
Social isolation has been linked to an increased vulnerability to psychological distress 
among geriatric patients83 and an increase in mortality among both geriatric and oncology 
patients. 84,85  Additionally studies of geriatric assessment show that 14-40% of older 
patients have depressive symptoms. Depression among older patients with cancer is 
associated with receipt of sub-optimal therapy86, increased toxicity to chemotherapy72, 
and increased mortality72. An assessment of the social support and psychological state of 
an older cancer patient is therefore essential as an appropriate intervention is likely to 
improve outcomes among older patients with cancer. 
 
Polypharmacy 
Age-related physiological changes include a decrease in total body water, an increase in 
body fat, a decrease in renal function, a decrease in hepatic mass and blood flow, and 
decrease in bone marrow reserve. Polypharmacy is prevalent among older patients. In the 
older cancer patient age-related changes in physiology, polypharmacy and cancer therapy 
can contribute to drug interactions and adverse drug events. A CGA of an older cancer 
patient should therefore include a review of prescribed medications with the 
discontinuation of nonessential medications, evaluation of potential drug interactions, and 
a review of expected side effects from prescribed medications. 
 
Below is a table of validated instruments for evaluation of the domains described above 
that will be utilized in this study. 
 

 
CASE 10107 12/28/2018 
Page 17 of 85 
 
 
 
 
 
Table 2: Validated Comprehensive Geriatric Assessment Instruments and Corresponding 
Domains 
Instrument 
Domain 
Lawton’s nine-item Instrumental Activities of Daily Living 
(IADL)87 
 
 
 
Functional Status 
 
Katz’s Activity of Daily Living (ADL)88 
 
Timed up and go test89 
 
Karnofsky Physician-Rated Performance Rating Scale (KPS)90 
 
Number of falls in the last 6 months91 
 
Mini-nutritional assessment (MNA)92 
 
Nutritional Status  
Assessment 
 
Body Mass Index93 
 
Percent Unintentional Weight Loss in the Last 6 Months82 
Medical Outcomes Study (MOS) Social Support Subscale 
(Emotional/information and Tangible subscales)94 
 
Social Functioning 
and Support 
 
 
MOS Social Activity Limitations Measure95 
 
Charlson Comorbidity Index96 
 
Comorbidity 
 
Cumulative Index Rating Scale Geriatrics (CIRS-G)97 
 
Folstein’s Mini-mental State Examination (MMSE)98  
 
Cognitive Function 
Assessment 
 
Clock Drawing Test99,100 
 
Geriatric Depression Scale (GDS)101 
Assessment of 
Emotional/Psycholog
ical state 
 
Functional Pain Scale93 
 
Pain Assessment 
 
List of Medications 
 
Poly-pharmacy 

 
CASE 10107 12/28/2018 
Page 18 of 85 
 
 
 
 
 
 
2.0 
OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVE 
2.1.1 Evaluate the three-year cumulative incidence of cardiac events in women 60 
years and older with Her2-positive breast cancer who receive single agent 
trastuzumab in the adjuvant setting. 
 
2.2      SECONDARY OBJECTIVES 
           2.2.1   Evaluate the one-year cumulative incidence of asymptomatic cardiac left  
           ventricular dysfunction in women 60 years and older with Her2-positive breast 
           cancer who receive single agent trastuzumab in the adjuvant setting. 
 
2.2.2 Evaluate long-term cardiac toxicity (five-year cumulative incidence of 
cardiac events) in women 60 years and older with Her2-positive breast cancer who 
receive single agent trastuzumab in the adjuvant setting. 
 
           2.2.3   Assess the relation between physiologic markers of chronic heart failure 
           and trastuzumab-related cardiac dysfunction in women 60 years and older with 
           Her2-positive breast cancer who receive single agent trastuzumab. 
 
 
Table 2: Validated Comprehensive Geriatric Assessment Instruments and Corresponding 
Domains 
Instrument 
Domain 
Minnesota Leisure Time Activity Questionnaire 
 
 
 
Cardiovascular Health 
Study Frailty Index102 
 
Questions on exhaustion 
 
Grip Strength 
15ft walk speed  
 
Unintentional weight loss in 12 months 
 
 
Vulnerable Elders Survey103,104 
 
Assessment of 
Vulnerability 
 
Functional Assessment of Cancer Therapy (FACT-B)105 
 
Quality of Life 

 
CASE 10107 12/28/2018 
Page 19 of 85 
 
 
 
2.2.4 Assess the relation between pro-inflammatory cytokines and trastuzumab-
related cardiac dysfunction in women 60 years and older with Her2-positive 
breast cancer. 
 
2.2.5  Determine the effect of single agent trastuzumab on the Health-related 
Quality of Life (HRQOL), functional, cognitive, and mental status of women 60 
years and older with Her2-positive breast cancer. 
 
2.2.6   Determine the five-year disease-free and overall survival in women 60 
years and older with Her2-positive breast cancer who receive single agent 
trastuzumab in the adjuvant setting. 
 
3.0      STUDY DESIGN 
 
3.1 
DESCRIPTION OF THE STUDY 
This is an open label, single arm, multi-institutional, phase II pilot study.  One hundred 
and twenty-four patients 60 years and older with early-stage HER2+ invasive breast 
cancer who undergo appropriate primary tumor therapy (mastectomy or lumpectomy) 
with either sentinel or axillary lymph node dissection, will be enrolled and undergo 
treatment with single agent Trastuzumab at 8mg/kg IV loading dose, followed by 6mg/kg 
IV every three weeks to complete 52 weeks of treatment. Patients will receive additional 
adjuvant radiation therapy and/or endocrine therapy according to standard institutional 
practice.  Patients will be followed prospectively for five years after entry into study or 
until death, whichever comes first.  
 
Participating institutions include the Seidman Cancer Center and its satellites, Cleveland, 
Ohio, University of Pittsburgh, Pittsburgh, Pennsylvania, Wake Forest University, 
Winston-Salem, North Carolina and University of Miami, Florida. 
 
3.2 
RATIONALE FOR STUDY  
As described in section 1.1, older patients bear a disproportionate burden of the incidence 
and mortality of cancer. However, they are consistently under-represented in clinical 
trials, particularly, breast cancer clinical trials of chemotherapy. This has led to a paucity 
of efficacy data and a lack of definitive recommendations for the use of adjuvant 
chemotherapy in women 70 yrs and older with breast cancer.14  Consistent with other 
breast cancer clinical trials of chemotherapy8,13, trastuzumab was administered to only 
274 patients (6%) who were 65 years and older (141 (adjuvant) and 133 (metastatic)) out 
of 4443 women who participated in clinical trials of trastuzumab that led to FDA-
approval.106 Besides cardiac dysfunction, limitations in data collection and differences in 
study design of the two studies of trastuzumab in adjuvant treatment of breast cancer 
precluded a determination of whether the toxicity profile of trastuzumab in older patients 
was different from younger patients. The reported clinical experience was also not 
adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of 
trastuzumab treatment in older patients was different from that observed in patients <65 
years of age.. Other clinical trials of trastuzumab have also been largely limited to 
younger patients. A total of 16% of patients enrolled in the HERA trial were older than 
60 years of age and BCIRG006 limited patient enrollment to those who were less than 70 

 
CASE 10107 12/28/2018 
Page 20 of 85 
 
 
 
years old.106 The need, therefore, for clinical trials of trastuzumab specifically developed 
for older patients cannot be overemphasized.  
 
Results from a Phase II study, demonstrates the efficacy and safety of single agent 
trastuzumab as a first-line agent in the metastatic setting. In this study 114 women with 
HER2-overexpressing metastatic breast cancer were randomized to receive first-line 
treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a 
higher 8 mg/kg loading dose, followed by 4mg/kg weekly. Randomization was used to 
ensure that estimates of the efficacy outcomes within each dose level would not be biased 
by assigning patients with worse prognosis to the higher dose group. Response rates 
in111 assessable patients with 3+and 2+HER2 overexpression by immunohistochemistry 
(IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), 
respectively. The response rates in108 assessable patients with and without HER2 gene 
amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 
23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. There was no clear 
evidence of a dose-response relationship for response, survival, or adverse events. 
Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease 
and did not require additional intervention after discontinuation of trastuzumab. This 
study demonstrates the efficacy and safety of single agent trastuzumab in the metastatic 
setting and forms the basis for the need for further exploration of single agent 
trastuzumab in the adjuvant setting, particularly among older patients who may have pre-
existing cardiac disease that may not allow the administration of trastuzumab in 
combination with chemotherapy. Also since advanced aged has been identified as a risk 
factor for the development of trastuzumab-related cardiac toxicity19, a cautious approach 
is needed when clinical trials of trastuzumab, that specifically focuses on older patients, 
are designed and hence the decision to utilize trastuzumab as a single agent in this trial.  
 
A Phase I PK study (H0407g) supported a weekly dosing schedule that was implemented 
in all subsequent Phase II and Phase III clinical trials. A weight-based dose schedule was 
adopted after two Phase II trials (H0551g and H0552g) suggested that inter-subject 
variability in trastuzumab PK was related to body weight.  These findings resulted in a 
trastuzumab dose schedule of a 4 mg/kg loading dose followed by a weekly 2 mg/kg 
maintenance dose utilized in the two pivotal Phase III trials (H0648g and H0649g) that 
were the basis of the BLA filing  and subsequent FDA approval of trastuzumab for 
HER2+ metastatic breast cancer. Subsequently, two Phase II studies utilized a loading 
dose of 8 mg/kg trastuzumab followed by a 6 mg/kg maintenance dose administered 
every 3 weeks (q3 week) as a single-agent40, and in combination with paclitaxel 
(175 mg/m2)58.The efficacy and safety results from these Phase II studies with q3 week 
dosing 
do 
not 
appear 
to 
be 
different 
from 
those 
with 
weekly 
dose-
schedules16,17,49.Similarly, in the adjuvant setting trials utilizing a weekly dose 
schedule19,48, a 3 weekly dose schedule18, or a combination of both47 have all 
demonstrated efficacy.  
 
Because of the lack of safety and efficacy data on trastuzumab use among older women 
with breast cancer, the demonstrated efficacy of trastuzumab as a single agent in the 
metastatic setting, the association between the risk of trastuzumab-related cardiac toxicity 
and advanced age, and the need for a pragmatic yet effective dosing schedule that 
encourages clinical trials participation among older breast cancer patients, we have 

 
CASE 10107 12/28/2018 
Page 21 of 85 
 
 
 
developed an exploratory study to evaluate the safety and efficacy of single agent 
trastuzumab therapy at 8mg/kg loading dose, then 6mg/kg every 3 weeks for a total of 52 
weeks as adjuvant treatment for older breast cancer patients with HER2-positive breast 
cancer who are unwilling or unable to undergo treatment with chemotherapy.  
 
3.3    ASSESSMENTS 
        3.3.1  DEMOGRAPHIC AND BASELINE ASSESSMENTS 
 
        Assessments prior to registration 
 Subject to sign the informed consent form 
 Initiate completion of study eligibility form 
 Documentation of immunohistochemical (IHC) staining for HER2 protein of 
3+ intensity or HER2 gene amplification by FISH testing. 
 
Note: Subject must be documented as having HER2 overexpression prior to 
initiation of additional screening assessments outlined subsequently in this 
section. Assessment for HER2 expression or gene amplification should be 
performed by laboratories with demonstrated proficiency in the specific 
technology being utilized. Centralized testing is not required. 
 
A written informed consent form must also be signed by all participants prior to 
screening assessments, and before any study-specific assessments are initiated. 
 
        Screening Assessments 
 Demographic data: date of birth, race, gender, height in centimeters, body 
weight in kilograms, and ECOG Performance Status. 
 Medical history including details of malignancy: date of diagnosis, primary 
tumor type, histology, ER and PR status, stage of cancer, relevant prior 
surgical procedures, and prior and concomitant medications within 3 weeks 
of first dose of trastuzumab. 
 Baseline Echocardiogram (ECHO) or MUGA scan may be completed within 
3 months of current breast cancer diagnosis. The same method used at 
screening should be used throughout the study period. 
 
 
        Assessments within 21 days prior to first dose 
 Physical examination 
 Medical history, ECOG Performance Status 
 Vital signs (blood pressure, pulse rate, body temperature, height, and body 
weight) 
 Baseline laboratory tests (complete blood count (CBC), electrolytes, liver 
function tests, and physiological markers of cardiac function 
 Baseline Quality of Life and Comprehensive Geriatric Assessment  
 
Testing for physiologic cardiac markers (IL-6, TNF-alpha, Troponin-I, and BNP) will be 
centralized. Testing will be done at the Translational Research Core Laboratory at the 
Case Comprehensive Cancer Center Cleveland, Ohio. All serum samples for such tests 

 
CASE 10107 12/28/2018 
Page 22 of 85 
 
 
 
will therefore require shipping to the Case Comprehensive Cancer Center. Please see 
appendix D for instructions on how to handle serum samples and shipment details. 
 
Note: After all baseline and screening evaluations have been completed, determine if the 
subject is eligible for the study by reviewing the inclusion and exclusion criteria. 
 
3.3.2 ASSESSMENTS DURING STUDY CONDUCT 
 
            Assessments every 3 weeks during trastuzumab monotherapy 
 Vital signs (blood pressure, pulse rate, body temperature, and body weight) 
 Record any non-serious and serious adverse events (AE) and assign 
appropriate toxicity grade (NCI CTCAE version 3, published March 31, 
2003) 
 Hematology (CBC with differential) 
 Complete Metabolic profile 
 
             Assessments every 6 weeks during trastuzumab monotherapy 
 Serum cardiac physiologic markers 
 Limited history 
 Physical examination 
 ECOG Performance Status 
 
             Assessment every 4 weeks until return of normal cardiac function 
 Echocardiogram (ECHO) or MUGA scan for patients with significant left 
      ventricular cardiac dysfunction requiring trastuzumab to be with held 
 
              Assessment every 3 months until end of year one 
 Echocardiogram (ECHO) or MUGA scan 
  
             Assessment every 6 months until end of year one 
 Quality of Life and Comprehensive Geriatric Assessment  
 Cardiac history 
  
           Assessment every 6 months for years 2-5 or until disease-free or survival 
           Endpoint is reached, whichever comes first 
 Hematology (CBC with differential) 
 Complete Metabolic profile  
 Limited history including cardiac history 
 Physical examination 
 ECOG Performance Status 
 Vital signs (blood pressure, pulse rate, body temperature, and body weight) 
 Record any non-serious and serious adverse events (AE) and assign 
appropriate toxicity grade (NCI CTCAE version 3, published March 31, 
2003) 
 
 
 

 
CASE 10107 12/28/2018 
Page 23 of 85 
 
 
 
           Assessment at 60 months 
 cardiac history 
 physical examination 
 cardiac markers 
 ECHO or MUGA scan 
 
3.4 OUTCOME MEASURES 
   
3.4.1.  PRIMARY OUTCOME MEASURE 
The primary outcome measure is the three-year cumulative incidence of cardiac events 
and is defined by any one of the following events; 
 Definitive cardiac death; due to CHF, MI, or documented arrhythmia  
 Any possible/probable cardiac death over the three-year follow-up period 
defined as a sudden unexpected death within 24 hours after a definitive 
cardiac event , and without definitive documented alternative cause.  
 Signs and symptoms of congestive heart failure (CHF). CHF will be defined 
as follows: New York Heart Association (NYHA) class III or IV symptoms 
with either a decrease from baseline in LVEF of more than 10 percentage 
points to less than 55% or a decrease of more than 5 percentage points to less 
than the lower limit of normal. Class III is characterized by symptoms of 
dyspnea with activities such as climbing a flight of stairs, whereas class IV 
symptoms are present at rest. LVEF will be determined with either a MUGA 
or echocardiogram. 
 
Cardiac Assessment for primary outcome measure 
 MUGA scans or echocardiogram will be required at study entry, at 3, 6, 9,  
and at 12months after study entry to assess primary outcome measure. 
 Additional MUGA scans or echocardiograms after 12 months will be at 
treating physician’s discretion except for one dditional MUGA scan or 
echocardiogram that will be performed at 60 months for long-term cardiac 
monitoring.  
 Patients who develop significant left ventricular dysfunction will have 
MUGA scans at four week intervals until return of normal function.  
 Cardiac history every 6 months until end of study. 
 
Analysis of primary outcome measure 
Descriptive statistics, such as means, median, range, and frequencies, will be used to 
describe subjects’ cardiac toxicity profile. The incidence of cardiac dysfunction and its 
confidence interval will be estimated using Wilson’s method.107 Potential factors that 
predict the incidence will be identified by Cox proportional hazards regression.  
 
3.4.2   SECONDARY OUTCOME MEASURES 
 
3.4.2.1. 
The one-year cumulative incidence of asymptomatic left ventricular cardiac 
dysfunction defined as an asymptomatic decrease in LVEF from baseline of at 
least ten percentage points to below the lower limit of normal or an absolute 

 
CASE 10107 12/28/2018 
Page 24 of 85 
 
 
 
decrease of >15 percentage points leading to a permanent discontinuation of 
trastuzumab before completion of one year of trastuzumab therapy. 
 
3.4.2.2. 
The five-year cumulative incidence of asymptomatic left ventricular cardiac 
dysfunction defined as an asymptomatic decrease in LVEF from baseline of at 
least ten percentage points to below the lower limit of normal or an absolute 
decrease of >15 percentage points at 60 months.. 
 
3.4.2.3. 
The five-year cumulative incidence of cardiac events and defined as above 
under section 3. 4.1.  
 
3.4.2.4. 
Mean change in plasma cardiac markers from baseline to mid-treatment, and 
from baseline to end of treatment.  
 
3.4.2.5. 
Mean change in pro-inflammatory cytokines from baseline to mid treatment, 
and from baseline to end of treatment. Similar analysis as above will be done. 
 
3.4.2.6. 
Mean change in QOL and CGA scores from baseline to mid treatment, and 
from baseline to end of treatment. Differences in QOL and GCA scores will 
be examined by paired t-test. 
  
3.4.2.7. 
Disease-free survival (DFS) defined as the time from initiation of treatment to 
the date of first loco-regional or distant treatment failure, ignoring any 
intervening contralateral breast cancers or other second primary cancers. 
Deaths without evidence of recurrence will be treated censoring events.                 
                 
                  Appearance of DCIS or LCIS either in the ipsilateral or in the contralateral 
                  breast will not be considered as an event for DFS (but must be reported on the 
                  Follow-Up Form). 
 
3.4.2.8. 
Overall survival defined as the time from initiation of treatment to the date of 
death from any cause and censored to the date of last follow-up for survivors.  
 
Diagnosis of treatment failure 
The diagnosis of first treatment failure depends on evidence of recurrent disease, which 
can be classified as either suspicious or acceptable. In either case, this should be specified 
and reported. Acceptable evidence of treatment failure according to site is defined below. 
Any events not included in this section are considered unacceptable as evidence of 
recurrent disease. Treatment failures include: local, regional, and distant failures. To 
ensure consistency with definitions used in pivotal trials of trastuzumab therapy 
intervening contra-lateral breast cancers and second primary cancers will not be 
considered treatment failures.19 The date of treatment failure is the time of first 
appearance of a suspicious lesion, later proven to be a definitive recurrence or metastasis. 
All events described below should be recorded on the Follow-up Form 
 
 
 
 

 
CASE 10107 12/28/2018 
Page 25 of 85 
 
 
 
Local failure 
Local failure is defined as a tumor recurrence in any soft tissues of the ipsilateral (or in 
the case of bilateral, either) conserved breast or the chest wall, mastectomy scar, and/or 
skin. 
 
Acceptable for recurrence in ipsilateral conserved breast: positive cytology or histology 
Acceptable for recurrence in chest wall, mastectomy scar, and/or skin: positive cytology 
or histology or evidence of new lesions (by CT or MRI) without any obvious benign 
etiology. 
 
Suspicious: a visible or palpable lesion. 
Appearance of DCIS or LCIS either in the ipsilateral or in the contralateral breast is not 
considered a treatment failure. 
 
Treatment after local relapse for patients who received breast-conserving surgery: 
Patients may continue to receive the protocol treatment after resection of a relapse in the 
ipsilateral conserved breast, an option that reflects the controversy concerning therapy for 
reappearance of disease in the ipsilateral breast. Continued treatment is only allowed 
when there is no evidence of loco-regional disease outside the breast or of distant disease 
at the time of breast relapse. Details of the local treatment for the conserved breast 
relapse must be recorded on the Follow-up Form. Patients who develop a local relapse 
other than a relapse in the ipsilateral conserved breast should change therapy. 
 
Regional failure 
Regional failure is defined as a tumor recurrence in the ipsilateral axillary lymph nodes, 
extranodal soft tissue of the ipsilateral axilla, ipsilateral internal mammary lymph nodes, 
and/or ipsilateral supraclavicular lymph nodes. For patients with bilateral breast cancer at 
randomization, failure in the previously-listed regional nodes should be recorded as 
regional failure (rather than distant) on the Follow-Up Form. The side (right or left) of the 
nodes should be recorded. 
 
Acceptable: positive cytology or histology or evidence of new lesions by CT or MRI 
without a benign etiology. 
Suspicious: a visible or palpable lesion. 
 
Contralateral breast failure 
Appearance of invasive breast cancer ,DCIS or LCIS in the contralateral breast is not 
considered an event for DFS.  
 
Distant failure 
Tumors in all areas other than those defined above are considered distant metastases. The 
following criteria apply: 
 
Bone marrow 
Acceptable: positive cytology, aspiration or biopsy. 
Suspicious: 
unexplained 
depression 
of 
peripheral 
blood 
counts 
and/or 
a 
leucoerythroblastic blood picture. 
 

 
CASE 10107 12/28/2018 
Page 26 of 85 
 
 
 
Lung 
Acceptable: positive cytology or histology or a positive CT or MRI without obvious 
benign etiology or evidence of progressive disease. (Progressive disease is confirmed by 
two X-rays with the second showing worsening disease.) 
Suspicious: new radiological lesion(s). 
 
Pleura 
Acceptable: positive cytology or histology. 
Suspicious: new pleural effusion. 
 
Bone 
Acceptable: positive cytology or histology or a positive X-ray, MRI, or CT, one bone 
scan with new multiple lesions and no obvious benign etiology. 
Suspicious: skeletal symptoms or positive scan showing only one new lesion (until 
confirmed by other imaging study). 
 
Liver 
Acceptable: positive cytology or histology, or positive CT or MRI without an obvious 
benign etiology, or evidence of progressive disease by ultrasound. (Progressive disease in 
this case is confirmed by two ultrasounds with the second showing worsening disease). 
Suspicious: any two of the following: hepatomegaly on physical examination, equivocal 
ultrasound and abnormal liver function test. 
 
Central nervous system 
Acceptable: positive cytology or histology. Positive MRI or CT when the clinical picture 
is suspicious. 
Suspicious: any other clinical findings suggestive of this diagnosis. 
 
Distant lymph nodes, not including ipsilateral supraclavicular lymph nodes, or, for cases 
with bilateral invasive cancers, supraclavicular or axillary nodes on either side. 
Acceptable: positive cytology or histology, or enlarged lymph nodes in CT or MRI, or 
progressive disease by physical exam without an obvious benign etiology. 
Suspicious: evidence of enlarged lymph nodes by physical exam. 
For patients with bilateral breast cancer at randomization, failure in the axillary lymph 
nodes, extranodal soft tissue of the axilla, internal mammary lymph nodes, and/or 
supraclavicular lymph nodes on either the right or left side should be recorded as regional 
failure (rather than distant) on the Follow-Up Form. The side (right or left) of the 
recurrence should be recorded. 
 
Other sites 
Acceptable: positive cytology or histology or evidence of progressive disease if only 
indirect means of diagnosis were used (e.g., X-ray). 
Suspicious: clinical and radiological evidence of a tumor. 
 
Second (non-breast) primary 
Any positive diagnosis of a second (non-breast) primary is not considered a treatment 
failure. Patients may continue to receive the protocol treatment after a second (nonbreast) 
primary is diagnosed. 

 
CASE 10107 12/28/2018 
Page 27 of 85 
 
 
 
Death without cancer event 
Any death without a prior cancer event described in 3.4.5.2 above is not considered a 
treatment failure. 
 
Other noteworthy events 
The following events should be recorded on the Follow-up Form. These events are NOT 
considered treatment failures, but must be recorded. 
 ipsilateral and contralateral breast cancer in situ 
 cervical carcinoma in situ 
  bladder cancer in situ 
 basal or squamous cell carcinoma of the skin           
 
Assessment schedule for plasma cardiac markers 
 
                Every 6 weeks during trastuzumab monotherapy 
 N-terminal Brain Natriuretic Protein (NT-proBNP) 
 Troponin-I 
 
Analysis: 
Pearson’s correlation will be used to determine the correlation between cardiac 
markers and LVEF, and logistic regression to determine if cardiac markers can 
predict for cardiotoxicity. 
 
Assessment Schedule for Pro-inflammatory Cytokines 
 
    Every 6 weeks during trastuzumab monotherapy 
  Interleukin-6 (IL-6) 
 Tumor Necrosis Factor Alpha (TNF-) 
 
    Analysis: 
Pearson’s correlation will be used to determine the correlation between pro-
inflammatory cytokines and LVEF, and logistic regression to determine if   
cardiac markers can predict for cardiotoxicity 
 
Assessment Schedule for QOL and CGA Assessments 
 
Assessment at baseline (prior to the first dose of Trastuzumab) 
 Quality of Life and Comprehensive Geriatric Assessment  
 
Assessment at 6 months 
 Quality of Life and Comprehensive Geriatric Assessment  
 
Assessment at 12 months 
 Quality of Life and Comprehensive Geriatric Assessment  
       
                Analysis 
                Differences in QOL and GCA scores will be examined by paired t-test. 

 
CASE 10107 12/28/2018 
Page 28 of 85 
 
 
 
                Cox proportional hazards regression models will be used to test domains of the 
                CGA as potential predictors of cardiac toxicity and disease-free survival. 
 
3.5      SAFETY PLAN 
Patients will be evaluated at each study visit for the duration of their participation in the 
study (see Section 4.0 (Study Calendar)). 
 
Specific potential safety issues for this trial are outlined below. 
 
3.5.1 Cardiac Dysfunction.  
            Signs and symptoms of cardiac dysfunction were observed in a number of women who 
received Trastuzumab alone or in combination with chemotherapy, most often 
anthracycline-based treatment.  Cardiac dysfunction was observed most frequently 
among patients who received Trastuzumab plus AC chemotherapy (28%), compared with 
those who received AC alone (7%), Trastuzumab plus paclitaxel (11%), paclitaxel alone 
(1%), or Trastuzumab alone (7%).  Severe disability or fatal outcome due to cardiac 
dysfunction was observed in ~1% of all patients. 
 
The nature of the observed cardiac dysfunction was similar to the syndrome of 
anthracycline-induced cardiomyopathy.  The signs and symptoms of cardiac dysfunction 
usually responded to treatment.  Complete and partial responses were observed among 
patients with cardiac dysfunction.  The risk appears to be independent of tumor response 
to therapy.  Analysis of the clinical database for predictors of cardiac dysfunction 
revealed only advanced age and exposure to an anthracycline as possible risk factors.  In 
the clinical trials, most patients with cardiac dysfunction responded to appropriate 
medical therapy, often including discontinuation of Trastuzumab.  In many cases, patients 
were able to resume treatment with Herceptin.  In a subsequent study using weekly 
paclitaxel and Trastuzumab as first-line treatment for metastatic breast cancer, the 
observed incidence of serious cardiac dysfunction was 3% (N=95).108  Since the 
occurrence of cardiac dysfunction in the Trastuzumab plus chemotherapy trial was an 
unexpected observation, no information is available regarding the most appropriate 
method for monitoring cardiac function in patients receiving Trastuzumab. Significant 
advances in the understanding and treatment of CHF have been made in the past several 
years, with many of the new drugs demonstrating the ability to normalize cardiac 
function. Patients who develop symptoms of congestive heart failure while on 
Trastuzumab should be treated according to the HFSA guidelines (Appendix D).  
             
            Management of Cardiac Safety for Adjuvant Breast Cancer Protocols 
All patients must have a MUGA scan or ECHO at baseline, and on a regular schedule 
throughout the course of the study.  Investigators are strongly urged to schedule MUGA 
scans/ECHOs at the same radiology facility where the patient’s baseline MUGA 
scan/ECHO was done whenever possible.  MUGA scans/ECHOs are required at protocol-
specified time points and after any patient has any of the following: discontinuation of 
protocol therapy, congestive heart failure, breast cancer recurrence, or a second primary 
cancer.  When a cardiac event occurs, the Cardiac Report Form must be faxed in within 
14 days of learning of the event.   
 

 
CASE 10107 12/28/2018 
Page 29 of 85 
 
 
 
Post surgical radiation therapy may be required in patients at risk for recurrence.  
Whenever possible, irradiation to the internal mammary nodes should be avoided because 
of the concern for possible additional cardiotoxicity from the combination of 
Trastuzumab and radiation therapy.  Efforts should be taken to ensure that the volume of 
the heart irradiated is minimal.  Investigators are encouraged to discuss cardiac toxicity 
concerns with their radiation oncologists to ensure careful planning of the ports of left-
sided lesions.   
 
Cardiac Safety Criteria for initiation of Herceptin 
Asymptomatic Patients 
If a patient does not have significant symptoms related to LV dysfunction, 
administration of Trastuzumab will depend on the absolute change in LVEF 
between baseline and follow-up assessments. 
Trastuzumab should be initiated in an asymptomatic patient if: 
a) The LVEF increased or stayed the same; 
b) The LVEF decreased by <15 percentage points but is still at or above 
the lower limit of normal for the radiology facility. 
 
Trastuzumab is PROHIBITED in an asymptomatic patient if: 
a) The LVEF decreased <15 percentage points and is below the limit of 
normal for the radiology facility: 
b) The LVEF decreased by 16 percentage points or more (regardless of 
lower limits of normal for the radiology facility)  
 
Symptomatic Patients 
If a patient has significant symptoms related to left ventricular (LV) dysfunction, 
cardiac ischemia, or arrhythmia, initiation of trastuzumab is prohibited. 
 
Management of Symptomatic Cardiac Changes.   
Patients who develop signs and symptoms of CHF should have Trastuzumab held and 
should receive treatment for CHF as prescribed by the HFSA (e.g., ACE inhibitors, 
angiotensin-II receptor blockers, -blockers, diuretics, and cardiac glycosides, as needed; 
see Appendix C for HFSA guidelines).  Consideration should be given to obtaining a 
cardiac consultation.   
 
If the symptoms of CHF resolve with treatment, and cardiac function improves, 
trastuzumab may be continued after discussion with the patient concerning the risks and 
benefits of continued therapy.  If the patient is benefiting clinically from trastuzumab, the 
benefit of continued treatment may outweigh the risk of cardiac dysfunction.  If 
trastuzumab is restarted, continued surveillance with noninvasive measures of LVEF 
(MUGA or ECHO) is strongly recommended until cardiac function has normalized. 
 
Management of Asymptomatic Decreases in LVEF.   
Trastuzumab may be continued in patients experiencing an asymptomatic absolute 
decrease in LVEF of <20 percentage points from baseline, when the ejection fraction 
remains within the imaging center’s range of normal limits.  Repeat measures of LVEF 

 
CASE 10107 12/28/2018 
Page 30 of 85 
 
 
 
should be obtained using the methodology selected at baseline.  Close follow-up of such 
patients is recommended.  Patients with an asymptomatic absolute decrease in LVEF of 
20 percentage points or an ejection fraction below the range of normal limits, should 
have trastuzumab held and be considered for treatment of incipient CHF as prescribed by 
the HFSA (e.g., ACE inhibitors, angiotensin-II receptor blockers, -blockers, diuretics, 
and cardiac glycosides, as needed; see Appendix C for HFSA guidelines).  In light of the 
variability inherent in the assessment of ejection fraction, consideration should be given 
to repeating the study to confirm an observed decline.  Repeat measures of LVEF should 
be obtained using the same methodology selected at baseline.  If trastuzumab has been 
discontinued for an asymptomatic decline in LVEF, a repeat measure of LVEF will be 
obtained in 1 month to determine if the decline has resolved. 
 
If cardiac function improves, trastuzumab may be restarted after discussion with the 
patient concerning the risks and benefits of continued therapy.  If the patient is benefiting 
clinically from trastuzumab, the benefit of continued treatment may outweigh the risk of 
cardiac dysfunction. If trastuzumab is restarted, continued surveillance with noninvasive 
measures of LVEF (MUGA or ECHO), using the methodology selected at baseline, is 
strongly recommended until cardiac function has normalized. 
 
 Table 3 below summarizes rules governing trastuzumab suspension in the event of 
asymptomatic decline in LVEF 
 
3.5.2  Infusion-Associated Symptoms. During the first infusion with trastuzumab, a 
symptom complex consisting of chills and/or fever is observed in approximately 
40% of patients. Other signs and/or symptoms may include nausea, vomiting, 
pain, rigors, headache, cough, dizziness, rash, and asthenia. These symptoms are 
usually mild to moderate in severity, and occur infrequently with subsequent 
trastuzumab 
infusions. 
These 
symptoms 
can 
be 
treated 
with 
an 
analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such 
as diphenhydramine.  
Table 3: Asymptomatic Decrease in LVEF: Percentage Points from Baseline 
Relationship of 
LVEF 
to 
radiology 
facility’s LLN 
Decrease 
of 
<10 
percentage points 
Decrease of 10 to 15 
percentage points 
Decrease 
of 
16 
percentage points 
Within 
normal 
limits 
Continue 
Continue 
Hold 
and 
repeat 
MUGA/echocardiogram 
after 4 weeks 
1-5 percentage 
points 
below 
LLN 
Continue 
and 
repeat 
MUGA/echocardiogram 
after 4 weeks 
Hold 
and 
repeat 
MUGA/echocardiogram 
after 4 weeks 
Hold 
and 
repeat 
MUGA/echocardiogram 
after 4 weeks 
 6 percentage 
points 
below 
LLN 
Continue 
and 
repeat 
MUGA/echocardiogram 
after 4 weeks 
Hold 
and 
repeat 
MUGA/echocardiogram 
after 4 weeks 
Hold 
and 
repeat 
MUGA/echocardiogram 
after 4 weeks 

 
CASE 10107 12/28/2018 
Page 31 of 85 
 
 
 
3.5.3  Serious Infusion-Associated Events. Serious adverse reactions to trastuzumab 
infusion including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, 
reduced oxygen saturation and respiratory distress have been reported 
infrequently.   In rare cases (4 per 10,000), these events were associated with a 
clinical course culminating in a fatal outcome. Serious reactions have been treated 
with supportive therapy such as oxygen, beta-agonists, corticosteroids and 
withdrawal of trastuzumab as indicated. 
3.5.4  Hematologic Toxicity and Neutropenic Infections In the clinical trials, an 
increased incidence of anemia was observed in patients receiving trastuzumab 
plus chemotherapy compared with patients receiving chemotherapy alone.  The 
majority of these anemia events were mild or moderate in intensity and reversible; 
none resulted in discontinuation of trastuzumab therapy.   
In the clinical trials, the per-patient incidences of moderate to severe neutropenia 
and of febrile neutropenia were higher in patients receiving trastuzumab in 
combination with myelosuppressive chemotherapy as compared to those who 
received chemotherapy alone. In the post marketing setting, deaths due to sepsis 
in patients with severe neutropenia have been reported in patients receiving 
trastuzumab and myelosuppressive chemotherapy, although in controlled clinical 
trials (pre- and post-marketing), the incidence of septic deaths was not 
significantly increased. The pathophysiologic basis for exacerbation of  
neutropenia has not been determined; the effect of trastuzumab on the 
pharmacokinetics of chemotherapeutic agents has not been fully evaluated.  
Secondary acute leukemia or myelodysplastic syndrome has been reported in 4 of 
approximately 1200 patients who participated in trastuzumab clinical trials.  
Patients treated with chemotherapeutic agents are known to be at increased risk 
for secondary leukemia.  The observed incidence of leukemia among 
trastuzumab-treated patients appears to be consistent with the expected incidence 
of leukemia among patients treated with chemotherapy for metastatic breast 
cancer (7). Therefore, the contribution of trastuzumab to the etiology of acute 
leukemia or myelodysplastic syndrome in these cases is unclear. 
 
Management of Hematologic Toxicities 
Care should be taken to carefully monitor the patient’s hematologic status 
throughout the course of the trial.  Use of hematopoietic growth factors to 
ameliorate hematologic toxicity is at the discretion of the physician investigator 
and should be in accordance with the American Society of Clinical Oncologists 
(ASCO) guidelines.  
 
Please refer to the HERCEPTIN Investigator Brochure for a detailed description 
of the safety profile of Herceptin. 
 
See Section 5 (Assessment of Safety) for complete details of the safety evaluation 
for this study. 

 
CASE 10107 12/28/2018 
Page 32 of 85 
 
 
 
3.6 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration (FDA) Good Clinical Practices (GCPs), and local ethical and legal 
requirement 

 
CASE 10107 12/28/2018 
Page 33 of 85 
 
 
 
4.0 STUDY PARAMETERS AND CALENDAR 
Table 4: Study Calendar for Screening, Treatment and Surveillance Period 
 
Screening 
Treatment 
Surveillance 
Pre study 
period 
 
Week 1 
  
 
Weeks 2-51 
 
Week 52 
End of 
Treatment 
 
Year 2 to end 
of year 3 
 
Year 4 to end  
of Year 5 
 
Eligibility  
 
 
 
 
 
 
 
Review study 
procedures 
 
 
 
 
 
 
 
 
Sign informed consent 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
Baseline history and 
Physical Examination 
 
 
 
 
 
 
 
 
Cardiac History 
 
 
 
 
Every 6 
months 
 
 
 
Every 6 
months 
 
Every 6 
months 
Administer QOL and 
CGA tools 
 
 
 
Every 6 
months 
 
 
 
 
 
 
CBC, Complete 
Metabolic profile 
 
 
 
 
 
Every 3 
weeks 
 
 
 
Every 6 
months 
 
Every 6 
months  
 
Cardiac markers 
 
 
 
 
 
Every 6 
weeks 
 
 
 
† 
Cardiac 
Markers only 
@60mths 
 
MUGA/Echo* 
 
 
 
 
Every 3 
months 
 
 
 
 
 
@60mths 
Loading dose  of 
trastuzumab  
 
 
 
 
 
 
 
Maintenance dose  of 
trastuzumab  
 
 
 
Every 3 
weeks 
 
 
 
 
Limited physical 
examination and 
history 
 
 
 
Every 6 
weeks 
 
 
  
Every 6 
months 
 
Every 6 
months 
Assessment of adverse 
events 
 
 
Every 3 
weeks 
 
 
 
 
 
†Cardiac markers will not be tested during the surveillance period 
*MUGA/ECHO measurements will be done every 4 weeks for patients who develop significant left ventricular cardiac 
dysfunction requiring trastuzumab to be held. 

 
CASE 10107 12/28/2018 
Page 34 of 85 
 
 
 
5.0      MATERIALS AND METHODS 
5.1 
SUBJECTS 
5.1.1 Inclusion Criteria 
Patients will be included in the study based on the following criteria: 
 Women with histologically confirmed adenocarcinoma of the breast  
 Immunohistochemical staining for Her2 protein of 3+ intensity or Her2 gene 
amplification of ≥ 2.0 by FISH testing. 
 Life expectancy > 6 months, age ≥60 years 
 ECOG performance status 
2

 
 Node positive disease irrespective of tumor size 
 Node negative disease: 
                        TNM Stage (AJCC Cancer Staging Manual 6th edition) T1b-T4, N0-3, M0, 
                   irrespective of hormonal status 
 
 Baseline LVEF ≥ lower limit of normal for a particular institution 
 Complete surgical removal of invasive cancer by mastectomy or lumpectomy  
 Complete staging work-up with CT of chest, abdomen, and pelvis plus bone 
scan or alternatively with PET scan for stage II and higher disease, or as 
determined by symptoms for all other stages. Additional staging work-up as 
per symptoms. 
 Adequate bone marrow function as indicated by the following: 
ANC >1000/L  
Platelets 100,000/L 
Hemoglobin >10 g/dL 
 Adequate liver function, as indicated by bilirubin 1.5 ULN 
Adequate renal function, as indicated by creatinine 1.5 upper limit of 
normal (ULN) 
 AST or ALT <2 ULN unless related to primary disease. 
 Signed informed consent 
 

 
CASE 10107 12/28/2018 
Page 35 of 85 
 
 
 
5.1.2 Exclusion Criteria 
 Enrollment after more than 120 days from the last day of mastectomy or 
lumpectomy 
 Patients able to tolerate and willing to receive chemotherapy 
 Prior chemotherapy for current malignancy  
 Prior herceptin therapy 
Active cardiac disease 
 Myocardial infarction  (asymptomatic changes on EKG suggestive of old MI 
is not an exclusion) 
 Angina pectoris requiring anti-anginal treatment  
 Documented congestive heart failure (CHF) 
 Current use of any therapy specifically for CHF 
 Cardiac arrhythmia requiring medication 
 Current uncontrolled hypertension (diastolic >100 mmHg or systolic > 200 
mmHg) 
 Clinically significant valvular abnormality (associated with New York Heart 
Association (NYHA) class II, III, or IV symptoms) 
 Clinically significant pericardial effusion (associated with New York Heart 
Association (NYHA) class II, III, or IV symptoms) 
Past cardiac disease 
 Prior myocardial infarction  (asymptomatic changes on EKG suggestive of old 
MI is not an exclusion) 
 Prior history of CHF 
 History of cardiomyopathy 
Other diseases and conditions 
 Evidence of metastatic breast cancer (clinical or radiological evidence) 
 Active infection 
 Concomitant malignancies or previous malignancies within the last 3 years, 
with the exception of adequately treated basal or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix. 
 Hypersensitivity to trastuzumab 
 

 
CASE 10107 12/28/2018 
Page 36 of 85 
 
 
 
5.1.3   Inclusion of Women and Minorities 
This study will be open to women of all ethnic backgrounds who meet eligibility 
criteria.  Accrual targets will not be specific for ethnic groups. 
 
5.2 
REGISTRATION PROCEDURES 
This is a single arm trial that does not require randomization. Case 
Comprehensive Cancer Center will be the coordinating institution for the study. 
To enter eligible patients on study, investigators from participating institutions 
listed on the cover sheet will register patients by contacting the Study Coordinator 
at (216) 844-1545. The following information will be requested: a registration 
card, copy of the informed consent which may be obtained by investigators of 
participating institutions or their designee, and a copy of the signed eligibility 
checklist. These must be submitted prior to a patient starting treatment. These 
documents can be faxed to (216) 201-5013. All patients enrolled on the study will 
be entered into a secure database at Case Comprehensive Cancer Center called 
Oncore database. 
 
5.3      TREATMENT PLAN 
 
 5.3.1      Trastuzumab Administration and Supportive Measures 
 
               5.3.1.1  Loading dose of trastuzumab: Patients will 
                            receive an 8mg/kg IV loading dose on day 1. 
  
               5.3.1.2  Maintenance Phase of trastuzumab:  
                            Every 3 week schedule: 6 mg/kg IV every 3 weeks to complete  
                            52 weeks of treatment  
 
               5.3.1.3   The initial dose of trastuzumab will be administered over 90 
                             minutes.  If this first dose is well tolerated, subsequent infusion 
                             times may be shortened to 30 minutes.  If the initial or a 
                             subsequent dose is not well tolerated (i.e. fevers, chills, or  
                             rigors), subsequent infusion times may be shortened only after a  
                             dose is well tolerated. 
 
                          5.3.1.4   If during the maintenance phase with trastuzumab monotherapy 
                                        a dose of trastuzumab is delayed the dose of trastuzumab should 
                                        not be made up and reloading doses are not to be given.  
 
                         5.3.1.5     Treatment is permitted in an asymptomatic patient if: 
 The LVEF increased or stayed the same OR 
 The LVEF decreased by 15 percentage points, but is still at 
or above the radiology facility’s lower limit of normal 
(LLN) 
 
                        5.3.1.6   Treatment is prohibited in an asymptomatic patient if: 
 The LVEF decreased by 15 percentage point and is 
below the radiology facility’s lower limit of normal limit 

 
CASE 10107 12/28/2018 
Page 37 of 85 
 
 
 
                                                     
 The LVEF decreased by 16 percentage point or more, 
regardless of the radiology facility’s LLN 
 
See Table under section 3.5.1 
 
5.4      STUDY TREATMENT  
Genentech will supply Herceptin. 
 
           5.4.1   Herceptin Formulation 
Herceptin is a sterile, white to pale yellow, preservative-free lyophilized powder 
for intravenous (IV) administration.  Each vial of Herceptin contains 440 mg of 
trastuzumab, 9.9 mg of L-histidine HCl, 6.4 mg of L-histadine, 400 mg of 
,-trehalose dihydrate, and 1.8 mg of polysorbate 20, USP.  Reconstitution with 
20 mL of the supplied Bacteriostatic Water for Injection (BWFI) USP, containing 
1.1% benzyl alcohol as a preservative, yields 21 mL of a multidose solution 
containing 21 mg/mL trastuzumab, at a pH of ~6. 
 
           5.4.2   Herceptin Dosage, Preparation, Administration, and Storage  
           a. Dosage 
The recommended initial loading dose is 8 mg/kg Herceptin administered as a 
90-minute infusion.  The recommended maintenance Herceptin dose is 6 mg/kg 
q3wk and can be administered as a 30-minute infusion if the initial loading dose 
was well tolerated.  Herceptin may be administered in an outpatient setting.  DO 
NOT ADMINISTER AS AN IV PUSH OR BOLUS (see ADMINISTRATION).  
b.  Preparation 
Use appropriate aseptic technique.  Each vial of Herceptin should be reconstituted 
with 20 mL of BWFI, USP, 1.1% benzyl alcohol preserved, as supplied, to yield a 
multidose solution containing 21 mg/mL Herceptin.  Immediately upon 
reconstitution with BWFI, the vial of Herceptin must be labeled in the area 
marked “Do not use after” with the future date that is 28 days from the date of 
reconstitution. 
 
If the patient has known hypersensitivity to benzyl alcohol, Herceptin must be 
reconstituted with Sterile Water for Injection (see PRECAUTIONS).  Herceptin 
which has been reconstituted with SWFI must be used immediately and any 
unused portion discarded.  Use of other reconstitution diluents should be avoided. 
Determine the dose of Herceptin needed, based on a loading dose of 8 mg 
Herceptin/kg body weight or a maintenance dose of 6 mg Herceptin/kg body 
weight.  Calculate the correct dose using  21 mg/mL Herceptin solution.  
Withdraw this amount from the vial and add it to an infusion bag containing 250 
mL of 0.9% sodium chloride, USP.  DEXTROSE (5%) SOLUTION SHOULD 
NOT BE USED.  Gently invert the bag to mix the solution.  The reconstituted 
preparation results in a colorless to pale yellow transparent solution.  Parenteral 
drug products should be inspected visually for particulates and discoloration prior 
to administration. 

 
CASE 10107 12/28/2018 
Page 38 of 85 
 
 
 
No incompatibilities between Herceptin and polyvinylchloride or polyethylene 
bags have been observed. 
            c. Administration 
Treatment may be administered in an outpatient setting by administration of an 8 
mg/kg Herceptin loading dose by intravenous (IV) infusion over 90 minutes.  DO 
NOT ADMINISTER AS AN IV PUSH OR BOLUS.  Patients should be 
observed for fever and chills or other infusion-associated symptoms (see 
ADVERSE REACTIONS).  If prior infusions are well tolerated subsequent doses 
of 6 mg/kg Herceptin q3wk may be administered over 30 minutes.  
 
Table 5 
Herceptin Infusion Time and Post-Infusion Observation Period 
Herceptin Dose 
Infusion Time 
(minutes) 
Post-Infusion 
Observation Period 
(minutes) 
First infusion 
8 mg/kg 
90 
60 
Second infusion 
6 mg/kg 
30 a 
30 a 
Third and 
subsequent 
infusions 
6 mg/kg 
30 a 
None a 
a Only if previous dose was well tolerated. 
 
Herceptin should not be mixed or diluted with other drugs.  Herceptin 
infusions should not be administered or mixed with Dextrose solutions. 
d.  Storage 
Vials of Herceptin are stable at 2C–8C (36F–46F) prior to reconstitution.  Do 
not use beyond the expiration date stamped on the vial.  A vial of Herceptin 
reconstituted with BWFI, as supplied, is stable for 28 days after reconstitution 
when stored refrigerated at 2C–8C (36F–46F), and the solution is preserved 
for multiple use.  Discard any remaining multi-dose reconstituted solution after 28 
days.  If unpreserved SWFI (not supplied) is used, the reconstituted Herceptin 
solution should be used immediately and any unused portion must be discarded.  
DO NOT FREEZE HERCEPTIN THAT HAS BEEN RECONSTITUTED. 
 
The solution of Herceptin for infusion diluted in polyvinylchloride or 
polyethylene bags containing 0.9% sodium chloride for injection, USP, may be 
stored at 2C–8C (36F–46F) for up to 24 hours prior to use.  Diluted Herceptin 
has been shown to be stable for up to 24 hours at room temperature 15C–25C; 
however, since diluted Herceptin contains no effective preservative the 
reconstituted and diluted solution should be stored refrigerated (2C–8C). 

 
CASE 10107 12/28/2018 
Page 39 of 85 
 
 
 
          
 5.4.3   Herceptin Dosage Modification 
 No dose modifications are permitted.  
 
 No cardioprotective drugs are permitted. There are no data for the use 
of cardioprotective agents such as dexrazoxane (Zinecard) 
 
5.4.4   Toxicities  
                      5.4.4.1  Infusion-associated symptoms 
 
     5.4.4.1.1  During the first infusion, a symptom complex of fever 
and/or chills may occur. These are usually mild-to-
moderate and may be accompanied by nausea, 
vomiting, 
headache, 
dizziness, 
rigors, 
pain, 
hypotension, rash, and asthenia.  These symptoms 
occur infrequently during subsequent infusions.   
 
    5.4.4.1.2  Serious adverse reactions to Trastuzumab infusion 
include 
dyspnea, 
hypotension, 
wheezing, 
bronchospasm, 
tachycardia, 
reduced 
oxygen 
saturation, and respiratory distress have been reported 
infrequently.  In rare cases (4 per10,000) these events 
were associated with a clinical course culminating in 
fatal outcome.   
 
 
                     5.4.4.2  Cardiac Dysfunction 
 
    5.4.4.2.1   Trastuzumab may result in clinically manageable left 
ventricular systolic dysfunction, and occasionally 
advanced congestive heart failure (CHF) in a small 
proportion of patients. The incidence and severity of 
cardiac dysfunction has been greatest in patients who 
received Trastuzumab in combination with an 
anthracycline.  In the pooled NSABP/NCCTG 
experience, the risk of cardiac events was 4% among 
those treated with chemotherapy and trastuzumab, as 
compared with .6% for those given chemotherapy 
alone. There are data suggesting that the risk is lower 
when 
sequential 
chemotherapy 
followed 
by 
trastuzumab is given Furthermore, older patients and 
those patients with borderline normal LVEF at baseline 
may be at greater risk for cardiac events.  The 
incidence of class III or IV cardiac dysfunction was 
2% for those receiving concurrent paclitaxel plus 
trastuzumab.22  The risk of cardiac toxicity is 

 
CASE 10107 12/28/2018 
Page 40 of 85 
 
 
 
substantially 
lower 
in 
patients 
who 
received 
trastuzumab alone.  Cardiac dysfunction appears to 
improve in most patients who receive supportive 
medical treatment. 
 
                5.4.4.2.2  Individual patients should have their MUGA  
                                scans/echocardiograms performed at the same  
                                radiology facility to eliminate variability between 
                                facilities. 
 
                5.4.4.2.3  Asymptomatic decrease in LVEF: 
                                Decision to continue or stop is based on the measured  
                                ejection fraction as it relates to the radiology facility’s  
                                LLN and change in ejection fraction from baseline. 
                                See section 3.5.1 for guidelines for performing MUGA  
                                scan/echocardiogram and management of patients who 
                                have an asymptomatic decrease inLVEF from baseline. 
 
5.4.4.2.4 If trastuzumab is not started or discontinued during 
therapy, MUGA scan/echocardiogram still needs to be 
done at 12 weeks and at 1 year. 
 
                                    5.4.4.2.5    Trastuzumab must be permanently discontinued when  
                                                      two consecutive “hold” categories occur. 
  
                                    5.4.4.2.6    Trastuzumab must be permanently discontinued when  
                                                      three intermittent “hold” categories occur. 
 
5.4.4.2.7    At the discretion of the investigator, trastuzumab may  
                                                      also be permanently discontinued prior to the  
                                                      occurrence of three intermittent “hold” categories. 
 
5.4.4.2.8   If LVEF is maintained at a “continue and repeat 
                 MUGA/echocardiogram” or improves from a “hold” to  
                 a “continue and repeat MUGA/echocardiogram”  
                 category, additional MUGA scans/echocardiogram prior 
                 to the next scheduled MUGA scan/echocardiogram will  
                 be at the discretion of the investigator. 
 
5.4.4.3  Symptomatic decrease in LVEF 
 
5.4.4.3.1   Grade 3 CHF 
5.4.4.3.1.1  Monitor for signs and symptoms of CHF (i.e. 
                   dyspnea, tachycardia, cough, neck vein 
                   distention, cardiomegaly, hepatomegaly,  
                   paroxysmal nocturnal dyspnea, orthopnea,  
                   peripheral edema, etc) 
5.4.4.3.1.2  If patient develop these signs and symptoms, 

 
CASE 10107 12/28/2018 
Page 41 of 85 
 
 
 
                   hold treatment. 
5.4.4.3.1.3  Confirm diagnosis of CHF with either a  
                   MUGAscan/echocardiogram.  A chest x-ray is also 
                   required.  Once a diagnosis of CHF is confirmed, 
                   trastuzumab must be permanently discontinued and  
                   reported as an adverse event. 
5.4.4.3.1.4  Follow-up at 3, 6, and 12 months from time of CHF 
                   diagnosis with MUGA scan/echocardiogram. 
 
5.4.4.3.2 
Grade 4 CHF (severe refractory CHF or requiring 
intubation) 
5.4.4.3.2.1   Discontinue treatment, and report as an 
                    adverse event. 
5.4.4.3.2.2   Follow-up at 3, 6, and 12 months with 
                    MUGA/echocardiogram. 
 
                     5.4.4.4  Ischemia 
 
5.4.4.4.1 Grade 1 
5.4.4.4.1.1  Continue treatment with frequent monitoring. 
 
                                5.4.4.4.2 Grade 2 
5.4.4.4.2.1  Hold treatment and conduct cardiac  
                   evaluation. 
5.4.4.4.2.2  Based on this evaluation, treatment may be 
                   continued at the discretion of the investigator. 
 
5.4.4.4.3 Grade 3 or 4 
5.4.4.4.2.3  Discontinue treatment. 
 
5.4.4.5      Arrhythmia 
 
5.4.4.5.1 Grade 1 
5.4.4.5.1.1  Continue treatment with careful monitoring OR  
                   hold treatment and conduct cardiac evaluation. 
5.4.4.5.1.2  Based on cardiac evaluation, treatment with 
                   trastuzumab and may continue or discontinue at the 
                                                            discretion of the investigator. 
 
5.4.4.5.2 Grade 2 
        5.4.4.5.2.1  Hold treatment and conduct cardiac evaluation. 
5.4.4.5.2.2  Based on cardiac evaluation, treatment with 
                   trastuzumab may continue or discontinue at the 
                  discretion of the investigator. 
 
5.4.4.5.3 Grade 3 or 4 
5.4.4.5.3.1   Discontinue trastuzumab. 
 

 
CASE 10107 12/28/2018 
Page 42 of 85 
 
 
 
5.4.4.6   Myocardial Infarction 
5.4.4.6.1  Discontinue treatment 
 
5.4.4.7   Fever 
5.4.4.7.1 Grade 1 (38C - 39C [100.4 - 102.2F] OR Grade 2 
(39.1C - 40C [102.3 - 104F] 
5.4.4.7.1.1 Stop infusion and give antipyretics.  Once 
                  temperature is <38C, resume infusion at a 
                  slower rate. 
 
5.4.4.7.2  Grade 3 (>40C [104]) OR Grade 4 (40C [104F]  
                for 24 hours) 
5.4.4.7.2.1 Stop infusion immediately and give 
                  antipyretics 
5.4.4.7.2.2 Monitor patient for a minimum of one hour 
5.4.4.7.2.3 If temperature drops to <38C within 3 hours, 
                  resume infusion at a slower rate. 
5.4.4.7.2.4 If fever does not resolve within 3 hours, 
                  inpatient monitoring is strongly recommended. 
5.4.4.7.2.5 If temperature drops to <38C within 3 days,  
                  re-challenge at a slower rate. 
5.4.4.7.2.6 If temperature remains >38C after 3 days,  
                  abandon this administration and subsequent 
                  administration is at the discretion of the 
                  investigator 
 
 
 
5.4.4.8   Chills 
 
                             5.4.4.8.1 Treat with acetaminophen and/or diphenhydramine 
                                            hydrochloride. Meperidine may be given at the 
                                            investigator’s discretion. 
 
5.4.4.9   Gastrointestinal 
 
5.4.4.9.1 Diarrhea 
5.4.4.9.1.1 Any grade 
           Any anti-diarrheal medication may be given 
           at the investigator’s discretion. 
 
5.4.4.10  Allergy/Immunology 
 
5.4.4.10.3 Allergic reaction/hypersensitivity (including drug fever) 
                                  Stop the infusion and give diphenhydramine 
                Hydrochloride. If toxicity resolves within 3 hours, 
                treatment in next dose is allowed at a slower rate and 
                under close observation. If toxicity does not resolve in 3 
                hours, overnight observation is recommended and  

 
CASE 10107 12/28/2018 
Page 43 of 85 
 
 
 
                treatment in the next dose under close observation is at the  
                discretion of the investigator. 
 
5.4.4.11  Pulmonary 
 
      5.4.4.11.1 Any (e.g. Adult Respiratory Distress 
               Syndrome[ARDS], pneumonitis/pulmonary 
               infiltrates, etc) 
 
               Delay trastuzumab until cause is known. If  
               pneumonitis/fibrosis, or pulmonary infiltrate is confirmed,  
               and the relationship to trastuzumab cannot be excluded,  
               trastuzumab must be permanently discontinued.  
 
5.4.4.12 
Hematologic Toxicity 
5.4.4.12.1  Anemia 
 
                  An increased incidence of anemia has been 
                  observed in patients receiving trastuzumab plus 
                  chemotherapy compared with patients receiving 
                  chemotherapy alone. The majority of these 
                  anemia events were mild or moderate in intensity 
                  and reversible.  None resulted in discontinuation of  
                  trastuzumab. 
 
5.4.4.12.2  Neutropenia 
 
                In randomized controlled clinical trials designed to 
                assess the impact of the addition of trastuzumab to 
                chemotherapy, the incidence of moderate to severe 
                neutropenia and of febrile neutropenia were higher in 
                patients receiving trastuzumab in combination with  
                chemotherapy as compared to those who received 
                chemotherapy alone. The pathophysiologic basis for 
                exacerbation of neutropenia has not been determined. 
 
                                5.4.4.12.3   Secondary acute leukemia or myelodysplastic 
                  syndrome 
 
                  Incidence of approximately 4 in 1200 patients who 
participated in trastuzumab clinical trials. Patients treated 
with chemotherapeutic agents are known to be at 
increased risk of secondary leukemia.  The observed 
incidence of leukemia among trastuzumab-treated 
patients appears to be consistent with the expected 
incidence of leukemia among patients treated with 
chemotherapy for metastatic breast cancer.25  The 
contribution of trastuzumab to the etiology of acute 

 
CASE 10107 12/28/2018 
Page 44 of 85 
 
 
 
leukemia or myelodysplastic syndrome in these cases is 
unclear. 
     
  5.4.5   Herceptin Overdosage 
There is no experience with overdosage in human clinical trials. Single doses     
higher than 500 mg have not been tested. 
 
5.5  ANCILLARY THERAPY 
 
 5.5.1      Patients should receive full supportive care, including transfusions of  
               blood or blood products, antibiotics, antiemetics, etc., when  
               appropriate. 
 
 5.5.2      Treatment with other chemotherapeutic agents or biologic agents may 
               not be administered except for hormonal therapy given for patients 
               with hormone positive disease, steroids given for adrenal failure, 
               hormones administered for non- disease-related conditions 
              (insulin for diabetes, synthroid for hypothyroidism);  and intermittent  
               use of dexamethasone as an antiemetic 
 
      5.5.3      Use of Growth Factors 
 
 5.5.3.1   Erythropoetin (EPO) and Related Agents. The use of EPO is 
               permitted at the discretion of the treating physician. 
 
 5.5.3.2   Filgrastim (G-CSF) and Related Agents. The use of filgrastim is  
               permitted at the discretion of the treating physician 
 
5.6  CONCOMITANT AND EXCLUDED THERAPY 
5.6.1   Radiation Therapy 
                    5.6.1.1    Patients who undergo lumpectomy (breast conserving 
           surgery) must receive breast radiation therapy. This may 
           be performed according to local institutional standards. 
           Patients may be treated with conventional, whole breast  
           radiation, or partial breast radiation, administered by  
           external beam or brachytherapy.   
 
                     5.6.1.2    Radiation therapy will begin after completion of primary 
           surgery (lumpectomy or mastectomy if indicated)  
 
5.6.1.3 Patients undergoing mastectomy may receive chest wall 
                                    and nodal radiation according to local institutional 
           standards.   
 
                     5.6.1.4    Patients may receive adjuvant trastuzumab as per  
           protocol during radiotherapy. 
     

 
CASE 10107 12/28/2018 
Page 45 of 85 
 
 
 
 
5.7 
STUDY ASSESSMENTS 
            See section 3.3 for study assessments            
 
5.8 
DISCONTINUATION OF PROTOCOL-SPECIFIED THERAPY 
Trastuzumab may be discontinued for any of the following reasons: 
 Recurrent disease 
 Unacceptable toxicity 
 Patient election to discontinue therapy (for any reason) 
 Physician’s judgment 
 
5.9 
SUBJECT DISCONTINUATION 
Even after a patient agrees to take part in this study, she may stop study therapy or 
withdraw from the study at any time. If she stops study therapy but still allows the 
study doctor to submit follow-up information, she should continue to be followed 
according to the study schedule. Alternatively, she may choose to have no further 
interaction regarding the study. In this case, the investigator must provide 
documentation of the patient's decision to fully withdraw from the study in the 
case report form. No special tests are needed at the time of discontinuation. 
Patients who choose to discontinue the study cannot resume participation at a later 
date. 
 
Since this is a non-randomized study, patients who fully withdraw from the study 
should be replaced. 
 
The reason for premature discontinuation of a subject must be recorded on the 
Case Report Form. 
 
5.10 
STUDY DISCONTINUATION 
Genentech Study Center, and the Principal Investigator have the right to terminate 
this study at any time. Reasons for terminating the study may include the 
following: 
 The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects 
 Subject enrollment is unsatisfactory 
 Data recording are inaccurate or incomplete 
 Study protocol not followed 
 
5.11 
        STATISTICAL METHODS 
5.11.1          Study Design 
This is an open label, single arm, phase II pilot study evaluating the safety and 
efficacy of single agent adjuvant trastuzumab at 8mg/kg IV loading dose, 
followed by 6mg/kg IV every three weeks to complete 52 weeks of treatment, 
among women 60 years and older.   
 

 
CASE 10107 12/28/2018 
Page 46 of 85 
 
 
 
 
5.11.2        End Points 
 
5.11.2.1      Primary End-point 
 
The primary outcome measure is the incidence of cardiac events over a three-year 
follow-up period and is defined by any one of the following events; 
 Definitive cardiac death; due to CHF, MI, or documented arrhythmia  
 Any possible/probable cardiac death over the three-year follow-up 
      period defined as a sudden unexpected death within 24 hours after a 
      definitive cardiac event , and without definitive documented alternative  
      cause.  
 Signs and symptoms of congestive heart failure (CHF). CHF will be 
defined as follows: New York Heart Association (NYHA) class III or IV 
symptoms with either a decrease from baseline in LVEF of more than 10 
percentage points to less than 55% or a decrease of more than 5 
percentage points to less than the lower limit of normal. Class III is 
characterized by symptoms of dyspnea with activities such as climbing a 
flight of stairs, whereas class IV symptoms are present at rest. 
 
5.11.2.2      Secondary End-points 
 
 The three-year cumulative incidence of asymptomatic left ventricular 
cardiac dysfunction defined as an asymptomatic decrease in LVEF from 
baseline of at least ten percentage points to below the lower limit of 
normal or an absolute decrease of >15 percentage points leading to a 
permanent discontinuation of trastuzumab before completion of one year 
of therapy. 
 
 The five-year cumulative incidence of cardiac events for long term 
cardiac monitoring and defined as above under section 5.11.2.1 
 
 Mean change in plasma cardiac markers from baseline to mid treatment, 
and from baseline to end of treatment. 
 Mean change in pro-inflammatory cytokines from baseline to mid 
treatment, and from baseline to end of treatment.  
 Mean change in QOL and CGA scores from baseline to mid        
treatment, and from baseline to end of treatment.  
 Disease-free survival (DFS) defined as the time from treatment initiation 
to the date of first loco-regional or distant treatment failure, ignoring any 
intervening contra-lateral breast cancers or other second primary 
cancers. Deaths without evidence of recurrence will be treated as 
censoring events. 

 
CASE 10107 12/28/2018 
Page 47 of 85 
 
 
 
 Overall survival defined as the time from treatment initiation to the date 
of death from any cause and censored to the date of last follow-up for 
survivors. 
        
5.11.3         Sample Size Justification 
The target accrual of this study is 124 patients. The primary endpoint used in the sample 
size calculation is the cumulative incidence of cardiac events over a three-year period. 
We hypothesize that the incidence (P) of cardiac events in this trial will be no bigger than 
4% and that incidence of cardiac events bigger than 10% is considered unacceptable. 
With a type I error of 0.05, the estimated sample size based on a two-sided chi-square test 
is 113. With 10% attrition rate, the sample size required for this study is 124 patients. 
With 124 patients, the power to test the null hypothesis H0: P ≤ 0.04 vs. Ha: P > 0.1 is 
above 80%. By the accrual rate of 7 patients per institution per year, the enrollment is 
expected to complete within about 3.5 years. Our acceptable cardiac toxicity rate of 4% is 
derived from NSABP-B3120 study, in which the three-year cumulative incidence of 
symptomatic cardiac dysfunction was 4.1%. Our unacceptable cardiac toxicity rate of 
10% is derived from an overall cardiac dysfunction rate of up to 7%21,22 associated with 
the use of single agent trastuzumab in the metastatic setting.  
 
Early Stopping Rules 
A formal interim analysis plan will be used to monitor the cardiotoxicity rate, defined as 
the number of cardiotoxicity events divided by the person-years of follow-up at that time. 
This is an estimate of the hazard of cardiotoxicity, assuming an exponential distribution 
for time to cardiotoxicity.  The timing of the interim analyses will be based on the 
number of cardiotoxicity events; analyses will occur when the cumulative number of 
events is 3, 6, 9, as well as at one year after enrollment of the last patient.  Thus, there 
will be up to three interim analyses.  At each interim analysis, we will use an exact one-
sided Poisson test to test the null hypothesis that the exponential hazard is less than or 
equal to 0.0136 (corresponding to a 4% 3-year event rate) versus the alternative 
hypothesis that it is 0.0351 or higher (corresponding to a 10% 3-year cardiotoxicity event 
rate). A Lan-DeMets type I error spending function with overall type I error rate of 0.05 
will be used to determine the significance level used at each analysis.  If the null 
hypothesis is rejected, then the trial will be stopped.   If the 3-year cardiotoxicity event 
rate is 10%, with 124 patients enrolled uniformly over two years and followed an 
additional 3 years, and allowing for 10% exponential loss due to death or dropout over 3 
years, approximately 12 (11.78) cardiotoxicity events within 3-years of enrollment will 
be observed by the end of the study.  Therefore, the interim analyses occurring at 3, 6, 
and 9 cumulative events correspond approximately to information times of 0.25, 0.50, 
and 0.75.  Alternatively, if the true 3-year cardiotoxicity rate is 4%, then the expected 
total number of cardiotoxicities observed over 3 years among the 124 patients is only 4.7.  
Although interim analyses will be based on testing the exponential hazard, for the 
primary analysis the 3-year incidence of cardiotoxicity will be estimated using the 
Kaplan-Meier method. 
 
 
 
 

 
CASE 10107 12/28/2018 
Page 48 of 85 
 
 
 
5.11.4    ACCRUAL ESTIMATES AND RATE 
  
Accrual estimates 
Five institutions are participating in this study. With an accrual rate of 7 patients per 
institution per year we expect to accrue 124 participants into the study within 3.5 years.  
 
5.11.5    Statistical Analysis 
 Descriptive statistics, such as means, median, range, and frequencies, will 
be used to describe subjects’ cardiac toxicity profile.  
 Time to incidence of cardiac events will be measured from the date of 
treatment initiation to the date of cardiac event and censored at the date of 
last follow-up or the date of death due to non cardiac causes for those who 
do not have a cardiac event. The cumulative incidence of cardiac events  
and its 95% confidence interval will be estimated using Kaplan-Meier104.  
 Potential factors that predict the incidence of cardiac toxicity will be 
identified by multivariable Cox proportional hazards analysis.109 
 Pearson’s correlation will be used to determine the correlation between 
cardiac markers and LVEF. 
 The difference in mean QOL and CGA scores from baseline to mid 
treatment, and from baseline to end of treatment will be examined by 
paired t-test. 
 The Kaplan-Meier method110 will be used to estimate disease-free survival 
and overall survival.  
 Cox proportional hazards regression models109 will be used to test selected 
variables as potential predictors of disease-free-survival and overall 
survival. 
 All eligible subjects who received at least one dose of trastuzumab will be 
included in survival (time-to-event) analysis.  
 All statistical testing will be two-sided and level of significance will be 
assumed at 5%.  
 
5.11.6    Missing Data 
Completion of all scheduled protocol forms is part of the routine delinquency 
assessment for all collaborating institutions. Adherence to the assessment 
schedule will be encouraged by means of proactive reminders to the 
participating institutions. The Data coordinating staff at Case Comprehensive 
Cancer Center will continue to monitor missing information at different 
assessment points. If the proportion of missing information is related to specific 
centers or specific assessments, interventions will be developed in order to 
correct problems in the data collection process and to bring delinquent centers 
back in line with the protocol. If all efforts to collect information on a scheduled 
questionnaire fail, the center will be required to submit a Missing Data Form to 
the study coordinator at Case Comprehensive Cancer Center. Despite these 
precautions, a certain amount of missing data is expected. The information from 
patients with missing data will be reviewed in order to determine whether the 
data analytic procedures will be biased. Subjects with missing data will be 
reviewed for imbalances in factors such as treatment adherence, collaborating 

 
CASE 10107 12/28/2018 
Page 49 of 85 
 
 
 
center, and reasons for non-adherence. Mean scores on the primary measures 
will be compared for patients with or without missing data at different 
assessment points in order to investigate whether missing data is arising from a 
systematic error and likely to introduce a bias into the analysis. If no missing 
data mechanism can be detected following this review, the data will be analyzed 
assuming the missing data are at random. In the case of item non-response, 
summed scores will be computed using the mean from the other items in the 
analysis. If a missing data mechanism appears to be present, we will undertake 
to develop an appropriate analytic strategy to control for the potential bias and, 
if possible, to impute the missing values. The appropriateness of alternative 
strategies will depend upon both the pattern (e.g., item non-response versus 
intermittent missing forms versus complete dropouts) and the severity of the 
missing data problem. For example, an appropriate strategy could 
involve the stratification of the patients in the study in terms of the completeness 
of their data for key time periods (e.g., 6 months or 1 year) and the comparison 
of results from separate analyses for each group or it could involve the 
implementation of more sophisticated imputation procedures designed to model 
a missing data mechanism within the framework of a repeated measure analysis.
 We will also present sensitivity analyses based on varying assumptions about 
the missing-data mechanism. 
 
 5.12     DATA QUALITY ASSURANCE 
We will conduct the trial according to the ICH Good Clinical Practice 
guidelines. Keeping accurate and consistent records is essential in a multi-
institutional study. To ensure good quality data, all randomization, baseline, 
intervention, and follow-up forms will be signed by an investigator at each site 
or their designee.  Monthly registration reports will be generated to monitor 
patient accruals and completeness of registration data. Routine data quality 
reports will be generated to assess missing data and inconsistencies. Accrual 
rates and accuracy of evaluations and follow-up will be monitored periodically 
throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. Random-sample data 
quality and protocol compliance audits will be conducted by the study team 
twice a year. 
 
5.13      DATA SAFETY AND MONITORING PLAN 
This protocol will adhere to the policies of the Seidman Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI regulations. The data and safety 
committee will review all serious adverse events and toxicity reports as well as 
annual reviews. 
 
6. 
REPORTING OF ADVERSE EVENTS 
 
6.1 
ADVERSE EVENT AND REPORTING DEFINITIONS 
With the occurrence of an adverse event, the first concern will be for the safety of 
the subject.  Investigators are required to report to Genentech Drug Safety any 
serious adverse event, whether expected or unexpected, and which is assessed 
by the investigator to be reasonably or possibly related to or caused by 

 
CASE 10107 12/28/2018 
Page 50 of 85 
 
 
 
Herceptin.  All events meeting these criteria will be reported for the time period 
beginning with any amount of exposure to Herceptin through the protocol-defined 
follow-up period.  Serious criteria, definitions, and guidance for reporting follow. 
An adverse event (AE) is any untoward medical occurrence in a subject 
participating in an investigational study or protocol regardless of causality 
assessment.  An adverse event can be an unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, syndrome or disease 
associated with or occurring during the use of an investigational product whether 
or not considered related to the investigational product. 
 
Serious adverse events (SAE) are adverse events occurring at any dose which 
meet one or more of the following serious criteria: 
 
Results in death (i.e. the AE caused or led to death) 
 
Is life-threatening (i.e. the AE placed the subject at immediate risk of death; it 
does not apply to an AE which hypothetically might have caused the death if it 
were more severe) 
 
Requires or prolongs inpatient hospitalization (i.e. the AE required at least a 24-
hour inpatient hospitalization or prolonged a hospitalization beyond the expected 
length of stay; hospitalizations for elective medical/surgical procedures, 
scheduled treatments, or routine check-ups are not SAEs by this criterion) 
 
Is disabling (i.e. the AE resulted in a substantial disruption of the subject’s ability 
to carry out normal life functions) 
 
Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus 
of a subject exposed to the study drug prior to conception or during pregnancy) 
 
Does not meet any of the above serious criteria but may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed above 
 
Expected adverse events are those adverse events that are listed or characterized 
in the Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or 
current Investigator Brochure (I.B.).  This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B.  For 
example, under this definition, hepatic necrosis would be unexpected if the P.I. or 
I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
6.2 
REPORTING OF SERIOUS ADVERSE EVENTS ASSOCIATED WITH 
             HERCEPTIN 
 All SAEs that are serious and reasonably or probably related to the use of  

 
CASE 10107 12/28/2018 
Page 51 of 85 
 
 
 
Herceptin (this applies to both expected and unexpected events) should be   
recorded on a MedWatch 3500 Form (Appendix D) and faxed to: 
Genentech Drug Safety Contact Line 
Tele: 1-888-835-2555 
Fax:  (650) 225-4682/ (650) 225-4683  
AND: 
           Cynthia Owusu, Principal Investigator 
           Tele: 1-216-844-7670 
            Fax: 1-216- 844-5234 
AND: 
                      Leda Dumadag, Study Coordinator 
 
 
  
 
     
                      Tele : 1-216 844-8098 
                       Fax: 216-201-4341 
MedWatch 3500 Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500 form: 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report by any of the 
following methods: 
 Adding to the original MedWatch 3500 report and submitting as follow-up 
 Adding supplemental summary information and submitting it as follow-up 
with the original MedWatch 3500 form  
 Summarizing new information and faxing it with a cover letter including 
subject identifiers (i.e. D.O.B. initial, subject number), protocol description 
and number, if assigned, brief adverse event description, and notation that 
additional or follow-up information is being submitted). The patient identifiers 
are important so that the new information is added to the correct initial report) 
 

 
CASE 10107 12/28/2018 
Page 52 of 85 
 
 
 
Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the subject for whom and adverse event was reported.  For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative 
noted above. 
Study Drug Relationship: 
The investigator will determine which events are associated with the use of study drug.  
For reporting purposes, an AE should be regarded as possibly related to the use of 
Herceptin if the investigator believes: 
 There is a clinically plausible time sequence between onset of the AE and 
Herceptin administration; and/or 
 There is a biologically plausible mechanism for Herceptin to cause or 
contribute to the AE; and 
 The AE cannot be attributed solely to concurrent/underlying illness, other 
drugs, or procedures. 
Reporting to the FDA in compliance with 21 CFR 321 .32 (FDA reporting of 
IND safety report).   
The sponsor shall notify the FDA: 
 Written reports of any adverse experience associated with the use of the drug that 
is both serious and unexpected. 
 The sponsor shall notify the FDA by telephone or facsimile transmission of any 
unexpected fatal or life-threatening experience as associated with the use of the 
drug as soon as possible  but in no event later than 7 calendar days after the 
sponsors initial receipt of the information. 
 If the results of a sponsor’s investigation shows that an adverse drug experience 
not initially determined to be reportable, is so reportable , the sponsor shall report 
such experience in a written safety report as soon as possible, but no later than 15 
calendar days after the determination is made. 
   
7. 
INVESTIGATOR REQUIREMENTS 
7.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with Genentech or 
a Genentech representative: 
 Original U.S. FDA Form 1572 for each site (for all studies conducted under 
U.S. Investigational New Drug [IND] regulations), signed by the Principal 
Investigator 
The names of any sub-investigators must appear on this form.  
Investigators must also complete all regulatory documentation as required 
by local and national regulations. 

 
CASE 10107 12/28/2018 
Page 53 of 85 
 
 
 
 Current curriculum vitae of the Principal Investigator 
 Written documentation of IRB approval of protocol and informed consent 
document 
 A copy of the IRB-approved informed consent document from all 
participating institutions 
 A signed Clinical Research Agreement 
 
7.2 
STUDY COMPLETION 
The following materials are requested by Genentech when a study is considered complete 
or terminated: 
 A summary, prepared by the Principal Investigator, of the study, and/or a 
study manuscript, and/or a study abstract submitted to scientific conferences. 
 
7.3 
INFORMED CONSENT 
An informed consent template will be provided, and the final IRB-approved document 
must be provided to Genentech for regulatory purposes. 
 
The informed consent document must be signed by the subject or the subject’s legally 
authorized representative before his or her participation in the study.  The case history for 
each subject shall document that informed consent was obtained prior to participation in 
the study.  A copy of the informed consent document must be provided to the subject or 
the subject's legally authorized representative.  If applicable, it will be provided in a 
certified translation of the local language. 
 
Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 
7.4 
INSTITUTIONAL 
REVIEW 
BOARD 
OR 
ETHICS 
COMMITTEE 
APPROVAL 
This protocol, the informed consent document, and relevant supporting information must 
be submitted to the IRB for review and must be approved before the study is initiated.  
The study will be conducted in accordance with U.S. FDA, applicable national and local 
health authorities, and IRB requirements. 
 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate, but in any case 
the IRB must be updated at least once a year.  The Principal Investigator must also keep 
the IRB informed of any significant adverse events. 
 
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to serious adverse 
events that are not already identified in the Investigator Brochure and that are considered 
possibly or probably related to the molecule or study drug by the investigator. Some IRBs 
may have other specific adverse event requirements that investigators are expected to 
adhere.  Investigators must immediately forward to their IRB any written safety report or 
update provided by Genentech (e.g., IND safety report, Investigator Brochure, safety 
amendments and updates, etc.). 
 

 
CASE 10107 12/28/2018 
Page 54 of 85 
 
 
 
7.5 
STUDY MONITORING REQUIREMENTS 
Site visits may be conducted by an authorized Genentech representative to inspect study 
data, subjects’ medical records, and CRFs in accordance with current U.S. GCPs and the 
respective local and national government regulations and guidelines (if applicable). 
 
The Principal Investigator will permit authorized representatives of Genentech, the U.S. 
FDA, and the respective national or local health authorities to inspect facilities and 
records relevant to this study. 
 
7.6 
DATA MANAGEMENT ISSUES 
A data coordinator will be assigned to the study. The data manager will have the 
responsibilities which include study compliance, data collection, abstraction and entry, 
data reporting, regulatory monitoring, problem resolution and prioritization, and 
coordinate the activities of the protocol study team. Case Comprehensive Cancer Center 
will be the coordinating institution for this study. All data collected for this study  will be 
transferred via fax (216 844 8599) and will be entered into a secure database (Oncore) at 
the Case Comprehensive Cancer Center. In addition source documentation will be  
available to support the computerized patient record. Source documentation will be stored 
in a locked filing cabinet under the supervision of the Principal Investigator.   
 
7.7 
STUDY MEDICATION ACCOUNTABILITY (IF APPLICABLE) 
Trastuzumab will be provided by Genentech.  
 
7.8 
DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. 
 
Upon the subject’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, Genentech, and the 
IRB for each study site, if appropriate. 
 
7.9 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining 
to the conduct of this study and the distribution of investigational drug, including CRFs, 
consent forms, laboratory test results, and medication inventory records, must be retained 
by the Principal Investigator for 2 years after marketing application approval.  If no 
application is filed, these records must be kept 2 years after the investigation is 
discontinued and the U.S. FDA and the applicable national and local health authorities 
are notified.  Genentech will notify the Principal Investigator of these events. 
 
8. 0       PROTECTION OF HUMAN SUBJECTS 
All institutional, FDA, and Federal regulations concerning informed consent and peer 
judgment will be fulfilled. 
 
 

 
CASE 10107 12/28/2018 
Page 55 of 85 
 
 
 
8.1        ETHICS 
The trial will be conducted in full agreement with the principles of the Declaration of 
Helsinki and International Committee on Harmonization guidelines for good clinical 
practice. The trial protocol will be approved by the institutional review board. Written 
informed consent will be obtained from each subject before start of the study after 
explaining the objectives, methods, and potential benefits/risks of the study. It will also 
be explained to subjects that they are free to refuse participation in the study or withdraw 
from the study at any time. A patient’s decision not to participate or choosing to 
withdraw from the study will in no way compromise the patient’s continued care.  
 
8.2        PRIVACY AND CONFIDENTIALITY 
All information collected during the study will be maintained in a confidential manner in 
compliance with regulations enacted pursuant to the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). Patient records may be inspected by auditing 
agencies to satisfy regulatory requirements. 
 

 
CASE 10107 12/28/2018 
Page 56 of 85 
 
 
 
9.0        REFERENCES 
 
 
 
1. 
Yancik R: Cancer burden in the aged: an epidemiologic and demographic 
overview. Cancer 80:1273-83, 1997 
 
2. 
Muss HB: Older age--not a barrier to cancer treatment. N Engl J Med 
345:1127-8, 2001 
 
3. 
Chu KC, Tarone RE, Kessler LG, et al: Recent trends in U.S. breast cancer 
incidence, survival, and mortality rates. J Natl Cancer Inst 88:1571-9, 1996 
 
4. 
Bouchardy C, Rapiti E, Fioretta G, et al: Undertreatment strongly 
decreases prognosis of breast cancer in elderly women. J Clin Oncol 21:3580-7, 2003 
 
5. 
Townsley C, Pond GR, Peloza B, et al: Analysis of treatment practices for 
elderly cancer patients in Ontario, Canada. J Clin Oncol 23:3802-10, 2005 
 
6. 
Uyar D, Frasure HE, Markman M, et al: Treatment patterns by decade of 
life in elderly women (> or =70 years of age) with ovarian cancer. Gynecol Oncol 
98:403-8, 2005 
 
7. 
Talarico L, Chen G, Pazdur R: Enrollment of elderly patients in clinical 
trials for cancer drug registration: a 7-year experience by the US Food and Drug 
Administration. J Clin Oncol 22:4626-31, 2004 
 
8. 
Lewis JH, Kilgore ML, Goldman DP, et al: Participation of patients 65 
years of age or older in cancer clinical trials. J Clin Oncol 21:1383-9, 2003 
 
9. 
Diab SG, Elledge RM, Clark GM: Tumor characteristics and clinical 
outcome of elderly women with breast cancer. J Natl Cancer Inst 92:550-6, 2000 
 
10. 
Gennari R, Curigliano G, Rotmensz N, et al: Breast carcinoma in elderly 
women: features of disease presentation, choice of local and systemic treatments 
compared with younger postmenopasual patients. Cancer 101:1302-10, 2004 
 
11. 
Giordano SH, Hortobagyi GN, Kau SW, et al: Breast cancer treatment 
guidelines in older women. J Clin Oncol 23:783-91, 2005 
 
12. 
Surveillance, Epidermiology and End Results (SEER) Program 
(www.seer.cancer.gov) SEER*Stat Database: Mortality -All COD, Public-Use With 
State, Total U.S. (1969-2002), National Cancer Institue, DCCPS, Surveillance Research 
Program, Cancer Statistics Branch , released April 2005. Underlying mortality data 
provided by NCHS (www.cdc.gov/nchs). 
.  
 
13. 
Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 
65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-7, 1999 
 
14. 
National Comprehensive Cancer Network. Clinical Practice Guidelines in 
Breast Cancer. Version 2. 2005 
 
15. 
Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation 
of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-
82, 1987 
 
16. 
Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a 
monoclonal antibody against HER2 for metastatic breast cancer that overexpresses 
HER2. N Engl J Med 344:783-92, 2001 
 
17. 
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 20:719-26, 2002 

 
CASE 10107 12/28/2018 
Page 57 of 85 
 
 
 
 
18. 
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after 
adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-72, 
2005 
 
19. 
Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant 
chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-84, 
2005 
 
20. 
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 23:7811-9, 2005 
 
21. 
Perez EA, Rodeheffer R: Clinical cardiac tolerability of trastuzumab. J 
Clin Oncol 22:322-9, 2004 
 
22. 
Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the 
trastuzumab clinical trials experience. J Clin Oncol 20:1215-21, 2002 
 
23. 
Trastuzumab (herceptin). South San Francisco, C.A.: Genentech, 2006 
(package insert).  
 
24. 
Telli ML, Hunt SA, Carlson RW, et al: Trastuzumab-related 
cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 25:3525-33, 
2007 
 
25. 
Cross M, Dexter TM: Growth factors in development, transformation, and 
tumorigenesis. Cell 64:271-80, 1991 
 
26. 
Kallioniemi OP, Kallioniemi A, Kurisu W, et al: ERBB2 amplification in 
breast cancer analyzed by fluorescence in situ hybridization. Proc Natl Acad Sci U S A 
89:5321-5, 1992 
 
27. 
Pauletti G, Godolphin W, Press MF, et al: Detection and quantitation of 
HER-2/neu gene amplification in human breast cancer archival material using 
fluorescence in situ hybridization. Oncogene 13:63-72, 1996 
 
28. 
Hynes NE: Amplification and overexpression of the erbB-2 gene in human 
tumors: its involvement in tumor development, significance as a prognostic factor, and 
potential as a target for cancer therapy. Semin Cancer Biol 4:19-26, 1993 
 
29. 
Di Fiore PP, Pierce JH, Kraus MH, et al: erbB-2 is a potent oncogene 
when overexpressed in NIH/3T3 cells. Science 237:178-82, 1987 
 
30. 
Hudziak RM, Schlessinger J, Ullrich A: Increased expression of the 
putative growth factor receptor p185HER2 causes transformation and tumorigenesis of 
NIH 3T3 cells. Proc Natl Acad Sci U S A 84:7159-63, 1987 
 
31. 
Guy CT, Webster MA, Schaller M, et al: Expression of the neu 
protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. 
Proc Natl Acad Sci U S A 89:10578-82, 1992 
 
32. 
Drebin JA, Link VC, Stern DF, et al: Down-modulation of an oncogene 
protein product and reversion of the transformed phenotype by monoclonal antibodies. 
Cell 41:697-706, 1985 
 
33. 
Drebin JA, Link VC, Greene MI: Monoclonal antibodies specific for the 
neu oncogene product directly mediate anti-tumor effects in vivo. Oncogene 2:387-94, 
1988 
 
34. 
Fendly BM, Winget M, Hudziak RM, et al: Characterization of murine 
monoclonal antibodies reactive to either the human epidermal growth factor receptor or 
HER2/neu gene product. Cancer Res 50:1550-8, 1990 

 
CASE 10107 12/28/2018 
Page 58 of 85 
 
 
 
 
35. 
Jurianz K, Maslak S, Garcia-Schuler H, et al: Neutralization of 
complement regulatory proteins augments lysis of breast carcinoma cells targeted with 
rhumAb anti-HER2. Immunopharmacology 42:209-18, 1999 
 
36. 
Pegram MD, Lopez A, Konecny G, et al: Trastuzumab and 
chemotherapeutics: drug interactions and synergies. Semin Oncol 27:21-5; discussion 92-
100, 2000 
 
37. 
Pietras RJ, Fendly BM, Chazin VR, et al: Antibody to HER-2/neu receptor 
blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 
9:1829-38, 1994 
 
38. 
Arteaga CL, Winnier AR, Poirier MC, et al: p185c-erbB-2 signal enhances 
cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an 
oncogenic receptor tyrosine kinase and drug-induced DNA repair. Cancer Res 54:3758-
65, 1994 
 
39. 
Hancock MC, Langton BC, Chan T, et al: A monoclonal antibody against 
the c-erbB-2 protein enhances the cytotoxicity of cis-diamminedichloroplatinum against 
human breast and ovarian tumor cell lines. Cancer Res 51:4575-80, 1991 
 
40. 
Baselga J, Norton L, Albanell J, et al: Recombinant humanized anti-HER2 
antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin 
against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58:2825-
31, 1998 
 
41. 
Pegram MD, Finn RS, Arzoo K, et al: The effect of HER-2/neu 
overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer 
cells. Oncogene 15:537-47, 1997 
 
42. 
Burris HA, 3rd: Dual kinase inhibition in the treatment of breast cancer: 
initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9 Suppl 3:10-5, 
2004 
 
43. 
Rusnak DW, Lackey K, Affleck K, et al: The effects of the novel, 
reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, 
on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol 
Cancer Ther 1:85-94, 2001 
 
44. 
Wood ER, Truesdale AT, McDonald OB, et al: A unique structure for 
epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among 
protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 
64:6652-9, 2004 
 
45. 
Konecny GE, Pegram MD, Venkatesan N, et al: Activity of the dual 
kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-
treated breast cancer cells. Cancer Res 66:1630-9, 2006 
 
46. 
Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for 
HER2-positive advanced breast cancer. N Engl J Med 355:2733-43, 2006 
 
47. 
Press MF BL, Sauter G, Zhou JY, Eiermann W, Pienkowski T, Crown J, 
Robert N, Bee V, Taupin H, Vilalobos I, Seelig S, Pegram M, Slamon DJ.: 
Topoisomerase II-alpha gene amplification as a predictor of responsiveness to 
anthracycline-containing chemotherapy in the Cancer International Research Group 006 
clinical trial of trastuzumab (herceptin) in the adjuvant setting, San Antonio Breast 
Conference. San Antonio, Texax, 2005, pp Abstract 1045 
 
48. 
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al: Adjuvant docetaxel 
or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809-20, 
2006 

 
CASE 10107 12/28/2018 
Page 59 of 85 
 
 
 
 
49. 
Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the 
efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have 
HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy 
for metastatic disease. J Clin Oncol 17:2639-48, 1999 
 
50. 
Tripathy D, Slamon D, Leyland-Jones B, et al: Treatment beyond 
progression in the Herceptin pivotal combination chemotherapy trial. Breast Cancer Res 
Treat 2000; 64:32.  
 
51. 
Chevallier B, Fumoleau P, Kerbrat P, et al: Docetaxel is a major cytotoxic 
drug for the treatment of advanced breast cancer: a phase II trial of the Clinical Screening 
Cooperative Group of the European Organization for Research and Treatment of Cancer. 
J Clin Oncol 13:314-22, 1995 
 
52. 
Akerley W, Sikov WM, Cummings F, et al: Weekly high-dose paclitaxel 
in metastatic and locally advanced breast cancer: a preliminary report. Semin Oncol 
24:S17-87-S17-90, 1997 
 
53. 
Seidman AD, Fornier M, Hudis C, et al: Phase II trial of weekly 1-hour 
Taxol and Herceptin for metastatic breast cancer: toward further exploitation of proven 
synergistic antitumor activity.  Cancer Invest 1999;17(Suppl 1):44-45.  
 
54. 
Nicholson BP, Thor AD, Goldstein LJ, et al: Weekly docetaxel and 
rhuMAb HER2 combination therapy as first- or second-line therapy for metastatic breast 
cancer. Proc Am Soc Clin Oncol 2000; 19:139a.  
 
55. 
Kuzur ME, Albain KS, Huntington MO, et al: A phase II trial of docetaxel 
and Herceptin in metastatic breast cancer patients overexpressing HER-2. Proc Am Soc 
Clin Oncol 2000; 19:131a.  
 
56. 
Burstein HJ, Kuter I, Campos SM, et al: Clinical activity of trastuzumab 
and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin 
Oncol 19:2722-30, 2001 
 
57. 
Bruno R, Washington CB, Lu JF, et al: Population pharmacokinetics of 
trastuzumab in patients with HER2+ metastatic breast cancer. Cancer Chemother 
Pharmacol 56:361-9, 2005 
 
58. 
Leyland-Jones B, Gelmon K, Ayoub JP, et al: Pharmacokinetics, safety, 
and efficacy of trastuzumab administered every three weeks in combination with 
paclitaxel. J Clin Oncol 21:3965-71, 2003 
 
59. 
Vogel C, Cobleigh MA, Tripathy D, et al: First-line, single-agent 
Herceptin(R) (trastuzumab) in metastatic breast cancer. a preliminary report. Eur J 
Cancer 37 Suppl 1:25-29, 2001 
 
60. 
Crone SA, Zhao YY, Fan L, et al: ErbB2 is essential in the prevention of 
dilated cardiomyopathy. Nat Med 8:459-65, 2002 
 
61. 
Chien KR: Stress pathways and heart failure. Cell 98:555-8, 1999 
 
62. 
Lee KF, Simon H, Chen H, et al: Requirement for neuregulin receptor 
erbB2 in neural and cardiac development. Nature 378:394-8, 1995 
 
63. 
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 23:7820-6, 2005 
 
64. 
Cardinale D, Sandri MT, Colombo A, et al: Prognostic value of troponin I 
in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. 
Circulation 109:2749-54, 2004 

 
CASE 10107 12/28/2018 
Page 60 of 85 
 
 
 
 
65. 
Perik PJ, Lub-De Hooge MN, Gietema JA, et al: Indium-111-labeled 
trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-
positive metastatic breast cancer. J Clin Oncol 24:2276-82, 2006 
 
66. 
Satoh M, Nakamura M, Saitoh H, et al: Tumor necrosis factor-alpha-
converting enzyme and tumor necrosis factor-alpha in human dilated cardiomyopathy. 
Circulation 99:3260-5, 1999 
 
67. 
Birks EJ, Burton PB, Owen V, et al: Elevated tumor necrosis factor-alpha 
and interleukin-6 in myocardium and serum of malfunctioning donor hearts. Circulation 
102:III352-8, 2000 
 
68. 
Torre-Amione G, Kapadia S, Benedict C, et al: Proinflammatory cytokine 
levels in patients with depressed left ventricular ejection fraction: a report from the 
Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 27:1201-6, 1996 
 
69. 
National Comprehensive Cancer Network. Clinical Practice Guidelines in 
Senior Adult Oncology. Version 1. 2005 
 
70. 
Reuben DB, Rubenstein LV, Hirsch SH, et al: Value of functional status 
as a predictor of mortality: results of a prospective study. Am J Med 93:663-9, 1992 
 
71. 
Maione P, Perrone F, Gallo C, et al: Pretreatment quality of life and 
functional status assessment significantly predict survival of elderly patients with 
advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of 
the multicenter Italian lung cancer in the elderly study. J Clin Oncol 23:6865-72, 2005 
 
72. 
Freyer G, Geay JF, Touzet S, et al: Comprehensive geriatric assessment 
predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian 
carcinoma: a GINECO study. Ann Oncol 16:1795-800, 2005 
 
73. 
Repetto L, Fratino L, Audisio RA, et al: Comprehensive geriatric 
assessment adds information to Eastern Cooperative Oncology Group performance status 
in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol 
20:494-502, 2002 
 
74. 
Satariano WA, Ragland DR: The effect of comorbidity on 3-year survival 
of women with primary breast cancer. Ann Intern Med 120:104-10, 1994 
 
75. 
Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine versus 
vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin 
Oncol 18:2529-36, 2000 
 
76. 
Extermann M, Overcash J, Lyman GH, et al: Comorbidity and functional 
status are independent in older cancer patients. J Clin Oncol 16:1582-7, 1998 
 
77. 
Gupta SK, Lamont EB: Patterns of presentation, diagnosis, and treatment 
in older patients with colon cancer and comorbid dementia. J Am Geriatr Soc 52:1681-7, 
2004 
 
78. 
Gorin SS, Heck JE, Albert S, et al: Treatment for breast cancer in patients 
with Alzheimer's disease. J Am Geriatr Soc 53:1897-904, 2005 
 
79. 
Robb C, Callen L, Vranas P, et al: Patterns of Care and Survival in Cancer 
Patients with Cognitive Impairment. in submission, 2007 
 
 
80. 
Newman AB, Yanez D, Harris T, et al: Weight change in old age and its 
association with mortality. J Am Geriatr Soc 49:1309-18, 2001 
 
81. 
Landi F, Onder G, Gambassi G, et al: Body mass index and mortality 
among hospitalized patients. Arch Intern Med 160:2641-4, 2000 

 
CASE 10107 12/28/2018 
Page 61 of 85 
 
 
 
 
82. 
Dewys WD, Begg C, Lavin PT, et al: Prognostic effect of weight loss 
prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J 
Med 69:491-7, 1980 
 
83. 
Kornblith AB, Herndon JE, 2nd, Weiss RB, et al: Long-term adjustment 
of survivors of early-stage breast carcinoma, 20 years after adjuvant chemotherapy. 
Cancer 98:679-89, 2003 
 
84. 
Kroenke CH, Kubzansky LD, Schernhammer ES, et al: Social networks, 
social support, and survival after breast cancer diagnosis. J Clin Oncol 24:1105-11, 2006 
 
85. 
Seeman TE, Berkman LF, Kohout F, et al: Intercommunity variations in 
the association between social ties and mortality in the elderly. A comparative analysis of 
three communities. Ann Epidemiol 3:325-35, 1993 
 
86. 
Goodwin JS, Zhang DD, Ostir GV: Effect of depression on diagnosis, 
treatment, and survival of older women with breast cancer. J Am Geriatr Soc 52:106-11, 
2004 
 
87. 
Lawton MP: Scales to measure competence in everyday activities. 
Psychopharmacol Bull 24:609-14, 1988 
 
88. 
Katz S, Ford AB, Moskowitz RW, et al: Studies Of Illness In The Aged. 
The Index Of Adl: A Standardized Measure Of Biological And Psychosocial Function. 
Jama 185:914-9, 1963 
 
89. 
Podsiadlo D, Richardson S: The timed "Up & Go": a test of basic 
functional mobility for 
frail elderly persons. Journal of the American Geriatric Society; 39(2):142-8 
1991 
 
90. 
karnofsky D, Burchenal J: The clinical evalaution of chemotherapeutic 
agents in cancer. In C.M. Macleod, (Ed.), Evaluation of chemotherapeutic agents. New 
York: Columbia University Press.191-205, 1948 
 
91. 
Naeim A, Reuben D: Geriatric syndromes and assessment in older cancer 
patients. Oncology (Williston Park) 15:1567-77, 1580; discussion 1581, 1586, 1591, 
2001 
 
92. 
Guigoz Y, Nourhashemi F, Vellas B: (Mini Nutritional Assessment): 
update. Facts research and interventions in geriatrics 1997. Serdi Publishing Company, 
1997:105-7.  
 
93. 
Landi F, Zuccala G, Gambassi G, et al: Body mass index and mortality 
among older people living in the community. J Am Geriatr Soc 47:1072-6, 1999 
 
94. 
Sherbourne CD, Stewart AL: The MOS social support survey. Soc Sci 
Med 32:705-14, 1991 
 
95. 
Stewart A, Ware JE, Jr.: Measuring functioning and well-being: The 
Medical Outcomes Study Approach. Durham, NC: Duke University Press. 1992 
 
96. 
Charlson ME, Pompei P, Ales KL, et al: A new method of classifying 
prognostic comorbidity in longitudinal studies: development and validation. J Chronic 
Dis 40:373-83, 1987 
 
97. 
Miller MD, Paradis CF, Houck PR, et al: Rating chronic medical illness 
burden in geropsychiatric practice and research: application of the Cumulative Illness 
Rating Scale. Psychiatry Res 41:237-48, 1992 
 
98. 
Folstein MF, Folstein SE, McHugh PR: "Mini-mental state". A practical 
method for grading the cognitive state of patients for the clinician. J Psychiatr Res 
12:189-98, 1975 

 
CASE 10107 12/28/2018 
Page 62 of 85 
 
 
 
 
99. 
Kirby M, Denihan A, Bruce I, et al: The clock drawing test in primary 
care: sensitivity in dementia detection and specificity against normal and depressed 
elderly. Int J Geriatr Psychiatry 16:935-40, 2001 
 
100. 
Richardson HE, Glass JN: A comparison of scoring protocols on the Clock 
Drawing Test in relation to ease of use, diagnostic group, and correlations with Mini-
Mental State Examination. J Am Geriatr Soc 50:169-73, 2002 
 
101. 
Yesavage JA, Brink TL, Rose TL, et al: Development and validation of a 
geriatric depression screening scale: a preliminary report. J Psychiatr Res 17:37-49, 1982 
 
102. 
Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence 
for a phenotype. J Gerontol A Biol Sci Med Sci 56:M146-56, 2001 
 
103. 
Saliba D, Orlando M, Wenger NS, et al: Identifying a short functional 
disability screen for older persons. J Gerontol A Biol Sci Med Sci 55:M750-6, 2000 
 
104. 
Min LC, Elliott MN, Wenger NS, et al: Higher vulnerable elders survey 
scores predict death and functional decline in vulnerable older people. J Am Geriatr Soc 
54:507-11, 2006 
 
105. 
Overcash J, Extermann M, Parr J, et al: Validity and reliability of the 
FACT-G scale for use in the older person with cancer. Am J Clin Oncol 24:591-6, 2001 
 
106. 
Trastuzumab (herceptin). South San Francisco, C.A.: Genentech, 2006 
(Investigator Brochure) 
 
107. 
Brown LD, Cai TT, DasGupta A: Interval estimation for a binomial 
proportion. Statistical Science, vol. 16, 101-133, 2001.  
 
108. 
Seidman AD, Fornier MN, Esteva FJ, et al: Weekly trastuzumab and 
paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 
immunophenotype and gene amplification. J Clin Oncol 19:2587-95, 2001 
 
109. 
Cox DR: Regression models and life-tables (with discussion). J. Royal 
Stat. Soc. B, 34:187-220, 1972.  
 
110. 
Kaplan EL, Meier P: Nonparametric estimation from incomplete 
observations. Journal of the American Statistical Association, 1958; 53:457-481. 1958 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CASE 10107 12/28/2018 
Page 63 of 85 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A 
National Cancer Institute Common Toxicity Criteria 
obtained from http://ctep.cancer.gov/forms/CTCAEv3.pdf  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CASE 10107 12/28/2018 
Page 64 of 85 
 
 
 
APPENDIX B 
HFSA Guidelines 
Recommendations for Pharmacological Therapy: 
Left Ventricular Systolic Dysfunction 
 
ß-Adrenergic Receptor Blockers 
 
Background for Recommendations 
 
The single most significant addition to the pharmacological management of heart failure 
since the publication of previous guidelines involves the use of ß-receptor antagonists. 
This represents a noteworthy departure from traditional doctrine in which ß-blocking 
agents were classified as contraindicated in the setting of left ventricular systolic 
dysfunction. A solid foundation of both clinical and experimental evidence now firmly 
supports their use in heart failure with the aim of reducing both morbidity and mortality 
(16,22,23). 
 
ß-Blocker therapy for heart failure has been advocated by some investigators since the 
1970s (24). During the subsequent 2 decades, many small- to medium-sized placebo-
controlled trials, which used a variety of agents, showed several common findings: 1) the 
use of ß-blockers in mild to moderate heart failure was generally safe when initiated at 
low doses and gradually up titrated under close observation; 2) improvement in left 
ventricular ejection fraction was observed in all trials that lasted at least 3 months; and 3) 
there was wide variability in the effects of ß blockade on exercise tolerance but 
improvement in outcome and symptomatic benefits was noted in many studies. These 
generally positive findings stimulated additional, large-scale clinical trials that have 
provided an impressive body of evidence that supports the use of ß-blockers in patients 
with heart failure caused by left ventricular systolic dysfunction. The recommendations 
that follow are derived from nearly 2 decades of research that include basic science data, 
animal models, and clinical trial experience in over 10,000 patients (25,26). 
 
Although this is a major advance in efficacy, identification of appropriate candidates for 
ßblocker therapy is essential to ensure safe and effective treatment. Prescribing 
physicians should understand the potential risks of ß-blocker therapy, as well as the 
benefits. The interested practitioner who is unfamiliar with ß-blocker initiation and 
titration may first seek further education and counsel from sources such as the Heart 
Failure Society of America or local and regional heart failure specialty centers. 
 
Recommendation 1. ß-blocker therapy should be routinely administered to clinically 
stable patients with left ventricular systolic dysfunction (left ventricular ejection 
fraction less than or equal to 40%) and mild to moderate heart failure symptoms (ie, 
NYHA class II-III, Appendix A) who are on standard therapy, which typically 
includes ACE inhibitors, diuretics as needed to control fluid retention, and digoxin 
(Strength of Evidence = A). 
 
The most persuasive outcome in heart failure management remains all-cause mortality. 
Combined endpoints, including mortality or hospitalization and mortality or 
hospitalization for heart failure, have also emerged as key outcomes. These latter 

 
CASE 10107 12/28/2018 
Page 65 of 85 
 
 
 
endpoints reflect a more comprehensive assessment of the influence of therapy on quality 
of life and disease progression and are assuming more importance as mortality rates 
decline with treatment advances. The substantial beneficial effect of ß-blocker therapy on 
these endpoints has been well shown in clinical trials of symptomatic patients (NYHA 
class II - III) treated with carvedilol, bisoprolol, or metoprolol controlled 
release/extended release (CR/XL) (27-29). Trials with these agents encompass the 
combined, worldwide experience with ß-blocker therapy in patients with chronic 
heart failure who were stable on background therapy, including ACE inhibitors (over 
90%) and diuretics (over 90%). Digoxin was common as background therapy, 
particularly in studies conducted in the United States. Trial results indicate that both 
selective and nonselective ßblockers, with and without ancillary properties, have 
significant efficacy in heart failure. ß-Blocking agents with intrinsic sympathomimetic 
activity appear to have a negative impact on survival and should not be used in heart 
failure patients. 
 
Metoprolol. The MDC Study was an early trial that included 383 patients with heart 
failure caused by nonischemic causes, NYHA class II-III symptoms, and a left ventricular 
ejection fraction of less than or equal to 40% (30). Patients with coronary artery disease 
were excluded. Study results showed a 34% reduction in risk in patients treated with 
metoprolol, although this strong trend toward benefit (P = .058) was entirely attributable 
to a reduction in the frequency of cardiac transplantation listing in the treatment group. In 
fact, the absolute number of deaths in the metoprolol group was higher than in the 
placebo group (23 v 19, P = .69). 
 
The MERIT-HF Trial evaluated the effect of metoprolol CR/XL with all-cause mortality 
as the primary endpoint. The trial included 3,991 patients with NYHA class II-IV heart 
failure, although 96% of the study patients were functional class II or III (31). In this 
study, investigators were allowed to select the starting dose of metoprolol CR/XL. 
Seventy-nine percent chose 25 mg as the starting dose for class II patients, and 77% 
chose 12.5 mg for class III-IV patients. The target dose was 200 mg and doses were up-
titrated over a period of 8 weeks. Premature discontinuation of blinded therapy occurred 
in 13.9% of those treated with metoprolol CR/XL and 15.3% of those in the placebo 
group (P = .90). The study results revealed a 34% reduction in mortality in the 
metoprolol group (relative risk of .66; 95% confidence interval [CI], .53 to .81; p=.0062 
after adjustment for interim analyses), with annual mortality rates of 11% in the placebo 
and 7.2% in the metoprolol CR/XL group (29). 
 
Bisoprolol. The CIBIS Study evaluated the effects of bisoprolol in 641 patients with left 
ventricular systolic dysfunction caused by ischemic or nonischemic causes and NYHA 
class III-IV heart failure (32). The primary endpoint was all-cause mortality, and 
hospitalization for worsening heart failure was one of the secondary outcomes of interest. 
The initial bisoprolol dose was 1.25 mg/day, which was increased to a maximum dose of 
5 mg/day. The trial found no significant reduction in all-cause mortality in patients 
treated with bisoprolol (20% reduction bisoprolol v placebo, P = .22) (32). The risk of 
hospitalization was significantly reduced by 34% (28% placebo group v 19% bisoprolol 
group, P < .01). 
 

 
CASE 10107 12/28/2018 
Page 66 of 85 
 
 
 
 The favorable trends seen in CIBIS led to the larger CIBIS II Study, which ultimately 
was prematurely terminated as a result of a significant reduction in mortality in the 
bisoprolol arm (28). These results were obtained in 2,647 patients who were followed for 
an average of 1.3 years. Over 80% of the patients were judged to be NYHA class III at 
enrollment. Background therapy included ACE inhibitors in 96% and diuretic in 99% of 
the study patients, whereas 52% were taking digoxin. In contrast to the original CIBIS 
study, CIBIS II had a similar starting dose of 1.25 mg but had a greater target dose of 10 
mg daily of bisoprolol. More stringent criteria for defining ischemic cardiomyopathy 
were used. Treatment with bisoprolol reduced the annual mortality rate by 34% (13.2% 
placebo v 8.8% bisoprolol; hazard ratio .66; 95% CI, .54 to .81; P< .0001). 
Hospitalizations for worsening heart failure were also decreased by 32% (18% placebo v 
12% bisoprolol, hazard ratio .64; 95% CI, .53 to .79; P< .0001). Although a post hoc 
analysis of the CIBIS Study had suggested benefit might be consigned to patients without 
coronary disease, the survival benefit, with significant reductions apparent in both 
ischemic or nonischemic patients, was not influenced by disease origins. 
 
Carvedilol. Carvedilol, a nonselective ß-
-blocker, has been extensively 
investigated for treatment of heart failure caused by left ventricular systolic dysfunction. 
In the United States carvedilol trials, 4 separate study populations were examined and the 
data from 1,094 patients were combined to evaluate the effect of carvedilol therapy on 
the clinical progression of heart failure (27). Clinical progression was defined as 
worsening heart failure leading to death, hospitalization, or, in one study, a sustained 
increase in background medications. Patients with a left ventricular ejection fraction of 
35% or less and NYHA class II-IV were eligible if they tolerated 6.25 mg of carvedilol 
twice per day for a 2-week, open-label, run-in period. Although this run-in phase biased 
the ultimately randomized patient population, less than 8% of eligible patients failed the 
open-label challenge. Target dosages for the studies were 50 to 100 mg/day of carvedilol 
that were administered in divided doses twice daily. Patients completing the run-in period 
were randomized based on results from their 6- minute walk test into mild, moderate, or 
severe trials. These studies were prematurely terminated (median follow-up 6.5 months) 
by the Trial Data and Safety Monitoring Board because of reduced mortality across the 4 
combined trials of patients treated with carvedilol. 
 
Data from these combined trials indicated a substantial benefit from carvedilol treatment. 
The risk of mortality was 65% lower (7.8% placebo v 3.2% carvedilol; 95% CI, 39% to 
80%; P< .001) and the combined risk of hospitalization or death was reduced by 38% 
(20% on placebo v 14% on carvedilol; 95% CI, 18% to 53%; P< .001). A significant 
mortality reduction was also noted when deaths that occurred in the run-in period were 
included in the analysis. The statistical validity of the survival analysis across the trials 
has been questioned because mortality was not the primary endpoint, and only 1 of the 4 
trials achieved a significant result when analyzed based on the primary endpoint. 
Nevertheless, the magnitude of the survival benefit and the reduction in hospitalization 
were impressive. The survival benefit was not influenced by the cause of disease, age, 
gender, or baseline ejection fraction. Overall, 7.8% of the placebo group and 5.7% of the 
carvedilol group discontinued study medication. Data from the individual trials, 
PRECISE and MOCHA, which evaluated patients with moderate to severe heart failure, 
found that carvedilol reduced the risk of the combined endpoint of mortality or heart 
failure hospitalization by 39% to 49% (33,34). The MOCHA Study provided strong 

 
CASE 10107 12/28/2018 
Page 67 of 85 
 
 
 
evidence for increased benefit from higher dosages (25 mg twice per day) versus lower 
dosages (6.25 mg twice per day) of carvedilol, so up titration of carvedilol dosages to 25 
mg twice per day is generally recommended. However, favorable effects were noted at 
6.25 mg twice per day, so intolerance of high doses should not be a reason for 
discontinuation of therapy. 
 
The Australia-New Zealand Carvedilol Trial enrolled 415 patients with ischemic 
cardiomyopathy and a left ventricular ejection fraction of less than 45% (35). Although 
patients with NYHA functional classes I-III were eligible, the majority enrolled were 
NYHA functional class I (30%) or II (54%). ACE inhibitors were used in 86% of the 
participants, whereas 76% were on diuretic therapy, and 38% were on digoxin. This trial 
also had a run-in phase during which 6% of the patients discontinued ß-blocker therapy. 
During an average follow-up of 19 months, carvedilol decreased the combined risk of all-
cause mortality or any hospitalization by 26% (relative risk .74; 95% CI, .57 to .95; P= 
.02). Overall mortality was 12.5% in the placebo group and 9.6% in the carvedilol group 
which was not statistically significant (relative risk .76; 95% CI, .42 to 1.36; P > .10). 
 
Unreported or Ongoing Trials. Studies that are underway will provide additional data 
concerning specific aspects of the efficacy of ß-blocker therapy in heart failure. The 
effect of bucindolol on mortality and morbidity in patients with moderate to severe heart 
failure has been evaluated in the BEST Study. This study enrolled a substantial number 
of women so the potential influence of gender on the efficacy of ß-blocker therapy can be 
investigated. The trial has been stopped, and no results are available for analysis. 
     
The COPERNICUS Trial is designed to assess the effect of carvedilol treatment on 
disease progression and survival in patients with advanced heart failure with symptoms at 
rest or on minimal exertion. The COMET protocol is a 3,000 patient study that directly 
compares the survival benefit of carvedilol versus metoprolol. This trial will provide 
important data concerning the relative efficacy of a selective ß-blocker versus a 
nonselective ß-blocker with ancillary properties. 
 
Recommendation 2. ß-blocker therapy should be considered for patients with left 
ventricular systolic dysfunction (left ventricular ejection fraction less than or equal 
to 40%) who are asymptomatic (ie, NYHA class I) and standard therapy, including 
ACE inhibitors (Strength of Evidence = C). 
 
Data from the SOLVD Prevention Trial prospectively illustrated the efficacy of ACE 
inhibitors in delaying the onset of heart failure symptoms and the need for treatment or 
hospitalization for heart failure in asymptomatic patients with a left ventricular ejection 
fraction less than or equal to 35% (36). Similar controlled, clinical trial data that support 
the use of a ß-blocker in this clinical circumstance are not available. However, significant 
support for the use of ßblocker therapy in patients with asymptomatic left ventricular 
dysfunction can be derived from clinical trials in coronary artery disease and 
hypertension. Previous data indicate that ß-blocker therapy should be used in patients 
after myocardial infarction (MI) and in patients with myocardial revascularization who 
have good symptomatic and functional recovery but residual ventricular systolic 
dysfunction. Trials in hypertension indicate that ß-blocker therapy decreases the risk of 
developing heart failure. Given the potential of ß-blockers to retard disease progression 

 
CASE 10107 12/28/2018 
Page 68 of 85 
 
 
 
and improve ventricular function, the risk to benefit ratio seems sufficiently low to 
support ß-blocker use in asymptomatic patients with left ventricular dysfunction, 
especially when the dysfunction is marked, and coronary artery disease is present. 
 
Recommendation 3. To maximize patient safety, a period of clinical stability on 
standard therapy should occur before ß-blocker therapy is instituted. Initiation of 
ß-blocker therapy in patients with heart failure requires a careful baseline 
evaluation of clinical status (Strength of Evidence = B). 
 
Initiation of ß-blocker therapy has the potential to worsen heart failure signs and 
symptoms. This risk increases with the underlying severity of the heart failure that is 
present. To minimize the likelihood of worsening failure, a period of treatment with 
standard therapy and evidence of clinical stability without acute decompensation or fluid 
overload is recommended before initiation of ß-blocker therapy. The majority of the 
large-scale, ß-blocker heart failure trials required that chronic heart failure be present 3 
months or more before initiation of ß-blocker therapy. Patients enrolled in these trials 
were typically treated with ACE inhibitors (if tolerated), diuretic, and digoxin for at least 
2 months and were observed to be clinically stable for 2 to 3 weeks before beginning ß-
blocker therapy. Thus, many heart failure clinicians favor a minimum of 2 to 4 weeks of 
clinical stability on standard therapy before ß-blocker therapy is instituted. Likewise, 
most clinicians discourage the initiation of ß-blocker therapy in the hospital setting after 
treatment for new or decompensated heart failure (with or without associated inotrope 
administration). Some experienced clinicians initiate ß-blocker therapy in the hospital in 
selected patients who have responded well to inpatient treatment and who can be 
followed closely after discharge. 
 
Recommendation 4. There is insufficient evidence to recommend the use of ß-
blocker therapy for inpatients or outpatients with symptoms of heart failure at rest 
(ie, NYHA class IV) (Strength of Evidence = C). 
 
ß-Blocker therapy cannot be routinely recommended for NYHA class IV patients because 
there are currently no clinical trial data to indicate favorable long-term efficacy and 
safety of ßblocker therapy in this patient population. A substantial body of observational 
data indicates that successful institution of ß-blocker therapy in patients with this degree 
of heart failure is problematic. If used, these agents may precipitate deterioration, and 
patients so treated should be monitored by a physician who has expertise in heart failure. 
The number of patients with class IV heart failure at the time of ß-blocker initiation in 
controlled clinical trials is small. Available trials, which report data on patients with 
severe heart failure mostly labeled as NYHA class III, show the potential problems of ß-
blocker therapy in this part of the heart failure spectrum. This experience is reflected in a 
14-week study that evaluated the effects of ß-blocker therapy in 56 patients (51 NYHA 
class III and 5 NYHA class IV at randomization) with severe left ventricular dysfunction 
(average left ventricular ejection fraction of 16% ± 1% and left ventricular filling 
pressure of 24 mm Hg ± 1 mm Hg) (37). These patients had significant impairment of 
exercise capacity (mean VO2 max of 13.6 mL/kg/min ± 0.6 mL/kg/min) despite ACE-
inhibitor, digoxin and diuretic therapy. Patients were believed to be clinically stable 
(requiring no medication adjustments) for a 2-week period before an open-label challenge 
was conducted. Seven patients (12%) failed to complete the open-label, run-in period, 

 
CASE 10107 12/28/2018 
Page 69 of 85 
 
 
 
during which 5 died and 2 had nonfatal adverse reactions. Clinical parameters did not 
distinguish these patients from those who were able to continue in the trial. Eighteen of 
the 49 patients (37%) completing the run-in period experienced worsened dyspnea or 
fluid retention during this phase. Also, 22% experienced dizziness and required 
medication adjustment, which delayed up-titration during the run-in. Subsequently, an 
additional 12% of the patients randomized to carvedilol withdrew from the blinded arm 
of the study. One of the United States carvedilol trials studied patients with severe left 
ventricular dysfunction who had markedly reduced exercise capacity as assessed by the 
6-minute walk test (38). In this trial, 131 patients with a mean left ventricular ejection 
fraction of 22% and severe impairment in quality of life underwent a 2-week, open-label 
challenge phase of 6.25 mg of carvedilol twice per day. Ten of these 131 patients (8%) 
were unable to complete this run-in phase, most because of worsening heart failure, 
dyspnea, or dizziness. Subsequently, 11% of the patients randomized to carvedilol 
withdrew, as did a similar number of patients (11%) in the placebo group. In the recently 
completed large-scale BEST Trial, the mortality trend in NYHA class III-IV patients 
favored the ß-blocker bucindolol, but the difference from placebo was not significant. 
Further analysis of these preliminary findings is necessary, but the data suggest that the 
striking benefit of ß-blockers in mild-to-moderate heart failure may not be extrapolated to 
those with severe symptoms. 
 
Recommendation 5. ß-Blocker therapy should be initiated at low doses and up-
titrated slowly, generally no sooner than at 2-week intervals. Clinical reevaluation 
should occur at each titration point and with worsening of patient symptoms. 
Patients who develop worsening heart failure or other side effects after drug 
initiation or during titration require adjustment of concomitant medications. These 
patients may also require a reduction in ß-blocker dose and, in some cases, 
temporary or permanent withdrawal of this therapy (Strength of Evidence = B). 
 
 ß-Blocker therapy should be initiated at doses substantially less than target doses. 
Clinical trials required patient reassessment at up-titration of each dose. This careful 
evaluation by trained nurses and/or heart failure specialists likely contributed to the 
relatively low withdrawal rates and safety profiles observed in the clinical trials. 
Treatment for symptomatic deterioration may be required during ß-blocker titration, but 
with appropriate adjustments in therapy, most patients can be maintained and generally 
achieve target doses. There is a risk of worsening heart failure, and vasodilatory side 
effects may occur with certain agents. Worsening heart failure is typically reflected by 
increasing fatigue, lower exercise tolerance, and weight gain. Increased diuretic doses 
may be required for signs and symptoms of worsened fluid retention. Treatment options 
also include temporary down-titration of the ß-blocker to the last tolerated dose. Abrupt 
withdrawal should be avoided. A minimum period of stability of 2 weeks should occur 
before further up-titration is attempted. Hypotensive side effects may often resolve with 
reduction in diuretic dose. Temporary reductions in ACE inhibitor dose may be helpful 
for symptomatic hypotension not obviated by staggering the schedule of vasoactive 
medications. Administration of carvedilol with food may alleviate vasodilatory side 
effects as well. 
  

 
CASE 10107 12/28/2018 
Page 70 of 85 
 
 
 
If ß-blocker treatment is interrupted for a period exceeding 72 hours and the patient is 
still judged a candidate for this therapy, drug treatment should be reinitiated at 50% of the 
previous dose. Subsequent up-titration should be conducted as previously described. 
 
Recommendation 6. In general, patients who experience a deterioration in clinical 
status or symptomatic exacerbation of heart failure during chronic maintenance 
treatment should be continued on ß-blocker therapy (Strength of Evidence = C). 
 
Clinical decompensation that occurs during stable maintenance therapy is less likely 
caused by chronic ß-blocker therapy than other factors (diet or medication 
noncompliance, ischemia, arrhythmia, comorbid disease, infection, or disease 
progression). In these situations, maintaining the current ß-blocker dose while relieving 
or compensating for the precipitating factor(s) is most often the best course. Data from 
patients randomized to continue or discontinue ß-blocker therapy in this setting are not 
currently available. However, studies of the withdrawal of ß-blocker therapy in patients 
with persistent left ventricular systolic dysfunction but improved and stable clinical heart 
failure have revealed a substantial risk of worsening heart failure and early death after 
discontinuation of ß-blocker therapy (39,40). 
 
Recommendation 7. Patient education regarding early recognition of symptom 
exacerbation and side effects is considered important. If clinical uncertainty exists, 
consultation with clinicians who have expertise in heart failure and/or specialized 
programs with experience in ß-blocker use in patients with heart failure is 
recommended (Strength of Evidence = B). 
 
In certain patients, frequent return visits for dose-titration may be difficult to 
accommodate in a busy clinical practice. Trained personnel, including nurse practitioners, 
physicians’ assistants, and pharmacists with physician supervision, may more efficiently 
perform patient education and reevaluation during up-titration. Heart failure specialty 
programs are more likely to have the resources to provide this follow-up and education 
(41). Consultation or referral may be particularly beneficial when the clinical heart failure 
status of the patient is uncertain or problems arise during initiation of therapy or dose-
titration that may cause unwarranted discontinuation of therapy. Ideal patients for ß-
blocker therapy should be compliant and have a good understanding of their disease and 
their overall treatment plan. Patients should be aware that symptomatic deterioration is 
possible early in therapy and that symptomatic improvement may be delayed for weeks to 
months. 
 
Unresolved Therapeutic Issues 
 
Combining ß-Blocking Agents With Amiodarone Therapy. Concomitant use of 
amiodarone was generally precluded in the trials evaluating carvedilol and most other ß-
blockers. However, the use of this agent for rate control of atrial arrhythmia or for 
maintenance of sinus rhythm is common in heart failure patients. Drug interactions 
between ß-blockers and amiodarone are possible, including symptomatic bradycardia, 
and may limit the maximum tolerated dose of the ß-blocker. When the combination is 
used, the smallest effective dose of amiodarone should be employed. Given the lack of a 

 
CASE 10107 12/28/2018 
Page 71 of 85 
 
 
 
clear survival benefit, amiodarone is not a substitute for ß-blocker therapy in heart failure 
patients who are candidates for this therapy. 
 
Implantation of Cardiac Pacemakers. Given the strength of evidence that supports ß-
blocker therapy in patients with symptomatic heart failure, some physicians would 
consider pacemaker implantation when symptomatic bradycardia or heart block occur 
during the initiation of this therapy, although no data are available to support such use. 
Consideration should be given, after weighing risks and benefits, to the withdrawal of 
other drugs that may have bradycardia effects. 
Duration of Therapy. Whether patients experiencing marked improvement in left 
ventricular systolic dysfunction and heart failure symptoms during therapy can be 
successfully withdrawn from ß-blocker therapy remains to be established. Concern 
continues that such patients would experience worsening after ß-blocker withdrawal, 
either in systolic function or symptoms, over a time period that is undefined. Until 
clinical trial data indicate otherwise, the duration of ßblocker therapy must be considered 
indefinite. 
 
Digoxin 
Background for Recommendations 
Although little controversy exists as to the benefit of digoxin in patients with 
symptomatic left ventricular systolic dysfunction and concomitant atrial fibrillation, the 
debate continues over its current role in similar patients with normal sinus rhythm. 
Recent information regarding digoxin’s mechanism of action and new analyses of clinical 
data from the DIG Trial and the combined PROVED and RADIANCE Trial databases 
provide additional evidence of favorable efficacy that was unavailable to previous 
guideline committees (42-47). In fact, this information has recently formed the basis of 
Food and Drug Administration (FDA) approval of digoxin for the treatment of mild to 
moderate heart failure (48). Digoxin, a drug that is inexpensive and can be given once 
daily, represents the only orally effective drug with positive inotropic effects approved 
for the management of heart failure. The committee’s consensus is that digoxin, when 
used in combination with other standard therapy, will continue to play an important role 
in the symptomatic management of the majority of patients with heart failure. 
 
The efficacy of digoxin for the treatment of heart failure caused by systolic dysfunction 
has traditionally been attributed to its relatively weak positive inotropic action that comes 
from inhibition of sodium-potassium adenosine triphosphatase (ATPase) that results in an 
increase in cardiac myocyte intracellular calcium. However, in addition to positive 
inotropy, digitalis has important, neurohormonal-modulating effects in patients with 
chronic heart failure, including a sympathoinhibitory effect that cannot be ascribed to its 
inotropic action (49,50). Digoxin also ameliorates autonomic dysfunction as evidenced 
by studies of heart rate variability, which indicates increased parasympathetic and 
baroreceptor sensitivity during therapy (51). 
 
Recommendation 1. Digoxin should be considered for patients who have symptoms 
of heart failure (NYHA class II-III, Strength of Evidence = A and NYHA class IV, 
Strength of Evidence = C) caused by left ventricular systolic dysfunction while 
receiving standard therapy. 
 

 
CASE 10107 12/28/2018 
Page 72 of 85 
 
 
 
Digoxin increases left ventricular ejection fraction and alleviates symptomatic heart 
failure as evidenced by drug-related improvement in exercise capacity and reductions in 
heart-failure associated hospitalization and emergency room visits. Digoxin should be 
used in conjunction with other forms of standard heart failure therapy including ACE 
inhibitors, diuretics and ß-blockers. 
 
The DIG Trial, a randomized, double-blind, placebo-controlled trial in over 7,000 
patients with heart failure, showed a neutral effect on the primary study endpoint and 
mortality from any cause during an average follow-up of approximately 3 years (42). In 
the main trial, 6,800 patients with left ventricular ejection fraction less than or equal to 
45% were randomized to digoxin or placebo, in addition to diuretics and ACE inhibitors. 
A total of 1,181 deaths occurred on digoxin (34.8%) and 1,194 on placebo (35.1%) for a 
risk ratio of .99 (95% CI, .91 to 1.07; P = .80). These results differ from other oral agents 
with inotropic properties that have been associated with an adverse effect on mortality. In 
addition, the need for hospitalization and co intervention (defined as increasing the dose 
of diuretics and ACE inhibitors or adding new therapies for worsening heart failure) was 
significantly lower in the digoxin group, even in those patients who were not previously 
taking digoxin. Fewer patients on digoxin compared with placebo were hospitalized for 
worsening heart failure (26.8%v 34.7%; risk ratio .72; 95% CI, .66 to .79; P < .001). 
These long-term data are consistent with recent results obtained from an analysis of the 
combined PROVED and RADIANCE databases (45). In this analysis, patients who 
continued digoxin as part of triple therapy with diuretics and an ACE inhibitor were 
much less likely to develop worsening heart failure (4.7%) than those treated with a 
diuretic alone (39%, P < .001), diuretic plus digoxin (19%, P = .009) or diuretic plus an 
ACE inhibitor (25%, P = .001). 
 
Although there are no clinical trial data (level A evidence) for the efficacy of digoxin in 
patients with NYHA Class IV heart failure, there is evidence that digoxin works across 
the spectrum of left ventricular systolic dysfunction. A prespecified subgroup analysis of 
patients enrolled in the DIG Trial with evidence of severe heart failure (as manifested by 
left ventricular ejection fraction less than 25%, or cardiothoracic ratio [CTR] greater than 
.55) showed the benefit of digoxin (48). The following reductions in the combined 
endpoint of all-cause mortality or hospitalization were seen on digoxin compared with 
placebo: 16% reduction (95% CI, 7% to 24%) in patients with a left ventricular ejection 
fraction of less than 25%, and a 15% reduction (95% CI, 6% to 23%) in patients with a 
CTR of greater than .55 (43). Reductions in the risk of the combined endpoint of heart-
failure related mortality or hospitalization were even more striking: 39% (95% CI, 29% 
to 47%) for patients with left ventricular ejection fraction less than 25%, and 35% (95% 
CI, 25% to 43%) for patients with a CTR greater than .55 (48).  
 
Evidence for the efficacy of digoxin in patients with mild symptoms of heart failure has 
been provided by a recent retrospective, cohort analysis of the combined PROVED and 
RADIANCE data (52). The outcome of patients in these trials who were randomized to 
digoxin withdrawal or continuation was categorized by using a prospectively obtained 
heart failure score based on clinical signs and symptoms. Patients in the mild heart failure 
group (heart failure score of 2 or less) who were randomized to have digoxin withdrawn 
were at increased risk of treatment failure and had deterioration of exercise capacity and 
left ventricular ejection fraction compared with patients who continued digoxin (all P < 

 
CASE 10107 12/28/2018 
Page 73 of 85 
 
 
 
.01). Patients in the moderate heart failure  group who had digoxin withdrawn were 
significantly more likely to experience treatment failure than either patients in the mild 
heart failure group or patients who continued digoxin (both P < .05). These data suggest 
that patients with left ventricular systolic dysfunction benefit from digoxin despite only 
mild clinical evidence of heart failure. 
 
In summary, a large body of evidence supports the efficacy of digoxin in patients with 
symptomatic heart failure caused by left ventricular systolic dysfunction. Digoxin has 
been shown to decrease hospitalizations, as well as emergency room visits; decrease the 
need for co intervention; and improve exercise capacity (42-44,53,54). Taken as a whole, 
these clinical trial data provide support for digoxin’s beneficial effect on morbidity and 
neutral effect on mortality (42). 
 
Recommendation 2. In the majority of patients, the dosage of digoxin should be .125 
mg to .25 mg daily (Strength of Evidence = C). 
 
Recent data suggest that the target dose of digoxin therapy should be lower than 
traditionally assumed. Although higher doses may be necessary for maximal 
hemodynamic effects (55), beneficial neurohormonal and functional effects appear to be 
achieved at relatively low serum digoxin concentrations (SDC) typically associated with 
daily doses of .125 mg to .25 mg of digoxin (55-57). The utility of lower SDC is 
supported by recent clinical trial data; the mean SDC achieved in the RADIANCE Trial 
was 1.2 ng/mL and in the DIG Trial was 0.8 ng/mL (42,44). Recent retrospective, cohort 
analysis of the combined PROVED and RADIANCE databases indicates that patients 
with a low SDC (less than .9 ng/mL) were no more likely to experience worsening 
symptoms of heart failure on maintenance digoxin than those with a moderate (.9 to 1.2 
ng/mL) or high (greater than 1.2 ng/mL) SDC (41). All SDC groups were significantly 
less likely to deteriorate during follow-up compared with patients withdrawn from 
digoxin.  
 
Therefore, patients with left ventricular systolic dysfunction and normal sinus rhythm 
should be started on a maintenance dosage of digoxin (no loading dose) of .125 or .25 mg 
once daily based on ideal body weight, age, and renal function For patients with normal 
renal function, a dosage of digoxin of .25 mg/day will be typical. Many patients with 
heart failure have reduced renal function and should begin on .125 mg daily. In addition, 
patients with a baseline conduction abnormality, or who are small in stature or elderly, 
should be started at .125 mg/day, which can be up-titrated if necessary. Once dosing has 
continued for a sufficient period for serum concentration to reach steady state (typically 
in 2 to 3 weeks), some clinicians consider the measurement of a SDC, especially in 
elderly patients or those with impaired renal function in which the digoxin dose is often 
not predictive of SDC. SDC measurements may be considered when 1) a significant 
change in renal function occurs; 2) a potentially interacting drug (amiodarone, quinidine, 
or verapamil) is added or discontinued; or 3) confirmation of suspected digoxin toxicity 
is necessary in a patient with signs or symptoms and/or electrocardiographic changes 
consistent with this diagnosis. Samples for trough SDC should be drawn more than 6 
hours after dosing. Otherwise, the result is difficult to interpret because the drug may not 
be fully distributed into tissues. 
 

 
CASE 10107 12/28/2018 
Page 74 of 85 
 
 
 
Recommendation 3. In patients with heart failure and atrial fibrillation with a rapid 
ventricular response, the administration of high doses ofdigoxin (greater than .25 
mg) for the purpose of rate control is not recommended. When necessary, additional 
rate control should be achieved by the addition of ß-blocker therapy or amiodarone 
(Strength of Evidence= C). 
 
Digoxin continues to be the drug of choice for patients with heart failure and atrial 
fibrillation. However, the traditional practice of arbitrarily increasing the dose (and SDC) 
of digoxin until ventricular response is controlled should be abandoned because the risk 
of digoxin toxicity increases as well. Digoxin alone is often inadequate to control 
ventricular response in patients with atrial fibrillation, and the SDC should not be used to 
guide dosing to achieve rate control. Therefore, digoxin should be dosed in the same 
manner as in a patient with heart failure and normal sinus rhythm. 
Digoxin slows ventricular response to atrial fibrillation through enhancement of vagal 
tone. However, with exertion or other increases in sympathetic activity, vagal tone may 
decrease and ventricular rate accelerate. Addition of a ß-blocker or amiodarone 1) 
complements the pharmacological action of digoxin and provides more optimal rate 
control; 2) allows the beneficial clinical effects of digoxin to be maintained; and 3) limits 
the risk of toxicity that may occur if digoxin is dosed to achieve a high SDC (58). For 
patients who have a contraindication to ßblockers, amiodarone is a reasonable alternative. 
If amiodarone is added, the dose of digoxin should be reduced, and the SDC should be 
monitored so that the serum concentration can be maintained in the desired range. Some 
clinicians advocate the short-term, intravenous administration of diltiazem for the acute 
treatment of patients with very rapid ventricular response, especially those with 
hemodynamic compromise. This drug is not indicated for long-term management because 
its negative inotropic effects may worsen heart failure.  
 
Unresolved Therapeutic Issues 
 
Combination With ß-blockers. ß-Blocker therapy has become pivotal in the 
management of heart failure. However, the majority of patients enrolled in controlled 
clinical trials that study the efficacy of digoxin were not taking ß-blockers. Therefore, it 
is uncertain whether or not digoxin should be routinely included as part of a ß-blocker 
regimen for symptomatic heart failure caused by left ventricular systolic dysfunction. 
There are attractive features of combining digoxin with ß-blocker therapy in the treatment 
of heart failure. The majority of heart failure patients have coronary artery disease and 
may be at risk for transient episodes of myocardial ischemia that could cause 
catecholamine release and sudden cardiac death. Combining digoxin with a ß-blocker 
may preserve the beneficial effects of digoxin on the symptoms of heart failure while 
minimizing the potential detrimental effects of this therapy on catecholamine release in 
the setting of ischemia (47). 
 
Combination with Diuretics. Non-potassium-sparing diuretics can produce electrolyte 
abnormalities such as hypokalemia and hypomagnesemia, which increases the risk of 
digoxin toxicity. The combination of digoxin with a potassium- sparing diuretic would be 
a potentially safer alternative. Further study will be necessary to carefully elucidate the 
efficacy and safety of combining digoxin with these agents. 

 
CASE 10107 12/28/2018 
Page 75 of 85 
 
 
 
Anticoagulation and Antiplatelet Drugs 
Background for Recommendations 
 
Patients with heart failure are recognized to be at increased risk for thromboembolic 
events that can be arterial or venous in origin. In addition to atrial fibrillation and poor 
ventricular function (which promote stasis and increase the risk of thrombus formation), 
patients with heart failure have other manifestations of hypercoagulability. Evidence of 
heightened platelet activation; increased plasma and blood viscosity; and increased 
plasma levels of fibrinopeptide A, ßthromboglobulin, D-dimer, and von Willebrand 
factor (59-61) have been found in many patients. Despite a predisposition, estimates 
regarding the incidence of thromboemboli in patients with heart failure vary substantially 
between 1.4 and 42 per 100 patient years (62-65). Although variability in the reported 
incidence likely results from differences in the populations studied and the methods used 
to identify these events, the consensus is that pulmonary and systemic emboli are not 
common in heart failure patients. Traditionally, the issue of anticoagulation in patients 
with heart failure centered on warfarin. Growing recognition of the importance of 
ischemic heart disease as a cause of heart failure suggests that the role of antiplatelet 
therapy must be considered in patients with this syndrome as well. 
 
Previous guidelines have recommended warfarin anticoagulation in patients with heart 
failure complicated by atrial fibrillation and in heart failure patients with prior 
thromboembolic events (18,19). Warfarin anticoagulation specifically was not 
recommended in patients with heart failure in the absence of these indications. There 
have been no randomized, controlled trials of warfarin in patients with heart failure. 
Therefore, recommendations regarding its use, in the absence of atrial fibrillation or 
clinically overt systemic or pulmonary thromboemboli, must be made on the basis of 
cohort data and expert opinion. The likely incidence of thromboembolic events and the 
possibility of averting them with warfarin are important considerations for any guideline 
recommendation. In addition, the potential beneficial effects of warfarin on coronary 
thrombotic events, independent of embolic phenomenon, must be taken into account. The 
substantial clinical trial data that reflect the beneficial effects of antiplatelet therapy in 
patients with ischemic heart disease suggest that new guideline recommendations for 
heart failure should address the role of this form of therapy in patients with left 
ventricular dysfunction. 
 
Anticoagulation 
 
Recommendation 1. All patients with heart failure and atrial fibrillation should be 
treated with warfarin (goal, international normalized ratio (INR) 2.0 to 3.0) unless 
contraindicated (Strength of Evidence = A). 
 
The committee agrees with previous guideline recommendations that concern warfarin 
therapy in patients with heart failure complicated by atrial fibrillation. The benefit of 
warfarin anticoagulation in this setting is well established through several randomized 
trials (66). Patients with heart failure commonly have atrial fibrillation. Warfarin 
anticoagulation should be implemented in all of these patients unless clear 
contraindications exist. 
 

 
CASE 10107 12/28/2018 
Page 76 of 85 
 
 
 
Recommendation 2. Warfarin anticoagulation merits consideration for patients with 
left ventricular ejection fraction of 35% or less. Careful assessment of the risks and 
benefits of anticoagulation should be undertaken in individual patients (Strength of 
Evidence = B). 
 
Cohort analyses examining the relationship between warfarin use and noncoronary 
thromboembolism in patients with heart failure have not consistently yielded positive 
findings (62,63,65,67-69). It is possible that the lack of consistent benefit was related to 
the low incidence of identifiable embolic events in these populations. However, these 
studies do not make a convincing argument for the use of warfarin to prevent embolic 
events in the absence of atrial fibrillation or a previous thromboembolic episode. 
 
In contrast, a recent cohort analysis of the SOLVD population focused on the relation 
between warfarin use and the risk of all-cause mortality rather than risk for embolic 
events (70). After adjustment for baseline differences, patients treated with warfarin at 
baseline had a significantly lower risk of mortality during follow-up (adjusted hazard 
ratio .76; 95% CI, .65 to .89, P = .0006). In addition to a mortality benefit, warfarin use 
was also associated with a significant reduction in the combined endpoint of death or 
hospitalization for heart failure (adjusted hazard ratio .82; 95% CI, .72 to .93, P = .002). 
In the SOLVD population, the benefit associated with warfarin use was not significantly 
influenced by 1) presence or absence of symptoms (treatment trial v prevention trial), 2) 
randomization to enalapril or placebo, 3) gender, 4) presence or absence of atrial 
fibrillation; 5) age, 6) ejection fraction, 7) NYHA class, or 8) origins of disease. 
  
The benefit associated with warfarin use in the cohort analysis of the SOLVD population 
was related to a reduction in cardiac mortality. Specifically, there was a significant 
reduction among warfarin users in deaths that were identified as sudden, in deaths 
associated with heart failure, and in fatal MI. In contrast (yet in agreement with previous 
cohort analyses), there was no significant difference in deaths considered cardiovascular 
but noncardiac, including pulmonary embolism and fatal stroke. Some caution is needed 
in consideration of this finding because the number of cardiovascular deaths that were 
noncardiac was far less than the number of cardiac deaths. 
 
Reduction in ischemic events is one potential explanation for the apparent benefit from 
warfarin in the SOLVD Study. Warfarin users showed a reduced rate of hospitalization 
for unstable angina or nonfatal MI. Prior investigations of patients after acute MI showed 
that warfarin anticoagulation, when started within 4 weeks, reduces the incidence of fatal 
and nonfatal coronary events, as well as pulmonary embolus and stroke (71). 
 
As with other post hoc, cohort analyses, it is possible that the findings from the SOLVD 
Study may result from differences between the treatment groups that were not identified 
and for which statistical correction could not adequately adjust. For this reason, evidence 
from any cohort study must be considered less powerful compared with evidence derived 
from randomized, controlled trials. Nevertheless, in the absence of randomized data, the 
SOLVD cohort analysis represents reasonable evidence to support more aggressive use of 
warfarin anticoagulation than previously recommended in patients with reduced left 
ventricular ejection fraction and sinus rhythm. The data from this analysis provide no 
information regarding the ideal warfarin dose in this patient population. Therefore, the 

 
CASE 10107 12/28/2018 
Page 77 of 85 
 
 
 
dosing recommendation should likely conform to that derived from previous randomized 
trials performed in patients without mechanical prosthetic  valves (INR 2.0 to 3.0). 
 
Antiplatelet Drugs 
 
Recommendation 1. With regard to the concomitant use of ACE inhibitors and 
acetylsalicylic acid (ASA), each medication should be considered on its own merit 
for individual patients. Currently, there is insufficient evidence concerning the 
potential negative therapeutic interaction between ASA and ACE inhibitors to 
warrant withholding either of these medications in which an indication exists 
(Strength of Evidence =C). 
 
Strong evidence supports the clinical benefit of aspirin in ischemic heart disease and 
atherosclerosis (72-75). However, recent post hoc analyses of large randomized trials 
involving ACE inhibitors in heart failure and post-MI suggest the possibility of an 
adverse drug interaction between ASA and ACE inhibitors (76-78). A retrospective 
cohort analysis of the SOLVD Study found that patients on antiplatelet therapy (assumed 
to be ASA in the great majority of patients) derived no additional survival benefit from 
the addition of enalapril. Data from CONSENSUS II and GUSTO-1 in post-MI patients, 
suggest not only no additive benefit, but the possibility of a negative effect on mortality 
from the combination of ASA and ACE inhibition. In contrast, an unadjusted, 
retrospective registry study in patients with chronic coronary artery disease did not 
support an adverse interaction (79). Interestingly, in an adjusted analysis of the subset of  
patients with heart failure in this study, the beneficial effects of aspirin seemed less 
evident in patients taking ACE inhibitors. Despite these provocative post hoc findings, no 
prospective studies have yet been reported that concern the possible adverse interaction 
between ACE inhibitors and aspirin. To date, there is no clear evidence of harm from the 
combination of ASA and ACE inhibitors in patients with heart failure (76). 
 
There is also some evidence that the potential interaction between ASA and ACE 
inhibitors may be dose related. A recent meta-analysis of all hypertension and heart 
failure patients who have received both ASA and ACE inhibitors suggests that ASA at 
doses equal to or less than 100 mg showed no interaction with ACE inhibitors (80). Any 
interaction, if observed, occurred at higher doses of aspirin. 
 
A potential mechanism for the hypothesized adverse interaction between ASA and ACE 
inhibitors in patients with heart failure involves prostaglandin synthesis. ACE inhibition 
is believed to augment bradykinin which, in turn, stimulates the synthesis of various 
prostaglandins that may contribute vasodilatory and other salutary effects. In the presence 
of ASA, the bradykinin-induced increase in prostaglandins should be attenuated or 
blocked, which potentially reduces the benefits of ACE inhibition. Invasive 
hemodynamic monitoring has shown that the acute hemodynamic effect of enalapril is 
blunted by concomitant administration of aspirin (81). Another possibility is that ASA 
and ACE inhibitors act in a similar fashion in heart failure, therefore no added benefit is 
gained from the combination. ACE inhibitors appear to reduce ischemic events in heart 
failure patients possibly through antithrombotic effects, which could mimic those of 
antiplatelet agents. Recent study results that suggest ASA may have independent 

 
CASE 10107 12/28/2018 
Page 78 of 85 
 
 
 
beneficial action on ventricular remodeling support the hypothesis of similar mechanisms 
of action for ACE inhibitors and ASA (82). 
 
Development of the adenosine diphosphate (ADP) antagonists, ticlopidine and 
clopidogrel, provides alternative therapy for platelet inhibition that does not appear to 
influence prostaglandin synthesis (83). In direct comparison with aspirin, large-scale 
clinical trial results have established the efficacy of clopidogrel in the prevention of 
vascular events in patients with arteriosclerotic disease (84). Clinical data are limited 
with ADP antagonists in heart failure. However, hemodynamic evaluation found a similar 
reduction in systemic vascular resistance in heart failure patients treated with the 
combination of ACE inhibitors and ticlopidine versus ACE inhibitors alone, which 
suggests no adverse hemodynamic interaction with ACE inhibition with this type of 
antiplatelet compound (85). Definitive resolution of the therapeutic implications of the 
ASA/ACE inhibitor interaction and the appropriate alternative therapy, if any, in heart 
failure awaits the results of additional clinical research studies. 
 
Angiotensin II Receptor Blockers 
 
Background for Recommendations 
 
Angiotensin ll (AT) receptor blockers (ARBs) differ in their mechanism of action 
compared with ACE inhibitors. Rather than inhibiting the production of AT by blockade 
of ACE, ARBs block the cell surface receptor for AT. ARBs that are currently available 
are selective and only effectively inhibit the AT1 subtype of this receptor. Theoretical 
benefits of ARBs include receptor blockade of AT produced by enzymes other than ACE 
and maintenance of ambient AT to maintain or increase stimulation of AT2 receptors. 
AT1 receptor antagonism is important because this receptor appears to mediate the 
classical adverse effects associated with AT in heart failure. In contrast, the AT2 receptor 
subtype appears to counterbalance AT1 receptor stimulation by causing vasodilation and 
inhibiting proliferative and hypertrophic responses (86). Thus, the selective receptor 
blockade of the current ARBs may be particularly advantageous. Theoretical concerns 
about ARB therapy include the potential deleterious effects of increased AT levels and 
AT2 receptor-mediated enhancement of apoptosis. Whether ARBs have beneficial effects 
similar to ACE inhibitors on the course of coronary artery disease remains to be 
determined. ARBs may or may not influence bradykinin concentrations, which are 
anticipated to rise with ACE inhibitor therapy and may contribute to their efficacy. 
 
The hemodynamic actions of ARBs have, thus far, been similar to ACE inhibitors for 
reduction of blood pressure in hypertension and lowering of systemic vascular resistance 
in heart failure (87). ARBs have a similar mild-to-modest effect on exercise capacity and 
produce a comparable reduction in norepinephrine relative to ACE inhibitors (88). 
 
Recommendation 1. ACE inhibitors rather than ARBs continue to be the agents of 
choice for blockade of the renin-angiotensin system in heart failure, and they 
remain the cornerstone of standard therapy for patients with left ventricular 
systolic dysfunction with or without symptomatic heart failure (Strength of 
Evidence = A). 
 

 
CASE 10107 12/28/2018 
Page 79 of 85 
 
 
 
At present, it is not possible to predict where ARBs will ultimately reside among 
accepted therapies for heart failure. Although the initial small ELITE Trial suggested a 
greater benefit from a losartan dosage of 50 mg daily than from a captopril dosage of 50 
mg 3 times daily on mortality in elderly patients with heart failure (89), the ELITE II 
Mortality Trial, which included more than 3,000 patients (90), showed no comparative 
benefit from losartan and a trend for a better outcome and fewer sudden deaths with 
captopril (91). This result provides no evidence that the low dose (50 mg ) of losartan that 
was tested is better than an ACE inhibitor for treating heart failure, but it does not 
exclude the efficacy of a higher dose designed to provide continuous inhibition of the 
AT1 receptor. Tolerability of losartan was better than of captopril, primarily because of 
an ACEinhibitor cough. But the well-established efficacy of the ACE inhibitors on 
outcome in the post-MI period, in diabetes, in atherosclerosis, and in heart failure 
mandates that this drug group remains agents of choice for inhibiting the renin-
angiotensin system in heart failure. The RESOLVD Trial suggested no major differences 
in efficacy of candesartan and enalapril, with a trend favoring enalapril during the study 
period of 43 weeks (92). The OPTIMAAL and VALIANT Studies will provide 
information specifically about the role of ARBs versus ACE inhibitors in the post-MI 
population. 
 
Currently, ACE inhibitors continue to be regarded as the therapy of choice to inhibit the 
renin-angiotensin system in patients with asymptomatic and symptomatic left ventricular 
dysfunction. There is no current rationale to recommend initiating ARBs in patients with 
new onset heart failure or for switching from a tolerated ACE-inhibitor regimen to an 
ARB in patients with chronic heart failure. 
 
Recommendation 2. All efforts should be made to achieve ACE inhibitor use in 
patients with heart failure caused by left ventricular dysfunction. Patients who are 
truly intolerant to ACE inhibitors should be considered for treatment with the 
combination of hydralazine and isosorbide dinitrate (Hyd-ISDN) (Strength of 
Evidence = B) or an ARB (Strength of Evidence = C). 
 
Previous large-scale trials do not specifically address the role of ARB and Hyd-ISDN in 
patients who are intolerant to ACE inhibitors. One arm of the CHARM Study has been 
specifically designed to test the effectiveness of candesartan in patients with systolic 
dysfunction who are intolerant to ACE inhibitors. The primary endpoint in this study will 
be a composite of cardiovascular death and time until first hospitalization for heart 
failure. For now, ARBs offer a reasonable alternative in the heart failure or post-MI 
patient who is truly intolerant to ACE inhibition. Intolerance because of cough should 
always trigger a careful reevaluation for congestion. If congestion is present, cough 
should abate with increases in diuretic that should allow ACE-inhibitor use to continue 
(93). It should be emphasized that patients intolerant to ACE inhibitor because of renal 
dysfunction, hyperkalemia, or hypotension are often intolerant to ARBs as well. ACE 
inhibitor intolerance because of persistent symptomatic hypotension in advanced heart 
failure may represent severe dependence on the hemodynamic support of the renin-
angiotensin system, which generally would predict hypotension with ARB use as well. 
 
The combination of Hyd-ISDN has not been studied in the post-MI population, but 
sufficient experience exists to support its use in the ACE-inhibitor-intolerant patient with 

 
CASE 10107 12/28/2018 
Page 80 of 85 
 
 
 
symptomatic heart failure. Hydralazine blocks the development of nitrate tolerance, 
which argues for the use of combination therapy. Although they were not studied alone in 
a heart failure mortality trial, oral nitrates represent another reasonable alternative for 
patients intolerant to both ACE inhibitors and hydralazine. 
 
Unresolved Therapeutic Issues  
 
Combination Therapy With ACE Inhibitors and ARBs. Interest has grown in the 
potential utility of combining ACE inhibitors and ARBs in patients with heart failure. 
Initial data suggest that the combination yields more vasodilation and decreased blood 
pressure than either agent alone. The addition of losartan to an ACE inhibitor has been 
found to improve exercise capacity compared with an ACE inhibitor alone (94). 
Preliminary data from the RESOLVD Trial suggest that ventricular dilation and 
neuroendocrine activation may be best reduced with combination therapy, but other 
endpoints were not clearly affected. Trials are currently underway to determine the 
safety, as well as benefit, of more complete blockade of the renin-angiotensin system. 
The Val-HeFT Trial is a large-scale investigation of the effect of valsartan in addition to 
ACE inhibitors on morbidity and mortality in symptomatic patients with heart failure 
caused by systolic dysfunction. One arm of the CHARM Study will also examine the 
effect of the addition of candesartan in patients with symptomatic, systolic dysfunction 
treated with an ACE inhibitor. Preliminary data from the RESOLVD Trial suggest that 
combination therapy may be even more efficacious when used in conjunction with ß-
blocker treatment. Results from Val-HeFT and CHARM in the subset of patients treated 
with ß-blocker therapy will provide more information concerning this strategy. 
 
Combination therapy represents a rational option when treating severe hypertension or 
other vasoconstriction but cannot, at present, be recommended as routine therapy in the 
absence of a proven superiority to ACE-inhibitor therapy alone. 
 

 
CASE 10107 12/28/2018 
Page 81 of 85 
 
 
 
HFSA Guidelines 
Appendix B 
Criteria for NYHA functional classification for chronic heart failure patients, 
functional capacity (130) 
 
CLASS 1  
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea. 
 
CLASS 2  
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation or dyspnea. 
 
CLASS 3  
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation or dyspnea. 
 
CLASS 4  
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased. 

 
CASE 10107 12/28/2018 
Page 82 of 85 
 
 
 
HFSA Guidelines 
Appendix B 
Glossary of Clinical Trials 
 
AVID  
 
 
Antiarrhythmics Versus Implantable Defibrillators 
BEST  
 
 
Beta-blocker Evaluation of Survival Trial 
CAMIAT  
 
 
Canadian Amiodarone Myocardial Infarction Arrhythmia 
Trial 
CAPRIE  
 
 
Clopidogrel vs Aspirin in Patients at Risk of Ischemic 
Events 
CASH  
 
 
Cardiac Arrest Study Hamburg 
CHF-STAT   
 
Congestive Heart Failure-Survival Trial of Antiarrhythmic 
Therapy 
CHARM  
Candesartan Cilexetil in Heart Failure Assessment of 
Reduction in Mortality and Morbidity 
CIBIS  
 
 
Cardiac Insufficiency BIsoprolol Study 
CIBIS II  
 
 
Cardiac Insufficiency Bisoprolol Study II 
CIDS  
 
 
Canadian Implantable Defibrillator Study 
COMET  
 
 
Carvedilol or Metoprolol European Trial 
CONSENSUS  
 
Cooperative North Scandinavian Enalapril Survival Study 
CONSENSUS II  
 
Cooperative New Scandinavian Enalapril Survival Study II 
COPERNICUS  
 
Carvedilol Prospective Randomized Cumulative Survival 
Trial 
DEFINITE   
 
Defibrillators in Nonischemic Cardiomyopathy Treatment 
Evaluation 
DIAMOND   
 
Danish Investigation of Arrhythmia and Mortality on 
Dofetilide 
DIG   
 
 
Digitalis Investigation Group 
ELITE  
 
 
Evaluation of Losartan In The Elderly 
ELITE II  
 
 
Losartan Heart Failure Survival Study - ELITE II 
EMIAT  
 
  
Infarction Amiodarone Trial 
GESICA  
 
 
Grupo de Estudio de Sobrevida en Insuficiencia Cardiaca 
en Argentina 
GUSTO 1  
Global Utilization of Streptokinase and TPA for Occluded 
coronary arteries 
MADIT  
 
 
Multicenter Automatic Defibrillator Implantation Trial 
MADITII  
 
 
Multicenter Automatic Defibrillator Implantation Trial II 
MDC  
Metoprolol in Dilated Cardiomyopathy trial 
MERIT-HF  
Metoprolol CR/XL Randomized Intervention Trial in Heart 
Failure 
MOCHA  
Multicenter Oral Carvedilol in Heart-failure Assessment 
MTT  
Myocarditis Treatment Trial 
OPTIMALL  
Optimal Therapy in Myocardial Infarction with the 
Angiotensin II Antagonist Losartan 
PRECISE  
Prospective Randomized Evaluation of Carvedilol In 
Symptoms and Exercise 
PROVED  
Prospective Randomized study Of Ventricular failure and 
the Efficacy of Digoxin 

 
CASE 10107 12/28/2018 
Page 83 of 85 
 
 
 
RADIANCE  
Randomized Assessment of Digoxin on Inhibitors of the 
Angiotensin Converting Enzyme 
RALES  
Randomized Aldactone Evaluation Study 
RESOLVD  
Randomized Evaluation of Strategies for Left Ventricular 
Dysfunction 
SAVE  
Survival And Ventricular Enlargement 
SCD-HeFT  
Sudden Cardiac Death in Heart Failure: Trial of 
prophylactic amiodarone versus implantable defibrillator 
therapy 
SOLVD  
 
 
Studies Of Left Ventricular Dysfunction 
SWORD  
 
 
Survival With Oral D-sotalol 
ValHeFT  
 
 
Valsartan Heart Failure Trial 
VALIANT   
 
Valsartan in Acute Myocardial Infarction 

 
CASE 10107 12/28/2018 
Page 84 of 85 
 
 
 
 
 
APPENDIX C 
FDA MedWatch 3500 Form 

 
CASE 10107 12/28/2018 
Page 85 of 85 
 
 
 
 
APPENDIX D 
Handling and Shipping Instructions for Serum Bound For 
Case Comprehensive Cancer Center 
 
Sample Handling Instructions 
 
Herceptin trial CASE 10107 
 
Collection and processing 
Draw one 4.5 mL serum separator tube for TNFalpha, IL-6 and Troponin levels, and one 
4.5ml EDTA-containing tube for BNP determination per time point. Allow serum 
separator tubes to clot for 30 minutes at room temperature before centrifugation. 
Centrifuge all tubes at 1500 x g at 4° C for 10 min. Divide the serum and plasma each 
into four 0.5 mL aliquots (use 1.8ml screw cap cryovials). Store at -70° C or colder, and 
batch ship every month. Ship Mon-Wed only to the address below. Label the aliquots in 
indelible marker as follows: 
 
Patient ID, initials (FML) 
 
 
Patient ID, initials (FML) 
Date, draw time 
 
 
 
Date, draw time 
Timepoint 
 
 
 
 
Timepoint 
Serum (TNF, IL-6, Troponin) 
 
Plasma (BNP) 
Dr. Owusu, Herceptin  
 
 
Dr. Owusu, Herceptin 
 
Shipping Address 
ATTN: Erin Hohler 
University Hospitals of Cleveland 
Rainbow Babies and Children’s Hospital,  room 693 
11100 Euclid Ave 
Cleveland, OH 44106 
Please include a Shipping Manifest (see template provided). 
 
Please email Erin Hohler the tracking number on day of shipment erin.hohler@case.edu. 
Please call Erin Hohler if there are any questions 216-844-5562. 
 
 
IL-6, TNFalpha, Troponin and BNP Analytical Method 
Serum levels of IL-6 and TNFalpha are determined using commercially available multi-
plex enzyme-linked immunosorbent assay (ELISA) kits (Meso-Scale Discovery, 
Gaithersburg, MD). All samples are run in duplicate with appropriate controls. Analytes 
are detected and quantitated using a MesoScale Discovery electrochemiluminesence 
instrument model Sector 2400 Imager. Troponin analyses are run on an automated 
analyzer using immunoassay technique (StreamLab system, Siemens, USA). The BNP is 
determined using a chemiluminesce automated analyzer (Centaur analyzer, Siemans, 
USA).