Clinical trial NCT00912340
Conditions: Breast Cancer
Keywords: Breast Cancer
Sponsor: Emory University
Start date: 2009-05-01; Completion date: 2017-07-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well everolimus with or without trastuzumab works in treating patients with breast cancer that has not responded to hormone therapy and has spread from where it started to other places in the body. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. Giving everolimus and adding trastuzumab at the time of disease progression may be an effective treatment for breast cancer.

Detailed description:
Breast cancer is the most common type of invasive cancer in women, with more than 1 million cases and almost 600,000 deaths occurring worldwide annually. Breast cancer that has spread to other parts of the body (metastasized) is usually not curable. Patients with a type of metastatic breast cancer that has hormone receptors on the surface of the cancer cells are usually treated with the drug tamoxifen, which interferes with the function of these hormone receptors. However, the average survival time for these patients remains at around 36 months.

In patients who no longer respond to tamoxifen (hormone-refractory breast cancer), the cancer drug trastuzumab (Herceptin), which acts on a protein called human epidermal growth factor receptor 2 (HER2), may have some activity. In addition, studies suggest that the drug everolimus, which acts on a pathway within cancer cells that is important for growth of the tumor, may make the cancer cells more sensitive to treatment with trastuzumab. Thus, the two drugs may act together to increase their anti-cancer potential.

Arms: arm 1: Patients receive trastuzumab IV over 30 minutes once every 3 weeks and continue to receive their most recent hormone therapy. Patients achieving disease progression receive everolimus PO daily in combination with trastuzumab and hormone therapy. arm 2: Patients receive everolimus PO daily and continue their most recent hormone therapy. Patients achieving disease progression receive trastuzumab IV over 30-90 minutes once every 3 weeks in combination with everolimus and hormone therapy. arm 3: Patients receive trastuzumab IV over 30 minutes once every 3 weeks and everolimus PO daily while continuing to receive their most recent hormone therapy.
Interventions: intervention 1: Everolimus intervention 2: Trastuzumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_001.pdf: 
 
 
PROTOCOL 
STUDY TITLE: 
Randomized phase II trial of trastuzumab or 
EVEROLIMUS in hormone-refractory metastatic 
breast cancer 
 


CONFIDENTIAL 
 
This is a {Institution or Cooperative Group Name} document that contains 
confidential information.  It is intended solely for the recipient clinical 
investigator(s) and must not be disclosed to any other party.  This material may 
be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from {Institution or Cooperative Group 
Name}. 
 
Protocol:  TRASTUZUMAB®—{Emory Winship Cancer Institute} 
HERCEPTIN® - Emory Winship Cancer Institute                               
                             3/7/2014 
2 
STUDY DRUG: 
HERCEPTIN® (Trastuzumab) 
EVEROLIMUS (EVEROLIMUS) 
SUPPORT PROVIDED BY: 
Genentech, Inc. 
Novartis (EVEROLIMUS only) 
INVESTIGATOR: 
Ruth O‟Regan, MD Emory Winship Cancer 
Institute, 1365 Clifton Road, Atlanta, GA 30322.        
Tel: (404)778-5994  Fax: (404)778-5530, 
roregan@emory.edu 
SUB-INVESTIGATORS: 
Amelia Zelnak, MD (Emory) 
Elisavet Paplomata, MD (Emory) 
Virginia Kaklamani, MD (Northwestern University) 
 
STATISTICIAN 
Yuan Liu, PhD 
RESEARCH COORDINATOR: 
Regina Mosley 
 
STUDY NUMBER: 
WCI1524-08/H4459S 


CONFIDENTIAL 
 
This is a {Institution or Cooperative Group Name} document that contains 
confidential information.  It is intended solely for the recipient clinical 
investigator(s) and must not be disclosed to any other party.  This material may 
be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from {Institution or Cooperative Group 
Name}. 
 
Protocol:  TRASTUZUMAB®—{Emory Winship Cancer Institute} 
HERCEPTIN® - Emory Winship Cancer Institute                               
                             3/7/2014 
3 
PROTOCOL VERSION/DATE: 
Version #1 5/14/2008 
Version #2 11/15/2008 
Version # 3 03/24/2009 
Version #4 08/24/2010 
Version #5 11/01/2010 
Version #6 01/19/2011 
Version #7 07/19/2011 
Version #8 10/12/2011 
Version #9 1/9/2012 
Version #10 8/31/2012 
Version #11 3/7/2014 
 


  Page 4 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
TABLE OF CONTENTS  
                                                                                                                         Page 
1. 
INTRODUCTION ............................................................................................ 
7 
1.1 
Disease Background.............................................................................. 
7 
1.2 
Mechanisms of hormone-resistance ...................................................... 
7 
1.3 
Rationale for use of trastuzumab in hormone-refractory disease .........       8 
1.4 
Rationale of mTOR inhibition in hormone-refractory and HER2-positive 
breast cancer..........................................................................................       8 
1.5 
Trastuzumab clinical Experience   ........................................................       9 
1.5.1      Safety  .....................................................................................       9 
1.5.2      Clinical Pharmacokinetics of Trastuzumab  ........................... 
10 
1.6 
Everolimus and mTOR inhibition .........................................................     11  
1.6.1       PI3K/AKT/mTOR pathway as a molecular target in cancer .     11 
1.6.2       Overview of EVEROLIMUS ................................................. 
12 
1.6.3       Preclinical studies of EVEROLIMUS ................................... 
12 
1.6.4       Clinical experience with EVEROLIMUS .............................. 
14 
               1.6.4.1      EVEROLIMUS pharmacokinetics ........................ 
14 
               1.6.4.2      Pharmacodynamic studies ..................................... 
15 
               1.6.4.3      Phase I and II oncology studies ............................ 
16 
1.6.5       EVEROLIMUS combination with trastuzumab .................... 
18 
1.7 
Correlative Studies ................................................................................     18 
 
2. 
OBJECTIVES ...................................................................................................     19 
2.1 
Primary Objectives................................................................................     19 
2.2 
Secondary Objectives............................................................................     19 
 
3. 
STUDY DESIGN..............................................................................................     20 
3.1 
Description of the Study .......................................................................     20  
3.2 
Rationale for Study Design ...................................................................     20 
3.3 
Outcome Measures................................................................................     20 
3.3.1       Primary Outcome Measure ....................................................     21 
3.3.2 
Secondary Outcome Measures ...............................................     21 
         3.4       Safety Plan ............................................................................................     21 
                     3.4.1      Trastuzumab ............................................................................ 
21 
                                   3.4.1.1       Cardiac Dysfunction .............................................     21 
                                   3.4.1.2       Management of Cardiac Safety ............................. 
22 
                                   3.4.1.3       Infusion-Associated Symptoms ............................     24 
                     3.4.2      Everolimus .............................................................................. 
25 
                                   3.4.2.2        Management of stomatitis/oral mucositis/ 
                                                      mouth ulcers .........................................................     25                                       
                                   3.4.2.3        Management of hyperlipidemia and hyperglycemia 26 
                                   3.4.2.4        Management of non-infectious pneumonitis ....... 
28 
3.5 
Compliance With Laws and Regulations ..............................................     29 
 
4. 
MATERIALS AND METHODS ......................................................................     29 
4.1 
Subjects .................................................................................................     29 
4.1.1 
Subject Selection 
 


  Page 5 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
TABLE OF CONTENTS (cont’d) 
 
Page 
4.1.2 
Inclusion Criteria ................................................................... 
29 
                                
 
                                                                                                  
4.1.3 
Exclusion Criteria ..................................................................     30  
4.2 
Method of Treatment Assignment ........................................................     31 
4.3 
Study Treatment ....................................................................................     31 
4.3.1      Trastuzumab Formulation .......................................................     31 
4.3.2      Dosage, Preparation, Administration, and Storage .................     32 
4.3.3      Dosage Modification ...............................................................     33 
                     4.3.4      Overdosage……………………………………………….          34 
                     4.3.5      Everolimus…………………………………………………       34 
4.4     Concomitant and Excluded Therapy .......................................................     34 
            4.4.1      Antineoplastic Therapy ...........................................................     35 
            4.4.2      Bisphosphonates ..................................................................... 
36 
            4.4.3      Hematopoietic Growth and Antibiotics .................................. 
36 
            4.4.4      Anti-emetics ............................................................................ 
36 
            4.4.5      Analgesics ............................................................................... 
36 
 
4.4.6      Systemic corticosteroids ......................................................... 
36 
 
4.4.7      P-glycoprotein (P-gp) inhibitors .............................................     36 
 
4.4.8      Cytochrome p450 enzymes ..................................................... 
36 
4.5 
Study Assessments ................................................................................     39 
4.5.1 
Assessments during Treatment ..............................................     39 
4.5.2 
Follow-Up Assessments.........................................................     39 
4.6 
Discontinuation of Protocol-Specified Therapy ...................................     39 
4.7 
Subject Discontinuation ........................................................................     40 
4.8 
Study Discontinuation ...........................................................................     40 
4.9 
Statistical Methods ................................................................................     40 
4.9.1 
Efficacy Analysis ...................................................................     40 
 
4.9.1.1      Primary Endpoint .................................................. 
40 
 
4.9.1.2      Secondary Endpoint .............................................. 
41 
 
4.9.1.3      Correlative Studies ................................................ 
41              
4.9.2 
Safety Analysis ......................................................................     43 
4.9.3 
Missing Data ..........................................................................     43 
4.10 
Data Quality Assurance ........................................................................     43 
4.11 
Data and Safety Monitoring Plan ..........................................................     43 
4.11.1     Monitoring of Subsite(s) ........................................................ 
44 
4.11.2     Data Safety and Monitoring Committee at Emory ................     44 
 
5. 
REPORTING OF ADVERSE EVENTS ..........................................................     45 
5.1 
Adverse Event and Reporting Definitions ............................................     45 
5.2 
Reporting of Serious Adverse Events Associated With the Trastuzumab 46  
5.2.1 
MedWatch 3500 Reporting Guidelines .................................     47 
 
6. 
INVESTIGATOR REQUIREMENTS .............................................................     48 


  Page 6 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
TABLE OF CONTENTS (cont'd)                                                       
 Page 
6.1 
Study Initiation......................................................................................     48 
6.2 
Study Completion .................................................................................     49 
6.3 
Informed Consent..................................................................................     49 
6.4 
Institutional Review Board or Ethics Committee Approval .................     49 
6.5 
Study Monitoring  Requirements …………………………………….     50                                        
6.6 
Study Medication Accountability .........................................................     50                                       
6.7 
Disclosure of Data.................................................................................     50 
6.8 
Retention of Records.............................................................................     50 
 
REFERENCES ..........................................................................................................     52 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.....................................................................................     54 
 
LIST OF TABLES 
Table 1-1 
Mechanisms of Hormone-Resistance ................................................ 
7 
Table 1-2 
p-S6, p-4E-BP1 and p-Akt expression at various doses of 
 
EVEROLIMUS .................................................................................. 
15 
Table 1-3 
Adverse events suspected to be drug –related in > 10% of patients 
 
with advanced cancers reported in Phase I EVEROLIMUS monotherapy 
studies (C2101, C2102, and C2107) .................................................. 
16 
Table 3-1 
Management of Cardiac Toxicity of Trastuzumab ............................ 
23 
Table 3-2 
Management of  infusion reactions associated with trastuzumab ...... 
24 
Table 3-3 
Criteria of dose-modification in case of suspected 
EVEROLIMUSeverolimus toxicity  
 
and re-initiation of EVEROLIMUS treatment ................................... 
27 
Table 3-4 
Management of non-infectious pneumonitis ..................................... 
28 
Table 4-1 
Trastuzumab Infusion Time and Post-Infusion Observation Period.. 
33 
Table 4-2 
Clinically relevant drug interaction: substrates, inducers, and inhibitors 
 
of isoenzyme CYP3A……………………………………………….    38 
 
APPENDICES  
Appendix A: Study Flowchart 
Appendix B:  Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
Appendix C: NCI Common Toxicity Criteria 
Appendix D: HFSA Guidelines for CHF Treatment 
Appendix E: FDA Medwatch 3500 Form 
 
 
 
 
 


  Page 7 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
1. 
INTRODUCTION 
1.1 
The median survival for hormone receptor-positive metastatic breast cancer has improved 
significantly over the past 15 years (1).  However, eventually all hormone receptor-positive 
metastatic breast cancers develop resistance to hormonal therapies (acquired resistance).  Most 
patients who are considered to have hormone-refractory metastatic breast cancer are treated with 
chemotherapy, which is generally minimally effective and has inherent increases in toxicity. A 
better understanding of the molecular mechanisms responsible for hormone-resistance could lead 
to the discovery of more effective, less toxic therapies. 
 
1.2   Mechanisms of hormone-resistance 
Much of our current understanding of the molecular mechanisms responsible for hormone-
resistance comes from clinical and pre-clinical models of selective estrogen receptor modulator 
(SERM)- resistance.  
 
Transfection of HER2 into estrogen receptor (ER)-positive breast cancer cells renders them 
resistant to tamoxifen (2).  Breast cancers that have high levels of HER2 expression are felt to be 
somewhat intrinsically resistant to hormonal therapies, including tamoxifen and aromatase 
inhibitors (3,4).  These findings suggest the likely possibility that HER2 plays a significant role 
in de novo hormone-resistance. 
 
There is increasing data to suggest that an increase in HER2 protein expression plays a role in 
acquired hormone-resistance.  SERM-resistant breast cancer cells in vitro and in vivo have an 
increase in the expression of members of the epidermal growth factor family, including HER2, 
compared to SERM-sensitive breast cancer cells (5).   
 
We recently analyzed primary and metastatic breast cancers in patients treated with tamoxifen 
for HER2 expression.  As can been seen in table 1-1 below there was a significant increase in the 
level of expression of HER2 protein in the metastatic tamoxifen-treated breast cancers (6).  This, 
together with the preclinical data outlined above confirms a likely role of HER2 in cancers with 
acquired hormone-resistance.  
 
Table 1-1 Mechanisms of Hormone-Resistance 
 
At diagnosis At recurrence 
p 
ER 
79% 
59% 
P=0.035 
PR 
34% 
22% 
P=0.13 
HER2/neu 
(2+,3+) 
27% 
53% 
P=0.01 
 
 


  Page 8 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 
1.3   Rationale for use of trastuzumab in hormone-refractory disease 
Although preclinical and clinical tamoxifen-resistant breast cancers exhibit an incremental 
increase in HER2 (5,6), the degree of over-expression is at most 2+ by IHC  
and is not gene amplified.  However, trastuzumab inhibits SERM-stimulated breast cancer 
growth in vivo, despite the low level of HER2 protein expression (7). The use of trastuzumab in 
this model was associated with an increase in apoptosis. 
 
Although the presence of HER2 gene amplification is an important predictor of outcome to 
trastuzumab-based chemotherapy and to single agent trastuzumab in patients with metastatic 
breast cancer, emerging data suggests this may not be the case for patients with early stage breast 
cancer.  Paik et al (8) recently correlated disease-free survival (DFS) in the NSABP B-31 trial in 
patients treated with adjuvant trastuzumab-based chemotherapy with HER2 expression and 
amplification.  The use of adjuvant trastuzumab-based chemotherapy improved DFS compared 
to chemotherapy alone by greater than 50% regardless of whether cancers were HER2 gene-
amplified or not, and regardless of the level of expression of HER2 protein. Most interestingly, 
DFS was improved by 50% with the use of trastuzumab-based chemotherapy compared to 
chemotherapy alone in patients with tumors that did not exhibit HER2 gene amplification and 
had only 1+ expression of HER2 protein.   
 
The fact that cancers with low to moderate levels of HER2 expression, such as those seen in 
hormone-resistant cancers, may respond to trastuzumab supports this proposal to examine the 
use of trastuzumab in hormone-refractory breast cancers. 
 
1.4 Rationale of mTOR inhibition in hormone-refractory and HER2-positive breast cancer 
An increase in downstream signaling has been documented in tamoxifen-resistant preclinical 
models, through constitutive activation of the Akt pathway, PTEN loss and an increase in 
upstream receptors, including members of the EGFR and IGFR families (9).  mTOR inhibition 
has been demonstrated to be more effective preclinically in cell lines with increased Akt 
signaling, PTEN loss and/or increased upstream signaling (10,11).  Additionally, mTOR 
inhibitors, such as Rapamycin and Everolimus, have been demonstrated to increase Akt activity, 
while decreasing downstream effectors of cell signaling (12, 13).  This increase in Akt activity is 
felt to be due to a feedback mechanism (12,13).  Therefore, the concept of using an mTOR 
inhibitor with an agent that blocks upstream signaling via the Akt pathway is a rational 
combination which is currently being examined in patients with trastuzumab-resistant HER2-
positive metastatic breast cancer. 
 
In summary, hormone-resistance is mutifactorial but increased expression of HER2 and 
downstream signaling appear to play an important role.  Based on these findings, together with 
the findings of Paik et al (8) demonstrating that trastuzumab is effective in cancers with low to 
moderate HER2 protein expression, we propose that the use of trastuzumab alone or in 
combination with mTOR inhibition could circumvent hormone-resistance in patients with 
metastatic breast cancer. 
 
1.5 
Trastuzumab Clinical Experience 
The clinical benefit of Trastuzumab in women with metastatic breast cancer has been 
demonstrated in two pivotal studies.  


  Page 9 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 
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 (14). 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 (15). 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 (16). 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 + 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 that in the pivotal clinical trials 
 
1.5.1 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 Trastuzumab 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 


  Page 10 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
were usually mild to moderate in severity and controlled with acetaminophen, diphenhydramine, 
or meperidine. These symptoms were uncommon with subsequent infusions. However, in the 
postapproval 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 postmarketing 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.   
 
Trastuzumab appears to be relatively nonimmunogenic. Only 1 of 903 patients evaluated 
developed neutralizing antibodies to Trastuzumab. The development of anti-Trastuzumab 
antibodies in this patient was not associated with clinical signs or symptoms.  
 
1.5.2 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 
in 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 g/mL 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) (17). 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 


  Page 11 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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-agent (18), and in combination with paclitaxel (175 mg/m2) (19), confirmed that a two-
compartment model best describes the PK of trastuzumab.  Model-independent analysis of the 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 
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-schedules (14,15,20).  In the trastuzumab q3 weekly 
monotherapy study (18), 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 paclitaxel (19), 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. 
1.6 
EVEROLIMUS AND mTOR INHIBITION 
1.6.1 PI3K / AKT / mTOR pathway as a molecular target in cancer 
mTOR (mammalian target of rapamycin) is a key protein kinase present in all cells which 
regulates cell growth, proliferation and survival. mTOR is mainly activated via the P13 
kinase pathway through AKT/PKB and the tuberous sclerosis complex (TSC1/2). 
Mutations in these components or in PTEN, a negative regulator of P13 kinase, may 
result in their dysregulation.  Abnormal functioning of various components of the 
signaling pathways contributes to the  
pathophysiology of numerous human cancers. Various preclinical models have confirmed 
the role of this pathway in tumor development. 
mTOR (mammalian target of rapamycin) is a serine-threonine kinase which is a member 
of the larger PI3K (phosphatidylinositol 3-kinase) family and present in all cells. The 
main known functions of mTOR include the following (21):  


  Page 12 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 mTOR functions as a sensor of mitogens, growth factors and energy and nutrient 
levels, facilitating cell-cycle progression from G1-S phase in appropriate growth 
conditions. 
 The PI3K (mTOR) pathway itself is frequently dysregulated in many human cancers, 
and oncogenic transformation may sensitize tumor cells to mTOR inhibitors.  
 The mTOR pathway is involved in the production of pro-angiogenic factors e.g. 
vascular endothelial growth factor (VEGF) and in endothelial cell growth and 
proliferation directly. 
 Through inactivating eukaryotic initiation factor 4E binding proteins and activating 
the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, 
including the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased 
expression of HIF-1. 
In breast cancer, overactivation of PI3K or Akt1 can be as high as 40%, whereas 
mutations or loss of heterozigozity at PTEN locus are much less frequent (22). 
Preclinical rationale is established for the combination of an mTOR inhibitor with 
trastuzumab; loss of PTEN predicts resistance to trastuzumab (23). It has been shown that 
in PTEN-deficient cells PI3K inhibition rescued trastuzumab resistance in vitro and in 
vivo (24-25). 
There is evidence that PI3K-AKT pathway activity contributes to ErbB2-associated 
tumor growth, and resistance to ErbB2 inhibition (26-27). 
1.6.2    Overview of EVEROLIMUS 
EVEROLIMUS (everolimus) is a derivative of rapamycin. EVEROLIMUS has been in 
clinical development since 1996 as an immunosuppressant in solid organ transplantation.  
It is approved in Europe since 2003 (trade name: Certican) for the prevention of organ 
rejection in patients with renal and cardiac transplantation.  Approval for Certican was 
also granted in Australia, South Africa, the Middle East, Central and South America, the 
Caribbean and some Asian countries. 
EVEROLIMUS is being investigated as an anticancer agent based on its potential to act 
 directly on the tumor cells by inhibiting tumor cell growth and proliferation 
 indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF production and VEGF-induced proliferation of 
endothelial cells)  
1.6.3    Preclinical studies of EVEROLIMUS 
EVEROLIMUS inhibits the proliferation of a range of human tumor cell lines in-vitro 
including lines originating from lung, breast, prostate, colon, melanoma and 
glioblastoma.  IC50s range from sub/low nM to µM. EVEROLIMUS also inhibits the 
proliferation of human umbilical vein endothelial cells (HUVECS) in vitro, with 
particular potency against VEGF-induced proliferation suggesting that EVEROLIMUS 
may also act as an antiangiogenic agent. The antiangiogenic activity of EVEROLIMUS 
was confirmed in vivo. EVEROLIMUS selectively inhibited VEGF-dependent 


  Page 13 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
angiogenic response at well tolerated doses. Mice with primary and metastatic tumors 
treated with EVEROLIMUS showed a significant reduction in blood vessel density when 
compared to controls. 
The potential of EVEROLIMUS as an anticancer agent was shown in rodent models. 
EVEROLIMUS is orally bioavailable, residing longer in tumor tissue than in plasma in a 
s.c mouse xenograft model, and demonstrating high tumor penetration in a rat pancreatic 
tumor model.  The pharmacokinetic profile of EVEROLIMUS indicates sufficient tumor 
penetration, above that needed to inhibit the proliferation of endothelial cells and tumor 
cell lines deemed sensitive to EVEROLIMUS in vitro. 
EVEROLIMUS administered daily p.o. was a potent inhibitor of tumor growth, at well 
tolerated doses, in 11 different mouse xenograft models (including pancreatic, colon, 
epidermoid, lung and melanoma) and two syngeneic models (rat pancreatic, mouse 
orthotopic melanoma).  These models included tumor lines considered sensitive and 
“relative resistant” in vitro.  In general, RAD was better tolerated in mouse xenograft 
models than standard cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), while 
possessing similar anti-tumor activity.  Additionally, activity in a VEGF-impregnated s.c. 
implant model of angiogenesis and reduced vascularity (vessel density) of 
EVEROLIMUS-treated tumors (murine melanoma) provided evidence of in vivo effects 
of angiogenesis. 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
EVEROLIMUS. Molecular analysis has revealed that relative sensitivity to 
EVEROLIMUS in vitro correlates with the degree of phosphorylation (activation) of the 
AKT/PKB protein kinase and the S6 ribosomal protein; in some cases (i.e., GBM) there 
is also a correlation with PTEN status.  
In vivo studies investigating the anti-tumor activity of EVEROLIMUS in experimental 
animal tumor models showed that EVEROLIMUS monotherapy typically reduced tumor 
cell growth rates rather than produced regressions or  stable disease. These effects 
occurred within the dose range of 2.5 to 10 mg/kg, p.o. once a day. 
In preclinical models, the administration of EVEROLIMUS is associated with reduction 
of protein phosphorylation in target proteins downstream of mTOR, noteably 
phosphorylated-S6 (p-S6) and p-4E-BP1, and occasionally with an increase in the 
phosphorylation AKT, a protein upstream of the mTOR signaling pathway. Study 
[CEVEROLIMUSA2107] explored MPD (molecular pharmacodynamic) changes in 
tumor at different doses and schedules of EVEROLIMUS (weekly 20, 50 and 70 mg or 
daily 5 and 10 mg). 
All significant adverse events observed in toxicology studies with EVEROLIMUS in 
mice, rats, monkeys and minipigs were consistent with its anticipated pharmacological 
action as an antiproliferative and immunosuppressant and at least in part reversible after a 
2 or 4-week recovery period with the exception of the changes in male reproductive 
organs, most notably testes. 


  Page 14 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
1.6.4    Clinical experience with EVEROLIMUS 
1.6.4.1 EVEROLIMUS pharmacokinetics 
The pharmacokinetic characteristics of EVEROLIMUS have been extensively 
investigated in the context of the drug‟s development as an immunosuppressant in solid 
organ transplantation where EVEROLIMUS was administered twice daily as a part of an 
immunosuppressant, multi-drug regimen consistently including cyclosporin A and 
glucocorticoids. Recent Phase I studies provide steady-state pharmacokinetics for both 
the weekly and daily schedules at varying dose levels in patients with advanced cancers. 
EVEROLIMUS is rapidly absorbed after oral administration, with a median time to peak 
blood levels (tmax) of 1-2 hours postdose. The extent of absorption is estimated at above 
11%.  The area under the blood concentration-time curve (AUC) is dose-proportional 
over the dose range tested while maximum blood concentration Cmax appears to plateau at 
dose levels higher than 20 mg. The terminal half-life in cancer patients averaged 30 
hours, which is similar to that in healthy subjects. Inter-patient variability is moderate 
with the coefficient of variation (CV) of approximately 50%.  A high-fat meal altered the 
absorption of EVEROLIMUS with 1.3 hour delay in tmax, a 60% reduction in Cmax and a 
16% reduction in AUC. In whole blood, approximately 80% of EVEROLIMUS is 
contained in red blood cells. Of the fraction of drug contained in plasma, 74% is protein-
bound. The apparent distribution volume (Vz/F) after a single dose was 4.7 L/kg. 
EVEROLIMUS is eliminated by metabolism, mainly by hydroxylation, then excreted 
into the feces >80%. 
EVEROLIMUS is mainly metabolized by CYP3A4 in the liver and to some extent in the 
intestinal wall. EVEROLIMUS is also a substrate of P-glycoprotein (P-gp). Therefore, 
absorption and subsequent elimination of systematically  
absorbed EVEROLIMUS may be influenced by medicinal products that interact with 
CYP3A4 and/or P-glycoprotein. In vitro studies showed that EVEROLIMUS is a 
competitive inhibitor of CYP3A4 and of CYP2D6 substrates, potentially increasing the 
concentrations of medicinal products eliminated by these enzymes. In two phase III 
clinical trials in patients following kidney transplantation, strong inhibitors of CYP3A4 
(azoles, antifungals, cyclosporine, erythromycin) have been shown to reduce the 
clearance of EVEROLIMUS therapy thereby increasing EVEROLIMUS blood levels. 
Similarly, Rifampin, a strong inducer of CYP3A4, increases the clearance of 
EVEROLIMUS thereby reducing EVEROLIMUS blood levels. Caution should be 
exercised when co-administering EVEROLIMUS with CYP3A4 inhibitors or inducers. 
Pharmacokinetic drug to drug interactions with cancer agents are being evaluated in 
ongoing phase Ib studies. Based on currently available results, gemcitabine (study 2101 
part 2) and paclitaxel (study 2104) did not alter EVEROLIMUS pharmacokinetics to a 
clinically relevant extent whereas imatinib notably increased EVEROLIMUS exposure 
with a mean increase in AUC by a multiple of 3.7 for EVEROLIMUS administered 
weekly and two-fold for EVEROLIMUS administered daily (study 2206). Exposure to 
EVEROLIMUS in the presence of letrozole did not exceed that in monotherapy (study 
2108). Co-administration of EVEROLIMUS did not influence pharmacokinetics of 


  Page 15 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
gemcitabine, imatinib or letrozole. Exposure to paclitaxel in the presence of 
EVEROLIMUS was slightly decreased (average by 23%). 
EVEROLIMUS pharmacokinetics in transplant patients was investigated in special 
populations such as subjects with hepatic or renal impairment, various ethnic groups and 
pediatric renal transplant patients. In subjects with mild–moderate hepatic impairment, 
mean AUC to EVEROLIMUS is increased by 3-fold whilst renal impairment does not 
affect the pharmacokinetics of EVEROLIMUS. Age, weight (both over the adult range) 
and gender do not affect the pharmacokinetics of EVEROLIMUS to a clinically relevant 
extent. Also, pharmacokinetics does not alter in Japanese or Asian patients whereas black 
patients have 21% higher clearance compared to non-blacks. In children, the apparent 
clearance of EVEROLIMUS increases linearly with body surface. The clearance per 
square meter of body surface area is 12-fold higher compared with adult patients. 
1.6.4.2 Pharmacodynamic studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition in a peripheral 
biomarker (S6 kinase inhibition in peripheral blood mononuclear cells) suggests that 5-10 
mg daily should be an adequate dose to produce a high-degree of sustained target 
inhibition. Furthermore, molecular pharmacodynamic (MPD) studies using IHC in 
biopsied tumor tissue assessed the degree of inhibition and its duration (for p-S6, p-4E-
BP1 and p-Akt expression) with the daily and weekly dosing. The pathologist was 
blinded for the biopsy sequence. There was almost  
complete inhibition of p-S6 at all doses and schedules studied (p=0.001). Preliminary 
results suggest a dose-related decrease in p-4E-BP1 and increase in p-Akt expression 
with maximal effect at 10 mg daily and ≥ 50 mg weekly. The study results are provided 
in Table 1-2. 
Table 1-2 
p-S6, p-4E-BP1 and p-Akt expression at various doses of EVEROLIMUS 
Dose of 
Everolimus 
 
p-S6 
inhibition 
(mean %) 
p-4E-BP1 
inhibition 
(mean %) 
p-Akt activation  (mean 
%) 
Daily 5 mg 
(n=3) 
100.0 
48.0 
22.2 
Daily 10 mg 
(n=6) 
92.5 
58.2 
45.5 
Weekly 20 
mg (n=5) 
96.7 
5.9 
32.7 
Weekly ≥ 50 
mg (n=6) 
100.0 
63.8 
63.1 
Reference:  EVEROLIMUS Investigator‟s Brochure 2005 


  Page 16 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
1.6.4.3  Phase I and II oncology studies 
Data are available from phase I clinical studies of EVEROLIMUS given as a single agent 
to 147 patients with advanced solid tumors. Such studies included various doses and 
schedules (weekly dosing, range 5-70 mg and daily dosing 5-10 mg). Approximately, 
46% of patients reported rash or erythema and 40% of the patients presented with 
stomatitis/mucositis. The most frequent adverse events suspected to be drug-related 
observed in three studies using EVEROLIMUS as a single agent are listed in Table 1-3. 
Table 1-3  Adverse events suspected to be drug-related in ≥10% of patients with advanced 
cancers reported in Phase I EVEROLIMUS monotherapy studies (C2101, C2102 and 2107)  
 
Weekly 
 
Daily 
 
Total 
n=147 
 
5-30 mg 
n=30 
50 mg 
n=18 
70 mg 
n=38 
 
5mg 
n=16 
10 mg 
n=45 
 
No. Pts with AEs 
 
 
 
 
 
 
 
 
Any event 
23 (1) 
17 (2) 
38 (10) 
 
14 (1) 
43 (14) 
 
135 (28) 
By event 
 
 
 
 
 
 
 
 
- 
Rash  
5 
8 
18 
 
10 
27 (1) 
 
68 (1) 
- 
Stomatitis/mucositis 
6 
8 (2) 
16 (2) 
 
6 (1) 
23 (3) 
 
59 (8) 
- 
Fatigue 
8 
7 (1) 
14 (1) 
 
1 
17 (1) 
 
47 (3) 
- 
Nausea 
5 
4 
8 
 
2 
18 (1) 
 
37 (1) 
- 
Anorexia 
1 
6 
10 
 
3 
15 
 
35 
- 
Diarrhea 
1 
7 
7 
 
- 
9 
 
24 
- 
Vomiting 
4 
5 
5 
 
- 
10 
 
24 
- 
Headache 
7 
4 
6 
 
6 
4 
 
20 
- 
Pruritus 
2 
1 
6 
 
3 
4 
 
16 
- 
Infections1 
1 
3 
3 (1) 
 
1 
6 (2) 
 
14 (3) 
- 
Constipation 
- 
1 
2 
 
2 
9 
 
14 
The numbers of patients (by dose level and dose schedule) who have reported grade ≥31 
toxicities is given in brackets. 
1. events included in brackets reached no more than grade 3 severity 
2 Infections noted as drug-related included: 
 
 
Herpes simplex:  
5 pts (1 at 50 mg/wk; 1 at 5mg/d; 3 at 10 mg/d) 
 
 
Oral candidiasis: 
5 pts (1 at 50 mg/wk; 3 at 70 mg/wk, 1 at 10 mg/d) 
 
 
Pneumonia (gr3)  
1 pt (10 mg/d) 
 
 
Pustular rash 
1 pt (20 mg/wk) 
 
 
Rhinitis 2 pts (50 mg/wk) 
 
 
URT Infection 1 pt (50 mg/wk 
 
 
Urinary Tract Infect 
 1 pt (50 mg/wk) 
 
Reduced blood cell counts at the initiation of treatment are frequent but remain mostly 
within the normal range or limited to grade 1 although a grade 3 neutropenia was a DLT 
in one patient as was a grade 3 thrombocytopenia in a patient receiving EVEROLIMUS 
with letrozole where pharmacodynamic interaction is unlikely. This suggest that some 
patients may be particularly sensitive to the myelosuppressive effect of EVEROLIMUS 
making it necessary to monitor carefully blood cell counts at initiation of treatment. 


  Page 17 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
Metabolic changes (hyperlipidemia and hyperglycemia) may be observed during 
treatment with EVEROLIMUS. Both events may be medically managed. Hyperlipidemia 
has been reported as an ADR in 10% of patients although review of the laboratory values 
suggests that as many as a quarter of patients develop grade 1-2 hyperlipidemia on 
treatment, mostly hypercholesterolemia. Hyperglycemia has been reported as an adverse 
event in 7% of patients. Grade 3 hyperglycemia has been observed, especially in 
diabetics receiving EVEROLIMUS treatment. Therefore, patients with diabetes should 
have their blood glucose monitored carefully and their medications adjusted, as needed, 
to maintain adequate control of their blood glucose levels.  
In Novartis-sponsored clinical trials, symptomatic non-infectious pneumonitis has been 
reported as a serious adverse event in less than 1% of patients out of approximately 1000 
cancer patients treated with EVEROLIMUS as of April 30, 2006. This adverse event has 
been noted in the Investigators‟ Brochure. Corticosteroids were often administered to the 
patients with symptomatic pneumonitis.  
Novartis has recently received reports of low grade non-infectious pneumonitis in cancer 
patients treated with EVEROLIMUS. Most of these reports involve patients with no 
respiratory symptoms (CTC grade 1 pneumonitis: radiographic findings only) or mild 
severity (CTC grade 2: symptomatic, not interfering activities of daily living), and were 
from two investigator-sponsored (private IND) trials, as follows: 
 In a study of patients with advanced renal cell carcinoma receiving 10 p.o. mg/day, 
15/20 patients reviewed by an independent radiologist were noted to have lung 
infiltrates consistent with pneumonitis on routine chest CT scans performed to follow 
the patients‟ thoracic metastases. 
 In a study of patients with advanced breast cancer, 7/18 patients treated with 
EVEROLIMUS 10 mg/d and 2/16 patients treated with EVEROLIMUS 70 mg/week, 
had findings consistent with pneumonitis. In this study, two patients, one on the daily 
RAD arm and one on the weekly EVEROLIMUS arm, developed severe (grade 3) 
pneumonitis which resolved after EVEROLIMUS was discontinued.  
In both studies, most patients had radiological changes with mild or no symptoms and 
have continued EVEROLIMUS treatment without developing symptoms. The reason for 
an increased rate of reported low-grade pneumonitis among oncology patients in these 
studies is unclear.  Both studies included serial chest CT scans allowing prolonged, 
detailed evaluation of the lung parenchyma; the dosage and drug exposure in these phase 
2 trials is generally longer than in the phase 1 experience. In addition, the dosage of 
EVEROLIMUS used in the treatment of cancer patients is substantially higher than that 
given routinely in the organ transplant setting.  Everolimus (EVEROLIMUS) is approved 
at a daily dose of 0.75 mg twice a day guided by therapeutic drug monitoring (3-8 ng/ml) 
in combination with cyclosporine microemulsion in many regions of the world for renal 
and cardiac transplantation. In phase 3 trials investigating everolimus in renal and cardiac 
transplantation, the overall reported rate of pneumonitis ranged from 0.0 to 1.4%. The 
spontaneous reporting rate for pneumonitis following exposure to commercially available 
everolimus in transplantation is very low (0.08% or 84.4 events/100,000 patient-years). 
Refer to the latest version of the EVEROLIMUS Investigator‟s Brochure and safety 
letters (Investigator Notifications) for the most up to date information available. 


  Page 18 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
1.6.5    EVEROLIMUS combination with trastuzumab 
To investigate the potential for EVEROLIMUS/trastuzumab combinations, trastuzumab-
sensitive ErbB2-overexpressing breast carcinoma cells (BT474, SKBR3), with known 
sensitivity to EVEROLIMUS (IC50 for antiproliferative activity = sub nM), were 
incubated with increasing concentrations of trastuzumab in the presence of an optimal 
EVEROLIMUS concentration and effects on proliferation were analyzed. In both lines, 
increased antiproliferative effects were observed with the combination as compared to the 
single agents. Statistical analysis indicated significant positive interactions between 
EVEROLIMUS and trastuzumab (p < 0.001 BT474; p = 0.035 SKBR3, two-way 
ANOVA). Based on this promising in vitro data, the combination was also assessed in an 
athymic mouse BT474 orthotopic mammary tumor model. Ten estrogen pellet-bearing 
animals per group were treated three times per week (MWF) with EVEROLIMUS 
(5mg/kg p.o.), trastuzumab (2 mg/kg i.p.), the combination or vehicle control. Antitumor 
activity was observed with the single agents and was increased with the combination; a 
result indicating positive interaction between the two agents that reached near 
significance (p = 0.060, two-way ANOVA). A second experiment also showed increased 
activity of the combination. Based on body weights, treatments were well tolerated. 
Taken together, these data suggest that combinations of EVEROLIMUS and trastuzumab 
may have application in the treatment of ErbB2/HER2-overexpressing breast cancer 
patients, although further dose/regimen optimization may be required. 
The ability of everolimus to re-sensitize HER2-positive breast cancers to trastuzumab has 
recently been evaluated (28).  Patients with HER2-positive cancers who had been 
previously treated with both taxanes and trastuzumab were treated with paclitaxel and 
trastuzumab in combination with everolimus (phase 1 schedule 5mg daily, 10mg daily or 
30mg weekly).  There were two DLTs, one patient with febrile neutropenia who received 
5mg daily dose of everolimus and one patient with a confusional state who received 
30mg weekly dose.  Other toxicities included stomatitis and anemia.  Out of 13 patients 
eligible for efficacy assessment, 46% had a partial response and 91% of patients had 
disease control for > 16 weeks.  This trial will proceed to a phase 2 trial in which patients 
with taxane and trastuzumab-resistant HER2-positive metastatic breast cancer will be 
treated with paclitaxel, trastuzumab and everolimus 10mg daily. This data supports the 
hypothesis that mTOR inhibition can re-sensitize HER2-positive cancers to trastuzumab. 
1.7 
Correlative Studies 
 
1.7.1 Biopsies or surgical specimens at the time of initial diagnosis wil be evaluated for the 
expression of HER2, ER, PR, EGFR, and downstream effector proteins, including Akt, PI3K, 
PTEN, MAPK, mTOR, S6, 4-EBP.  Total and phosphorylated proteins will be measured.   
 
1.7.2. Patients must have a biopsy of their cancer in the metastatic setting to assess HER2-
expression.  In general, it can be difficult to obtain biopsies in patients with metastatic breast 
cancer because of an inaccessibility of metastatic sites amenable to biopsy without increased 
morbidity.  This may be especially true in these patients with hormone receptor-positive disease, 
which may have bone as the only site of metastases. 
1.7.3 Pre-treatment biopsies will be evaluated for the expression of HER2, ER, PR, EGFR, and 
downstream effector proteins, including Akt, PI3K, PTEN, MAPK, mTOR, S6, 4-EBP.  Total 
and phosphorylated proteins will be measured.   


  Page 19 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 
1.7.4 Post-treatment biopsies will be evaluated for the expression of HER2, ER, PR, EGFR, 
and downstream effector proteins, including Akt, PI3K, PTEN, MAPK, mTOR, S6, 4-EBP.  
Total and phosphorylated proteins will be measured. 
 
1.7.5 We will compare the expression of these proteins in the primary biopsy/surgical 
specimen with the pre-treatment biopsies.  Based on our preliminary studies, we anticipate an 
increase in HER2 and EGFR, with a concomitant decrease in ER and PR in the pre-treatment 
biopsies, compared to the primary specimens. 
 
1.7.6 Response to trastuzumab and everolimus will be correlated with the expression of total 
and phosphorylated proteins (HER2, ER, PR, EGFR, and downstream effector proteins, 
including Akt, PI3K, PTEN, MAPK, mTOR, S6, 4-EBP).   
 
2. 
OBJECTIVES 
To evaluate the benefit of trastuzumab or everolimus with hormonal therapy in patients 
with hormone-refractory breast cancer. 
 
2.1 
PRIMARY OBJECTIVES 
 Assess the response rate of trastuzumab or everolimus in combination with hormonal 
therapy  in patients with hormone-refractory metastatic breast cancer 
 
2.2 
SECONDARY OBJECTIVES 
 Assess the clinical benefit rate (response rate plus stable disease for ≥ 24 weeks) of 
trastuzumab or everolimus in combination with hormonal therapy  in patients with 
hormone-refractory metastatic breast cancer 
 Assess time to progression of trastuzumab or everolimus in combination with hormonal 
therapy in patients with hormone-refractory metastatic breast cancer 
 Correlate response rate and clinical benefit in patients with hormone-refractory breast 
cancer treated with trastuzumab or everolimus with the expression of HER2 and 
downstream effector proteins in pre-treatment biopsies  
 Assess the response rate, clinical benefit rate and time to progression in patients treated 
with trastuzumab in combination with everolimus following disease progression on 
trastuzumab or everolimus in combination with hormonal therapy in patients with 
hormone-refractory metastatic breast cancer 
 Evaluate the safety of trastuzumab and/or everolimus in combination with hormonal 
therapy in patients with hormone-refractory metastatic breast cancer 
 
 
3. 
STUDY DESIGN 
 Patients will continue to take most recent hormonal therapy (tamoxifen, anastrozole, 
letrozole, exemestane, fulvestrant, etc) 
 Patients will be randomized to receive IV trastuzumab (6mg/kg three weekly (loading 
dose 8mg/kg) or everolimus 10mg daily PO 


  Page 20 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 Patients will be asked to have a biopsy performed prior to study entry (but must have had 
a biopsy in the metastatic setting demonstrating 1+ or 2+ HER2-expression by IHC) and 
when they come off study (both biopsies are optional) 
 At the time of disease progression patients randomized to receive trastuzumab will 
continue trastuzumab and start everolimus in combination with hormonal therapy; at the 
time of disease progression patients randomized to receive everolimus will continue 
everolimus and start trastuzumab in combination with hormonal therapy 
 
3.1 
Description of the Study 
This is a randomized, open-label phase II trial in patients with hormone-refractory 
metastatic breast cancer (defined as disease progression within 6 months of most recent 
hormonal therapy).  Patients will continue most recently prescribed hormonal therapy and 
will be randomized to receive trastuzumab (6mg/kg every 3 weeks) or everolimus 10 mg 
daily.  Thirty-nine patients will be recruited to each arm. Patients will be followed for 
response rate, clinical benefit, time to progression and safety. 
At the time of disease progression on either arm, patients will be offered combination 
therapy with trastuzumab and everolimus and will continue on hormonal therapy 
 
3.2 
Rationale for Study Design 
Acquired resistance to hormonal therapy is associated with an increase in the expression 
of HER2 protein. In preclinical models, trastuzumab inhibits breast cancer growth despite 
the fact that HER2 is only moderately expressed.  This is the rationale for evaluating the 
use of trastuzumab in hormone-refractory metastatic breast cancer.  The PI3-kinase 
pathway has been demonstrated to be involved in hormone-resistance and mTOR 
inhibitors are currently in phase 3 trials of patients with hormone receptor-positive 
metastatic breast cancer. In preclinical models, mTOR inhibition using everolimus is 
associated with an increase in Akt signaling, which can sensitize cancer cells to upstream 
inhibition, with trastuzumab. 
3.3 
Outcome Measures 
Response rate will be measured after 6 and then every 12 weeks using RECIST criteria 
(see appendix B), and is the primary endpoint. 
Clinical benefit (response rate plus stable disease) will be assessed after 6 weeks then 
every 3 months (12 weeks). 
Patients will be followed for time to progression. 
Patients who receive combination therapy with trastuzumab and everolimus at disease 
progression will have response rate and clinical benefit rate assessed after 6 and then 
every 3 months (12 weeks). Patients will be followed for time to progression. 
The safety of the combination of trastuzumab and/or everolimus in combination with 
hormonal therapy will be monitored continuously over the study period. 


  Page 21 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 
3.3.1 Primary Outcome Measure 
Assess the response rate of trastuzumab or  everolimus in combination with hormonal 
therapy in patients with hormone-refractory metastatic breast cancer.  Response rate will 
be measured after 8, 16, and 24 weeks of therapy and then every 3 months (12 weeks) 
using RECIST criteria. 
 
3.3.2 Secondary Outcome Measures 
3.3.2.1 Assess the clinical benefit rate of trastuzumab or  everolimus in combination with 
hormonal therapy in patients with hormone-refractory metastatic breast cancer. Clinical 
benefit will be measured after 8, 16, and 24  weeks of therapy and then every 3 months 
using RECIST criteria. 
3.3.2.2 Assess time to progression of trastuzumab or everolimus in combination with 
hormonal therapy in patients with hormone-refractory metastatic breast cancer 
3.3.2.3 Assess the response rate, clinical benefit rate and time to progression in patients 
treated with trastuzumab in combination with everolimus following disease progression 
on trastuzumab or everolimus in combination with hormonal therapy after 8, 16, and 24  
weeks of therapy and then every 3 months using RECIST criteria   
3.3.2.4 Correlate response rate and clinical benefit rate in patients with hormone-
refractory breast cancer treated with trastuzumab or everolimus with the expression of 
HER2 and downstream effector proteins in pre-treatment biopsies  
3.3.2.5 Evaluate safety of trastuzumab and/or everolimus and hormonal therapy 
 
 
3.4 
Safety Plan 
Patients will be evaluated at each study visit for the duration of their participation in the 
study (see Section 4.5 and Appendix A, Study Flowchart). 
Specific potential safety issues for this trial are outlined below. 
3.4.1 Trastuzumab  
3.4.1.1Cardiac 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 


  Page 22 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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 Trastuzumab.  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) (Seidman et al. 2001).  
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.  
3.4.1.2 Management of Cardiac Safety 
 All patients must have a baseline evaluation of cardiac function including a measurement 
of LVEF by either MUGA or ECHO prior to entry into the study.  Only patients with 
normal LVEF (≥50% or institutional normal) should be entered into this study.  All 
should have regular cardiac monitoring throughout the study. It is suggested that the first 
evaluation occur 3 months after the initiation of Trastuzumab therapy.  During the course 
of Trastuzumab therapy, patients should be monitored for signs and symptoms of CHF 
(i.e., dyspnea, tachycardia, new unexplained cough, neck vein distention, cardiomegaly, 
hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and rapid 
unexplained weight gain).  The diagnosis must be confirmed using the same method used 
to measure LVEF at baseline (either ECHO or MUGA).     
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).  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) for example after 4 weeks and then every 3 months 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 should be obtained using the methodology selected at 
baseline.  Close follow-up of such patients is recommended.  Patients with an a 


  Page 23 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
symptomatic 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).  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 3-1 Management of Cardiac Toxicity of Trastuzumab 
 
Ejection fraction 
Procedure 
Symptoms of CHF 
 
Hold trastuzumab 
Treat with CHF medications 
Consider cardiology consult 
If ejection fraction increases to 
normal range consider restarting 
trastuzumab based on breast 
cancer risk 
If ejection fraction doesn‟t 
increase to normal range, patient 
will be removed from the study 
Asymptomatic 
 
 
 
Decrease of less 20 percentage 
points but within range of normal 
limits 
Continue trastuzumab 
Repeat ejection fraction 
measurement in 4 weeks 
 
Decrease of ≥ 20 percentage 
points and/or below range of 
normal 
Hold trastuzumab 
Treat with CHF medications 
Repeat ejection fraction 
measurement in 4 weeks 
If ejection fraction increases to 
normal range consider restarting 
trastuzumab based on breast 


  Page 24 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
cancer risk 
If ejection fraction doesn‟t 
increase to normal range, patient 
will be removed from the study 
 
3.4.1.3 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.  
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. 
Table 3-2 Management of infusion reactions associated with trastuzumab 
Grade of reaction 
Procedure 
Mild to moderate 
Treat with analgesic/antipyretic and/or 
antihistamine 
Serious 
Supportive care 
Withdrawal of trastuzumab may be 
necessary 
 
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 


  Page 25 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
of 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 Trastuzumab. 
3.4.2 Everolimus 
Adverse events most frequently observed with EVEROLIMUS are rash, stomatitis/oral 
mucositis, fatigue, headache, anorexia, nausea, vomiting, diarrhea and infections.  
Overall, the most frequently observed  laboratory abnormalities include neutropenia, 
thrombocytopenia, hypercholesterolemia, and/or hypertriglyceridemia. The majority of 
these AEs have been of mild to moderate severity (CTC grade 1-2).  
3.4.2.2  Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to EVEROLIMUS should be treated using 
local supportive care. Please note that investigators in earlier trials have described the 
oral toxicities associated with EVEROLIMUS as mouth ulcers, rather than mucositis or 
stomatitis. If  examination reveals mouth ulcers rather than a more general inflammation 
of the mouth, please classify the adverse event as such. Please follow the paradigm below 
for treatment of stomatitis/oral mucositis/mouth ulcers: 
1. For 
mild 
toxicity 
(grade 
1), 
use 
conservative 
measures 
such 
as  
non-alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution. 
2. For more severe toxicity (grade 2 in which case patients have pain but are able to 
maintain adequate oral alimentation, or grade 3 in which case patients cannot 
maintain adequate oral alimentation), the suggested treatments are topical analgesic 
mouth treatments (i.e., local anesthetics such as, benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, 
such as triamcinolone oral paste 0.1% (Kenalog in Orabase®). 


  Page 26 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong inhibition of 
EVEROLIMUS metabolism, therefore leading to higher EVEROLIMUS exposures. 
Therefore, topical antifungal agents are preferred if an infection is diagnosed. 
Similarly, antiviral agents such as acyclovir should be avoided unless a viral infection 
is diagnosed. 
3.4.2.3 Management of hyperlipidemia and hyperglycemia  
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 
hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 hypertriglyceridemia 
(>2.5 x upper normal limit) should be treated with a statin or appropriate lipid-lowering 
medication, in addition to diet. Patients should be monitored clinically and through serum 
biochemistry for the development of rhabdomyolysis and other adverse events as 
required in the product label/data sheets for HMG-CoA reductase inhibitors.  Note: 
Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine kinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy 
should be determined for individual patients based on their risk of cardiovascular 
complications of hyperlipidemia.  Grade 3 hyperglycemia has been observed in patients 
receiving EVEROLIMUS therapy. In almost all cases the affected patients had an 
abnormal fasting glucose at baseline. Based on this finding, we suggest that optimal 
glucose control should be achieved before starting a patient on EVEROLIMUS and 
should be monitored during EVEROLIMUS therapy. 
 
 
 
 
 
 


  Page 27 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
Table 3-3 
Criteria for dose-modification in case of suspected EVEROLIMUS toxicity 
and re- initiation of EVEROLIMUS treatment 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
(except pneumonitis – refer to Table 3-2) 
If the toxicity is tolerable to the patient, maintain at 
10mg daily. If the toxicity is intolerable to patient, 
interrupt EVEROLIMUS until recovery to grade 1. 
Then reintroduce EVEROLIMUS at 5mg daily. 
If event returns to grade 2, then  interrupt 
EVEROLIMUS until recovery to grade 1. Then 
reintroduce EVEROLIMUS at 5mg every other day. 
Grade 3 
(except hyperlipidemia* and pneumonitis see Table 3-2) 
Interrupt EVEROLIMUS until recovery to grade 1. 
Then reintroduce EVEROLIMUS at  5mg every other 
day. For pneumonitis consider the use of a short course 
of corticosteroids. 
Grade 4 
Discontinue EVEROLIMUS. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, ≥ 50x109/L)  
Interrupt EVEROLIMUS until recovery to grade 1 
(>75 x109/L). Then reintroduce EVEROLIMUS at 5mg 
daily.  If thrombocytopenia again returns to grade 2,  
interrupt EVEROLIMUS until recovery to grade 1. 
Then reintroduce EVEROLIMUS at 5mg every other 
day 
G r a d e  3  T h r o m b o c y t o p e n i a  ( p l a t e l e t s  < 5 0 ,  ≥ 2 5  x 1 0 9 / L )  
Interrupt EVEROLIMUS until recovery to grade ≤1 
(platelets ≥ 75 x109/L).  Then resume  EVEROLIMUS 
at 5mg every other day.  If grade 3 thrombocytopenia 
recurs, discontinue EVEROLIMUS. 
Grade 4 Thrombocytopenia (platelets < 25 x109/L) 
Discontinue EVEROLIMUS. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt EVEROLIMUS until recovery to grade 1 ( 
neutrophils ≥ 1.5 x 109/L). Then resume 
EVEROLIMUS at 5mg daily.  If ANC again returns to 
Grade 3, hold EVEROLIMUS until the ANC ≥ 1.5 x 
109/L.  Then resume EVEROLIMUS dosing at  5mg 
every other day.  Discontinue patient from study 
therapy for a third episode of grade 3 neutropenia. 
Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Interrupt EVEROLIMUS until recovery to grade  1  
(neutrophils ≥ 1.5 x 109/L). Then resume 
EVEROLIMUS at 5mg every other day. If grade 3 or 
grade 4 neutropenia occurs despite this dose reduction, 
discontinue EVEROLIMUS. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt EVEROLIMUS until resolution of fever and 
neutropenia to grade ≤ 1. Hold further EVEROLIMUS 
until the ANC ≥ 1,500/mm3 and fever has resolved. 
Then resume EVEROLIMUS at  5mg every other day. 
If febrile neutropenia recurs, discontinue 
EVEROLIMUS. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue EVEROLIMUS. 
Any hematological or non-hematological toxicity requiring 
interruption for ≥ 3 weeks 
Discontinue EVEROLIMUS 


  Page 28 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
3.4.2.4 Management of non-infectious pneumonitis 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious 
pneumonitis (grade 2 = not interfering with activities of daily living or grade 3 = 
interfering with activities of daily living and oxygen indicated) have been noted in 
patients receiving EVEROLIMUS therapy.  .  Non-infectious pneumonitis has been 
associated with EVEROLIMUS and other mTOR inhibitors. In order to monitor for 
asymptomatic (grade 1) pulmonary infiltrates, a chest X-ray every 3 months is required if 
a CT scan of chest is not used for disease evaluations. Additional chest X-rays/CT scans 
may be done, when clinically necessary. If non-infectious pneumonitis develop, 
consultation with a pulmonologist should be considered. Management of non-infectious 
pneumonitis suspected to be associated with EVEROLIMUS and dose modifications 
instructions are provided in Table 3-4.   
 
Table 3-4 
Management of non-infectious pneumonitis 
 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis 
EVEROLIMUS Dose Adjustment 
Grade 1 
CT scans with lung windows. 
No specific therapy 
is required 
Administer 100% of EVEROLIMUS 
dose. 
Grade 2 
CT scan with lung windows.  
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat each 
subsequent Cycle until return 
to within normal limits. 
Consider a bronchoscopy.  
Symptomatic only. 
Rule out infection. 
Prescribe 
corticosteroids if 
cough is 
troublesome. 
Reduce EVEROLIMUS dose until 
recovery to < grade 1. 
EVEROLIMUS may also be 
interrupted if symptoms are 
troublesome. Patients will be 
withdrawn from the study if they fail 
to recover to < grade 1 within 3 
weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest.; Repeat each 
subsequent Cycle until return 
to within normal limits. 
Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Hold treatment until recovery to < 
grade 1. May restart protocol 
treatment within 3 weeks at a 
reduced dose (by one level) if 
evidence of clinical benefit.  Patients 
will be withdrawn from the study if 
they fail to recover to ≤ grade 1 
within 3 weeks. 
 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation at rest. Repeat 
each subsequent Cycle until 
return to within normal limits. 
Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Discontinue treatment. 
All interruptions or changes to study drug administration must be recorded. 


  Page 29 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
3.5 
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 
requirements. 
4. 
MATERIALS AND METHODS 
4.1 
Subjects 
4.1.1 Subject Selection 
4.1.2 Inclusion Criteria 
Patients will be included in the study based on the following criteria: 
 Hormone-refractory metastatic breast cancer defined as disease progression within 6 
months from starting most recent hormonal therapy 
 At least 2 prior endocrine therapies, including in the adjuvant setting.  Patients must 
have had at least one hormonal agent in the metastatic setting 
 Candidate for hormonal therapy (ER and/or PR-positive at primary diagnosis and at 
metastatic diagnosis where tissue is available) 
 HER2/neu-negative breast cancer by standard criteria (IHC < 3+ or FISH-negative if 
IHC 3+) at primary diagnosis  
 Must have a biopsy in the metastatic setting with HER2 expression of 1+ or 2+ by 
IHC 
 If biopsy of metastatic lesion is performed prior to study entry, HER2 expression by 
IHC must be 1+ or 2+. 
 Histologically confirmed, measurable or evaluable disease.  If disease is measurable 
RECIST criteria should be used (please refer to Appendix B). 
 Life expectancy > 6 months 
 Age >18 years 
 ECOG performance status 
2

 
 Adequate bone marrow function as indicated by the following: 
ANC >1500/L  
Platelets 100,000/L 
Hemoglobin >10 g/dL  
 Adequate renal function, as indicated by creatinine 1.5 upper limit of normal 
(ULN) 
 Adequate liver function, as indicated by bilirubin 1.5 ULN 
 INR ≤ 1.3 (or ≤ 3 on anticoagulants) 
 AST or ALT <2 ULN unless related to primary disease. 


  Page 30 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 Signed informed consent 
 Adequate birth control 
 Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides 
≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient 
can only be included after initiation of appropriate lipid lowering medication. 
4.1.3 Exclusion Criteria 
Patients will be excluded from the study based on the following criteria: 
 Prior treatment with trastuzumab or other HER2-directed therapies or with an mTOR 
inhibitor within 12 months of study entry (when cancer was not definitely hormone 
refractory) 
 HER2 0 or 3+ by IHC on pre-treatment biopsy of metastatic lesion (if performed) 
 Active infection 
 Uncontrolled central nervous system metastases 
 Life-threatening, visceral metastases 
 Pregnant or lactating women 
 Prior chemotherapy within the last 4 weeks  
 Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator 
lesion (unless objective disease recurrence or progression within the radiation portal 
has been documented since completion of radiation). 
 Concomitant malignancies or previous malignancies within the last 5 years, with the 
exception of adequately treated basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix. 
 History of significant cardiac disease, cardiac risk factors or uncontrolled arrhythmias 
 Ejection fraction <50% or below the lower limit of the institutional normal range, 
whichever is lower 
 Hypersensitivity to trial medications 
 Emotional limitations 
 Prior treatment with any investigational drug within the preceding 4 weeks. 
Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent 
 uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
 liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis 
 A known history of HIV seropositivity 


  Page 31 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of EVEROLIMUS (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel 
resection) 
 Patients with an active, bleeding diathesis 
 Female patients who are pregnant or breast feeding, or adults of reproductive 
potential who are not using effective birth control methods. If barrier contraceptives 
are being used, these must be continued throughout the trial by both sexes. Hormonal 
contraceptives are not acceptable as a sole method of contraception.  (Women of 
childbearing potential must have a negative urine or serum pregnancy test within 7 
days prior to administration of EVEROLIMUS) 
 Patients who have received prior treatment with an mTOR inhibitor (sirolimus, 
temsirolimus, everolimus). 
 Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, 
resulting in dyspnea at rest 
 Taking any of the following agents: 
 chronic treatment with systemic steroids or another immunosuppressive agent 
 live vaccines  
 drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A  
 
4.1.4 Patient Registration and Randomization 
Each site must submit the following study documentation prior to beginning patient 
enrollment on the study: 
 
 
 IRB approval letter 
 IRB approved informed consent(s) and HIPAA 
 IRB assurance number 
 Study specific FDA Form 1572 for PI 
 Current CV (within 1 year of date, signed and dated) for PI and Co-Investigators 
listed on FDA Form 1572 
 Medical Licenses for PI and Co-Investigators listed on 1572  
 Lab License, certificates, and Normal Lab Values (NLV) for labs listed on FDA 
Form 1572 
 Signed original Financial Disclosure Form for PI and Co-Investigators listed on 
FDA Form 1572  
 Signed original Signed Investigator Signature Page   
 
All original documents will be kept on file in the WCI Clinical Trials Office. 
All copies of the above should be filed in a study-specific regulatory binder at the site. 


  Page 32 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 
 
Registration and Randomization Procedure: 
 
All regulatory documents (as stated in Section 4.0) must be received and approved by 
Emory before patient registration will be permitted for each site.  When a suitable 
candidate has been identified for enrollment, the following steps should be taken: 
 
 Obtain signed informed consent and authorization for the release of personal health 
information from patient or guardian.   
 
 Complete the eligibility criteria and verify that all eligibility requirements as stated 
above have been met. 
 
 Submit the following to Emory via fax at 404-778-4389: 
 Signed informed consent 
 Authorization for the release of personal health information from parent or 
guardian. 
 Completed Eligibility Criteria Form. 
 
 Following receipt of completed Eligibility Criteria form, Emory will assign study-
specific patient ID and randomize patient to trastuzumab or everolimus.  Site will 
receive email notification of patient ID and assigned study arm via email within 48 
hours (2 business days) of submission of Eligibility Criteria form. 
 
4.2 
Method of Treatment Assignment  
Patients will be randomly assigned to receive either trastuzumab or everolimus.  
 
4.3 
Study Treatment  
Trastuzumab and everolimus will be provided free of charge by Genentech and Novartis.  
The Sponsor Investigator of the study will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance 
with 21 Code of Federal Regulations (C.F.R.), Part 312.57 and 312.62 and Genentech 
requirements. 
 
4.3.1 Trastuzumab Formulation 
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for 
intravenous (IV) administration.  Each vial of Trastuzumab contains  400 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. 
 


  Page 33 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
4.3.2 Trastuzumab Dosage, Preparation, Administration, and Storage  
a. Dosage 
The recommended initial loading dose is 8 mg/kg (for q3wk dosing schedules) 
Trastuzumab administered as a 90-minute infusion.  The recommended maintenance 
Trastuzumab dose is 6 mg/kg q3wk and can be administered as a 30-minute infusion if 
the initial loading dose was well tolerated.  Trastuzumab 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 Trastuzumab 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 Trastuzumab.  
Immediately upon reconstitution with BWFI, the vial of  
Trastuzumab 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, Trastuzumab must be 
reconstituted with Sterile Water for Injection (see PRECAUTIONS).  Trastuzumab 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 Trastuzumab needed, based on a loading dose of 8 mg 
Trastuzumab /kg body weight for q3wk dosing schedules and the recommended 
maintenance dose of 6 mg Trastuzumab/kg body weight for q3wk dosing schedules. 
Calculate the correct dose using 21 mg/mL Trastuzumab 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. 
No incompatibilities between Trastuzumab and polyvinylchloride or polyethylene bags 
have been observed. 
c. Administration 
Treatment may be administered in an outpatient setting by administration of a 4 mg/kg 
Trastuzumab loading dose for weekly dosing schedules (OR 8 mg/kg Trastuzumab 
loading dose for q3wk dosing schedules) by intravenous (IV) infusion over 90 minutes.  
DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.  If Trastuzumab is being 
administered concomitantly with chemotherapy, Trastuzumab administration should 
precede chemotherapy administration.  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 2 mg/kg Trastuzumab weekly (OR 6 mg/kg 


  Page 34 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
Trastuzumab q3wk) may be administered over 30 minutes. If  chemotherapy is 
discontinued during the treatment phase, either because of completing a planned number 
of cycles of chemotherapy, or because of chemotherapy related toxicity,  Trastuzumab 
should  be continued until \ disease progression or unacceptable toxicity related 
specifically to Trastuzumab.    
 
Table 4-1 
Trastuzumab Infusion Time and Post-Infusion Observation Period 
Trastuzumab 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. 
 
Trastuzumab should not be mixed or diluted with other drugs.  Trastuzumab 
infusions should not be administered or mixed with Dextrose solutions. 
d. Storage 
Vials of Trastuzumab 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 Trastuzumab 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 
Trastuzumab solution should be used immediately and any unused portion must be 
discarded.  DO NOT FREEZE TRASTUZUMAB THAT HAS BEEN 
RECONSTITUTED. 
The solution of Trastuzumab 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 Trastuzumab has been shown to be 
stable for up to 24 hours at room temperature 15C–25C; however, since diluted 
Trastuzumab contains no effective preservative the reconstituted and diluted solution 
should be stored refrigerated (2C–8C). 
4.3.3 Trastuzumab Dosage Modification 
Dose modification of Trastuzumab is not permitted.   


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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 
4.3.4 Trastuzumab Overdosage 
There is no experience with overdosage in human clinical trials.  Single doses higher than 
500 mg have not been tested. 
4.3.5 Everolimus 
Everolimus will be supplied by Novartis as tablets in 5mg strength. The drug will be 
packaged in blisters containing 10 tablets per blister. Blisters and packaging labels will be 
compliant with local regulations and be printed in local language. They will supply no 
information about the patient. 
Upon receipt, everolimus should be stored according to the instructions specified on the 
drug labels. Everolimus should be opened only at the time of administration as the drug is 
both hygroscopic and light-sensitive. 
These instructions should also be made clear to the patient for storage and self-
administration of everolimus at home. 
4.4 
Concomitant and Excluded Therapy 
All medications and non-drug therapies taken within 30 days prior to starting study 
treatment should be reported to the Principal Investigator. 
The investigator should instruct the patient to notify the study site about any new 
medications (including over-the-counter drugs and herbal/alternative medications) he/she 
takes after the start of study treatment. Patients must be instructed not to take any 
additional medications (including over-the-counter products and herbal/alternative 
medications) during the trial without prior consultation with the investigator. All 
medications (other than study treatments) and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the patient starts study 
treatment must be listed on the Concomitant medications/Significant non-drug therapies 
after start of study drug eCRF. 
The following restrictions apply during the entire duration of the study: 
 No other investigational therapy should be given to patients. 
 No anticancer agents other than the study medication should be given to patients. If 
such agents are required for a patient then the patient must first be withdrawn from 
the study. 
 Concurrent administration of EVEROLIMUS and strong CYP3A4 inhibitors (such as 
ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin,,rifabutin) 
should be avoided. Provided there is no alternative treatment available, patients 
should be closely monitored for potential toxicities. 
 Concurrent administration of EVEROLIMUS and moderate CYP3A4 inhibitors (such 
as erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and 
moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin) should 


  Page 36 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
also be avoided if possible, or used subject to caution (e.g. increased frequency of 
safety monitoring, temporary interruption of EVEROLIMUS). 
 Competitive inhibition could occur when EVEROLIMUS is combined with drugs 
which are also CYP3A4 substrates. Therefore caution should be exercised in such 
cases. 
 Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be 
avoided, if possible, or used subject to caution (e.g. increased frequency of safety 
monitoring, temporary interruption of EVEROLIMUS).  
 Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity 
and should therefore be avoided.  
 In addition, patients should avoid Seville oranges and star fruit, as well as the juice of 
these fruits, which are potent CYP3A4-inhibitors.  
 EVEROLIMUS may affect the response to vaccinations making the response to the 
vaccination less effective. Live vaccines should be avoided while a patient is treated 
with EVEROLIMUS. 
 Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no 
interaction with EVEROLIMUS is expected. However, drug-drug interaction studies 
between macrolide antibiotics and warfarin have produced mixed outcomes and the 
disparity in these findings has led to the conclusion that multiple factors may alter the 
clearance of warfarin. The coadministration of EVEROLIMUS and oral 
anticoagulants is possible but should be subject to verification of coagulation (INR) 
once steady state 
4.4.1 
Antineoplastic therapy 
The administration of anticancer agents other than study medication, including 
chemotherapy, investigational agents, and biologic agents is NOT permitted while 
patients are enrolled in this study. The need for other anti-cancer therapy will be 
attributed to disease progression and will require the patient to be withdrawn from study 
treatment.  
Palliative radiotherapy for local peripheral metastases not being used as target lesions is 
permitted, but the need for such therapy may be an indication of disease progression and 
should be discussed prior to administration. Radiotherapy for central metastases (e.g., 
vertebral, mediastinal) is not permitted. Patients requiring such therapy prior to 
completion of the study should be considered to have progression of disease and study 
treatment should be discontinued.  
No other investigational cancer medication/therapies should have been taken within the 
last 4 weeks prior to study entry and any cancer medication / therapies given to a patient 
within 4 weeks after the last dose of study treatment also must be recorded. 


  Page 37 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
4.4.2      Bisphosphonates 
Patients who enter the study on bisphosphonates may continue this therapy. The need to 
start bisphosphonate therapy on study will be considered as an indication of disease 
progression and the patient will be discontinued from protocol therapy.  
4.4.3     Hematopoietic growth factors and antibiotics 
Hematopoietic growth factors and antibiotics should not be administered prophylactically 
during cycle 1 for patients undergoing study treatment and should be used in future 
cycles only in patients with documented cytopenia in previous cycles in accordance with 
the guidelines established by the American Society of Clinical Oncology, available on the 
following website [http://www.asco.org/ac/1,1003,_12-002138,00.asp]. Exception is 
made for recombinant erythropoietin-like product (such as Procrit®) which may be 
received throughout the study. 
4.4.4      Anti-emetics  
Approximately 25% of patients experience nausea when treated with EVEROLIMUS 
alone and 16% experience vomiting. The majority of nausea and vomiting events is of 
Grade 1 or 2. EVEROLIMUS is best classified as having moderate emetogenic potential, 
therefore prophylactic treatment with appropriate anti-emetic agents as per local 
institutional guidelines is recommended.  
4.4.5    Analgesics 
Baseline analgesics for tumor-related pain should be maintained during the study.  
However, an increase in analgesic use or a step up on the WHO analgesic ladder for 
control of tumor-related pain may indicate disease progression. If an increase in analgesic 
medication from baseline is required during the study, the patient should be evaluated for 
progression of disease. 
4.4.6     Systemic corticosteroids 
Prolonged (greater than 2 weeks in duration) treatment with systemic corticosteroid 
treatment is not allowed during the study. Prolonged treatment with topical steroids 
should be discussed with the Principal Investigator. 
4.4.7      P-glycoprotein (P-gp) inhibitors 
Patients receiving any concomitant medications known to inhibit P-gp function (e.g., 
verapamil, diltiazem, nicardipine, cyclosporine, quinine) will not be excluded from the 
study but these medications should be avoided. 
4.4.8      Cytochrome p450 enzymes 
EVEROLIMUS is mainly metabolized by CYP3A4 in the liver and to some extent in the 
intestinal wall. Therefore the following advice should be followed: 


  Page 38 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 Wherever possible, drugs or substances known to be inhibitors or inducers of the 
isoenzyme CYP3A should be avoided as systemic therapy in association with 
EVEROLIMUS as these can alter its metabolism (see Table 4-2). 
 Patients should also refrain from herbal/alternative remedies and grapefruit juice   


  Page 39 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
Table 4-2 
Clinically relevant drug interaction: substrates, inducers and inhibitors of 
isoenzyme CYP3A 
Substrates 
Antibiotics1:  
clarithromycin* 
erythromycin  
 
telithromycin* 
 
Anti-arrhythmics: 
quinidine 
 
Benzodiazepines: 
alprazolam 
diazepam 
midazolam 
triazolam 
 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
 
HIV Protease Inhibitors: 
indinavir* 
ritonavir* 
saquinavir* 
 
Prokinetic: 
cisapride 
 
Antihistamines: 
astemizole 
Calcium Channel Blockers: 
amlodipine 
diltiazem 
felodipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
 
HMG CoA Reductase Inhibitors2:  
 
cerivastatin 
lovastatin 
 
simvastatin 
 
Miscellaneous: 
 
buspirone 
 
haloperidol  
methadone 
pimozide  
quinine 
 
sildenafil 
tamoxifen 
trazodone 
vincristine
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin 
Rifabutin* 
Rifampin* 
St John‟s wort 
Troglitazone 
Inhibitors 
Amiodarone 
Cimetidine 
Clarithromycin 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Seville orange juice or product 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
 


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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: 
properties and polymorphisms, Naunyn Schmiedebergs Arch Pharmacol. 2004 
Jan;369(1):89-104 and [http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 
13, 2006] 
* asterisk denotes strong inhibition/ induction 
Please note: 
 
Strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% 
decrease in clearance of sensitive CYP substrates 
 
Moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 
50-80% decrease in clearance  of sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary according to conditions).  
1. Macrolide antibiotics: Azithromycin is not a CYP3A substrate. It may therefore be 
employed where antibiotherapy with a macrolide is desirable in a patient being treated 
with EVEROLIMUS 
.2. Statins: Atorvastatin and pravastatin may be administered concomitantly with 
EVEROLIMUS, since a PK interaction study has shown that there is no relevant PK 
interaction 
 
4.5 
Study Assessments 
 Evaluation of subject‟s cardiac function by either MUGA or echocardiogram 
4.5.1 Assessments during Treatment 
 Monitor CBC, chemistries, etc. per institutional guidelines. 
 Repeat measurements of LVEF using the same methodology as used at baseline will 
be obtained at 3 months (Week 12) following initiation of Trastuzumab and thereafter 
as clinically indicated.  If Trastuzumab is discontinued for a decline in LVEF, a repeat 
measure of LVEF will be obtained in 1 month to assess whether the decline has 
resolved. 
4.5.2 Follow-Up Assessments 
Patients will have repeat staging performed at 6-weeks and then every 3 months with CT 
scans ± bone scans or PET scans.  Repeat staging may be performed earlier if there is 
clinical evidence to suggest disease progression. 
4.6 
Discontinuation of Protocol-Specified Therapy 
Protocol-specified therapy may be discontinued for any of the following reasons: 
 Progressive disease 


  Page 41 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 Unacceptable toxicity 
 Patient election to discontinue therapy (for any reason) 
 Physician‟s judgment 
 
4.7 
Subject Discontinuation 
Patients may discontinue taking one (or more) of the study treatments for the reason of an 
adverse event and yet continue to receive the other treatments if this is felt to be in the 
best interests of the patient.  
Each study treatment discontinuation will be captured separately in the corresponding 
Drug Administration CRF. All discontinuations from the study must be recorded in the 
Study Completion CRF.  
Patients may voluntarily withdraw from the study or be discontinued from it at the 
discretion of the investigator at any time.  The reason for premature discontinuation of a 
subject must be recorded on the CRF. 
 
4.8 
Study Discontinuation 
The Principal Investigator or the study sponsors 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 
 
4.9 
Statistical Methods 
 
4.9.1 Efficacy Analysis  
4.9.1.1 Primary Endpoint 
The primary objective of this study is to conduct phase II trials to evaluate response rate in each of the 
two arms. One stage design will be adopted for these trials conduct. For each arm, we will test the null 
hypothesis that the response rate is 1.0% versus the alternative hypothesis that the response rate is 
10.0%.   A sample size of 34 patients achieves 86% power to detect a difference of 0.09 using a one-
sided binomial test. The target significance level is 0.1. The actual significance level achieved by this 
test is 0.045. For the secondary objective of the study where patients are given the other agent after they 
progress, we expect that about 50% of the patients will progress.  Therefore, a sample size of 17 patients 


  Page 42 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
treated with the two agents achieves 52% power to detect a difference of 0.0900 using a one-sided 
binomial test the same target significance level as the primary objective. 
 
This trial will be monitored by the WCI DSMB.  Based on the probability of disease progression 
at 8 weeks being no more than 75%, if 9 or 10 patients have progressive disease at 6 weeks out 
of the first 10 enrolled patients, this arm will be closed. The probability of observing 9 or 10 
patients with disease progression at 8 weeks is 0.24 if the probability of disease progression at 6 
weeks is 0.0.75. Patients will be evaluable for response after 6, 8, 16 and then every 12 weeks.  
 
Randomization procedure 
Patients will be randomly assigned to the two arms with equal probability.  A random sequence 
of numbers will be generated so that the two arms have the same number of patients.  
 
4.9.1.2  Secondary Endpoints 
The secondary objectives of this study are to (i) Assess time to progression of trastuzumab alone 
or everolimus alone in combination with hormonal therapy in patients with hormone-refractory 
metastatic breast cancer, (ii) Correlate response rate and clinical benefit in patients with 
hormone-refractory breast cancer treated with trastuzumab alone or everolimus alone with the 
expression of HER2 and downstream effector proteins in pre-treatment biopsies, (iii) assess time 
to progression, response rate and clinical benefit rate of trastuzumab and everolimus in 
combination with endocrine therapy in patients with hormone-refractory metastatic breast cancer 
with disease progression on prior trastuzumab or everolimus, and (iv) Evaluate safety of 
combination of trastuzumab and/or everolimus with hormonal therapy and For (i), Kaplan-Meier 
curves will be used to estimate the survival curve of time to progression in each of the two arms. 
We then estimate the median time to progression by constructing a 95% confidence interval. 
For (ii), in each arm, ordinary logistic regression will be carried out to correlate response with 
HER2 expression and key biomarkers obtained from pre-treatment biopsies after adjusting for 
relevant baseline covariates such as age, etc… The dependent variable is response which is 
binary, and the independent variables of interest are HER2 expression and key biomarkers 
expressions. We will also correlate time to progression with HER2 expression and key biomarker 
levels using the Cox proportional hazards model. 
For (iii), The tolerability and safety of trastuzumab and/or everolimus will be monitored by the 
WCI DSMB. 
 
4.9.1.3 Correlative studies  
Patients are required to have a biopsy as standard of care before starting the study treatment, and 
be asked to have a biopsy when they discontinue treatment.   
Primary diagnostic biopsies and surgical specimens, pre-treatment and post-treatment biopsies 
will be evaluated for the expression of targeted proteins (see section 1.7).  We will compare the 
expression of these proteins in the primary  
biopsy/surgical specimen with the pre-treatment biopsies, and in the pre-treatment biopsies 
compared to the post-treatment biopsies.  
Biopsy specimens will be shipped to Emory University and Dr Ruth O‟Regan at: 1365 Clifton 
Road,  Atlanta, GA 30322. The tissue selected to be shipped should be invasive breast cancer. 
Tissue will be shipped as paraffin embedded tissue and fresh tissue (if available).  
 


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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
4.9.2 Safety Analysis 
Patients will be followed continuously for adverse events which will be graded according to 
ECOG grading system through the Winship Cancer Institute DSMB.  An analysis of safety will 
be performed after 10 patients have been enrolled.   The incidence of clinically significant CHF 
will monitored continuously. Symptomatic CHF is defined as the occurrence of objective 
findings on clinical examination (e.g., rales, S3, elevated jugular venous pressure) and confirmed 
by chest X-ray and either MUGA or ECHO.  Difference in risk based on prior anthracycline 
exposure as well as risk factors such as ECHO performance status and smoking status will be 
explored. 
4.9.3 Missing Data 
Any missing data will be excluded from the statistical analysis. 
4.10 
Data Quality Assurance 
Accurate, consistent, and reliable data will be ensured through the use of standard practices and 
procedures. 
4.11 
Data and Safety Monitoring Plan 
The data safety monitoring plan will be implemented by Dr. Ruth O‟Regan, the Principal 
Investigator (P.I.) of this study.  The plan is based on self-monitoring, internal CTO real time 
monitoring using the quality assurance committee, and monitoring via Winship Cancer Institute 
(“WCI”) Data Safety Monitoring Committee (DSMC) as per WCI CTO standard operating 
procedure. Dr. O‟Regan and the investigators, the clinical research coordinator and the 
regulatory affairs coordinator will meet at least on a monthly basis to review and discuss study 
data to ensure subject safety. The research coordinators will maintain one spread sheet which 
will summarize all the patient data for patients actively being treated on the trial as well as a 
roadmap detailing pending tests/treatments for each individual patient. During the weekly 
meeting the group will review the eligibility criteria for each new patient. In addition, during 
these meeting the group will review all the toxicity (AE/SAE) logs, case report form completion 
and roadmap for each patient on the trial. Documentation of the discussions during these 
meetings are completed, filed and forwarded to the Winship Cancer Institute (“WCI”) Data 
Safety Monitoring Committee (DSMC) at WCI. The WCI has two internal monitoring 
committees. The first is the quality assurance and quality monitoring committee which will 
perform a review of the first and then on a regular ongoing basis for selected patient enrolled on 
the trial to confirm that the trial is being conducted appropriately. The second monitoring process 
involves DSMC. The WCI DSMC is responsible for providing data safety-monitoring oversight 
for this protocol. Any comments that are generated by the WCI DSMC are forwarded to the 
IRB.  The P.I. and the study investigators will discuss any required modifications to this study at 
the weekly meetings. No modifications to this study are implemented until they are submitted for 
review and approved by the Emory University IRB. The comments from the WCI DSMC are 
forwarded to the IRB at the time of the annual renewal of this study or sooner if warranted and 
requested by the WCI DSMC.    
  
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
oversee the conduct of this study. This committee will review all pertinent aspects of study 
conduct including patient safety, compliance with protocol, data collection and efficacy. The 


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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
committee will review the charts of 10% of patients enrolled to the study and two of the first 5 
patients entered to the study. Reviews will occur annually for studies that are low risk or 
moderate risk. High risk studies will be reviewed every 6 months. The committee reserves the 
right to conduct additional audits if necessary at any time-point. The Principal Investigator is 
responsible for notifying the DSMC about the accrual of patients when the first 5 have been 
entered to the study. The PI will also notify the DSMC of the study status within 2 months before 
the next annual review is due. The charter for the Winship DSMC is available upon request to 
the investigator or other study-related personnel. 
             
The WCI DMSC does not tolerate protocol deviations, but does recognize that they occur 
unintentionally. Any protocol violations are reviewed and reported to the WCI DSMC, IRB, and 
all other designated regulatory agencies as required by the study protocol.    
  
All study data reviewed and discussed during these meetings with the PI and the investigators 
and the WCI DSMC is kept confidential. Any breach in confidentiality during the conduct of the 
study is reported to the PI, WCI DSMC, sponsor, and the IRB. 
 
4.11.1   Monitoring of Subsite(s) 
At the study initiation, the PI, regulatory specialist and research coordinators will perform a 
site initiation teleconference. During this teleconference, the Emory team will review the 
study, enrollment, reporting, and regulatory compliance. The subsites will have internal 
monitoring meetings. These meetings will include the investigators, the clinical research 
coordinator and the regulatory affairs coordinator will meet at least on a monthly basis to 
review and discuss study data to ensure subject safety. The research coordinators will 
maintain one spread sheet which will summarize all the patient data for patients actively 
being treated on the trial as well as a roadmap detailing pending tests/treatments for each 
individual patient. The spread sheet will be shared with Emory PI. Teleconferences will be 
conducted at least once monthly between the PI at Emory and the research team at the 
subsites. The purpose of the meetings is to discuss the enrollment, regulatory updates, 
monitor toxicities, and evaluate the progress of the trial. The minutes from the teleconference 
will be maintained in the regulatory binder for the study. In addition electronic copies will be 
sent via email to the principal investigators at each site. 
4.11.2   Data Safety and Monitoring Committee at Emory 
The Monitoring Committee consists of faculty members, a research nurse, the Clinical Trials 
Director and/or Associate Director, the Medical Director of Clinical Trials, the Director of 
the Phase I Program and The Regulatory and Compliance Manager The Monitoring 
Committee reviews all auditing, Data and Safety Monitoring Board (DSMB) composition 
and reports, and recommends corrective action if needed to the PI. The Monitoring 
Committee may initiate an external audit of any trial at any time if it determines such action 
to be necessary. The Monitoring Committee will review all internally audited trials annually. 
Egregious data insufficiency is reported to the Associate Director of Clinical Research who 
notifies the CTRC as part of the CTRC PRMS function. If deficiencies are discovered during 
the annual review, the Monitoring Committee will first inform the PI. If the deficiencies 
cannot be corrected, the Monitoring Committee will involve the PI‟s direct supervisor and 


  Page 45 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
may refer the protocol to the Associate Director of Clinical Research for corrective action 
including possible termination of the trial. The Associate Director of Clinical Research has 
the authority to terminate trials for cause. 
 
5. 
REPORTING OF ADVERSE EVENTS 
5.1 
Adverse Event and Reporting Definitions 
An adverse event (AE) is any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  An adverse event can be any 
unfavorable and unintended sign (eg, including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the drug, without any 
judgment about causality.  This includes any newly occurring event or previous condition 
that has increased in severity or frequency since the administration of drug. 
 
An adverse event is considered a serious adverse event (SAE) if it results in any of the 
following outcomes: 
1) Results in death 
2) Is a life-threatening (ie, its occurrence places the patient or subject at immediate risk 
of death) 
3) Requires inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions  
5) Is a congenital anomaly/birth defect 
6) Is an important medical event that may not result in death, be life threatening, or 
require hospitalization but may be considered serious when, based upon medical 
judgment, may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
Suspected Adverse Event 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, „reasonable possibility‟ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
Unexpected Adverse Events  
An adverse event is considered “unexpected” if it is not listed in the investigator brochure 
or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk information described 
in the general investigational plan or elsewhere in the current application. 
 
5.1.1 Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 


  Page 46 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
4.0 (Appendix D) will be utilized for AE reporting.  If specific grading is not available in 
the CTCAE for a particular AE‟s severity/intensity, the investigator is to revert to the 
general definitions of Grade 1 through 5 and use his/her best medical judgment.  The 5 
general grades are: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = 
life-threatening or disabling, Grade 5 = death related to AE. 
 
Attribution of the AE: 
Investigators are required to assess whether there is a reasonable possibility that tivozanib 
caused or contributed to the adverse event.  The following general guidance may be used. 
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment. 
 Unlikely – The AE is doubtfully related to the study treatment. 
 Unrelated – The AE is clearly NOT related to the study treatment. 
 
5.2 
Reporting of Serious Adverse Events Associated with Trastuzumab 
All SAEs that are serious and reasonably or probably related to the use of 
Trastuzumab (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: 
Dr Ruth ORegan 
Tel: 404-778-1900 
AND: 
 
Novartis Pharmaceuticals CS&E 
 FAX (888-299-4565), 
The principal investigator has the obligation to report all serious adverse events to the 
FDA, IRB, and Novartis Pharmaceuticals Clinical Safety and Epidemiology Department 
(CS&E). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form).  
 
All events must be reported, by FAX (888-299-4565), to Novartis Pharmaceuticals 
CS&E Department within 24 hours of learning of it’s occurrence. This includes 
serious, related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 


  Page 47 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
experiences. All deaths during treatment or within 30 days following completion of 
active protocol therapy must be reported within 5 working days. 
 
Any serious adverse event occurring after the patient has provided informed consent and 
until 4 weeks after the patient has stopped study participation must be reported. This 
includes the period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g. treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication). 
 
Serious adverse events occurring more than 4 weeks after study discontinuation need 
only be reported if a relationship to the Novartis study drug (or therapy) is suspected.  
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the product manufacturer by the investigator. 
 
AND   Emory IRB 
1599-001-1AV 
 
Institutional Review Board 
Emory University, 1599 Clifton Road, 
 
Atlanta, GA 30322 
 
Tel: 404-712-0720 
 
Fax: 404-727-1358 
 
Email: IRB@emory.edu 
 
Webpage:  http://emory.edu/IRB/ 
 
5.2.1 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 


  Page 48 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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) 
Occasionally Genentech or Novartis 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 or Novartis 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 
Trastuzumab or everolimus if the investigator believes: 
 There is a clinically plausible time sequence between onset of the AE and the study 
drug administration; and/or 
 There is a biologically plausible mechanism for the study drug to cause or contribute 
to the AE; and 
 The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures. 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
Study Initiation 
Before the start of this study, the following documents must be on file with Genentech or 
a Genentech representative and Novartis: 
 Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any sub-investigators must appear on this form.  Investigators must 
also complete all regulatory documentation as required by local and national 
regulations. 
 Current curriculum vitae of the Principal Investigator 


  Page 49 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 Written documentation of IRB approval of protocol and informed consent document 
 A copy of the IRB-approved informed consent document 
 A signed Clinical Research Agreement 
 
6.2 
Study Completion 
The following materials are requested by Genentech and Novartis 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. 
 
6.3 
Informed Consent 
An informed consent template will be provided, and the final IRB-approved document 
must be provided to Genentech and Novartis 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. 
 
6.4 
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. 
Dr O‟Regan 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.  Dr O‟Regan 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 


  Page 50 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
to adhere.  Investigators must immediately forward to their IRB any written safety report 
or update provided by Genentech and Novartis (e.g., IND safety report, Investigator 
Brochure, safety amendments and updates, etc.). 
 
6.5 
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, Novartis, 
the U.S. FDA, and the respective national or local health authorities to inspect facilities 
and records relevant to this study. 
6.6 
Study Medication Accountability (If Applicable) 
If study drug will be provided by Genentech, the recipient will acknowledge receipt of 
the drug by returning the INDRR-1 form indicating shipment content and condition.  
Damaged supplies will be replaced. 
Accurate records of all study drug dispensed from and returned to the study site should be 
recorded by using the institution‟s drug inventory log or the NCI drug accountability log. 
All partially used or empty containers should be disposed of at the study site according to 
institutional standard operating procedure.  Return unopened, expired, or unused study 
drug with the Inventory of Returned Clinical Material form as directed by Genentech and 
Novartis for everolimus.  
6.7 
Disclosure of Data 
Subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. 
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, 
Novartis and the IRB for each study site, if appropriate. 
 
6.8 
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 and Novartis will notify the Principal Investigator of these 
events. 


  Page 51 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with U.S. FDA IND regulations and with the record retention 
policies of the relevant national and local health authorities. 


  Page 52 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
REFERENCES 
 
1. Andre F, Slimane K, Bachelot T, et al. Breast cancer with synchronous metastases: trends 
in survival over a 14 year period.  J Clin Oncol 22:3302-8, 2004 
2. Benz CC, Scott GK, Sarup JC, et al. Estrogen-dependent, tamoxifen-resistant 
tumorigenic growth of MCF-7 cells transfected with HER2/neu.  Breast Cancer Res Treat 
24:85-95, 1992 
3. De Laurentiis M, Arpino G, Massarelli E, et al.  A meta-analysis on the interaction 
between HER2 expression and response to endocrine therapy in advanced breast cancer. 
Clin Cancer Res 11:4741-8, 2005 
4. Mackay JR, Kaufman B, Clemens M, et al.  Trastuzumab prolongs progression free 
survival in hormone-dependent and HER2-positive metastatic breast cancer. SABCS 
2006, Abstract 3 
5. Schafer JM, Bentrem DJ, Takei H, et al.  A mechanism of drug resistance to tamoxifen in 
breast cancer.  J Steroid Biochem Mol Biol 83:75-83, 2002 
6. Kaklamani VG, Cicconi J, Gradishar W, et al.  Increased HER2 expression in women 
with recurrent ER-positive breast cancer.  Proc ASCO 2007, Abstract 10516 
7. O‟Regan, RM, Osipo, C, Ariazi, E, et al. Development and Therapeutic Options for the 
Treatment of Raloxifene-stimulated Breast Cancer in Athymic Mice.  Clinical Cancer 
Research 12:2255-63, 2006 
8. Paik S, Kim C, Jeong J, et al. Benefit from adjuvant trastuzumab may not be confined to 
patients with IHC 3+ and/or FISH-positive tumors. Central testing results of NSABP B-
31. Proc ASCO 2007, Abstract 511 
9. deGraffenried LA, Friedrichs WE, Russell DH, et al.  Inhibition of mTOR Activity 
Restores Tamoxifen Response in Breast Cancer Cells with Aberrant Akt Activity.  Clin. 
Cancer Res. 10: 8059-8067, 2004 
10. Zhou X, Tan M, Hawthorne VS, et al.  Activation of the Akt/Mammalian Target of 
Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in 
Breast Cancers.  Clin. Cancer Res 10: 6779-6788, 2004 
11. Neshat MS, Mellinghoff IK, Tran C, et al.  Enhanced sensitivity of PTEN-deficient 
tumors to inhibition of FRAP/mTOR.  Proc Natl Acad Sci USA 98:10314-9, 2001 
12.  Sun SY, Rosenberg LM, Wang X, et al.  Activation of Akt and eIF4E survival pathways 
by rapamycin-mediated mammalian target of rapamycin inhibition.  Cancer Res 65:7052-
8, 2005 
13. O‟Reilly KE, Rojo F, She QB, et al.  mTOR inhibition induces upstream receptor 
tyrosine kinase signaling and activates Akt.  Cancer Res 66:1500-8, 2006 
14.  Cobleigh M, Vogel CL, Tripathy D, et al.  Multinational study of the efficacy and safety 
of humanized anti-Her2-overexpressing metastatic breast cancer that has progressed after 
chemotherapy for metastatic disease.  J Clin Oncol 1999;17:1-10. 
15. 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 2001; 344:783-792. 
16. Tripathy D, Slamon D, Leyland-Jones B, et al. Treatment beyond progression in the 
Trastuzumab pivotal combination chemotherapy trial. Breast Cancer Res Treat 2000; 
64:32. 
 
 


  Page 53 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
17. Gelmon K, Arnold A, Verma S, et al. Pharmacokinetics (PK) and safety of trastuzumab 
(Herceptin) when administered every three weeks to women with metastatic breast 
cancer. Oral presentation at the 37th Annual Meeting of the American Society of Clinical 
Oncology, May12-15 in San Francisco, California 2001.  
18.  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 1998; 58:2825-
2831 
19. Leyland-Jones B, Hemmings F, Arnold A, et al. Pharmacokinetics of Trastuzumab 
administered with paclitaxel every three weeks. Breast Cancer Res Treat 2000; 64:124. 
20. 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. 2002;20:719-26.  
21. Bjornsti M-A, Houghton PJ.  The TOR pathway: A target for cancer chemotherapy. 
Nature Reviews Cancer 2004;4:335-348. 
22. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human 
cancer. Nat Rev Cancer 2002;2:489-501. 
23. Pandolfi PP. Breast cancer - Loss of PTEN predicts resistance to treatment, 2004. 
24.  Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by 
trastuzumab,and loss of PTEN predicts trastuzumab resistance in patients .Cancer Cell 
2004;6:117-127 
25. Lu C-H, Wyszomierski SL, Tseng ML, et al. Preclinical testing of clinically applicable 
strategies for overcoming herceptin resistance caused by PTEN deficiency. Clin Cancer 
Res. 2007 13:5883-8.  
26. Hermanto U, Zong SC, Wang LH ErbB2-overexpressing human mammary carcinoma 
cells display an increased requirement for the phosphatidyliniositol 3-kinase signaling 
pathway in anchorage-independent growth. Oncogene 2001;20:7551-7562. 
27. Bacus SS, Altomare DA, Lyass L, et al. AKT2 is frequently upregulated in HER-2/neu-
positive breast cancers and may contribute to tumor aggresiveness by enhancing cell 
survival Oncogene 2002;21:3532-3540. 
28. Andre F, Campone M, Hurwitz SA, et al.  Multicenter phase 1 clinical trial of daily and 
weekly EVEROLIMUS in combination with weekly paclitaxel and trastuzumab in 
patients with HER2-overexpressing metastatic breast cancer with prior resistance to 
trastuzumab.  Proc ASCO Abstract 1003, 2008 
 
 
 
 
 


  Page 54 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
FIGURE 1 
STUDY SCHEMA 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
•Metastatic  
breast cancer 
•Disease progression  
within ≤6 months of  
starting last endocrine 
therapy1 
•≥ 2 prior endocrine  
therapies2 
•ER and/or PR-
positive3 
and HER2-negative4 
at Dx 
R
Continue 
most 
recent 
endocrine 
therapy  
Trastuzumab6 
(n = 39) 
Everolimus7 
n = 39 
BX
5
Add  
Everolimus7 
(n = 20) 
Add  
Trastuzumab6 
(n = 20) 
PD 
PD 
(1) Any endocrine therapy allowed.  
(2) Patients must have had at least one line of endocrine therapy for metastatic disease.  
(3) On primary and subsequent biopsies,  
(4) HER2 ≤ 2+ by IHC and/or FISH-negative 
(5) Biopsies optional prior to study entry and at study discontinuation (but must have a biopsy in 
the metastatic setting demonstrating HER2 1+ or 2+ by IHC 
(6) Trastuzumab IV 8 mg loading dose-> 6 mg 3 weekly 
(7) Everolimus 10 mg daily PO 


  Page 55 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
APPENDIX A 
Study Flowchart 
 
 
 
Days –14 
to –2 
Day 1  
 
 
 
Daily  
 
Every 3 
Weeks 
Every 12 
Weeks 
Study 
Termination
10 
Trastuzumab (HERCEPTIN®)   
administration 
 
X 
 
X1 
 
 
Everolimus (EVEROLIMUS) 
 
X 
X 
 
 
 
Hormonal therapy 
 
X 
X2 
X2 
 
 
Complete medical history 
X 
X 
 
X 
 
 
Complete physical exam 
X 
X 
 
X 
 
 
Clinical assessment 
X 
X 
 
X 
 
 
Weight, height 
X 
X 
 
X 
 
 
ECOG performance status 
X 
X 
 
X 
 
 
Toxicity evaluation 
X 
X 
 
X 
 
 
Vital signs 
X 
X 
 
X 
 
 
ECG (12-lead) 
X9 
 
 
 
 
 
MUGA scan/echocardiogram 
X9 
 
 
 
X3 
 
Serum pregnancy test  
X 
 
 
 
 
 
Tumor assessment 
X4,9 
 
 
 
X4 
X 
Hematology (CBC, diff., 
platelets) 
X5 
 
 
X 
 
 
Coagulation (PT/INR) 
X6 
 
 
 
 
 
Chemistry panel (including lipid 
panel) 
X7 
 
 
X7 
 
 
Biopsy 
X8 
 
 
 
 
X8 
 


  Page 56 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
(1) Trastuzumab 6mg/kg 3 weekly following loading dose 8mg/kg. 
(2) Any prior hormonal therapy is allowed (for example: tamoxifen, toremifene, anastrozole, 
 letrozole, fulvestrant, estrogen, megestrol acetate, androgens). 
(3) Assessment of ejection fraction (by MUGA, first pass or ECHO) must be done at 
 baseline, 3 months ± 2 days (Week 12) following initiation of trastuzumab and then 
every 12 weeks if clinically indicated.  Any patient with symptoms suggestive of cardiac 
failure should be worked up immediately. 
(4) Staging will be performed using CT scans: chest, abdomen and pelvis. First staging 
assessment will be done at baseline, after 6 weeks ± 2 days, then every 12 weeks ± 2 
days until progression.   
        (5)  Hematology should include hemoglobin, hematocrit, red blood cells (RBC), platelets,  
              total and differential white blood cells. 
      (6)  The coagulation profile should include a prothrombin time (PT/INR). 
      (7)  Chemistry Panel should include: potassium, magnesium (optional), calcium, chloride, 
bicarbonate,  creatinine, blood urea nitrogen, fasting glucose, albumin, total protein, AST, 
ALT, total bilirubin, alkaline phosphatase, fasting lipid profile (triglycerides, total 
cholesterol, HDL, and LDL).  These assessments should be performed at screening and 
Day 1 of each cycle.  Fasting lipid profile should only be repeated every 3 cycles. 
      (8)  Patients will be asked to have an optional biopsy at baseline and when they come off  
study.  In order to be eligible all patients must have a biopsy in the metastatic setting 
demonstrating 1+ or 2+ expression of HER2 
(9) EKG (12-lead), MUGA scan/Echocardiogram, and Tumor assessment: within 4 weeks of 
baseline 
      (10)  Νo long-term follow-up is required but patients will be followed off study.


  Page 57 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
APPENDIX B 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
 
 
The RECIST criteria should be used to assess response to treatment.  Only subjects with 
measurable disease should be entered in the study.  Measurable disease is defined as the 
presence of one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as 2.0 cm with conventional techniques (or as 1.0 cm by 
spiral CT).  Evaluable lesions should be followed for the assessment of response.  Non-
measurable lesions include bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, lymphangitic carcinomatosis, abdominal masses that are not 
confirmed by CT, and cystic lesions. 
All measurable lesions, up to a maximum of 5 lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  A sum of the longest diameter for all target lesions will be 
calculated and reported as the baseline sum longest diameter.  The baseline sum longest 
diameter will be used as the reference by which to characterize the objective tumor 
response. 
 Complete response (CR) 
Disappearance of all evidence of tumor for at least two cycles of therapy.  Tumor 
markers must be normal. 
 Partial response 
At least a 30% decrease in the sum of the longest diameter of target lesions, 
taking a reference the baseline sum longest diameter. 
 Stable disease (SD)  
Neither sufficient shrinkage to qualify for partial response nor sufficient increase 
to qualify for progressive disease, taking as reference the smallest sum longest 
diameter since the treatment started. 
 Progressive disease (PD) 
At least a 20% increase in the sum of the longest diameter of target lesions, taking 
as reference the smallest sum longest diameter recorded since the beginning of 
treatment or the appearance of one or more new lesions. 


  Page 58 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
APPENDIX B (cont’d) 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
 
 Clinical progressive disease 
Subjects, who in the opinion of the treating physician investigator have had a 
substantial decline in their performance status and have clinical evidence of 
progressive disease may be classified as having progressive disease. 


  Page 59 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
APPENDIX C 
National Cancer Institute Common Toxicity Criteria 
obtained from http://ctep.cancer.gov/forms/CTCAEv3.pdf  


 
  Page 60 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
APPENDIX D 
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 uptitrated 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 ßblockade 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. 


 
  Page 61 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
Combined endpoints, including mortality or hospitalization and mortality or 
hospitalization for heart failure, have also emerged as key outcomes. These latter 
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). 


 
  Page 62 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
    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 and 
-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 
evidence for increased benefit from higher dosages (25 mg twice per day) versus lower 


 
  Page 63 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
dosages (6.25 mg twice per day) of carvedilol, so uptitration 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 
and improve ventricular function, the risk to benefit ratio seems sufficiently low to 


 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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 


 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
was conducted. Seven patients (12%) failed to complete the open-label, run-in period, 
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. 
Clinicalreevaluation 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. 


 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
    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 


 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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. 
 


 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
    Digoxin increases left ventricular ejection fraction and alleviates symptomatic heart 
failure as evidenced by drug-related improvement in exercise capacity and reductions in 
heart-failureassociated 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 cointervention (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 < 
.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 


 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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 cointervention; 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. 
 
Recommendation 3. In patients with heart failure and atrial fibrillation 
with a rapid ventricular response, the administration of high doses of 
digoxin (greater than .25 mg) for the purpose of rate control is not 
recommended. When necessary, additional rate control should be achieved 


 
  Page 70 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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. 
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 


 
  Page 71 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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. 
 
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). 
 


 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
    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 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 


 
  Page 73 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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 
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 


 
  Page 74 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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). 
 
    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 


 
  Page 75 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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 
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). 


 
  Page 76 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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. 
 


 
  Page 77 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
HFSA Guidelines 
Appendix D 
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. 


 
  Page 78 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
HFSA Guidelines 
Appendix D 
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 


 
  Page 79 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
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 


 
  Page 80 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       3/7/2014 
 
APPENDIX E 
FDA MedWatch 3500 Form 

Prot_SAP_000.pdf: 
 
PROTOCOL 
STUDY TITLE: 
Phase II trial of EVEROLIMUS ± Trastuzumab in 
hormone-refractory metastatic breast cancer 
 
 


STUDY DRUG: 
HERCEPTIN® (Trastuzumab) 
EVEROLIMUS (EVEROLIMUS) 
SUPPORT PROVIDED BY: 
Genentech, Inc. 
Novartis (EVEROLIMUS only) 
INVESTIGATOR: 
Elisavet Paplomata, MD Emory Winship Cancer 
Institute, 1365 Clifton Road, Atlanta, GA 30322.        
Tel: (404)686-8210  Fax: (404)778-4389, 
epaplom@emory.edu 
SUB-INVESTIGATORS: 
Keerthi Gogineni, MD (Emory) 
Jane Meisel, MD (Emory) 
Cesar Augusto Santa-Maria, MD (Northwestern 
University) 
Ruth O’Regan, MD (University of Wisconsin) 
STATISTICIAN 
Yuan Liu, PhD 
RESEARCH COORDINATOR: 
Rebecca Gerkin, RN 
 
STUDY NUMBER: 
WCI1524-08/H4459S 
CONFIDENTIAL 
 
This is a {Institution or Cooperative Group Name} document that contains confidential information.  It is 
intended solely for the recipient clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical investigations; any other proposed use 
requires written consent from {Institution or Cooperative Group Name}. 
 
Protocol:  TRASTUZUMAB®—{Emory Winship Cancer Institute} 
HERCEPTIN® - Emory Winship Cancer Institute                                                            03/08/2016 
2 


PROTOCOL VERSION/DATE: 
Version #1 to #10            8/31//2012 
Version #11                              3/7/2014 
Version #12                              10/29/2014 
Version #13                              12/12/2014 
Version #14                              1/14/2015 
Version #15                              3/23/2015 
Version #16                              5/3/2015 
Version #17                              7/14/2015 
Version #18                              8/10/2015 
Version #19                              03/08/2016 
 
CONFIDENTIAL 
 
This is a {Institution or Cooperative Group Name} document that contains confidential information.  It is 
intended solely for the recipient clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical investigations; any other proposed use 
requires written consent from {Institution or Cooperative Group Name}. 
 
Protocol:  TRASTUZUMAB®—{Emory Winship Cancer Institute} 
HERCEPTIN® - Emory Winship Cancer Institute                                                            03/08/2016 
3 


TABLE OF CONTENTS  
                                                                                                                         Page 
1. 
INTRODUCTION ............................................................................................ 
7 
1.1 
Disease Background.............................................................................. 
7 
1.2 
Mechanisms of hormone-resistance ...................................................... 
7 
1.3 
Rationale for use of trastuzumab in hormone-refractory disease .........       8 
1.4 
Rationale of mTOR inhibition in hormone-refractory and HER2-positive 
breast cancer..........................................................................................       8 
1.5 
Trastuzumab clinical Experience   ........................................................       9 
1.5.1      Safety  .....................................................................................       9 
1.5.2      Clinical Pharmacokinetics of Trastuzumab  ........................... 
10 
1.6 
Everolimus and mTOR inhibition .........................................................     11  
1.6.1       PI3K/AKT/mTOR pathway as a molecular target in cancer .     11 
1.6.2       Overview of EVEROLIMUS ................................................. 
12 
1.6.3       Preclinical studies of EVEROLIMUS ................................... 
12 
1.6.4       Clinical experience with EVEROLIMUS .............................. 
14 
               1.6.4.1      EVEROLIMUS pharmacokinetics ........................ 
14 
               1.6.4.2      Pharmacodynamic studies ..................................... 
15 
               1.6.4.3      Phase I and II oncology studies ............................ 
16 
1.6.5       EVEROLIMUS combination with trastuzumab .................... 
18 
1.7 
Correlative Studies ................................................................................     18 
 
2. 
OBJECTIVES ...................................................................................................     19 
2.1 
Primary Objectives................................................................................     19 
2.2 
Secondary Objectives............................................................................     19 
 
3. 
STUDY DESIGN..............................................................................................     19 
3.1 
Description of the Study .......................................................................     20  
3.2 
Rationale for Study Design ...................................................................     20 
3.3 
Outcome Measures................................................................................     20 
3.3.1       Primary Outcome Measure ....................................................     21 
3.3.2 
Secondary Outcome Measures ...............................................     21 
         3.4       Safety Plan ............................................................................................     21 
                     3.4.1      Trastuzumab ............................................................................ 
21 
                                   3.4.1.1       Cardiac Dysfunction .............................................     21 
                                   3.4.1.2       Management of Cardiac Safety ............................. 
22 
                                   3.4.1.3       Infusion-Associated Symptoms ............................     24 
                     3.4.2      Everolimus .............................................................................. 
25 
                                   3.4.2.2        Management of stomatitis/oral mucositis/ 
                                                      mouth ulcers .........................................................     25                                       
                                   3.4.2.3        Management of hyperlipidemia and hyperglycemia 26 
                                   3.4.2.4        Management of non-infectious pneumonitis ....... 
28 
3.5 
Compliance With Laws and Regulations ..............................................     29 
 
4. 
MATERIALS AND METHODS ......................................................................     29 
4.1 
Subjects .................................................................................................     29 
4.1.1 
Subject Selection 
 
  Page 4 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


TABLE OF CONTENTS (cont’d) 
 
Page 
4.1.2 
Inclusion Criteria ................................................................... 
29 
                                
 
                                                                                                  
4.1.3 
Exclusion Criteria ..................................................................     30  
4.2 
Method of Treatment Assignment ........................................................     31 
4.3 
Study Treatment ....................................................................................     31 
4.3.1      Trastuzumab Formulation .......................................................     31 
4.3.2      Dosage, Preparation, Administration, and Storage .................     32 
4.3.3      Dosage Modification ...............................................................     33 
                     4.3.4      Overdosage……………………………………………….          34 
                     4.3.5      Everolimus…………………………………………………       34 
4.4     Concomitant and Excluded Therapy .......................................................     34 
            4.4.1      Antineoplastic Therapy ...........................................................     35 
            4.4.2      Bisphosphonates ..................................................................... 
36 
            4.4.3      Hematopoietic Growth and Antibiotics .................................. 
36 
            4.4.4      Anti-emetics ............................................................................ 
36 
            4.4.5      Analgesics ............................................................................... 
36 
 
4.4.6      Systemic corticosteroids ......................................................... 
36 
 
4.4.7      P-glycoprotein (P-gp) inhibitors .............................................     36 
 
4.4.8      Cytochrome p450 enzymes ..................................................... 
36 
4.5 
Study Assessments ................................................................................     39 
4.5.1 
Assessments during Treatment ..............................................     39 
4.5.2 
Follow-Up Assessments.........................................................     39 
4.6 
Discontinuation of Protocol-Specified Therapy ...................................     39 
4.7 
Subject Discontinuation ........................................................................     40 
4.8 
Study Discontinuation ...........................................................................     40 
4.9 
Statistical Methods ................................................................................     40 
4.9.1 
Efficacy Analysis ...................................................................     40 
 
4.9.1.1      Primary Endpoint .................................................. 
40 
 
4.9.1.2      Secondary Endpoint .............................................. 
41 
 
4.9.1.3      Correlative Studies ................................................ 
41              
4.9.2 
Safety Analysis ......................................................................     43 
4.9.3 
Missing Data ..........................................................................     43 
4.10 
Data Quality Assurance ........................................................................     43 
4.11 
Data and Safety Monitoring Plan ..........................................................     43 
4.11.1     Monitoring of Subsite(s) ........................................................ 
44 
4.11.2     Data Safety and Monitoring Committee at Emory ................     44 
 
5. 
REPORTING OF ADVERSE EVENTS ..........................................................     45 
5.1 
Adverse Event and Reporting Definitions ............................................     45 
5.2 
Reporting of Serious Adverse Events Associated With the Trastuzumab 46  
5.2.1 
MedWatch 3500 Reporting Guidelines .................................     47 
 
6. 
INVESTIGATOR REQUIREMENTS .............................................................     48 
  Page 5 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


TABLE OF CONTENTS (cont'd)                                                       
 Page 
6.1 
Study Initiation......................................................................................     48 
6.2 
Study Completion .................................................................................     49 
6.3 
Informed Consent..................................................................................     49 
6.4 
Institutional Review Board or Ethics Committee Approval .................     49 
6.5 
Study Monitoring  Requirements …………………………………….     50                                        
6.6 
Study Medication Accountability .........................................................     50                                       
6.7 
Disclosure of Data.................................................................................     50 
6.8 
Retention of Records.............................................................................     50 
 
REFERENCES ..........................................................................................................     52 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.....................................................................................     54 
 
LIST OF TABLES 
Table 1-1 
Mechanisms of Hormone-Resistance ................................................ 
7 
Table 1-2 
p-S6, p-4E-BP1 and p-Akt expression at various doses of 
 
EVEROLIMUS .................................................................................. 
15 
Table 1-3 
Adverse events suspected to be drug –related in > 10% of patients 
 
with advanced cancers reported in Phase I EVEROLIMUS monotherapy 
studies (C2101, C2102, and C2107) .................................................. 
16 
Table 3-1 
Management of Cardiac Toxicity of Trastuzumab ............................ 
23 
Table 3-2 
Management of  infusion reactions associated with trastuzumab ...... 
24 
Table 3-3 
Criteria of dose-modification in case of suspected 
EVEROLIMUSeverolimus toxicity  
 
and re-initiation of EVEROLIMUS treatment ................................... 
27 
Table 3-4 
Management of non-infectious pneumonitis ..................................... 
28 
Table 4-1 
Trastuzumab Infusion Time and Post-Infusion Observation Period.. 
33 
Table 4-2 
Clinically relevant drug interaction: substrates, inducers, and inhibitors 
 
of isoenzyme CYP3A……………………………………………….    38 
 
APPENDICES  
Appendix A: Study Flowchart 
Appendix B:  Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
Appendix C: NCI Common Toxicity Criteria 
Appendix D: HFSA Guidelines for CHF Treatment 
Appendix E: FDA Medwatch 3500 Form 
 
 
 
 
 
  Page 6 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


1. 
INTRODUCTION 
1.1 
The median survival for hormone receptor-positive metastatic breast cancer has improved 
significantly over the past 15 years (1).  However, eventually all hormone receptor-positive 
metastatic breast cancers develop resistance to hormonal therapies (acquired resistance).  Most 
patients who are considered to have hormone-refractory metastatic breast cancer are treated with 
chemotherapy, which is generally minimally effective and has inherent increases in toxicity. A 
better understanding of the molecular mechanisms responsible for hormone-resistance could lead 
to the discovery of more effective, less toxic therapies. 
 
1.2   Mechanisms of hormone-resistance 
Much of our current understanding of the molecular mechanisms responsible for hormone-
resistance comes from clinical and pre-clinical models of selective estrogen receptor modulator 
(SERM)- resistance.  
 
Transfection of HER2 into estrogen receptor (ER)-positive breast cancer cells renders them 
resistant to tamoxifen (2).  Breast cancers that have high levels of HER2 expression are felt to be 
somewhat intrinsically resistant to hormonal therapies, including tamoxifen and aromatase 
inhibitors (3,4).  These findings suggest the likely possibility that HER2 plays a significant role 
in de novo hormone-resistance. 
 
There is increasing data to suggest that an increase in HER2 protein expression plays a role in 
acquired hormone-resistance.  SERM-resistant breast cancer cells in vitro and in vivo have an 
increase in the expression of members of the epidermal growth factor family, including HER2, 
compared to SERM-sensitive breast cancer cells (5).   
 
We recently analyzed primary and metastatic breast cancers in patients treated with tamoxifen 
for HER2 expression.  As can been seen in table 1-1 below there was a significant increase in the 
level of expression of HER2 protein in the metastatic tamoxifen-treated breast cancers (6).  This, 
together with the preclinical data outlined above confirms a likely role of HER2 in cancers with 
acquired hormone-resistance.  
 
Table 1-1 Mechanisms of Hormone-Resistance 
 
At diagnosis At recurrence 
p 
ER 
79% 
59% 
P=0.035 
PR 
34% 
22% 
P=0.13 
HER2/neu 
(2+,3+) 
27% 
53% 
P=0.01 
 
 
  Page 7 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
1.3   Rationale for use of trastuzumab in hormone-refractory disease 
Although preclinical and clinical tamoxifen-resistant breast cancers exhibit an incremental 
increase in HER2 (5,6), the degree of over-expression is at most 2+ by IHC  
and is not gene amplified.  However, trastuzumab inhibits SERM-stimulated breast cancer 
growth in vivo, despite the low level of HER2 protein expression (7). The use of trastuzumab in 
this model was associated with an increase in apoptosis. 
 
Although the presence of HER2 gene amplification is an important predictor of outcome to 
trastuzumab-based chemotherapy and to single agent trastuzumab in patients with metastatic 
breast cancer, emerging data suggests this may not be the case for patients with early stage breast 
cancer.  Paik et al (8) recently correlated disease-free survival (DFS) in the NSABP B-31 trial in 
patients treated with adjuvant trastuzumab-based chemotherapy with HER2 expression and 
amplification.  The use of adjuvant trastuzumab-based chemotherapy improved DFS compared 
to chemotherapy alone by greater than 50% regardless of whether cancers were HER2 gene-
amplified or not, and regardless of the level of expression of HER2 protein. Most interestingly, 
DFS was improved by 50% with the use of trastuzumab-based chemotherapy compared to 
chemotherapy alone in patients with tumors that did not exhibit HER2 gene amplification and 
had only 1+ expression of HER2 protein.   
 
The fact that cancers with low to moderate levels of HER2 expression, such as those seen in 
hormone-resistant cancers, may respond to trastuzumab supports this proposal to examine the 
use of trastuzumab in hormone-refractory breast cancers. 
 
1.4 Rationale of mTOR inhibition in hormone-refractory and HER2-positive breast cancer 
An increase in downstream signaling has been documented in tamoxifen-resistant preclinical 
models, through constitutive activation of the Akt pathway, PTEN loss and an increase in 
upstream receptors, including members of the EGFR and IGFR families (9).  mTOR inhibition 
has been demonstrated to be more effective preclinically in cell lines with increased Akt 
signaling, PTEN loss and/or increased upstream signaling (10,11).  Additionally, mTOR 
inhibitors, such as Rapamycin and Everolimus, have been demonstrated to increase Akt activity, 
while decreasing downstream effectors of cell signaling (12, 13).  This increase in Akt activity is 
felt to be due to a feedback mechanism (12,13).  Therefore, the concept of using an mTOR 
inhibitor with an agent that blocks upstream signaling via the Akt pathway is a rational 
combination which is currently being examined in patients with trastuzumab-resistant HER2-
positive metastatic breast cancer. 
 
In summary, hormone-resistance is mutifactorial but increased expression of HER2 and 
downstream signaling appear to play an important role.  Based on these findings, together with 
the findings of Paik et al (8) demonstrating that trastuzumab is effective in cancers with low to 
moderate HER2 protein expression, we propose that the use of trastuzumab alone or in 
combination with mTOR inhibition could circumvent hormone-resistance in patients with 
metastatic breast cancer. 
 
1.5 
Trastuzumab Clinical Experience 
The clinical benefit of Trastuzumab in women with metastatic breast cancer has been 
demonstrated in two pivotal studies.  
  Page 8 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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 (14). 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 (15). 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 (16). 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 + 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 that in the pivotal clinical trials 
 
1.5.1 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 Trastuzumab 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 
  Page 9 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


were usually mild to moderate in severity and controlled with acetaminophen, diphenhydramine, 
or meperidine. These symptoms were uncommon with subsequent infusions. However, in the 
postapproval 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 postmarketing 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.   
 
Trastuzumab appears to be relatively nonimmunogenic. Only 1 of 903 patients evaluated 
developed neutralizing antibodies to Trastuzumab. The development of anti-Trastuzumab 
antibodies in this patient was not associated with clinical signs or symptoms.  
 
1.5.2 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 
in 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 g/mL 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) (17). 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 
  Page 10 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


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-agent (18), and in combination with paclitaxel (175 mg/m2) (19), confirmed that a two-
compartment model best describes the PK of trastuzumab.  Model-independent analysis of the 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 
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-schedules (14,15,20).  In the trastuzumab q3 weekly 
monotherapy study (18), 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 paclitaxel (19), 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. 
1.6 
EVEROLIMUS AND mTOR INHIBITION 
1.6.1 PI3K / AKT / mTOR pathway as a molecular target in cancer 
mTOR (mammalian target of rapamycin) is a key protein kinase present in all cells which 
regulates cell growth, proliferation and survival. mTOR is mainly activated via the P13 
kinase pathway through AKT/PKB and the tuberous sclerosis complex (TSC1/2). 
Mutations in these components or in PTEN, a negative regulator of P13 kinase, may 
result in their dysregulation.  Abnormal functioning of various components of the 
signaling pathways contributes to the  
pathophysiology of numerous human cancers. Various preclinical models have confirmed 
the role of this pathway in tumor development. 
mTOR (mammalian target of rapamycin) is a serine-threonine kinase which is a member 
of the larger PI3K (phosphatidylinositol 3-kinase) family and present in all cells. The 
main known functions of mTOR include the following (21):  
  Page 11 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


• mTOR functions as a sensor of mitogens, growth factors and energy and nutrient 
levels, facilitating cell-cycle progression from G1-S phase in appropriate growth 
conditions. 
• The PI3K (mTOR) pathway itself is frequently dysregulated in many human cancers, 
and oncogenic transformation may sensitize tumor cells to mTOR inhibitors.  
• The mTOR pathway is involved in the production of pro-angiogenic factors e.g. 
vascular endothelial growth factor (VEGF) and in endothelial cell growth and 
proliferation directly. 
• Through inactivating eukaryotic initiation factor 4E binding proteins and activating 
the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, 
including the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased 
expression of HIF-1. 
In breast cancer, overactivation of PI3K or Akt1 can be as high as 40%, whereas 
mutations or loss of heterozigozity at PTEN locus are much less frequent (22). 
Preclinical rationale is established for the combination of an mTOR inhibitor with 
trastuzumab; loss of PTEN predicts resistance to trastuzumab (23). It has been shown that 
in PTEN-deficient cells PI3K inhibition rescued trastuzumab resistance in vitro and in 
vivo (24-25). 
There is evidence that PI3K-AKT pathway activity contributes to ErbB2-associated 
tumor growth, and resistance to ErbB2 inhibition (26-27). 
1.6.2    Overview of EVEROLIMUS 
EVEROLIMUS (everolimus) is a derivative of rapamycin. EVEROLIMUS has been in 
clinical development since 1996 as an immunosuppressant in solid organ transplantation.  
It is approved in Europe since 2003 (trade name: Certican) for the prevention of organ 
rejection in patients with renal and cardiac transplantation.  Approval for Certican was 
also granted in Australia, South Africa, the Middle East, Central and South America, the 
Caribbean and some Asian countries. 
EVEROLIMUS is being investigated as an anticancer agent based on its potential to act 
• directly on the tumor cells by inhibiting tumor cell growth and proliferation 
• indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF production and VEGF-induced proliferation of 
endothelial cells)  
1.6.3    Preclinical studies of EVEROLIMUS 
EVEROLIMUS inhibits the proliferation of a range of human tumor cell lines in-vitro 
including lines originating from lung, breast, prostate, colon, melanoma and 
glioblastoma.  IC50s range from sub/low nM to µM. EVEROLIMUS also inhibits the 
proliferation of human umbilical vein endothelial cells (HUVECS) in vitro, with 
particular potency against VEGF-induced proliferation suggesting that EVEROLIMUS 
may also act as an antiangiogenic agent. The antiangiogenic activity of EVEROLIMUS 
was confirmed in vivo. EVEROLIMUS selectively inhibited VEGF-dependent 
  Page 12 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


angiogenic response at well tolerated doses. Mice with primary and metastatic tumors 
treated with EVEROLIMUS showed a significant reduction in blood vessel density when 
compared to controls. 
The potential of EVEROLIMUS as an anticancer agent was shown in rodent models. 
EVEROLIMUS is orally bioavailable, residing longer in tumor tissue than in plasma in a 
s.c mouse xenograft model, and demonstrating high tumor penetration in a rat pancreatic 
tumor model.  The pharmacokinetic profile of EVEROLIMUS indicates sufficient tumor 
penetration, above that needed to inhibit the proliferation of endothelial cells and tumor 
cell lines deemed sensitive to EVEROLIMUS in vitro. 
EVEROLIMUS administered daily p.o. was a potent inhibitor of tumor growth, at well 
tolerated doses, in 11 different mouse xenograft models (including pancreatic, colon, 
epidermoid, lung and melanoma) and two syngeneic models (rat pancreatic, mouse 
orthotopic melanoma).  These models included tumor lines considered sensitive and 
“relative resistant” in vitro.  In general, RAD was better tolerated in mouse xenograft 
models than standard cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), while 
possessing similar anti-tumor activity.  Additionally, activity in a VEGF-impregnated s.c. 
implant model of angiogenesis and reduced vascularity (vessel density) of 
EVEROLIMUS-treated tumors (murine melanoma) provided evidence of in vivo effects 
of angiogenesis. 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
EVEROLIMUS. Molecular analysis has revealed that relative sensitivity to 
EVEROLIMUS in vitro correlates with the degree of phosphorylation (activation) of the 
AKT/PKB protein kinase and the S6 ribosomal protein; in some cases (i.e., GBM) there 
is also a correlation with PTEN status.  
In vivo studies investigating the anti-tumor activity of EVEROLIMUS in experimental 
animal tumor models showed that EVEROLIMUS monotherapy typically reduced tumor 
cell growth rates rather than produced regressions or  stable disease. These effects 
occurred within the dose range of 2.5 to 10 mg/kg, p.o. once a day. 
In preclinical models, the administration of EVEROLIMUS is associated with reduction 
of protein phosphorylation in target proteins downstream of mTOR, noteably 
phosphorylated-S6 (p-S6) and p-4E-BP1, and occasionally with an increase in the 
phosphorylation AKT, a protein upstream of the mTOR signaling pathway. Study 
[CEVEROLIMUSA2107] explored MPD (molecular pharmacodynamic) changes in 
tumor at different doses and schedules of EVEROLIMUS (weekly 20, 50 and 70 mg or 
daily 5 and 10 mg). 
All significant adverse events observed in toxicology studies with EVEROLIMUS in 
mice, rats, monkeys and minipigs were consistent with its anticipated pharmacological 
action as an antiproliferative and immunosuppressant and at least in part reversible after a 
2 or 4-week recovery period with the exception of the changes in male reproductive 
organs, most notably testes. 
  Page 13 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


1.6.4    Clinical experience with EVEROLIMUS 
1.6.4.1 EVEROLIMUS pharmacokinetics 
The pharmacokinetic characteristics of EVEROLIMUS have been extensively 
investigated in the context of the drug’s development as an immunosuppressant in solid 
organ transplantation where EVEROLIMUS was administered twice daily as a part of an 
immunosuppressant, multi-drug regimen consistently including cyclosporin A and 
glucocorticoids. Recent Phase I studies provide steady-state pharmacokinetics for both 
the weekly and daily schedules at varying dose levels in patients with advanced cancers. 
EVEROLIMUS is rapidly absorbed after oral administration, with a median time to peak 
blood levels (tmax) of 1-2 hours postdose. The extent of absorption is estimated at above 
11%.  The area under the blood concentration-time curve (AUC) is dose-proportional 
over the dose range tested while maximum blood concentration Cmax appears to plateau at 
dose levels higher than 20 mg. The terminal half-life in cancer patients averaged 30 
hours, which is similar to that in healthy subjects. Inter-patient variability is moderate 
with the coefficient of variation (CV) of approximately 50%.  A high-fat meal altered the 
absorption of EVEROLIMUS with 1.3 hour delay in tmax, a 60% reduction in Cmax and a 
16% reduction in AUC. In whole blood, approximately 80% of EVEROLIMUS is 
contained in red blood cells. Of the fraction of drug contained in plasma, 74% is protein-
bound. The apparent distribution volume (Vz/F) after a single dose was 4.7 L/kg. 
EVEROLIMUS is eliminated by metabolism, mainly by hydroxylation, then excreted 
into the feces >80%. 
EVEROLIMUS is mainly metabolized by CYP3A4 in the liver and to some extent in the 
intestinal wall. EVEROLIMUS is also a substrate of P-glycoprotein (P-gp). Therefore, 
absorption and subsequent elimination of systematically  
absorbed EVEROLIMUS may be influenced by medicinal products that interact with 
CYP3A4 and/or P-glycoprotein. In vitro studies showed that EVEROLIMUS is a 
competitive inhibitor of CYP3A4 and of CYP2D6 substrates, potentially increasing the 
concentrations of medicinal products eliminated by these enzymes. In two phase III 
clinical trials in patients following kidney transplantation, strong inhibitors of CYP3A4 
(azoles, antifungals, cyclosporine, erythromycin) have been shown to reduce the 
clearance of EVEROLIMUS therapy thereby increasing EVEROLIMUS blood levels. 
Similarly, Rifampin, a strong inducer of CYP3A4, increases the clearance of 
EVEROLIMUS thereby reducing EVEROLIMUS blood levels. Caution should be 
exercised when co-administering EVEROLIMUS with CYP3A4 inhibitors or inducers. 
Pharmacokinetic drug to drug interactions with cancer agents are being evaluated in 
ongoing phase Ib studies. Based on currently available results, gemcitabine (study 2101 
part 2) and paclitaxel (study 2104) did not alter EVEROLIMUS pharmacokinetics to a 
clinically relevant extent whereas imatinib notably increased EVEROLIMUS exposure 
with a mean increase in AUC by a multiple of 3.7 for EVEROLIMUS administered 
weekly and two-fold for EVEROLIMUS administered daily (study 2206). Exposure to 
EVEROLIMUS in the presence of letrozole did not exceed that in monotherapy (study 
2108). Co-administration of EVEROLIMUS did not influence pharmacokinetics of 
  Page 14 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


gemcitabine, imatinib or letrozole. Exposure to paclitaxel in the presence of 
EVEROLIMUS was slightly decreased (average by 23%). 
EVEROLIMUS pharmacokinetics in transplant patients was investigated in special 
populations such as subjects with hepatic or renal impairment, various ethnic groups and 
pediatric renal transplant patients. In subjects with mild–moderate hepatic impairment, 
mean AUC to EVEROLIMUS is increased by 3-fold whilst renal impairment does not 
affect the pharmacokinetics of EVEROLIMUS. Age, weight (both over the adult range) 
and gender do not affect the pharmacokinetics of EVEROLIMUS to a clinically relevant 
extent. Also, pharmacokinetics does not alter in Japanese or Asian patients whereas black 
patients have 21% higher clearance compared to non-blacks. In children, the apparent 
clearance of EVEROLIMUS increases linearly with body surface. The clearance per 
square meter of body surface area is 12-fold higher compared with adult patients. 
1.6.4.2 Pharmacodynamic studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition in a peripheral 
biomarker (S6 kinase inhibition in peripheral blood mononuclear cells) suggests that 5-10 
mg daily should be an adequate dose to produce a high-degree of sustained target 
inhibition. Furthermore, molecular pharmacodynamic (MPD) studies using IHC in 
biopsied tumor tissue assessed the degree of inhibition and its duration (for p-S6, p-4E-
BP1 and p-Akt expression) with the daily and weekly dosing. The pathologist was 
blinded for the biopsy sequence. There was almost  
complete inhibition of p-S6 at all doses and schedules studied (p=0.001). Preliminary 
results suggest a dose-related decrease in p-4E-BP1 and increase in p-Akt expression 
with maximal effect at 10 mg daily and ≥ 50 mg weekly. The study results are provided 
in Table 1-2. 
Table 1-2 
p-S6, p-4E-BP1 and p-Akt expression at various doses of EVEROLIMUS 
Dose of 
Everolimus 
 
p-S6 
inhibition 
(mean %) 
p-4E-BP1 
inhibition 
(mean %) 
p-Akt activation  (mean 
%) 
Daily 5 mg 
(n=3) 
100.0 
48.0 
22.2 
Daily 10 mg 
(n=6) 
92.5 
58.2 
45.5 
Weekly 20 
mg (n=5) 
96.7 
5.9 
32.7 
Weekly ≥ 50 
mg (n=6) 
100.0 
63.8 
63.1 
Reference:  EVEROLIMUS Investigator’s Brochure 2005 
  Page 15 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


1.6.4.3  Phase I and II oncology studies 
Data are available from phase I clinical studies of EVEROLIMUS given as a single agent 
to 147 patients with advanced solid tumors. Such studies included various doses and 
schedules (weekly dosing, range 5-70 mg and daily dosing 5-10 mg). Approximately, 
46% of patients reported rash or erythema and 40% of the patients presented with 
stomatitis/mucositis. The most frequent adverse events suspected to be drug-related 
observed in three studies using EVEROLIMUS as a single agent are listed in Table 1-3. 
Table 1-3  Adverse events suspected to be drug-related in ≥10% of patients with advanced 
cancers reported in Phase I EVEROLIMUS monotherapy studies (C2101, C2102 and 2107)  
 
Weekly 
 
Daily 
 
Total 
n=147 
 
5-30 mg 
n=30 
50 mg 
n=18 
70 mg 
n=38 
 
5mg 
n=16 
10 mg 
n=45 
 
No. Pts with AEs 
 
 
 
 
 
 
 
 
Any event 
23 (1) 
17 (2) 
38 (10) 
 
14 (1) 
43 (14) 
 
135 (28) 
By event 
 
 
 
 
 
 
 
 
- 
Rash  
5 
8 
18 
 
10 
27 (1) 
 
68 (1) 
- 
Stomatitis/mucositis 
6 
8 (2) 
16 (2) 
 
6 (1) 
23 (3) 
 
59 (8) 
- 
Fatigue 
8 
7 (1) 
14 (1) 
 
1 
17 (1) 
 
47 (3) 
- 
Nausea 
5 
4 
8 
 
2 
18 (1) 
 
37 (1) 
- 
Anorexia 
1 
6 
10 
 
3 
15 
 
35 
- 
Diarrhea 
1 
7 
7 
 
- 
9 
 
24 
- 
Vomiting 
4 
5 
5 
 
- 
10 
 
24 
- 
Headache 
7 
4 
6 
 
6 
4 
 
20 
- 
Pruritus 
2 
1 
6 
 
3 
4 
 
16 
- 
Infections1 
1 
3 
3 (1) 
 
1 
6 (2) 
 
14 (3) 
- 
Constipation 
- 
1 
2 
 
2 
9 
 
14 
The numbers of patients (by dose level and dose schedule) who have reported grade ≥31 
toxicities is given in brackets. 
1. events included in brackets reached no more than grade 3 severity 
2 Infections noted as drug-related included: 
 
 
Herpes simplex:  
5 pts (1 at 50 mg/wk; 1 at 5mg/d; 3 at 10 mg/d) 
 
 
Oral candidiasis: 
5 pts (1 at 50 mg/wk; 3 at 70 mg/wk, 1 at 10 mg/d) 
 
 
Pneumonia (gr3)  
1 pt (10 mg/d) 
 
 
Pustular rash 
1 pt (20 mg/wk) 
 
 
Rhinitis 2 pts (50 mg/wk) 
 
 
URT Infection 1 pt (50 mg/wk 
 
 
Urinary Tract Infect 
 1 pt (50 mg/wk) 
 
Reduced blood cell counts at the initiation of treatment are frequent but remain mostly 
within the normal range or limited to grade 1 although a grade 3 neutropenia was a DLT 
in one patient as was a grade 3 thrombocytopenia in a patient receiving EVEROLIMUS 
with letrozole where pharmacodynamic interaction is unlikely. This suggest that some 
patients may be particularly sensitive to the myelosuppressive effect of EVEROLIMUS 
making it necessary to monitor carefully blood cell counts at initiation of treatment. 
  Page 16 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


Metabolic changes (hyperlipidemia and hyperglycemia) may be observed during 
treatment with EVEROLIMUS. Both events may be medically managed. Hyperlipidemia 
has been reported as an ADR in 10% of patients although review of the laboratory values 
suggests that as many as a quarter of patients develop grade 1-2 hyperlipidemia on 
treatment, mostly hypercholesterolemia. Hyperglycemia has been reported as an adverse 
event in 7% of patients. Grade 3 hyperglycemia has been observed, especially in 
diabetics receiving EVEROLIMUS treatment. Therefore, patients with diabetes should 
have their blood glucose monitored carefully and their medications adjusted, as needed, 
to maintain adequate control of their blood glucose levels.  
In Novartis-sponsored clinical trials, symptomatic non-infectious pneumonitis has been 
reported as a serious adverse event in less than 1% of patients out of approximately 1000 
cancer patients treated with EVEROLIMUS as of April 30, 2006. This adverse event has 
been noted in the Investigators’ Brochure. Corticosteroids were often administered to the 
patients with symptomatic pneumonitis.  
Novartis has recently received reports of low grade non-infectious pneumonitis in cancer 
patients treated with EVEROLIMUS. Most of these reports involve patients with no 
respiratory symptoms (CTC grade 1 pneumonitis: radiographic findings only) or mild 
severity (CTC grade 2: symptomatic, not interfering activities of daily living), and were 
from two investigator-sponsored (private IND) trials, as follows: 
• In a study of patients with advanced renal cell carcinoma receiving 10 p.o. mg/day, 
15/20 patients reviewed by an independent radiologist were noted to have lung 
infiltrates consistent with pneumonitis on routine chest CT scans performed to follow 
the patients’ thoracic metastases. 
• In a study of patients with advanced breast cancer, 7/18 patients treated with 
EVEROLIMUS 10 mg/d and 2/16 patients treated with EVEROLIMUS 70 mg/week, 
had findings consistent with pneumonitis. In this study, two patients, one on the daily 
RAD arm and one on the weekly EVEROLIMUS arm, developed severe (grade 3) 
pneumonitis which resolved after EVEROLIMUS was discontinued.  
In both studies, most patients had radiological changes with mild or no symptoms and 
have continued EVEROLIMUS treatment without developing symptoms. The reason for 
an increased rate of reported low-grade pneumonitis among oncology patients in these 
studies is unclear.  Both studies included serial chest CT scans allowing prolonged, 
detailed evaluation of the lung parenchyma; the dosage and drug exposure in these phase 
2 trials is generally longer than in the phase 1 experience. In addition, the dosage of 
EVEROLIMUS used in the treatment of cancer patients is substantially higher than that 
given routinely in the organ transplant setting.  Everolimus (EVEROLIMUS) is approved 
at a daily dose of 0.75 mg twice a day guided by therapeutic drug monitoring (3-8 ng/ml) 
in combination with cyclosporine microemulsion in many regions of the world for renal 
and cardiac transplantation. In phase 3 trials investigating everolimus in renal and cardiac 
transplantation, the overall reported rate of pneumonitis ranged from 0.0 to 1.4%. The 
spontaneous reporting rate for pneumonitis following exposure to commercially available 
everolimus in transplantation is very low (0.08% or 84.4 events/100,000 patient-years). 
Refer to the latest version of the EVEROLIMUS Investigator’s Brochure and safety 
letters (Investigator Notifications) for the most up to date information available. 
  Page 17 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


1.6.5    EVEROLIMUS combination with trastuzumab 
To investigate the potential for EVEROLIMUS/trastuzumab combinations, trastuzumab-
sensitive ErbB2-overexpressing breast carcinoma cells (BT474, SKBR3), with known 
sensitivity to EVEROLIMUS (IC50 for antiproliferative activity = sub nM), were 
incubated with increasing concentrations of trastuzumab in the presence of an optimal 
EVEROLIMUS concentration and effects on proliferation were analyzed. In both lines, 
increased antiproliferative effects were observed with the combination as compared to the 
single agents. Statistical analysis indicated significant positive interactions between 
EVEROLIMUS and trastuzumab (p < 0.001 BT474; p = 0.035 SKBR3, two-way 
ANOVA). Based on this promising in vitro data, the combination was also assessed in an 
athymic mouse BT474 orthotopic mammary tumor model. Ten estrogen pellet-bearing 
animals per group were treated three times per week (MWF) with EVEROLIMUS 
(5mg/kg p.o.), trastuzumab (2 mg/kg i.p.), the combination or vehicle control. Antitumor 
activity was observed with the single agents and was increased with the combination; a 
result indicating positive interaction between the two agents that reached near 
significance (p = 0.060, two-way ANOVA). A second experiment also showed increased 
activity of the combination. Based on body weights, treatments were well tolerated. 
Taken together, these data suggest that combinations of EVEROLIMUS and trastuzumab 
may have application in the treatment of ErbB2/HER2-overexpressing breast cancer 
patients, although further dose/regimen optimization may be required. 
The ability of everolimus to re-sensitize HER2-positive breast cancers to trastuzumab has 
recently been evaluated (28).  Patients with HER2-positive cancers who had been 
previously treated with both taxanes and trastuzumab were treated with paclitaxel and 
trastuzumab in combination with everolimus (phase 1 schedule 5mg daily, 10mg daily or 
30mg weekly).  There were two DLTs, one patient with febrile neutropenia who received 
5mg daily dose of everolimus and one patient with a confusional state who received 
30mg weekly dose.  Other toxicities included stomatitis and anemia.  Out of 13 patients 
eligible for efficacy assessment, 46% had a partial response and 91% of patients had 
disease control for > 16 weeks.  This trial will proceed to a phase 2 trial in which patients 
with taxane and trastuzumab-resistant HER2-positive metastatic breast cancer will be 
treated with paclitaxel, trastuzumab and everolimus 10mg daily. This data supports the 
hypothesis that mTOR inhibition can re-sensitize HER2-positive cancers to trastuzumab. 
1.7 
Correlative Studies 
 
1.7.1 Biopsies or surgical specimens at the time of initial diagnosis wil be evaluated for the 
expression of HER2, ER, PR, EGFR, and downstream effector proteins, including Akt, PI3K, 
PTEN, MAPK, mTOR, S6, 4-EBP.  Total and phosphorylated proteins will be measured.   
 
1.7.2. Patients must have a biopsy of their cancer in the metastatic setting to assess HER2-
expression.  In general, it can be difficult to obtain biopsies in patients with metastatic breast 
cancer because of an inaccessibility of metastatic sites amenable to biopsy without increased 
morbidity.  This may be especially true in these patients with hormone receptor-positive disease, 
which may have bone as the only site of metastases. 
1.7.3 Pre-treatment biopsies will be evaluated for the expression of HER2, ER, PR, EGFR, and 
downstream effector proteins, including Akt, PI3K, PTEN, MAPK, mTOR, S6, 4-EBP.  Total 
and phosphorylated proteins will be measured.   
  Page 18 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
1.7.4 Post-treatment biopsies will be evaluated for the expression of HER2, ER, PR, EGFR, 
and downstream effector proteins, including Akt, PI3K, PTEN, MAPK, mTOR, S6, 4-EBP.  
Total and phosphorylated proteins will be measured. 
 
1.7.5 We will compare the expression of these proteins in the primary biopsy/surgical 
specimen with the pre-treatment biopsies.  Based on our preliminary studies, we anticipate an 
increase in HER2 and EGFR, with a concomitant decrease in ER and PR in the pre-treatment 
biopsies, compared to the primary specimens. 
 
1.7.6 Response to trastuzumab and everolimus will be correlated with the expression of total 
and phosphorylated proteins (HER2, ER, PR, EGFR, and downstream effector proteins, 
including Akt, PI3K, PTEN, MAPK, mTOR, S6, 4-EBP).   
 
2. 
OBJECTIVES 
To evaluate the benefit of everolimus with hormonal therapy in patients with hormone-
refractory breast cancer. 
 
2.1 
PRIMARY OBJECTIVES 
• Assess the response rate everolimus in combination with hormonal therapy  in patients 
with hormone-refractory metastatic breast cancer 
 
2.2 
SECONDARY OBJECTIVES 
• Assess the clinical benefit rate (response rate plus stable disease for ≥ 24 weeks) of 
everolimus in combination with hormonal therapy  in patients with hormone-refractory 
metastatic breast cancer 
• Assess time to progression of everolimus in combination with hormonal therapy in 
patients with hormone-refractory metastatic breast cancer 
• Correlate response rate and clinical benefit in patients with hormone-refractory breast 
cancer treated with everolimus with the expression of HER2 and downstream effector 
proteins in pre-treatment biopsies  
• Assess the response rate, clinical benefit rate and time to progression in patients treated 
with trastuzumab in combination with everolimus following disease progression on 
everolimus in combination with hormonal therapy in patients with hormone-refractory 
metastatic breast cancer 
• Evaluate the safety of everolimus alone or with trastuzumab in combination with 
hormonal therapy in patients with hormone-refractory metastatic breast cancer 
 
 
3. 
STUDY DESIGN 
• Patients will continue to take most recent hormonal therapy (tamoxifen, anastrozole, 
letrozole, exemestane, fulvestrant, etc) 
• Patients receive everolimus 10mg daily PO 
  Page 19 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


• Patients will be asked to have a biopsy performed prior to study entry (but must have had 
a biopsy in the metastatic setting demonstrating 1+ or 2+ HER2-expression by IHC) and 
when they come off study (both biopsies are optional) 
• At the time of disease progression patients will continue everolimus and start trastuzumab 
(6mg /kg three weekly with 8mg/kg loading dose) in combination with hormonal therapy 
 
3.1 
Description of the Study 
This is an open-label phase II trial in patients with hormone-refractory metastatic breast 
cancer (defined as disease progression within 6 months of most recent hormonal therapy).  
Patients will continue most recently prescribed hormonal therapy and receive everolimus 
10 mg daily.  Thirty-four patients will be recruited*. Patients will be followed for 
response rate, clinical benefit, time to progression and safety. 
At the time of disease progression patients will be offered combination therapy with 
trastuzumab and will continue on hormonal therapy. 
*Prior to protocol version 12, the study had 2 arms:  Patients were randomized to receive 
trastuzumab (6mg/kg every 3 weeks) or everolimus 10 mg daily.  Thirty-nine patients 
were the target enrollment goal for each arm for a total of 78 subjects.  Protocol version 
12 modified the study to a single-arm study.  The discontinued tratuzumab arm had 
already enrolled subjects prior to this modification.  The on-going  enrollment target for 
the evrolimus arm was subsequently adjusted to 34.   
 
3.2 
Rationale for Study Design 
Acquired resistance to hormonal therapy is associated with an increase in the expression 
of HER2 protein. In preclinical models, trastuzumab inhibits breast cancer growth despite 
the fact that HER2 is only moderately expressed.  This is the rationale for evaluating the 
use of trastuzumab in hormone-refractory metastatic breast cancer.  The PI3-kinase 
pathway has been demonstrated to be involved in hormone-resistance and mTOR 
inhibitors are currently in phase 3 trials of patients with hormone receptor-positive 
metastatic breast cancer. In preclinical models, mTOR inhibition using everolimus is 
associated with an increase in Akt signaling, which can sensitize cancer cells to upstream 
inhibition, with trastuzumab. 
3.3 
Outcome Measures 
Response rate will be measured after 6 and then every 12 weeks using RECIST criteria 
(see appendix B), and is the primary endpoint. 
Clinical benefit (response rate plus stable disease) will be assessed after 6 weeks then 
every 3 months (12 weeks). 
Patients will be followed for time to progression. 
  Page 20 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


Patients who receive combination therapy with trastuzumab and everolimus at disease 
progression will have response rate and clinical benefit rate assessed after 6 and then 
every 3 months (12 weeks). Patients will be followed for time to progression. 
The safety of the combination of trastuzumab and/or everolimus in combination with 
hormonal therapy will be monitored continuously over the study period. 
 
3.3.1 Primary Outcome Measure 
Assess the response rate everolimus in combination with hormonal therapy in patients 
with hormone-refractory metastatic breast cancer.  Response rate will be measured after 6 
and then every 12 weeks of therapy and then every 3 months (12 weeks) using RECIST 
criteria. 
 
3.3.2 Secondary Outcome Measures 
3.3.2.1 Assess the clinical benefit rate of everolimus in combination with hormonal 
therapy in patients with hormone-refractory metastatic breast cancer. Clinical benefit will 
be measured after 6 and then every 12 weeks of therapy and then every 3 months using 
RECIST criteria. 
3.3.2.2 Assess time to progression of everolimus in combination with hormonal therapy 
in patients with hormone-refractory metastatic breast cancer 
3.3.2.3 Assess the response rate, clinical benefit rate and time to progression in patients 
treated everolimus in combination with hormonal therapy with the addition of 
trastuzumab at disease progression after 6 and then every 12 weeks of therapy and then 
every 3 months using RECIST criteria   
3.3.2.4 Correlate response rate and clinical benefit rate in patients with hormone-
refractory breast cancer treated with everolimus with the expression of HER2 and 
downstream effector proteins in pre-treatment biopsies  
3.3.2.5 Evaluate safety of everolimus alone or with trastuzumab and hormonal therapy 
 
 
3.4 
Safety Plan 
Patients will be evaluated at each study visit for the duration of their participation in the 
study (see Section 4.5 and Appendix A, Study Flowchart). 
Specific potential safety issues for this trial are outlined below. 
3.4.1 Trastuzumab  
3.4.1.1Cardiac 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 
  Page 21 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


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 Trastuzumab.  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) (Seidman et al. 2001).  
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.  
3.4.1.2 Management of Cardiac Safety 
 All patients must have a baseline evaluation of cardiac function including a measurement 
of LVEF by either MUGA or ECHO prior to entry into the study.  Only patients with 
normal LVEF (≥50% or institutional normal) should be entered into this study.  All 
should have regular cardiac monitoring throughout the study. It is suggested that the first 
evaluation occur 3 months after the initiation of Trastuzumab therapy.  During the course 
of Trastuzumab therapy, patients should be monitored for signs and symptoms of CHF 
(i.e., dyspnea, tachycardia, new unexplained cough, neck vein distention, cardiomegaly, 
hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and rapid 
unexplained weight gain).  The diagnosis must be confirmed using the same method used 
to measure LVEF at baseline (either ECHO or MUGA).     
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, β-
blockers, diuretics, and cardiac glycosides, as needed).  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) for example after 4 weeks and then every 3 months is strongly 
recommended until cardiac function has normalized.   
  Page 22 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


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 should be obtained using the methodology selected at 
baseline.  Close follow-up of such patients is recommended.  Patients with an a 
symptomatic 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, β-blockers, diuretics, and cardiac glycosides, as needed).  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 3-1 Management of Cardiac Toxicity of Trastuzumab 
 
Ejection fraction 
Procedure 
Symptoms of CHF 
 
Hold trastuzumab 
Treat with CHF medications 
Consider cardiology consult 
If ejection fraction increases to 
normal range consider restarting 
trastuzumab based on breast 
cancer risk 
If ejection fraction doesn’t 
increase to normal range, patient 
will be removed from the study 
Asymptomatic 
 
 
 
Decrease of less 20 percentage 
points but within range of normal 
limits 
Continue trastuzumab 
Repeat ejection fraction 
measurement in 4 weeks 
 
Decrease of ≥ 20 percentage 
points and/or below range of 
Hold trastuzumab 
  Page 23 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


normal 
Treat with CHF medications 
Repeat ejection fraction 
measurement in 4 weeks 
If ejection fraction increases to 
normal range consider restarting 
trastuzumab based on breast 
cancer risk 
If ejection fraction doesn’t 
increase to normal range, patient 
will be removed from the study 
 
3.4.1.3 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.  
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. 
Table 3-2 Management of infusion reactions associated with trastuzumab 
Grade of reaction 
Procedure 
Mild to moderate 
Treat with analgesic/antipyretic and/or 
antihistamine 
Serious 
Supportive care 
Withdrawal of trastuzumab may be 
necessary 
 
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-
  Page 24 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


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 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 Trastuzumab. 
3.4.2 Everolimus 
Adverse events most frequently observed with EVEROLIMUS are rash, stomatitis/oral 
mucositis, fatigue, headache, anorexia, nausea, vomiting, diarrhea and infections.  
Overall, the most frequently observed  laboratory abnormalities include neutropenia, 
thrombocytopenia, hypercholesterolemia, and/or hypertriglyceridemia. The majority of 
these AEs have been of mild to moderate severity (CTC grade 1-2).  
3.4.2.2  Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to EVEROLIMUS should be treated using 
local supportive care. Please note that investigators in earlier trials have described the 
oral toxicities associated with EVEROLIMUS as mouth ulcers, rather than mucositis or 
stomatitis. If  examination reveals mouth ulcers rather than a more general inflammation 
of the mouth, please classify the adverse event as such. Please follow the paradigm below 
for treatment of stomatitis/oral mucositis/mouth ulcers: 
1. For 
mild 
toxicity 
(grade 
1), 
use 
conservative 
measures 
such 
as  
non-alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution. 
  Page 25 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


2. For more severe toxicity (grade 2 in which case patients have pain but are able to 
maintain adequate oral alimentation, or grade 3 in which case patients cannot 
maintain adequate oral alimentation), the suggested treatments are topical analgesic 
mouth treatments (i.e., local anesthetics such as, benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, 
such as triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong inhibition of 
EVEROLIMUS metabolism, therefore leading to higher EVEROLIMUS exposures. 
Therefore, topical antifungal agents are preferred if an infection is diagnosed. 
Similarly, antiviral agents such as acyclovir should be avoided unless a viral infection 
is diagnosed. 
3.4.2.3 Management of hyperlipidemia and hyperglycemia  
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 
hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 hypertriglyceridemia 
(>2.5 x upper normal limit) should be treated with a statin or appropriate lipid-lowering 
medication, in addition to diet. Patients should be monitored clinically and through serum 
biochemistry for the development of rhabdomyolysis and other adverse events as 
required in the product label/data sheets for HMG-CoA reductase inhibitors.  Note: 
Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine kinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy 
should be determined for individual patients based on their risk of cardiovascular 
complications of hyperlipidemia.  Grade 3 hyperglycemia has been observed in patients 
receiving EVEROLIMUS therapy. In almost all cases the affected patients had an 
abnormal fasting glucose at baseline. Based on this finding, we suggest that optimal 
glucose control should be achieved before starting a patient on EVEROLIMUS and 
should be monitored during EVEROLIMUS therapy. 
 
 
 
 
 
 
  Page 26 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


Table 3-3 
Criteria for dose-modification in case of suspected EVEROLIMUS toxicity 
and re- initiation of EVEROLIMUS treatment 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
(except pneumonitis – refer to Table 3-2) 
If the toxicity is tolerable to the patient, maintain at 
10mg daily. If the toxicity is intolerable to patient, 
interrupt EVEROLIMUS until recovery to grade ≤1. 
Then reintroduce EVEROLIMUS at 5mg daily. 
If event returns to grade 2, then  interrupt 
EVEROLIMUS until recovery to grade ≤1. Then 
reintroduce EVEROLIMUS at 5mg every other day. 
Grade 3 
(except hyperlipidemia* and pneumonitis see Table 3-2) 
Interrupt EVEROLIMUS until recovery to grade ≤1. 
Then reintroduce EVEROLIMUS at  5mg every other 
day. For pneumonitis consider the use of a short course 
of corticosteroids. 
Grade 4 
Discontinue EVEROLIMUS. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, ≥ 50x109/L)  
Interrupt EVEROLIMUS until recovery to grade ≤1 
(>75 x109/L). Then reintroduce EVEROLIMUS at 5mg 
daily.  If thrombocytopenia again returns to grade 2,  
interrupt EVEROLIMUS until recovery to grade ≤1. 
Then reintroduce EVEROLIMUS at 5mg every other 
day 
Gr a de  3 Thr om boc ytope nia  ( pla te le ts < 50,  ≥ 25 x10 9 /L )  
Interrupt EVEROLIMUS until recovery to grade ≤1 
(platelets ≥ 75 x109/L).  Then resume  EVEROLIMUS 
at 5mg every other day.  If grade 3 thrombocytopenia 
recurs, discontinue EVEROLIMUS. 
Grade 4 Thrombocytopenia (platelets < 25 x109/L) 
Discontinue EVEROLIMUS. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt EVEROLIMUS until recovery to grade ≤1 ( 
neutrophils ≥ 1.5 x 109/L). Then resume 
EVEROLIMUS at 5mg daily.  If ANC again returns to 
Grade 3, hold EVEROLIMUS until the ANC ≥ 1.5 x 
109/L.  Then resume EVEROLIMUS dosing at  5mg 
every other day.  Discontinue patient from study 
therapy for a third episode of grade 3 neutropenia. 
Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Interrupt EVEROLIMUS until recovery to grade ≤ 1  
(neutrophils ≥ 1.5 x 109/L). Then resume 
EVEROLIMUS at 5mg every other day. If grade 3 or 
grade 4 neutropenia occurs despite this dose reduction, 
discontinue EVEROLIMUS. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt EVEROLIMUS until resolution of fever and 
neutropenia to grade ≤ 1. Hold further EVEROLIMUS 
until the ANC ≥ 1,500/mm3 and fever has resolved. 
Then resume EVEROLIMUS at  5mg every other day. 
If febrile neutropenia recurs, discontinue 
EVEROLIMUS. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue EVEROLIMUS. 
Any hematological or non-hematological toxicity requiring 
interruption for ≥ 3 weeks 
Discontinue EVEROLIMUS 
  Page 27 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


3.4.2.4 Management of non-infectious pneumonitis 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious 
pneumonitis (grade 2 = not interfering with activities of daily living or grade 3 = 
interfering with activities of daily living and oxygen indicated) have been noted in 
patients receiving EVEROLIMUS therapy.  .  Non-infectious pneumonitis has been 
associated with EVEROLIMUS and other mTOR inhibitors. In order to monitor for 
asymptomatic (grade 1) pulmonary infiltrates, a chest X-ray every 3 months is required if 
a CT scan of chest is not used for disease evaluations. Additional chest X-rays/CT scans 
may be done, when clinically necessary. If non-infectious pneumonitis develop, 
consultation with a pulmonologist should be considered. Management of non-infectious 
pneumonitis suspected to be associated with EVEROLIMUS and dose modifications 
instructions are provided in Table 3-4.   
 
Table 3-4 
Management of non-infectious pneumonitis 
 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis 
EVEROLIMUS Dose Adjustment 
Grade 1 
CT scans with lung windows. 
No specific therapy 
is required 
Administer 100% of EVEROLIMUS 
dose. 
Grade 2 
CT scan with lung windows.  
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat each 
subsequent Cycle until return 
to within normal limits. 
Consider a bronchoscopy.  
Symptomatic only. 
Rule out infection. 
Prescribe 
corticosteroids if 
cough is 
troublesome. 
Reduce EVEROLIMUS dose until 
recovery to < grade 1. 
EVEROLIMUS may also be 
interrupted if symptoms are 
troublesome. Patients will be 
withdrawn from the study if they fail 
to recover to < grade 1 within 3 
weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest.; Repeat each 
subsequent Cycle until return 
to within normal limits. 
Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Hold treatment until recovery to < 
grade 1. May restart protocol 
treatment within 3 weeks at a 
reduced dose (by one level) if 
evidence of clinical benefit.  Patients 
will be withdrawn from the study if 
they fail to recover to ≤ grade 1 
within 3 weeks. 
 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation at rest. Repeat 
each subsequent Cycle until 
return to within normal limits. 
Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Discontinue treatment. 
All interruptions or changes to study drug administration must be recorded. 
  Page 28 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


3.5 
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 
requirements. 
4. 
MATERIALS AND METHODS 
4.1 
Subjects 
4.1.1 Subject Selection 
4.1.2 Inclusion Criteria 
Patients will be included in the study based on the following criteria: 
• Hormone-refractory metastatic breast cancer defined as disease progression within 6 
months from starting most recent hormonal therapy 
• At least one line of endocrine therapy in the metastatic setting 
• Candidate for hormonal therapy (ER and/or PR-positive at primary diagnosis and at 
metastatic diagnosis where tissue is available) 
• HER2/neu-negative breast cancer by standard criteria (IHC < 3+ or FISH-negative if 
IHC 3+) at primary diagnosis  
• Must have a biopsy in the metastatic setting with HER2 expression of 1+ or 2+ by 
IHC 
• If biopsy of metastatic lesion is performed prior to study entry, HER2 expression by 
IHC must be 1+ or 2+. 
• Histologically confirmed, measurable or evaluable disease.  If disease is measurable 
RECIST criteria should be used (please refer to Appendix B). 
• Life expectancy > 6 months 
• Age >18 years 
• ECOG performance status 
2
≤
 
• Adequate bone marrow function as indicated by the following: 
ANC >1500/µL  
Platelets ≥100,000/µL 
Hemoglobin >10 g/dL  
• Adequate renal function, as indicated by creatinine ≤1.5× upper limit of normal 
(ULN) 
• Adequate liver function, as indicated by bilirubin ≤1.5× ULN 
• INR ≤ 1.3 (or ≤ 3 on anticoagulants) 
• AST or ALT <2× ULN unless related to primary disease. 
  Page 29 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


• Signed informed consent 
• Adequate birth control 
• Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides 
≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient 
can only be included after initiation of appropriate lipid lowering medication. 
4.1.3 Exclusion Criteria 
Patients will be excluded from the study based on the following criteria: 
• Prior treatment with trastuzumab or other HER2-directed therapies or with an mTOR 
inhibitor within 12 months of study entry (when cancer was not definitely hormone 
refractory) 
• HER2 0 or 3+ by IHC on pre-treatment biopsy of metastatic lesion (if performed) 
• Active infection 
• Uncontrolled central nervous system metastases 
• Life-threatening, visceral metastases 
• Pregnant or lactating women 
• Prior chemotherapy within the last 4 weeks  
• Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator 
lesion (unless objective disease recurrence or progression within the radiation portal 
has been documented since completion of radiation). 
• Concomitant malignancies or previous malignancies within the last 5 years, with the 
exception of adequately treated basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix. 
• History of significant cardiac disease, cardiac risk factors or uncontrolled arrhythmias 
• Ejection fraction <50% or below the lower limit of the institutional normal range, 
whichever is lower 
• Hypersensitivity to trial medications 
• Emotional limitations 
• Prior treatment with any investigational drug within the preceding 4 weeks. 
Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent 
• uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
• liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis 
• A known history of HIV seropositivity 
  Page 30 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


• Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of EVEROLIMUS (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel 
resection) 
• Patients with an active, bleeding diathesis 
• Female patients who are pregnant or breast feeding, or adults of reproductive 
potential who are not using effective birth control methods. If barrier contraceptives 
are being used, these must be continued throughout the trial by both sexes. Hormonal 
contraceptives are not acceptable as a sole method of contraception.  (Women of 
childbearing potential must have a negative urine or serum pregnancy test within 7 
days prior to administration of EVEROLIMUS) 
• Patients who have received prior treatment with an mTOR inhibitor (sirolimus, 
temsirolimus, everolimus). 
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, 
resulting in dyspnea at rest 
• Taking any of the following agents: 
• chronic treatment with systemic steroids or another immunosuppressive agent 
• live vaccines  
• drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A  
 
4.1.4 Patient Registration and Randomization 
Each site must submit the following study documentation prior to beginning patient 
enrollment on the study: 
 
 
• IRB approval letter 
• IRB approved informed consent(s) and HIPAA 
• IRB assurance number 
• Study specific FDA Form 1572 for PI 
• Current CV (within 1 year of date, signed and dated) for PI and Co-Investigators 
listed on FDA Form 1572 
• Medical Licenses for PI and Co-Investigators listed on 1572  
• Lab License, certificates, and Normal Lab Values (NLV) for labs listed on FDA 
Form 1572 
• Signed original Financial Disclosure Form for PI and Co-Investigators listed on 
FDA Form 1572  
• Signed original Signed Investigator Signature Page   
 
All original documents will be kept on file in the WCI Clinical Trials Office. 
All copies of the above should be filed in a study-specific regulatory binder at the site. 
  Page 31 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
 
Registration and Randomization Procedure: 
 
All regulatory documents (as stated in Section 4.0) must be received and approved by 
Emory before patient registration will be permitted for each site.  When a suitable 
candidate has been identified for enrollment, the following steps should be taken: 
 
 Obtain signed informed consent and authorization for the release of personal health 
information from patient or guardian.   
 
 Complete the eligibility criteria and verify that all eligibility requirements as stated 
above have been met. 
 
 Submit the following to Emory via fax at 404-778-4389: 
• Signed informed consent 
• Authorization for the release of personal health information from parent or 
guardian. 
• Completed Eligibility Criteria Form. 
 
 Following receipt of completed Eligibility Criteria form, Emory will assign study-
specific patient ID and randomize patient to trastuzumab or everolimus.  Site will 
receive email notification of patient ID and assigned study arm via email within 48 
hours (2 business days) of submission of Eligibility Criteria form. 
 
4.2 
 
4.2 
Study Treatment  
Trastuzumab and everolimus will be provided free of charge by Genentech and Novartis.  
The Sponsor Investigator of the study will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance 
with 21 Code of Federal Regulations (C.F.R.), Part 312.57 and 312.62 and Genentech 
requirements. 
 
4.3.1 Trastuzumab Formulation 
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for 
intravenous (IV) administration.  Each vial of Trastuzumab contains  400 mg of 
trastuzumab, 9.9 mg of L-histidine HCl, 6.4 mg of L-histadine, 400 mg of α,α-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. 
 
  Page 32 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


4.3.2 Trastuzumab Dosage, Preparation, Administration, and Storage  
a. Dosage 
The recommended initial loading dose is 8 mg/kg (for q3wk dosing schedules) 
Trastuzumab administered as a 90-minute infusion.  The recommended maintenance 
Trastuzumab dose is 6 mg/kg q3wk and can be administered as a 30-minute infusion if 
the initial loading dose was well tolerated.  Trastuzumab 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 Trastuzumab 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 Trastuzumab.  
Immediately upon reconstitution with BWFI, the vial of  
Trastuzumab 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, Trastuzumab must be 
reconstituted with Sterile Water for Injection (see PRECAUTIONS).  Trastuzumab 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 Trastuzumab needed, based on a loading dose of 8 mg 
Trastuzumab /kg body weight for q3wk dosing schedules and the recommended 
maintenance dose of 6 mg Trastuzumab/kg body weight for q3wk dosing schedules. 
Calculate the correct dose using 21 mg/mL Trastuzumab 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. 
No incompatibilities between Trastuzumab and polyvinylchloride or polyethylene bags 
have been observed. 
c. Administration 
Treatment may be administered in an outpatient setting by administration of a 4 mg/kg 
Trastuzumab loading dose for weekly dosing schedules (OR 8 mg/kg Trastuzumab 
loading dose for q3wk dosing schedules) by intravenous (IV) infusion over 90 minutes.  
DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.  If Trastuzumab is being 
administered concomitantly with chemotherapy, Trastuzumab administration should 
precede chemotherapy administration.  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 2 mg/kg Trastuzumab weekly (OR 6 mg/kg 
  Page 33 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


Trastuzumab q3wk) may be administered over 30 minutes. If  chemotherapy is 
discontinued during the treatment phase, either because of completing a planned number 
of cycles of chemotherapy, or because of chemotherapy related toxicity,  Trastuzumab 
should  be continued until \ disease progression or unacceptable toxicity related 
specifically to Trastuzumab.    
 
Table 4-1 
Trastuzumab Infusion Time and Post-Infusion Observation Period 
Trastuzumab 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. 
 
Trastuzumab should not be mixed or diluted with other drugs.  Trastuzumab 
infusions should not be administered or mixed with Dextrose solutions. 
d. Storage 
Vials of Trastuzumab 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 Trastuzumab 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 
Trastuzumab solution should be used immediately and any unused portion must be 
discarded.  DO NOT FREEZE TRASTUZUMAB THAT HAS BEEN 
RECONSTITUTED. 
The solution of Trastuzumab 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 Trastuzumab has been shown to be 
stable for up to 24 hours at room temperature 15°C–25°C; however, since diluted 
Trastuzumab contains no effective preservative the reconstituted and diluted solution 
should be stored refrigerated (2°C–8°C). 
4.3.3 Trastuzumab Dosage Modification 
Dose modification of Trastuzumab is not permitted.   
  Page 34 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
4.3.4 Trastuzumab Overdosage 
There is no experience with overdosage in human clinical trials.  Single doses higher than 
500 mg have not been tested. 
4.3.5 Everolimus 
Everolimus will be supplied by Novartis as tablets in 5mg strength. The drug will be 
packaged in blisters containing 10 tablets per blister. Blisters and packaging labels will be 
compliant with local regulations and be printed in local language. They will supply no 
information about the patient. 
Upon receipt, everolimus should be stored according to the instructions specified on the 
drug labels. Everolimus should be opened only at the time of administration as the drug is 
both hygroscopic and light-sensitive. 
These instructions should also be made clear to the patient for storage and self-
administration of everolimus at home. 
4.4 
Concomitant and Excluded Therapy 
All medications and non-drug therapies taken within 30 days prior to starting study 
treatment should be reported to the Principal Investigator. 
The investigator should instruct the patient to notify the study site about any new 
medications (including over-the-counter drugs and herbal/alternative medications) he/she 
takes after the start of study treatment. Patients must be instructed not to take any 
additional medications (including over-the-counter products and herbal/alternative 
medications) during the trial without prior consultation with the investigator. All 
medications (other than study treatments) and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the patient starts study 
treatment must be listed on the Concomitant medications/Significant non-drug therapies 
after start of study drug eCRF. 
The following restrictions apply during the entire duration of the study: 
• No other investigational therapy should be given to patients. 
• No anticancer agents other than the study medication should be given to patients. If 
such agents are required for a patient then the patient must first be withdrawn from 
the study. 
• Concurrent administration of EVEROLIMUS and strong CYP3A4 inhibitors (such as 
ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin,,rifabutin) 
should be avoided. Provided there is no alternative treatment available, patients 
should be closely monitored for potential toxicities. 
• Concurrent administration of EVEROLIMUS and moderate CYP3A4 inhibitors (such 
as erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and 
moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin) should 
  Page 35 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


also be avoided if possible, or used subject to caution (e.g. increased frequency of 
safety monitoring, temporary interruption of EVEROLIMUS). 
• Competitive inhibition could occur when EVEROLIMUS is combined with drugs 
which are also CYP3A4 substrates. Therefore caution should be exercised in such 
cases. 
• Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be 
avoided, if possible, or used subject to caution (e.g. increased frequency of safety 
monitoring, temporary interruption of EVEROLIMUS).  
• Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity 
and should therefore be avoided.  
• In addition, patients should avoid Seville oranges and star fruit, as well as the juice of 
these fruits, which are potent CYP3A4-inhibitors.  
• EVEROLIMUS may affect the response to vaccinations making the response to the 
vaccination less effective. Live vaccines should be avoided while a patient is treated 
with EVEROLIMUS. 
• Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no 
interaction with EVEROLIMUS is expected. However, drug-drug interaction studies 
between macrolide antibiotics and warfarin have produced mixed outcomes and the 
disparity in these findings has led to the conclusion that multiple factors may alter the 
clearance of warfarin. The coadministration of EVEROLIMUS and oral 
anticoagulants is possible but should be subject to verification of coagulation (INR) 
once steady state 
4.4.1 
Antineoplastic therapy 
The administration of anticancer agents other than study medication, including 
chemotherapy, investigational agents, and biologic agents is NOT permitted while 
patients are enrolled in this study. The need for other anti-cancer therapy will be 
attributed to disease progression and will require the patient to be withdrawn from study 
treatment.  
Palliative radiotherapy for local peripheral metastases not being used as target lesions is 
permitted, but the need for such therapy may be an indication of disease progression and 
should be discussed prior to administration. Radiotherapy for central metastases (e.g., 
vertebral, mediastinal) is not permitted. Patients requiring such therapy prior to 
completion of the study should be considered to have progression of disease and study 
treatment should be discontinued.  
No other investigational cancer medication/therapies should have been taken within the 
last 4 weeks prior to study entry and any cancer medication / therapies given to a patient 
within 4 weeks after the last dose of study treatment also must be recorded. 
  Page 36 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


4.4.2      Bisphosphonates 
Patients who enter the study on bisphosphonates may continue this therapy. The need to 
start bisphosphonate therapy on study will be considered as an indication of disease 
progression and the patient will be discontinued from protocol therapy.  
4.4.3     Hematopoietic growth factors and antibiotics 
Hematopoietic growth factors and antibiotics should not be administered prophylactically 
during cycle 1 for patients undergoing study treatment and should be used in future 
cycles only in patients with documented cytopenia in previous cycles in accordance with 
the guidelines established by the American Society of Clinical Oncology, available on the 
following website [http://www.asco.org/ac/1,1003,_12-002138,00.asp]. Exception is 
made for recombinant erythropoietin-like product (such as Procrit®) which may be 
received throughout the study. 
4.4.4      Anti-emetics  
Approximately 25% of patients experience nausea when treated with EVEROLIMUS 
alone and 16% experience vomiting. The majority of nausea and vomiting events is of 
Grade 1 or 2. EVEROLIMUS is best classified as having moderate emetogenic potential, 
therefore prophylactic treatment with appropriate anti-emetic agents as per local 
institutional guidelines is recommended.  
4.4.5    Analgesics 
Baseline analgesics for tumor-related pain should be maintained during the study.  
However, an increase in analgesic use or a step up on the WHO analgesic ladder for 
control of tumor-related pain may indicate disease progression. If an increase in analgesic 
medication from baseline is required during the study, the patient should be evaluated for 
progression of disease. 
4.4.6     Systemic corticosteroids 
Prolonged (greater than 2 weeks in duration) treatment with systemic corticosteroid 
treatment is not allowed during the study. Prolonged treatment with topical steroids 
should be discussed with the Principal Investigator. 
4.4.7      P-glycoprotein (P-gp) inhibitors 
Patients receiving any concomitant medications known to inhibit P-gp function (e.g., 
verapamil, diltiazem, nicardipine, cyclosporine, quinine) will not be excluded from the 
study but these medications should be avoided. 
4.4.8      Cytochrome p450 enzymes 
EVEROLIMUS is mainly metabolized by CYP3A4 in the liver and to some extent in the 
intestinal wall. Therefore the following advice should be followed: 
  Page 37 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


• Wherever possible, drugs or substances known to be inhibitors or inducers of the 
isoenzyme CYP3A should be avoided as systemic therapy in association with 
EVEROLIMUS as these can alter its metabolism (see Table 4-2). 
• Patients should also refrain from herbal/alternative remedies and grapefruit juice   
  Page 38 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


Table 4-2 
Clinically relevant drug interaction: substrates, inducers and inhibitors of 
isoenzyme CYP3A 
Substrates 
Antibiotics1:  
clarithromycin* 
erythromycin  
 
telithromycin* 
 
Anti-arrhythmics: 
quinidine 
 
Benzodiazepines: 
alprazolam 
diazepam 
midazolam 
triazolam 
 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
 
HIV Protease Inhibitors: 
indinavir* 
ritonavir* 
saquinavir* 
 
Prokinetic: 
cisapride 
 
Antihistamines: 
astemizole 
Calcium Channel Blockers: 
amlodipine 
diltiazem 
felodipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
 
HMG CoA Reductase Inhibitors2:  
 
cerivastatin 
lovastatin 
 
simvastatin 
 
Miscellaneous: 
 
buspirone 
 
haloperidol  
methadone 
pimozide  
quinine 
 
sildenafil 
tamoxifen 
trazodone 
vincristine
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
Inhibitors 
Amiodarone 
Cimetidine 
Clarithromycin 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Seville orange juice or product 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
 
  Page 39 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: 
properties and polymorphisms, Naunyn Schmiedebergs Arch Pharmacol. 2004 
Jan;369(1):89-104 and [http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 
13, 2006] 
* asterisk denotes strong inhibition/ induction 
Please note: 
 
Strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% 
decrease in clearance of sensitive CYP substrates 
 
Moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 
50-80% decrease in clearance  of sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary according to conditions).  
1. Macrolide antibiotics: Azithromycin is not a CYP3A substrate. It may therefore be 
employed where antibiotherapy with a macrolide is desirable in a patient being treated 
with EVEROLIMUS 
.2. Statins: Atorvastatin and pravastatin may be administered concomitantly with 
EVEROLIMUS, since a PK interaction study has shown that there is no relevant PK 
interaction 
 
4.5 
Study Assessments 
• Evaluation of subject’s cardiac function by either MUGA or echocardiogram 
4.5.1 Assessments during Treatment 
• Monitor CBC, chemistries, etc. per institutional guidelines. 
• Repeat measurements of LVEF using the same methodology as used at baseline will 
be obtained at 3 months (Week 12) following initiation of Trastuzumab and thereafter 
as clinically indicated.  If Trastuzumab is discontinued for a decline in LVEF, a repeat 
measure of LVEF will be obtained in 1 month to assess whether the decline has 
resolved. 
4.5.2 Follow-Up Assessments 
Patients will have repeat staging performed at 6-weeks and then every 12 weeks with CT 
scans ± bone scans or PET scans.  Repeat staging may be performed earlier if there is 
clinical evidence to suggest disease progression. 
4.6 
Discontinuation of Protocol-Specified Therapy 
Protocol-specified therapy may be discontinued for any of the following reasons: 
• Progressive disease 
  Page 40 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


• Unacceptable toxicity 
• Patient election to discontinue therapy (for any reason) 
• Physician’s judgment 
 
4.7 
Subject Discontinuation 
Patients may discontinue taking one (or more) of the study treatments for the reason of an 
adverse event and yet continue to receive the other treatments if this is felt to be in the 
best interests of the patient.  
Each study treatment discontinuation will be captured separately in the corresponding 
Drug Administration CRF. All discontinuations from the study must be recorded in the 
Study Completion CRF.  
Patients may voluntarily withdraw from the study or be discontinued from it at the 
discretion of the investigator at any time.  The reason for premature discontinuation of a 
subject must be recorded on the CRF. 
 
4.8 
Study Discontinuation 
The Principal Investigator or the study sponsors 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 
 
4.9 
Statistical Methods 
 
4.9.1 Efficacy Analysis  
4.9.1.1 Primary Endpoint 
The primary objective of this study is to to evaluate response rate. One stage design will be adopted for 
these trials conduct. We will test the null hypothesis that the response rate is 1.0% versus the alternative 
hypothesis that the response rate is 10.0%.   A sample size of 34 patients achieves 86% power to detect a 
difference of 0.09 using a one-sided binomial test. The target significance level is 0.1. The actual 
significance level achieved by this test is 0.045. For the secondary objective of the study where patients 
are given trastuzumab after disease progression, we expect that about 50% of the patients will progress.  
Therefore, a sample size of 17 patients treated with the two agents achieves 52% power to detect a 
  Page 41 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


difference of 0.0900 using a one-sided binomial test the same target significance level as the primary 
objective. 
 
This trial will be monitored by the WCI DSMBThe probability of observing 9 or 10 patients with 
disease progression at 8 weeks is 0.24 if the probability of disease progression at 6 weeks is 
0.0.75. Patients will be evaluable for response after 6, and then every 12 weeks.  
 
 
4.9.1.2  Secondary Endpoints 
The secondary objectives of this study are to (i) Assess time to progression of everolimus  in 
combination with hormonal therapy in patients with hormone-refractory metastatic breast cancer, 
(ii) Correlate response rate and clinical benefit in patients with hormone-refractory breast cancer 
treated with everolimus with the expression of HER2 and downstream effector proteins in pre-
treatment biopsies, (iii) assess time to progression, response rate and clinical benefit rate of 
trastuzumab in combination with endocrine therapy in patients with hormone-refractory 
metastatic breast cancer with disease progression on prior everolimus, and (iv) Evaluate safety of 
combination of everolimus with and without trastuzumab with hormonal therapy and For (i), 
Kaplan-Meier curves will be used to estimate the survival curve of time to progression. We then 
estimate the median time to progression by constructing a 95% confidence interval. 
For (ii), ordinary logistic regression will be carried out to correlate response with HER2 
expression and key biomarkers obtained from pre-treatment biopsies after adjusting for relevant 
baseline covariates such as age, etc… The dependent variable is response which is binary, and 
the independent variables of interest are HER2 expression and key biomarkers expressions. We 
will also correlate time to progression with HER2 expression and key biomarker levels using the 
Cox proportional hazards model. 
For (iii), The tolerability and safety of everolimus with and without trastuzumab will be 
monitored by the WCI DSMB. 
 
4.9.1.3 Correlative studies  
Patients are required to have a biopsy as standard of care before starting the study treatment, and 
be asked to have a biopsy when they discontinue treatment.   
Primary diagnostic biopsies and surgical specimens, pre-treatment and post-treatment biopsies 
will be evaluated for the expression of targeted proteins (see section 1.7).  We will compare the 
expression of these proteins in the primary  
biopsy/surgical specimen with the pre-treatment biopsies, and in the pre-treatment biopsies 
compared to the post-treatment biopsies.  
Biopsy specimens will be shipped to Emory University and Dr. Elisavet Paplomata at: 1365 
Clifton Road,  Atlanta, GA 30322. The tissue selected to be shipped should be invasive breast 
cancer. Tissue will be shipped as paraffin embedded tissue and fresh tissue (if available).  
 
4.9.2 Safety Analysis 
Patients will be followed continuously for adverse events which will be graded according to 
ECOG grading system through the Winship Cancer Institute DSMB.  An analysis of safety will 
be performed after 10 patients have been enrolled.   The incidence of clinically significant CHF 
will monitored continuously. Symptomatic CHF is defined as the occurrence of objective 
findings on clinical examination (e.g., rales, S3, elevated jugular venous pressure) and confirmed 
  Page 42 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


by chest X-ray and either MUGA or ECHO.  Difference in risk based on prior anthracycline 
exposure as well as risk factors such as ECHO performance status and smoking status will be 
explored. 
4.9.3 Missing Data 
Any missing data will be excluded from the statistical analysis. 
4.10 
Data Quality Assurance 
Accurate, consistent, and reliable data will be ensured through the use of standard practices and 
procedures. 
4.11 
Data and Safety Monitoring Plan 
The data safety monitoring plan will be implemented by Dr. Elisavet Paplomata, the Principal 
Investigator (P.I.) of this study.  The plan is based on self-monitoring, internal CTO real time 
monitoring using the quality assurance committee, and monitoring via Winship Cancer Institute 
(“WCI”) Data Safety Monitoring Committee (DSMC) as per WCI CTO standard operating 
procedure. Dr. Paplomata and the investigators, the clinical research coordinator and the 
regulatory affairs coordinator will meet at least on a monthly basis to review and discuss study 
data to ensure subject safety. The research coordinators will maintain one spread sheet which 
will summarize all the patient data for patients actively being treated on the trial as well as a 
roadmap detailing pending tests/treatments for each individual patient. During the weekly 
meeting the group will review the eligibility criteria for each new patient. In addition, during 
these meeting the group will review all the toxicity (AE/SAE) logs, case report form completion 
and roadmap for each patient on the trial. Documentation of the discussions during these 
meetings are completed, filed and forwarded to the Winship Cancer Institute (“WCI”) Data 
Safety Monitoring Committee (DSMC) at WCI. The WCI has two internal monitoring 
committees. The first is the quality assurance and quality monitoring committee which will 
perform a review of the first and then on a regular ongoing basis for selected patient enrolled on 
the trial to confirm that the trial is being conducted appropriately. The second monitoring process 
involves DSMC. The WCI DSMC is responsible for providing data safety-monitoring oversight 
for this protocol. Any comments that are generated by the WCI DSMC are forwarded to the 
IRB.  The P.I. and the study investigators will discuss any required modifications to this study at 
the weekly meetings. No modifications to this study are implemented until they are submitted for 
review and approved by the Emory University IRB. The comments from the WCI DSMC are 
forwarded to the IRB at the time of the annual renewal of this study or sooner if warranted and 
requested by the WCI DSMC.    
  
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
oversee the conduct of this study. This committee will review all pertinent aspects of study 
conduct including patient safety, compliance with protocol, data collection and efficacy. The 
committee will review the charts of 10% of patients enrolled to the study and two of the first 5 
patients entered to the study. Reviews will occur annually for studies that are low risk or 
moderate risk. High risk studies will be reviewed every 6 months. The committee reserves the 
right to conduct additional audits if necessary at any time-point. The Principal Investigator is 
responsible for notifying the DSMC about the accrual of patients when the first 5 have been 
entered to the study. The PI will also notify the DSMC of the study status within 2 months before 
  Page 43 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


the next annual review is due. The charter for the Winship DSMC is available upon request to 
the investigator or other study-related personnel. 
             
The WCI DMSC does not tolerate protocol deviations, but does recognize that they occur 
unintentionally. Any protocol violations are reviewed and reported to the WCI DSMC, IRB, and 
all other designated regulatory agencies as required by the study protocol.    
  
All study data reviewed and discussed during these meetings with the PI and the investigators 
and the WCI DSMC is kept confidential. Any breach in confidentiality during the conduct of the 
study is reported to the PI, WCI DSMC, sponsor, and the IRB. 
 
4.11.1   Monitoring of Subsite(s) 
At the study initiation, the PI, regulatory specialist and research coordinators will perform a 
site initiation teleconference. During this teleconference, the Emory team will review the 
study, enrollment, reporting, and regulatory compliance. The subsites will have internal 
monitoring meetings. These meetings will include the investigators, the clinical research 
coordinator and the regulatory affairs coordinator will meet at least on a monthly basis to 
review and discuss study data to ensure subject safety. The research coordinators will 
maintain one spread sheet which will summarize all the patient data for patients actively 
being treated on the trial as well as a roadmap detailing pending tests/treatments for each 
individual patient. The spread sheet will be shared with Emory PI. Teleconferences will be 
conducted at least once monthly between the PI at Emory and the research team at the 
subsites. The purpose of the meetings is to discuss the enrollment, regulatory updates, 
monitor toxicities, and evaluate the progress of the trial. The minutes from the teleconference 
will be maintained in the regulatory binder for the study. In addition electronic copies will be 
sent via email to the principal investigators at each site. 
4.11.2   Data Safety and Monitoring Committee at Emory 
The Monitoring Committee consists of faculty members, a research nurse, the Clinical Trials 
Director and/or Associate Director, the Medical Director of Clinical Trials, the Director of 
the Phase I Program and The Regulatory and Compliance Manager The Monitoring 
Committee reviews all auditing, Data and Safety Monitoring Board (DSMB) composition 
and reports, and recommends corrective action if needed to the PI. The Monitoring 
Committee may initiate an external audit of any trial at any time if it determines such action 
to be necessary. The Monitoring Committee will review all internally audited trials annually. 
Egregious data insufficiency is reported to the Associate Director of Clinical Research who 
notifies the CTRC as part of the CTRC PRMS function. If deficiencies are discovered during 
the annual review, the Monitoring Committee will first inform the PI. If the deficiencies 
cannot be corrected, the Monitoring Committee will involve the PI’s direct supervisor and 
may refer the protocol to the Associate Director of Clinical Research for corrective action 
including possible termination of the trial. The Associate Director of Clinical Research has 
the authority to terminate trials for cause. 
 
  Page 44 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


5. 
REPORTING OF ADVERSE EVENTS 
5.1 
Adverse Event and Reporting Definitions 
An adverse event (AE) is any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  An adverse event can be any 
unfavorable and unintended sign (eg, including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the drug, without any 
judgment about causality.  This includes any newly occurring event or previous condition 
that has increased in severity or frequency since the administration of drug. 
 
An adverse event is considered a serious adverse event (SAE) if it results in any of the 
following outcomes: 
1) Results in death 
2) Is a life-threatening (ie, its occurrence places the patient or subject at immediate risk 
of death) 
3) Requires inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions  
5) Is a congenital anomaly/birth defect 
6) Is an important medical event that may not result in death, be life threatening, or 
require hospitalization but may be considered serious when, based upon medical 
judgment, may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
Suspected Adverse Event 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
Unexpected Adverse Events  
An adverse event is considered “unexpected” if it is not listed in the investigator brochure 
or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk information described 
in the general investigational plan or elsewhere in the current application. 
 
5.1.1 Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 (Appendix D) will be utilized for AE reporting.  If specific grading is not available in 
the CTCAE for a particular AE’s severity/intensity, the investigator is to revert to the 
general definitions of Grade 1 through 5 and use his/her best medical judgment.  The 5 
general grades are: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = 
life-threatening or disabling, Grade 5 = death related to AE. 
  Page 45 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
Attribution of the AE: 
Investigators are required to assess whether there is a reasonable possibility that 
trastuzumab caused or contributed to the adverse event.  The following general guidance 
may be used. 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
 
5.2 
Reporting of Serious Adverse Events Associated with Trastuzumab 
All SAEs that are serious and reasonably or probably related to the use of 
Trastuzumab (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: 
Dr. Elisavet Paplomata 
Tel: 404-778-1900 
AND: 
 
Novartis Pharmaceuticals CS&E 
 FAX (888-299-4565), 
The principal investigator has the obligation to report all serious adverse events to the 
FDA, IRB, and Novartis Pharmaceuticals Clinical Safety and Epidemiology Department 
(CS&E). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form).  
 
All events must be reported, by FAX (888-299-4565), to Novartis Pharmaceuticals 
CS&E Department within 24 hours of learning of it’s occurrence. This includes 
serious, related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 
experiences. All deaths during treatment or within 30 days following completion of 
active protocol therapy must be reported within 5 working days. 
 
  Page 46 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


Any serious adverse event occurring after the patient has provided informed consent and 
until 4 weeks after the patient has stopped study participation must be reported. This 
includes the period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g. treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication). 
 
Serious adverse events occurring more than 4 weeks after study discontinuation need 
only be reported if a relationship to the Novartis study drug (or therapy) is suspected.  
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the product manufacturer by the investigator. 
 
AND   Emory IRB 
1599-001-1AV 
 
Institutional Review Board 
Emory University, 1599 Clifton Road, 
 
Atlanta, GA 30322 
 
Tel: 404-712-0720 
 
Fax: 404-727-1358 
 
Email: IRB@emory.edu 
 
Webpage:  http://emory.edu/IRB/ 
 
5.2.1 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:   
  Page 47 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


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) 
Occasionally Genentech or Novartis 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 or Novartis 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 
Trastuzumab or everolimus if the investigator believes: 
• There is a clinically plausible time sequence between onset of the AE and the study 
drug administration; and/or 
• There is a biologically plausible mechanism for the study drug to cause or contribute 
to the AE; and 
• The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures. 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
Study Initiation 
Before the start of this study, the following documents must be on file with Genentech or 
a Genentech representative and Novartis: 
• Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any sub-investigators must appear on this form.  Investigators must 
also complete all regulatory documentation as required by local and national 
regulations. 
• Current curriculum vitae of the Principal Investigator 
• Written documentation of IRB approval of protocol and informed consent document 
  Page 48 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


• A copy of the IRB-approved informed consent document 
• A signed Clinical Research Agreement 
 
6.2 
Study Completion 
The following materials are requested by Genentech and Novartis 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. 
 
6.3 
Informed Consent 
An informed consent template will be provided, and the final IRB-approved document 
must be provided to Genentech and Novartis 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. 
 
6.4 
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. 
Dr. Paplomata 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.  Dr. Paplomata 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 
  Page 49 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


or update provided by Genentech and Novartis (e.g., IND safety report, Investigator 
Brochure, safety amendments and updates, etc.). 
 
6.5 
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, Novartis, 
the U.S. FDA, and the respective national or local health authorities to inspect facilities 
and records relevant to this study. 
6.6 
Study Medication Accountability (If Applicable) 
If study drug will be provided by Genentech, the recipient will acknowledge receipt of 
the drug by returning the INDRR-1 form indicating shipment content and condition.  
Damaged supplies will be replaced. 
Accurate records of all study drug dispensed from and returned to the study site should be 
recorded by using the institution’s drug inventory log or the NCI drug accountability log. 
All partially used or empty containers should be disposed of at the study site according to 
institutional standard operating procedure.  Return unopened, expired, or unused study 
drug with the Inventory of Returned Clinical Material form as directed by Genentech and 
Novartis for everolimus.  
6.7 
Disclosure of Data 
Subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. 
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, 
Novartis and the IRB for each study site, if appropriate. 
 
6.8 
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 and Novartis will notify the Principal Investigator of these 
events. 
  Page 50 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with U.S. FDA IND regulations and with the record retention 
policies of the relevant national and local health authorities. 
  Page 51 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


REFERENCES 
 
1. Andre F, Slimane K, Bachelot T, et al. Breast cancer with synchronous metastases: trends 
in survival over a 14 year period.  J Clin Oncol 22:3302-8, 2004 
2. Benz CC, Scott GK, Sarup JC, et al. Estrogen-dependent, tamoxifen-resistant 
tumorigenic growth of MCF-7 cells transfected with HER2/neu.  Breast Cancer Res Treat 
24:85-95, 1992 
3. De Laurentiis M, Arpino G, Massarelli E, et al.  A meta-analysis on the interaction 
between HER2 expression and response to endocrine therapy in advanced breast cancer. 
Clin Cancer Res 11:4741-8, 2005 
4. Mackay JR, Kaufman B, Clemens M, et al.  Trastuzumab prolongs progression free 
survival in hormone-dependent and HER2-positive metastatic breast cancer. SABCS 
2006, Abstract 3 
5. Schafer JM, Bentrem DJ, Takei H, et al.  A mechanism of drug resistance to tamoxifen in 
breast cancer.  J Steroid Biochem Mol Biol 83:75-83, 2002 
6. Kaklamani VG, Cicconi J, Gradishar W, et al.  Increased HER2 expression in women 
with recurrent ER-positive breast cancer.  Proc ASCO 2007, Abstract 10516 
7. O’Regan, RM, Osipo, C, Ariazi, E, et al. Development and Therapeutic Options for the 
Treatment of Raloxifene-stimulated Breast Cancer in Athymic Mice.  Clinical Cancer 
Research 12:2255-63, 2006 
8. Paik S, Kim C, Jeong J, et al. Benefit from adjuvant trastuzumab may not be confined to 
patients with IHC 3+ and/or FISH-positive tumors. Central testing results of NSABP B-
31. Proc ASCO 2007, Abstract 511 
9. deGraffenried LA, Friedrichs WE, Russell DH, et al.  Inhibition of mTOR Activity 
Restores Tamoxifen Response in Breast Cancer Cells with Aberrant Akt Activity.  Clin. 
Cancer Res. 10: 8059-8067, 2004 
10. Zhou X, Tan M, Hawthorne VS, et al.  Activation of the Akt/Mammalian Target of 
Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in 
Breast Cancers.  Clin. Cancer Res 10: 6779-6788, 2004 
11. Neshat MS, Mellinghoff IK, Tran C, et al.  Enhanced sensitivity of PTEN-deficient 
tumors to inhibition of FRAP/mTOR.  Proc Natl Acad Sci USA 98:10314-9, 2001 
12.  Sun SY, Rosenberg LM, Wang X, et al.  Activation of Akt and eIF4E survival pathways 
by rapamycin-mediated mammalian target of rapamycin inhibition.  Cancer Res 65:7052-
8, 2005 
13. O’Reilly KE, Rojo F, She QB, et al.  mTOR inhibition induces upstream receptor 
tyrosine kinase signaling and activates Akt.  Cancer Res 66:1500-8, 2006 
14.  Cobleigh M, Vogel CL, Tripathy D, et al.  Multinational study of the efficacy and safety 
of humanized anti-Her2-overexpressing metastatic breast cancer that has progressed after 
chemotherapy for metastatic disease.  J Clin Oncol 1999;17:1-10. 
15. 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 2001; 344:783-792. 
16. Tripathy D, Slamon D, Leyland-Jones B, et al. Treatment beyond progression in the 
Trastuzumab pivotal combination chemotherapy trial. Breast Cancer Res Treat 2000; 
64:32. 
 
 
  Page 52 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


17. Gelmon K, Arnold A, Verma S, et al. Pharmacokinetics (PK) and safety of trastuzumab 
(Herceptin) when administered every three weeks to women with metastatic breast 
cancer. Oral presentation at the 37th Annual Meeting of the American Society of Clinical 
Oncology, May12-15 in San Francisco, California 2001.  
18.  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 1998; 58:2825-
2831 
19. Leyland-Jones B, Hemmings F, Arnold A, et al. Pharmacokinetics of Trastuzumab 
administered with paclitaxel every three weeks. Breast Cancer Res Treat 2000; 64:124. 
20. 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. 2002;20:719-26.  
21. Bjornsti M-A, Houghton PJ.  The TOR pathway: A target for cancer chemotherapy. 
Nature Reviews Cancer 2004;4:335-348. 
22. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human 
cancer. Nat Rev Cancer 2002;2:489-501. 
23. Pandolfi PP. Breast cancer - Loss of PTEN predicts resistance to treatment, 2004. 
24.  Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by 
trastuzumab,and loss of PTEN predicts trastuzumab resistance in patients .Cancer Cell 
2004;6:117-127 
25. Lu C-H, Wyszomierski SL, Tseng ML, et al. Preclinical testing of clinically applicable 
strategies for overcoming herceptin resistance caused by PTEN deficiency. Clin Cancer 
Res. 2007 13:5883-8.  
26. Hermanto U, Zong SC, Wang LH ErbB2-overexpressing human mammary carcinoma 
cells display an increased requirement for the phosphatidyliniositol 3-kinase signaling 
pathway in anchorage-independent growth. Oncogene 2001;20:7551-7562. 
27. Bacus SS, Altomare DA, Lyass L, et al. AKT2 is frequently upregulated in HER-2/neu-
positive breast cancers and may contribute to tumor aggresiveness by enhancing cell 
survival Oncogene 2002;21:3532-3540. 
28. Andre F, Campone M, Hurwitz SA, et al.  Multicenter phase 1 clinical trial of daily and 
weekly EVEROLIMUS in combination with weekly paclitaxel and trastuzumab in 
patients with HER2-overexpressing metastatic breast cancer with prior resistance to 
trastuzumab.  Proc ASCO Abstract 1003, 2008 
 
 
 
 
 
  Page 53 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


FIGURE 1 
STUDY SCHEMA 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
•Metastatic  
breast cancer 
•Disease progression  
within ≤6 months of  
starting last endocrine 
therapy1 
•≥ 2 prior endocrine  
therapies2 
•ER and/or PR-
positive3 
and HER2-negative4 
at Dx 
R
Continue 
most 
recent 
endocrine 
therapy  
 
Everolimus7 
n = 34 
BX
5
Add  
Trastuzumab6 
(n = 20) 
PD 
(1) Any endocrine therapy allowed.  
(2) Patients must have had at least one line of endocrine therapy for metastatic disease.  
(3) On primary and subsequent biopsies,  
(4) HER2 ≤ 2+ by IHC and/or FISH-negative 
(5) Biopsies optional prior to study entry and at study discontinuation (but must have a biopsy in 
the metastatic setting demonstrating HER2 1+ or 2+ by IHC 
(6) Trastuzumab IV 8 mg loading dose-> 6 mg 3 weekly 
(7) Everolimus 10 mg daily PO 
  Page 54 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


APPENDIX A 
Study Flowchart 
 
 
 
Days 
–14 to 
1 
Day 1  
 
 
 
Daily  
 
Every 4 
weeks 
while on 
everolimus  
Every 3 
weeks while 
on 
trastuzumab 
Every 
12 
Weeks 
Study 
Terminatio
n10 
Trastuzumab (HERCEPTIN®)   
administration 
 
X 
 
 
X1 
 
 
Everolimus (EVEROLIMUS) 
 
X 
X 
 
 
 
Hormonal therapy 
 
X 
X2 
 
 
 
Complete medical history 
X 
X 
 
X 
 
 
Complete physical exam 
X 
X 
 
X 
 
 
Clinical assessment 
X 
X 
 
X 
 
 
Weight, height 
X 
X 
 
X 
 
 
ECOG performance status 
X 
X 
 
X 
 
 
Toxicity evaluation 
X 
X 
 
X 
 
 
Vital signs 
X 
X 
 
X 
 
 
ECG (12-lead) 
X9 
 
 
 
 
 
MUGA scan/echocardiogram 
X9 
 
 
 
X3 
 
Serum pregnancy test  
X 
 
 
 
 
 
Tumor assessment 
X4,9 
 
 
 
X4 
X 
Hematology (CBC, diff., 
platelets) 
X5 
 
 
X 
 
 
Coagulation (PT/INR) 
X6 
 
 
 
 
 
Chemistry panel (including lipid 
panel) 
X7 
 
 
X7 
 
 
Biopsy 
X8 
 
 
 
 
X8 
 
  Page 55 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


(1) Trastuzumab 6mg/kg 3 weekly following loading dose 8mg/kg. Given at disease 
progression. Initially the patients will be seen in clinic every 4 weeks while on 
everolimus alone. After the addition of Trastuzumab the schedule will switch to 3 weeks 
to coincide with trastuzumab infusions.  
(2) Any prior hormonal therapy is allowed (for example: tamoxifen, toremifene, anastrozole, 
 letrozole, fulvestrant, estrogen, megestrol acetate, androgens). 
(3) Assessment of ejection fraction (by MUGA, first pass or ECHO) must be done at 
 baseline, 3 months ± 1 week (Week 12) following initiation of trastuzumab and then 
every 12 weeks if clinically indicated.  Any patient with symptoms suggestive of cardiac 
failure should be worked up immediately. 
(4) Staging will be performed using CT scans: chest, abdomen and pelvis. First staging 
assessment will be done at baseline, after 6 weeks ± 2 days, then every 12 weeks ± 1 
week until progression.   
        (5)  Hematology should include hemoglobin, hematocrit, red blood cells (RBC), platelets,  
              total and differential white blood cells. 
      (6)  The coagulation profile should include a prothrombin time (PT/INR). 
      (7)  Chemistry Panel should include: potassium, magnesium (optional), calcium, chloride, 
bicarbonate,  creatinine, blood urea nitrogen, fasting glucose, albumin, total protein, AST, 
ALT, total bilirubin, alkaline phosphatase, fasting lipid profile (triglycerides, total 
cholesterol, HDL, and LDL).  These assessments should be performed at screening and 
Day 1 of each cycle.  Fasting lipid profile should only be repeated every 2 cycles for 
patients on everolimus only and every 3 cycles for patients on everolimus plus 
trastuzumab 
      (8)  Patients will be asked to have an optional biopsy at baseline and when they come off  
study.  In order to be eligible all patients must have a biopsy in the metastatic setting 
demonstrating 1+ or 2+ expression of HER2 
(9) EKG (12-lead), MUGA scan/Echocardiogram, and Tumor assessment: within 4 weeks of 
baseline 
      (10)  Νo long-term follow-up is required but patients will be followed off study.
  Page 56 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


APPENDIX B 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
 
 
The RECIST criteria should be used to assess response to treatment.  Only subjects with 
measurable disease should be entered in the study.  Measurable disease is defined as the 
presence of one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥2.0 cm with conventional techniques (or as ≥1.0 cm by 
spiral CT).  Evaluable lesions should be followed for the assessment of response.  Non-
measurable lesions include bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, lymphangitic carcinomatosis, abdominal masses that are not 
confirmed by CT, and cystic lesions. 
All measurable lesions, up to a maximum of 5 lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  A sum of the longest diameter for all target lesions will be 
calculated and reported as the baseline sum longest diameter.  The baseline sum longest 
diameter will be used as the reference by which to characterize the objective tumor 
response. 
• Complete response (CR) 
Disappearance of all evidence of tumor for at least two cycles of therapy.  Tumor 
markers must be normal. 
• Partial response 
At least a 30% decrease in the sum of the longest diameter of target lesions, 
taking a reference the baseline sum longest diameter. 
• Stable disease (SD)  
Neither sufficient shrinkage to qualify for partial response nor sufficient increase 
to qualify for progressive disease, taking as reference the smallest sum longest 
diameter since the treatment started. 
• Progressive disease (PD) 
At least a 20% increase in the sum of the longest diameter of target lesions, taking 
as reference the smallest sum longest diameter recorded since the beginning of 
treatment or the appearance of one or more new lesions. 
  Page 57 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


APPENDIX B (cont’d) 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
 
• Clinical progressive disease 
Subjects, who in the opinion of the treating physician investigator have had a 
substantial decline in their performance status and have clinical evidence of 
progressive disease may be classified as having progressive disease. 
  Page 58 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


APPENDIX C 
National Cancer Institute Common Toxicity Criteria 
obtained from http://ctep.cancer.gov/forms/CTCAEv3.pdf  
  Page 59 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
APPENDIX D 
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 uptitrated 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 ßblockade 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. 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
Combined endpoints, including mortality or hospitalization and mortality or 
hospitalization for heart failure, have also emerged as key outcomes. These latter 
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). 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
    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 and 
-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 
evidence for increased benefit from higher dosages (25 mg twice per day) versus lower 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
dosages (6.25 mg twice per day) of carvedilol, so uptitration 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 
and improve ventricular function, the risk to benefit ratio seems sufficiently low to 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
was conducted. Seven patients (12%) failed to complete the open-label, run-in period, 
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. 
Clinicalreevaluation 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. 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
    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 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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. 
 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
    Digoxin increases left ventricular ejection fraction and alleviates symptomatic heart 
failure as evidenced by drug-related improvement in exercise capacity and reductions in 
heart-failureassociated 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 cointervention (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 < 
.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 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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 cointervention; 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. 
 
Recommendation 3. In patients with heart failure and atrial fibrillation 
with a rapid ventricular response, the administration of high doses of 
digoxin (greater than .25 mg) for the purpose of rate control is not 
recommended. When necessary, additional rate control should be achieved 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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. 
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 
  Page 70 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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. 
 
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). 
 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
    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 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 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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 
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 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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). 
 
    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 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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 
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). 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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. 
 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
HFSA Guidelines 
Appendix D 
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. 
  Page 77 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
HFSA Guidelines 
Appendix D 
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 
  Page 78 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
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 
  Page 79 of 80 
HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016 


 
 
APPENDIX E 
FDA MedWatch 3500 Form 
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HERCEPTIN® - Emory Winship Cancer Institute                                                       03/08/2016