A Phase II Study Using Talimogene Laherparepvec for Inflammatory Breast Cancer (IBC) or Non-IBC Patients With Inoperable Local Recurrence
Phase: PHASE2
Conditions: Malignant Chest Wall Neoplasm, Recurrent Breast Carcinoma, Recurrent Inflammatory Breast Carcinoma, Stage IV Breast Cancer AJCC v6 and v7, Stage IV Inflammatory Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center

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A phase II study using talimogene laherparepvec for 
inflammatory breast cancer or non-inflammatory breast cancer 
patients with inoperable local recurrence 
Protocol 2014-0034 
(Amgen ID 20139079) 
 
PI: Naoto T. Ueno, M.D., Ph.D. 
 
Department of Breast Medical Oncology 
 Unit 1354, Houston 
The University of Texas MD Anderson Cancer Center 
Telephone: 713-792-8754 
Fax: 713-794-4538 
E-mail address: nueno@mdanderson.org 
 
Co-PI:  Nuhad Ibrahim, M.D. 
               Bora Lim, MD. 
Collaborators: 
Savitri Krishnamurthy, M.D. 
James M. Reuben, Ph.D.  
Vicente Valero, MD 
Diane D. Liu, M.S. 
Yu Shen, Ph.D. 
Gary Whitman, MD  
Mark Dryden, MD  
 
Study sponsor: The University of Texas MD Anderson Cancer Center 
Study Supporter: Amgen Inc. 
 
 

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Table of Contents 
1.0 Objective ................................................................................................................................... 4 
1.1 Primary objectives ................................................................................................................. 4 
1.2 Secondary objectives ............................................................................................................. 4 
1.3 Correlative studies ................................................................................................................. 4 
2.0 Background ............................................................................................................................... 5 
2.1  Overview of breast cancer local recurrence ......................................................................... 5 
2.2  Potential anti-breast cancer drug for targeting local disease ................................................ 6 
3.0 Rationale ................................................................................................................................... 6 
4.0 Product drug information .......................................................................................................... 7 
4.1  Mechanism of action of talimogene laherparepvec.............................................................. 7 
4.2. Description of talimogene laherparepvec ............................................................................. 8 
4.3. Drug supply and storage ....................................................................................................... 9 
4.4. Effects of talimogene laherparepvec in human .................................................................. 10 
4.5. Registration and marketing experience .............................................................................. 15 
4.6. Important Identified and Potential Risks, Adverse Drug Reaction (ADRs) ...................... 16 
5.0. Patient eligibility .................................................................................................................... 16 
5.1. Inclusion criteria ................................................................................................................. 16 
5.2 Exclusion criteria................................................................................................................. 17 
6.0. Treatment plan ....................................................................................................................... 20 
6.1 Talimogene laherparepvec injection .................................................................................... 20 
6.2. Lesion injection .................................................................................................................. 22 
6.3. Dose management .............................................................................................................. 22 
6.4 Permanent Discontinuation of Treatment and Withdrawal of patients from study ............. 25 
6.5 The end of study .................................................................................................................. 26 
7.0. Pretreatment evaluation (within 6 weeks prior to study enrollment) ..................................... 26 
7.1. Informed consent/ patient registration................................................................................ 26 
7.2. Pretreatment evaluation ...................................................................................................... 26 
8.0. Evaluation during study ......................................................................................................... 27 
8.1. Evaluation during talimogene laherparepvec: .................................................................... 28 
8.2. Evaluation of distant metastases (before cycle 5) .............................................................. 28 
8.3 Study Calendar .................................................................................................................... 29 
9.0. Criteria for response, overall response and disease control ................................................... 30 
10.0. Investigational drug management ........................................................................................ 32 
10.1. Prescription....................................................................................................................... 32 
10.2. Treatment compliance ...................................................................................................... 32 
10.3. Packaging and labeling .................................................................................................... 32 
10.4. Storage and accountability ............................................................................................... 33 
11.0. Safety monitoring and reporting .......................................................................................... 33 
11.1. Adverse events .................................................................................................................. 33 
11.2. Serious adverse event (SAE) reporting ............................................................................ 34 
11.3 Investigator Communication with Amgen ........................................................................ 35 
12.0. Data management................................................................................................................. 38 
12.1. Data collection and entry.................................................................................................. 38 
12.2. Data confidentiality plan .................................................................................................. 38 

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13.0. Statistical consideration ....................................................................................................... 39 
13.1. Statistical design ............................................................................................................... 39 
13.2 Primary endpoint ............................................................................................................... 41 
13.3. Secondary endpoints ........................................................................................................ 41 
14.0. Reference ............................................................................................................................. 41 
15.0 Appendices ............................................................................................................................ 44 
15.1 Sample Fax Cover Sheet for Individual Safety Reports (Amgen Global Safety) ............. 44 
15.2 Sample of Report Form for Herpetic Event with Accidental Exposure of Close Contact or 
HCP to Talimogene Laherparepvec ........................................................................................... 45 
15.3 Sample of Pregnancy Notification Worksheet .................................................................. 49 
15.4 Sample of Lactation Notification Worksheet .................................................................... 50 
15.5 Sample Fax Cover Form for Aggregate Safety Reporting ................................................ 51 
15.6   The Rule of Nines ........................................................................................................... 52 
15.7  Talimogene Laherparepvec Storage and Handling .......................................................... 53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 Objective 
1.1 Primary objectives  
To determine the efficacy of talimogene laherparepvec in inflammatory breast cancer or non-
inflammatory breast cancer patients with inoperable local recurrence measured by the overall 
response rate 
1.2 Secondary objectives 
• 
To determine the efficacy of talimogene laherparepvec in inflammatory breast cancer or 
non-inflammatory breast cancer patients with inoperable local recurrence measured by the 
overall disease control rate 
• 
To determine the rate of local overall response and disease control rate, progression-free 
survival (PFS), and overall survival (OS) in all patients. 
• 
To determine the rate of local overall response and disease control rate, PFS, and OS in 
patients without distant metastases. 
• 
To determine the rate of local overall response and dsease control rate, PFS, and OS in 
patients with distant metastases. 
• 
To determine the safety of talimogene laherparepvec injection to local disease. 
 
1.3 Correlative studies 
• 
To determine the effect of talimogene laherparepvec on injection sites and distant 
metastatic sites by evaluating immune function and apoptosis with immune cell surface 
markers and cytokines. Talimogene laherparepvec induces systemic immune reaction 
through activation of dendritic cell, and enhance cellular immunity. Cytotoxic T-
lymphocyte (CTL) is estimated to offense distant cancer cells via apoptosis mechanism 
and humoral immunity was not determined to involve in this systemic immunity. However, 
the activation of dendritic cells may subsequently activate NK-cells and B-cells. Other 
leukocyte such as neutrophil and monocyte are currently undetermined their function 
within systemic immune reaction induced by talimogene laherparepvec (Figure 1). 
• 
To assess changes in the following: 
o Serum or plasma levels of interleukin (IL)-2, IL-12, tumor necrosis factor (TNF)-
alpha (α), and interferon (IFN)- alpha (α);  (Reuben’s Lab) 
o Phenotype for T-cell subsets (CD3, CD4, CD8, CD25) and NK-cell subsets (CD16, 
CD56), which will be determined via multiparameter FACS analysis (percentage 
and absolute numbers) in peripheral blood at Dr. James Reuben's laboratory of MD 
Anderson. 
o Serum analysis of herpes simplex virus (HSV) type 1 serology with 
immunoglobulin (Ig)G and IgM (ELISA)  
• 
To assess distant tumor tissue changes by evaluating necrosis and immune cell infiltration 
(T-/B-/NK-Cell, macrophage, dendritic cell) by immunohistochemistry assay (CD3, CD4, 
CD8, CD20, CD16, CD56, Granzyme B, cleaved caspase 3, and Ki-67) when distant 
tumor sample is obtained. If the sample volume is ample, additional 
immunohistochemistry assays will be performed for CD45RO, TIA-1, FoxP3, CD25, OX-

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40, CD57, CD1a, CD208, myeloperoxidase, CD68, COX-2, MHC Class I and MHC Class 
II in Dr. Savitri Krishnamurthy's laboratory at MD Anderson. 
 
Figure 1:Systemic immune response expected to be related to talimogene laherparepvec administration
 
Talimogene laherparepvec induces systemic immune reaction through activation of dendritic cell, and enhance cellular immunity 
(IL-2, IL-12, TNF-a, IFN-a, CD3, CD4, CD8, CD25,CD45RO, TIA-2, FoxP3, OX40, CD1a). Cytotoxic T-lymphocyte (CTL) is 
estimated to offense distant cancer cells by apoptosis mechanism (cleaved caspase3) and humoral immunity was not determined to 
involved this systemic immunity. However, the activation of dendritic cells (CD208, MHC class I and II) may subsequently 
activate NK-cells (CD16, CD56, Granzyme B, CD57) and B-cells (CD20). Other leukocyte such as neutrophil (myeloperoxidase) 
and monocyte (CD68) are currently undetermined their function within systemic immune reaction induced by talimogene 
laherparepvec. 
 
2.0 Background  
2.1  Overview of breast cancer local recurrence 
2.1.1  Breast cancer local recurrence 
Recurrent breast cancer is commonly incurable, and multimodality treatment options have been 
developed. Following mastectomy or breast-conserving surgery, the 10-year incidence of 
locoregional recurrence (LRR) is about 13%1. The local recurrence rate of inflammatory breast 
cancer (IBC) is higher than that of locally advanced non–inflammatory breast cancer 2. In 
particular, breast cancer patients with LRR have been found to have 5-year disease-free survival 
(DFS) rates of 13%-37% and OS rates of 21%-50%3-5. Moreover, the outcome is poorer after 
LRR than after local disease only6, and concomittant distant metastases carry an even more 
dismal outcome. In this protocol, we propose a new treatment modality to increase the control 
rate of measurable and non-measurable disease and to prolong outcomes.                                                      

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2.1.2  Current management for local recurrence 
Many breast cancer patients would have mastectomy and others would have conservative 
surgery. However, IBC is generally treated with mastectomy when diagnosed, some locally 
advanced non-IBC patients with local recurrence who previously underwent breast-conserving 
surgery might have undergo mastectomy for local recurrence7, although many patients with local 
recurrence would prefer to receive chemotherapy and/or radiation therapy as a salvage treatment 
because of their inoperable status. Some studies have reported LRR rates following neoadjuvant 
chemotherapy and breast-conserving surgery to be as high as 26%. More recent reports 
document rates of 7%-16%, largely equivalent to those seen in patients undergoing initial 
mastectomy8-14. Furthermore, systemic therapy for local recurrence may be preferred for 
marginally surgical candidates since minor residual disease before radiation therapy is a better 
prognostic indicator in this population15, although NCCN guideline defined systemic treatment 
would be secondary to local treatment. In addition, breast cancer patients with local recurrence 
frequently have distant metastases, and these patients are candidates for systemic treatment. 
2.1.3  Evaluation of treatment effects on locally recurrent breast cancer 
A proportion of patients with locally recurrent breast cancer have non-measurable disease. As 
long as we accrue only patients with locally recurrent breast cancer, we will include those who 
have only non-measurable local lesions. Defining the overall response rate in this population 
would be difficult; however, it is reasonable to define the rate of control for measurable and 
immeasurable disease with PFS and OS. In addition, some biological agents such as imatinib 
have cytostatic effects on gastrointestinal stromal tumor but lack tumor shrinkage properties; that 
is, although the size of tumors are similar, the agents induce tumor necrosis. The proposed study 
agent is expected to induce tumor necrosis and yield overall response rate and disease control 
rate that is a reasonable surrogate for its efficacy.   
2.2  Potential anti-breast cancer drug for targeting local disease 
Patients with locally recurrent breast disease frequently undergo multimodal treatment at the first 
occurrence of breast cancer, and because local treatment modalities such as surgical intervention 
and radiation are difficult to add, they subsequently receive systemic therapy. Talimogene 
laherparepvec (JS1/ICP34.5-/ICP47-/GM-CSF; OncoVEXGM-CSF) was developed to eliminate 
solid tumors and has since been considered as a potential treatment option for body surface 
tumors. In addition to talimogene laherparepvec injected area, this agent would modify immune 
response and could work on distant metastases. Hence, locally recurrent breast disease matches 
as target disease for talimogene laherparepvec regardless of concomitant distant metastases, 
hence talimogene laherparepvec is possible new local treatment option. 
3.0 Rationale 
Local recurrence of breast cancer can result in substantial morbidity and also frequently leads to 
systemic metastases. Modalities used to treat locally recurrent breast cancer include 
chemotherapy, hormone therapy, radiation therapy, and surgery. Compared with distant 
metastases, local recurrence is staged as possible curative status if additional surgery is available, 
however this opportunity is limited for patients with minor local disease having had conservative 

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surgery. In addition, survival improvement has not well been demonstrated due to lack of new 
modality of local treatment.  
Current treatment modalities for locally recurrent breast cancer depend on the operability of 
lesions, disease aggressiveness, previous chemotherapy or radiation therapy, and histologic 
subtypes; thus, a new modality for treating local disease is needed, since systemic therapy is 
currently the last resort intervention. Talimogene laherparepvec is immunotherapy with a dual 
mechanism of generating local tumor lysis and systemic antitumor immune response. In a 
previous phase I study, talimogene laherparepvec as a single agent was shown to induce tumor 
necrosis in breast cancer. 
The purpose of this study is to determine the local and systemic antitumor efficacy of talimogene 
laherparepvec in locally recurrent breast cancer patients with or without distant metastases, as 
evidenced by improved overall response rates. This will be the first study to use biopsy of distant 
disease to demonstrate whether systemic immune modulation has antitumor efficacy in breast 
cancer patients. We will also evaluate the antitumor effects of talimogene laherparepvec via 
comprehensive imaging such as chest x-ray, ultrasound, computed tomography (CT), and 
positron emission tomography 16/CT as clinically indicated. In addition, we will conduct multiple 
biological correlative studies to understand the role of immune response activated by talimogene 
laherparepvec in breast cancer. Patients with initially inoperable local recurrence can be 
candidates for surgery with curative intent if their tumors become operable.  
4.0 Product drug information 
4.1  Mechanism of action of talimogene laherparepvec  
Talimogene laherparepvec, which is a genetically modified HSV type 1 (HSV1), has dual 
mechanisms for eliminating solid tumors (Figure 2). First, HSV1 in which the neurovirulence 
factor ICP34.5 is inactivated has the potential to cause tumor lysis in several tumor models. 
Second, ICP47 deletion via the up-regulation of US11, which occurs following this mutation, 
functions to block antigen processing in HSV-infected cells, so the immune stimulating 
properties of the virus are expected17. In addition, US11 gene expression enhances tumor-
selective viral replication18, and GM-CSF is a potent immune stimulator and enhances immune 
response17 by activating dendritic cell and promoting antigen presentation to CD4+ or CD8+ T 
cells. Activated CD8+ cytotoxic T cells are expected to offense distant tumor cells. The infected 
neoplastic cells are killed via replicating virions, and release them. As viruses kill neoplastic 
cells, cross-resistance with other treatment modalities, such as chemotherapy, hormonal therapy, 
and radiation therapy, does not arise. Thus, immunotherapy could complement current standard 
treatment options. 
Oncolytic replication-competent HSV can infect and kill tumor cells, but normal cells are not 
terminated by the cytopathic effects of HSV, as shown in an in vitro investigation of the efficacy 
and toxicity of oncolytic HSV in breast cancer19. A phase 1 study of talimogene laherparepvec 
(14 cases of breast cancer out of 30 total cases)18, revealed no major responses in any cases, 
including melanoma; however, four patients with breast cancer had local disease stabilization. In 
the phase 1 study, talimogene Laherparepvec was shown to be effective up to 6 cm from the 

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injection site. Considering side effects and viral replication, the investigators concluded that 
talimogene laherparepvec injections every 2-3 weeks were appropriate for future clinical trials.  
 
Figure 2: Mechanism of talimogene laherparepvec against local and distant tumor20  
 
Talimogene laherparepvec (OncoVEXGM-CSF) is attenuated herpes simplex virus type 1 (HSV) and modified to 
replicate only in tumor cells. This has two separate treatment strategies and the first is oncolytic potential due to 
amplified HSV in tumor cells. After the tumorlysis occurred, talimogene laherparepvec activate dendritic cells with GM-
CSF effect, and antigen would be presented through dendritic cell to CD4+ and CD8+ T cells. Activated CD8+ cytotoxic 
T-cell induces systemic immunity for breast cancer located at distant organ as second option. 
 
4.2. Description of talimogene laherparepvec 
The preparation and testing of the cell banks, viral seed stock, and talimogene laherparepvec 
clinical material were conducted in accordance with current Good Manufacturing Practices 
(cGMP), relevant the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 21 guidelines, European Directives, and the U.S. 
Pharmacopeia and Title 21 Code of U.S. federal regulations. In particular, the European 
Pharmacopoeia (Ph Eur) monograph on viral vaccine testing, ICH considerations on oncolytic 
viruses, and U.S. Food and Drug Administration (FDA) Points to Consider – Characterization of 
Cell Lines Used to Produce Biologicals (1993) have been followed for the safety testing of 
talimogene laherparepvec. 
Talimogene laherparepvec has been extensively characterized using growth curves, buoyant 
density gradients, restriction mapping, size exclusion chromatography, epitope mapping, Western 
blotting, and electron microscopy. Additionally, the talimogene laherparepvec genome has been 
sequenced (Figure 3). Talimogene laherparepvec has been formulated in phosphate buffered 
saline (PBS) and a sugar stabilizer for direct intratumoral injection. The talimogene 
laherparepvec formulation is summarized in Table 1. 
 
Figure 3: Schematic diagram of Talimogene laherparepvec 

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The sequenced result of talimogene laherparepvec 
 
Table 1: Talimogene laherparepvec formulation 
Talimogene laherparepvec is intended for direct injection into suitable non-neurological solid 
tumors. Dose schedules may vary for different tumors and indications. The initial dose should 
usually be lower than subsequent doses.  
 
4.3. Drug supply and storage 
Talimogene laherparepvec is provided as a sterile frozen liquid in a single-use 2.0 mL cyclic 
olefin polymer plastic resin vial . Each vial contains talimogene laherparepvec at a nominal 
concentration of 106 plaque forming unit (PFU)/mL or 108 PFU/mL in solution for intratumoral 
injection. Talimogene laherparepvec doses (1 mL extractable volume) will be applied. Vials will 
be sealed with elastomeric stoppers (with a fluoropolymer laminated plug and a crosslinked 
silicon top), and an aluminum seal with a flip-off dust cover. The vial caps are color coded to 
easily distinguish between the 106 PFU/mL (light green) and 108 PFU/mL (royal blue) vial 
concentrations. 
 
Talimogene laherparepvec should be stored away from light and according to the storage and 
expiration information provided on the label that is affixed to the package containing the 
investigational product. 
Talimogene laherparepvec should be thawed per the instructions provided in the  Appendices 
section 15.7 and/or the package insert in Appendix P in PDOL. Vials should be checked for 
cracks or damage that may occur during the thawing process if not performed properly. Damaged 

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product should not be administered and after confirmation from Amgen, damaged vials should be 
destroyed on site. 
4.4. Effects of talimogene laherparepvec in human  
4.4.1. Talimogene laherparepvec clinical study 
Fifteen clinical studies have been or are being conducted with at least 1 subject enrolled as of 30 
June 2015. Seven studies are complete, 7 studies are ongoing, and 1 was terminated early.  
Among the ongoing studies is the non-interventional registry study to investigate the long-term 
survival and safety of subjects previously treated with talimogene laherparepvec in any study. In 
addition to these 15 studies, two expanded access protocols, one each in the US and EU, are also 
ongoing. 
 
Table 2: Summary of clinical studies

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*NCT numbers: 005/04: NCT00402025; 005/05: NCT00769704; 006/09: NCT01161498 
 
 
4.4.2. Pharmacodynamics and pharmacokinetics in humans 
In previous clinical studies of talimogene laherparepvec, samples were taken at protocol-
specified times before and after talimogene laherparepvec was administered to assess viral 
shedding, biodistribution, and the sero-status of patients with regard to HSV. Occasionally, 
investigational swabs and tissue samples (biopsies) were analyzed for the presence of talimogene 
laherparepvec at the request of the investigator.  
 
4.4.3. Safety and efficacy of talimogene laherparepvec in phase 1 study of solid tumor 
Study 001-01 was a phase 1, open-label study to evaluate the safety, biodistribution, and 
biological activity of 3 dose levels of talimogene laherparepvec in patients with advanced solid 
tumors with metastases in the skin or subcutaneous tissue. In part 1 of the study, a single dose of 
talimogene laherparepvec was administered to cohorts of 4 patients. The first dose group 
received talimogene laherparepvec at a dose of 106 PFU/mL, the second dose group received 107 
PFU/mL, and the third dose group received 108 PFU/mL. In part 2 of the study, the patients 
received up to 3 doses administered every 14 days at the following 3 dose levels: group A 
received 106, 107, and107 PFU/mL; group B received 108, 108, and 108 PFU/mL; and group C 
received 106, 108, and 108 PFU/mL. The investigational product was administered directly into a 
cutaneous or subcutaneous tumor. 
 
Thirty patients participated in the study. Of those, 14 had adenocarcinoma of the breast, 9 had 
malignant melanoma, 4 had squamous cell carcinoma of the head and neck, and 3 had various 
other solid tumors. A total of 8 patients withdrew from the study prematurely: 3 (10%) withdrew 

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owing to progressive disease, 2 (6%) withdrew owing to serious adverse events, 1 (3%) 
withdrew consent, and 2 (6%) withdrew for other reasons. 
Almost all the patients (29 of 30; 97%) experienced at least 1 adverse event during the study. 
Most of the adverse events reported were mild or moderate in severity. The most commonly 
reported adverse events across all treatment groups were pyrexia (19 patients; 63%), neoplasm 
progression (9patients; 30%), rigors (8 patients; 27%), post-procedural complications (8 patients; 
27%), nausea (7patients; 23%), anorexia (7 patients; 23%), vomiting (6 patients; 20%), and 
injection site reaction (6 patients; 20%). 
Of 30 patients, 16 (53%) had serious adverse events. The most frequently reported serious 
adverse events were neoplasm progression (13%), post-procedural complications (13%), pyrexia 
(13%), dyspnea (10%), and injection site reaction (7%). All other serious adverse events were 
reported in one patient each. Two patients withdrew from the study prematurely owing to serious 
adverse events, and 5 deaths were reported; of those deaths, 3 were attributed to disease 
progression, 1 to aspiration pneumonia, and 1 to an accidental overdose of analgesia. 
There was no meaningful difference in the overall incidence of adverse events following the first 
and second injections, with 27 of 30 patients (90%) reporting adverse events after the first 
injection and 13 of 15 patients (87%) reporting adverse events after the second injection. There 
was, however, a reduction following the third injection, with 11 of 15 patients (73%) reporting 
adverse events. 
In the first 2 single-dose groups (106 and 107 PFU/mL), the 4 patients (3 receiving 107 PFU/mL 
and 1 receiving 106 PFU/mL) who were seronegative to HSV-1 at study entry all developed flu-
like symptoms such as fatigue, rigors, and pyrexia as well as erythema around the injected lesion. 
Two seronegative patients who received talimogene laherparepvec at 107 PFU/mL developed an 
erythematous rash with scattered vesicles in the skin. Shedding of the virus from some of the 
injected nodules also occurred; however, the virus was not detected on the outer dressing of the 
injection site. The events were transient and self-limiting, and no sequelae were noted. It was 
therefore concluded that seronegative patients should receive a lower initial dose (i.e., 106 
PFU/mL) of talimogene laherparepvec. 
In analyses to detect virus via specific quantitative PCR in blood, results were positive at one or 
more time points for 10 of 30 patients. Urine was positive for virus at one or more time points for 
2 patients. Generally, in the repeated-dose part of the study, virus was noted only within 8 hours 
after the injection. 
Four patients experienced shedding of live virus from the injection site, although in all cases, this 
was contained within the occlusive dressing, and no virus was detected on swabs of the outside 
of the dressing. Three of these patients were seronegative at baseline; 2 of the patients were 
given a first dose of talimogene laherparepvec at 107 PFU/mL, 1 received 108 PFU/mL, and 1 
received 106 PFU/mL. Three patients had transient cutaneous vesicles or vesicle-like areas at 
various sites including the mouth, nose, forehead, cheek, right buttock, back, and sternum during 
weeks 2 and 3 of the study. Two of these patients were seronegative for HSV1 at enrollment and 
given a single dose of talimogene laherparepvec at 107 PFU/mL. The third patient who had 
vesicle-like areas was also seronegative at enrollment and was given 3 doses of talimogene 

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laherparepvec (106 PFU/mL, 107 PFU/mL, and 107 PFU/mL). Swabs were taken from these sites, 
but no virus was detected. In subsequent studies, a first dose of 106 PFU/mL has been 
administered, followed by higher doses of 108 PFU/mL, after this higher dose shedding is seen 
only rarely. Swabs were also taken from sites other than the injected nodule for 4 additional 
patients, and virus was not detected in any of these patients. 
The secondary objective of the study was to identify signs of biological activity of the virus in 
the treated patients. Tumor response was assessed using Response Evaluation Criteria in Solid 
Tumors (RECIST; version 1.1). 
Eight patients (27%) had stable disease, 19 patients (63%) had progressive disease, and 3 (10%) 
were not evaluable. In addition to tumor assessments, the study also defined a response if tumor 
necrosis was seen in a biopsy. Nineteen patients had biopsies containing tumor tissue. Of these, 
13 biopsies (68%) showed evidence of partial or extensive tumor necrosis. One additional tumor-
containing biopsy showed apoptosis. Thus, 14 of 19 patients (74%) with biopsies containing 
tumor tissue had necrosis or apoptosis. 
HSV was detected by the use of a polyclonal antibody to stain biopsies taken from talimogene 
laherparepvec–injected tumors. Virus was shown to co-locate with areas of necrosis in the tumor; 
all biopsies with necrosis stained strongly for HSV. Non-necrotic and non-tumor tissues in the 
biopsies very rarely stained for HSV. 
Tumor biopsies were stained for a variety of T cells (expressing CD3, CD4, CD8, CD30, and 
CD68 markers). All biopsies were positive for these cells. However, no obvious patterns emerged 
and, in the absence of baseline data, it is not possible to conclude that T cell levels were elevated 
as a result of treatment. 
Quantitative PCR also was performed to evaluate the presence of hGM-CSF mRNA in order to 
measure talimogene laherparepvec –encoded GM-CSF versus endogenous GM-CSF. Of 13 
biopsies with partial or extensive tumor necrosis, 11 (84.6%) showed measurable quantities of 
talimogene laherparepvec encoded GM-CSF mRNA, and the level of mRNA expressed was dose 
dependent (i.e., more GM-CSF mRNA was expressed after administration of higher doses of 
talimogene laherparepvec). Additionally, seronegative patients expressed more GM-CSF mRNA 
than did seropositive patients. 
4.5. Registration and marketing experience 
Talimogene laherparepvec has received regulatory approval for marketing in US and Europe.  
US:  
Talimogene laherparepvec is approved in melanoma. Intralesional injection of talimogene 
laherparepvec, also known as IMLYGIC®, has been approved by the United States Food and 
Drug Administration (FDA) for the local treatment of unresectable cutaneous, subcutaneous, and 
nodal lesions in adult patients with melanoma recurrent after initial surgery.  However, it has not 
been shown to increase OS or have an effect on metastases to internal organs including the liver 
and lungs. 
 
Europe:  

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IMLYGIC® is indicated for the treatment of adults with unresectable melanoma that is regionally 
or distantly metastatic (Stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral 
disease the first oncolytic viral therapy. It is proposed that IMLYGIC®, be initiated and 
supervised by a qualified physician experienced in the treatment of cancer.   
4.6. Important Identified and Potential Risks, Adverse Drug Reaction (ADRs)  
Consult the current Investigator’s Brochure (IB) for the full information on Identified and 
Potential Risks of talimogene laherparepvec and Adverse Drug Reaction (ADRs). 
5.0. Patient eligibility  
Up to 36 patients will be enrolled in the study. Patients must to meet the following criteria to be 
eligible for the study. 
5.1. Inclusion criteria 
5.1.1. Histologic confirmation of breast carcinoma. 
5.1.2. Histologic confirmation of recurrence of chest wall / cutaneous, subcutaneous or nodal 
tumors disease with or without distant metastasis.  
5.1.3 Patients must have failed at least 1 systemic regimen or have clinical stable disease with 
capecitabine, hormonal therapy (with or without mTOR inhibitor or CDK4/6 inhibitor), or anti 
HER-2 therapy (trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) for at least 2 
months after their diagnosis of locoregional/metastatic disease. 
5.1.4. Concurrent radiation therapy is permitted after the study treatment is initiated so long as 
the planned radiation field doesn’t overlap with planned injection sites. 
5.1.5. Age 18 years or older. 
5.1.6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 
5.1.7. Adequate hematologic function 
• 
Absolute neutrophil count ≧ 1.0 x109/L. If patient is taking CDK4/6 inhibitor or 
capecitabine, there is a need for maintaining ANC ≥ 1.0 consistently for at least 2 
months without dose changes. 
• 
Platelet count ≧  75 x 109/L. If patient is taking CDK4/6 inhibitor, ado-trastuzumab 
emtansine or capecitabine, there is a need for maintaining platelet count ≥ 75 x 109/L 
without dose changes. 
• 
Hemoglobin ≧ 8.0 g/L 
• 
International normalization ratio (INR) or prothrombin time (PT)/ partial thromboplastin 
time (PTT)/ activated PTT (aPTT) ≦ 1.5 x ULN, unless the subject is receiving 
anticoagulant therapy, in which case PT and PTT/aPTT must be  within therapeutic 
range of intended use of anticoagulants 
5.1.8. Adequate renal function 

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•  Serum creatinine  1.5 x upper limit of normal (ULN), OR 24-hour creatinine clearance 
 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note: Creatinine clearance 
need not be determined if the baseline serum creatinine is ≦ 1.5 x ULN. Creatinine 
clearance should be determined per institutional standard). 
5.1.9. Adequate hepatic function 
• 
Aspartate aminotransferase (AST) ≦ 2.5 x upper limit of normal (ULN) if liver 
metastases present  
• 
Alanine aminotransferase (ALT) ≦ 2.5 x ULN if liver metastases present  
• 
Total bilirubin ≦ 1.5 x ULN, OR direct bilirubin ≤ ULN for a subject with total 
bilirubin level > 1.5 x ULN 
 
5.1.10 Subjects must be candidate for intralesional injection into cutaneous, subcutaneous or 
nodal tumors with or without image ultrasound guidance defined as one or more of the following 
At least 1 injectable lesion ≥5 mm in longest diameter, multiple injectable lesions that in 
aggregate have a longest diameter of ≥ 5 mm.  
5.1.11. Female patients of childbearing potential must have a negative urine or serum pregnancy 
test no more than 3 days prior to starting study drug. 
5.1.12. Patients must be able and willing to give written informed consent. 
5.2 Exclusion criteria 
5.2.1. Patients who have operable disease with curable intent, and/or are candidates for radiation 
therapy for local control. 
5.2.2. Patients receiving concurrent anti-cancer therapy (chemotherapy except Capecitabine or 
ado-trastuzumab emtansine , immunotherapy) while taking the study medication, or have 
previously received talimogene laherparepvec or any other oncolytic virus. 
 
5.2.3. Patients with metastatic sites that necessitate chemotherapy (except Capecitabine or ado-
trastuzumab emtansine) .  
 
5.2.4. Known active central nervous metastases. Subjects with previously treated brain 
metastases may participate provided they are stable (without evidence of progression by imaging 
for at least four weeks prior to the first dose of  trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, and are not 
using steroids >10 mg/day of prednisone or equivalent. The exception does not include 
carcinomatosus meningitis which is excluded regardless of clinical stability. 
 
5.2.5. More than three lesions per organ for visceral metastases except for lung or lymph 
node. 
 
5.2.6. History or evidence of active autoimmune disease that has required systemic treatment 
(i.e., use of corticosteroids, immunosuppressive drugs or  disease modifying agents) 

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Replacement therapy (eg, thyroxine for hypothyroidism, insulin for diabetes or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form 
of systemic treatment for autoimmune disease. 
5.2.7. A concurrent disease or condition that would render the patient inappropriate for study 
participation or any serious medical disorder that would interfere with the patient’s safety. 
5.2.8. History of other malignancy within the past 5 years  with the following exceptions: 
• Adequately treated non melanoma skin cancer without evidence of disease at the 
time of enrollment 
• Adequately treated cervical carcinoma in situ without evidence of disease at the 
time of enrollment 
• Adequately treated breast ductal carcinoma in situ without evidence of disease at 
the time of enrollment 
• Prostatic intraepithelial neoplasia without evidence of prostate cancer at the time 
of enrollment. 
5.2.9. Active infection that necessitates intravenous or oral antibiotics. 
5.2.10. Evidence of immune suppression  as following: 
• 
Known human immunodeficiency virus (HIV) infection or AIDS 
• 
Known leukemia or lymphoma 
• 
Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease. 
• 
Concurrent opportunistic infection. 
• 
Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses 
> 10 mg/day of prednisone or equivalent within 7 days prior to the initiation of study 
treatment. 
• 
Known hepatitis B or C infection 
• 
Congenital or acquired cellular and/or humoral immune deficiency. 
• 
Other signs or symptoms of immune system suppression 
5.2.11. Active herpetic skin lesions or prior complication of HSV-1 infections (e.g. herpetic 
encephalitis or keratitis). 
5.2.12. Currently pregnant or breast-feeding, or planning to become pregnant during study 
treatment and through 3 months after the last dose of study treatment.  
5.2.13 Female subject of childbearing potential who is unwilling to use acceptable method(s) of 
effective contraception during study treatment and through 3 months after the last dose of 
talimogene laherparepvec. (Women of not childbearing potential: post-menopausal [age > 55 
years with cessation of menses > 12 months or < 55 years but not spontaneous menses for at 
least 2 years or < 55 years and spontaneous menses within the past 1 year, but currently 
amenorrheic (eg, spontaneous or secondary to hysterectomy), and with postmenopausal 
gonadotropin levels (luteinizing hormone and follicle-stimulating hormone levels > 40 IU/L) or 
postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal 

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range" for the laboratory involved] or who have had a hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy). 
 5.2.14 Sexually active subjects and their partners unwilling to use male or female latex condom 
to avoid potential viral transmission during sexual contact while on treatment and within 3 
months after treatment with talimogene laherparepvec. 
5.2.15. Currently enrolled in another clinical trial for investigational drugs, procedures or device 
(excluding non-cancer treatment trials) or receipt of an investigational agent or device within 4 
weeks of the initiation of study treatment 
5.2.16. Intermittent or chronic treatment with antiherpetic drugs, except for topical agents. 
5.2.17. Patients who is known sensitive to any of the products or components to be administered 
during treatment with talimogene laherparepvec. 
 
5.2.18. Chronic oral or systemic steroid medication use at a dose of >10 mg/d of prednisone or 
equivalent [steroids with low systemic absorption (e.g. triamcinolone hexacetonide) injected into 
joint space are allowed] 
 
5.2.19. Prior therapy with tumor vaccine, or received live vaccine within 28 days prior to the 
initiation of study treatment. 
5.2.20 Subjects who are unwilling to minimize exposure with his/her blood or other body fluids 
to individuals who are at higher risks for HSV-1 induced complications such as 
immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or 
infants under the age of 3 months, during talimogene laherparepvec treatment and through 30 
days after the last dose of talimogene laherparepvec. 
5.2.21 Prior immunosuppressive, chemotherapy, radiotherapy (in which the field encompassed a 
planned injection site), biological cancer therapy (monoclonal antibodies), or major surgery 
within 28 days prior to enrollment or has not recovered to CTCAE grade 1 or better from adverse 
event due to cancer therapy administered more than 28 days prior to enrollment.  
 
5.2.22 Prior radiotherapy in which the field does not overlap the injection sites or non-
immunosuppressive targeted therapy within 14 days prior to enrollment or has not recovered to 
CTCAE grade 1 or better from adverse event due to cancer therapy administered more than 14 
days prior to enrollment  
  
5.2.23 Patients who have extensive skin disease, defined as total area of skin involvement/ 
lesions that comprise >10% of body surface area. Refer to “Rule of Nines” in Appendix 15.6 that 
will be the guide for specific percentages per body part(s). Skin involvement comprising >5% to 
upper anterior chest wall or >5% to upper posterior back is excluded.  
 

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6.0. Treatment plan 
6.1 Talimogene laherparepvec injection 
Talimogene laherparepvec will be given via intra-tumoral injection at visible locally recurrent 
breast cancer site and skin metastases if indicated at an initial dose of 106 PFU/mL for all sample 
size of 35. If patient has multiple lesions the lesion selection as the following: 
1) If the largest lesion is > 5cm, only this lesion will be used for injection;  
2) If the largest lesion is < 5.0 cm, we will prioritize the size of the lesions (from large to 
small), and administer talimogene laherparepvec based on injection guideline in Table 3 
below. The maximum dose of each course should not exceed 4.0 mL.   
3) If patients do not have distant metastases, the lesion of lowest priority for injection 
should be left uninjected at least until it is biopsied. 
 
The injection dose will not be affected by patients’ actual body weight. The second talimogene 
laherparepvec dose will be administered 108 PFU/mL on day 22, and talimogene laherparepvec 
will be administered every 2 weeks after the second course with same dose with the maximum 
dose of 4.0 mL for each course (Figure 4). The injection dose varies according to the tumor 
spread area and using the talimogene laherparepvec injection volume guideline based on tumor 
size (Table  3). Distribution of the injection to separate sites will be permitted if the lesion is 
more than 5.0 cm diameter and/or multiple lesions.  When disease diameter is greater than 5.0 
cm and difficult to inject uniformly, we divide disease location tetrameric injection site with 1.0 
mL administration each. On each treatment day, injections should be prioritized as follows:  
• 
any new injectable tumor that has appeared since the previous injection 
• 
by tumor size, beginning with the largest tumor and then the second largest tumor if 
agent available, otherwise treat in the following courses 
• 
by tumor size, when similar size tumor exist, prioritize one and then the other tumor if 
agent available, otherwise treat in the following courses 
• 
by tumor size, when huge tumor exist (greater than 10.0 cm), inject talimogene 
laherparepvec at different site for aiming uniform distribution in the following course. 
• 
any previously uninjectable tumor(s) that is now injectable  
 
Within the guidelines of the algorithm in Table 3 and the prioritization model above, each lesion 
should be injected with the maximum amount possible at each visit before moving on to the next 
lesion, subject to tumor-specific limitations (such as the inability to inject the full amount into 
the lesion). Lesions should be injected until the maximum volume per day (4.0 mL) has been 
reached or there are no further injectable lesions, whichever comes first. 
Lesion site preparation 

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• 
Talimogene laherparepvec is to be administered only by intralesional injection into 
cutaneous, subcutaneous and nodal lesions with or without image ultrasound guidance.  
Talimogene laherparepvec must not be administered into visceral organ metastases. 
• 
The injection site may be pre-treated with a topical anesthetic agent or an injectable 
local anesthetic; however, a local anesthetic must not be injected directly into the 
lesion.  Please note that the anesthetic should not be mixed together with talimogene 
laherparepvec in the same syringe. Talimogene laherparepvec does not require any 
routine premedication. 
• 
Swab the lesion and surrounding areas with alcohol, allow to dry. 
• 
Talimogene laherparepvec is administered by HCP 
 
 
 Figure 4: Timeline of talimogene laherparepvec injection 
 
    * Talimogene laherparepvec is administered lower dose for the first course due to possible sero-negative status. 
  ** Biopsy from local disease. 
*** Biopsy from distant metastases if available or local disease of non-injection site (optional) 
 
Table 3. Talimogene laherparepvec injection volume guideline based on tumor size 
Tumor Size (longest dimension) 
Maximum Injection Volume 
> 5.0 cm 
4.0 mL 
> 2.5 cm to 5.0 cm 
2.0 mL 
> 1.5 cm to 2.5 cm 
1.0 mL 
> 0.5 cm to 1.5 cm 
0.5 mL 
≤ 0.5 cm 
0.1 mL 

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6.2. Lesion injection 
• 
All personnel handling talimogene laherparepvec or material contaminated with talimogene 
laherparepvec must observe safety precautions (e.g., wear a laboratory coat, safety glasses 
and gloves) in accordance with local/regional or BSL classification guidelines for 
administration. 
• 
Inject talimogene laherparepvec intralesionally (Table 4.): 
a)  A single point of insertion is recommended; multiple insertion points may be used if 
the tumor is larger than the radial reach of the needle. 
b) Talimogene laherparepvec should be injected along multiple different tracks within 
the lesion in order to obtain as wide a dispersion as possible. 
c)  Distribute talimogene laherparepvec within the lesion through the insertion point 
using the radial reach of the needle in different directions to evenly distribute. 
• 
Avoid premature extraction of the needle.  
• 
After dosing, the injection site should be swabbed with alcohol and pressure should be 
applied with gauze for several seconds after injection.    
• 
The injection site should be covered with an absorbent pad and dry occlusive dressing. 
Please ensure a fresh pair of gloves is worn when handling the absorbent pad and dressing 
to prevent cross contamination with talimogene laherparepvec.  Please also ensure that the 
outside of the dressing is wiped down with an alcohol swab to further minimize any cross 
contamination. 
 
• 
Discard materials used during injection (eg, gloves, needles, gauze) in accordance 
with local/regional or BSL classification guidelines. 
 
Table 4. Schematic illustration of Talimogene laherparepvec injection 
 
6.3. Dose management  
Subjects should be assessed clinically for adverse events/toxicity prior to each dose using the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  Complete blood count 
with differential and chemistry panels including liver function laboratory tests (ALT, AST, and 
total bilirubin) should be obtained according to the schedule of assessment in the protocol, and 

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the results should be checked before each scheduled dose of talimogene laherparepvec.  Dosing 
will occur only if these test values are acceptable per the protocol. 
6.3.1 Dose Limiting Toxicities (DLTs) 
Toxicity should be evaluated according to CTCAE version 4.0. DLTs should be defined based on 
CTCAE and should include events assessed as related to talimogene laherparepvec during 
treatment and up to 4 weeks after the last talimogene laherparepvec injection. 
The following herpetic events are defined as DLTs: 
• Serious herpetic events such as herpetic encephalitis, encephalomyelitis or disseminated   
herpetic infection.  
• Any herpetic event confirmed related to talimogene laherparepvec that requires treatment 
with acyclovir or similar anti-viral agent, Talimogene laherparepvec treatment should be 
suspended if treatment is required with systemic acyclovir or other anti-virals, If ongoing 
treatment is required, talimogene laherparepvec treatment should be permanently 
discontinued. Herpetic events due to wild-type HSV-1 or wild-type HSV-2 which require 
acyclovir and are not due to talimogene laherparepvec (as confirmed by PCR testing) 
should not be considered as DLTs caused by talimogene laherparepvec 
• Grade 3 or greater immune-mediated adverse events 
• Any grade plasmacytoma at or near the injection site or evidence of impaired wound 
healing at the injection site 
• Grade 3 or greater allergic reactions considered at least possibly related to talimogene 
laherparepvec 
• Grade 4 non-hematologic toxicity.  
• Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care;  
- Grade 3 fatigue will not be classified as DLT, irrespective of duration.  
• Any Grade 3 or higher non-hematologic laboratory value if the abnormality:  
- fails to respond to medical intervention, or  
- leads to hospitalization, or  
- persists for > 1 week unless deemed not clinically important per both investigator 
and sponsor.  
• Grade 3 or 4 febrile neutropenia.  
• Grade 4 thrombocytopenia associated with a bleeding event deemed at least possibly 
related to talimogene laherparepvec and requiring intervention.  
• Any other intolerable toxicity leading to permanent discontinuation of talimogene 
laherparepvec.  
• Grade 5 toxicity (i.e. death).  
 
If an unexpected DLT deemed at least possibly related to talimogene laherparepvec occurs, 
talimogene laherparepvec administration should be delayed until the DLT has resolved to at least 
CTCAE (v. 4.0) grade 1 or has returned to baseline. 

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All necessary supportive care shall be available to subjects. Additional treatment modifications 
should be considered depending upon the subject’s clinical situation. Talimogene laherparepvec 
treatment should be continued based on the potential risk/benefit assessment of the subject.   
6.3.2. Dose reduction 
Dose reductions with regards to changes in the concentrations of talimogene laherparepvec are 
not permitted. However, patients may require a reduction in the volume injected due to a disease 
response or due to local toxicity at the injection site. However, if in the course of administration 
of talimogene laherparepvec the subject cannot tolerate the full dose due to an injection-related 
adverse event such as pain, the total volume given should be recorded, and the reason for 
intolerance should be documented as an adverse event.  
6.3.3 Dosage Adjustments, Delays, Rules for Withholding or RestartingIf talimogene 
laherparepvec treatment was deayed by >2 week, that dose will be deemed to have been missed 
and the subject will proceed to the next scheduled treatment visit. 
Dose reductions of talimogene laherparepvec is not permitted, other than a reduction in the 
volume injected due to a disease response. 
If a subject experiences any of the following treatment-related toxicities, talimogene 
laherparepvec administration should be delayed until the toxicity has resolved to at least CTCAE 
grade 1 or baseline:  
• Grade 2 or greater immune-mediated adverse events, with the exception of vitiligo.  
• Grade 2 or greater allergic reactions.  
• Any other grade 3 or greater hematologic or non-hematologic toxicity.  
 
Subjects who are receiving talimogene laherparepvec may not receive systemic antiherpetic 
drugs (eg, acyclovir, valacyclovir, famciclovir), but may receive a topically administered 
antiherpetic drug more than 20 cm from a talimogene laherparepvec injection site. Dosing should 
be permanently discontinued if, in the opinion of the investigator, the subject develops clinical 
evidence of any systemic herpes infection (such as encephalitis or disseminated infection). 
If the subject requires corticosteroid dosing of >10 mg prednisone daily (or equivalent, eg,  
1.5 mg dexamethasone) for any reason, talimogene laherparepvec dosing must be withheld until 
the corticosteroid dose has decreased to <10 mg prednisone daily (or equivalent). 
Talimogene laherparepvec treatment should be continued based on the potential benefit/risk 
assessment of the subject.  
If talimogene laherparepvec dosing is delayed by more than 6weeks from the date of the planned 
dose (i.e., approximately 8 weeks from the previous dose) due to the occurrence of an adverse 
event that is considered related to talimogene laherparepvec, the subject must be permanently 
withdrawn from talimogene laherparepvec treatment. 

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If talimogene laherparepvec dosing is delayed by more than 6 weeks from the date of the planned 
dose (i.e., approximately 8 weeks from the previous dose) for reasons other than treatment-
related toxicity, the case must be reviewed by the principle investigator to determine if the 
subject can resume talimogene laherparepvec therapy. 
Patient will be allowed to continue, capecitabine, hormonal therapy and/or anti-HER-2 therapy 
while receiving study drug.  
6.4 Permanent Discontinuation of Treatment and Withdrawal of patients from study 
Talimogene laherparepvec is to be permanently discontinued for patients meeting any of the 
following criteria: 
• The patient, for any reason, requires treatment with another anticancer therapeutic agent for 
the study disease (other than the exceptions noted in the protocol, if applicable). In this case, 
discontinuation from the treatment occurs immediately upon the introduction of the new 
agent.  
• Confirmed PDA grade 2 or greater Immune-mediated adverse events (with the exception of 
vitiligo) or allergic reactions attributed to talimogene laherparepvec that would require a dose 
delay of greater than 6 weeks from the date of the planned dose (i.e., approximately 8 weeks 
from the previous dose).   
▪ Note: immune-mediated glomerulonephritis, vasculitis, and pneumonitis and 
exacerbation of psoriasis have been observed in subjects receiving talimogene 
laherparepvec in clinical trials.  Most of these subjects had a history of other 
autoimmune disease and/or prior treatment with agents that offered plausible 
alternative etiologies, however, immune-mediated adverse events can potentially 
involve any organ system. 
• Any other talimogene laherparepvec-related non-hematologic or hematologic toxicities grade 
3 or greater occur that, in the opinion of the investigator, would require a dose delay of 
greater than 4 weeks from the date of the planned dose (i.e., approximately 6 weeks from the 
previous dose). 
• The subject develops clinical evidence of any systemic herpes infection (such as encephalitis 
or disseminated infection). 
• A female subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception (for those subjects who are able to conceive). 
• A female subject breast feeds while on study treatment. 
• Concurrent medical illness that, in the judgment of the investigator, would make continued 
treatment with talimogene laherparepvec dangerous for the subject. 
• For additional information related special warnings and precautions for the use of talimogene 
laherparepvec please refer to the latest version of the Talimogene Laherparepvec 
Investigator’s Brochure. 
• Dosing noncompliance:  If dosing compliance is not 100% (administration of talimogene 
laherparepvec on the scheduled date +/- 3 days in the absence of toxicity), the study 
treatment should be discontinued for the patient.  
• Complete remission of locally recurrent disease with or without distant disease 
• Patient withdraws consent. In the event that a patient withdraws consent, the reason(s) for 
withdrawal must be documented. Patients must be informed that their participation in the 

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study is voluntary and that they may choose not to take part in the study or to stop taking part 
at any time. If a patient chooses not to take part in the study or to stop at any time, his/her 
future medical care or medical benefits will not be affected.  
6.5 The end of study 
  
6.5.1. Definition of the end of the study 
Previous talimogene laherparepvec single agent study showed that the median time to response 
was 4.1 months, and 50 % of these responders had  progressive disease (PD) (defined by 
modified WHO criteria) prior to response.  In this study talimogene laherparepvec administration 
will continue for at least 10 cycles (approximately 5 months) unless uncontrolled disease 
progression is observed. Beyond 10 cycles, progressive disease will be measured based on 
RECIST ver1.1. 
6.5.2. Uncontrolled disease progression   
Uncontrolled disease progression is defined as rapid growth of multiple measurable or non-
measurable new lesions, or sum of the longest diameter of existing targeted lesions is >40% from 
the baseline.  
 
Immunotherapeutic agents such as talimogene laherparepvec may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions 
 
7.0. Pretreatment evaluation (within 6 weeks prior to study enrollment) 
7.1. Informed consent/ patient registration  
The study will be discussed with the patient, and any patient wishing to participate must give 
informed consent prior to any study-related procedures or change in treatment. A signed, 
Institutional Review Board approved, informed consent form must be obtained from patients 
before any study specific procedures or registration for study treatment can occur.  All patients 
will be registered in the Clinical Oncology Research system.  
7.2. Pretreatment evaluation  
7.2.1. Complete medical history and physical examination including breast examination, vital 
signs, height, weight, demographics, and adverse events.  
7.2.2. We will document concurrent medications as a standard of care but not for protocol 
purposes. Concurrent medications will not be included in the final analysis. However, we will 

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document and report any unexpected severe toxicity that is deemed to be related to the 
concurrent medication.  
7.2.3. Documentation of ECOG PS, menopausal status, and date of last menstrual period. 
7.2.4. The breast will be carefully and clinically measured, and the location of the involved area 
will be described. Location and size of the tumor, axillary and supraclavicular node status, and 
clinical TNM stage will be recorded. Locally recurrent breast tumors and skin lesions should be 
recorded with medical photography. Measurements should be bi-dimensional and expressed in 
centimeters. 
7.2.5. Complete blood count (CBC), differential count, and platelet count;  
7.2.6. Chemical profiles- simultaneous multichannel autoanalyzer (SMA) (Na, K, blood urea 
nitrogen (BUN), creatinine, Mg, calcium, AST, ALT, LDH, total bilirubin) 
7.2.7. If a female patient is of childbearing potential, a urine or blood pregnancy test should be 
performed no more than 3 days before the start of treatment. 
7.2.8. Levels of tumor markers (e.g., cancer antigen CA 27.29) will be assessed.  
7.2.9. Chest x-ray. 
7.2.10. PET/CT or chest and abdominal CT scan if clinically indicated. 
7.2.11. Bone scan only if PET/CT is not performed. 
7.2.12. Breast sonography with axillary assessment if clinically indicated 
7.2.13. Ultrasound-guided core biopsy of local recurrence if samples (i.e., paraffin block or 5-10 
unstained slides from the local recurrence) are not available. The imaging physician will perform 
the biopsy if indicated at MD Anderson. 
7.2.14. HSV serology: serum HSV type 1 IgG. 
7.2.15. Systemic immunity in serum or plasma levels of, IL-2, IL-12, TNF-alpha (α), IFN- alpha 
(α); and phenotype for T-cell subsets (CD3, CD4, CD8, CD25), and natural killer-cell subsets 
(CD16, CD56) will be determined via multiparameter fluorescence activated cell sorting (FACS) 
analysis (percentage and absolute numbers) in Dr. James Reuben's laboratory at MD Anderson.  
7.2.16. Photography of the local recurrence in the chest wall. 
  
8.0. Evaluation during study  
The window for all assessments and treatments should be completed within 5 days of the 
scheduled time.  

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Patients will be allowed to continue current hormonal therapy, selected chemotherapy, targeted 
agents and/or anti-HER-2 therapy, which will be administered as standard of care, (per physician 
discretion) while receiving study drug.  
8.1. Evaluation during talimogene laherparepvec: 
8.1.1. Patients will have a CBC, differential count and platelet count before each cycle.   
8.1.2. Patients may repeat the CBC, differential count and platelet count until recovery of these 
measures before the next cycle (absolute neutrophil counts ≧ 1,000 and platelets ≧ 100,000 per 
mm3).  
8.1.3. Medical history and physical examination with vital signs, weight, and PS before cycles 2 
and 5 and every additional 2 cycles of treatments. 
8.1.4. Digital photography of chest lesions before cycles 2, 5, and every additional 2 cycles of 
treatment. 
8.1.5. Toxic effects will be assessed before each cycle. 
8.1.6. SMA (Na, K, BUN, creatinine, Mg, calcium, AST, ALT, glucose, LDH, and total bilirubin) 
will be performed before each cycle. 
8.1.7. Levels of tumor markers (e.g., cancer antigen CA 27.29) will be assessed before cycle 5 
and every additional 4 cycles of treatment. 
8.1.8. Systemic immunity in serum or plasma levels of GM-CSF, IL-2, IL-12, TNF-alpha (α), 
IFN- alpha (α); and phenotype for T-cell subsets (CD3, CD4, CD8, CD25), and NK-cell subsets 
(CD16, CD56) will be determined via multiparameter FACS analysis (percentage and absolute 
numbers) before cycle 5 and at the end of study in Dr. James Reuben's laboratory at MD 
Anderson. 
8.1.9. PET-CT or CT of bone/ abdomen/chest should be performed before cycle 5 and before 
every additional 4 cycles of treatment as clinically indicated. 
8.1.10. Disease assessment will be done at the end of cycle 4, cycle 8 and cycle 10. 
 
8.2. Evaluation of distant metastases (before cycle 5) 
If a patient has distant metastasis, every effort will be made to obtain tissues from an easily 
accessible metastatic site. If patient does not have distant metastasis or distant metastasis is not 
accessible, core biopsy of local lesions will be needed to collect tumor tissue. Every effort will 
be made to obtain biopsy tissue before cycle 5 for at least 60% of enrolled patients. 
A pathologist collaborator will be notified before the biopsy and will handle the resected 
specimen. Every attempt will be made to identify any tumor change such as necrosis. 
Hematoxylin and Eosin staining will be performed with formalin-fixed paraffin-embedded 

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blocks to determine tumor, and immunohistochemical (IHC) staining will be made for immunity 
assessment. IHC assays will include CD3, CD4, and CD8 for T-cell immunity assessment, CD20 
for B-cell immunity assessment, and CD16, CD56, and Granzyme B for NK cell immunity 
assessment. Cleaved caspase 3 staining for an apoptosis assay, Ki67 for a proliferation assay, and 
HSV antigen staining will be performed. If the remaining sample is ample, CD45RO, TIA-1, 
FoxP3, CD25, OX-40, CD56, CD57, CD1a, CD208, myeloperoxidase, CD68, COX-2, MHC 
Class I, and MHC Class II will also be assessed in Dr. Savitri Krishnamurthy’s laboratory at MD 
Anderson. 
8.3 Study Calendar 
  
Evaluation and 
treatment 
Screening 
Cycle 1 
 Day 1 
Cycle 2 
(D22+/-5 
days) 
 
Cycle 5 
(D64 +/- 
5 days) 
 
Cycle 7 
and 
every 2 
cycles 
Follow 
up9 
Time 
Baseline 
(within 6 
weeks) 
Prior to  talimogene laherparepvec 
injection 
Patients 
will be 
monitored 
for 1 year 
after 
removal 
from the 
study or 
until death, 
whichever 
occurs first.  
Eligibility, screening, consent, and 
registration 
X 
  
  
  
  
Medical history  
X 
  
  
  
  
Staging with tumor measurements 
X 
  
  
  
  
Photography of chest wall 
X1 
  
X 
X 
X 
Biopsy of local recurrence [HE, 
IHC] 
X8 
  
  
X8 
  
Biopsy of easily accessible distant 
metastasis [HE, IHC] 
  
  
  
X8  
  
Correlative immune study 
X 
  
  
X7 
  
Physical examinations, vital signs 
X 
X2 
X 
X 
X 
ECOG PS 
X 
X2  
X 
X 
X 
Hematology assessment  and 
Biochemical profiles3,5 
X 
X2  
X 
X 
X 
Tumor markers (CA27.29)11, IgG 
(baseline only) 
X 
  
  
X 
X11 
Chest X-ray; Breast sonography13  
X 
 
 
 
 
Pregnancy test if applicable10 
X 
  
  
  
  
PET-CT or CT scan of bone/ 
abdomen/chest as clinically 
indicated 
X 
  
  
X 
X4 
Disease assessment 12 
 
 
 
X 
X 

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Protocol 2014-0034 
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Adverse events5 
X 
X 
X 
X 
X 
Talimogene Laherparepvec 
injection6 
 
X 
X 
X 
X 
1. Within 1 week prior to treatment  
2. No need to repeat if within 7 days from baseline 
3. Hematology include CBC, differential count and platelet count; and biochemical profiles SMA include Na, K, BUN, creatinine, 
Mg, calcium, AST, ALT, LDH, total bilirubin 
4. Repeat every 4 cycles as clinical indicated 
5. Before each cycle. Reporting exposure to talimogene laherparepvec and should be collected for the duration of the study and 
safety f/u 
6. Starting cycle 2, Talimogene Laherparepvec injection will be given every 2 weeks until disease progression 
7. Correlative immune study will be repeated before cycle 5 and at the end of study if available. 
8. Core biopsy of local recurrence at baseline if samples (i.e., paraffin block or 5-10 unstained slides) from the local recurrence 
are not available. Core biopsy of either distant metastasis or local recurrent lesions before cycle 5 based on patient status.  
9. a. Safety Follow-Up: should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of 
a new anti-cancer treatment, whichever comes first. Safety Follow-Up Visit can be done in the clinic, or by phone if patient is 
not willing to come to the clinic for follow up. 
      b. Unexpected AEs: Patients removed from study for unexpected adverse events will be monitored until AE is resolved or 
stabilized. 
    c. Survival Follow-Up: approximately every 3 months patient survival information will be followed by chart reviewing, or by 
phone up to 1 year. 
10. Female patients of childbearing potential must have a negative urine or blood pregnancy test no more than 3 days prior to starting 
study drug. 
11. Tumor markers (CA 27.29) will be assessed at baseline, before cycle 5 and every additional 4 cycles of treatment. IgG and IgM 
will be tested at baseline only 
12. Disease assessment will be performed at the end of cycle 4, cycle 8 and cycle 10 
13. Breast sonography with axillary assessment if clinically indicated 
Abbreviation; HE: hematoxilin and eosin staining, IHC: immunohistochemical staining,: talimogene laherparepvec 
9.0. Criteria for response, overall response and disease control 
Response must be evaluated using RECIST ver.1.1.Tumor lesions must be accurately measured 
in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a 
minimum size of 10 mm by CT scan (irrespective of scanner type) and magnetic resonance 
imaging (MRI) (no less than double the slice thickness and a minimum of 10 mm), 10 mm caliper 
measurement by clinical examination (when superficial), and 20 mm by chest X-ray (if clearly 
defined and surrounded by aerated lung). 
Tumor lesions must be accurately measured in at least one dimension of local recurrence and 
skin metastases if applicable. These will be measured by caliper, and the extent of disease should 
be recorded on a photograph with a scale marker and injection marker. If these lesions are 
immeasurable, their extent should also be recorded on a photograph with a scale marker and 
injection marker to assess the rate of overall response. 
9.1. Complete Response (CR): Disappearance of all target and non-target lesions at a minimum 
of 4 weeks.  
9.2. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of the 
target lesions at a minimum of 4 weeks, taking as a reference the baseline sum of the longest 
diameter with target. 

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Protocol 2014-0034 
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9.3. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease (PD), taking as a reference the smallest sum of the longest 
diameter since the treatment started with target lesions. 
9.4. Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). In the previous phase III melanoma study, PD (defined by modified 
WHO criteria) prior to response was observed in about 50% of responders, and median time to 
response was 4.1 months. Thus, for this study purpose, a true PD will be confirmed at the end of 
cycle 10 (approximately 5 months) as long as patients tolerated the treatment. 
9.5. Criteria for Overall Response   
Response definition among measurable and non-measurable disease combination. Overall 
response will be defined as a sum of the 3 response types. 
 
Non-measurable 
disease  
Measurable disease  
  
(i.e., bone) 
(i.e., lung, liver, lymph nodes) 
Type I  
None 
CR or PR,  
measurable disease only 
  
 
Type II 
CR, 
None 
non-measurable disease only 
 
  
Type III 
CR, 
CR or PR,  
Both measurable and non-
measurable disease 
 
 
A patient with PD of measurable disease prior to end of cycle 10 would be considered to have 
overall response if the PD is not confirmed at the end of cycle 10.  
9.6. Criteria for Disease Control   
Disease control definition among measurable and non-measurable disease combination 
Controlled Disease  
Non-measurable 
disease  
Measurable disease  
  
(i.e., bone) 
(i.e., lung, liver, lymph nodes) 
Type I  
None 
CR or PR, or SD ≥  4 months 
measurable disease only 
  
or no true PD ( at cycle10) 
Type II 
CR, 
None 
non-measurable disease only 
or SD ≥ 4 M 
  
Type III 
CR, 
CR or PR, or SD ≥  4 months  
Both measurable and non-
measurable disease 
or SD ≥ 4 M 
or no true PD ( at cycle10) 

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A patient with PD of measurable disease prior to end of cycle 10 would be considered to have 
disease control if the PD is not confirmed at the end of cycle 10.  
9.7. Response will not be considered evaluable in the following categories: 
9.7.1. Early Deaths: Patients who die within the first 2 weeks of the initiation of drug therapy 
owing to concurrent disease. These cases will be considered treatment failures in the intent-to-
treat analysis. 
9.7.2. Lost to Follow-up:  Patients for whom there is inadequate information to judge tumor 
response because of loss of contact with our institution (>2 months after a missed appointment) 
and with referring physician in spite of repeated attempts to locate them. These cases will be 
considered treatment failures in the intent-to-treat analysis. 
9.7.3. Major Protocol Violation:  Patients who significantly deviate from the treatment program 
by either adding or deleting another agent or another therapeutic maneuver or by modifying 
substantially the dosage and schedule of the drug under evaluation. Patients who do not fulfill the 
requirements outlined under Patient Eligibility are also included in this category. 
9.8. Down staging is defined as a change in the tumor extent that results in reclassification of the 
primary tumor and/or regional lymph node metastases into a different (lower) T, N, or M 
subgroup. 
9.9. All subjective toxic effects encountered during the study will be evaluated according to the 
CTCAE version 4.0. Objective toxic effects will be considered as the maximum numerical 
deviation from the normal range. 
9.10. The survival of patients will be measured from the date of registration.  
9.11. Patients will be monitored for 1 year after removal from the study or until death, whichever 
occurs first. Patients removed from study for unexpected adverse events will be monitored until 
AE is resolved or stabilized. 
10.0. Investigational drug management  
10.1. Prescription 
Talimogene laherparepvec will be provided by Amgen Inc. and dispensed by the investigational 
pharmacy at MD Anderson.  
10.2. Treatment compliance  
The study drug must be dispensed only by an appropriately qualified person to patients in the 
study.  The drug is to be used in accordance with the protocol by patients who are under the 
direct supervision of an investigator.  
10.3. Packaging and labeling  
Talimogene laherparepvec medication labels will comply with legal requirements.   

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10.4. Storage and accountability 
Talimogene laherparepvec will be supplied to the pharmacy of the investigational site/institution 
by Amgen Inc. Talimogene laherparepvec should be stored away from light and according to the 
storage and expiration information (where required) provided on the label that is affixed to the 
package containing the investigational product. See detailed information in Appendices section 
15.7 and/or the package insert in Appendix P in PDOL 
The study drug must be stored in a secure area with limited access. It will be administered only 
to patients entered into the clinical study, at no cost to the patients, in accordance with the 
conditions specified in this protocol.   
The investigational pharmacy will maintain accurate records of the dates and amounts of 
shipments of the study drug, recipients of the drug (patient-by-patient accounting), and any study 
treatment accidentally or deliberately destroyed.  At the end of the study, the amount of study 
drug supplied, dispensed, and subsequently destroyed or returned to MD Anderson’s 
investigational pharmacy must be reconciled. Used or expired study drug will be disposed per 
MD Anderson Cancer Center policy.  
11.0. Safety monitoring and reporting 
11.1. Adverse events  
AEs will be assessed according to the CTCAE version 4.0 before each cycle. All study 
participants who have received any dose of talimogene laherparepvec will be evaluable for 
safety. Unexpected adverse events including laboratory adverse events deemed clinically 
significant by the investigator will be graded and recorded.  
An AE is an undesirable medical occurrence (sign, symptom, or diagnosis) or worsening of a 
pre-existing medical condition (e.g., diabetes, congestive heart failure, rheumatoid arthritis) that 
occurs after the initiation of the investigational product, regardless of whether it is considered to 
be related to the investigational product. The worsening of an existing medical condition occurs 
when a condition that was present at baseline (e.g., cancer, diabetes, migraine headaches, gout) 
becomes more severe, more frequent, or increased in duration during treatment with the 
investigational product. Grade 2 or higher non-hematologic AEs and grade 3 or higher 
hematologic AEs will be recorded upon observation by the investigator or reported by the patient 
(regardless of whether they are attributed to investigational product), documented in the patient’s 
medical record, and recorded in CORe. Grade 2 or higher abnormal lab values will be recorded 
as AEs; and grade 1 abnormal laboratory values will not be recorded as AEs, however, any 
clinical consequences of the abnormality and related grade 1 abnormality should be recorded as 
AEs. Hospitalization for elective surgery or routine clinical procedures that are not the result of 
an AE (e.g., surgical insertion of a central line) need not be considered AEs and should not be 
recorded as an AE. Disease progression should not be recorded as AEs. The Investigator is 
responsible for verifying and providing source documentation for all adverse events and 
assigning attribution for each event for all subjects enrolled on the trial. 

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11.2. Serious adverse event (SAE) reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse experience 
as it occurred. It does not include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
• 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of attribution (within 5 working days of knowledge of the event). 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of the 
event to the Safety Project Manager in the IND Office.   
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws consent. 
Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 

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Protocol 2014-0034 
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• 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
• 
The gene therapy reporting addendum (“Additional Reporting Form for Serious Adverse 
Events on Gene Transfer Trials”) must be included with each SAE submitted. 
 
Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
11.3 Investigator Communication with Amgen 
 
11.3.1 Safety reporting to Amgen  
The PI and the research team is responsible for compliance with expedited reporting 
requirements for serious and unexpected and related adverse events (SUSARs), for generation of 
SAE reports including narratives, and for periodic reporting to Amgen of SAEs as outlined in 
Table 5 and Table 6 below. Individual safety reports (Table 5) should be accompanied by the Fax 
Cover Form provided in Appendix 15.1, and sent to Amgen Global Safety, utilizing the fax or 
email information provided on the cover page. Aggregate safety reporting (Table 6) including 
listings, tabulations and summary reports should be scanned and accompanied by the Fax Cover 
Form provided in Appendix 15.5, and sent to Amgen NASCR, utilizing the email information 
provided on the cover page. 
In addition to the requirements outlined in Table 5 and 6, Sponsor/Investigators are required to 
report direct exposures to talimogene laherparepvec (e.g., needle stick, splash back) of herpetic 
illness and all suspected herpetic events (refer to Section 11.3.2 ‘Accidental Exposures to 
Talimogene Laherparepvec and Herpetic Events’). 
 
MDA SAE form will be used for the reporting of these events. Anytime a report (i.e. herpetic, 
pregnancy, or lactation event) is submitted to Amgen (even though it may not be an SAE by 
definition), a copy must be provided to the IND Office at the same time. 
Table 5. Expedited Reporting Requirements for Interventional Studies 
Safety Data  
Timeframe for Submission to Amgen  
Suspected Unexpected Serious Adverse 
Reaction (SUSARs)  
Individual reports sent to Amgen at time of 
expedited reporting to IRB and/or FDA.  

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Protocol 2014-0034 
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Serious Adverse Events (SAEs) (related)  
Individual reports sent to Amgen at time of 
expedited reporting to IRB and/or FDA  
Pregnancy/Lactation  
Individual reports sent within 10 days of 
Sponsor/Investigator awareness. (Refer to 
Appendix 15.3 and Appendix 15.4 for Amgen 
template forms)  
Individual reports should be faxed to 1-888-814-8653 or scanned and sent via email to svc-ags-
in-us@amgen.com 
Table 6. Aggregate Reports 
Safety Data  
Timeframe for submission to Amgen  
Adverse events (all serious and non-serious 
adverse events, regardless of relatedness)  
Line listing and summary tabulation of all 
adverse events sent annually AND at end of 
study  
US IND Annual Safety Report  
Annually  
Other Aggregate Analyses  
(any report containing safety data generated 
during the course of the study)  
At time of ISS sponsor submission to 
anybody governing research conduct (e.g., 
RA, IRB, etc.)  
Final (End of Study) Report, including:  
 Unblinding data for blinded studies  
 Reports of unauthorized use of a marketed 
product  
 
At time of ISS sponsor submission to 
anybody governing research conduct (e.g., 
RA, IRB, etc.) but not later than 1 calendar 
year after study completion  
Aggregate reports should be submitted via email to the Amgen NASCR manager, accompanied 
by the Fax Cover Form in Appendix 15.5 
Please refer to the ICH Guidelines E2A for safety related definitions and terminology: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E
2A_Guideline.pdf. 
 
11.3.2 Accidental Exposures to Talimogene Laherparepvic and Herpetic Event Reporting 
In order to better assess and understand the potential risks to treated patients and/or third parties 
following the treatment of clinical trial subjects with talimogene laherparepvec, special reporting 
procedures apply for accidental exposures to talimogene laherparepvec and for suspected 
herpetic events. See Table 7 for a summary of reporting requirements. Clinicians should review 
the Imlygic package insert (available online) for additional information on the safe handling of 
talimogene laherparepvec.  
 
Accidental Exposure of HCPs to Talimogene Laherparepvec  

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Protocol 2014-0034 
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HCPs involved in your clinical trial who were directly exposed to talimogene laherparepvec 
(e.g., needle stick, splash back) but who are without signs or symptoms of herpetic illness should 
be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442). 
Suspected Herpetic Events  
Suspected herpetic events must be reported to Amgen within 24 hours of awareness. 
Reporting is required for: (1) suspected herpetic events in treated patients; (2) suspected herpetic 
events in at risk HCPs with direct or indirect exposure and (3) suspected herpetic events in 
treated patient’s close contacts, as outlined in Table 7. An example of the Suspected 
IMLYGIC™ (Talimogene laherparepvec) or Herpes Virus Associated Adverse Event can be 
found in Appendix 15.2.  
 
In addition to reporting these events, suspected herpetic lesions should be swabbed and 
submitted for qPCR testing for the detection of talimogene laherparepvec. Samples should be 
collected using appropriate technique and a flocked swab from site supplies. This test is likely to 
be more reliable if performed within the first three days of symptom appearance, however, all 
lesions should be swabbed, regardless of the timing of presentation. Amgen does not require 
qPCR or other testing for wild type HSV-1.  
➢ Reporting Process for ISS Treated Patients:  
- Any suspected herpetic lesion should be reported to Amgen at 1-855-IMLYGIC (1-
855-465-9442), evaluated by the Sponsor/Investigator and swabbed for qPCR testing.  
- Once an initial report has been made, additional materials will be provided, including 
reporting forms and supplies needed for shipment of swab samples. Amgen will 
require patient consent for qPCR testing, which must be obtained prior to swabbing.  
➢ Reporting Process for HCPs and Close Contacts:  
Sponsor/Investigator should advise any HCPs and/or Close Contacts with suspected 
herpetic lesions to contact their personal physician to facilitate reporting to Amgen. 
Suspected herpetic lesions can be reported by the Sponsor / Investigator, personal 
physician or exposed individual to Amgen at 1-855-IMLYGIC (1-855-465-9442). Once 
an initial report has been made, additional materials will be provided, including 
reporting forms and supplies needed for the shipment of swab samples. Amgen will 
require patient consent for qPCR testing, which must be obtained prior to swabbing. 
 
Table 7. Accidental Exposure & Herpetic Event Reporting Requirement Summary 
Exposed 
Person  
Reporter  
Timeframe 
for Reporting 
to Amgen  
Report 
Mechanism  
Timing of 
Swab 
Collection  
qPCR 
Testing?  
Responsible 
Party for 
Lesion 
Swabbing  
qPCR Test 
Result 
Distribution*  
Treated 
Patients with 
suspected 
herpetic 
lesions  
Sponsor / 
Investigator  
Within 24 
hours of 
Sponsor / 
Investigator 
awareness  
Contact 
Amgen at 1-
855-
IMLYGIC (1-
855-465-
9442) to 
report event  
Collect swabs 
from 
suspected 
lesions 
(ideally within 
3 days of 
appearance of 
symptoms)  
Yes, if 
consent 
obtained  
Sponsor / 
Investigator  
Sponsor / 
Investigator 
and Amgen  

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Protocol 2014-0034 
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HCP directly 
exposed to 
product (e.g., 
needle stick, 
splash back) 
without signs 
or symptoms 
of herpetic 
illness  
HCP’s 
Personal 
Physician or 
impacted 
person  
Within 24 
hours of 
Reporter 
awareness  
Contact 
Amgen at 1-
855-
IMLYGIC (1-
855-465-
9442) to 
report event  
N/A  
N/A  
N/A  
N/A  
HCP directly 
or indirectly 
exposed to 
product with 
suspected 
herpetic 
lesions  
HCP’s 
Personal 
Physician or 
impacted 
person  
Within 24 
hours of 
Reporter 
awareness  
Contact 
Amgen at 1-
855-
IMLYGIC (1-
855-465-
9442) to 
report event  
Collect swabs 
from 
suspected 
lesions 
(ideally within 
3 days of 
appearance of 
symptoms)  
Yes, if 
consent 
obtained  
HCP or HCP’s 
Personal 
Physician  
HCP’s 
Personal 
Physician and 
Amgen  
Close Contact 
(eg caregiver, 
spouse, child) 
with 
suspected 
herpetic 
lesions  
Sponsor / 
Investigator, 
Close 
Contact’s 
Personal 
Physician or 
Close Contact  
Within 24 
hours of 
Reporter 
awareness  
Contact 
Amgen at 1-
855-
IMLYGIC (1-
855-465-
9442) to 
report event  
Collect swabs 
from 
suspected 
lesions 
(ideally within 
3 days of 
appearance of 
symptoms)  
Yes, if 
consent 
obtained  
Sponsor / 
Investigator, 
Close 
Contact’s 
Personal 
Physician  
Sponsor / 
Investigator, 
Close 
Contact’s 
Personal 
Physician and 
Amgen  
*The laboratory conducting the qPCR testing on behalf of Amgen is Viracor.  
12.0. Data management 
12.1. Data collection and entry 
Data collected from the study will be entered in PDMS or CORe.  
The Principal Investigator is responsible for assuring that the data entered into the database are 
complete and accurate and that data entry is performed in a timely manner.  
Demographic information, age, sex, race, and date of birth; date of initial breast cancer 
diagnosis, surgery, local recurrence, and distant metastases if indicated; end date of 
chemotherapy including targeting agents, radiation therapy, or hormone therapy; menopausal 
status; clinical and pathologic stage of initial breast cancer; initial tumor histology, nuclear grade, 
estrogen receptor status, progesterone receptor status, and HER2 status; lymphatic invasion, 
vascular invasion, and tumor margins; previous chemotherapy regimens including targeting 
agents, type of surgery, and type of radiation therapy, hormone therapy, etc.; date of treatment, 
treatment response, levels of overall response, and AEs [>/=2 non-hematologic and >/=3 
hematological AEs] will be collected. Grade 2 or higher abnormal lab values will be recorded as 
AEs; and grade 1 abnormal laboratory values will not be reported as AEs; however, any clinical 
consequences of the abnormality should be reported as AEs. Concomitant medications will not 
be entered in the case report form, captured only in the medical record. 
12.2. Data confidentiality plan 
All laboratory and clinical data gathered in this protocol will be stored in a password-protected 
database. All patient information will be handled using anonymous identifiers. Linkage to patient 
identity will be possible only after accessing a password-protected database. Access to the 
database will be available only to individuals directly involved in the study. 
 

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Protocol 2014-0034 
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Information gathered for this study will not be reused or disclosed to any other person or entity, 
or for other research. Once the research has been completed, identifiers will be retained for as 
long as is required by law and by institutional regulations, and at that point will be destroyed. 
13.0. Statistical consideration  
13.1. Statistical design 
The primary objective of this phase II trial is to assess the efficacy of talimogene laherparepvec 
as a single agent in locally recurrent IBC and non-IBC patients. The primary endpoint is the rate 
of overall response. 
The overall response rate is defined as the percentage of CR, PR in overall patients. Patients will 
be evaluated for  disease control  at the end of cycle 4 (2 months), cycle 8 (4 months) and cycle 
10 (5 months). If patients have measurable disease only and achieve CR or PR, they will be 
considered Response Type I. If patients have non-measurable disease only, and achieved CR, 
they will be considered as Response Type II. If patients have both measurable and non-
measurable disease and achieve CR or PR at the measurable disease sites, and achieved CR at 
the non-measurable disease site, they will be considered as Response Type III. If patients have 
mixed responses such as progression of measurable disease and no progression of  non-
measurable disease at 5 months or vice versa, they will be considered to have uncontrolled 
disease. The Overall Response rate will de defined as a sum of the 3 response types. 
The trial will be conducted using a two-stage design and the overall response rate will be 
estimated accordingly. It is assumed that the talimogene laherparepvec single agent will have a 
response rate of 20%. A response rate of 5% or lower will be considered treatment failure and 
the regimen will be rejected under this circumstance. 13 patients will be enrolled to the first 
stage. The study accrual will be delayed until all 13 patients are evaluable for reponse. A 
summary report will be submitted to the medical monitor in the IND office. If no patients 
achieve an overall response to the treatment, the trial will be stopped and the regimen will be 
declared as ineffective.  If there are 1 or more patients achieve an overall response, 22 more 
patients will be enrolled to the study to reach a total of 35 treated patients.  By the end of the 
study, the new regimen will be rejected if less than or equal to 3/35 patients achieve overall 
response and will not be considered worthy of further investigation otherwise.  
 
We have reviewed the 8 patients treated thus far, and determined that 1 of those 8 patients would 
not be eligible per the current proposed revised criteria due to extensive (≥5% Total Body 
Surface) skin lesion and will be replaced. As such, the overall sample size will be increased to 
36 by one more patient. The afore mentioned one patient that is still evaluable for toxicity and 
efficacy in the overall end analysis, but not as a part of the evaluation for the 13 patients treated 
in the first stage. The above two-stage design statistical analysis plan will not change.  
 
The operating characteristics of the trial are given as follows. When the true response rate is 5% 
the probability of stopping the trial early is 51% and the probability of claiming the regimen to 
be promising is 8.4%.  On the other hand, if the response rate is 20%, the probability to stop the 
trial early is 5% and the probability of claiming the regimen to be promising is 90%.  The 

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expected sample sizes are 23.7 and 33.8 when the true overall response  rates are 5% and 20%, 
respectively  
We will monitor severe toxicity, grade 3 or greater possibly, probably or definitely treatment 
related toxicities with CTCAE ver.4.0, by cohorts of 5 patients for the whole patient population 
(N=36) for the first cycle. A summary report will be submitted to the medical monitor in the IND 
office. The stopping boundary is calculated based on the beta-binomial distribution.  We assume 
that number of patients who develop severe toxicity follows a binomial distribution with 
probability p, and p has a prior distribution of beta (0.20, 0.80).  We consider that the probability 
of severe toxicity greater than 20% is excessive to the patients.  The stopping boundary is chosen 
to stop the trial if the data indicate that there is a high probability that excessive toxicity-i.e., 
probability (p>0.20|data) ≧90%.  The trial will be stopped and the treatment will be considered 
too toxic if the number of patients with severe toxic effects exceeds >=3/5, 4/10, 6/15, 7/20, 
8/25, 10/30, and 11/35 for the first cycle.  The operating characteristics are provided, based on 
5,000 simulations.  For example, if the true toxicity rate is 10%, the probability to stop the trial 
early due to toxicity is very low, 2% and an average of 34.5 patients will be treated on trial. On 
the other hand, if the true severe toxicity rate is 30%, the probability of stopping the trial early 
would be 62% with an average of 21.5 patients treated. When the true severe toxicity rate is 
20%, we will have a 21% chance of terminating the trial early with an average of 30.3 patients 
treated.  However if the toxicity rate is as high as 40%, then we will have a 91% chance to stop 
the trial early and with an average of only 13.5 patients treated. 
 
Secondary objectives includes determining the overall disease control rate, local overall response 
rate and disease control rate, PFS, and OS in all patients; the local overall response rate and 
disease control rate, PFS, and OS in patients without distant metastases; and the local overall 
response rate and disease control rate, PFS, and OS in patients with distant metastases for 
defining the local efficacy of talimogene laherparepvec injection among breast cancer patients 
with inoperable local recurrence after surgery. In addition, this includes safety and tolerability of 
talimogene laherparepvec in these patients. The definition of PFS is time from treatment 
initiation until disease progression or death and this progression needs to be confirmed after the 
end of cycle 10. For example, patients who showed progress at 2 months but responded as PR at 
5 months, we determine this as PR. In contrast, patients who showed progress at 2 months and 
was confirmed PD at 5 months, we determine this as PD at 2 months. The definition of OS is 
time from treatment initiation until any cause of death. 
Analysis plan: 
By the end of the study, the overall response rate will be estimated with 95% confidence 
intervals for all evaluabe  patients and for patients with or without distant metastasis, separately. 
PFS and OS from registration will also be estimated using Kaplan-Meier method with 95% 
confidence intervals.    
Biomarker endpoints will be measured in tissue and in surrogate blood or plasma before and 
after the treatment. Correlation between biomarkers from various markers and between tissue 
and blood/plasma will be assessed by Pearson or Spearman rank correlation coefficients for 

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continuous biomarkers and by chi-square or Fisher’s exact test for discrete covariates. The 
associations between markers or change in the level of markers and overall response status will 
first be assessed graphically and then tested using a t-test/analysis of variance or Wilcoxon rank 
sum test/Kruskal-Wallis test, when appropriate.  Repeated measures analysis including mixed 
effects modeling will be performed to analyze biomarkers change over time. We may also 
evaluate the association between the changes in the level of marker and the overall response 
status. 
13.2 Primary endpoint 
The rate of overall response for measurable and immeasurable disease in all patients.  
13.3. Secondary endpoints 
13.3.1. overall  disease control rate, PFS, and OS in all patients 
13.3.2. Local overall response rate and disease control rate, PFS, and OS in all patients. 
13.3.3. Local overall response rate and disease control rate, PFS, and OS in patients without 
distant metastases. 
13.3.4. Local overall response rate and disease control rate, PFS, and OS in patients with distant 
metastases. 
13.3.5. Toxicity 
 
14.0. Reference 
1. 
Clemons M, Hamilton T, Mansi J, Lockwood G, Goss P. Management of recurrent 
locoregional breast cancer: oncologist survey. Breast 2003;12:328-37. 
2. 
Cristofanilli M, Valero V, Buzdar AU, et al. Inflammatory breast cancer (IBC) and 
patterns of recurrence: understanding the biology of a unique disease. Cancer 2007;110:1436-44. 
3. 
Valagussa P, Tess JD, Rossi A, Tancini G, Banfi A, Bonadonna G. Adjuvant CMF effect 
on site of first recurrence, and appropriate follow-up intervals, in operable breast cancer with 
positive axillary nodes. Breast cancer research and treatment 1981;1:349-56. 
4. 
Goldhirsch A, Gelber RD, Price KN, et al. Effect of systemic adjuvant treatment on first 
sites of breast cancer relapse. Lancet 1994;343:377-81. 
5. 
Whelan T, Clark R, Roberts R, Levine M, Foster G. Ipsilateral breast tumor recurrence 
postlumpectomy is predictive of subsequent mortality: results from a randomized trial. 
Investigators of the Ontario Clinical Oncology Group. International journal of radiation 
oncology, biology, physics 1994;30:11-6. 
6. 
Wapnir IL, Anderson SJ, Mamounas EP, et al. Prognosis after ipsilateral breast tumor 
recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel 
Project node-positive adjuvant breast cancer trials. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology 2006;24:2028-37. 

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7. 
Weksberg DC, Allen PK, Hoffman KE, et al. Outcomes and Predictive Factors for 
Salvage Therapy After Local-Regional Recurrence Following Neoadjuvant Chemotherapy and 
Breast Conserving Therapy. Annals of surgical oncology 2013. 
8. 
Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-
regional disease in women with operable breast cancer: findings from National Surgical 
Adjuvant Breast and Bowel Project B-18. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 1997;15:2483-93. 
9. 
Danforth DN, Jr., Zujewski J, O'Shaughnessy J, et al. Selection of local therapy after 
neoadjuvant chemotherapy in patients with stage IIIA,B breast cancer. Annals of surgical 
oncology 1998;5:150-8. 
10. 
Huang EH, Strom EA, Perkins GH, et al. Comparison of risk of local-regional recurrence 
after mastectomy or breast conservation therapy for patients treated with neoadjuvant 
chemotherapy and radiation stratified according to a prognostic index score. International journal 
of radiation oncology, biology, physics 2006;66:352-7. 
11. 
Cance WG, Carey LA, Calvo BF, et al. Long-term outcome of neoadjuvant therapy for 
locally advanced breast carcinoma: effective clinical downstaging allows breast preservation and 
predicts outstanding local control and survival. Annals of surgery 2002;236:295-302; discussion 
-3. 
12. 
Chen AM, Meric-Bernstam F, Hunt KK, et al. Breast conservation after neoadjuvant 
chemotherapy: the MD Anderson cancer center experience. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2004;22:2303-12. 
13. 
Ishitobi M, Ohsumi S, Inaji H, et al. Ipsilateral breast tumor recurrence (IBTR) in patients 
with operable breast cancer who undergo breast-conserving treatment after receiving 
neoadjuvant chemotherapy: risk factors of IBTR and validation of the MD Anderson Prognostic 
Index. Cancer 2012;118:4385-93. 
14. 
Min SY, Lee SJ, Shin KH, et al. Locoregional recurrence of breast cancer in patients 
treated with breast conservation surgery and radiotherapy following neoadjuvant chemotherapy. 
International journal of radiation oncology, biology, physics 2011;81:e697-705. 
15. 
Skinner HD, Strom EA, Motwani SB, et al. Radiation dose escalation for loco-regional 
recurrence of breast cancer after mastectomy. Radiat Oncol 2013;8:13. 
16. 
Cataliotti L, Buzdar AU, Noguchi S, et al. Comparison of anastrozole versus tamoxifen 
as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: 
the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) trial. Cancer 2006;106:2095-
103. 
17. 
Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced 
oncolytic, immune stimulating, and anti-tumour properties. Gene therapy 2003;10:292-303. 
18. 
Hu JC, Coffin RS, Davis CJ, et al. A phase I study of OncoVEXGM-CSF, a second-
generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-
stimulating factor. Clinical cancer research : an official journal of the American Association for 
Cancer Research 2006;12:6737-47. 
19. 
Wang J, Hu P, Zeng M, Rabkin SD, Liu R. Oncolytic herpes simplex virus treatment of 
metastatic breast cancer. International journal of oncology 2012;40:757-63. 
20. 
Robert Hans IA FA, Thomas A et al. OPTiM: A randomized phase III trial of talimogene 
laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating 

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factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. ASCO 
annual meeting 2013. 
21. 
Costa SD, Loibl S, Kaufmann M, et al. Neoadjuvant chemotherapy shows similar 
response in patients with inflammatory or locally advanced breast cancer when compared with 
operable breast cancer: a secondary analysis of the GeparTrio trial data. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2010;28:83-91. 
22. 
Jacobs MA, Stearns V, Wolff AC, et al. Multiparametric magnetic resonance imaging, 
spectroscopy and multinuclear ((2)(3)Na) imaging monitoring of preoperative chemotherapy for 
locally advanced breast cancer. Academic radiology 2010;17:1477-85. 
23. FIH study 001/01: Hu JCC et al. Clin Cancer Res 2006;6737 12(22) November 15, 2006 
24. 004/04 Phase I/II study SCCHN: Harrington KJ et al. Clin Cancer Res. 2010;16(15):4005-
4015 
25. 005/05: Andtbacka RH, et al. Talimogene Laherparepvec Improves Durable Response Rate 
in Patients with Advanced Melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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15.0 Appendices  
15.1 Sample Fax Cover Sheet for Individual Safety Reports (Amgen Global Safety) 
 

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15.2 Sample of Report Form for Herpetic Event with Accidental Exposure of Close Contact 
or HCP to Talimogene Laherparepvec 
 

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15.3 Sample of Pregnancy Notification Worksheet 
 

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15.4 Sample of Lactation Notification Worksheet 
 

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15.5 Sample Fax Cover Form for Aggregate Safety Reporting 
 
 

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15.6   The Rule of Nines 
Guide that will be used to calculate the percentage of total body surface area (TBSA) of skin 
disease involvement. See figure 1 below.  
• 
Head/neck - 9%  
• 
Each arm - 9%  
• 
Anterior thorax - 18%  
• 
Posterior thorax - 18%  
• 
Each leg - 18%  
• 
Perineum - 1%  
• 
A patient's palm is approximately 1% and can be used for estimating patchy areas 
 
Figure 1. Rule of Nines 
 
 

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15.7  Talimogene Laherparepvec Storage and Handling
 

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