Combination Immunotherapy With Herceptin and the HER2 Vaccine E75 in Low and Intermediate HER2-expressing Breast Cancer Patients to Prevent Recurrence
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: George E. Peoples

 
CONFIDENTIAL 
 
PROTOCOL TITLE: 
Combination immunotherapy with Herceptin and the 
HER2 vaccine E75 in low and intermediate HER2-
expressing breast cancer patients to prevent 
recurrence  
STUDY DRUGS: 
HERCEPTIN® (Trastuzumab) 
E75 peptide (KIFGSLAFL, HER2/neu, 369-377) 
GM-CSF (Leukine®, Berlex) 
SPONSORS: 
Genentech, Inc. 
Galena Biopharma, Inc. 
IND NUMBER: 
 
IND SPONSOR/INVESTIGATOR 
PROGRAM DIRECTOR: 
 
 
 
 
BB-IND#14919 
 
 
George E. Peoples, MD, FACS 
Cancer Insight, LLC 
110 E. Houston Street, Floor 7 
San Antonio, TX 78205 
210-557-4291 
georgepeoples2@hotmail.com 
 
 
 
MEDICAL MONITOR: 
 
 
Cancer Insight, LLC 
 
PROTOCOL VERSION/DATE: 
SPONSOR STUDY NUMBER: 
3.1/ 05 March 2017 
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TABLE OF CONTENTS 
 
  
   Page 
1. 
INTRODUCTION ............................................................................................ 
5 
1.1 
Disease Background ........................................................................... 
5 
1.2 
HER2 and Breast Cancer .................................................................... 
6  
1.3 
Herceptin Clinical Experience ............................................................. 
7 
1.4 
Safety .................................................................................................. 
8 
1.5 
Clinical Pharmacokinetics of Trastuzumab ......................................... 
9 
1.6 
E75 Background .................................................................................. 
10 
1.7 
HER2-Directed Therapies in HER2 Low-Expressing Tumors ............. 
12 
1.8 
Combined HER2-Directed Therapy ..................................................... 
13 
2. 
OBJECTIVES .................................................................................................. 
14 
2.1 
Primary Objectives .............................................................................. 
14 
2.2 
Secondary Objectives ......................................................................... 
14 
3. 
STUDY DESIGN ............................................................................................. 
15 
3.1 
Description of the Study ...................................................................... 
15 
3.2 
Rationale for Study Design .................................................................. 
16 
3.3 
Outcome Measures ............................................................................. 
16 
3.3.1 
Primary Outcome Measure .................................................. 
16 
3.3.2 
Secondary Outcome Measures ............................................ 
17 
3.3.3 
Ancillary Safety Outcome Measures .................................... 
17 
3.4 
Safety Plan .......................................................................................... 
17 
 
3.4.1 
Cardiac Dysfunction ............................................................. 
17 
 
3.4.2 
Management of Cardiac Safety ............................................ 
18 
 
 
3.4.2.1 
Adjuvant Breast Cancer Protocols ...................... 
18 
3.5 
Dose Reductions of Vaccine Component ............................................ 
21 
3.6 
Compliance with Laws and Regulations ............................................. 
21 
4. 
MATERIALS AND METHODS ........................................................................ 
22 
4.1 
Subjects .............................................................................................. 
22 
4.1.1 
Subject Selection .................................................................. 
22 
4.1.2 
Inclusion Criteria ................................................................... 
23  
4.1.3 
Exclusion Criteria ................................................................. 
23 
4.2 
Method of Treatment Assignment ....................................................... 
24 
4.3 
Study Treatment .................................................................................. 
24 
4.3.1 
Herceptin Formulation .......................................................... 
25 
4.3.2 
Herceptin Dosage, Preparation, Administration, and Storage 25 
4.3.3 
Herceptin Dosage Modification ............................................. 
27 
4.3.4 
Herceptin Overdosage ......................................................... 
27 
4.3.5 
Vaccine ................................................................................. 
27 
4.3.6 
Inoculation Series - Administration ....................................... 
29 
4.3.7 
Booster Inoculations ............................................................. 
29 
4.4       Study Assessments ............................................................................ 
29 
4.4.1 
Assessments during Treatment ............................................ 
30 
4.4.2 
Follow-Up Assessments ....................................................... 
31 
4.4.3 
Human Biological Specimens ............................................... 
31 
4.4.4 
Specimen Processing ........................................................... 
32 
4.4.5 
HLA-A2/A3/A24/A26 Testing ................................................ 
33 
4.4.6 
Dimer Assay ......................................................................... 
33 

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4.4.7 
ELISPOT Assay ................................................................... 
33 
4.4.8 
Local Reaction ...................................................................... 
33 
4.4.9 
DTH Reaction ....................................................................... 
34 
4.5 
Discontinuation of Protocol-Specified Therapy ................................... 
34 
4.6 
Subject Discontinuation ....................................................................... 
35 
4.7 
Study Discontinuation ......................................................................... 
36 
4.8 
Statistical Methods ..............................................................................  
36 
4.8.1 
Analysis of the Conduct of the Study .................................... 
36 
4.8.2 
Analysis of Treatment Group Comparability ......................... 
37 
4.8.3 
Efficacy Analysis .................................................................. 
37 
4.8.4 
Safety Analysis ..................................................................... 
39 
4.8.5 
Planned Analyses ................................................................. 
40 
4.8.6 
Missing Data ......................................................................... 
41 
4.8.7       Determination of Sample Size ………………………………..     41 
4.9 
Data Quality Assurance ...................................................................... 
42 
5. 
REPORTING OF ADVERSE EVENTS ........................................................... 
42 
5.1 
Adverse Event and Reporting Definitions ........................................... 
42 
5.2 
Reporting of Serious Adverse Events Associated with this Study ....... 
43 
5.2.1 
MedWatch 3500A Reporting Guidelines .............................. 
44 
5.3 
Reporting Requirements for IND Holders ............................................ 
45 
6. 
INVESTIGATOR REQUIREMENTS ............................................................... 
46 
6.1 
Study Initiation ..................................................................................... 
46 
6.2 
Study Completion ................................................................................ 
46 
6.3 
Informed Consent ................................................................................ 
46 
6.4 
Institutional Review Board or Ethics Committee Approval .................. 
46 
6.5 
Study Monitoring Requirements .......................................................... 
48 
6.6 
Data Collection .................................................................................... 
48 
6.7 
Study Medication Accountability ......................................................... 
49 
6.8 
Disclosure of Data ............................................................................... 
49 
6.9 
Retention of Records .......................................................................... 
49 
6.10 
Publications ......................................................................................... 
49 
6.11 
Changes to the Protocol ...................................................................... 
50 
REFERENCES ........................................................................................................ 
51 
 
TABLES  
Table 1: 
Herceptin Infusion Time and Post-Infusion Observation Period ......... 
26 
 
TRIAL APPENDICES 
Appendix A: 
Herceptin and Vaccination Timeline 
Appendix B:  NCI Common Terminology Criteria for Adverse Events, v4.03 
Appendix C.1: Study Flowchart 
Appendix C.2: Patient Visit Chart 
Appendix D: 
HFSA Guidelines for CHF Treatment 
Appendix E: 
NCCN Guidelines for Adjuvant Breast Cancer Treatment 
Appendix F: 
Study Randomization and Stratification Schema 
Appendix G: E75 + GM-CSF and DTH Formulation Plan 
Appendix H: 
Leukine Package Insert 
Appendix I: 
Performance Status Criteria 
Appendix J: 
Case Report Forms (Free standing electronic documents) 

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Appendix K: 
Data Safety Monitoring Plan (Free standing document) 
Appendix L: 
Adverse Event Reporting Algorithm 
Appendix M: FDA Medwatch 3500A Form Link 
Appendix N: 
Genentech Drug Safety – Reporting instructions for IND Sponsor 
Appendix O: PI Agreement and Signature Page 
 
 

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1. 
INTRODUCTION 
1.1 
DISEASE BACKGROUND 
Breast cancer is, by far, the most commonly diagnosed malignancy in women (excluding 
cancers of the skin), and it is the second leading cause of cancer mortality among women.  
The American Cancer Society estimated that there were over 200,000 new cases of breast 
malignancy diagnosed in 2009, with an estimated 40,000 women expected to die from this 
disease each year (American Cancer Society 2009).   
While nodal status is still the most important prognostic factor in breast cancer, other 
parameters such as HER2 expression are known to impact disease recurrence and 
ultimately survival (O’Shaughnessy et al. 2006).  HER2 is expressed in approximately 70-
80% of breast cancers and over-expressed in 20-30% of breast cancers (Slamon et al. 
1989).   
In addition to traditional therapies such as surgery, chemotherapy, radiation, and hormonal 
therapy, novel approaches to the management of this disease have recently shown 
promise.  One such approach has been to use the body’s own immune mechanisms to 
target and kill tumor cells.  Trastuzumab (Herceptin), a monoclonal antibody (mAb) that 
binds the HER2 protein product, is designed to do just that, and recently published reports 
indicate that it affords a significant disease-free survival (DFS) benefit to high-risk node-
negative (NN) and node-positive (NP) breast cancer patients (Piccart-Gebhart et al. 2005, 
Romond et al. 2005).  In both settings, Herceptin has been shown to decrease the 
recurrence rate by approximately 50%.  Unfortunately, Herceptin can only be used in a 
minority of breast cancer patients, specifically those that over-express the HER2 protein.  
These results have served to fuel ongoing research into immunologic approaches to cancer 
treatment ranging from the administration of mAbs, such as Herceptin, to the development 
of anti-cancer vaccines. 
Advances in the understanding of the immune response to cancer have led to the 
genesis of other immunotherapeutic approaches as well.  Specifically, the development 
of anti-cancer vaccines holds promise as an adjuvant and preventive therapy for breast 
cancer patients at high risk for recurrence after primary therapy (Khoo et al. 2006).  
HER2 has also been shown to be the source of multiple immunogenic peptides to 
include E75, GP2, and the wild type AE37 (Fisk et al. 1995, Peoples et al. 1995, 
Mittendorf et al. 2009).  AE37 includes a four amino-acid modification that increases its 
effectiveness (Humphreys et al. 2000, Kallinteris et al. 2006).  E75, GP2, and AE37 
peptides have all been utilized as the basis of separate anti-cancer vaccines combined 
with the immunoadjuvant, granulocyte macrophage colony-stimulating factor (GM-CSF), 
and tested by our group in Phase I/II trials.  E75 has been shown to reduce clinical 
recurrences in the adjuvant setting similar in magnitude to the benefit proven with 
Herceptin (Peoples et al. 2008)  
While Herceptin has previously been reserved for HER2 3+ expressing tumors, emerging 
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(Paik et al. 2008).  In our vaccine trials, we have shown that HER2-derived, CD8-eliciting, 
peptide-based vaccines used in the adjuvant setting may decrease the recurrence rate in 
breast cancer patients with tumors expressing any level of HER2, especially HER2 1+ and 
2+ tumors (Benavides et al. 2009).  Finally, in ongoing Phase II trials of our HER2 vaccines,  
30 patients with HER2 3+ tumors treated with standard of care Herceptin followed by HER2 
vaccination, have had no breast cancer recurrences in 48 months of follow up (Sears et al. 
2011).  Given this potential of patients with HER2 1+ and 2+ expressing tumors to respond 
to both Herceptin and HER2-derived peptide vaccines, we believe that the combination of 
Herceptin and a HER2-derived, CD8-eliciting peptide vaccine could potentially show a 
dramatic improvement in preventing breast cancer recurrence. 
1.2 
HER2 AND BREAST CANCER 
Growth factors and their receptors play critical roles in development, cell growth, 
differentiation, and apoptosis (Cross et al. 1991).  Such receptors span the cell membrane, 
with the extracellular domain binding specific growth factors and the intracellular domain 
transmitting growth signals.  Interaction of the extracellular domain with its cognate ligand 
often results in intracellular activation of tyrosine kinase activity.  Overexpression of human 
epidermal growth factor receptor 2 (HER2, also known as erbB2, neu, and p185HER2) is 
observed in approximately 25-30% of human breast cancers (Slamon et al. 1987).  HER2 
overexpression has been reported to only rarely occur in the absence of gene amplification 
(Kallioniemi et al. 1992; Pauletti et al. 1996).  High level of HER2 expression has been 
correlated with poor clinical outcome (Slamon et al. 1987).  
Several lines of evidence support a direct role for HER2 overexpression in the 
pathogenesis and poor clinical course of human tumors (Hynes 1993).  When the mutated 
gene is transfected into murine fibroblast (NIH 3T3) cells, it causes transformation, and the 
resulting cells are tumorigenic in the nude mice (Di Fiore et al. 1987; Hudziak et al. 1987).  
Additionally, transgenic mice that overexpress the rodent homolog of the human HER2 
gene develop breast cancer (Guy et al. 1992).  Finally, specific antibodies to the 
extracellular domain of HER2 inhibit the experimental growth of tumors that overexpress 
the gene (Drebin et al. 1985, 1988; Fendly et al. 1990).  These data suggest a direct role 
for HER2 in both malignant transformation and enhanced tumorigenicity.  Therefore, a 
strategy to antagonize the abnormal function of overexpressed HER2 was developed to 
improve the course of patients with HER2-overexpressing tumors.  Monoclonal antibodies 
directed against the HER2 protein were developed and humanized to minimize the 
likelihood of immunogenicity.  One of these antibodies (Herceptin) was very effective in 
inhibiting both in vitro and in vivo proliferation of human breast cancer tumor cells 
overexpressing the HER2 protein and in mediating antibody-dependent cellular cytotoxicity 
in the presence of human effector cells (Jurianz et al. 1999). 
There is substantial preclinical evidence that inhibition of signal transduction pathways can 
potentiate the cytotoxic activity of chemotherapeutic drugs.  Indeed, Herceptin has been 
shown to have synergy, in vitro and in vivo, with several chemotherapeutic drugs including 
cisplatin, doxorubicin, thiotepa, etoposide, vinorelbine, and taxanes (Pegram et al. 2000; 
Pietras et al. 1994; Arteaga et al. 1994; Hancock et al. 1991; Baselga et al. 1998; Pegram 

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et al. 1997).  Given this promising preclinical data, Herceptin was tested in the clinic both as 
a single agent and in combination with chemotherapy. 
1.3 
HERCEPTIN CLINICAL EXPERIENCE 
The clinical benefit of Herceptin in women with metastatic breast cancer has been 
demonstrated in two pivotal studies.  
A large Phase II trial (H0649g) assessed the activity of Herceptin as a single agent in 222 
women with HER2 overexpressing metastatic breast cancer with progressive disease after 
one or more chemotherapy regimens (Cobleigh et al. 1999).  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 Herceptin in 
combination with chemotherapy as first-line treatment.  Patients who were anthracycline-
naïve were randomized to receive either anthracycline plus cyclophosphamide (AC) or 
Herceptin plus AC.  Patients who had received prior anthracyclines in the adjuvant setting 
were randomized to receive either paclitaxel or Herceptin plus paclitaxel.  Patients 
randomized to Herceptin 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), Herceptin 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 Herceptin 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 Herceptin upon disease progression (Tripathy et al. 2000).  Fever/chills were 
observed with the initial Herceptin infusion in approximately 25% of patients.  Class III or IV 
cardiac dysfunction was observed in 16% of the Herceptin + AC subgroup; increasing age 
was an associated risk factor for the development of cardiotoxicity in this treatment cohort.  
Based on these data, Herceptin 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 Herceptin 
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pivotal clinical trials.  Since initiation of the pivotal clinical trials, docetaxel has become a 
commonly used taxane in the treatment of metastatic breast cancer (Chevallier et al. 1995) 
and new data have emerged on the weekly use of paclitaxel (Akerley et al. 1997).  
Herceptin has been studied in combination with paclitaxel and docetaxel using a variety of 
doses and schedules with promising results (Seidman et al. 1999; Nicholson et al. 2000; 
Kuzur et al. 2000).  In addition, the combination of Herceptin with vinorelbine has recently 
been studied (Burstein et al. 2001).  In this study, 30 of 40 women treated with Herceptin (4 
mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose 
adjusted each week for neutrophil count) responded to therapy, for an overall response rate 
of 75% (95% confidence interval 57% to 89%).  Neutropenia was the only grade IV toxicity. 
No patients had symptomatic heart failure.  Grade 2 cardiotoxicity was observed in 3 
patients; prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-
existing cardiac function were associated with this toxicity. 
1.4 
SAFETY 
Experience with Herceptin administration has shown that the drug is relatively safe.  The 
most significant safety signal observed during clinical trials was cardiac dysfunction 
(principally clinically significant congestive heart failure [CHF]), particularly when Herceptin 
was given in combination with an anthracycline-containing regimen.  Much of the cardiac 
dysfunction was reversible on discontinuation of Herceptin.  
In addition, during the first infusion with Herceptin, a symptom complex most commonly 
consisting of fever and/or chills was observed in approximately 40% of patients.  The 
symptoms were usually mild to moderate in severity and controlled with acetaminophen, 
diphenhydramine, or meperidine.  These symptoms were uncommon with subsequent 
infusions.  However, in the post-approval setting, more severe adverse reactions to 
Herceptin 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, Herceptin 
should be used during pregnancy only if the potential benefit to the mother outweighs the 
potential risk to the fetus.  In the post-marketing setting, oligohydramnios (decreased 
amniotic fluid) has been reported in women who received Herceptin 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 Herceptin and 
oligohydramnios has not been established.   
Herceptin appears to be relatively nonimmunogenic.  Only 1 of 903 patients evaluated 
developed neutralizing antibodies to Herceptin.  The development of anti-Herceptin 
antibodies in this patient was not associated with clinical signs or symptoms.  

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1.5 
CLINCAL 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 µg/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) {ref: Lu et al.}.  A linear two-compartment model best 
described the concentration-time data, and accounted for the accumulation of trastuzumab 
serum concentrations seen in the Phase II and Phase III clinical studies.  A covariate 
analysis was conducted using the subjects from these single agent studies to evaluate the 
effect of pathophysiologic covariates (e.g. age, weight, shed antigen) on the PK parameter 
estimates.  The covariates, that significantly influenced clearance, were the level of shed 
antigen and the number of metastatic sites.  Volume of distribution was significantly 
influenced by weight and shed antigen level.  Additionally, data from the Phase III study, 
H0648g, were added to assess the influence of concomitant chemotherapy on trastuzumab 
PK.  Importantly, chemotherapy (AC or paclitaxel) did not significantly alter trastuzumab 
PK.  The estimated half-life of trastuzumab based on the final model was 28.5 days. 
Analysis of data obtained from two Phase II studies which utilized a loading dose of 
8 mg/kg trastuzumab followed by a 6 mg/kg maintenance dose administered every 3 weeks 
(q3 week) as a single-agent (Baselga et al. 1998), and in combination with paclitaxel 
(175 mg/m2) (Leyland-Jones et al. 2000), 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 

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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 (Slamon et al. 2001; 
Cobleigh et al. 1999).  In the trastuzumab q3 weekly monotherapy study (Baselga et al. 
1998), 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 (Leyland-Jones et al. 2000), 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 
E75 BACKGROUND 
E75 is a nine amino-acid peptide derived from the HER2/neu protein (369-377) (Fisk et al. 
1995) and is the most studied CTL epitope from this tumor-associated antigen both in vitro 
and in vivo.  Zaks and Rosenberg, in an early study, looked at vaccinating patients with the 
E75 peptide in an effort to determine its efficacy (Zaks et al. 1998).  In this study, metastatic 
breast, ovarian, and colorectal cancer patients were given 1 mg of peptide mixed with 
incomplete Freud’s adjuvant subcutaneously every 3-4 weeks for a total of four doses.  
Three of four patients demonstrated peptide-specific CTL responses; however, these cells 
did not lyse HER2-positive tumor cells.  No clinical response data was disclosed.   
Knutson and Disis also investigated the E75 peptide but mixed with GM-CSF which was 
chosen as an adjunct to stimulate an immune response based on previous animal studies 
(Disis et al. 1996).  It is thought to potentiate the immunologic response by promoting the 
transformation of dermally present Langerhans cells into mature antigen-presenting 
dendritic cells (DC).  The E75 + GM-CSF vaccine was given to six metastatic breast and 
ovarian cancer patients (Knutson et al. 2002).  The vaccine resulted in E75-specific CTL 
responses in two of four evaluable patients.  No clinical response information was given. 
Murray et al then used the same E75 epitope combined with GM-CSF as an adjuvant in a 
Phase I trial to examine the toxicity of this formulation as well as its ability to promote a 
detectable CTL-mediated E75-specific immune response (Murray et al. 2003).  A total of 14 
patients with stage IV breast or ovarian carcinoma underwent vaccination with escalating 
doses of the peptide combined with 250 mcg GM-CSF.  The formulation was found to be 
safe with no grade 3 or 4 toxicity reported.  Eight of those receiving the vaccine were 
evaluated for CTL activity directed against the E75 peptide, and four of the eight patients 
showed CTL-mediated lytic activity.  Furthermore, these CTL were shown to remain for 
between one and 12 months following completion of the vaccine.  Of interest, these 
advanced stage patients continued to undergo disease surveillance at short intervals 

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throughout the study.  Despite the promising immunologic response, no clinical response 
was noted, but there was a trend toward delayed time to progression. 
All of the previously described studies were performed primarily in patients with metastatic 
disease and known residual tumor burden.  While they demonstrate that the desired 
immune response could be elicited in the majority of patients, minimal clinical results were 
obtained or reported.  This is likely related to the advanced stage of disease in the patients 
in whom these trials were conducted.  Our approach has shifted focus from the treatment of 
late-stage disease to disease prevention among breast cancer patients considered to be at 
high risk for recurrence.  E75 peptide admixed with GM-CSF has been previously shown to 
be a safe formulation which can induce an immune response.  Because of its effectiveness 
and simplicity of design, this vaccine strategy was investigated as a possible adjunct after 
standard therapy to help reduce the risk of recurrence.   
A total of 53 patients with NP breast cancer were reported initially in our first adjuvant 
vaccine study (Peoples et al. 2005).  All patients had previously undergone traditional 
therapy including surgery, chemotherapy, and/or radiation therapy as appropriate.  At time 
of enrollment, all patients were without any evidence of disease.  Because of the HLA-A2 
restriction of the E75 peptide, the patients were HLA typed after enrollment and then placed 
in either the treatment arm (HLA-A2+) or the observation group (HLA-A2-).  Interestingly, 
there seemed to be some differences in the two groups with HLA-A2+ patients having 
generally worse prognostic tumor characteristics (larger, higher histologic grade, less 
hormonal sensitivity).  As a result of these differences, the treatment arm tended to have 
less hormonal therapy (a treatment known to reduce recurrence).  These patients received 
the E75 peptide admixed with GM-CSF according to a two-stage design with escalating 
doses in the first stage and alterations in the vaccine schedule in the second stage.  Again, 
this vaccination formula was shown to be safe and well tolerated.  Clonal expansion of E75-
specific CTL was noted along with CTL-mediated E75-directed lysis of HER2/neu-
expressing tumors.  Perhaps most striking, however, were the clinical results as related to 
disease recurrence.  Keeping in mind the generally worse prognostic variables of the 
treatment arm, there were no deaths among those vaccinated versus two in the observation 
group.  Furthermore, only two of 24 (8%) vaccinated patients developed recurrence versus 
six of 29 (21%) in the observation group (p=0.19).  At a median follow-up of 22 months, the 
DFS among those vaccinated was 85.7% in contrast to 59.5% for those in the control 
group.  These early results are compelling and indicate a tendency for this vaccination 
strategy to prevent recurrence among high-risk patients.   
The E75 vaccine was also evaluated in NN breast cancer patients in a separate but almost 
identical trial.  In an analysis of the combined results of the two E75 trials to determine the 
safety and effectiveness of the E75 vaccine (Peoples et al. 2008), a total of 171 patients 
were enrolled with 90 in the NP trial and 81 in the NN trial.  During this trial, the E75 peptide 
was determined to bind to the HLA-A3 molecule in addition to HLA-A2.  As such, the 
vaccine was extended to HLA-A3+ patients as well.  A total of 90 patients received the E75 
vaccine (45 NP and 45 NN) while 81 were in the prospectively followed observation arm of 
the studies (45 NP and 36 NN).  Combined toxicity was minimal with local reactions being 
grade 1 (86%) and grade 2 (14%).  Systemic toxicity was grade 0 (16%), 1 (70%), 2 (13%), 

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and 3 (1%).  All patients demonstrated in vitro immunologic responses and in vivo delayed 
type hypersensitivity (DTH) responses post-vaccination, though variable.  For all 171 
patients, the clinical recurrence rate for the vaccinated patients was 5.6% (5/90) compared 
to 14.8% (12/81) for the observation patients (p=0.04) at a median of 20 months.  These 
combined results suggest that the E75 vaccine can be administered safely with minimal 
local or systemic toxicity.  In vitro functional assays and in vivo DTH reactions indicate good 
immunologic responses to the vaccine, but most importantly, the E75 vaccine appears to 
reduce recurrences in disease-free, conventionally treated breast cancer patients.  These 
results are similar to the Herceptin results with an approximate 50% reduction in recurrence 
rates in vaccinated NP and high-risk NN breast cancer patients.  However, the vaccine was 
used in patients with all levels of HER2/neu expression, not only those with over-
expression.   
Recently we have reported updated results from these two trials (Clifton et al. 2010).  A 
total of 188 patients have been enrolled with 109 (58%) HLA-A2+/A3+ patients in the 
vaccine arm and 79 (42%) HLA-A2/A3- patients in the control arm.  A 24-month landmark 
analysis revealed a recurrence rate of 6.5% in vaccinated patients compared to a 
recurrence rate of 14.5% in control patients (p=0.08).  This benefit also appears to be 
durable with a persistent 35% relative risk reduction in breast cancer recurrences in 
vaccinated patients at 57 months of median follow-up.  In subset analyses, patients found 
to derive the most benefit from vaccination included HER2 low or intermediate expressors 
(IHC 1+ or 2+), low grade tumors (grade 1 or 2), patients optimally dosed, and patients who 
underwent booster inoculations.   
The E75 vaccine will next be tested in a large, randomized multi-center Phase III industry-
sponsored clinical trial. 
With the initial success of E75 in phase II trials and the successful extension of the vaccine 
population from HLA-A2+ patients only to include HLA-A3+ patients (described above), 
other preclinical work has been done with E75 and additional common HLA alleles.  In fact, 
Sotiropoulou et al have confirmed CTL precursor frequencies from cancer patients 
responding to E75 in not only HLA-A2+ and HLA-A3+ patients, but also HLA-A26+ patients.  
Furthermore, their lab as well as ours has confirmed the algorithm predictions from both the 
SYFPEITHI & BIMAS systems that E75 binds to HLA-A24 as well.  These data suggest that 
just as the E75 benefit was extended to HLA-A3+ patients, it may also extend to HLA-A24+ 
and 26+ patients.  These two alleles are particularly prevalent in the Asian population.  
Therefore, we intend to also collect clinical data on the use of the vaccine in these two new 
patient populations. 
 
1.7     HER2-DIRECTED THERAPIES IN HER2 LOW-EXPRESSING TUMORS 
While Herceptin has shown significant clinical benefit in the adjuvant setting for breast 
cancer patients with HER2 3+ expressing tumors, there has been some suggestion that 
patients with HER2 2+ expressing tumors may benefit as well from adjuvant Herceptin.  In 
an exploratory analysis of the NSABP trial B-31 (Romond et al. 2005), 174 patients who 

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were subsequently found to be HER2-negative (negative on FISH and less than IHC 3+)  
may have derived a benefit from adjuvant Herceptin therapy with a hazard ratio for disease 
recurrence of 0.34 (95% CI, 0.14 to 0.80; p=0.014) (Paik et al, 2008).  This finding has 
resulted in the initiation of the NSABP trial B-47 to evaluate the efficacy of Herceptin in 
HER2 low-expressing tumors. 
HER2-derived, CD8-eliciting, peptide-based vaccines also appear to have benefit in 
patients with HER2 low-expressing tumors.  Patients from our E75 vaccine trials were 
stratified by HER2 expression levels (Benavides et al. 2009).  Patients with HER2 low-
expressing tumors (IHC 1+, IHC 2+ or FISH<2.0) (n=100; 56 vaccine, 44 control) were 
compared with HER2 overexpressors (n=51; 29 vaccine, 22 control).  Low-expressors had 
larger maximum immunological responses to E75 vaccination than over-expressors 
(p=0.04).  This analysis also found that vaccinated IHC 1+ patients had increased long-
term immunity (p=0.08).  In addition to improved immunity compared to over-expressors, 
patients with low-expressing tumors had a mortality benefit compared to low-expressing 
control patients (p=0.08), a benefit present even in IHC 1+ vaccinated patients (p=0.05). 
1.8 
COMBINED HER2-DIRECTED THERAPY 
While both Herceptin and E75 each have been shown to have clinical benefit in HER2-
expressing breast cancer, the novel concept of combining these two immunotherapies is 
appealing and worthy of investigation.  While Herceptin and E75 share the same 
immunologic target, the specific immunologic mechanisms of action for these therapies are 
different.  This complementary approach to immune-mediated therapy in breast cancer may 
provide a clinically beneficial synergism. 
The combination of Herceptin with HER2-targeted vaccines has been evaluated in 
preclinical testing (Mittendorf et al. 2006).  HER2-expressing tumor cells were incubated 
overnight with Herceptin in concentrations of 10 mcg/mL and 50 mcg/mL.  Cytotoxicity of 
both pretreated and untreated tumor cells was measured using peripheral blood 
mononuclear cells from healthy, HLA-A2+ donors as well as from patients vaccinated with 
E75.  Cytotoxicity by peptide-specific cytotoxic T lymphocytes from non-vaccinated patients 
was increased by 5.6% (10 mcg/mL) and 15.3% (50 mcg/mL) (p=0.002) in pretreated cells 
over untreated cells.  Using peripheral blood mononuclear cells from E75-vaccinated 
patients, peptide-specific cytotoxicity was 34.2% in untreated cells compared to 40.6% (10 
mcg/mL) (p=0.035) and 40.7% (50 mcg/mL) (p=0.0005) in pretreated cells.  These findings 
suggest a synergism may exist with the combination of Herceptin and HER2 vaccination. 
The safety of the combination of Herceptin and HER2-derived peptide vaccines has been 
evaluated in early clinical trials.  The administration of trastuzumab concurrently with a 
HER2 CD4+ helper T cell-eliciting vaccine composed of multiple peptides (one of which 
contains  the E75 epitope) to metastatic breast cancer patients over-expressing HER2 
(n=22) was found to be safe (Disis et al. 2009).  Over 99% of toxicity was grade 1 or 2.  
Median LVEF was unchanged pre- to post-treatment, with three patients (15%) 
experiencing asymptomatic decreases in LVEF; no patient experienced symptoms of left 
ventricular dysfunction.  Experience in our Phase I trial evaluating the combination of 

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trastuzumab and a cytotoxic T cell-eliciting HER2 peptide vaccine in the adjuvant setting 
has not shown any added cardiac toxicity with combination therapy during vaccine dose 
escalation.  Finally, in preliminary Phase II trial results of the combination of Herceptin and 
either HER2 CD4+ helper or CD8+ T cell-eliciting vaccines conducted by our group, no 
additive cardiac toxicity has been found (Mittendorf et al. 2010).   
These early clinical trials have shown promise of efficacy in combination therapy as well.  
Disis and colleagues demonstrated prolonged increases in peptide-specific immunity after 
vaccination, as well as epitope-spreading within the HER2 protein and to other non-HER2 
tumor antigens (Disis et al. 2004).  Finally, we have investigated sequential therapy with 
Herceptin followed by HER2 vaccination in the adjuvant setting in our ongoing Phase II 
trials.  Of 62 patients who received standard of care Herceptin, the 32 who received no 
vaccine have experienced a 12.5% breast cancer recurrence rate (4/32) – comparable with 
reported rates of similarly staged and treated patients.  In contrast, of the 30 patients who 
were vaccinated with either E75+GM-CSF (n=12) or GP2+GM-CSF (n=18) after completing 
Herceptin therapy, the recurrence rate is 0% (0/30) (p=0.065) (Sears et al. 2011).   
The emerging evidence suggesting that patients with low-expressing HER2 breast cancer 
respond to Herceptin or HER2 vaccination combined with the encouraging results 
suggesting synergism in combination therapy are intriguing and are worthy of further 
investigation.  Therefore, we believe that HER2 1+ and 2+ breast cancer patients, who 
have already shown a response to vaccination and possibly to Herceptin alone, could 
potentially show a dramatic response to the combination of Herceptin and E75 with the 
immunoadjuvant GM-CSF and that the combination can be delivered safely. 
2. 
OBJECTIVES 
In this study, we intend to assess the ability of the combination of Herceptin and the HER2 
vaccine E75 (administered with the immunoadjuvant GM-CSF) given in the adjuvant setting 
to prevent recurrences in NP (or NN if negative for both estrogen (ER) and progesterone 
(PR) receptors) breast cancer patients with tumors that express low (1+) or intermediate 
(2+) levels of HER2.  Enrolled patients will be randomized to receive Herceptin and E75 + 
GM-CSF or Herceptin with GM-CSF alone (no E75).  The safety of the combination therapy 
will be documented, specifically to ensure that no additive cardiac toxicity results from 
combination HER2-directed therapy.  Efficacy will be documented by comparing the DFS 
and immunological responses between treatment groups. 
2.1 
PRIMARY OBJECTIVES 
The primary efficacy endpoint is to compare DFS at 24 months between treatment groups.  
The primary safety issue is to prove there is no additive cardiac toxicity with combination 
HER2-directed therapy.   
2.2 
SECONDARY OBJECTIVES 
A secondary endpoint of the trial is to compare DFS at 36 months.  Immunologic responses 
to the vaccine will also be documented and correlated to clinical benefit. 

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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
The study will be a multi-center, prospective, randomized, single-blinded, placebo-
controlled Phase II trial of Herceptin + E75/GM-CSF versus Herceptin + GM-CSF alone.  
The vaccine to be used in this study, E75, is investigational and will be used in combination 
with Herceptin under the Investigational New Drug (IND) Application, BB-IND #14919.  The 
Sponsor/Investigator of this IND is Dr. George E. Peoples. 
Our target study population is NP (or NN if negative for both ER and PR) breast cancer 
patients with HER2 1+ and 2+ expressing tumors who are disease-free after standard of 
care therapy.  Disease-free subjects after or during standard of care multi-modality therapy 
will be screened and HLA-typed (consent #1).  E75 is a CD8-eliciting peptide vaccine that is 
restricted to HLA-A2+ or HLA-A3+ patients (approximately two-thirds of the US population).   
HLA-A2+/A3+/A24+/or A26+ patients who meet all other eligibility criteria will be randomized 
to receive Herceptin + E75/GM-CSF or Herceptin + GM-CSF alone (consent #2).  For both 
groups, Herceptin will be given every three weeks as monotherapy for one year, to be given 
upon completion of standard of care chemotherapy/radiotherapy (Appendix A).   The first 
Herceptin infusion must be given no sooner than three weeks and no later than 12 weeks 
after completion of standard of care therapy.  Herceptin will be dosed at the recommended 
initial loading dose of 8 mg/kg and at recommended maintenance doses of 6 mg/kg q3wk.  
Herceptin will be administered as described in Section 4.3.  Patients randomized to the 
E75/GM-CSF arm will receive vaccinations of E75 (1000 mcg) and GM-CSF (250 mcg) 
administered intradermally every three weeks for six total vaccinations, 30 -120 minutes 
after completion of Herceptin infusion.  With prior approval from the Principal Investigator, 
the vaccine may be administered 15 minutes after completion of Herceptin infusion.  The 
E75/GM-CSF vaccine series will begin in conjunction with the third Herceptin infusion.  
Starting the vaccine series after two rounds of Herceptin alone will allow for evaluation and 
observation for toxicities related specifically to Herceptin.  In extenuating circumstances, 
the first vaccination may be delayed to the fourth or fifth Herceptin infusion with prior 
approval from the Principal Investigator.  Those patients randomized to the GM-CSF alone 
arm will receive vaccinations of GM-CSF (250 mcg) administered in an identical manner to 
those receiving E75/GM-CSF.  Patients will be blinded as to whether they are receiving 
E75/GM-CSF or GM-CSF alone.   
Upon completion of the vaccination series, booster inoculations (same dose and route) will 
be administered every six months x4 for total combination (Herceptin and vaccine) 
treatment duration of 30 months (Appendix A).  The first booster inoculation will occur with 
the final Herceptin infusion, with subsequent boosters timed every six months from the first 
booster.  Booster inoculations will occur for patients randomized to receive E75/GM-CSF as 
well as patients randomized to receive GM-CSF alone, and will consist of the same 
treatment drugs and dosing (i.e., E75/GM-CSF patients will be boosted with E75/GM-CSF 
while GM-CSF alone patients will be boosted with GM-CSF alone).  Patient blinding will be 
maintained throughout the study.   

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Patients will be followed for safety issues, immunologic response and clinical recurrence.  
Patients will be assessed 48-72 hours after each inoculation for reaction to the inoculation 
as well as documentation of any adverse effects experienced (Appendix A).  Immunologic 
response will be monitored primarily by in vivo delayed type hypersensitivity (DTH) 
reactions but also may be documented by other immunologic assays.  All patients will be 
followed for a total of 36 months to document disease-free status.   
We plan to enroll 300 patients (150 in each treatment arm) at a planned accrual rate of 10-
12 patients per month (approximately 0.5-1 enrollment per study site per month).  With 
accrual beginning in approximately April 2013, enrollment of the last patient would be 
expected in approximately August 2017 followed by a three-year follow-up period.  The 
duration of the trial is expected to be seven years. 
3.2 
RATIONALE FOR STUDY DESIGN 
The recurrence rate among NP breast cancer patients with HER2 1+ and 2+ expressing 
tumors after standard of care therapy is reported to be 20% at 24 months.  Herceptin alone 
(with GM-CSF) may have some benefit and decrease the rate to 15% (Baselga et al. 1998, 
Burstein et al. 2001, Cobleigh et al. 1999, Kuzur et al. 2000, Nicholson et al. 2000, Paik et 
al. 2008, Pegram et al. 2000, Pegram et al. 1997, Piccart-Gebhart et al. 2005, Romond et 
al. 2005, Seidman et al. 1999, Seidman et al. 2001).  However, based on preliminary data, 
the combination of Herceptin + E75/GM-CSF virtually eliminated recurrences.  For planning 
purposes, if the combination reduces the recurrence rate to 5%, then in order to show a 
statistical difference between 15% vs. 5%, a sample size of 150 patients per arm would be 
required or a study size of 300 patients (see statistical plan). 
3.3 
OUTCOME MEASURES 
3.3.1 Primary Outcome Measure 
 
The primary clinical outcome of DFS will be determined by patients’ own physicians 
in the medical and surgical and/or the hematology/oncology clinics at the individual 
study sites during their routine follow-up screening.  This will occur for all enrolled 
patients, regardless of randomization, approximately every three months for the first 
24 months after completion of primary therapies and every six months thereafter with 
clinical exam, laboratory and radiographic surveillance (e.g., CT, bone, and 
mammographic scans) as indicated.  This follow-up strategy is standard of care for 
these patients.  If records are not available, patients, or their referring physicians, will 
be contacted to discern their disease status.  All enrolled patients, regardless of 
randomization, will be followed for clinical recurrence for three years after initiation of 
Herceptin therapy.  The recurrence rate and time to recurrence from date of initial 
Herceptin treatment for the patients randomized to receive Herceptin + E75/GM-CSF 
will be compared to the cohort of patients randomized to receive Herceptin + GM-
CSF alone.  The primary objective of the trial is DFS at 24 months with a secondary 
objective of DFS at 36 months. 

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3.3.2 Secondary Outcome Measures 
Secondary outcome measures include immunologic responses and safety of 
combination HER2 therapy.  Immune responses will be primarily documented using 
the DTH reaction but also may be measured using the dimer assay and ELISPOT 
assay.  Each of these measurements would be performed regardless of 
randomization.  Detailed descriptions of these assays/tests are described in Section 
4.4.4 – 4.4.9.  Dimer and ELISPOT measurements may be performed prior to 
initiating the vaccination series as well as prior to the fourth inoculation, and at one 
month after completion of the primary series.  Additionally, these assays may be 
performed pre- and post- each booster and at completion of the study.  Alternatively, 
these assayed timepoints may also be performed all at once on frozen cells and may 
be collected from selected sites only.  DTH reactions will be measured prior to 
initiation of the vaccination series, 3-4 weeks after completion of the primary series, 
and 3-4 weeks after the second and fourth boosters (Appendix A).  Immunologic 
responses in the patients randomized to receive Herceptin + E75/GM-CSF will be 
compared to the cohort of patients randomized to receive Herceptin + GM-CSF 
alone. 
Cardiac toxicity of combination therapy will also be assessed.  Each patient, 
regardless of randomization, will undergo cardiac assessment (ejection fraction) at 
baseline (MUGA preferred, ECHO allowed, consistency required) and at 3, 6, 12, 
and 24 months.  Cardiac assessment will continue every six months if a patient 
experiences a greater than 10% reduction from baseline for the duration of the trial 
or until resolution.   
3.3.3 Ancillary Safety Outcome Measures 
Standard local and systemic toxicities will be collected and graded per the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 graded 
toxicity scale (Appendix B).  For both the regular inoculations and the booster 
inoculations, patients will be monitored for 30 minutes after the inoculation with vital 
signs taken as needed.  Patients will either return to the vaccine clinic at their 
respective study site or be contacted by phone  for questioning regarding any 
systemic and local toxicity, during the initial 48-72 hours after inoculation.  If they 
return to their study site, the local reaction at the inoculation sites will be examined 
and measured.  For patients that do not return to the study site, a tool will be given 
and instructions provided to measure the local reaction.  Serious adverse events will 
be reported as described in Section 5. 
3.4 
SAFETY PLAN 
Patients will be evaluated at each study visit for the duration of their participation in the 
study (Appendix C.1, C.2). 
Specific potential safety issues for this trial are outlined below. 
3.4.1 Cardiac Dysfunction 

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Signs and symptoms of cardiac dysfunction were observed in a number of women 
who received Herceptin alone or in combination with chemotherapy, most often 
anthracycline-based treatment.  Cardiac dysfunction was observed most frequently 
among patients who received Herceptin plus AC chemotherapy (28%), compared 
with those who received AC alone (7%), Herceptin plus paclitaxel (11%), paclitaxel 
alone (1%), or Herceptin alone (7%).  Severe disability or fatal outcome due to 
cardiac dysfunction was observed in ~1% of all patients. 
The nature of the observed cardiac dysfunction was similar to the syndrome of 
anthracycline-induced cardiomyopathy.  The signs and symptoms of cardiac 
dysfunction usually responded to treatment.  Complete and partial responses were 
observed among patients with cardiac dysfunction.  The risk appears to be 
independent of tumor response to therapy.  Analysis of the clinical database for 
predictors of cardiac dysfunction revealed only advanced age and exposure to an 
anthracycline as possible risk factors.  In the clinical trials, most patients with cardiac 
dysfunction responded to appropriate medical therapy, often including 
discontinuation of Herceptin.  In many cases, patients were able to resume treatment 
with Herceptin.  In a subsequent study using weekly paclitaxel and Herceptin as first-
line treatment for metastatic breast cancer, the observed incidence of serious 
cardiac dysfunction was 3% (n=95) (Seidmen et al. 2001).  Since the occurrence of 
cardiac dysfunction in the Herceptin plus chemotherapy trial was an unexpected 
observation, no information is available regarding the most appropriate method for 
monitoring cardiac function in patients receiving Herceptin.  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 CHF while on Herceptin should be treated 
according to the HFSA guidelines (Appendix D).  
3.4.2 Management of Cardiac Safety 
3.4.2.1 Adjuvant Breast Cancer Protocols 
All patients must have a cardiac assessment at baseline (MUGA preferred, ECHO 
allowed, consistency required), and on a regular schedule throughout the course of 
the study.  Investigators are strongly urged to schedule cardiac assessment studies 
at the same radiology facility where the patient’s baseline assessment was done 
whenever possible.  Cardiac assessment studies are required at protocol-specified 
time points and after any patient has any of the following: discontinuation of protocol 
therapy, CHF, breast cancer recurrence, or a second primary cancer.   
Post-surgical radiation therapy may be required in patients at risk for recurrence.  
Whenever possible, irradiation to the internal mammary nodes should be avoided 
because of the concern for possible additional cardiotoxicity from the combination of 
Herceptin and radiation therapy.  Efforts should be taken to ensure that the volume 
of the heart irradiated is minimal.  Investigators are encouraged to discuss cardiac 
toxicity concerns with their radiation oncologists to ensure careful planning of the 
ports of left-sided lesions.   

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Cardiac Safety Criteria for initiation of Herceptin 
Asymptomatic Patients 
If a patient does not have significant symptoms related to left ventricular (LV) 
dysfunction, administration of Herceptin will depend on the absolute change in LVEF 
between baseline and follow-up assessments. 
Herceptin should be initiated in an asymptomatic patient if: 
a) The LVEF increased or stayed the same 
b) The LVEF decreased by ≤15 percentage points but is still at or above the 
lower limit of normal for the radiology facility 
Herceptin is PROHIBITED in an asymptomatic patient if: 
a) The LVEF decreased ≤15 percentage points and is below the limit of 
normal for the radiology facility 
b) The LVEF decreased by 16 percentage points or more (regardless of 
lower limits of normal for the radiology facility)  
Symptomatic Patients 
If a patient has significant symptoms related to LV dysfunction, cardiac ischemia, or 
arrhythmia, initiation of Herceptin is prohibited. 
Management of Symptomatic Cardiac Changes.  Patients who develop signs and 
symptoms of CHF will be taken off treatment, but continued in the study for disease 
follow-up.  They will 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; see Appendix D for HFSA guidelines).  Consideration should 
be given to obtaining a cardiac consultation.  The patient will be followed until 
resolution as per treating physician and reported upon resolution of symptoms. 
Management of Asymptomatic Decreases in LVEF.  Herceptin 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 asymptomatic absolute decrease in 
LVEF of ≥20 percentage points (even if within the normal limits of the institution) or 
an ejection fraction below the range of normal limits, will be taken off treatment, but 
remain in the study for disease follow-up.  They will 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; see 

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Appendix D for HFSA guidelines).  In light of the variability inherent in the 
assessment of ejection fraction, consideration should be given to repeating the study 
to confirm an observed decline.  Repeat measures of LVEF should be obtained 
using the same methodology selected at baseline.  If Herceptin has been 
discontinued for an asymptomatic decline in LVEF, a repeat measure of LVEF will be 
obtained in one month to determine if the decline has resolved. 
Infusion-Associated Symptoms.  During the first infusion with Herceptin, 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 
Herceptin 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 Herceptin 
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 Herceptin 
as indicated. 
Hematologic Toxicity and Neutropenic Infections.  In the clinical trials, an 
increased incidence of anemia was observed in patients receiving Herceptin 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 Herceptin therapy.   
In the clinical trials, the per-patient incidences of moderate to severe neutropenia 
and of febrile neutropenia were higher in patients receiving Herceptin 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 Herceptin and 
myelosuppressive chemotherapy, although in controlled clinical trials (pre- and post-
marketing), the incidence of septic deaths was not significantly increased.  The 
pathophysiologic basis for exacerbation of neutropenia has not been determined; the 
effect of Herceptin 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 Herceptin clinical trials.  Patients 
treated with chemotherapeutic agents are known to be at increased risk for 
secondary leukemia.  The observed incidence of leukemia among Herceptin treated 
patients appears to be consistent with the expected incidence of leukemia among 
patients treated with chemotherapy for metastatic breast cancer.  Therefore, the 

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contribution of Herceptin to the etiology of acute leukemia or myelodysplastic 
syndrome in these cases is unclear. 
Management of Hematologic Toxicities.  Care should be taken to carefully 
monitor the patient’s hematologic status throughout the course of the trial.  Use of 
hematopoietic growth factors to ameliorate hematologic toxicity is at the discretion of 
the physician investigator and should be in accordance with the American Society of 
Clinical Oncologists (ASCO) guidelines.  
Please refer to the HERCEPTIN
® Investigator Brochure for a detailed description of 
the safety profile of Herceptin. 
See Section 5 for complete details of the safety evaluation for this study. 
3.5 
Dose Reductions of Vaccine Component 
For patients experiencing robust local reactions (>100 mm x 100 mm) or greater 
than or equal to grade 3 local or systemic reactions or greater than or equal to grade 
2 hypersensitivity reactions (as defined by NCI CTCAE version 4.03 graded toxicity 
scale (Appendix B)), the dose of GM-CSF will be reduced by 50% on subsequent 
inoculations.  If subsequent reactions occur necessitating dose reduction, the GM-
CSF dose will continue to be reduced serially by 50%.  For example, GM-CSF dose 
would first be reduced from 250 mcg to 125 mcg, with subsequent reductions to 62.5 
mcg, then 30 mcg and finally 0 mcg.  If dose reduction of GM-CSF is inadequate in 
limiting reactions, the E75 peptide dose (if applicable) will then be reduced by 50%.  
In our prior trial, approximately 10% of patients developed delayed hypersensitivity 
reactions (generalized urticaria 10-14 days after booster inoculation).  The majority 
of these patients were readily treated with anti-histamines or oral steroids and most 
continued with subsequent booster inoculations.  If dose reduction is performed for 
hypersensitivity reactions (generalized urticaria), antihistamines may be used before 
or after subsequent inoculations.  If urticaria persists with the use of anti-histamines 
and oral steroids, or intravenous steroids are required, or hospitalization is required, 
or in the opinion of the Principal Investigator, further inoculations will be 
discontinued. 
Dose reductions will continue for booster inoculations in the same manner as 
performed in the primary vaccination series, except for patients who underwent 
multiple dose reductions in the primary vaccine series, who will begin booster 
inoculations with an initial GM-CSF dose of 125 mcg. 
3.6 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug Administration 
(FDA) Good Clinical Practices (GCPs), and local and U.S. Army ethical and legal 
requirements. 

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4. 
MATERIALS AND METHODS 
4.1 
SUBJECTS 
Female patients (n=300) over the age of 18 years with a diagnosis of NP (or NN if negative 
for both ER and PR) breast cancer who have HER2 tumors which are 1+ or 2+ by IHC will 
be targeted.  All patients will have completed primary surgical and medical therapies.  
Patients will be recruited from the medical and surgical oncology and/or the 
hematology/oncology clinics at the individual study sites.  All patients will be properly 
consented.   
4.1.1 Subject Selection 
Potentially eligible patients, specifically NP (or NN if negative for both ER and PR) 
breast cancer patients with HER2 1+ or 2+ expressing tumors will be identified by 
staff in the medical and surgical and/or the hematology/oncology clinics at the 
individual study sites.  IHC testing of primary tumor is necessary for trial inclusion.  
To be eligible for enrollment, patients must have HER2 1+ or 2+ tumors.  For those 
with HER2 2+ tumors, FISH or Dual-ISH testing must also be performed. FISH or 
Dual-ISH results must be non-amplified (or ≤2.0).  HER2 2+ patients with FISH or 
Dual-ISH amplification (>2.0) will not be eligible for this trial.   
Patients who undergo neoadjuvant treatment regimens will be permitted in this trial.  
For patients who undergo pretreatment, eligibility will be determined from 
pretreatment clinical staging (or final pathologic staging if patient is up-staged). 
NP and NN patients must ultimately complete standard of care chemotherapy 
treatment per the National Comprehensive Cancer Network (NCCN) guidelines 
(Appendix E).  NN patients with ER/PR-negative tumors must undergo 
chemotherapy as dictated by standard of care for inclusion.  NN patients in whom 
chemotherapy is not administered will not be eligible for enrollment. 
A research nurse coordinator and/or study coordinator will approach these patients 
about being in the trial and will introduce the trial to the prospective volunteer.  If the 
volunteer is interested and appears eligible, the nurse will arrange an appointment to 
counsel the patient.  The nurse will thoroughly screen the patient for inclusion and 
exclusion eligibility criteria.  If the patient remains interested and eligible, informed 
consent will be obtained.  This screening process may begin prior to the patient 
completing their standard of care therapy. 
Written informed consent will be obtained from all study participants.  Prospective 
participants will be provided with a copy of the consent form to read.  The research 
nurse coordinator and/or study coordinator, or Principal Investigator (PI), will explain 
the study and review the consent form with the patient.  Patients will be given ample 
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Once written informed consent is obtained, the patient will be HLA-typed.  They will 
be asked for 6-8 cc of blood for HLA-A2/A3/A24/A26 screening (FACS analysis 
performed in the Cancer Vaccine Development Laboratory [CVDL], Department of 
Surgery, Uniformed Services University of the Health Sciences [USUHS], Bethesda, 
MD.  Alternatively, the analysis will be performed at M.D. Anderson Cancer Center 
(MDACC) by Dr. Beth Mittendorf.  If a patient submits a prior HLA-2/A3/A24/A26 
positive typing report from an outside CLIA certified lab, this will be accepted for 
screening.  Only HLA-A2, A3, A24, or A26 positive patients will be enrolled in the 
trial.  Those patients who are not HLA-A2, A3, A24, or A26 positive will be excluded.  
Patients will be counseled prior to obtaining consent that lack of HLA-A2, A3, A24, or 
A26 positivity will result in exclusion. 
4.1.2 Inclusion Criteria 
Patients will be included in the study based on the following criteria: 
• Women 18 years or older 
• Node-positive breast cancer (AJCC N1, N2, or N3) 
• Node-negative breast cancer if negative for both estrogen (ER) and progesterone 
(PR) receptors and have received chemotherapy as standard of care 
• Clinically cancer-free (no evidence of disease) after standard of care therapy 
(surgery, chemotherapy, radiation therapy as directed by NCCN guidelines).  
Hormonal therapy will continue per standard of care.  Neoadjuvant chemotherapy 
is allowed. 
• Recovery from any toxicity(ies) associated with prior adjuvant therapy. 
• HER2 expression of 1+ or 2+ by IHC.  FISH or Dual-ish testing must be 
performed on IHC 2+ tumors and shown to be non-amplified by FISH (≤2.0) or by 
Dual-ish (≤2.0). 
• HLA-A2, A3, A24, or A26 positive 
• LVEF >50%, or an LVEF within the normal limits of the institution’s specific 
testing (MUGA or ECHO) 
• ECOG 0,1 
• Signed informed consent 
• Adequate birth control (abstinence, hysterectomy, bilateral oophorectomy, 
bilateral tubal ligation, oral contraception, IUD, or use of condoms or diaphragms) 
• Must start study treatment (receive first Herceptin infusion) between 3-12 weeks 
from completion of standard of care therapy. 
4.1.3 Exclusion Criteria 
Patients will be excluded from the study based on the following criteria: 

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• 
Node-negative breast cancer (AJCC N0 or N0(i+)) unless negative for both 
estrogen (ER) and progesterone (PR) receptors and has received chemotherapy 
as standard of care 
• 
Clinical or radiographic evidence of  distant or residual breast cancer 
• 
HER2 negative (IHC 0) or HER2 3+ or FISH/Dual-ish amplified (FISH >2.0; 
Dual-ish >2.0) 
• 
HLA-A2, A3, A24 and A26 negative 
• 
History of prior Herceptin therapy 
• 
NYHA stage 3 or 4 cardiac disease 
• 
LVEF <50%, or less than the normal limits of the institution’s specific testing 
(MUGA or ECHO) 
• 
Immune deficiency disease or HIV, HBV, HCV 
• 
Receiving immunosuppressive therapy including chemotherapy, chronic 
steroids, methotrexate, or other known immunosuppressive agents 
• 
ECOG ≥2 
• 
Tbili >1.8, creatinine>2, hemoglobin<10, platelets<50,000, WBC<2,000 
• 
Pregnancy (assessed by urine HCG) 
• 
Breast feeding 
• 
Any active autoimmune disease, requiring treatment with the exception of vitiligo 
• 
Active pulmonary disease requiring medication to include multiple inhalers 
• 
Involved in other experimental protocols (except with permission of the other 
study PI) 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
If volunteers meet all inclusion criteria and none of the exclusion criteria and agree to 
participate, they will continue in the study.  Patients will be randomly assigned by 
designated Cancer Insight staff using a computer-generated randomization table to receive 
Herceptin + E75/GM-CSF or Herceptin + GM-CSF alone.  Randomization between the two 
treatment groups will occur in a 1:1 allocation ratio using an institutional balancing 
algorithm.  Randomization will be stratified by HER2 status (1+ or 2+) and nodal staging 
(N0 or N1 vs, N2 or N3) (Appendix F).  Patients will be blinded as to whether they are 
receiving Herceptin + E75/GM-CSF or Herceptin + GM-CSF alone. 
4.3. 
STUDY TREATMENT  
Commercial Herceptin drug will be used and provided free of charge by Genentech.  The 
Sponsor/Investigator of the study will ensure maintenance of complete and accurate 
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with 21 Code of Federal Regulations (C.F.R.), Part 312.57 and 312.62 and Genentech 
requirements. 
4.3.1 Herceptin Formulation 
Herceptin is a sterile, white to pale yellow, preservative-free lyophilized powder for 
intravenous (IV) administration.  Each vial of Herceptin contains 400 mg of 
tratuzumab, 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. 
4.3.2 Herceptin Dosage, Preparation, Administration, and Storage  
a. Dosage 
The recommended initial loading dose is 8 mg/kg (for q3wk dosing schedules) 
Herceptin administered as a 90-minute infusion.  The recommended maintenance 
Herceptin dose is 6 mg/kg q3wk and can be administered as a 30-minute infusion if 
the initial loading dose was well tolerated.  Herceptin may be administered in an 
outpatient setting.  DO NOT ADMINISTER AS AN IV PUSH OR BOLUS (see 
ADMINISTRATION).  If different from above the specific dose and regimen of 
Herceptin to be used should be described here.  For this study, a window of +/- 3 
days is permitted on the every 3 week dosing schedule. 
b. Preparation 
Use appropriate aseptic technique.  Each vial of Herceptin should be reconstituted 
with 20 mL of BWFI, USP, 1.1% benzyl alcohol preserved, as supplied, to yield a 
multidose solution containing 21 mg/mL Herceptin.  Immediately upon reconstitution 
with BWFI, the vial of Herceptin must be labeled in the area marked “Do not use 
after” with the future date that is 28 days from the date of reconstitution. 
If the patient has known hypersensitivity to benzyl alcohol, Herceptin must be 
reconstituted with Sterile Water for Injection (SWFI) (see PRECAUTIONS).  
Herceptin which has been reconstituted with SWFI must be used immediately and 
any unused portion discarded.  Use of other reconstitution diluents should be 
avoided. 
Determine the dose of Herceptin needed, based on a loading dose of 8 mg 
Herceptin/kg body weight or a maintenance dose of 6 mg Herceptin/kg body weight 
for q3wk dosing schedules.  Calculate the correct dose using 21 mg/mL Herceptin 
solution.  Withdraw this amount from the vial and add it to an infusion bag containing 
250 mL of 0.9% sodium chloride, USP.  DEXTROSE (5%) SOLUTION SHOULD 
NOT BE USED.  Gently invert the bag to mix the solution.  The reconstituted 
preparation results in a colorless to pale yellow transparent solution.  Parenteral drug 

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products should be inspected visually for particulates and discoloration prior to 
administration. 
No incompatibilities between Herceptin and polyvinylchloride or polyethylene bags 
have been observed. 
c. Administration 
Treatment may be administered in an outpatient setting by administration of a 8 
mg/kg Herceptin loading dose by IV infusion over 90 minutes.  DO NOT 
ADMINISTER AS AN IV PUSH OR BOLUS.  If Herceptin is being administered 
concomitantly with chemotherapy, Herceptin 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 6 mg/kg Herceptin q3wk (a window of +/- 3 
days is permitted) may be administered over 30 minutes.  
 
Table 1 
Herceptin Infusion Time and Post-Infusion Observation Period 
Herceptin Dose 
Infusion Time 
(minutes) 
Post-Infusion 
Observation Period 
(minutes) 
First infusion 
8 mg/kg 
90 
60 
Second infusion 
6 mg/kg 
30 a 
30 a 
Third and subsequent 
infusions 
6 mg/kg 
30 a 
None a 
a Only if previous dose was well tolerated. 
 
Herceptin should not be mixed or diluted with other drugs.  Herceptin 
infusions should not be administered or mixed with Dextrose solutions. 
d. Storage 
Vials of Herceptin are stable at 2°C–8°C (36°F–46°F) prior to reconstitution.  Do not 
use beyond the expiration date stamped on the vial.  A vial of Herceptin 
reconstituted with BWFI, as supplied, is stable for 28 days after reconstitution when 
stored refrigerated at 2°C–8°C (36°F–46°F), and the solution is preserved for 
multiple use.  Discard any remaining multi-dose reconstituted solution after 28 days.  
If unpreserved SWFI (not supplied) is used, the reconstituted Herceptin solution 
should be used immediately and any unused portion must be discarded.  DO NOT 
FREEZE HERCEPTIN THAT HAS BEEN RECONSTITUTED. 
The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene 
bags containing 0.9% sodium chloride for injection, USP, may be stored at 2°C–8°C 

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(36°F–46°F) for up to 24 hours prior to use.  Diluted Herceptin has been shown to be 
stable for up to 24 hours at room temperature 15°C–25°C; however, since diluted 
Herceptin contains no effective preservative the reconstituted and diluted solution 
should be stored refrigerated (2°C–8°C). 
4.3.3 Herceptin Dosage Modification 
Dose modification of Herceptin is not permitted.   
4.3.4 Herceptin Overdosage 
There is no experience with overdosage in human clinical trials.  Single doses higher 
than 500 mg have not been tested. 
 
4.3.5 Vaccine 
a. Dosage and Preparation 
The E75 vaccine (HER2/neu p369-377) will be supplied by Galena Biopharma.  The 
E75 acetate drug substance is a 9-amino acid peptide produced by solid-phase 
peptide synthesis. E75 acetate drug product is manufactured by Oso 
Biopharmaceuticals Manufacturing, Albuquerque, NM as a 1.5 mg/mL solution in 1 
mL water for injection (WFI) in a 2-mL glass vial.  The control is Water For Injection 
(WFI).  Prior to administration, 0.8 mL of the E75 acetate or control is mixed by the 
pharmacist or research nurse with 1 mL of reconstituted lyophilized Leukine® (250 
µg GM-CSF/mL in solution).  Immediately after mixing, the study drug is withdrawn 
into four 1 mL syringes and within  6 hours, a total of 1.6 mL is administered as 4 
intradermal injections.  The control vial contains 1 mL WFI.  The guidance for mixing 
E75 (or control) solution from lyophilized Leukine® 250 µg and test drug (E75 
solution or control) is stated in Appendix G.  Galena Biopharma, Inc. will supply both 
agents, the E75 and the GM-CSF. 
 
Leukine® (sargramostim) is a recombinant human granulocyte-macrophage colony 
stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a 
yeast (S. cerevisiae) expression system.  Biological potency is expressed in 
International Units (IU) as tested against the World Health Organization (WHO) First 
International Reference Standard.  The specific activity of GM-CSF is approximately 
2.8 x 106 IU/mL. See GM-CSF (Leukine® (sargramostim)) package insert and 
labeling (Appendix H) for additional details.  
 
GM-CSF is a potent cytokine that stimulates granulocytes (neutrophils, eosinophils 
and basophils) and monocytes, but not lymphocytes, erythrocytes, or platelets. 
Recombinant human GM-CSF is a 14.6 kDa globular protein consisting of 128 
amino acids containing 2 intramolecular disulfide bonds and 2 potential N-linked 
glycosylation sites.  Known adverse effects of GM-CSF include bone pain, allergic 
reactions, lethargy, malaise, anorexia, skin rashes, flushing, fever, and chills.  At 
doses higher than planned in this study, weight gain may be seen along with 

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breathing difficulties, blood clots, and collections of fluid around the heart or lungs, 
dyspnea, thromboembolic phenomena, and pleural and pericardial effusion. 
 
In the United States, GM-CSF is commercially available as Leukine® 
(sargramostim,expressed in yeast).  In some countries, GM-CSF is commercially 
available as molgramostim (expressed in bacteria).  For this study, Leukine® will be 
provided and exclusively used.  The Package Insert for Leukine® is enclosed in this 
Protocol as Appendix H. 
 
Allow the E75 acetate or control to warm to room temperature and the Leukine® to 
warm to room temperature.  Using aseptic technique with a 1 mL syringe and 
provided needle, withdraw 0.8 mL from the test drug vial (E75 or control) and inject 
the syringe containing 0.8 mL of test drug into the reconstituted Leukine.  Keeping 
the vial upright, slowly roll the Leukine/Test Drug vial between your hands.  Allow 
any foaming to dissipate before continuing.  Do not invert the vial.  This assures the 
complete mixing of the E75 acetate or control and Leukine® solutions (see detailed 
guidance in Appendix G for vaccine and DTH preparation).  Discard the mixing 
syringe and needle. 
 
Once E75 or the control have been mixed, the four provided 1 mL syringes are used 
to withdraw equal volumes into each, and thus a total of 1.6 mL of the solution is 
withdrawn for administration.  The syringes are now ready to be used for inoculation 
and must be used within 6 hours of mixing. 
 
If dose reduction of GM-CSF is required based on >100 mm x 100 mm  induration, 
and/or ≥Grade 3 toxicity at the injection site after the previous dose, the liquid 
Leukine® vial is diluted with an additional 1.0 mL WFI, using aseptic technique, and 
mixed gently by rolling the Leukine vial between your hands.  Allow any foaming to 
dissipate before continuing.  Do not invert the vial.  Subsequently, 1 mL is withdrawn 
and discarded and the remaining 1 mL is used for mixing following the same 
methodology above to make a 1.6 mL Leukine + E75 mixture.  Further dilutions 
(approximately 1:1) may be required if >10 cm erythema and induration and/or ≥ 
Grade 3 toxicity are observed on subsequent doses, the details of which will be 
provided in study instructions. 
 
b. Storage 
For detailed storage instruction of the vaccine and its components (E75 acetate in 
WFI and GM-CSF) please follow the instructions in the Investigator’s Brochure.  
Stability data support storage of E75 acetate in WFI and control to E75 acetate in 
WFI at -20°C (± 5°C) or 5°C (± 3°C).  Store study drug (E75 acetate in WFI, control 
to E75 acetate in WFI, and GM-CSF) as per appropriate storage temperature 
designated on clinical carton label. 
 
4.3.6 Inoculation Series - administration 

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Patients will receive 4 intradermal inoculations on the anterior or medial side of the 
same thigh.  The general area of inoculation will be at a location midway between 
the inguinal ligament and the knee. 
The 1.6 mL by volume vaccine (or GM-CSF alone) will be administered intradermally 
in four equal inoculums at four different sites in a square configuration 5 cm from 
each other.  Inoculations will be given every three weeks and will be administered in 
the same lymph node draining area (same arm or leg).  Timing of the inoculation 
series with Herceptin treatment will occur as outlined in Section 3.1 (see also 
Appendix A).  The dose will be 1000 mcg of E75 peptide and 250 mcg of GM-CSF.  
The research nurse coordinator will administer the inoculations sterilely in the 
vaccine or clinical laboratory facility located at each study site.  For female patients 
with childbearing potential, a urine pregnancy test will be performed before each 
inoculation.  If this test is positive at any time, the patient will be discontinued from 
the study. 
4.3.7 Booster Inoculations 
After completion of the six-inoculation primary vaccine series, patients will then 
receive a total of four booster inoculations to be administered, every 6 months x4 for 
total combination (Herceptin and/or Vaccine) treatment duration of 30 months  
(Appendix A).  As discussed in Section 3.1, the first booster inoculation will occur at 
the time of the final Herceptin infusion with subsequent boosters timed every 6 
months (± 2 weeks) from the first booster and should be administered in the same 
extremity as the primary series.  Booster inoculations will consist of the same 
intervention as each patient received during their regular inoculation series.  Patients 
enrolled to the E75/GM-CSF vaccine arm of the trial will receive four consecutive 
booster inoculations of 1000 mcg E75 peptide + 250 mcg GM-CSF, and patients 
enrolled to the GM-CSF alone arm will receive four consecutive booster inoculations 
of 250 mcg GM-CSF only.   
For patients with childbearing potential, a urine pregnancy test will be performed 
before each booster inoculation.  If this test is positive at any time, the patient will be 
discontinued from the study. 
4.4 
STUDY ASSESSMENTS 
Signed, IRB-approved informed consent must be obtained from patients prior to any 
pretreatment assessments.   
All patients will undergo a cardiac assessment at baseline (MUGA preferred, ECHO 
allowed, consistency require) and at 3, 6, 12, and 24 months.  Cardiac assessment will 
continue every six months if a patient experiences a greater than 10% reduction from 
baseline for the duration of the trial or until resolution.  There will be an allowable window of 
+/- 2 weeks for each study interval assessment test, beginning from the baseline MUGA or 
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All patients must have a Complete Blood Count (CBC) and Comprehensive Metabolic Panel 
(CMP) (20 cc of blood) within two months of trial initiation (date of enrollment for full 
participation) and, for female patients, a urine pregnancy test (upon consent to study), for 
screening and immediately prior to any vaccine inoculations or DTH.  Urine pregnancy tests 
will not be required for Herceptin infusions alone.  If the pregnancy test is positive, the patient 
will be excluded from the study.  Women who have had a hysterectomy, bilateral 
oopherectomy, tubal ligation, documented absence of menses for two years, or FSH 
hormonal laboratory results that verify menopause, will not be required to have pregnancy 
testing.  For patients who have a complete metastatic evaluation (CBC, LFTs, CXR, chest 
and abdomen CT, bone scan, and PET scan) available, all studies will be screened, but 
these studies are not required for enrollment.  Disease-free status will be assured by the 
patients’ primary treating/referring physician.  Overall health screen will be assessed utilizing 
the ECOG performance status grading system (Appendix I). 
To ensure eligibility, each patient will be HLA-typed.  They will be asked for 6-8 cc of blood 
for HLA-A2/A3/A24/A26 screening (FACS analysis performed in the CVDL at USUHS in 
Bethesda, MD or alternatively at UT M.D. Anderson as described in Section 4.4.5).   
All patients regardless of randomization may be assessed for baseline immunologic 
responses prior to receiving the first dose of Herceptin and prior to the first inoculation.  
This may occur at selected sites.  Specimen handling, processing, and assays are 
described in Sections 4.4.3, 4.4.4, 4.4.6 and 4.4.7. 
All patients will be tested for pre-inoculation DTH reaction against the E75 vaccine peptide 
as described in Section 4.4.9.  Reactions will be read 48-72 hours after placement of the 
peptide. 
4.4.1 Assessments during Treatment 
All patients will undergo cardiac assessment as per Section 3.4 at 0, 3, 6, 12, and 24 
months, +/- a 2 week window at each interval test, beginning from the baseline 
study.  Cardiac assessment will continue every six months if a patient experiences a 
greater than 10% reduction from baseline for the duration of the trial.  The safety 
assessments will be evaluated by the site-specific study investigators.  They will be 
responsible for assessment of patients with any toxicity reported to, or identified by, 
the study coordinators.  The coordinators will assess the patients prior to and after 
Herceptin infusion, prior to and  after vaccine inoculation, and will assess the patient 
48-72 hours after vaccine inoculation, and on an “as needed” basis.  The 
investigators will review all ECHO or MUGA results done at protocol time points, as 
well as any abnormal laboratory or image findings. 
For both the regular inoculations and booster series of shots, the patients will be 
monitored for 30 minutes following inoculation and vital signs taken as needed.  
Patients will either return to their study site or be contacted by phone for questioning 
regarding any systemic and local toxicity during the initial 48-72 hours after 
inoculation. If they return to the study site, the local reaction at the inoculation sites 
will be examined and measured. For patients that do not return to the study site, a 

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tool will be given, and instructions provided to measure the local reaction.   The NCI 
CTCAE version 4.03 graded toxicity scale (Appendix B) will be utilized to assess 
local and systemic toxicity.   
Blood samples will be obtained from all patients, regardless of randomization, to 
determine in vivo induction of peptide-specific immune responses as described in 
Sections 4.4.3, 4.4.4, 4.4.6 and 4.4.7.  This may occur at selected sites. 
4.4.2 Follow-Up Assessments 
The clinical endpoint of recurrence will be determined by patients’ own physicians in 
the medical and surgical and/or the hematology/oncology clinics at the individual 
study sites during routine follow-up screening of all enrolled patients, regardless of 
randomization, every three months for the first 24 months after completion of primary 
therapies and every six months thereafter with clinical exam, laboratory and 
radiographic surveillance, e.g., CT, bone, and mammographic scans as indicated.  
This follow-up strategy is standard of care for these patients.  The determination of 
recurrence will be per standard of care by the treating/referring physicians and 
communicated to the study investigators on a routine basis.  Documentation of the 
recurrence will be obtained.  Whenever possible, pathologic confirmation of 
recurrence will be obtained.  However, a patient will also be considered to have a 
recurrence if highly suggested on radiographic evaluation and treatment for the 
recurrence is initiated by the treating physician.  Documentation of the latter will be 
obtained.  Disease free survival (DFS) as described by the NCI is the length of time 
after treatment for a specific disease during which a patient survives with no sign of 
the disease.  For the purposes of this trial, the DFS will be calculated from initiation 
of Herceptin therapy until date of last follow-up.   If records are not available, 
patients, or their referring physicians, will be contacted to discern their disease 
status and every effort will be made to obtain documentation.  All enrolled patients, 
regardless of randomization, will be followed for clinical recurrence for up to three 
years from the date of initiation of Herceptin therapy.   This data will be added to the 
patient database. 
4.4.3  Human Biological Specimens 
In order to determine in vitro induction of peptide-specific immune responses in the 
vaccinated patients and GM-CSF-specific responses in the immunoadjuvant only 
patients, 50 cc of blood will be drawn prior to the first Herceptin dose, prior to first 
DTH #1 inoculation in the series, and before the fourth inoculation for immunologic 
studies to be performed in the CVDL at USUHS or at MDACC (Appendix A).  In 
addition, 50 cc of blood will be drawn at 3-4 weeks after completion of the primary 
inoculation series for immunologic studies.  Thus, a total of 200 cc of blood will be 
drawn related to the primary inoculation series, at selected sites.  De-identified 
patient blood samples showing only the unique study ID number are sent from study 
sites via overnight delivery to the CVDL/MDACC where immunologic response 
assays (see Sections 4.4.4, 4.4.6 and 4.4.7) are performed.  At no point will 
CVDL/MDACC personnel have access to patient identifiers.  All assays performed at 

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the CVDL/MDACC are for research purposes only.  These functions are conducted 
under a separate protocol approved by the USUHS Research Office as constituting 
non-human patients research or similar protocol at MDACC.    Fifty cc of blood will 
also be drawn before administration of each booster inoculation and as well as at 3-4 
weeks post-inoculation to record the immunologic response to each of 4 booster 
inoculations for a total of 400 cc of blood.  Therefore, a maximum of up to 600 cc of 
blood will be drawn from all patients regardless of randomization over 36 months for 
immunologic response assessment.  This blood will be in addition to the clinical 
laboratory tests (CBC and CMP) needed for enrollment screening.  The clinical tests 
will require a total of 20 cc.  The HLA typing requires 6-8 cc.  Therefore, a total of 
628 cc of blood will be required for the entire study.   
As noted above, de-identified blood tubes for research purposes will be labeled only 
with the patients’ unique study number and sent via overnight delivery to the 
CVDL/MDACC.  At no point will CVDL/MDACC personnel have access to patient 
identifiers.  Excess blood not used in assays will be frozen and stored under the 
unique protocol number and identifier for up to five years from collection for 
additional immunologic studies as needed.  No genetic testing will be performed on 
this material, and it will not be made available to any other unrelated investigator.  
Peripheral blood mononuclear cells (PBMC) can be isolated by ficoll gradient 
separation.  A small number may be tested immediately for peptide recognition.  
Some can be utilized to expand peripheral blood lymphocytes (PBL) in culture in low 
dose IL-2 and stimulated as necessary under different conditions.  Evidence of 
immunologic recognition of the vaccinated peptide may be assessed by clonal 
expansion (dimer or tetramer assays) and functional assays such as cytokine 
release/production (ELISPOT).  Other immunologic assays may be selectively 
assessed as well (e.g., antibody production).  Additionally, excess blood may also be 
utilized to assess new generations of vaccines.     
  
4.4.4  Specimen Processing 
Peripheral blood from patients are collected into BD Vacutainer CPT Cell 
Preparation Tubes (BD, Franklin Lakes, NJ) which contain an anticoagulant (sodium 
heparin or sodium citrate) with FICOLL HYPAQUE density gradient fluid and a 
polyester gel barrier.  The density gradient fluid and the gel barrier allow for the 
separation of PBMC from the red blood cells by a single step centrifugation process.  
The PBMC fraction will be collected by centrifugation and suspended in RPMI-1640 
(GIBCO, Invitrogen Corporation, Carlsbad, CA) with 10% FCS (Gemini Bio-Products, 
West Sacramento, CA) and antibiotics.  For the propagation of cultures the PBMC 
will be suspended at 1-2 x 106 cells/ml with or without 50 IU/ml of IL-2 (R&D 
Systems, Minneapolis, MN) being added at the beginning or at a later time.  The cell 
cultures are placed in a humidified incubator at 37ºC in 5% CO2 and maintained with 
the addition of media as needed and/or IL-2 every 2-3 days depending on the growth 
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4.4.5  HLA-A2/A3/A24/A26 Testing 
The expression of HLA-A2 by the patients is confirmed by staining peripheral blood 
mononuclear cells (PBMC) with anti-HLA-A2 monoclonal antibody, (clone BB7.2), 
directly conjugated to phycoerythrin (PE) or fluorescein-isothiocyanate (FITC) (BD 
Biosciences) at 4ºC for 60 minutes.  The expression of HLA-A3, A24, and A26 by the 
patients is confirmed by staining PBMC with the appropriate biotinylated-anti HLA-
allele monoclonal antibody (One Lambda Inc.) for 45 minutes after which the cells 
are washed and incubated for an additional 15 minutes with streptavidin-
phycoerythrin.  After incubation the cells are washed and analyzed on a FACSCanto 
II flow cytometer (BD Biosciences, San Diego, CA).  
4.4.6  Dimer Assay 
Fresh PBMC can be isolated and stained with HLA-A2:Ig DimerX reagent (Dimer) 
(BD PharMingen).  The HLA-A2:Ig DimerX is a recombinant fusion protein of two 
extracellular MHC Class I HLA-A2 domains that are fused together with the VH 
regions of mouse IgG1.  The Dimer will be “loaded” with the E75 or control peptides 
(E37 and Flu-M) and then incubated with fresh PBMC.  The PBMC will then be 
stained with FITC-labeled anti-mouse IgG1 and anti-CD8 PE and analyzed with two-
color flow cytometry to determine the percentage of CD8+ T cells which specifically 
recognize the E75 peptide. 
4.4.7  ELISPOT Assay 
Freshly isolated PBMC are cultured/stimulated overnight in complete medium (RPMI 
+ 5 %FCS + PSG) supplemented with IL-7 (20 ng/mL) with the individual peptides at 
25 μg/mL (E37, E75, GP2, Flu-M) or (AEN, AE36, AE37, tetanus toxoid) or PMA + 
Ionomycin in flat-bottom anti-human IFN-γ ELISPOT plates (BD PharMingen) at 5 x 
105 cells/well/200 μL in duplicate wells.  The plate is incubated at 37ºC overnight after 
which the wells will be washed and incubated with the biotinylated-anti-IFN-γ mAb for 
two hours.  The wells will be washed again and incubated with streptavidin-
conjugated HRP for one hour.  After a final wash the AEC-substrate solution will be 
added to the wells and allowed to develop for approximately 5-10 minutes at which 
time the wells will be washed with deionized water to stop the reaction.  The number 
of spots present in each well will be enumerated using the CTL ELISPOT analyzer 
(CTL Analyzers LLC, Cleveland, OH). 
4.4.8  Local Reaction 
Patients will also be assessed for evidence of in vivo immunologic response by 
evaluation of the injection site 48-72 hours after each inoculation (Appendix A).  The 
injection site reaction will be measured using the sensitive ball point pen method if 
the patient returns to the study site.  A digital photograph of the local reaction may 
be taken to document the reaction and for future reporting purposes.  It will in no way 
be visually identifiable as that patient.  Photographs will be labeled with the patient’s 
study number and will not include the face or distinguishing birthmarks or tattoos.  
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office in the vaccine or clinical laboratory facility at each site.  Per FDA regulations, 
each patient’s photograph will be kept for two years after submission of a New Drug 
Application (NDA) and then destroyed.  If the patient does not return to the study 
site, they will be contacted by phone 48-72 hours after inoculation for questioning 
regarding the reaction at the injection sites.  
4.4.9  DTH Reaction 
Regardless of randomization, a pre- and post-inoculation series DTH response 
(Appendix A) will be assessed of all patients with 100 mcg of E75 (without GM-CSF) 
injected intradermally at a site on the back or anterior thigh (opposite side from the 
vaccination site).  See detailed guidance (Appendix G) for vaccine and DTH 
preparation.  The DTH reaction will be measured at 48-72 hours using the sensitive 
ball point pen method and compared between pre-inoculation and post-inoculation 
time points.  Additionally, DTH responses will also be assessed 3-4 weeks after the 
second and fourth booster.  The low dose of peptide used in the DTH test is not 
expected to induce a long-term immune response; however, any response that is 
induced is expected to be transitory in nature.  A digital photograph of the local 
reaction will be taken to document the reaction and for future reporting purposes.  It 
will be labeled with the patient’s study number, will not visually identify the patient, 
and will not include the face or distinguishing birthmarks or tattoos.  Photographs will 
be electronically stored on a password protected computer in a locked office in the 
vaccine or clinical laboratory facility at each site.  As per FDA regulations, each 
patient’s photograph will be kept for two years after submission of a NDA and then 
destroyed.  These results will also be recorded in the immune response database. 
4.5 
DISCONTINUATION OF PROTOCOL-SPECIFIED THERAPY 
Protocol-specified therapy may be discontinued for any of the following reasons: 
• Progressive disease 
• Unacceptable toxicity as described in the protocol. 
• Please refer to sections 3.4-3.5 (Safety Plan) for the management of cardiac 
issues (symptomatic and asymptomatic), infusion-associated events, 
hematologic toxicity and neutropenic infections, as well as delayed 
hypersensitivity reactions.  Adverse events that do not respond to either dose 
modification (as described) or clinical management of the reaction will result in 
discontinuation from the study. 
• Please refer to section 4.6 (Subject Discontinuation) for a list of severe adverse 
reactions warranting discontinuation from the study.  
• Patient election to discontinue therapy (for any reason) 
• Physician’s judgment 

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4.6 
SUBJECT DISCONTINUATION 
Those patients who display significant reactions (i.e., severe anaphylactic reaction 
immediately after vaccine administration) or toxicities will be discontinued from the study as 
determined by the PI.  They will be followed by the study investigator until resolution of the 
adverse event. 
Inoculations will be immediately halted if any serious adverse reactions occur to include: 
death, life-threatening adverse drug experience (i.e., severe anaphylactic reaction 
immediately after vaccine administration), inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/incapacity, a congenital 
anomaly/birth defect, or other important medical events that may not result in death, be life-
threatening, or require hospitalization but which, when based upon appropriate judgment of 
the PI, be determined to jeopardize the patient or require medical or surgical intervention to 
prevent an outcome listed above.  Any death or grade 4 adverse drug experience found to 
be directly related to the experimental vaccine will result in suspension of patient enrollment 
to the study.  If the SAE is determined to be unrelated to the study drug, inoculations may 
be re-started if the patient desires to continue and it is safe for them to do so as determined 
by the PI and Sponsor. 
Per 3.5 (Dose Reductions of Vaccine Component (paragraph one), for robust local, 
systemic > Grade 3, and > Grade 2 hypersensitivity reactions, as evaluated under CTCAE 
v4.03, will result in dose reduction or discontinuation as discussed. 
In the event of cardiac toxicities, the determination for discontinuation is described in 
section 3.4.2.  Although prior history of vaccine therapy (with or without Herceptin TM) in 
Phase I and II studies has not shown evidence of cardiac toxicities, potential overlapping of 
study treatment will be monitored by ECHO or MUGA scans done every three months 
during vaccine therapy.  Any symptoms of CHF reported by patients, or observed by study 
coordinators, will be documented and reported to the investigators for a determination on 
relatedness to either HerceptinTM or the vaccine component.  While this attribution will be 
difficult on a per patient basis, the incidence between the Herceptin only arm will be 
compared to the Herceptin + vaccine arm to assess for additive toxicities.  The Principal 
Investigator will determine if safety permits continuation in study regardless of attribution, 
based on the parameters under Section 3.4 (Safety Plan).  If LVEF drops >20% or is below 
facility limits of normal or patient is symptomatic of CHF and requires treatment, the patient 
will be discontinued from treatment but remain on the study for disease follow-up.  Patients 
will be followed until the resolution of the toxicity. 
Patients may withdraw from the study at any time and for any reason.  A patient may be 
asked to withdraw from the study by the PI if they are not compliant with the timing of the 
inoculation series, observation period, or return visits to monitor for study-associated 
toxicities.  Additionally, if the PI determines that it is no longer safe for a patient to continue 
in the trial for any reason, they may be withdrawn.   
Because it is not known whether these inoculations might harm an unborn child, patients 
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enrolled into the study.  Women of childbearing age will take a urine pregnancy test before 
starting this study and prior to each inoculation; a positive test result will terminate the 
patient’s participation in the study.  Patients will be counseled to avoid becoming pregnant 
while participating in this study, and that in order to prevent pregnancy they should either 
have no sexual relations or use a reliable type of birth control.  They will be counseled that 
with the exception of hysterectomy, bilateral oopherectomy, or tubal ligation, birth control 
methods are not totally effective in preventing pregnancy, and that the only ways to 
completely avoid the risk of the vaccine or immunoadjuvant alone to an unborn baby are (1) 
avoid becoming pregnant, or (2) do not receive these inoculations.  Patients will be 
counseled to avoid becoming pregnant for at least 6 months after receiving the inoculations 
as pregnancy within this time after inoculation administration may be a risk to an unborn 
baby. 
If a patient is discontinued from the study for an adverse event or pregnancy, they will 
continue to be followed for resolution of adverse event and clinical recurrences as 
described in Section 4.4.2 unless the patient withdraws consent for further study evaluation.  
The reason for any premature discontinuation of a patient from the study will be recorded 
on the appropriate Case Report Form (Appendix J). 
4.7 
STUDY DISCONTINUATION 
Genentech Study Center, Galena Biopharma, the Data Safety Monitoring Board, 
Sponsor/Investigator and the Principal Investigator have the right to terminate this study at 
any time.  Reasons for terminating the study may include the following: 
• The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
• Subject enrollment is unsatisfactory 
• Data recording are inaccurate or incomplete 
• Study protocol not followed 
4.8 
STATISTICAL METHODS 
4.8.1 Analysis of the Conduct of the Study 
Safety Population 
The population of patients evaluable for safety will include all patients who receive at 
least one study inoculation 
Intention-to-Treat Population 
The Intention-to-Treat (ITT) population will include all patients who were randomly 
assigned; ITT analysis will be performed with each randomized patient evaluated in 
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Per-Protocol Population 
The Per-Protocol (PP) population is a subset of the ITT population.  Patients may be 
excluded from the PP population for the following reasons and others as determined 
prior to database lock: 
• Violations of eligibility criteria 
• Development of other malignancies 
• Early recurrences occurring prior to completion of the entire primary vaccine 
series 
• Receiving alternative disease-directed therapy without evidence of recurrence 
• Major deviation from prescribed vaccination scheduled (to include boosters) 
4.8.2 Analysis of Treatment Group Comparability 
Demographic characteristics of all patients in the ITT and PP populations will be 
tabulated including age, race, country/region, disease histology, tumor size, ER/PR 
status, grade, HER2 status, nodal status, AJCC staging, surgery extent, and prior 
disease-directed therapies to include chemotherapy, radiation therapy, hormonal 
therapy, and immunotherapy. 
Unless otherwise noted, continuous variables will be summarized using the number 
of patients, mean, standard deviation, median, minimum, and maximum; and 
categorical variables will be summarized using the frequency count and the 
percentage of patients in each category. 
Comparability between treatment groups for categorical variables will be assessed 
using a 2-sided Fisher’s Exact test or a singly-ordered exact test (e.g. ER/PR status, 
stage), and 2-sample t-tests for continuous variables. 
4.8.3 Efficacy Analysis 
a. Primary Endpoint 
The primary efficacy endpoint of the trial is DFS at 24 months, compared 
between the two treatment arms (Herceptin + E75/GM-CSF versus Herceptin + 
GM-CSF alone).  Time to recurrence will be measured from the date of the first 
Herceptin infusion. 
b. Secondary Endpoints 
Secondary endpoints of the trial are: 
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• Immunologic responses to vaccination between treatment arms will be 
measured and compared using the DTH reaction, secondary comparisons 
may be made using the dimer and ELISPOT assays. 
• Comparison of safety measures (MUGA or ECHO) related to combination 
therapy 
Efficacy parameters will be analyzed and summarized for both the ITT and PP 
populations.  Patients who entered the trial but did not meet inclusion criteria, or who 
did meet exclusion criteria will be excluded from efficacy analysis.   
Withdrawal 
Patients may withdraw or be discontinued from the study as discussed in Section 
4.7.  Patients who do withdraw or are discontinued will be included in the efficacy 
analyses unless a subject withdraws consent to participate.  In the instance of a 
subject withdrawing consent, any data collected will be excluded from analysis. 
Primary Efficacy 
The primary efficacy endpoint analysis of 24-month DFS will be compared between 
the two treatment arms using a proportional hazard model including the stratification 
factors to estimate the hazard ratio.  Hazard ratios and 95% two-sided confidence 
intervals will be presented.  The model will also examine two-way treatment 
interactions with the baseline stratification factors.  Kaplan-Meier curves will be 
generated to display time to events for each treatment group.  
The null and alternative hypotheses are:  
H0: hV / hC = 1 
Ha: hV / hC ≠ 1 
where hV is the constant Herceptin + E75/GM-CSF hazard rate and hC is the 
constant Herceptin + GM-CSF alone hazard rate.  Herceptin + E75/GM-CSF efficacy 
is demonstrated when hV / hC < 1; the alternative hypothesis is a 0.35 hazard ratio. 
A difference in the recurrence rate of 5% in patients treated with Herceptin + 
E75/GM-CSF versus 15% in those treated with Herceptin and GM-CSF alone will be 
considered significant.   
The PP population analyses will be the primary while ITT analyses will be 
confirmatory.   
The stratification factors are the following: 
• Nodal status (N0 or N1 versus N2 or N3) 
• HER2 1+ versus HER2 2+ 
 
Stratification will be performed to balance the treatment arms; however, the trial is 
designed to detect vaccine efficacy as measured by DFS at 24 months between the 
two treatment groups.  The study is not powered for subgroup analysis. 

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Confirmatory analyses will be performed using a stratified log rank test for each of 
the stratification factors.  
To explore the possibility of a treatment by investigative site interaction, the primary 
analysis will also be conducted by site for the ITT and PP populations.  Sites that 
have enrolled large numbers of patients relative to other trial centers will be identified 
to see if the results obtained at those investigative sites are influential.  Investigative 
sites that individually represent fewer than ten patients will be combined for this 
exploratory analysis; geographic region will be substituted if the average number of 
patients per site is fewer than ten. 
Secondary Efficacy 
Secondary efficacy objectives include the same analysis (DFS) at 36 months and 
comparison of the immunologic responses to the target antigen in both the treatment 
and control groups with correlation to clinical outcomes. 
The immunologic recognition by T-cells of the E75 peptide may be evaluated using a 
2-sample t-test to evaluate the mean increase in cell populations from the dimer 
assay and peptide-specific IFN-gamma release from pre-vaccination (R0) to each of 
the following time points: before the 4th inoculation (R3), one month after completion 
of the six inoculation vaccine series (R6), six months after completion of the primary 
vaccine series (RC6), 12 months after completion of the primary vaccine series 
(RC12), 18 months after completion of the primary vaccine series (RC18), 24 
months after completion (RC24), and 30 months after completion (RC30) (Appendix 
A). 
Booster inoculations will be administered after the RC6, RC12, RC18, and RC24 
blood samples have been drawn.  The response to the booster inoculations may be 
measured one month after each successive booster inoculation: Month 13 (RB1), 
Month 19 (RB2), Month 25 (RB3), and Month 31 (RB4) (Appendix A). 
The R3, R6, RC6, RC12, RC18, RC24, and RC30 assessments can be compared to 
pre-vaccination (R0) levels thereby using the patients as their own controls.  RB1, 
RB2, RB3, and RB4 can be compared to the pre-booster responses.  Evidence of in 
vivo immunologic response will also be assessed with the DTH reaction for each 
treatment group.  The treatment groups will be compared with respect to the 
percentage with a positive post-vaccination DTH as well as absolute DTH reaction 
sizes within the groups.  Expression percents will be compared using a two-sided 
Fisher Exact test while continuous outcomes such as mean DTH response will be 
compared using a paired t-test (using the patients as their own controls) and using 
an unpaired t-test to compare treatment groups for post-inoculation outcomes. 
All of the above analyses will also be performed comparing safety, immunologic 
response and clinical outcomes between study patients based on HLA type.  The 
HLA-A2 and/or HLA-A3 positive patients are the primary study population.  The HLA-
A24 and/or HLA-26 positive patients are an exploratory study population.  If these 
patient populations respond comparably to the vaccine, then all vaccinated patients 
will be included in the final analysis.   
4.8.4 Safety Analysis 
Safety parameters will be analyzed and summarized for the Safety Population.  

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Adverse events will be classified and graded using the NCI CTCAE version 4.03 for 
both local and systemic toxicities.  Only treatment-emergent AEs will be tabulated.  
All AEs will be included in the data listings, including onset timing (timing relative to 
study treatment administration), duration, severity, relationship, and resolution. 
The incidence and frequency of treatment-emergent: AEs, SAEs, severe AEs, AEs 
related to study drug (See Appendix N for causality assessment guidelines) , and 
AEs which lead to study discontinuation will be presented by treatment group.  
The incidence and frequency of treatment-emergent AEs will be summarized by 
treatment group using counts and percentages: 
• by system organ class and preferred term 
• by system organ class, preferred term, and maximum severity 
• by system organ class, preferred term, and strongest relationship to study drug. 
For the incidence, if a subject experiences the same event more than once, the 
event with the highest severity will be included in the severity tabulation, and the 
event with the highest relationship will be included in the relationship tabulation.  For 
the frequency, all AEs will be tabulated. 
A 2-sided Fisher Exact test will be used to compare the incidence of any expected 
AEs between the 2 treatment groups. 
Adverse events origination will be attributed to prior breast cancer therapy, study 
therapy, or surgery or shared as most appropriate.  The results will be tabulated be 
treatment group. 
Kaplan-Meier life tables will be used to compare the time to onset and the duration of 
any AE with >10% incidence.  
A singly ordered Kruskal-Wallis test will be used to compare the total number of AEs, 
SAEs, and related AEs per treatment group. 
The incidence of clinically significant CHF will be estimated for patients in pre-
specified treatment groups.  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. 
4.8.5 Planned Analyses 
There are four formal analyses planned for this trial.  The primary analysis of the trial 
will be conducted 24 months after the last patient is enrolled.  The secondary 
analysis will occur 36 months after the last patient is enrolled.  There are two interim 
analyses planned.  The first will be conducted when the 150th patient is randomized 
to assess for safety.  This interim analysis will look at the overall safety and 
specifically the cardiac safety measures between treatment arms.  If any significant 
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Additionally, the DSMB has the authority to stop the trial early for either safety 
concerns or efficacy.  Due to the long enrollment period, the second interim analysis 
will be conducted 6 months after the last patient is enrolled and will assess both 
safety and efficacy.  The stopping boundary for the latter analysis has been set with 
a p value = 0.005 resulting in a final p value = 0.048 for the primary analysis 
(O’Brien-Fleming). 
 
4.8.6 Missing Data 
Every reasonable attempt will be made to recover any missing data.  If any data 
remains missing that data point will be excluded from analysis for that patient.  
Subsequently measured data for a patient with missing data will be analyzed. 
4.8.7 Determination of Sample Size 
The primary endpoint of DFS at 24 months is used to determine the sample size and 
follow-up determination, based on the following background. 
The previously described Phase 2 NeuVax study (USMCI Clinical Trials Group Study 
I-01 and I-02) (n=188) has reported 26 DFS events and 8 deaths with a 60-month 
median follow-up; this translates into an 88% DFS for vaccinated patients versus 
78% for controls.  In 24-month landmark analysis, the vaccinated patients had a 
93.5% DFS compared to 85.5% in the control group.  The DFS hazard ratio was 0.54 
at 60 months and 0.45 at 24 months.  In this study, the 24 months was measured 
from enrollment which was on average 6 months from completion of all standard of 
care therapy or approximately one year from surgery.  This analysis equates to 3-
year analysis in studies that enroll at initiation of chemotherapy such as the 
Herceptin studies.  Unlike the Herceptin studies, this study enrolled both NP and 
high-risk NN patients which decreased the overall recurrence rate.  
The NSABP adjuvant Herceptin studies (n=3351 combined) reported an 87% DFS 
rate at three years, a 90% distant recurrence-free rate at three years, and a 91% OS 
rate at four years for the combined Herceptin groups (plus adjuvant chemotherapy) 
versus a 75% DFS rate at three years, an 82% distant recurrence-free rate at three 
years, and a 87% OS rate at four years for the combined chemotherapy control; the 
DFS hazard ratio was 0.48 (p<0.0001) while the OS hazard ratio was 0.67 
(p=0.015).  
The adjuvant Herceptin (HERA) study (n=5081 total) reported an 86% DFS rate at 
two years, a 91% distant recurrence free rate at two years, and a 96% OS rate at 
two years for the combined Herceptin groups (plus adjuvant chemotherapy) versus a 
77% DFS rate at two years, an 83% distant recurrence free rate at 2 years, and a 
85% OS rate at two years for the combined chemotherapy control; the DFS hazard 
ratio was 0.54 (p<0.0001) while the OS hazard ratio was 0.76 (p=0.26).  The 
recurrence rate among NP breast cancer patients with HER2 1+ and 2+ expressing 
tumors after standard of care therapy is reported to be 20% at 24 months, which is 
comparable to the two-year DFS of 77% observed in the HERA trial.   

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As described above, the 3-year DFS in the NSABP trial is equivalent to the 24-month 
DFS we intend to analyze as our primary endpoint in this trial based on differences 
in time of enrollment. 
Based on this data, we expect Herceptin alone (with GM-CSF) may have some 
benefit and decrease the recurrence rate to 15%, similar to that seen in the NSABP 
trial.  However, the combination of Herceptin + E75/GM-CSF based on preliminary 
data virtually eliminated recurrences (Sears et al, 2011).  For planning purposes, if 
the combination reduces the recurrence rate to 5%, then in order to show a 
statistical differences between recurrence rates of 15% versus 5%, a sample size of 
150 patients per arm would be required or a study size of 300 patients. 
The overall type 1 error rate of 5% will be preserved for the rejection of the null 
hypothesis in favor of the alternative hypothesis that Herceptin + E75/GM-CSF will 
prolong DFS over that of Herceptin + GM-CSF alone.  With this sample size, the 
power to detect our primary endpoint is 80%. 
4.9 
DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of standard 
practices and procedures.  Data collection procedures are described in Section 6.6.  Data 
monitoring and assurance procedures are described in the Data Safety Monitoring Plan 
(Appendix K). 
5. 
REPORTING OF ADVERSE EVENTS 
Reporting of adverse events will be performed in accordance with the Data Safety 
Monitoring Plan (Appendix K) and Sections 5.2 and 5.3 below. 
5.1 
ADVERSE EVENT AND REPORTING DEFINITIONS 
With the occurrence of an adverse event, the first concern will be for the safety of the 
subject.  Investigators are required to report to the IRB, medical monitor, clinical research 
organization (CRO) Quality Assurance Officer, or her designee and CRO Regulatory Affairs 
Officer any serious adverse event, whether expected or unexpected, and which is 
assessed by the investigator to be reasonably or possibly related to or caused by 
Herceptin or the vaccine components.  Elective surgeries resulting in hospitalization and 
unrelated to the study agents will not be reported as SAEs (e.g., breast reconstruction, 
etc.).  All events meeting the outlined criteria will be reported for the time period beginning 
with any amount of exposure to Herceptin or vaccine components through the protocol-
defined follow-up period.  The Regulatory Affairs Officer will then report the event to the 
Sponsor/Investigator.  The IND Sponsor/Investigator or Sponsor/Investigator’s 
representative will report these to the FDA and financial sponsors, Genentech Drug Safety 
and Galena Biopharma.  The reporting requirements/instructions of AEs from IND 
Sponsor/Investigator and/or representative to Genentech, Inc. are stated in Appendix N. 
Serious criteria, definitions, and guidance for reporting follow.   

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An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational study or protocol regardless of causality assessment.  An adverse event can 
be an unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, syndrome or disease associated with or occurring during the use of an 
investigational product whether or not considered related to the investigational product. 
Serious adverse events (SAE) are adverse events occurring at any dose which meet one 
or more of the following serious criteria: 
Results in death (i.e., the AE caused or led to death) 
Is life-threatening (i.e., the AE placed the subject at immediate risk of death; it does not 
apply to an AE which hypothetically might have caused the death if it were more severe) 
Requires or prolongs inpatient hospitalization (i.e., the AE required at least a 24-hour 
inpatient hospitalization or prolonged a hospitalization beyond the expected length of stay; 
hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion) 
Is disabling (i.e., the AE resulted in a substantial disruption of the subject’s ability to carry 
out normal life functions) 
Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed to the study drug prior to conception or during pregnancy) 
Does not meet any of the above serious criteria but may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
Unexpected adverse events are those not listed in the Package Insert or current IB.  This 
includes adverse events for which the specificity or severity is not consistent with the 
description in the Package Insert or IB.  For example, under this definition, hepatic necrosis 
would be unexpected if the Package Insert or Investigator Brochure only referred to 
elevated hepatic enzymes or hepatitis. 
5.2 
REPORTING OF SERIOUS ADVERSE EVENTS ASSOCIATED WITH THIS 
STUDY 
Each site PI will within 24 hours of notification of the event report any serious 
adverse event, whether expected or unexpected, and which is assessed by the 
investigator to be reasonably or possibly related to or caused by Herceptin or the 
vaccine components, occurring in patients enrolled at their respective study site to 
the Internal Review Board (IRB) of their site (see Adverse Event Reporting 
Algorithm, Appendix L).  This will be accomplished by submitting an adverse event 
report memorandum to the IRB per the IRB’s site-specific standard operating 
procedures.  The site PI will also, within 24 hours of notification of the event, forward 

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a copy of the serious adverse event report (CRF Form 3.1(g)) to the CRO Quality 
Assurance (QA) Officer or her designee, and to the CRO Regulatory Affairs Officer.  
In addition, the site PI will also follow the same reporting for all hypersensitivity 
events of grade 2 or greater in the primary series.  The QA Officer or her designee 
will then forward the report to the Sponsor/Investigator.  The Sponsor/Investigator or 
sponsor’s representative will review the serious adverse event to determine the need 
for expedited reporting to the FDA.  If expedited reporting is required, the site nurse 
coordinator will be notified by the QA Officer or her designee to complete an FDA 
Form 3500 (MedWatch) (Appendix L).  The Regulatory Affairs Officer will then 
submit the final report to the Sponsor/Investigator or Sponsor/Investigator’s 
representative who will report them to the FDA.  
 
5.2.1  FDA Form 3500A (MedWatch) Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (Section 5) of the MedWatch 3500A form: 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
Follow-up information:   
Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original FDA Form  3500A (MedWatch) report and submitting as 
follow-up 
• Adding supplemental summary information and submitting it as follow-up with 
the original  FDA form 3500A (MedWatch)  
• 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.) 
The CRO, Genentech, or Galena Biopharma 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 Quality 
Assurance (QA) Officer or her designee. 

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Study Drug Relationship: 
The Investigator will determine which events are associated with the use of study 
drug.  For reporting purposes, an AE should be regarded as possibly related to the 
use of Herceptin® or vaccine components if the Investigator believes: 
• There is a clinically plausible time sequence between onset of the AE and 
Herceptin and/or vaccine components administration; and/or 
• There is a biologically plausible mechanism for Herceptin and/or vaccine 
components to cause or contribute to the AE; and 
• The AE cannot be attributed solely to concurrent/underlying illness, other drugs, 
or procedures. 
5.3 
REPORTING REQUIREMENTS FOR IND HOLDERS  
Expedited IND Safety Reports: 
For Sponsored IND Studies, there are some additional reporting requirements for the FDA 
in accordance with the guidance set forth in 21 CFR § 600.80. 
Events meeting the following criteria need to be submitted to the FDA as expedited IND 
Safety Reports according to the following guidance and timelines: 
7 Calendar-Day Telephone or Fax Report:  The Sponsor is required to notify the FDA of 
any fatal or life-threatening adverse event that is unexpected and assessed by the 
investigator to be possibly related to the use of the investigational product.  An 
unexpected adverse event is one that is not already described in the Package Insert or 
Investigator Brochure for Herceptin and Investigator Brochure for vaccine.  Such events are 
to be reported by the sponsor to the FDA and Genentech within 7 calendar days of first 
learning of the event.   
15 Calendar-Day Written Report:  The Sponsor is also required to notify the FDA and all 
participating investigators, in a written IND Safety Report, of any serious, unexpected AE 
that is considered reasonably or possibly related to the use of the study agents.  An 
unexpected adverse event is one that is not already described in the Package Insert or 
Investigator Brochure for Herceptin and/or Investigator Brochure for vaccine.   
• Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed with 
the IND concerning similar events should be analyzed and the significance of the 
new report in light of the previous, similar reports commented on.   
• Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Genentech Drug Safety, and all participating investigators within 15 calendar 
days of first learning of the event.  The FDA prefers these reports on a MedWatch 
3500A Form but alternative formats are acceptable (e.g., summary letter). 

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6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with the IND sponsor, 
or sponsor representative, Galena Biopharma, and Genentech or a Genentech 
representative: 
• Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any sub-investigators must appear on this form.  Investigators must 
also complete all regulatory documentation as required by local and national 
regulations. 
• Current curriculum vitae of the Principal Investigator 
• Written documentation of IRB approval of protocol and informed consent document 
• A copy of the IRB approved informed consent document 
• A signed Clinical Research Agreement 
6.2 
STUDY COMPLETION 
The following materials are requested by Galena Biopharma and Genentech when a study 
is considered complete or terminated: 
• A summary, prepared by the Principal Investigator, of the study, and/or a study 
manuscript, and/or a study abstract submitted to scientific conferences. 
6.3 
INFORMED CONSENT 
An informed consent template will be provided, and the final IRB approved document must 
be provided to the sponsor 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 

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study will be conducted in accordance with U.S. FDA, applicable national and local health 
authorities, and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case the 
IRB must be updated at least once a year.  The Principal Investigator must also keep the 
IRB informed of any significant adverse events. 
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to serious adverse 
events that are not already identified in the Investigator Brochure and that are considered 
possibly or probably related to the molecule or study drug by the investigator.  Some IRBs 
may have other specific adverse event requirements that investigators are expected to 
adhere.  Investigators must immediately forward to their IRB any written safety report or 
update provided by Genentech and Galena Biopharma (e.g., IND safety report, Investigator 
Brochure, safety amendments and updates, etc.). 
Ethics and Regulatory Considerations 
The protocol will be reviewed and approved by the IRB or Independent Ethics Committee 
(IEC) of each participating center prior to study initiation.  A list of IRB/IEC members should 
be obtained by the investigator and provided to the sponsor and sponsor representative. 
 
Any documents that the IRB/IEC may need to fulfill its responsibilities, such as protocol 
amendments and/or information from the sponsor will be submitted to the IRB/IEC.  The 
IRB/IEC’s written unconditional approval of the study protocol and the informed consent 
form will be in the possession of the investigator and the sponsor before the study is 
initiated.  The IRB/IEC’s unconditional approval statement will be transmitted by the 
investigator or designee to the sponsor/sponsor representative prior to shipment of study 
drug supplies to the site.  This approval document must refer to the study by exact protocol 
title and protocol version number/date and must identify the documents reviewed and the 
date of review. 
 
Protocol modifications or changes may not be initiated without prior written IRB/IEC 
approval except when necessary to eliminate immediate hazard to the patients.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification 
was submitted and IRB/IEC acknowledgement/approval should be obtained and transmitted 
to the Sponsor/Investigator or Sponsor/Investigator’s representative. 
 
The IRB/IEC must be informed by the principal investigator of any changes or revisions of 
informed consent form or other documents originally submitted for review; serious, 
unexpected or expected, and reasonably or possibly related adverse experiences occurring 
during the study; any new information that may affect adversely the safety of the patients or 
the conduct of the study; annual updates and/or request for re-approval; and when the study 
has been completed.  

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6.5 
STUDY MONITORING REQUIREMENTS 
Site visits may be conducted by authorized Sponsor representative or Genentech and 
Galena Biopharma representatives to inspect study data, patient’s 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 Sponsor/Investigator, 
Galena Biopharma, Genentech, the U.S. FDA, and the respective national or local health 
authorities to inspect facilities and records relevant to this study. 
6.6 
DATA COLLECTION 
Clinical nurses at each study site will be provided with Source Document Flow Sheets to 
capture data at enrollment and for each study visit (Appendix G).  Data collected on the 
Flow Sheets will be entered into an Electronic Data Capture (EDC) system by the site.  The 
URL for the EDC system is https://cancerinsight.eclinicalhosting.com/OpenClinica.  It can 
be accessed with any web browser.  User name and password will be generated by 
OpenClinica and sent via email to appropriate site personnel prior to enrolling the first 
patient. 
Database Management 
Data must be submitted within 72 hours of the data collection visit.  Data entry will begin 
with the patient’s second informed consent visit.  Please see CRF guidelines for specific 
information.  
Tracking data to ensure the highest quality is important.  Although some data fields on the 
Flow Sheets will not be entered into EDC, they must be captured on the Flow Sheets for 
monitoring purposes.  Edit Checks will fire in real time as data is being entered in the EDC 
system to ensure quality data is complete, consistent, and clean.  In addition to edit checks, 
queries will be generated as Discrepancy Notes by the data manager and monitors.  Sites 
will have ten business days to update a query.  It is the responsibility of the coordinator at 
each site to ensure that all data has been submitted.  The CRO QA Officer or Sponsor’s 
representative will perform an audit of the site-specific Flow Sheets and will match them 
against source documents to ensure the quality of data coming to the Database Manager in 
the EDC per the internal monitoring plan.  
The database, hosted by OpenClinica, resides in a SAS 70 Type II data center and meets 
ISO 17799 standards for information security.  The EDC system is HIPAA and 21 CFR part 
11 compliant with robust audit logs, controlled user access and electronic 
signature/password management.  In addition to the site user, the Data Manager, the 
Monitors, the Overall Study PI and Sponsor/Sponsor representative have access to the 
database.  Each user is assigned a role which grants limited access and functionalities 
dependent upon that specific role. Data extracted from the database may be accessed by 
other study collaborators and investigators at the discretion of the Overall Study Principal 
Investigator. 

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Data Safety Monitoring Plan 
A Data Safety Monitoring Plan (DSMP) (Appendix K) describing the CRO internal 
monitoring plan includes data safety and integrity and site initiation/QA monitoring, as well 
as external monitoring plan - the Data Safety Monitoring Board (DSMB) charter and 
responsibilities. 
6.7 
STUDY MEDICATION ACCOUNTABILITY 
If the study drug will be provided by Genentech and Galena Biopharma, 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 
Galena Biopharma. 
6.8 
DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted above is prohibited. 
Upon the subject’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, Genentech, Galena 
Biopharma, and the IRB for each study site, if appropriate. 
6.9 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to 
the conduct of this study and the distribution of investigational drug, including CRFs, 
consent forms, laboratory test results, and medication inventory records, must be retained 
by the Principal Investigator for two years after marketing application approval.  If no 
application is filed, these records must be kept two years after the investigation is 
discontinued and the U.S. FDA and the applicable national and local health authorities are 
notified.  The sponsor will notify the Principal Investigator of these events. 
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. 
6.10 PUBLICATIONS 
 

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The investigator must agree to send to the Sponsor/Investigator or Sponsor/Investigator’s 
representative, for review all manuscripts, abstracts and presentations using data from this 
study prior to their submission.  The Sponsor/Investigator or Sponsor/Investigator’s 
representative reserves the right to delete from such materials any part or parts deemed to 
be confidential or proprietary. 
 
6.11 CHANGES TO THE PROTOCOL 
The protocol may not be modified without written approval of the Sponsor/Investigator or 
Sponsor/Investigator’s representative, or the study director.  All changes to the protocol 
must be submitted to the FDA, the overseeing IRB, and local IRB/IEC.  Additionally, 
changes must be approved by overseeing IRB prior to their implementation.  Documentation 
of IRB/IEC approval must be sent to the Sponsor/Investigator or Sponsor/Investigator’s 
representative, and the Study Director immediately upon receipt. 
Any changes and modifications to the informed consent language must be reviewed and 
approved by the Sponsor/Investigator or Sponsor/Investigator’s representative, and the 
Study Director prior to submission to the local IRB. 

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Herceptin pivotal combination chemotherapy trial. Breast Cancer Res Treat 2000; 64:32. 
Zaks TZ and Rosenberg SA. Immunization with a peptide epitope (p369-377) from HER-
2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-
2/neu+ tumors. Cancer Res 1998;58:4902-4908. 

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APPENDIX A 
Herceptin and Vaccination Timeline 
 
 
 
 
 
 
 
 
\

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APPENDIX B 
NCI Common Terminology Criteria for Adverse Events, v4.03 
obtained from http://ctep.cancer.gov/forms/CTCAEv4.03.pdf  
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
 
 
 

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APPENDIX C.1 
Study Flowchart 
 
 
Days –60 
to –1 
Week 1  
(Day 0) 
DTH  inoculations 
(4) 
2 
Every 3 
Weeks 
Every 3 
Months 
Every 6 
Months 
If Clinically 
Indicated 
Final Visit in 
36th month 
Hematology (CBC, diff., platelets) 
X 
 
 
 
 
 
 
 
Chemistry panel (CMP) 
X 
 
 
 
 
 
 
 
HLA blood draw for typing 
During study screening process/patient identification process. 
Immunological Samples1 
 
X1 
X1 
X1 
 
X1  
 
 
Herceptin administration (q3 weeks x 18) 3 
 
 
 
X3 
 
 
 
 
DTH administration/Photos2 
 
 
X2 
 
 
 
 
 
Vaccine administration3 
 
 
 
X3 
 
 
 
 
Booster inoculations 4 
 
 
 
 
 
X4 
 
 
Post-Booster Immunological Samples1  
 
 
 
 
 
X1 
 
 
Complete medical history (treating 
physician) 
X 
 
 
 
 
 
X 
 
Complete physical exam (treating physician, 
based on SOC) 
X 
 
 
 
X 
X 
X 
 
Clinical assessment-Study nurse visit3,4,9 
 
X 
X3 
X3 
 
X4 
 
X9 
Weight, height (treating physician) 
X 
 
 
 
 
 
X 
 
ECOG performance status 
 
X 
 
 
 
 
 
 
Toxicity evaluation8,9 
 
 
X8 
X8 
 
X8 
X8 
X9 
Vital signs8 
 
 
X8 
X8 
 
X8 
 
 
MUGA scan or ECHO, consistency required5 
X5 
 
 
 
X5 
X5 
X5 
 
Chest X-ray (AP, lateral)/EKG 
 
 
 
 
 
 
X 
 
Urine pregnancy test (if applicable)6  
 
X6 
X6 
X6 
 
X6 
 
 

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Tumor assessment (treating physician) 
X7 
 
 
 
 
 
X 
 
Disease status monitoring7,9 
X7 
 
 
 
X7 
X7 
X7 
X9 
1Immunological samples will be drawn , prior to initiation of Herceptin, prior to DTH #1, prior to inoculation #4, prior to DTH  #2 and every six months  prior to each of 4 boosters.  Samples 
are also drawn 3-4 weeks post each booster.   
  
2DTH #1 given prior to third Herceptin infusion,  DTH #2 given 3-4 weeks after 6
th vaccine inoculation, DTH #3 given 3-4 weeks after booster #2 and DTH#4 given 3-4 weeks after booster 
#4.   The final two will be given after the collection of the post booster blood sample at the same visit.  DTHs do not need to be scheduled on day of Herceptin infusion. 
 
3Vaccine inoculation administered every 3 weeks for 6 inoculations during Herceptin treatment schedule.   Vaccine inoculations to begin after 3
rd Herceptin infusion, except with prior 
approval from Sponsor to begin at 4
th or 5
th infusion time point.  Vaccine inoculations given within 30-120 minutes after completion of infusion. (With prior approval from the Principal 
Investigator, the vaccine may be administered 15 minutes after completion of Herceptin infusion). 
4Booster inoculations will be given after initial series, every 6 months x4, Booster #1 to be given with thefinal Herceptin infusion.  Subsequent boosters will be given every 6 months (+/- 2 
weeks) from Booster #1      
5MUGA scans or ECHO, consistency required will be done at baseline prior to enrollment and at 3, 6, 12, and 24 months. If EF change > 10%, continue with MUGA or Echo every 6 months 
through trial. 
6 Urine HCG waived if hysterectomy, bilateral oopherectomy, tubal ligation, documented absence of menses for two years, or FSH lab results verifying menopause. 
7Must be free of disease “NED” prior to enrollment per physician.  Disease status monitored every 3 months from consent for 18 months, then every 6 months until study completed by study 
coordinator/nurse 
8Toxicity evaluation done with 30 minutes of observation following inoculation with vital signs as needed  and during return visit or by phone call 48-72 hours after inoculation.  Delayed 
adverse event reporting per protocol. 
9Final study assessment in month 36 by study nurse with toxicity assessment and disease status update 
 
 

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APPENDIX C.2 
Patient Visit Chart 
CLINIC VISIT 
PROCEDURES 
TOTAL 
Visit 
# 
Time Req 
(hr) 
Time Point  
Purpose 
Herceptin 
IV 
Infusion  
MUGA 
SCAN 
or 
EjCHO 
Toxicity 
Eval 
Nursing 
Visit 
Urine
HCG
1 
Blood Draws 
Inoc 
DTH 
Test 
# of Shots 
This Visit 
Time for Inoc 
+ Follow-Up 
  
  
  
•Pre CBC/CMP   Informed Consent Document 
• Gather baseline data. 
• Draw blood for HLA typing . 
 
 
  
  
  
Pre-
Inoc 
Post
-Inoc 
  
  
  
  
1 
2 
Baseline 
 
X 
 
X 
X 
 X 
  
  
  
0 
N/A 
START HERCEPTIN INFUSIONS  
 
2 
2 
Starting Time 
Point 
R0 (1) immunology sample then First Herceptin infusion 
X 
 
 
 
 
X 
 
 
 
0 
N/A 
3 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
 
START PRE-INOCULATION BLOOD DRAWS AND INOCULATIONS AFTER HERCEPTIN INFUSIONS X6 
4
 
0.5 
1-2 wks prior 
to Herceptin #3
 
• Draw blood R0 (2) to record immunologic activity before DTH skin test 
#1. 
• Administer DTH skin test #1. 
 
 
X  
 X 
 X 
 X 
  
  
X 
1 
0.5 hrs over 
1 day 
5 
0.25 
48-72 hrs later 
• Examine DTH skin test site for any local reaction and 
photograph. 
 
 
 
X 
X 
 
 
 
 
 
 
0.25 hrs 
62 
2.5 
Approx q3 
weeks 
• Administer inoculation #1 after Herceptin infusion #3
2 
X 
 
X 
X 
 X 
 
  
 X 
  
4 
2.75 hrs over 
2-3 days 
7
4 
0.25 
48-72 hrs  later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
  
  
  
  
  
0 
8 
2.5 
Approx q3 
weeks 
 
• Administer inoculation #2 after Herceptin infusion. 
X 
 
X 
X 
X 
 
  
X 
  
4 
2.75 hrs over 
2-3 days 
9
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
  
  
  
  
  
0 
10 
2.5 
Approx q3 
weeks 
 
• Administer inoculation #3 after Herceptin infusion. 
X 
X 
X 
X 
X 
 
  
X 
  
4 
2.75 hrs over 
2-3 days 
11
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
  
  
  
  
  
0 
12 
2.5 
Approx q3 
weeks 
• Draw blood to record immunologic response to inoculation #3. 
• Administer inoculation #4 after Herceptin infusion. 
X 
 
X 
X 
X 
X 
  
X 
  
4 
2.75 hrs over 
2-3 days 
13
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
  
  
  
  
  
0 
14 
2.5 
Approx q3 
weeks 
 
• Administer inoculation #5 after Herceptin infusion. 
X 
 
X 
X 
X 
 
  
X 
  
4 
2.75 hrs over 
2-3 days 
15
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
  
  
  
  
  
0 
16 
2.5 
Approx q3 
weeks 
• 
• Administer inoculation #6 after Herceptin infusion. 
X 
 
X 
X 
X 
 
  
X 
  
4 
2.75 hrs over 
2-3 days 
17
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
 
X 
 
X 
  
  
  
  
  
 
0 
18 
1 
Approx q3 
weeks 
• Draw blood to record immunologic response to #6.  
• Administer DTH skin test #2 after Herceptin infusion. 
X 
X 
X 
X 
  
X  
   
  
X 
1 
0.75 hrs over 
2-3 days 

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19 
0.25 
48-72 hrs later 
• Examine the DTH skin test site for any local reaction and photograph. 
 
 
X 
X 
  
  
 
  
  
0 
20 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
 
21 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
N/A 
22 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
23 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
 
24 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
 
25 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
 
26 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
 
27 
1 
Approx q3 
weeks 
Herceptin infusion 
X 
 
 
 
 
 
 
 
 
0 
 
RESUME IMMUNOLOGY BLOOD DRAWS AND ADMINISTRATION OF BOOSTER INOCULATIONS 
283 
2.5 
Month 12 from  
Starting Time 
Point  
(±2 weeks) 
• Draw blood to record immunologic levels pre-Booster #1 inoculation. 
• Final Herceptin infusion (see comment 3 below). 
• Administer Booster #1 inoculation. 
X 
X 
X 
X 
 X 
 X 
 
 X 
  
4 
3.25 hrs over 
4 weeks 
29
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
 
 
 
 
 
0 
30 
0.5 
3-4 weeks later 
• Draw blood to record immunologic response to Booster #1 inoculation. 
 
 
 
X 
  
 
X 
  
  
0 
31 
1.5 
Month 18 
(±2 weeks) 
• Draw blood to record immunologic levels pre-Booster #2 inoculation. 
• Administer Booster #2 inoculation. 
 
 
X 
X 
X 
X 
 
 
X 
 
4 
 3 hrs over 
4 weeks 
32
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
 
 
 
 
 
0 
33 
1 
3-4 weeks later 
• Draw blood to record immunologic response to Booster #2 inoculation 
then administer DTH #3. 
 
 
 
X 
X  
  
X 
  
X  
1 
34 
.25 
48-72 hrs later 
• Examine DTH skin test site for any local reaction and photograph 
 
 
 
X 
 
 
 
 
 
0 
35 
1.5 
Month 24 
(±2 weeks) 
• Draw blood to record immunologic levels pre-Booster #3 inoculation. 
• Administer Booster #3 inoculation. 
 
X 
X 
X 
X 
X 
 
X 
 
4 
2.25 hrs over 
4 weeks 
36
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
 
 
 
 
 
0 
37 
0.5 
3-4 weeks later 
• Draw blood to record immunologic response to Booster #3 inoculation. 
 
 
 
X 
  
  
X 
  
  
0 
38 
1.5 
Month 30 
(±2 weeks) 
• Draw blood to record immunologic levels pre-Booster #4 inoculation. 
• Administer Booster #4 inoculation. 
 
X* 
X 
X 
X 
X 
 
X 
 
4 
 3 hrs over 
4 weeks 
39
4 
0.25 
48-72 hrs later 
• Examine the inoculation site for a local reaction.
4 
 
 
X 
X 
 
 
 
 
 
0 
40 
1 
3-4 weeks later 
• Draw blood to record immunologic response to Booster #4 inoculation 
then administer DTH#4. 
 
 
 
X 
X  
  
X 
  
X  
1 
41 
.25 
48-72 hrs later 
• Examine DTH skin test site for any local reaction and photograph 
 
 
 
X 
 
 
 
 
 
0 
42 
.5-1 
Month 36 
 
• Final study assessment 
 
X* 
X 
X 
 
 
 
 
 
0 
End Study 

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#  VISITS: 30-42
4#  INOCULATIONS: 
48 
#  BLOOD DRAWS: 12 
 
1 Urine HCG if applicable per protocol 
2 Herceptin/vaccine combination may begin at 4
th or 5
th infusion time point if clinically indicated with prior Sponsor approval 
3 To allow PI flexibility in scheduling, total Herceptin infusions will be 17-18, approximately every three weeks 
4 Patients have the option to return to their study site or be contacted by phone for questioning regarding any systemic and local toxicity during the initial 48-72 hours after inoculation. 
*NOTE: If ejection fraction >10% reduction from baseline, then continue MUGA or ECHO every 6 months for duration of study 

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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, AppendixD.1) 
who are on standard therapy, which typically includes ACE inhibitors, 
diuretics as needed to control fluid retention, and digoxin (Strength of 
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The most persuasive outcome in heart failure management remains all-cause mortality. 
 
Combined endpoints, including mortality or hospitalization and mortality or hospitalization 
for heart failure, have also emerged as key outcomes. These latter 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 

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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). 
 
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 a-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 

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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 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 

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(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 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. 
 

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Recommendation 4. There is insufficient evidence to recommend the use of ß-
blocker therapy for inpatients or outpatients with symptoms of heart failure at 
rest (ie, NYHA class IV) (Strength of Evidence = C). 
 
ß-Blocker therapy cannot be routinely recommended for NYHA class IV patients because 
there are currently no clinical trial data to indicate favorable long-term efficacy and safety of 
ßblocker therapy in this patient population. A substantial body of observational data 
indicates that successful institution of ß-blocker therapy in patients with this degree of heart 
failure is problematic. If used, these agents may precipitate deterioration, and patients so 
treated should be monitored by a physician who has expertise in heart failure. 
 
The number of patients with class IV heart failure at the time of ß-blocker initiation in 
controlled clinical trials is small. Available trials, which report data on patients with severe 
heart failure mostly labeled as NYHA class III, show the potential problems of ß-blocker 
therapy in this part of the heart failure spectrum. This experience is reflected in a 14-week 
study that evaluated the effects of ß-blocker therapy in 56 patients (51 NYHA class III and 5 
NYHA class IV at randomization) with severe left ventricular dysfunction (average left 
ventricular ejection fraction of 16% ± 1% and left ventricular filling pressure of 24 mm Hg ± 
1 mm Hg) (37). These patients had significant impairment of exercise capacity (mean VO2 
max of 13.6 mL/kg/min ± 0.6 mL/kg/min) despite ACE-inhibitor, digoxin and diuretic 
therapy. Patients were believed to be clinically stable (requiring no medication adjustments) 
for a 2-week period before an open-label challenge was conducted. Seven patients (12%) 
failed to complete the open-label, run-in period, 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. 
 

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Recommendation 5. ß-Blocker therapy should be initiated at low doses and 
up-titrated slowly, generally no sooner than at 2-week intervals.  Clinical 
reevaluation should occur at each titration point and with worsening of patient 
symptoms. Patients who develop worsening heart failure or other side effects 
after drug initiation or during titration require adjustment of concomitant 
medications. These patients may also require a reduction in ß-blocker dose 
and, in some cases, temporary or permanent withdrawal of this therapy 
(Strength of Evidence = B). 
 
ß-Blocker therapy should be initiated at doses substantially less than target doses. Clinical 
trials required patient reassessment at up-titration of each dose. This careful evaluation by 
trained nurses and/or heart failure specialists likely contributed to the relatively low 
withdrawal rates and safety profiles observed in the clinical trials. 
 
Treatment for symptomatic deterioration may be required during ß-blocker titration, but with 
appropriate adjustments in therapy, most patients can be maintained and generally achieve 
target doses. There is a risk of worsening heart failure, and vasodilatory side effects may 
occur with certain agents. Worsening heart failure is typically reflected by increasing 
fatigue, lower exercise tolerance, and weight gain. Increased diuretic doses may be 
required for signs and symptoms of worsened fluid retention. Treatment options also 
include temporary down-titration of the ß-blocker to the last tolerated dose. Abrupt 
withdrawal should be avoided. A minimum period of stability of 2 weeks should occur 
before further up-titration is attempted. Hypotensive side effects may often resolve with 
reduction in diuretic dose. Temporary reductions in ACE inhibitor dose may be helpful for 
symptomatic hypotension not obviated by staggering the schedule of vasoactive 
medications. Administration of carvedilol with food may alleviate vasodilatory side effects as 
well. 
 
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. 

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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 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 

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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. 
 
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 

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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 that patients with left 

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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. 
 

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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 
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.  
 

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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 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, 

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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). 
 
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 

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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 
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 

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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 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. 
 

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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 outcome in the post-MI period, in diabetes, in 
atherosclerosis, and in heart failure mandates that this drug group remains agents of choice 
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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 

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data suggest that the combination yields more vasodilation and decreased blood pressure 
than either agent alone. The addition of losartan to an ACE inhibitor has been found to 
improve exercise capacity compared with an ACE inhibitor alone (94). Preliminary data 
from the RESOLVD Trial suggest that ventricular dilation and neuroendocrine activation 
may be best reduced with combination therapy, but other endpoints were not clearly 
affected. Trials are currently underway to determine the safety, as well as benefit, of more 
complete blockade of the renin-angiotensin system. The Val-HeFT Trial is a large-scale 
investigation of the effect of valsartan in addition to ACE inhibitors on morbidity and 
mortality in symptomatic patients with heart failure caused by systolic dysfunction. One arm 
of the CHARM Study will also examine the effect of the addition of candesartan in patients 
with symptomatic, systolic dysfunction treated with an ACE inhibitor. Preliminary data from 
the RESOLVD Trial suggest that combination therapy may be even more efficacious when 
used in conjunction with ß-blocker treatment. Results from Val-HeFT and CHARM in the 
subset of patients treated with ß-blocker therapy will provide more information concerning 
this strategy. 
 
Combination therapy represents a rational option when treating severe hypertension or 
other vasoconstriction but cannot, at present, be recommended as routine therapy in the 
absence of a proven superiority to ACE-inhibitor therapy alone. 
 

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HFSA Guidelines 
Appendix D.1 
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. 

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Appendix D.2 
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 HamburgCHF-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 TrialGESICA  Grupo de Estudio 
de Sobrevida en Insuficiencia Cardiaca en Argentina 
GUSTO 1  
Global Utilization of Streptokinase and TPA for Occluded coronary arteriesMADIT 
  
 
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 
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 

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VALIANT  
 
 
Valsartan in Acute Myocardial Infarction 
APPENDIX E 
NCCN Guidelines for Adjuvant Breast Cancer Treatment 
 
 
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 
 
 
For hormone receptor positive, NP breast cancer see BINV-6 or BINV-9 
 
For hormone receptor negative, NP breast cancer see BINV-8 or BINV-9 
 
For hormone receptor negative, NN breast cancer see BINV-8 or BINV-9 
 
 
 
 
 
 

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APPENDIX F 
Study Randomization and Stratification Schema 

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APPENDIX G 
E75 + GM-CSF Formulation Plan 
 
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Combination immunotherapy with Herceptin® and the HER2 vaccine E75 
in low and intermediate HER2 expressing breast cancer patients to prevent recurrence 
 
Dosing Preparation Instructions 
 
Dosing Summary:   
The study treatment is 1000 mcg of E75 peptide (nelipepimut-S) mixed with 250 mcg of lyophilized Leukine® (sargramostim, 
GM-CSF) or placebo (water for injection) mixed with Leukine, administered in four separate 0.4 mL intradermal injections.  
 
The E75 peptide is provided as 1.5 mg/mL of E75 acetate (contains a 1.42 mg/mL solution of the E75 peptide). Using aseptic 
technique, 0.8 mL of E75 acetate solution (1136 mcg E75 peptide) is added to the re-constituted Leukine. Taking into account 
vial losses, this procedure will yield a total dose of approximately 1010 mcg of E75 peptide in a volume of 1.6 mL.  
 
Stability:   
Once prepared, administer the E75 peptide/placebo and lyophilized Leukine mixture within 6 hours.   
 
Materials:  
 
1. 
Randomized Test Drug kit with Subject ID number. This kit contains either a single 1.0 mL vial of E75 acetate solution 
(1.5 mg/mL) or a single 1.0 mL vial of placebo. 
2.  
Lyophilized Leukine kit with Subject ID number. This kit contains a single vial of lyophilized Leukine (250 µg). 
3.  
Ancillary Supplies: 7-1.0 mL TB syringes, 5-3/8 inch 26G needles, 4-2 inch 21G needles, 2-3 mL luer lock syringes.  
 
Dose Preparation:  
 
NOTE: DO NOT INVERT ANY STUDY DRUG VIALS DURING PREPARATION 
 
1. 
Remove cap from vial of SWFI and wipe septum with alcohol prep pad. 
2. 
Remove cap from vial of lyophilized Leukine (250 µg) and wipe with alcohol prep pad. 
3. 
Attach a 2 inch 21G needle to a 1.0 mL TB syringe and draw up 1.0 mL from the vial of SWFI. 
4. 
Using the needle and syringe from step #3, insert the needle into the Leukine vial.  
• 
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• 
DO NOT INVERT VIAL at any time. Roll the vial slowly between your hands to mix, taking care to be sure all 
powder is dissolved in the vial.  
• 
Reconstitution of lyophilized Leukine should take approximately 2 minutes. DO NOT SHAKE OR VORTEX.  
5. 
Remove cap from vial of Test Drug (E75 acetate, 1.5 mg/mL or placebo) and wipe septum with alcohol prep pad.  
6. 
Attach a 2 inch 21G needle to a 1.0 mL TB syringe. Leaving vial upright (do not invert), insert the 2 inch needle all the 
way down to the bottom of the vial and withdraw 0.8 mL into the syringe.   
7. 
Using the needle and syringe from step #6, slowly inject the 0.8 mL of Test Drug into the reconstituted Leukine vial.  
8. 
Keeping the vial upright, slowly roll the Leukine/Test Drug vial between your hands. Allow any foaming to dissipate 
before continuing. 
9. 
Attach a 2 inch 21G needle to a 3.0 mL syringe and draw 2.0 mL of air into the syringe. Inject 2.0 mL of air into the 
upright Leukine/Test Drug vial. DO NOT INVERT THE VIAL. Insert the 2 inch needle down to the bottom of the vial 
and slowly withdraw the entire contents of the vial making sure all liquid is removed.  
10. 
Using the needle and syringe containing the Leukine/Test Drug from step #9, top-fill four 1.0 mL TB syringes with 0.4 
mL of the Leukine/Test Drug in each syringe.  
11. 
Attach a new sterile 3/8 inch 26G needle to each syringe containing 0.4 mL of Leukine/Test Drug.  Appropriately label 
each syringe and dispense syringes for intradermal administration of study drug.  The syringes must be used within 6 
hours of mixing.  
 
 
 

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Guidance for DTH Preparation from  
E75 Acetate Solution 1.5mg/1mL Vial 	  
 
To Prepare the DTH skin test, withdraw 0.07mL of the 1.5mg/1.0mL E75 acetate solution.  The DTH 
skin test is administered intradermally using 0.07 mL (100 µg) of the E75 acetate solution. 
 
Supplies:   All DTH skin test kits will contain an active vial, which contains 1.0 mL of E75 acetate in WFI at 
1.5 mg/mL, Some DTH kits will contain a second vial which is a control vial containing 1.0 mL of Water For 
Injection (WFI).  If the DTH kit contains the WFI, discard the WFI in the kit per your institution’s policy. 
 
E75 acetate solution preparation: 
 
1. Remove cap from 1.5 mg/1mL E75 acetate solution and wipe with alcohol prep pad 
2.  Open 1 mL syringe with needle attached and uncap the needle 
3.  Draw > 0.07 mL of air into the syringe and inject into the E75 acetate solution vial 
4. Withdraw 0.07 mL of E75 acetate solution into the syringe  
5. Remove the syringe and the needle from the vial 
6. Drawback syringe plunger to capture hub volume into syringe 
7. Remove and discard needle 
8. Attach a new, sterile needle to the syringe containing 0.07 mL (100 µg) E75 acetate solution for intradermal 
administration 
 

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APPENDIX H 
Leukine® Package Insert 
 

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APPENDIX I 
Performance Status Criteria 
 
 
 
ECOG Performance Status Criteria 
 
Score 
Description 
 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework, office work 
 
2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities.  Up and about more than 50% of 
waking hours. 
 
3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours 
 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
 
 
 
 
 

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APPENDIX J 
Case Report Forms 
 
These are free standing electronic documents.

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APPENDIX K 
Data Safety Monitoring Plan 
 
This is a free standing document 

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REPORT IN WRITING WITHIN 24 HOURS:  
1. Local IRB 
2. Quality Assurance Officer 
3. Regulatory Affairs Officer 
4. Review by Sponsor/Investigator if need be for FDA and 
Med Watch  
ADVERSE EVENT 
SERIOUS 
§ 
Results in death 
§ 
Is life-threatening 
§ 
Requires inpatient hospitalization or prolongation of 
existing hospitalization 
§ 
Results in significant disability or incapacity 
§ 
Results in congenital anomaly or birth defect 
§ 
Causes cancer 
§ 
Is an overdose 
§ 
Any medical event which requires treatment to 
prevent one of the medical outcomes listed above
NON- 
SERIOUS 
EXPECTED 
UNRELATED 
RELATED 
Annual Progress Report/Continuing Review 
Annual Progress Report/Continuing Review 
UNEXPECTED 
RELATED 
REPORT IN WRITING WITHIN 48 HOURS:  
1. Local IRB 
2. Quality Assurance Officer 
3. Regulatory Affairs Officer 
4. Review by Sponsor/Investigator if need for FDA 
and Med Watch 
UNRELATED 
Annual Progress Report/Continuing Review 
APPENDIX L 
Adverse Event Reporting Algorithm  
 
 
 
 
 
 
 

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APPENDIX M 
FDA MedWatch 3500A Form Link 
 
 
http://www.fda.gov/downloads/Safety/MedWatch/DownloadForms/ucm082728.pdf  
 

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APPENDIX N 
SAFETY LANGUAGE INCLUDED IN THIS DOCUMENT IS MANDATORY 
AND MUST BE INCLUDED IN PROTOCOL 
SAFETY REPORTING OF ADVERSE EVENTS 
ASSESSMENT OF SAFETY 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse events 
(SAEs) that are considered related to {study drug}, all events of death, and any study specific issue of 
concern. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an 
investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
AEs not previously observed in the subject that emerge during the protocol-specified AE reporting period, 
including signs or symptoms associated with breast cancer that were not present prior to the AE 
reporting period. 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive procedures such 
as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with medication washout, no 
treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the investigator to have 
worsened in severity or frequency or changed in character during the protocol-specified AE reporting period. 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
It results in death (i.e., the AE actually causes or leads to death). 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have caused 
death.). 
It requires or prolongs inpatient hospitalization. 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the 
subject’s ability to conduct normal life functions). 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. 
It is considered a significant medical event by the investigator based on medical judgment (e.g., may 
jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during the 
study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. in accordance with 
CFR 312.32 (IND Safety Reports).  

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Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent is obtained 
and initiation of study treatment and ends 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only report SAEs that 
are attributed to prior study treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during questioning, or 
detected through physical examination, laboratory test, or other means will be reported appropriately. Each 
reported AE or SAE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria 
if applicable, suspected relationship to the {study drug} (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the following 
general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of the {study drug}, 
and the AE cannot be readily explained by the subject’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to the {study drug}; and/or the AE abates or 
resolves upon discontinuation of the {study drug} or dose reduction and, if applicable, reappears upon re-
challenge. 
No 
Evidence exists that the AE has an etiology other than the {study drug} (e.g., preexisting medical condition, 
underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal 
relationship to {study drug} administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package Insert or 
current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator Brochure 
(I.B.) or not identified. This includes adverse events for which the specificity or severity is not consistent with 
the description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if 
the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should be adopted. Examples 
of non-directive questions include:  
“How have you felt since your last clinical visit?” 
“Have you had any new or changed health problems since you were last here?”  
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid 
colloquialisms and abbreviations. 

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a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). 
However, if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis 
or syndrome at the time of reporting, it is ok to report the information that is currently available. If a diagnosis 
is subsequently established, it should be reported as follow-up information. 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 5.1.2), regardless of 
attribution, will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If the cause of 
death is unknown and cannot be ascertained at the time of reporting, report “Unexplained Death”. 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions should be 
reported as medical and surgical history. A preexisting medical condition should be re-assessed throughout 
the trial and reported as an AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent headaches”). 
d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an 
SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event 
responsible for the procedure, not the procedure itself, should be reported as the SAE. For example, if a 
subject is hospitalized to undergo coronary bypass surgery, record the heart condition that necessitated the 
bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for preexisting 
conditions 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study or 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the study. 
e. Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 6 months after 
receiving the inoculations  or after the last dose of study drug, a report should be completed and expeditiously 
submitted to the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as serious, and 
expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the {study drug} should be reported as an SAE. 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or discontinued 
study participation if attributed to prior {study drug} exposure. If the investigator should become aware of the 
development of cancer or a congenital anomaly in a subsequently conceived offspring of a female subject 
who participated in the study, this should be reported as an SAE.  
g. Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will agree to the 
reconciliation periodicity and format, but agree at minimum to exchange monthly line listings of cases 
received by the other party. If discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution. 
 

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h. AEs of Special Interest (AESIs) 
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety monitoring of the Product  
  
The Adverse Events of Special Interest are: 
 
 
SAE Reporting 
Investigators must report all SAEs to both Genentech and Galena within the timelines described below. The 
completed Medwatch/case report should be faxed immediately upon completion to Genentech Drug Safety at: 
 
(650) 225-4682 
OR 
(650) 225-5288 
AND 
drugsafety@galenabiopoharma.com 
 
Relevant follow-up information should be submitted to both Genentech and Galena Drug Safety as soon 
as it becomes available. 
Serious AE reports that are related to the study drugs and AEs of Special Interest (regardless of 
causality) will be transmitted to both Genentech and Galena within fifteen (15) calendar days of the 
Awareness Date. 
Serious AE reports that are unrelated to the study drugs will be transmitted to Genentech within thirty (30) 
calendar days of the Awareness Date. 
Additional Reporting Requirements to both Genentech and Galena include the following: 
Any reports of pregnancy following the start of administration with the study drugs will be transmitted to 
Genentech within thirty (30) calendar days of the Awareness Date.  
All Non-serious Adverse Events originating from the Study will be forwarded in an annual report to both 
Genentech and Galena. 
 
Note: Investigators should also report events to their IRB as required. 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include the following information within the Event Description (section 5) of the MedWatch 3500A form: 
Protocol description (and number, if assigned) 
Description of event, severity, treatment, and outcome if known 
Supportive laboratory results and diagnostics 
Investigator’s assessment of the relationship of the adverse event to each investigational product and 
suspect medication 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the following methods: 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
Adding supplemental summary information and submitting it as follow-up with the original MedWatch 
3500A form  
Summarizing new information and faxing it with a cover letter including patient identifiers (i.e. D.O.B. 
initial, patient number), protocol description and number, if assigned, brief 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 may contact the reporter for additional information, clarification, or current status of 
the patient for whom and adverse event was reported. For questions regarding SAE reporting, you may 
contact the Genentech Drug Safety representative noted above or the MSL assigned to the study. Relevant 

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follow-up information should be submitted to Genentech Drug Safety as soon as it becomes available and/or 
upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the FDA apply in 
accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration (FDA) as 
expedited IND Safety Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is unexpected 
and assessed by the investigator to be possibly related to the use of study drugs. An unexpected adverse 
event is one that is not already described in the study drugs Investigator Brochure. Such reports are to be 
telephoned or faxed to the FDA and Genentech within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written IND Safety 
Report, of any serious, unexpected AE that is considered reasonably or possibly related to the use of study 
drugs. An unexpected adverse event is one that is not already described in the study drugs investigator 
brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with regulation 21 CFR 
§ 312.32. All safety reports previously filed by the investigator with the IND concerning similar events should 
be analyzed and the significance of the new report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Genentech, and all 
participating investigators within 15 calendar days of first learning of the event. The FDA prefers these reports 
on a Medwatch 3500 form, but alternative formats are acceptable (e.g., summary letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to 
Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-5288 
 
And will be submitted to the Site IRBs. 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
 

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IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to Genentech. 
Copies of such reports should be faxed to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-5288 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech. This 
includes all IND annual reports and the Clinical Study Report (final study report). Additionally, any literature 
articles that are a result of the study should be sent to Genentech. Copies of such reports should be mailed to 
the assigned Clinical Operations contact for the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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E-mail:   
 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
 
AE / SAE FAX No: (650) 225-4682 
 
Alternate Fax No: (650) 225-5288 
 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 

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APPENDIX O 
 
 
PROTOCOL TITLE: 
Combination immunotherapy with Herceptin and the 
HER2 vaccine E75 in low and intermediate HER2-
expressing breast cancer patients to prevent 
recurrence 
STUDY DRUGS: 
HERCEPTIN® (Trastuzumab) 
E75 peptide (KIFGSLAFL, HER2/neu, 369-377) 
GM-CSF (Leukine®, Berlex) 
SPONSOR/INVESTIGATOR 
PROGRAM DIRECTOR 
George E. Peoples, MD 
 
 
 
PROTOCOL VERSION/DATE: 
3.1 / 05 March 2017 
 
INVESTIGATOR’S AGREEMENT / INVESTIGATOR’S SIGNATURE PAGE 
 
I have read the protocol described above.  I have fully discussed the objectives of this trial and the 
content of this protocol with the Sponsor or Sponsor’s representative.  I understand that the information 
in this protocol is confidential and should not be disclosed, other than to those directly involved in the 
execution or the ethical review of the trial, without written authorization from Cancer Vaccine 
Development Program.  It is, however, permissible to provide information to a patient in order to obtain 
consent. 
 
I agree to conduct this trial according to the protocol and to comply with its requirements, subject to 
ethical and safety considerations and guidelines, and to conduct the trial in accordance with all 
applicable regulations, and guidelines as stated in the protocol and other information supplied to me.  I 
understand that the Sponsor may decide to suspend or prematurely terminate the trial at any time, for 
whatever reason.  Such a decision will be communicated to me in writing.  Conversely, should I decide 
to withdraw from execution of the trial, I will communicate my intention immediately, in writing to the 
Sponsor.  
 
 
Signed:                                                                                    Date:                         
 
Investigator’s Name and Address: