A Phase 1/2 Study of Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
Phase: PHASE1
Conditions: Breast Cancer, Ductal Carcinoma, Invasive Breast Carcinoma, Invasive Ductal Breast Carcinoma
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
 
 
A Phase 1/2 Study of Talimogene laherparepvec in Combination with 
Neoadjuvant Chemotherapy in Triple Negative Breast Cancer 
NCT02779855 
 
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April 5, 2021 

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Local Protocol #:  
MCC18621 
 
TITLE:  A Phase 1/2 Study of Talimogene laherparepvec in Combination with Neoadjuvant 
Chemotherapy in Triple Negative Breast Cancer 
 
 
Coordinating Center: 
 
 
Moffitt Cancer Center 
 
*Principal Investigator: 
Hatem Soliman MD 
12902 Magnolia Drive 
Tampa, FL 33612 
 
Comprehensive Breast Program 
10920 N McKinley Dr. 
Tampa, Fl 33612 
Phone: 813-745-4933 
Fax: 813-745-7287 
Hatem.soliman@moffitt.org 
 
 
 
Protocol Version Date: 
v2.3 04/05/2021 
Amendment     # 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMA/SYNOPSIS 
 
TRIAL DESIGN: Phase 1 with 3+3 design, and Simon two stage phase 2. The phase 1 is a 
3+3 design with two dose levels (DL1: 106 PFU for all five injections, DL2: 106 PFU 1st 
injection followed by 108 PFU for remaining injections) 
STUDY POPULATION: Triple negative breast cancer, non-metastatic undergoing 
neoadjuvant chemotherapy with dose dense AC-T 
RATIONALE: Talimogene laherparepvec is an oncolytic virus that can result in direct 
tumor destruction along with stimulation of an immune response against tumor antigens 
that can lead to an influx of infiltrating T cells. Paclitaxel can lead to a similar effect in 
breast tumors treated with neoadjuvant therapy. These inflamed tumors appear to respond 
better to neoadjuvant therapy. The goal is to combine these therapies to enhance pathologic 
complete response rates. 
PRIMARY ENDPOINTS: Phase 1: Safety/toxicity, MTD/RP2D Phase 2: Pathologic 
complete response rate 
SECONDARY ENDPOINTS: Immunologic correlates by IHC and T cell receptor 
sequencing, 5 year RFS/OS, additional biomarkers 
STUDY TREATMENT: Patients will undergo weekly paclitaxel 80mg/m2 x 12 weeks 
initially and get up to 5 talimogene laherparepvec injections on weeks 1, 4, 6, 8, 10. This 
will be followed by 4 doses of dose dense doxorubicin/cyclophosphamide 60/600 mg/m2 
intravenously every 2 weeks. Patients will undergo two ultrasounds on an injection day, 
one to measure the tumor for dosing of the virus, and the second to guide the injection into 
the primary tumor where the virus will be injected. If no tumor can be visualized on 
ultrasound then no more virus injections will be given and the patient will proceed on with 
the rest of their chemotherapy as planned. An on treatment biopsy will be collected prior to 
week 6 treatment. Patients will then undergo surgery and will be assessed for the primary 
endpoint, pathological complete response. Patients will be followed for up to 5 years after 
completion of study therapy at least once every 6 months for recurrence, death, and any 
new herpetic infections by telephone and/or clinical evaluation during routine follow up 
visits. 
STATISTICS/SAMPLE SIZE: The phase I 3+3 design with two dose levels would enroll 
between 9-12 patients. The phase II Simon two stage optimal design would enroll 12 
evaluable patients in the first stage, and 25 evaluable patients in the second stage (total 
n=37). Four or more pathologic complete responses are required in the first stage and 15 or 
more pathologic complete responses are required to declare the trial positive upon 
completion of the second stage.  This is based on the null hypothesis complete response rate 
of 30%, alternative hypothesis with 45% complete response rate with a power of .70 and 
one sided type 1 error of .099.  

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TABLE OF CONTENTS 
 
SCHEMA/SYNOPSIS .................................................................................................................. 2 
1. 
OBJECTIVES ....................................................................................................... 8 
1. 
OBJECTIVES ....................................................................................................... 8 
2. 
BACKGROUND ................................................................................................... 8 
2.1 
 Study Disease ....................................................................................................... 8 
2.2 
 Study Agent .......................................................................................................... 9 
2.3 
 Other Agent(s) ................................................................................................... 12 
2.4 
 Rationale ............................................................................................................. 13 
3. 
PATIENT SELECTION .................................................................................... 13 
3.1 
 Eligibility Criteria ............................................................................................. 14 
3.2 
 Exclusion Criteria .............................................................................................. 14 
3.3 
Inclusion of Women and Minorities ................................................................. 15 
3.4    Patient Registration .............................................................................................. 16 
3.5    Removal of Patients From Study ......................................................................... 16 
Study early stopping criteria ......................................................................................... 16 
4. 
TREATMENT PLAN ........................................................................................ 16 
4.1 
 Study Agent Administration ............................................................................. 16 
4.2 
 Supportive Care Guidelines .............................................................................. 22 
4.3 
 Duration of Therapy .......................................................................................... 23 
5. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................... 23 
5.1 
  Talimogene laherparepvec ............................................................................... 23 
5.2 
  Other Agent(s) .................................................................................................. 24 
6.    PHARMACEUTICAL INFORMATION .......................................................................... 24 
6.1 Reported Adverse Events and Potential Risks for talimogene laherparepvec ... 24 
6.2     Talimogene laherparepvec description .............................................................. 30 
6.3    Commercial Agent(s) ............................................................................................ 36 
6.4 Temperature Monitoring ........................................................................................ 36 
Temperature Excursion – Definitions, Reporting and Management ............ 37 
7. 
STUDY CALENDAR .............................................. Error! Bookmark not defined. 
8. 
MEASUREMENT OF EFFECT ....................................................................... 42 
8.1. 
Definitions ........................................................................................................... 42 
8.2 
 Guidelines for Evaluation of Clinical Disease ................................................. 42 
8.3 
 Response Criteria .............................................................................................. 43 
8.4 
 Follow up evaluation ......................................................................................... 43 
8.5 
      Response Review ........................................................................................... 44 
9. 
REGULATORY AND REPORTING REQUIREMENTS ............................. 44 
9.1 Reporting Adverse Events .................................................................................................... 44 

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9.2 
Safety Data Exchange for Amgen ..................................................................... 45 
9.3  Interim analyses ...................................................................................................... 47 
10. 
STATISTICAL CONSIDERATIONS .............................................................. 48 
10.1 
Study Design/Endpoints ..................................................................................... 48 
10.2 
Sample Size/Accrual Rate .................................................................................. 48 
10.3 
Analysis of Secondary Endpoints ...................................................................... 49 
10.4     Reporting and Exclusions .................................................................................. 49 
10.5     Data analysis plan .............................................................................................. 49 
11. CORRELATIVE EXPERIMENTS: ................................................................................... 49 
11.  REFERENCES ..................................................................................................................... 52 
APPENDIX A Performance Status Criteria ........................................................................ BBB 
APPENDIX B TALIMOGENE LAHERPAREPVEC PI ......................................................... 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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AE 
Adverse Event 
ANCOV Analysis of Covariance 
CFR 
Code of Federal Regulations 
CIOMS Council for International Organizations of Medical Science 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICH E6 
International Conference on Harmonisation Guidance for Industry, Good 
Clinical Practice: Consolidated Guidance
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
ISO 
International Organization for Standardization 
LSMEA Least Squares Means 
MedDR
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute & Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 

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US 
United States 

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OBJECTIVES 
 
1.1. 
Primary endpoint(s): Phase 1: Determine the MTD/RP2D of talimogene 
laherparepvec administered with neoadjuvant paclitaxel-
doxorubicin/cyclophosphamide chemotherapy, safety/toxicity of the combination. 
Phase 2: Determine the efficacy (evaluated as pathologic complete response rates) of 
neoadjuvant talimogene laherparepvec in conjunction with neoadjuvant chemotherapy 
for early/locally advanced triple negative invasive breast cancer 
 
1.2. 
Secondary endpoints: 5 year recurrence free survival/overall survival, immune 
activation correlatives by IHC and T cell receptor sequencing 
 
2. BACKGROUND 
 
2.1. 
Study Disease 
 
Triple negative breast cancer (TNBC) comprises approximately 15-18 percent of 
breast cancer diagnoses.   TNBC is associated with a poorer prognosis overall and 
is an area of unmet need in breast cancer. It is typically more common among 
African-American women and/ or young women.  Almost a fifth of women 
diagnosed with TNBC are less than 40 years of age.  Overall, these tumors are 
typically high grade with a high proliferative rate, making them an ideal target for 
oncolytic immunotherapy.   
 
Current systemic treatment is a combination chemotherapy regimen using either 
docetaxel/cyclophosphamide for very early stage 1 disease or 
doxorubicin/cyclophosphamide/taxane combination therapy for higher risk 
disease.  Data from trials such as ECOG 1199, CALGB 9741, and recently 
SWOG 0221 suggest that the dose dense schedule of 
doxorubicin/cyclophosphamide followed by either dose dense or weekly 
paclitaxel is currently the optimal schedule for high risk disease.(1-3) This is the 
basis for the treatment schedule used in this study. Also, weekly paclitaxel with its 
more metronomic dosing and better tolerability may provide additional 
advantages when combining it with novel immunomodulatory agents. 
 
The historical rate of pathologic complete response (pCR) of TNBC to third 
generation anthracycline/taxane neoadjuvant chemotherapy is approximately 
30%. Data from TNBC patients post neoadjuvant therapy demonstrated that those 
patients who attained a pathologic complete response had an excellent prognosis.  
The FDA recently has issued in its draft guidance a framework for the rapid 
introduction of novel agents for TNBC by using the pCR rate as a surrogate for 
accelerated approvals (with full approval contingent on long term follow up data 
showing benefit). Also, the recurrence pattern of TNBC is early (peak risk is 2-3 
years from adjuvant therapy), so the follow up duration to see a difference in 
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these reasons that this pilot study is being performed in the neoadjuvant setting for 
TNBC.(4, 5)    
     
 
2.2. 
Study Agent 
 
Talimogene laherparepvec (IMLYGIC™, formerly known as OncoVEXGM-
CSF) (HSV-1 [strain JS1]/ICP34.5-/ICP47-/hGM-CSF) oncolytic immunotherapy 
is an immune-enhanced, oncolytic herpes simplex virus type 1 (HSV-1).  In the 
talimogene laherparepvec strain, the HSV-1 viral genes encoding ICP34.5 (a 
neurovirulence factor) and ICP47 (which blocks viral antigen presentation to 
major histocompatibility complex [MHC] class I and II molecules) have been 
functionally deleted.  In addition, deletion of the gene encoding ICP47 increases 
US11 expression, enhancing virus replication in cancer cells. The coding 
sequence for human granulocyte macrophage colony stimulating factor (GM-
CSF) is inserted in place of ICP34.5, to enhance the immune response to tumor 
antigens released after virus replication. Thus, the intended therapeutic strategy is 
to produce a direct oncolytic effect by replication of the virus in the tumor, and 
induction of an anti-tumor immune response enhanced by the local expression of 
GM-CSF.  The intended clinical effects include the destruction of injected tumors, 
the destruction of local, locoregional, and distant uninjected tumors, a reduction in 
the development of new metastases, a reduction in the rate of overall progression 
and of the relapse rate following the treatment of initially present disease, and 
prolonged overall survival. 
 
Talimogene laherparepvec is administered by direct injection into tumors. Dose 
schedules may vary depending upon the tumor type and whether talimogene is 
administered as monotherapy or as part of combination therapy. For melanoma, 
an optimized 106 plaque forming units (PFU)/mL (total injected volume 
dependent on tumor burden) followed by subsequent doses of 108 PFU/mL is 
used. Optimum combination therapy regimens are still being evaluated. For 
melanoma and other indications currently under active development, an optimized 
dosing regimen consists of a first dose of 106 plaque forming units (PFU)/mL 
(total injected volume dependent on injectable tumor burden) followed by 
subsequent doses of 108 PFU/mL (total injected volume dependent on injectable 
tumor burden).  This regimen is based on a phase 1 dose-ranging study (001/01) 
in which this regimen was identified as being well tolerated by both HSV-1 
seronegative and seropositive subjects. It is anticipated that this regimen will be 
used in most other oncology indications going forward, including talimogene 
laherparepvec in combination with other anti-cancer agents. 
 
Talimogene laherparepvec is a modified version of HSV-1.  HSV-1 has several 
advantages over other viruses for development as an oncolytic agent.  It infects a 
wide variety of cell types, has a rapid replication cycle resulting in cell lysis, 
allows the incorporation of single or multiple inserted genes, which may improve 

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the anti-tumor effect, and appropriate titers can be produced in quantities 
sufficient for clinical use. 
 
Nonclinical and clinical data have shown that selective deletion of HSV genes 
results in a non-pathogenic virus with promising properties for cancer therapy. (6-
12) BioVex has developed a clinical candidate virus with improved anti-tumor 
properties compared to previously available oncolytic viruses. 
 
The modifications resulting in the enhanced properties of talimogene 
laherparepvec include the following: 
 
o 
Use of a new isolate of HSV-1 (strain JS1) demonstrated in vitro to more 
effectively lyse a variety of human tumor cell lines than previous viruses used 
in clinical studies.(12-14) 
 
o 
Functional deletion of the HSV-1 gene encoding ICP47, improving the 
presentation of tumor antigens following oncolytic virus replication and 
intended to enhance the anti-tumor immune response.(15-18) 
 
o 
Insertion of the gene encoding human GM-CSF, thereby inducing the 
differentiation and proliferation of dendritic cell precursors in and around the 
injected tumor and intended to aid the induction of a systemic anti-tumor 
immune response. 
 
o 
Multiple safety features have also been incorporated into talimogene 
laherparepvec: 
 
o 
Functional deletion of ICP34.5, which functions as a virulence factor 
during HSV infection.  This functional deletion limits replication in non-
dividing cells and renders the virus non-pathogenic.  The safety of ICP34.5-
functionally deleted HSV has been shown in multiple clinical studies.(9-11, 
19, 20) 
 
o 
Insertion of the human GM-CSF coding sequence such that it replaces all 
of the gene encoding ICP34.5 to ensure that any potential recombination event 
between talimogene laherparepvec and wild-type virus could only result in a 
disabled, non-pathogenic virus and could not result in the generation of wild-
type virus carrying the gene for human GM-CSF. 
 
o 
The HSV thymidine kinase (TK) gene remains intact, which renders 
talimogene laherparepvec sensitive to anti-viral agents such as acyclovir. 
Therefore, acyclovir could be used to block virus replication, if necessary, 
although this has never been found to be needed in the subjects treated to date. 
 
Talimogene laherparepvec has been tested for efficacy in a variety of in vitro (cell 
line) and in vivo murine tumor models and has been shown to eradicate tumors or 

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substantially inhibit their growth at doses comparable to those used in clinical 
studies. Nonclinical evaluation has also confirmed that GM-CSF enhances the 
immune response generated, enhancing both injected and uninjected tumor 
responses, and that increased surface levels of MHC class I molecules result from 
the deletion of ICP47. Talimogene laherparepvec has been injected into normal 
and tumor-bearing mice to assess its safety.  In general, the virus has been well 
tolerated, and doses up to 1 x 107 PFU/dose have given no indication of any safety 
concerns. 
 
Safety data from the completed OPTiM phase 3 registration study demonstrated 
the most common side effects of talimogene laherparepvec monotherapy were 
chills (talimogene laherparepvec, 49%; GM-CSF, 9%), pyrexia (43%; 9%), 
injection-site pain (28%; 6%), nausea (36%; 20%), influenza-like illness (30%; 
15%), and fatigue (50%; 36%).Grade ≥ 3 adverse events occurred in 36% of 
subjects receiving talimogene laherparepvec and 21% of subjects receiving GM-
CSF. The only grade 3/4 adverse events occurring in ≥ 5 subjects was cellulitis 
(talimogene laherparepvec, n=6 [2.1%];GM-CSF, n=1 [<1%]). Of 10 fatal 
adverse events in the talimogene laherparepvec arm, eight were attributable to 
disease progression. The remaining two fatal adverse events (sepsis in the setting 
of salmonella infection; myocardial infarction) were not considered treatment-
related per investigator.(21)  
 
As of the 26 April 2018 data cutoff date for this investigator’s brochure, clinical 
studies of talimogene laherparepvec have been or are being conducted in several 
advanced tumor types (advanced solid tumors, melanoma, head and neck 
squamous cell carcinoma [HNSCC], pancreatic cancer, and hepatocellular 
carcinoma).  Cumulatively, an estimated total of 1253 subjects have received 
talimogene laherparepvec in clinical studies as of 26 April 2018.  Key efficacy and 
safety results for talimogene laherparepvec are summarized in the investigator 
brochure. 
 
Adverse event (AE): 86% were grade 1 or 2, but at least one grade 3 or 4 AE was 
observed in each patient. The investigators considered just two adverse events 
(pyrexia and fatigue) to be talimogene laherparepvec related and occurred in two 
or more patients. Across all cohorts and severity grades, the most frequent AEs 
were consistent with CRT delivery. The grade 3 or 4 AEs observed in ≥2 patients 
were unrelated to talimogene laherparepvec. The adverse event profile, therefore, 
may include events related to talimogene laherparepvec, chemotherapy, radiation, 
tumor-related signs and symptoms, disease progression, and/or a combination of 
these.  However, the concurrent use of talimogene laherparepvec, cisplatin, and 
external beam radiation therapy has not resulted in more frequent or more severe 
adverse events beyond those typically encountered with these other anti-cancer 
therapies.(6) Overall, most adverse events reported in subjects administered 
talimogene laherparepvec are non-serious and primarily include flu-like 
symptoms and injection site reactions. Most fatal adverse events reported in 

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subjects administered talimogene laherparepvec were reported in the setting of 
disease progression. 
 
After intratumoral injection, talimogene laherparepvec is generally cleared from 
subjects’ blood and urine within 48 hours. However it can be detected for up to 1 
week in the blood of 30% of patients and in the urine of 20% of patients.  A 
recent 20120324 study where pCR was used to detect TVEC 52% of the 60 
subjects tested had positive DNA with injection site swabs.  Of note however only 
1% were positive in the TCID50 (viral infectivity assay).  Overall, at any time 
point, a low percentage of subjects (13% [4/30]) had swabs that were positive for 
virus at the tumor site. In most cases, this was observed in seronegative subjects 
in the phase 1 study, in which a higher first dose of talimogene laherparepvec was 
administered than has been used in subsequent studies. Additional biodistribution 
and shedding data are currently being collected in Study 20120324. Talimogene 
laherparepvec DNA was detected with the lowest frequency in samples from the 
oral mucosa (1% of samples in 12% of subjects), the anogenital area (2% of 
samples in 15% of subjects, with almost all detected at a concentration below the 
lower limit of quantification of the assay), and from urine (3% of samples in 32% 
of subjects). 
   
No cases of confirmed infection of non-tumor tissue by talimogene laherparepvec 
in treated patients have been reported to date. In the pivotal clinical study, adverse 
events related to HSV infections were reported in 5.5% (n = 16) of subjects in the 
talimogene laherparepvec group and 1.6% (n = 2) in the GM-CSF group. Most of 
the cases were reported as oral herpes and 1 case each was reported as herpes 
simplex and herpetic keratitis in the talimogene laherparepvec group. The subject 
with herpetic keratitis had a history of this event prior to enrollment in the study. 
Whether the reported lesions were due to wild-type herpes or to talimogene 
laherparepvec could not be confirmed as viral testing was not performed.(21) As 
talimogene laherparpvec is now FDA approved in the US as Imlygic for 
melanoma, the prescribing insert can be found at 
http://pi.amgen.com/united_states/imlygic/imlygic_pi.pdf and as an appendix to 
this protocol. 
 
2.3. 
Other Agent(s) 
The treatment for triple negative breast cancer is based upon cytotoxic 
chemotherapy, as there are no hormone receptors or HER-2 pathways upon which 
to direct therapy.  However, there is no consensus standard of care treatment 
regimen for TNBC.  Treatments are similar to those in hormone-receptor positive 
disease, including anthracyclines and taxanes, both of which increase disease free 
survival and overall survival when given in sequence.  Doxorubicin given 
concomitantly with cyclophosphamide for four cycles has been shown to be 
equally as effective as cyclophosphamide, methotrexate, and 5-flourouracil over a 
six week cycle.  CALGB 9344 demonstrated that the addition of four cycles of 

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paclitaxel following four cycles of AC increased disease free survival and overall 
survival. 
 
The choice treatment and schedule used in this protocol is based upon the ECOG 
1199, CALGB 9741, and SWOG 0221 trials.  The ECOG trial compared four 
different taxane regimens to each other following dose-dense AC.  These four 
regimens were paclitaxel given weekly for twelve weeks or every three weeks for 
four cycles or docetaxel given weekly for twelve weeks or every three weeks for 
four cycles.  Of these taxane regimens, only paclitaxel given weekly was found to 
have a statistically significant five-year overall survival increase when compared 
to every 3 week paclitaxel (5-year OS: 89.7%).  CALGB 9741 also compared 
2x2, ultimately trying to determine conventional AC (every three weeks) vs dose-
dense AC (every two weeks with G-CSF support) with doxorubicin and 
cyclophosphamide administered sequentially vs concurrently.   Ultimately, an 
every two week (dose-dense) concurrent anthracycline based treatment was 
shown to be superior in terms of disease free survival, overall survival, and 
decreased risk of recurrence.  Additionally, there were fewer instances of febrile 
neutropenia in the dose-dense concurrent arm, likely due to G-CSF 
supplementation.  SWOG 0221 compared multiple arms for early stage breast 
cancer and recently reported on equivalent outcomes for the dose dense and 
weekly paclitaxel regimens.(1) 
 
2.4. 
Rationale 
 
Patients with triple negative breast cancer have a dichotomy of responses to 
treatment.  Those patients who respond well to treatment and achieve complete 
pathological response are unlikely to have relapse of disease in five years.  
Patients who do not achieve complete response with neoadjuvant therapy are far 
more likely to have relapse in the first 2-3 years and die from their disease.   
 
The goal of using talimogene laherparepvec is to achieve complete pathologic 
response in patients who may otherwise respond poorly to treatment.  Previously 
conducted head and neck studies combining talimogene laherparepvec virus with 
cisplatin and radiation (standard therapy for squamous cell head and neck cancer) 
have shown complete response after treatment and no viable disease on neck 
dissection in 14 out of 15 patients.(6)  By combining talimogene laherparepvec 
with standard neoadjuvant chemotherapy, the hope is for a similar response as 
seen in head and neck studies.   
 
The goal of injecting talimogene laherparepvec directly into the tumor is to 
stimulate both systemic and local anti-tumor response.  The insertion of a GM-
CSF gene into the viral genome, as described in the previous section, will ideally 
create a humoral response within the tumor augmenting treatment and furthering 
the pathway to a complete response of the tumor.   
 
3. PATIENT SELECTION 

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3.1. 
Eligibility Criteria 
 
3.1.1. Patients must have histologically or cytologically confirmed clinical stage T2-
3 N0-2 triple negative (estrogen receptor/progesterone receptor <1% HER2 0-
1 by IHC or unamplified by FISH) invasive ductal carcinoma.  
 
3.1.2. Patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm with conventional techniques or as >10 mm with spiral 
CT scan.  As well, patients must have primary tumor able to be visualized on 
ultrasound and amenable to direct injection.   
 
3.1.3. No prior history of an invasive breast cancer  
 
3.1.4. Adults ages: 18-70.   
 
3.1.5. ECOG performance status 0-1 (Karnofsky >70%; see Appendix A). 
 
3.1.6. Patients must have normal organ and marrow function as defined below: 
 
-leukocytes 
 
 
 
 
>3,000/µL 
-absolute neutrophil count 
>1,500/µL 
-platelets  
 
 
 
 
>100,000/µL 
-total bilirubin  
 
 
 
within normal institutional limits 
-AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
-creatinine  
 
 
 
 
within normal institutional limits 
OR 
-creatinine clearance  
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional 
normal 
 
 
 
- MUGA Scan or ECHO  
> EF of 50% 
 
3.1.7. The effects of talimogene laherparepvec on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason and because the 
other therapeutic agents used in this trial are known to be teratogenic, sexually 
active women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior 
to study entry and for the duration of study participation.  Should a woman 
become pregnant or suspect she is pregnant while participating in this study, 
she should inform her treating physician immediately. 
 
3.1.8. Ability to understand and the willingness to sign a written informed consent 
document. 
3.2. 
Exclusion Criteria 
 

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3.2.1. T4 tumors, known metastatic disease, recurrent disease, inflammatory breast 
cancer, multicentric disease, and/or synchronous bilateral breast cancer 
 
3.2.2. Patients with a second active malignancy, exceptions are localized non-
melanoma skin cancers or prior in situ carcinoma 
 
3.2.3. Patients receiving any other investigational agents or are unable to be treated 
with doxorubicin, cyclophosphamide, and paclitaxel. 
 
3.2.4. History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to talimogene laherparepvec or other agents used in the 
study. 
 
3.2.5. Patient with known active herpes simplex virus infections (prior 
uncomplicated oral HSV lesions are not an exclusion), prior complications 
from HSV infections such as encephalitis, or who require systemic antiviral 
therapy at the time of study enrollment should be excluded 
 
3.2.6. Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, known active hepatitis B/C infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
3.2.7. Patient on anticoagulation or with bleeding diathesis due to risk of hematomas 
at injection site 
 
3.2.8. Pregnant or nursing women are excluded from this study  
 
3.2.9. Immunocompromised patients may be at increased risk of herpetic infections 
when treated with talimogene laherparepvec. Therefore, HIV-positive patients, 
patients with acquired or congenital immunodeficiency conditions, those on 
chronic systemic immunosuppressants (requiring > 10mg of prednisone or 
equivalent/day),  
 
3.2.10. Those with active autoimmune disease are excluded from the study.  
 
3.2.11. 
Have received any live vaccine therapies used for the prevention of 
infectious disease within 28 days prior to enrollment and during treatment 
period. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, 
and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed. However, intranasal influenza 
vaccines (eg, Flu - Mist®) are live attenuated vaccines, and are not allowed 
3.3. 
 
Inclusion of Women and Minorities 
 

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Both men and women and members of all races and ethnic groups are eligible 
for this trial.  
 
3.4. 
Patient Registration 
Once clinical eligibility is confirmed, patients must sign an informed consent 
prior to registration indicating awareness of the investigation nature of the 
study and its inherent risks in keeping with the policies of the hospital and 
Federal regulations (Code of Federal Regulations Part 1X, Subpart B, Sections 
50.20-50.27).  The principal investigator in writing must approve request for 
an exemption to enroll a patient. 
 
3.5. 
Removal of Patients From Study Treatment 
 Patients may be removed from the study for any of the following reasons: 
 Progression of disease 
 Significant protocol violation 
 Patient non-compliance: defined as any deviation from the protocol 
without prior agreement of the principal investigator 
 Investigator non-compliance: defined as any significant medical or non-
medical deviation from the protocol without agreement of the sponsor 
 Patient’s request to withdraw from the study or refusal of further therapy 
 Herpetic infection requiring treatment with acyclovir or other similar anti-
viral agent 
 CTCAE grade 3 or above toxicity probably or definitely related to 
talimogene laherparepvec 
 If patient does not meet eligibility criteria 
 
3.6. 
Study early stopping criteria 
For efficacy if 3 or fewer patients attain a pathologic complete response out of the 
first 12 patients enrolled on phase 2 enrollment will be halted. For safety, there is 
an interim safety analysis upon completion of phase 1 and the first stage of phase 
2 (first 12 patients). If greater than 50% of patients experience a related G3-4 
event that causes > 14 day delay in chemotherapy or premature cessation of 
chemotherapy enrollment will be halted. 
 
4. TREATMENT PLAN 
 
4.1. Study Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events 
and potential risks for talimogene laherparepvec and neoadjuvant therapy are 
described in Section 6.  Appropriate dose modifications for talimogene 
laherparepvec and neoadjuvant therapy are described in Section 5.  No 
investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
Standard supportive care medications are allowed. 
 

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4.1.1. Talimogene laherparepvec 
 
The first and second injections of talimogene laherparepvec will be 
injected 3 weeks apart (+/- 3 days) to allow for seroconversion, then the 
remaining injections will be given every 2 weeks (+/- 3 days) directly into 
the primary tumor only for up to five injections total concurrent with the 
paclitaxel treatments.  The injections are not to be given during the 
doxorubicin/cyclophosphamide phase of neoadjuvant chemotherapy. This 
is done to avoid giving the injections during the more profound 
myelosuppression experienced during doxorubicin/cyclophosphamide and 
to allow eight weeks to elapse between the last injection and surgical 
resection of the primary lesion. This will minimize the risk of residual 
viral particles in the surgical site and significant pre-operative 
inflammation causing impaired wound healing. If there is no lesion 
visualized on ultrasound on a given injection day then no further 
talimogene laherparepvec should be injected and the remaining paclitaxel 
treatments should continue as planned. 
 
Phase 1 treatment plan: 
 
The phase 1 will use a 3+3 design with two dose levels of virus. For dose 
level one, patients will be enrolled and their treatment start dates staggered 
three weeks apart. Five weeks from the time the last patient in dose level 
one starts treatment must elapse before enrollment can commence for dose 
level two. If no DLTs are encountered in dose level one, then patients in 
dose level two can be enrolled and started concurrently, otherwise they too 
will be staggered three weeks apart. The paclitaxel weekly dose is fixed at 
80mg/m2. The first dose level will utilize the 106 PFU dose vials for all 
five injections. The second dose level will use the 106 PFU dose vial for 
the first injection then the 108 PFU vials for the remaining four injections. 
The DLT evaluation period for dose escalation will be during the first five 
weeks (the first two injections). The MTD dose level is defined as the 
highest dose level with ≤1 out of 6 patients experiencing a DLT.  This 
means if no DLTs are encountered in the first three patients enrolled in 
dose level one, then enrollment to dose level two should commence and 
six patients would be enrolled in dose level two.  If the first dose level 
experiences two or more DLTs then accrual to the protocol will be held 
until discussions with the FDA, Amgen, and the protocol safety committee 
can be held to determine if any feasible amendments can be made to 
resume accrual. Accrual to the phase 2 expansion cohort will begin 5 
weeks after the last phase 1 patient begins study therapy (completes the 
DLT evaluation period). A table is included with the 3+3 dose escalation 
rules.  
 
 
Number of Patients with 
 
Escalation Decision Rule 

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DLT 
at a Given Dose Level 
 
0 out of 3 
Enroll next 3 patients at the next higher dose level. 
 
> 2 out of 3 
 
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose 
(highest dose administered).   If only three patients 
were enrolled at the previous dose level, then three 
more patients can be enrolled to the previous dose 
level (for a total of six).  If six patients were already 
enrolled at the previous dose level then the previous 
dose level is the MTD. 
 
1 out of 3 
 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, enroll 3 
patients to the next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared 
the maximally administered dose.  If only three 
patients were enrolled at the previous dose level, 
then three more patients can be enrolled to the 
previous dose level (for a total of six).  If six 
patients were already enrolled at the previous 
dose level then the previous dose level is the 
MTD. 
 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
 
This is the MTD. At least 6 patients must be entered 
at this dose level in order to declare this.  
 
 
 
A DLT is defined as the following:  
 
Grade 3-4 toxicity probably or definitely related to talimogene 
laherparepvec which leads to chemotherapy treatment delays > 14 days or 
permanent cessation of neoadjuvant treatment with talimogene 
laherparepvec. 
 
Any grade active herpetic infection events requiring oral acyclovir 
treatment which are related to TVEC administration.  
 
Phase 2 treatment plan: 
 

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The MTD dose level will be used for all subsequent patients treated in the 
phase 2 portion of the study. 
  
Dosing and administration of talimogene laherparepvec for phase 1 and 2: 
 
The total volume of talimogene laherparepvec to be prepared will be based 
on investigator evaluation of injectable lesions and estimation of the total 
volume needed based on the talimogene laherparepvec Injection Volume 
Guideline Based on Tumor Size table.   
 
The maximum volume of talimogene laherparepvec administered at any 
dose is 4.0 mL for any individual lesion.  The maximum dose in any one 
treatment is 4.0 mL.  Use the maximum amount whenever lesions allow.  
 
The recommended volume of talimogene laherparepvec to be injected into 
the tumor is dependent on the size of the tumor on ultrasound on the day 
of injection and should be determined according to the injection volume 
guideline in the following table: 
 
 
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 
 
The following steps should be followed for drug administration:  
 
Materials Inventory 
o 
Laboratory coat, gloves and face shield, ISO gown,    
o 
Dosing syringe for injection filled with talimogene laherparepvec  
o 
22 gauge needle with appropriate length selected for injection by 
physician (larger bore or spinal needles may be used if required for 
intralesional injection) Subsequent injections may need different gauge 
needle. 
o 
Alcohol swabs 
o 
Absorbent pad and dry occlusive dressing 
o 
Injectable anesthetic as desired (i.e. lidocaine, benzocaine) 
o 
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Lesion site preparation 
o 
Talimogene laherparepvec will be injected intratumorally under 
US guidance with a radiologist and treating study physician.   The 
radiologist will aid in localizing/directing the needle under US to the 
lesion. The needle will traverse the longest diameter of the tumor. 
Once in place the study physician will inject the virus into the tumor.  
o 
Obtain three-dimensional measurements of the tumor by 
ultrasound and then indicate the appropriate volume of talimogene 
laherparepvec on the order form using the largest dimension, send to 
investigational pharmacy    
o 
Swab the injection site and surrounding areas with alcohol, allow 
to dry 
o 
The injection site/tract 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 tumor 
Lesion injection 
o 
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) 
o 
Inject talimogene laherparepvec intralesionally: 
a) 
 A single point of insertion will be used 
b) 
Talimogene laherparepvec should be injected along the needle 
insertion track as the needle is withdrawn through the tumor. The 
needle will traverse the longest diameter of the tumor. 
c) 
 Distribute talimogene laherparepvec within the lesion through the 
insertion point using the reach of the needle to inject across the longest 
diameter. The preparation of talimogene laherparepvec will be injected 
while the needle is being pulled back from the furthest radial distance. 
 
 
o 
Avoid premature extraction of needle  
o 
After dosing, the injection site should be swabbed with alcohol and 
pressure should be applied with gauze for several seconds after 
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o 
Please ensure that gloves worn by the person administering the 
injection is discarded and a fresh pair of gloves is worn prior to 
proceeding to the next step.   
o 
The injection site should be covered with a dry occlusive dressing 
Please ensure a fresh pair of gloves is worn when handling the 
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. 
o 
Dispose materials used during injection (e.g., gloves, needles, 
gauze) in accordance with local/regional, BSL and institutional 
requirements for biohazardous waste (e.g. red biohazard bin) 
o 
If the needle localization and injection is not successful, a second 
attempt will not be made. That injection will be omitted and the next 
attempt will occur according to study calendar.  
o 
If the lesion is not penetrable with the needle selected, that 
injection will be omitted and the next attempt will occur according to 
study calendar.  
Subject Counseling Information 
o 
Advise subjects on the potential for secondary exposure, e.g., 
broken skin. 
o 
Advise subjects on careful wound care.  Provide the subject with 
the current version of the Injection Site Care Instruction Document. 
o 
The presence of necrotic or ulcerating lesions may predispose the 
subject to local and/or systemic infections such as cellulitis, 
bacteremia, etc.  Advise subjects on careful wound care.  Infection 
precautions are recommended if tumor necrosis results in open 
wounds. 
o 
For Additional Information Related to Exposure to Talimogene 
Laherparepvec please refer to the latest version of your Investigator 
Brochure (IB) and Safety Data Sheet. 
 
4.1.2. Neoadjuvant chemotherapy 
 
Patients will be administered intravenous neoadjuvant therapy consisting 
of paclitaxel 80mg/m2 weekly (every 7 days +/- 1 day) for 12 weeks 
followed by doxorubicin 60mg/m2 every 2 weeks for 8 weeks, and 
cyclophosphamide 600mg/m2 every 2 weeks for 8 weeks.  Actual body 
weight dosing should be used to calculate dosing of chemotherapy agents. 
The neoadjuvant therapy should be administered whenever it is medically 
appropriate to do so, independent of whether the oncolytic virus injections 
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able to be given due to hypersensitivity reactions refractory to pre-
medications, substitution with nab-paclitaxel at the same dose is allowable 
as per usual institutional guidelines if deemed appropriate by the treating 
physician. 
 
4.1.3      On treatment biopsy 
 
 
 
 
   On week 6 of neoadjuvant therapy prior to injection of TVEC, patients will  
                     undergo an on treatment biopsy. The biopsy will be 2 14g cores placed         
             into formalin for processing.  
 
4.2. Supportive Care Guidelines 
 
Additionally, the patients will receive pegfilgrastim subcutaneously 6mg to be 
administered 24 hours after each doxorubicin and cyclophosphamide infusion.  
Filgrastim may be given as required for neutropenia (ANC<1500) while on 
weekly paclitaxel on days 3-4 of each weekly cycle. All standard premedications 
and antiemetics for chemotherapy agents are allowed to be given (including 
dexamethasone).  Premedication for paclitaxel should be 4mg of dexamethasone 
orally 30 minutes once prior to paclitaxel administration for the first two cycles. If 
no infusion reaction is experienced then dexamethasone can be omitted for the 
remaining paclitaxel cycles.  If grade 1-2 infusion reaction is encountered during 
the first two cycles and can be successfully treated with using standard 
antihistamine doses (as indicated on the study treatment order) then the 
dexamethasone should be continued for all 12 paclitaxel cycles. Grade 3 or higher 
infusion reactions to paclitaxel would require discontinuation of the study 
treatment. Grade 1-2 allergic reactions or febrile states caused by talimogene 
laherparepvec cytokine release can be treated with antihistamines and/or 
acetaminophen as required. In the event any cellulitis is suspected in the breast 
then appropriate antibiotic therapy should be instituted immediately and further 
injections stopped until the infection has resolved.  
 
 
Excluded Treatments, Medical Devices, and/or Procedures During Study 
Period 
 
Subjects must not use any of the following therapies during screening or treatment 
period, unless indicated otherwise: 
• other investigational agents 
• concurrent experimental or approved antitumor therapies other than the 
study drugs. 
• systemic immunosuppressive agents used on an ongoing basis during 
administration of talimogene laherparepvec (one time dexamethasone 
premedication during paclitaxel therapy is not excluded) 
• 
any live vaccine therapies used for the prevention of infectious 
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Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed. However, intranasal 
influenza vaccines (eg, Flu - Mist®) are live attenuated vaccines, and are 
not allowed 
• 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. 
 
4.3. Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue 
for   the full course of neoadjuvant chemotherapy or until one of the following 
criteria applies: 
 
 
Disease progression, 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse events(s), 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1. Talimogene laherparepvec   
If talimogene laherparepvec treatment was delayed due to adverse events or other 
reasons by > 1 week, that dose will be deemed to have been missed and the 
subject will proceed to the next scheduled treatment visit.  If grade 2 or higher 
toxicities (CTCAE 4.0) that are probably or definitely related to the oncolytic 
virus occur, talimogene laherparepvec administration should be delayed until the 
adverse event has resolved completely. Dosing of talimogene laherparepvec 
should be delayed for active herpetic cutaneous or mucosal lesions, herpes 
labialis, antiviral therapy, grade 2 or higher immune related adverse event (irAE) 
(except vitiligo), ANC<1000, platelets < 50K, active cellulitis, skin breakdown, 
significant pain, or hemorrhage in the region of the injected tumor and/or affected 
breast. Resumption of the injections upon resolution is at the discretion of the 
treating physicians and investigators. Treatment with talimogene laherparepvec 
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infection such as keratitis or encephalitis or grade 3 or 4 allergic reaction 
following injection. Patients with grade 1-2 allergic reactions can be pre-
medicated using antihistamines.  
 
There is no maximum allowable delay period that would automatically require 
complete cessation of the oncolytic therapy. If the condition of the patient returns 
to a state which is acceptable for resumption of injections and the patient is still 
undergoing therapy with weekly paclitaxel then any remaining injections can be 
given using the same dosing interval/schedule (i.e. a patient who had injection #2 
held at week 4 of paclitaxel is cleared to get injections at week 6 then she can get 
three more injections at week 6, 8, and 10). 
 
Dose reductions of talimogene laherparepvec are not permitted, other than with 
respect to a reduction in the volume injected due to a disease response.  
 
5.2. Other Agent(s) 
 
Dose modifications and delays for chemotherapy would follow standard 
institutional guidelines and recommendations based on the prescribing 
information for each cytotoxic agent. The decision to administer the neoadjuvant 
chemotherapy is based solely on whether it is medically appropriate to give the 
chemotherapy dose and not dependent on whether the patient can receive a 
talimogene laherparepvec injection on any given day. Since neoadjuvant 
chemotherapy is given with curative intent, maximal dose intensity/density of the 
chemotherapy with appropriate supportive care should be administered whenever 
possible.  
 
 
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1. Reported Adverse Events and Potential Risks for talimogene laherparepvec 
 
Identified Risk:  Injection Site Reactions 
Talimogene laherparepvec is administered by direct injection into cutaneous, 
subcutaneous, and nodal tumor masses.  Injection site adverse events may occur, 
such as erythema, local skin discoloration, induration, warmth, and pain.  
Infrequently, injected cutaneous tumor masses may undergo necrosis, 
predisposing the subject to local and/or systemic infections.  Similarly, injected 
pathologic lymph nodes may enlarge or become necrotic.  Uncommonly, necrotic 
lymph nodes may be the site of persistent drainage that requires corrective 
measures. In clinical studies, adverse events of “injection site pain” and “injection 
site reaction” were very common, occurring in ≥ 10% of talimogene 
laherparepvec-treated subjects.  Most events of injection site pain and injection 
site reaction in subjects receiving talimogene laherparepvec were mild to 
moderate in severity. Subjects seronegative at baseline for HSV-1, when given an 

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initial dose of talimogene laherparepvec at a concentration of 106 PFU, do not 
appear to experience more exaggerated injection site reactions than those who are 
seropositive at baseline.  
  
Important Identified Risk:  Accidental Exposure of Healthcare Providers (HCP) to 
Talimogene Laherparepvec 
A needle stick injury, spill, or splash back during administration may result in 
accidental exposure of HCPs to talimogene laherparepvec.  The ICP34.5 gene 
deletion is intended to allow only tumor selective replication and limited or no 
viral replication in normal tissues.  However, talimogene laherparepvec injection 
can result in signs or symptoms of primary infection at the site of exposure. 
A few reports of accidental exposure in study personnel have been received.  In 
one of the cases, the exposed physician developed clinical signs/symptoms of a 
herpetic whitlow-like lesion at the site of the accidental needle stick injury that 
resolved without sequelae.  An initial antibody assay was positive for an HSV-
type virus.  A confirmatory PCR assay was conducted 10 days after the accidental 
exposure and was positive for a virus with the ICP47 deletion, indicating that the 
virus was most likely talimogene laherparepvec.  None of the other exposed 
individuals reported signs or symptoms of infection.  In some cases oral acyclovir 
or valacyclovir was administered. 
 
Important Identified Risk: Cellulitis at Site of Injection 
Intralesional administration of talimogene laherparepvec by injection has been 
associated with cellulitis at the injection site.  In some cases, a local inflammatory 
reaction with localized tumor necrosis developed, and in other cases, a bacterial 
infection developed.  In the pivotal clinical study, the subject incidence of adverse 
events in the bacterial cellulitis category was 6.2% (n = 18) in the talimogene 
laherparepvec group and 1.6% (n = 2) in the GM-CSF group.  The most 
frequently reported preferred term was cellulitis (5.8% in the talimogene 
laherparepvec group and 1.6% in the GM-CSF group).  Seven subjects (2.4%) in 
the talimogene laherparepvec group and 1 subject (0.8%) in the GM-CSF group 
experienced serious adverse events of cellulitis. Fever, elevated white blood cell 
count, bacteremia or sepsis, and hospitalization for intravenous antibiotics were 
reported in 5 of the 7 cases in the talimogene laherparepvec group. 
 
Important Identified Risk: Disseminated Herpetic Infection in Severely 
Immunocompromised Individuals 
Patients with immunosuppression for any reason were excluded from clinical 
trials with talimogene laherparepvec.  Disseminated herpetic infection in severely 
immunocompromised individuals is defined as an important identified risk based 
on the nonclinical data and literature described below.  Evidence of lethal 
systemic viral infection was observed in 100% of severe combined 
immunodeficiency (SCID) mice (deficient in T and B cells) following 
intratumoral injection of talimogene laherparepvec in a mouse colon carcinoma 
xenograft model.  Similar findings were observed in up to 20% of BALB/c nude 
mice (primarily deficient in T-cell function) following intratumoral   injection of 

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talimogene laherparepvec in Ewing’s sarcoma and osteosarcoma xenograft 
models.  Viral inclusion bodies and/or necrosis in enteric neurons in the 
gastrointestinal tract, adrenal gland, and skin were observed in both mouse 
strains; and in pancreatic Islet cells, eye, pineal gland, and brain of SCID mice.  
Lethality in 100% of animals following intracutaneous injection of wild-type 
HSV-1 in nude mice has been reported (Hayashida et al, 1982; Yamamoto et al, 
1985).  The data in talimogene laherparepvec treated SCID mice indicate that 
severe toxicity associated with disseminated viral infection may occur in patients 
who are severely immunosuppressed.  The data in the  BALB/c nude mice suggest 
the potential for toxicity due to talimogene laherparepvec in patients with less 
severe immunosuppression.  Consistent with the general literature, these data 
indicate an important role of host defenses including T and B cells in the immune 
response to talimogene laherparepvec and HSV-1 viruses. 
 
Important Potential Risk:  Symptomatic Talimogene Laherparepvec Infection in 
Non-tumor Tissue in Treated Patients 
Talimogene laherparepvec is a modified HSV-1 virus, and is engineered to 
replicate selectively in tumor tissue.  However, if infection by talimogene 
laherparepvec of non-tumor tissue in treated patients were to occur, this could 
lead to development of clinical signs or symptoms that would be anticipated to be 
similar to signs or symptoms of wild-type herpes virus infection.  In mouse tumor 
models, viral lysis/tissue injury was limited to tumors.  No clinical or pathological 
evidence of symptomatic infection or injury to normal tissues was observed in 
nonclinical models dosed by repeated intratumoral, intravenous, or subcutaneous 
injection, including mice dosed with up to 107 PFU talimogene laherparepvec 
(~60-fold over the highest proposed clinical dose, on a PFU/kg basis) via weekly 
subcutaneous injection for up to 3 months. No cases of confirmed infection of 
non-tumor tissue by talimogene laherparepvec in treated patients have been 
reported to date.  In the pivotal clinical study, adverse events related to HSV 
infections were reported in 5.5% (n = 16) of subjects in the talimogene 
laherparepvec group and 1.6% (n = 2) in the GM-CSF group.  Most of the cases 
were reported as oral herpes and 1 case each was reported as herpes simplex and 
herpetic keratitis in the talimogene laherparepvec group.  The subject with 
herpetic keratitis had a history of this event prior to enrollment in the study.  
Whether the reported lesions were due to wild-type herpes or to talimogene 
laherparepvec could not be confirmed as viral testing was not performed. 
 
Important Potential Risk:  Transmission of Talimogene Laherparepvec from 
Patient to Close Contacts or HCPs Via Direct Contact with Injected Lesions or 
Body Fluids (eg, Blood or Urine) Resulting in Symptomatic Infection (Primary or 
Reactivation) 
Proximity of close contacts and HCPs to lesions in treated patients in the absence 
of effective barriers may result in the unintentional exposure of these individuals 
to talimogene laherparepvec.  Exposure may occur via direct contact with injected 
lesions or via contact with body fluids (eg, blood or urine).  The likelihood of 
transfer of talimogene laherparepvec to a close contact or HCP increases if the 

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contact has a break in the skin or mucous membranes.  Signs or symptoms of 
infection would be anticipated to be similar to signs and symptoms of wild-type 
HSV infection. 
 
Biodistribution by quantitative polymerase chain reaction (qPCR) testing in 
clinical studies indicated that low copy numbers of viral DNA were sporadically 
detected from 1hour to 1 week after intratumoral injection in blood and urine in 
30% of subjects across all studies.  Where subsequent samples were available, no 
viral DNA was detected at 2 weeks after injection.  Shedding results showed that 
talimogene laherparepvec was detected on the surface of injected lesions for up to 
2 weeks after injection in 8 of 72 (11%) subjects.  Virus was not detected on the 
exterior surface of tumor dressings at any time point tested. 
 
Biodistribution was evaluated after single and multiple dosing by intravenous, 
subcutaneous or intratumoral injection in mice.  Doses from 1 x 105 to 1 x 107 
PFU/mL were evaluated (0.6 to 60-fold higher compared to the maximum clinical 
dose).  Across the studies, viral DNA was found most commonly at the site of 
injection regardless of administration route, which in the case of the tumor may 
reflect viral replication following intratumoral administration.  Following 
intravenous administration of talimogene laherparepvec, viral DNA was detected 
in blood of 5 of 6 animals through 56 days of dosing.  After intratumoral 
injection, talimogene laherparepvec DNA was detected by PCR in tumor, blood, 
in tissues associated with immune related viral clearance (lymph nodes, spleen), 
and tissues with high blood perfusion (heart, lung, liver).  Viral DNA was found 
in the brain in 2 of 91 samples collected.  Viral DNA was not detected in bone 
marrow, eyes, lachrymal glands, nasal mucosa or feces at any time point.  
Following intratumoral injection, viral DNA was cleared from the blood of most 
animals within 2 weeks postdose and in all animals by 6 weeks after the last dose. 
 Following subcutaneous dosing, viral DNA was excreted in urine in 22% of 
animals within 24 hours postdose and all were negative at 4 weeks postdose. 
 
Important Potential Risk: Symptomatic Herpetic Infection Due to Latency and 
Reactivation of Talimogene Laherparepvec or Wild-type HSV-1 in Patients 
Infection of tumor or non-tumor tissue could potentially lead to the establishment 
of latency and subsequent reactivation of talimogene laherparepvec if the virus 
came into contact with axonal nerve terminals and was transported to neuronal 
cell bodies.  The genetic modifications made to talimogene laherparepvec do not 
prevent the virus from entering latency or subsequently reactivating.  However, 
HSV-1 strains deficient in the ICP34.5 gene are unable to replicate efficiently in 
non-tumor cells, including neurons, and are impaired for establishment and 
reactivation from latency when compared to wild-type HSV-1 (Chou et al, 1990; 
Perng et al, 1995; Perng et al, 1996, Robertson et al, 1992; Spivack et al, 1995).  
Thus, reactivated virus in nerve cells is expected to be less likely to lead to 
clinical signs or symptoms as compared to wild-type HSV-1. Co-infection of 
neurons already harbouring latent wild-type HSV-1 by talimogene laherparepvec 
could potentially stimulate the reactivation of latent wild-type HSV-1 in patients 

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with prior infection.  A febrile response associated with injection of talimogene 
laherparepvec might stimulate reactivation of wild-type HSV-1 in patients with 
prior exposure and latent HSV-1 infection. 
 
Biodistribution studies in mice have detected low levels of talimogene 
laherparepvec in trigeminal ganglia (at levels 0.2-1.2% found in concurrent blood) 
through 28 days in 1 of 6 animals following high dose intravenous administration 
(0.6 × 107 PFU, ~36-fold over the highest proposed clinical dose).  Talimogene 
laherparepvec was undetectable in trigeminal ganglia in mice after subcutaneous 
administration. 
 
In a mouse model, talimogene laherparepvec was detected in the spinal dorsal 
root ganglia following injection into the foot.  This suggests the virus had 
established latency in the nerve root innervating the site of injection.  The virus 
was reactivated in ex vivo cell culture.  The clinical applicability of these findings 
is not certain, as it is anticipated that host immunity will respond to protect the 
host from talimogene laherparepvec replication in non-tumor tissue in individuals 
with an intact immune system. 
 
Important Potential Risk:  Immune-mediated Adverse Events    
Based on review of adverse events suggestive of an immune-mediated etiology 
across melanoma studies, immune-mediated adverse events considered possibly 
related to talimogene laherparepvec were reported in 2% of subjects treated with 
talimogene laherparepvec, and included events of vasculitis, glomerulonephritis, 
acute renal failure, pneumonitis, and worsening psoriasis.  Other contributory 
factors were identified in several of these cases, including pre-existing immune-
mediated conditions, other concurrent medications, or intercurrent medical events. 
 
Important Potential Risk:  Talimogene Laherparepvec-mediated Anti-GM-CSF 
Antibody Response 
There is a theoretical concern that transgene-derived expression of GM-CSF 
could induce an immune response reactive with endogenous GM-CSF.  
Antibodies against GM-CSF have been detected sporadically in the general 
population (up to 9.6%) (Meager et al, 1999).  Case reports of cryptococcal 
meningitis and pulmonary alveolar proteinosis have been reported in association 
with auto-antibodies to GM-CSF   (Rosen et al, 2013).  Auto antibodies to GM-
CSF were demonstrated to reproduce the disease of pulmonary alveolar 
proteinosis in nonhuman primates (Trapnell et al, 2009). It is not known whether 
such phenomena could be expected with the limited exposure anticipated with 
transgene expression of GM-CSF from talimogene laherparepvec. 
 
Important Potential Risk: Plasma Cell Dyscrasia (Plasmacytoma) at the Injection 
Site 
A plasmacytoma was reported in 1 subject treated with talimogene laherparepvec 
in the pivotal clinical study.  A plasmacytoma developed in the area of the 
injected tumor on the scalp after 9 cycles of treatment with talimogene 

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laherparepvec.  Study treatment was permanently discontinued.  On medical 
review, the event was determined likely to be a secondary plasmacytoma which 
developed at the injection site due to recruitment of plasma cells in response to 
the talimogene laherparepvec injections in a subject who had a pre-existing 
(smoldering) multiple myeloma. 
 
Important Potential Risk:  Impaired Wound Healing at Site of Injection 
The local tissue response following repeated injections of a foreign protein can 
contribute to chronic inflammation, necrosis, and ulceration of tumor sites, and in 
the presence of other risk factors, delayed healing may result.  In the pivotal 
clinical study, the incidence of adverse events in the impaired wound healing 
category was 5.5% (n = 16) in the talimogene laherparepvec group and 2.4% (n = 
3) in the GM-CSF group.  Wound complication, wound secretion, and wound 
infection were reported in ≥ 1% of subjects in the talimogene laherparepvec 
group.  A serious adverse event of impaired healing was reported in an elderly 
subject following treatment with talimogene laherparepvec to a recurrent lower 
extremity melanoma lesion that resulted in a below the knee amputation 7 months 
after the last treatment.  The subject had a history of peripheral vascular disease, 
prior radiation at the site of injection, and recurrent cellulitis in the area, all which 
were considered possible contributory factors. 
 
Important Potential Risk:  Disseminated Herpetic Infection in Individuals with 
Deficiency in Cell-mediated Immunity Such as Human Immunodeficiency Virus 
(HIV)/Acquired Immunodeficiency Syndrome (AIDS), Lymphoma, or Leukemia, 
or Who Require High Dose Steroids or Other Immunosuppressive Treatments 
Such as Post Organ Transplant 
Talimogene laherparepvec is a recombinant replication-competent HSV-1 type 
virus which is engineered to replicate selectively in tumor cells.  Intratumoral 
injection of talimogene laherparepvec was 100% lethal in SCID mice (SCID 
model) and in up to 20% of athymic mice (nude mouse model).  Refer to the 
characterization of the important identified risk of “disseminated herpetic 
infection in severely immunocompromised individuals” for a description of 
results of nonclinical studies in SCID mice and BALB/c nude mice. The clinical 
relevance of these data to patients treated with talimogene laherparepvec is not 
clear.  Wild-type HSV-1 infection in immunocompromised individuals is 
associated with dissemination of the virus and serious, life-threatening toxicity.  
Patients with immunosuppression were excluded from clinical trials with 
talimogene laherparepvec. The potential risk and potential benefits of treatment of 
patients with HIV/AIDS, leukemia, lymphoma, or patients who require treatment 
with chronic high dose steroids or other immunosuppressive agents such as those 
used in the post transplant setting should be considered prior to treatment. 
Talimogene laherparepvec is contraindicated in patients with severe 
immunodeficiency. 
 
Important Potential Risk: Arterial bleeding (Carotid Artery Blowout Syndrome) 
has been reported following administration of talimogene laherparepvec in the 

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setting of recurrent squamous cell carcinoma of the head and neck (SCCHN). 
Subjects with tumors in direct contact or encasing a major blood vessel with 
ulceration and/or fungation into the skin surface, and subjects with a history of re-
irradiation for SCCHN or prior lymph node neck dissection to a field which 
involves the carotid arteries may be at increased risk for arterial hemorrhage if 
talimogene laherparepvec is injected into tumors near major blood vessels. Such 
high risk subjects should not be administered talimogene laherparepvec in the 
SCCHN setting. Consider the risks and benefits of treatment before administering 
talimogene laherparepvec to these subjects.  
 
6.2. Talimogene laherparepvec description 
Talimogene laherparepvec will be presented as a sterile, semi-translucent to opaque 
solution for injection (opacity is different for each concentration) preservative-free frozen 
liquid in a single use 2 mL cyclic olefin polymer (COP) plastic resin vial.  Each vial will 
contain talimogene laherparepvec at a nominal concentration of 106 PFU/mL or 108 
PFU/mL in an aqueous sodium phosphate buffer with sodium chloride, sorbitol and myo-
inositol added as stabilizers and water for injection (WFI).  Vials are appropriately filled 
to ensure that a sufficient deliverable dose is provided.  Each 2 mL vial will contain 
approximately 1.15 mL of talimogene laherparepvec with a 1.0 mL deliverable volume.  
Each vial is intended for single use only and will be available in one of two different 
presentations: 
Current supplies of talimogene laherparepvec 
is provided as a preservative-free solution in a 
single–use vial without a clear copolyester 
plastic sleeve.  The product label is found on 
the vial itself 
Future supplies of talimogene laherparepvec 
will be provided as a preservative-free 
solution in a single–use vial permanently 
inserted into a clear copolyester plastic sleeve. 
The product label will be found on the vial 
sleeve 
 
 
 
 
Note that the Closed System Transfer Device 
(CSTD) tested for use with the vial sleeve is 
the PhaSeal CSTD 
 
Vials will be sealed with gray rubber stoppers, Fluoropolymer-coated on the product side. 
 The vial caps will be color coded and may be used to help distinguish between the 106 

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PFU/mL and 108 PFU/mL vial concentrations.  The supply for 106 PFU/mL vials will be 
packaged separately from the supply for the 108 PFU/mL vials. 
 The 106 PFU/mL strength is supplied in a box containing 10 vials. 
 The 108 PFU/mL strength is supplied in a box containing 20 vials. 
The dimensions of the box (of both strengths) are approximately 12.7 x 12.7 x 5 cm 
(4.891 in. x 4.891 in. x 1.969 inches).  Due to the temperature at which talimogene 
laherparepvec packaging occurs no tamper-evident seal or closure seal will appear on the 
boxes.  Talimogene laherparepvec is sensitive to light and should be protected from light 
during storage. 
Product Labels for Investigational Product  
Information provided on the labels for talimogene laherparepvec will comply with ICH, 
GCP and local regulatory requirements. 
 
Figure 1 - Examples of Product Labels (talimogene laherparepvec):  
Examples of Vial Labels (talimogene laherparepvec):   
 
 
  
Examples of Carton Labels (talimogene laherparepvec):   

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Please note: 
• For vials supplied inserted into the vial sleeve, there may be a label attached to the vial 
in addition to a label on the outer sleeve.  The label on the plastic sleeve is the study label 
and content on the vial label should be disregarded.  
• The lot number printed on the Talimogene laherparepvec vials is the Labeled Drug 
Product (LDP) lot.  
• The lot number printed on the box label is the Finished Drug Product (FDP) lot number. 
 
Receipt and Storage of Investigational Product 
 
Talimogene laherparepvec is shipped frozen by air courier or truck transit in an 
approved shipper suitable for biological substance shipments.  The shipper will 
contain talimogene laherparepvec vials within their secondary packaging on dry 
ice.  The shipment will also contain two (2) TempTale data loggers, unpacking 
instructions, as well as all shipment related documentation which must be 
completed and returned to Amgen and/or filed at site as per the instructions on the 
relevant documentation. 
 
Shipping 
Talimogene laherparepvec is shipped frozen by air courier or truck transit in an 
approved shipper suitable for biological substance shipments.  The shipper will 
contain talimogene laherparepvec vials within their secondary packaging on dry 
ice.  The shipment will also contain two (2) TempTale data loggers, unpacking 
instructions, as well as all shipment related documentation which must be 
completed and returned to Amgen and/or filed at site as per the instructions on the 
relevant documentation. 
Initial supply requirements  
Initial drug supplies will be sent to the site once the site has been activated by 
Amgen Distribution and the Drug Request Form has been received by Amgen. 
Please allow one (1) business day to process the Drug Request Form.  Domestic 
or Canadian express shipments may take up to two (2) days transit time.  
Therefore, a total turnaround time for drug supply requests is expected to be three 

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(3) days. 
Resupply requirements  
Resupply of product(s) will occur once a Drug Shipment Request form is 
completed by the site and submitted to Amgen as per the details required on the 
form.  Re-supply will be made according to details provided on the Drug 
Shipment Request form. 
Receipt 
To ensure the stability of talimogene laherparepvec, vials must be received, 
unpacked and placed into storage within 90 seconds.  Detailed unpacking 
instructions are provided in each shipment.  The pharmacy team should have a 
plan of action to allow for quick and efficient transfer of the box of vials into the 
freezer (for example, by placing the shipper box close to the freezer before 
opening the shipper box and completing the next steps of the process).  Clinical 
trial sites are encouraged to review these instructions prior to receipt of clinical 
trial materials. 
Storage 
To ensure stability and quality are maintained, the product must be stored 
correctly upon receipt and for the duration of the study under the conditions 
specified below.   
Talimogene laherparepvec must be stored in a non-cycling freezer maintained at a 
set point of -80oC in a secured location until planned use.  Cycling, frost-free, 
auto defrost freezers must not be used since they cycle to warmer temperatures 
several times a day.  Vials should be kept within the secondary container to 
protect from light.   
Storage of Talimogene Laherparepvec - Freezer Set Point 
 
 
 
 
 
Talimogene laherparepvec is stable if maintained in accordance with the 
guidelines described in this document and the provided expiration date. 
To ensure GCP compliance with regards to the storage of biological products, 
talimogene laherparepvec should be segregated and stored on its own shelf in the 
freezer.  Sites should also refer to local guidance on storing clinical trial drugs. 
 
Destruction of Product at Site 
All used and unused (including expired) Investigational Product supplied by 
Amgen must be destroyed locally, following local capabilities and regulatory 
requirements.  Applicable product reconciled must be completed before 
destruction can occur.  Where available, place relevant local certificates of 
destruction in the appropriate section of the pharmacy file.  Imlygic (talimogene 
laherparepvec) has been defined as a GMO.  Please ensure all country/local 
regulations for destruction are followed. 
 
Freezer Set Point (ºC) 
Acceptable Variation  
Acceptable Range 
-80°C 
± 10°C 
-90°C to -70°C 

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Transfer and/or Transportation of Investigational Product  
Transfer of talimogene laherparepvec in original packaging or after preparation 
between clinical sites is not permissible.  Contact the study sponsor or Amgen to 
discuss alternatives for a shipment to arrive at the site where the product is 
needed. 
 
Drug Preparation and Administration Location 
Talimogene laherparepvec is open-label bulk supply that can be used across study 
subjects.  Talimogene laherparepvec is supplied in two concentrations.  For US 
sites, the talimogene laherparepvec Safety Data Sheet categorizes the drug as a 
Biosafety Level (BSL) 1, thus use of BSL 1 containment procedures is 
recommended.  
Unless otherwise directed by local regulations: 
•The use of a microbiological safety cabinet or hood for the dose preparation 
of talimogene laherparepvec is not required. 
•Talimogene laherparepvec may be safely drawn up into syringes in the room 
used for product administration, although this may also optionally occur 
elsewhere (eg, in the pharmacy). 
•Any side room away from other subjects can be used for talimogene 
laherparepvec administration. 
Materials Inventory 
o 
Sterile disposable needle to withdraw talimogene laherparepvec from vials 
o 
Sterile 22-24 gauge needle for injections 
o 
Sterile 1 mL to 5 mL syringe, based on injection strategy  
o 
Laboratory coat, gloves and safety glasses   
o 
Alcohol swabs 
Thawing of Frozen Vials  
To ensure proper usage of talimogene laherparepvec, the following instructions 
have been developed.   
o 
All personnel handling the talimogene laherparepvec or material 
contaminated with talimogene laherparepvec must observe safety precautions 
(e.g., wear a laboratory coat, safety glasses and gloves) 
o 
Determine which box labeled with the appropriate concentration, 106 
PFU/mL or 108 PFU/mL, is to be prepared  
o 
Remove the number of frozen vials from the box that have been calculated 
for administration and immediately (within 90 seconds) return the remaining 
vials to the freezer.  Care should be taken to avoid unintended thawing of vials 
that will not be used.  The time the vials are removed from the freezer must be 
recorded. 
o 
 Thaw frozen vials until liquid at room temperature [59°F to 86°F (15°C 
to 30°C)].  Thaw should take approximately 30 minutes.  Please ensure vial is 

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protected from light during the thaw process, using the original carton or a light 
protective bag (with adequate space, approximately 2.5cm between each vial). 
During the thaw: 
o 
Leave vials undisturbed, except to gently swirl to check for completion of 
thaw 
o 
Never shake vials vigorously, especially during the thawing process 
After the thaw: 
o 
Gently swirl the vial to ensure the contents are mixed to a homogeneous 
solution free of ice. 
o 
Carefully check the vial for damage (e.g., cracks).  Quarantine damaged 
vials and obtain further instructions for destruction and reporting. 
o 
Please refer below for the clinical handling storage times. 
o 
Dispose materials used in the thawing (e.g., gloves) following appropriate 
local/regional or BSL classification guidelines.  
Preparation of Dosing Syringe for Injection 
o 
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) 
o 
Talimogene laherparepvec dosing syringe must be properly labeled in 
accordance with current ICH GCP and local/regional or BSL requirements prior 
to dispensing for administration 
o 
Clean talimogene laherparepvec vial stopper with an alcohol swab 
o 
Withdraw appropriate volume of talimogene laherparepvec required with 
the appropriate number of sterile syringes and needles   
o 
Remove the needle used to withdraw the talimogene laherparepvec from 
the vial and attach a  sterile 22-24 gauge needle suitable for intralesional injection 
o 
Please refer below for the Clinical Handling Timelines.  Discard any 
prepared syringes not used for administration within the specific times stated. 
o 
Discard materials used in the preparation (e.g. gloves, needles) in 
accordance with local/regional or BSL classification guidelines.   
Clinical Handling Times Outside Labelled Storage Conditions 
General product handling considerations 
Thaw 
 
Thaw frozen talimogene laherparepvec vials at 15°C to 30°C (59°F to 86°F) protected from 
light until fully liquid (approx. 30 minutes at the stated temperature range).  Do not expose 
vials to higher temperatures. 
 
Swirl gently.  Do not shake. 
 
Do not refreeze thawed talimogene laherparepvec. 
Storage and Preparation 

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 
Store talimogene laherparepvec (in vial or syringe) protected from light at all times until 
administration. 
 
Due to the absence of a preservative in the formulation please minimize storage time in the 
syringe where possible.     
 
Please note that storage of 106 and 108 PFU/mL talimogene laherparepvec in the vial 
followed by in the syringe is permitted for the same storage condition only e.g. both vial and 
syringe stored in the refrigerator. When thawed 106 and 108 PFU/mL is stored in both vial and 
syringe, the storage time in syringe cannot exceed allowable syringe storage time and the 
cumulative vial and syringe storage time cannot exceed the total allowable storage time. See 
below for specific details on allowable durations for each container and temperature 
combination. 
Administration 
 
If talimogene laherparepvec is not administered within the timeframes and not handled at 
the temperatures indicated, then it must be discarded. 
 
Reporting of temperature excursions during clinical administration is not required. 
Total storage time for thawed 106 PFU/mL product 
2°C to 8°C (36°F to 46°F) 
up to 27°C (80°F)* 
12 hours 
(inclusive of 4 hours maximum in the syringe) 
4 hours 
(inclusive of 2 hours maximum in the syringe) 
Total storage time for thawed 108 PFU/mL product 
2°C to 8°C (36°F to 46°F) 
up to 27°C (80°F)* 
48 hours (inclusive of 8 hours maximum in the 
syringe) 
4 hours 
(inclusive of 4 hours maximum in the syringe) 
 
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator in the 
investigational pharmacy, must maintain a careful record of the inventory and 
disposition of all agents received from Amgen. 
 
6.3 
    Commercial Agent(s) 
 
Please refer to package insert for doxorubicin, cyclophosphamide, and paclitaxel 
for dosage forms, ingredients, solution preparation, and route of administration.  
Also refer to package insert for adverse events and safety information. 
Commercially available stocks will be used.  
 
6.4 Temperature Monitoring 
Temperature monitoring of the storage temperatures, via a manual or electronic 
temperature log, of all locations where talimogene laherparepvec is stored is 

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required.  Actual temperature, plus range of temperatures (minimum/maximum), 
must be documented. 
Due to the temperature sensitivity of talimogene laherparepvec, the chosen device 
specifications should be checked carefully to ensure the device covers the 
specified temperature ranges required.  Temperature monitoring equipment 
should be serviced and calibrated in accordance with the manufacturer’s 
guidelines and/or institutional policies. 
Freezer and refrigeration units used to store Product should be properly 
maintained (in accordance with manufacturer’s instructions).  
Temperature excursions described in this section apply only to frozen product in 
storage.  Vials that are removed from storage, thawed and prepared for patient 
administration should be monitored according to the guidelines provided per 
Clinical Handling Timelines.   
Temperature Excursion – Definitions, Reporting and Management  
A temperature excursion (TE) occurs when a Product is exposed to temperatures 
outside of its recommended storage range. 
The following rounding rules described below should be applied in all cases:  For 
example, a reading of -69.4°C would be rounded to -69°C and -90.5°C would be 
rounded to -91°C.  These would be considered temperature excursions.  
Alternatively, a temperature of -69.5°C would be rounded to -70°C and -90.4°C 
would be rounded to -90°C.  These would NOT be considered temperature 
excursions. 
Reporting Temperature Excursions  
Sites will report temperature excursions according to the instructions provided. 
 
 
Frozen Storage Temperature Excursion Limits 
Required Storage Range 
Temperature(s) outside 
required storage range 
Temperature excursion 
when the duration exceeds 
-80°C ±10°C 
< -90°C  
(colder than -90°C) 
0 minutes 
≥ -69°C to ≤ -45°C 
1512 cumulative hours (63 
cumulative days) 
          > -45°C 
(warmer than -45°C) 
0 minutes 
Note:  For temperature requirements during clinical handling/ IP preparation, 
refer to Clinical Handling Timelines. 
Temperatures colder than -90°C and warmer than -45°C 

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 Sites must report the excursion using the Investigator Sponsored Studies 
(ISS) Temperature Excursion Submission ensuring that all details on the 
form are completed fully and accurately.  This includes details of the 
exposure time of the IP at the various temperature ranges.  
 Send a copy of the completed form to the email address listed at the 
bottom of the form and file the original form in the relevant section of the 
Pharmacy File. 
Temperatures within the range -69°C to -45°C: 
 Sites should record each event within this range on the Temperature 
Excursion Tracking Log and following the instructions that accompany 
the form.  Each consignment should have a separate Tracking Log, as each 
shipment will need to be tracked separately. 
 Cumulative duration time of the temperature excursions within this range 
should be captured.  
 Once a cumulative period of 1512 hours has been reached, the site should 
submit the ISS Temperature Excursion Submission Form making sure all 
relevant details on the form are completed fully and accurately. 
(Important: Consider IP shipment timeframes when tracking TEs and 
order replacement stock in a timely manner). 
 Send a copy to the email address listed at the bottom of the form, and file 
the completed Temperature Excursion Submission Form(s) in the relevant 
section of the Pharmacy File. 
Temperature excursions of prepared IP, outside the Clinical Handling Timelines, 
should be documented but are not reportable as temperature excursions.  Instead, 
the affected products should be considered unfit for use and should be destroyed 
by the site. 
Management of Product(s) Exposed to a Suspected Temperature Excursion 
Under no circumstances should any product impacted by an actual or suspected 
temperature excursion be administered to or by subjects before a temperature 
excursion assessment is completed by Amgen.  Pending such an assessment, all 
product(s) suspected of being exposed to a temperature excursion should be 
quarantined under the appropriate storage conditions.   
Affected product should only be removed from quarantine when: 
 The excursion assessment has determined the product is suitable for use. 
In this case, the product can be removed from quarantine for continued 
use. 
 The excursion assessment has determined the product is NOT suitable for 

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use.  In this case, the product must be returned/destroyed according to 
institutional/site policies. 
Temperature Excursion Assessment by Amgen 
Amgen will provide written notification/instructions via a Product Impact Memo 
for each evaluated temperature excursion.  If subjects are currently on-study and 
receiving Product(s), review the next expected dosing visit to determine if 
immediate re-supply is required, then complete and submit the Drug Shipment 
Request form accordingly. Suspect Product(s) must not be administered to 
subjects until deemed acceptable by Amgen.  
 

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7. STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  
Scans and x-rays must be done within 4 weeks prior to the start of therapy.  In the event that 
the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of therapy. Informed consent can be obtained within 
28 days prior to treatment start. 
 
Pre-
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13-21 
q2 
wks 
Off 
Studyc 
Talimogene laherparepvec A 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Doxorubicin B 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Cyclophosphamide B 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Paclitaxel B 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medial History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
CBC w/ diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry a 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Anti HSV Ab 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
MUGA or ECHO + EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor Measurements 
X 
Tumor measurements by exam (if palpable) are repeated every study visit. 
Xc 
Radiologic evaluation d 
Xd 
US measurements should be performed while getting talimogene laherparepvec 
injections 
Xc 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor IHC for T cells 
X 
 
 
 
 
 
Xf 
 
 
 
 
 
 
 
X 
Immunohistochemistry of 
lymph nodes 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood sampling for 
biomarkerse 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
A: Talimogene laherparepvec:  Dose as assigned; administration schedule(only if tumor is visualized on US) (+/- 2 day window for 
scheduling issues) 
B: Paclitaxel 80mg/m2 IV weekly (+/- 1 day window for scheduling issues) x 12 followed by doxorubicin 60mg/m2 + 
cyclophosphamide 600mg/m2 IV q2 weeks x 4 
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium. 
b: Serum pregnancy test (women of childbearing potential). 
c: Off-study treatment evaluation should be completed within 30 days after last chemotherapy treatment. Patients will continue to be 
followed up post op to determine degree of pathologic response, note any perioperative complications, and also will be followed every 6 
months (+/- 1 month) for 5 years by telephone, review of follow up notes for recurrence status and latent herpetic infection. See section 
below for details. 
d. In addition to US, patients should get baseline staging scans (CT thorax/abd w/ contrast and bone scan or PET) when clinically 
indicated to rule out metastatic disease. If staging imaging is not clinically indicated it is not required.  See section below for details. 
e. blood sampling must be collection prior to drug administration 
f. to be collected prior to the week 6 treatment 

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Prestudy procedures evaluation: 
 
Informed consent, demographics, concominant meds, performance status, physical exam, vitals, 
height, weight, complete blood count, complete metabolic panel, serum pregnancy test, serum 
HSV1 Ab, EKG, tumor measurement by palpation/exam, blood sampling for biomarker testing 
request slides from tumor and lymph node (if done) biopsies for IHC analysis. Prestudy 
procedures can be completed same day as day 1 treatment if necessary. 
 
Radiologic scans/imaging including the US, MUGA/ECHO, staging scans (CT + bone scans or 
PET/CT) as clinically warranted for neoadjuvant patients per NCCN guidelines (stage 2B node 
positive or stage III patients, not stage I or IIA node negative patients with no signs/symptoms 
suspicious for metastatic disease) are done within 4 weeks of 1st study treatment day. 
 
Weeks 1,4,6,8,10 procedures: 
 
Complete blood count, complete metabolic panel, US measurement for dosing of talimogene 
laherparepvec, pharmacy to begin thawing/preparation of dose, clinic visit with concurrent meds, 
performance status, physical exam, vitals, weight, tumor measurement by palpation/exam, then 
US for injection localization into tumor, injection of talimogene laherparepvec into primary 
tumor (+/- 3 days around the scheduled paclitaxel administration day), administration of weekly 
paclitaxel dose (6-8 days from last paclitaxel dose for weeks 4,6,8,10). The talimogene 
laherparepvec can be given either before or after the paclitaxel depending on 
scheduling/readiness of radiology/pharmacy on the treatment day. Ideally all treatments are 
given on the same day but if scheduling doesn’t permit then the grace periods specified above 
can be used to stagger the paclitaxel and talimogene laherparepvec on different days (with the 
study clinic visit and safety labs done on the paclitaxel infusion day scheduled for that week) 
when required due to circumstances. A biopsy will be collected on week 6 prior to initiating 
treatment with talimogene laherparepvec. 
 
Weeks 2,3,5,7,9,11,12 procedures: 
Complete blood count, vitals, weight, administration of weekly paclitaxel dose (6-8 days from 
last paclitaxel dose). Blood for biomarker sampling will be collected pre-dose week 2, 5, and 9. 
 
Weeks 13 -21 procedures: 
Complete blood count, complete metabolic panel, clinic visit with concurrent meds, performance 
status, physical exam, vitals, weight, tumor measurement by palpation/exam every 2 weeks (+/- 
1 day)  x 4 on the same day as administration of standard of care dose dense 
doxorubicin/cyclophosphamide chemotherapy. 
 
Off study procedures: 
Complete blood count, complete metabolic panel, clinic visit with concurrent meds, performance 
status, physical exam, vitals, weight, within 30 days of last study treatment. Follow up of any 
treatment related adverse events until resolution, stabilization, or death for a minimum of 30 days 
post last study treatment. Data on any perioperative complications should be collected as well. 
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when available in the EMR to assess degree of pathologic response to neoadjuvant therapy.  
Long-term follow up for disease recurrence/vital status/occurrence of any suspected herpetic 
infectious events up to 5 years after the off study visit date by telephone contact and/or clinical 
assessment at least once every 6 months (+/- 1 month) should be done.  Patients and their close 
contacts should be instructed to notify the study team immediately regarding any suspected new 
herpetic infection events so that clinical evaluation of the event by the patient’s health care 
provider, PCR testing of any lesions, expedited reporting (within 24 hours of notification) to 
Amgen at 1-855-465-9442 and to the FDA, and treatment as clinically indicated can be 
completed. Long term follow up schedule will continue until 5 years after the off study visit date, 
death, or patient is lost to follow up whichever occurs first.  
 
8. MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be reevaluated for response every two weeks 
(with the exception of the 3 week interval between injection #1 and #2 which is three weeks) 
using physical exam and ultrasound (until the injections are completed or tumor is no longer 
visualized whichever occurs first).  In addition the patient’s response will be evaluated by a 
pathologist following surgical excision.  
 
8.1. 
Definitions 
 
 
Pathologic complete response 
 
Response and progression will be evaluated in this study using a primary endpoint of 
pathologic complete response defined as absence of residual invasive 
adenocarcinoma in the breast and ipsilateral lymph nodes (ypT0/isN0) following 
completion of all neoadjuvant systemic therapy. Other endpoints looking at rate of 
breast only pathologic complete response rate will be evaluated. 
 
8.2. Guidelines for Evaluation of Clinical Disease 
 
All measurements of a palpable lesion should be taken and recorded in metric 
notation using a ruler or calipers at each study visit.  If the lesion is not easily 
palpable or not present then it should be noted as such in the patient note.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Clinical measurement of palpable lesions:  This evaluation is primarily for 
assessing how the patient is responding overall to the therapy and ensuring that there 
is no evidence of clinical progression during treatment that would require referral 
back to the patient’s surgical team for resection.  
 
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determine dosing, and measurement of the primary lesion. Measurement should be tri 
dimensional and recorded on each ultrasound procedure note in the medical record. 
Lesions that are not visualized following the initiation of therapy should be noted as 
such.  
 
8.3. Response Criteria 
 
8.3.1. Evaluation of primary lesions 
 
Complete Response (pCR): Disappearance of histopathologic evidence of 
malignant cells in breast and axillary lymph 
nodes 
 
Partial Response (pPR):  
Evidence of residual invasive malignant cells in 
breast and/or axillary lymph nodes  
 
Progressive Disease (PD): 
Increase in size of primary lesion or axillary 
lymphadenopathy since the treatment started or 
the appearance of one or more new lesions 
 
Stable Disease (SD):  
 
No change in histopathologic examination of 
breast and axillary lymph nodes without 
increase in size or number of lesion(s). 
 
8.4. Follow up evaluation 
 
8.4.1. Pathologic evaluation 
 
Pathologic evaluation for post neoadjuvant therapy residual disease will be 
made upon completion of all neoadjuvant systemic therapy on the resected 
surgical specimen(s) and a synoptic pathology report will be generated per 
standard institutional practice. The ypTN staging information, presence of 
treatment effect in the tumor bed and any resected lymph nodes, estimated 
tumor volume reduction should be recorded in Oncore case report forms.  
 
8.4.2. Duration of follow up for patient outcomes 
 
Follow up of any treatment related adverse events until resolution, 
stabilization, or death for a minimum of 30 days post last study treatment. 
Data on any perioperative complications should be collected as well. Final 
tumor measurement/assessment will be done based on the post-operative 
pathology report when available in the EMR to assess degree of pathologic 
response to neoadjuvant therapy.  Long-term follow up for disease 
recurrence/vital status/occurrence of any suspected herpetic infectious events 
up to 5 years after the off study visit date by telephone contact and/or clinical 
assessment at least once every 6 months (+/- 1 month) should be done.   

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8.5. Response Review 
 
Pathology will be reviewed for response by Moffitt Cancer Center pathologists. 
 
9. REGULATORY AND REPORTING REQUIREMENTS 
 
This protocol is associated with an Investigational New Drug Application (“IND”) 
sponsored by either Moffitt Cancer Center or an Investigator.  IND Safety Reports are 
required for any adverse experience associated (or possibly associated) with the use 
of the investigational product(s) that is both serious and unexpected. To meet the IND 
Safety Reporting requirements set forth in 21 CFR §312.32,  FDA Form 3500A 
(MedWatch form) will be completed and provided to the Moffitt Office of 
Institutional Regulatory Affairs for Investigational Drugs and Devices. 
  
9.1.     Reporting Adverse Events 
 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory 
documents and case report forms will be monitored internally according to Moffitt 
Cancer Center Monitoring Policies. All adverse events will be documented in 
electronic medical records, and staff will maintain an adverse event log for each 
patient.  The principal or treating physician will determine toxicity grade and 
attribution of the adverse event to the study drug or standard of care chemotherapy, 
with final approval within ten working days of the assessment.  The completed and 
signed-off logs will be provided for data entry to the assigned data manager within 24 
hours of the sign off.  The adverse event data entry will be completed within five 
working days.  All adverse events must be followed to resolution or stabilization for a 
minimum of 30 days after last protocol treatment or death (whichever occurs first) 
and updated at the time of the next assessment, treatment, discontinuation, or 
completion.  All logs must be available for review and audit.  All deaths that occur 
while the subject is receiving the study drug and/or within30 days after administration 
will be reported as a serious adverse event.   
 
Serious Adverse Events will be reported to the Protocol Monitoring Committee, the 
FDA, the Manager of the Institutional Regulatory Affairs, and Amgen.  All SAEs will 
be reported to the Clinical Trial Office of Moffitt Cancer Center in 24 hours via 
Oncore.  Serious adverse events will be reported to the IRB according to IRB policy.  
This includes new herpetic infections in talimogene laherparepvec treated patients or 
their close contacts (see section 7 under long term follow up) as required by Amgen 
and the FDA. The initial report submitted via MedWatch form to the Office of 
Institutional Regulatory Affairs for Investigation Drugs and Devices must be as 
complete as possible, including details of the current illness and serious adverse 
event, and an assessment of the causal relationship between the event and the 
investigational product(s). Information not available at the time of the initial report 
(e.g., an end date for the adverse event or laboratory values received after the report) 
must be documented on a follow-up report. A final report to document resolution of 
the serious adverse event is required if it is not documented in the initial report. 

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9.2.      Safety Data Exchange for Amgen  
The Sponsor/Investigator is responsible for compliance with expedited reporting 
requirements for serious, 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 1 and Table 2 below.  Individual safety reports should 
be sent to Amgen Global Safety, utilizing the fax or email information provided on 
the cover page. Aggregate safety reporting including listings, tabulations and 
summary reports should be scanned and sent to Amgen NASCR accompanied by 
the Fax Cover Form In addition to the requirements outlined in tables below, 
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 ‘Accidental Exposures to Talimogene Laherparepvec and 
Herpetic Events’). 
Table 1.  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. 
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.  
Individual reports should be faxed to 1-888-814-8653 or scanned and sent via email to svc-ags-in-  
us@amgen.com 
Table 2. 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 any 
body governing research conduct (e.g., RA, 
IRB, etc.) but not later than 1 calendar year 
after study completion 
 
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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 3 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 
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 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 3.  
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.  

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Table 3. 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 
Distributio 
n* 
 
 
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 
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. 
 
9.3.        Interim analyses 
 
Safety interim analysis: The safety data will be analyzed upon completion of the 
phase 1 and also after the first twelve phase 2 patients have been treated. At either 
point, if greater than half of the treated patients experience a G3-4 toxicity related to 
talimogene laherparepvec which leads to chemotherapy treatment delays > 14 days or 
unplanned cessation of neoadjuvant treatment then accrual to the trial will be held 
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determine if accrual can resume. Any deaths on study treatment should trigger an 
immediate safety review and accrual hold until the event is fully investigated and a 
determination is made by the PI, study sponsor and protocol monitoring committee.  
 
10. STATISTICAL CONSIDERATIONS 
 
10.1. Study Design/Endpoints 
 
 
 
Phase 1 design:  
The phase one portion of the study uses a standard 3+3 design with the primary 
endpoints being safety/toxicity described using CTCAE 4.03 criteria and the MTD. 
Descriptive statistics including frequency of adverse events, number of treatments 
administered as planned, and patient demographics will be reported in tabular form. 
Patients receiving any study treatment will be evaluable for the safety endpoint.  
 
The primary endpoint of the phase 1 portion is to determine the MTD/RP2D of 
talimogene laherparepvec administered with neoadjuvant paclitaxel-
doxorubicin/cyclophosphamide chemotherapy, safety/toxicity of the combination. 
 
 
 
Phase 2 design: 
Simon's two-stage optimal design (Simon, 1989) will be used for sample size 
selection to test the null hypothesis that the true response rate is .30 vs. the alternative 
that the true response rate is 0.45. After testing the drug on 12 evaluable patients in 
the first stage, the trial will be terminated if 3 or fewer respond. If the trial goes on to 
the second stage, a total of 25 evaluable patients will be studied for a total of 37 
evaluable patients. If the total number responding is less than or equal to 14, the drug 
is rejected. This design yields a type I error rate of .0990 and power of .70 when the 
true response rate is .3.  The probability of early stopping is .49.  
 
The primary endpoint of the phase 2 portion of the study is the pathologic complete 
response rate (pCR, defined as absence of residual invasive carcinoma in the breast 
and ipsilateral draining lymph nodes) following the study treatment. This is to 
determine the efficacy of neoadjuvant talimogene laherparepvec in conjunction with 
neoadjuvant chemotherapy for early/locally advanced triple negative invasive breast 
cancer. 
The analysis of the primary endpoint as a binomial variable (pathologic complete 
response vs. pathologic non-complete response) will be calculated along with its’ 
95% confidence intervals based on the exact binomial distribution.  
 
10.2. Sample Size/Accrual Rate 
 
 
 
 
 
Phase 1: 
Between 9-12 patients will be accrued in the phase 1 portion of the study. The accrual 
rate is estimated at 1-2 patients per month.  
 
Phase 2: 

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In the first stage, 12 patients will be accrued. If there are 3 or fewer pathologic 
complete responses in these 12 patients, the study will be stopped.  Otherwise, 25 
additional patients will be accrued for a total of 37 evaluable patients. Non-evaluable 
patients may be replaced to reach the accrual target of evaluable patients with sponsor 
and IRB approval.  It is estimated that the center would accrue 1-2 patients per month 
for a total of 18 months.  We anticipate that some of those patients may be 
unevaluable, and we estimate that accrual should be completed in 24 months. 
 
10.3. Analysis of Secondary Endpoints 
 
Secondary endpoints include; 5 year recurrence free survival/overall survival, 
immune activation correlatives by IHC and T cell receptor sequencing. Additional 
blood sampling for biomarker analysis. 
 
10.4 
Reporting and Exclusions 
 
10.4.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with talimogene laherparepvec.   
 
10.4.2 
Evaluation of response.  All patients who have completed neoadjuvant 
chemotherapy and received at least three injections of talimogene (except in the 
case where the injections were stopped prior to the third injection due to 
resolution of the primary tumor on ultrasound) would be evaluable for the primary 
response endpoint. Patients should be categorized as pathologic 1) complete 
responder, 2) partial responders (any objective reduction in tumor burden with 
residual disease), 3) stable disease (no change), or 4) disease progression (any 
objective increase in primary lesion or development of new lesions on therapy). 
Patients who are not evaluable may be replaced with approval by the PI.    
 
10.5 
Data analysis plan 
The pCR will be calculated along with its 95% confidence intervals based on the 
exact binomial distribution.  Toxicity will be reported by type, frequency and 
severity.  Survival probabilities for the time-to-event data will be estimated using the 
Kaplan Meier method with standard errors using Greenwoods formula.  Other 
secondary endpoints will be summarized using descriptive statistics, and correlative 
analysis will be conducted using appropriate statistical methods.  
 
11. CORRELATIVE EXPERIMENTS: 
 
11.1. Immunohistochemistry analysis of breast tumor tissue:  
Background: Analysis of tumor tissues using immunohistochemistry have identified immune 
factors associated with clinical benefit from systemic therapy.  The immunoscore is a method 
to quantify the level of CD8+ and CD45RO+ T cells in tumor tissue. This system has shown 
promise in the prognostic evaluation of tumors such as colon cancer. The current correlative 
experiment will attempt to correlate the level of CD8+ and CD45RO+ infiltrates with 
pathologic complete response. In addition, staining of the post treatment resection specimen 

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for HSV viral proteins will be done to assess the level of viral replication at the tumor site 
and any available lymph nodes with grossly positive disease. These correlative studies will 
be performed on tissue samples from the diagnostic biopsy tissue collected from on treatment 
during a week 6 biopsy and grossly positive lymph nodes and resected breast tissue. 
Methods: The staining of the specimens will be adapted from the method used in Pages et al. 
JCO 2009 for the CD8+ and CD45RO+ infiltrate in the diagnostic core biopsy sample, a 
tissue sample from an on treatment core biopsy and the post treatment resected tumor area. 
Patient tissue staining will be carried out in our tissue core using a Vectra automated 
immunostainer after antibody optimization has been completed on appropriate controls.  An 
image analysis will be carried out using our HALO digital pathology analysis software 
algorithms to provide a score of positive staining events/area of viable tumor analyzed. The 
score between those with pathologic complete response and those without will be compared 
on the core biopsy and resected tumor. This analysis will require one-two, 4 micron slides 
and one H&E slide from each specimen (pre-treatment core biopsy, on treatment core biopsy 
and post treatment resected specimen with the region surrounding the injection site selected 
for sectioning).  
 
11.2 T cell repertoire analysis of tumor specimens: Background: Changes in the T cell 
repertoire occur during expansion of activated T cell clones to an antigenic stimulus (Speiser 
et al. J of Immunology 2006). Evaluation of the clonal diversity by sequencing the 
hypervariable CDR3 region of the T cell receptor can show if one or more immunodominant 
T cell clones emerge following treatment with talimogene laherparepvec.  Characterization of 
this shift in tumor infiltrating lymphocytes during treatment may provide useful information 
on the clinical benefit from talimogene laherparepvec injection into the primary tumor site. In 
addition, RNAseq on the whole exome will be performed to obtain transcriptomics on these same 
samples to identify changes in gene transcription from baseline on therapy along with mutations 
that can be used as additional potential immunologic pharmacodynamic and predictive 
biomarkers to therapy with talimogene laherparepvec. 
 
Methods: Five slides (5 microns each) from the diagnostic core biopsy and five slides from 
the resected tumor area and grossly positive lymph nodes will be sent for T cell receptor 
rearrangement sequencing to Adaptive Biotechnologies, 1551 EastLake Ave E, Suite 200 
Seattle WA 98102.   The RNAseq will be performed in the Moffitt Molecular Genomics Core 
using an Illumina Truseq whole exome assay optimized for RNA extracted from FFPE sections 
from these same tissue specimens (approximately 1 microgram of RNA input is required). One 
microgram of RNA will be collected from each specimen for each timepoint available. Gene 
expression analysis and mutation calls will be performed by Moffitt bioinformatics staff to 
analyze correlations with genomic data and clinicopathologic factors. 
    
 
11.3 Flow cytometry biomarker Sampling 
Background: Treatment of tumors with TVEC can lead to changes in tumor chemokines and 
host immune activation.  While we are analyzing these changes in the tumor 
microenvironment it is desirable to evaluate circulating PBMCs and plasma samples for 
changes in PBMC populations and circulating chemokines during the study treatment. 

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Methods: Three sodium heparin tubes and one plasma separator tube will be collected at 
baseline, pre-dose on weeks 2, 5 and 9. This blood will be processed (PBMCs will undergo 
Ficoll separation, 1mL of plasma will be separated into 250 microliter aliquots) in Dr. 
Czerniecki’s lab and stored in liquid nitrogen for batched analysis. Multiparameter flow 
cytometry will be performed on PBMCs for T cell subsets and functional activation. 
Cytometric bead assays will be performed on plasma aliquots for Th1/Th2 and chemokines. 
11.4 Analysis of response on breast ultrasound and MRI: 
Background:  As part of their routine care, a number of patients in the trial underwent 
breast ultrasounds and MRI before and after TVEC+NAC treatment prior to surgery.  
These can be analyzed to evaluate treatment response on this additional imaging 
modality.  An objective marker based on non-invasive multiparametric MRI (mpMRI) 
that can predict degree and spatial extent of tumor response to pre-operative TVEC+NAC 
could allow individual tailoring of neoadjuvant therapy and improved surgical margins in 
the future.  Imaging biomarkers predictive of pCR can also aid in prognostic evaluation. 
Methods:  Retrospective review of the medical records of patients enrolled in the trial 
will determine which patients have pre and post-treatment, presurgical breast ultrasounds 
and MRIs for analysis.  Reports and images will then be analyzed to evaluate treatment 
response.  Report and image analysis will involve qualitative and quantitative analysis.  
Quantitative analysis of images will involve multispectral cluster analysis of tumor 
habitats that is well developed in the IRAT (Image Response Assessment Team) Core at 
MCC and has been applied to analyze patients in the MCC# 18596 trial (evaluating breast 
tumor response to pre-operative radiation treatment) to date.  The MRI analysis involves 
pre-processing mpMRI to match voxel dimensions across patients, scans, and scan dates, 
then co-registering pre- and post-TVEC MRI images per patient to compute DCE-MRI 
parameter maps, compute ADC maps, and calibrate T2W intensities using reference 
normal tissues.  The primary approach involves analysis of tumor voxels using Self-
Organizing Maps (SOM), a technique that was developed through the IRAT Core.  These 
microhabitat quantitative analysis techniques will also be compared to standard 
quantitative analysis of tumor volume response (eg. volume calculated from three 
orthogonal dimension measurements noted in the reports).  MRI results will be compared 
to pathology reports to determine correlations. For ultrasound images changes in tumor 
size measurements at multiple timepoints from baseline will be analyzed to determine 
early predictors for complete pathologic response.  
    
 
 
 
 
 
 
 
 
 
 

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12. 
REFERENCES 
 
1. 
Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, et al. Long-Term 
Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable 
Breast Cancer. J Clin Oncol. 2015;33:2353-60. 
2. 
Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. 
Randomized trial of dose-dense versus conventionally scheduled and sequential versus 
concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive 
primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B 
Trial 9741. J Clin Oncol. 2003;21:1431-9. 
3. 
Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, et al. SWOG 
S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast 
cancer. J Clin Oncol. 2015;33:58-64. 
4. 
Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. The New England 
journal of medicine. 2010;363:1938-48. 
5. 
Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to 
neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin 
Oncol. 2008;26:1275-81. 
6. 
Harrington KJ, Hingorani M, Tanay MA, Hickey J, Bhide SA, Clarke PM, et al. Phase 
I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated 
stage III/IV squamous cell cancer of the head and neck. Clin Cancer Res. 2010;16:4005-15. 
7. 
Senzer NN, Kaufman HL, Amatruda T, Nemunaitis M, Reid T, Daniels G, et al. Phase II 
clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation 
oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 
2009;27:5763-71. 
8. 
Hu JC, Coffin RS, Davis CJ, Graham NJ, Groves N, Guest PJ, et al. A phase I study of 
OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte 
macrophage colony-stimulating factor. Clin Cancer Res. 2006;12:6737-47. 
9. 
MacKie RM, Stewart B, Brown SM. Intralesional injection of herpes simplex virus 1716 
in metastatic melanoma. Lancet. 2001;357:525-6. 
10. 
Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, et al. 
Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant 
glioma: results of a phase I trial. Gene therapy. 2000;7:867-74. 
11. 
Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D, et al. 
Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) 
in patients with recurrent malignant glioma. Gene therapy. 2000;7:859-66. 
12. 
Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL. Attenuated multi-mutated 
herpes simplex virus-1 for the treatment of malignant gliomas. Nature medicine. 1995;1:938-43. 
13. 
Liu BL, Robinson M, Han ZQ, Branston RH, English C, Reay P, et al. ICP34.5 deleted 
herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. 

MCC18621 
 
Protocol Version 2.3 
 
 
 
 
 
 
 
 
04/05/2021 
53 
Gene therapy. 2003;10:292-303. 
14. 
Spivack JG, Fareed MU, Valyi-Nagy T, Nash TC, O'Keefe JS, Gesser RM, et al. 
Replication, establishment of latent infection, expression of the latency-associated transcripts and 
explant reactivation of herpes simplex virus type 1 gamma 34.5 mutants in a mouse eye model. 
The Journal of general virology. 1995;76 ( Pt 2):321-32. 
15. 
Mohr I, Sternberg D, Ward S, Leib D, Mulvey M, Gluzman Y. A herpes simplex virus 
type 1 gamma34.5 second-site suppressor mutant that exhibits enhanced growth in cultured 
glioblastoma cells is severely attenuated in animals. Journal of virology. 2001;75:5189-96. 
16. 
Poppers J, Mulvey M, Khoo D, Mohr I. Inhibition of PKR activation by the proline-rich 
RNA binding domain of the herpes simplex virus type 1 Us11 protein. Journal of virology. 
2000;74:11215-21. 
17. 
He B, Chou J, Brandimarti R, Mohr I, Gluzman Y, Roizman B. Suppression of the 
phenotype of gamma(1)34.5- herpes simplex virus 1: failure of activated RNA-dependent protein 
kinase to shut off protein synthesis is associated with a deletion in the domain of the alpha47 
gene. Journal of virology. 1997;71:6049-54. 
18. 
Mohr I, Gluzman Y. A herpesvirus genetic element which affects translation in the 
absence of the viral GADD34 function. The EMBO journal. 1996;15:4759-66. 
19. 
Sundaresan P, Hunter WD, Martuza RL, Rabkin SD. Attenuated, replication-competent 
herpes simplex virus type 1 mutant G207: safety evaluation in mice. Journal of virology. 
2000;74:3832-41. 
20. 
Hunter WD, Martuza RL, Feigenbaum F, Todo T, Mineta T, Yazaki T, et al. Attenuated, 
replication-competent herpes simplex virus type 1 mutant G207: safety evaluation of 
intracerebral injection in nonhuman primates. Journal of virology. 1999;73:6319-26. 
21. 
Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. 
Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced 
Melanoma. J Clin Oncol. 2015;33:2780-8. 
 

MCC18621 
 
APPENDIX A 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 

13 
MCC18621 
 
APPENDIX B TALIMOGENE LAHERPAREPVEC PI 
 
 
1 
INDICATIONS AND USAGE 
 
IMLYGIC is a genetically modified oncolytic viral therapy indicated for the local treatment of 
unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent 
after initial surgery. 
 
Limitations of use: IMLYGIC has not been shown to improve overall survival or have 
an effect on visceral metastases. 
 
2 
DOSAGE AND ADMINISTRATION 
 
For intralesional injection only. Do not administer intravenously. 
 
2.1 
Dose 
Administer IMLYGIC by injection into cutaneous, subcutaneous, and/or nodal lesions that 
are visible, palpable, or detectable by ultrasound guidance. 
 
IMLYGIC is provided in single-use vials of 1 mL each in two different dose strengths: 
• 
106 (1 million) plaque-forming units (PFU) per mL (light green cap) – for initial 
dose only 
• 
108 (100 million) PFU per mL (royal blue cap) – for all subsequent doses 
 
Recommended Dose and Schedule 
The total injection volume for each treatment visit should not exceed 4 mL for all injected 
lesions combined. It may not be possible to inject all lesions at each treatment visit or over the 
full course of treatment. Previously injected and/or uninjected lesion(s) may be injected at 
subsequent treatment visits. The initial recommended dose is up to 4 mL of IMLYGIC at a 
concentration of 106 (1 million) PFU per mL. The recommended dose for subsequent 
administrations is up to 4 mL of IMLYGIC at a concentration of 108 (100 million) PFU per mL. 
The recommended dosing schedule for IMLYGIC is shown in Table 1. 

13 
MCC18621 
 
Table 1. Recommended Dose and Schedule for IMLYGIC 
 
 
 
 
Treatment 
 
 
 
Treatment 
Interval 
Maximum 
Injection 
Volume per 
Treatment 
Visit (all 
lesions 
combined) 
 
 
 
 
Dose Strength 
 
 
 
 
Prioritization of Lesions to be Injected 
Initial 
– 
4 mL 
106 (1 million) PFU 
per mL 
Inject largest lesion(s) first. 
Prioritize injection of remaining lesion(s) 
based on lesion size until maximum 
injection volume is reached or until all 
injectable lesion(s) have been treated. 
Second 
 
3 weeks after 
initial 
treatment 
4 mL 
 
108 (100 million) 
PFU per mL 
Inject any new lesion(s) (lesions that have 
developed since initial treatment) first. 
Prioritize injection of remaining lesion(s) 
based on lesion size until maximum 
injection volume is reached or until all 
injectable lesion(s) have been treated. 
All 
subsequent 
treatments 
(including 
reinitiation) 
2 weeks after 
previous 
treatment 
 
4 mL 
108 (100 million) 
PFU per mL 
Inject any new lesion(s) (lesions that have 
developed since previous treatment) first. 
Prioritize injection of remaining lesion(s) 
based on lesion size until maximum 
injection volume is reached or until all 
injectable lesion(s) have been treated. 
 
Dose Volume Determination (per Lesion) 
Use Table 2 to determine the volume of IMLYGIC injection for each lesion. 
Table 2.  Determination of IMLYGIC Injection Volume Based on Lesion Size 
Lesion Size 
(longest dimension) 
 
Injection Volume 
> 5 cm 
up to 4 mL 
> 2.5 cm to 5 cm 
up to 2 mL 
> 1.5 cm to 2.5 cm 
up to 1 mL 
> 0.5 cm to 1.5 cm 
up to 0.5 mL 
≤ 0.5 cm 
up to 0.1 mL 
When lesions are clustered together, inject them as a single lesion according to Table 2. 
Continue IMLYGIC treatment for at least 6 months unless other treatment is required or until 
there are no injectable lesions to treat. Reinitiate IMLYGIC treatment if new unresectable 
cutaneous, subcutaneous, or nodal lesions appear after a complete response. 

13 
MCC18621 
 
2.2 
Preparation and Handling 
Healthcare providers who are immunocompromised or pregnant should not prepare or 
administer IMLYGIC and should not come into direct contact with the IMLYGIC injection 
sites, dressings, or body fluids of treated patients [see Warnings and Precautions (5.1)]. 
 
Avoid accidental exposure to IMLYGIC and follow universal biohazard precautions for 
preparation, administration, and handling of IMLYGIC: 
• 
Wear personal protective equipment (protective gown or laboratory coat, 
safety glasses or face shield, and gloves) while preparing or administering 
IMLYGIC. 
• 
Avoid accidental exposure to IMLYGIC, especially contact with skin, 
eyes, and mucous membranes. 
o Cover any exposed wounds before handling. 
o In the event of an accidental occupational exposure (e.g., through a splash to the 
eyes or mucous membranes), flush with clean water for at least 15 minutes. 
o In the event of exposure to broken skin or needle stick, clean the affected area 
thoroughly with soap and water and/or a disinfectant. 
• 
Treat all IMLYGIC spills with a virucidal agent such as 1% sodium 
hypochlorite and blot using absorbent materials. 
• 
Dispose of all materials that may have come in contact with IMLYGIC 
(e.g., vial, syringe, needle, cotton gauze, gloves, masks, or dressings) in 
accordance with universal biohazard precautions. 
• Advise patients to place used dressings and cleaning materials into a sealed 
plastic bag and dispose in household waste. 
 
Thawing IMLYGIC Vials 
1. 
Determine the total volume required for injection, up to 4 ml [see Dosage and 
Administration (2.1)]. 
2. 
Thaw frozen IMLYGIC vials at room temperature [20º to 25ºC (68º to 77ºF)] until 
IMLYGIC is liquid (approximately 30 minutes). Do not expose the vial to higher 
temperatures. Keep the vial in original carton during thawing. 
3. 
Swirl gently. Do NOT shake. 
4. 
After thawing, administer IMLYGIC immediately or store in its original vial and 
carton, protected from light in a refrigerator [2° to 8°C (36° to 46°F)] for no longer than the 
specified duration in Table 3. Do not refreeze IMLYGIC after thawing. Discard any 
IMLYGIC vial left in the refrigerator longer than the specified times in Table 3. 
Table 3. Storage Times for Thawed IMLYGIC Vial at 2° to 8°C (36° to 46°F) 
106 (1million)PFUpermL 
108 (100million)PFUpermL 
12 hours 
48 hours 
5. 
Prepare sterile syringes and needles. A detachable needle of 18–26G may be used for 
IMLYGIC withdrawal and a detachable needle of 22–26G may be used for injection. Small 
unit syringes (e.g., 0.5 mL insulin syringes) are recommended for better injection control. 
6. 
Using aseptic technique, remove the vial cap and withdraw the product from the 
vial into the syringe(s), noting the total volume. Avoid generating aerosols when 
loading syringes with product, and use a biologic safety cabinet if available. 

13 
MCC18621 
 
 
2.3 
Administration 
Follow the steps below to administer IMLYGIC to patients: 
 
Pre-Injection 
1. 
Clean the lesion and surrounding  areas with an alcohol swab and let dry. 
2. 
Treat the injection site with a topical or local anesthetic agent, if necessary. Do not 
inject anesthetic agent directly into the lesion. Inject anesthetic agent around the periphery of 
the lesion. 
 
Injection 
1. 
Inject IMLYGIC intralesionally into cutaneous, subcutaneous, and/or nodal lesions that 
are visible, palpable, or detectable by ultrasound guidance. Using a single insertion point, 
inject IMLYGIC along multiple tracks as far as the radial reach of the needle allows within 
the lesion to achieve even and complete dispersion. Multiple insertion points may be used if 
a lesion is larger than the radial reach of the needle. 
 
Figure 1: Injection 
administration for 
cutaneous lesions 
 
 
Figure 2: Injection 
administration for 
subcutaneous lesions 
 
Figure 3: Injection 
administration for nodal 
lesions

 
MCC18621 
 
2. 
Inject IMLYGIC evenly and completely within the lesion by pulling the needle back 
without exiting the lesion. Redirect the needle as many times as necessary while injecting 
the remainder of the dose of IMLYGIC. Continue until the full dose is evenly and 
completely dispersed. 
3. 
When removing the needle, withdraw it from the lesion slowly to avoid leakage of 
IMLYGIC at the insertion point. 
4. 
Repeat steps 1-2 under pre-injection and steps 1-3 under injection for other lesions to be 
injected. 
5. 
Use a new needle any time the needle is completely removed from a lesion and 
each time a different lesion is injected. 
 
Post-Injection 
1. 
Apply pressure to the injection site(s) with sterile gauze for at least 30 seconds. 
2. 
Swab the injection site(s) and surrounding area with alcohol. 
3. 
Change gloves and cover the injected lesion(s) with an absorbent pad and dry occlusive 
dressing. 
4. 
Wipe the exterior of occlusive dressing with alcohol. 
5. 
Advise patients to: 
• 
Keep the injection site(s) covered for at least the first week after each 
treatment visit or longer if the injection site is weeping or oozing. 
• 
Replace the dressing if it falls off. 
3. 
DOSAGE FORMS AND STRENGTHS 
Initial dose only: 106 (1 million) PFU per mL solution in 1 mL single-use vial (light green cap) 
Subsequent doses: 108 (100 million) PFU per mL solution in 1 mL single-use vial (royal blue 
cap) 
4. 
CONTRAINDICATIONS 
• 
Immunocompromised Patients 
IMLYGIC is a live, attenuated herpes simplex virus and may cause life-threatening disseminated 
herpetic infection in patients who are immunocompromised. Do not administer IMLYGIC to 
immunocompromised patients, including those with a history of primary or acquired 
immunodeficient states, leukemia, lymphoma, AIDS or other clinical manifestations of infection 
with human immunodeficiency viruses, and those on immunosuppressive therapy [see 
Nonclinical Toxicology (13.2)]. 
 
• 
Pregnant Patients 
Do not administer IMLYGIC to pregnant patients. 
 
5. 
WARNINGS AND PRECAUTIONS 
 
• 
Accidental Exposure to IMLYGIC 
Accidental exposure may lead to transmission of IMLYGIC and herpetic infection. Accidental 
needle stick and splashback to the eyes have been reported in healthcare providers during 
preparation and administration of IMLYGIC. 
Healthcare providers, close contacts (household members, caregivers, sex partners, or persons 
sharing the same bed), pregnant women, and newborns should avoid direct contact with injected 

 
MCC18621 
 
lesions, dressings, or body fluids of treated patients [see Dosage and Administration (2.2)]. 
Healthcare providers who are immunocompromised or pregnant should not prepare or administer 
IMLYGIC. 
 
Caregivers should wear protective gloves when assisting patients in applying or changing 
occlusive dressings and observe safety precautions for disposal of used dressings, gloves, and 
cleaning materials [see Dosage and Administration (2.2)]. 
 
In the event of an accidental exposure to IMLYGIC, exposed individuals should clean the 
affected area thoroughly with soap and water and/or a disinfectant. If signs or symptoms of 
herpetic infection develop, the exposed individuals should contact their healthcare provider for 
appropriate treatment [see Warnings and Precautions (5.2)]. 
 
Patients should avoid touching or scratching injection sites or their occlusive dressings, as doing 
so could lead to inadvertent transfer of IMLYGIC to other areas of the body. 
 
• 
Herpetic Infection 
In clinical studies, herpetic infections (including cold sores and herpetic keratitis) have been 
reported in patients treated with IMLYGIC. Disseminated herpetic infection may also occur in 
immunocompromised patients [see Contraindications (4.1)]. 
 
Patients who develop suspicious herpes-like lesions should follow standard hygienic practices to 
prevent viral transmission. Patients or close contacts with suspected herpetic infections should 
also contact their healthcare provider to evaluate the lesions. Suspected herpetic lesions should 
be reported to Amgen at 
1-855-IMLYGIC (1-855-465-9442); patients or close contacts have the option of follow-up 
testing for further characterization of the infection. 
 
IMLYGIC is sensitive to acyclovir. Acyclovir or other antiviral agents may interfere with the 
effectiveness of IMLYGIC. Therefore, consider the risks and benefits of IMLYGIC treatment 
before administering antiviral agents to manage herpetic infection. 
• 
Injection Site Complications 
Necrosis or ulceration of tumor tissue may occur during IMLYGIC treatment. Cellulitis and 
systemic bacterial infection have been reported in clinical studies. Careful wound care and 
infection precautions are recommended, particularly if tissue necrosis results in open wounds. 
 
In clinical studies, impaired healing at the injection site has been reported. IMLYGIC may 
increase the risk of impaired healing in patients with underlying risk factors (e.g., previous 
radiation at the injection site or lesions in poorly vascularized areas). One patient had an 
amputation of a lower extremity 6 months after IMLYGIC injection due to an infected non-
healing wound. This wound area had been treated with surgery and radiation prior to IMLYGIC 
treatment and had previous wound complications. 
 
If there is persistent infection or delayed healing of the injection site(s), consider the risks and 
benefits of IMLYGIC before continuing treatment with IMLYGIC. 

 
MCC18621 
 
 
• 
Immune-Mediated Events 
IMLYGIC may result in immune-mediated events. In clinical studies, immune-mediated events, 
including glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been 
reported in patients treated with IMLYGIC. 
 
Consider the risks and benefits of IMLYGIC before initiating treatment in patients who have 
underlying autoimmune disease or before continuing treatment in patients who develop 
immune-mediated events. 
 
• 
Plasmacytoma at Injection Site 
In a clinical study, a plasmacytoma has been reported in proximity to the injection site after 
administration of IMLYGIC in a patient with smoldering multiple myeloma. 
 
Consider the risks and benefits of IMLYGIC in patients with multiple myeloma or 
in whom plasmacytoma develops during treatment. 
 
6. 
ADVERSE REACTIONS 
 
The most commonly reported adverse drug reactions (≥ 25%) in IMLYGIC-treated patients were 
fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain. 
 
The following adverse reactions are discussed in greater detail in another section of the label: 
Herpetic Infection [see Warnings and Precautions (5.2)] 
Injection Site Complications [see Warnings and Precautions (5.3)] 
 
• 
Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical 
trials of another drug and may not reflect the rates observed in practice. 
 
The safety of IMLYGIC was evaluated in 419 patients who received at least 1 dose of either 
IMLYGIC (n = 292) or subcutaneously administered granulocyte-macrophage colony-stimulating 
factor (GM-CSF) (n = 127) in an open-label, randomized clinical study of patients with stage 
IIIB, IIIC, and IV melanoma that was not considered to be surgically resectable [see Clinical 
Studies (14)]. The median duration of exposure to IMLYGIC was 23 weeks (5.3 months). 
Twenty-six patients were exposed to IMLYGIC for at least 1 year. 
Most adverse reactions reported were mild or moderate in severity and generally resolved 
within 72  hours. The most common grade 3 or higher adverse reaction was cellulitis [see 
Warnings and Precautions (5.3)]. 
 
Pyrexia, chills, and influenza-like illness can occur any time during IMLYGIC treatment 
but were more frequent during the first 3 months of treatment. 
Table 4 below lists adverse reactions with a 5% or greater incidence in the IMLYGIC 
arm compared to the GM-CSF arm in the clinical study [see Clinical Studies (14)]. 

 
MCC18621 
 
 
Table 4.  Adverse Reactions Reported with At Least a 5% Greater Incidence in Patients Treated 
with IMLYGIC Compared to GM-CSF 
 
IMLYGIC 
(n = 292) 
GM-CSF 
(n = 127) 
Adverse Reactions 
Any Grade 
n 
Grade 3 
n 
Any Grade 
n (%) 
Grade 3 
n (%) 
General disorders and administration site conditions 
Fatigue 
147 (50.3) 
6 (2.1) 
46 (36.2) 
1 (< 1) 
Chills 
142 (48.6)  
11 (8.7) 
 
Pyrexia 
125 (42.8)  
11 (8.7) 
 
Influenza-like illness 
89 (30.5) 
2 (< 1) 
19 (15.0)  
Injection site pain 
81 (27.7) 
2 (< 1) 
8 (6.3) 
 
Gastrointestinal disorders 
Nausea 
104 (35.6) 
1 (< 1) 
25 (19.7)  
Vomiting 
62 (21.2) 
5 (1.7) 
12 (9.5) 
 
Diarrhea 
55 (18.8) 
1 (< 1) 
14 (11.0)  
Constipation 
34 (11.6)  
8 (6.3) 
1 (< 1) 
Abdominal pain 
26 (8.9) 
2 (< 1) 
3 (2.4) 
 
Musculoskeletal and connective tissue disorders 
Myalgia 
51 (17.5) 
1 (< 1) 
7 (5.5) 
 
Arthralgia 
50 (17.1) 
2 (< 1) 
11 (8.7) 
 
Pain in extremity 
48 (16.4) 
4 (1.4) 
12 (9.5) 
1 (< 1) 
Nervous system disorders 
Headache 
55 (18.8) 
2 (< 1) 
12 (9.5) 
 
Dizziness 
28 (9.6) 
 
4 (3.2) 
 
Respiratory, thoracic, and mediastinal disorders 
Oropharyngeal pain 
17 (5.8) 
 
1 (< 1) 
 
Investigations 
Weight decreased 
17 (5.8) 
1 (< 1) 
1 (< 1) 
 
Other adverse reactions associated with IMLYGIC in the open-label, randomized study include 
glomerulonephritis, vitiligo, cellulitis, and oral herpes. 
7. 
DRUG INTERACTIONS 
 
IMLYGIC is sensitive to acyclovir. Acyclovir or other antiherpetic viral agents may interfere 
with the effectiveness of IMLYGIC. No drug interaction studies have been conducted with 
IMLYGIC. 
8. 
USE IN SPECIFIC POPULATIONS 
 
Pregnancy Risk Summary:  
Adequate and well-controlled studies with IMLYGIC have not been conducted in pregnant 
women. No effects on embryo-fetal development have been observed in a study conducted in 

 
MCC18621 
 
pregnant mice. The design of the study limits application of the animal data to humans [see 
Data]. 
 
In the U.S. general population, the estimated background risk of major birth defects and 
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 
 
Clinical Considerations 
If the patient becomes pregnant while taking IMLYGIC, the patient should be apprised of the 
potential hazards to the fetus and neonate. Women of childbearing potential should be advised 
to use an effective method of contraception to prevent pregnancy during treatment with 
IMLYGIC. 
 
If a pregnant woman has an infection with wild-type Herpes Simplex Virus Type 1 (HSV-1) 
(primary or reactivation), there is potential for the virus to cross the placental barrier and also 
a risk of transmission during birth due to viral shedding. Infections with wild-type HSV-1 
have been associated with serious adverse effects, including multi-organ failure and death, if 
a fetus or neonate contracts the wild-type herpes infection. While there are no clinical data to 
date on IMLYGIC infections in pregnant women, there could be a risk to the fetus or neonate 
if IMLYGIC were to act in the same manner. 
 
Data 
Animal Data 
No effects on embryo-fetal development were observed when IMLYGIC was intravenously 
administered during organogenesis to immunocompetent pregnant mice at doses up to 4 x 108 
(400 million) PFU per kg (60-fold higher, on a PFU per kg basis, compared to the maximum 
clinical dose). Levels of IMLYGIC DNA in pooled fetal blood were at or below the assay 
detection level. Study design limitations included: 1) administration of IMLYGIC expressing 
human granulocyte-macrophage colony-stimulating factor (huGM-CSF), which is not 
biologically active in mice; 2) unknown transplacental kinetics of IMLYGIC following 
intravenous administration in pregnant mice; and 3) unknown significance of IMLYGIC dose 
extrapolation from animal to human based on body weight. 
 
• 
Lactation 
Risk Summary 
There is no information regarding the presence of IMLYGIC in human milk, the effects on the 
breastfed infant, or the effects on milk production. The developmental and health benefits of 
breastfeeding should be considered along with the mother’s clinical need for IMLYGIC and 
any potential adverse effects on the breastfed infant from IMLYGIC or from the underlying 
maternal condition. 
 
ClinicalConsiderations 
Because medicinal products can be found in human milk, a decision should be made whether to 
discontinue nursing or to discontinue IMLYGIC while nursing. 
• 
Females and Males of Reproductive Potential 
No nonclinical or clinical studies were performed to evaluate the effect of IMLYGIC on fertility. 

 
MCC18621 
 
 
• 
Pediatric Use 
Safety and effectiveness of IMLYGIC have not been established in pediatric patients. 
 
• 
Geriatric Use 
In clinical studies, no overall differences in safety or efficacy were observed between geriatric 
patients (≥ 65 years old) and younger patients. 
 
• 
Renal Impairment 
No clinical studies have been conducted to evaluate the effect of renal impairment on the 
pharmacokinetics of IMLYGIC. 
 
• 
Hepatic Impairment 
No clinical studies have been conducted to evaluate the effect of hepatic 
impairment on the pharmacokinetics of IMLYGIC. 
 
10 
OVERDOSAGE 
 
There is no clinical experience with an overdose with IMLYGIC. Doses up to 4 mL at dose 
strength of 108 (100 million) PFU per mL every 2 weeks (maximum cumulative dose of 222.5 x 
108 PFU) have been administered in clinical studies, with no evidence of dose-limiting toxicity. 
The maximum dose of IMLYGIC that can be safely administered has not been determined. In the 
event of a suspected overdose, the patient should be treated symptomatically and supportive 
measures instituted as required [see Warnings and Precautions (5)]. 
 
11 
DESCRIPTION 
 
IMLYGIC (talimogene laherparepvec) is a sterile suspension for intralesional injection. 
IMLYGIC is a live, attenuated HSV-1 that has been genetically modified to express huGM-CSF. 
The parental virus for IMLYGIC was a primary isolate, which was subsequently altered using 
recombinant methods to result in gene deletions and insertions. 
 
Each vial contains 1 mL deliverable volume of IMLYGIC at either 1 x 106 (1 million) PFU per 
mL or 1 x 108 (100 million) PFU per mL concentrations and the following excipients: di-sodium 
hydrogen phosphate dihydrate (15.4 mg), sodium dihydrogen phosphate dihydrate (2.44 mg), 
sodium chloride (8.5 mg), myo-inositol (40 mg), sorbitol (20 mg), and water for injection. 
 
The 106 (1 million) PFU per mL vial of IMLYGIC contains a clear to semi-translucent liquid 
following thaw from its frozen state. The 108 (100 million) PFU per mL vial of IMLYGIC 
contains a semi-translucent to opaque liquid following thaw from its frozen state. The liquid in 
each vial may contain white, visible, variously shaped, virus-containing particles. 
 
Each vial of IMLYGIC may also contain residual components of VERO cells including DNA 
and protein and trace quantities of fetal bovine serum. 
 

 
MCC18621 
 
The product contains no preservative. 
12 
CLINICAL PHARMACOLOGY 
 
12.1 
Mechanism of Action 
IMLYGIC has been genetically modified to replicate within tumors and to produce the immune 
stimulatory protein GM-CSF. IMLYGIC causes lysis of tumors, followed by release of tumor-
derived antigens, which together with virally derived GM-CSF may promote an antitumor 
immune response. However, the exact mechanism of action is unknown. 
 
12.3 
Pharmacokinetics 
Biodistribution (withinthebody)andViralShedding(excretion/secretion) IMLYGIC viral DNA 
levels in various tissues and secretions were determined using a quantitative polymerase chain 
reaction (qPCR) assay. Infectious IMLYGIC at the injection sites and at some potential herpetic 
lesions was also quantified using viral infectivity assays. 
 
Nonclinical data 
Following repeat intratumoral administration in mice, IMLYGIC DNA was primarily detected 
in the tumor, blood, spleen, lymph node, liver, heart, and kidney. IMLYGIC DNA was not 
detected in bone marrow, eyes, lachrymal glands, nasal mucosa, or feces. The highest level of 
IMLYGIC DNA was found in the injected tumor. IMLYGIC DNA was found in the injected 
tumor through 84 days and in blood samples through 14 days after the last administration of 
IMLYGIC. 
 
Clinical data 
The biodistribution and shedding of intralesionally administered IMLYGIC are being 
investigated in an ongoing study measuring IMLYGIC DNA and virus in blood, oral mucosa, 
urine, injection site, and occlusive dressings. In the initial 20 patients with melanoma who 
received IMLYGIC intralesional injection at a dose and schedule similar to that of the clinical 
study [see Clinical Studies (14)], available data indicate that IMLYGIC DNA was present in the 
blood in 17 (85%) patients and in urine of 4 (20%) patients during the study. The peak levels of 
IMYLGIC DNA in the urine were detected on the day of treatment. Infectious IMLYGIC virus 
was detected at the site of injection in 3 (15%) patients at a single time point each, and all within 
the first week after the initial injection. The exterior of the occlusive dressings was positive for 
IMLYGIC DNA in 14 (70%) patients during the study; however, no infectious virus was 
detected on the exterior of the occlusive dressing. The number of patients with measurable 
levels of IMLYGIC DNA on the exterior of occlusive dressings declined over time with no 
measurable DNA by the third treatment in 13 patients tested. 
 
13 
NONCLINICAL TOXICOLOGY 
 
13.2 
Animal Toxicology and/or Pharmacology 
Repeated intratumoral administration at 2 x 108 (200 million) PFU per kg (30-fold maximum 
proposed clinical dose, extrapolated based on body weight) did not demonstrate any adverse 
effects in immunocompetent mice. Severe combined immunodeficient (SCID) mice administered 
repeat intratumoral injections of IMLYGIC at a dose of 30-fold maximum proposed clinical dose 

 
MCC18621 
 
developed systemic viral infection (viral inclusion bodies or necrosis in enteric neurons in the 
gastrointestinal tract, adrenal gland, skin, pancreatic islet cells, eye, pineal gland, and brain). 
 
14 
CLINICAL STUDIES 
 
The safety and efficacy of intralesional injections of IMLYGIC compared with subcutaneously 
administered GM-CSF was evaluated in a multicenter, open-label, randomized clinical study in 
patients with stage IIIB, IIIC, and IV melanoma that was considered to be not surgically 
resectable. IMLYGIC was injected into cutaneous, subcutaneous, or nodal melanoma lesions and 
was not injected into visceral lesions. Previous systemic treatment for melanoma was allowed. 
Patients with active cerebral metastases, bony metastases, extensive visceral disease, primary 
ocular or mucosal melanoma, evidence of immunosuppression, or receiving treatment with a 
systemic antiherpetic agent were excluded from the study. 
 
The study included 250 (57%) men and 186 (43%) women. The mean age was 63 (range: 22 to 
94) years. Most patients (98%) were white. Seventy percent (70%) of patients had baseline 
Eastern Cooperative Oncology Group (ECOG) performance status of zero. Seventy percent 
(70%) of patients had stage IV disease (27% M1a; 21% M1b; and 22% M1c), and 30% had stage 
III disease. Fifty-three percent (53%) of patients had received prior therapy for melanoma (other 
than or in addition to surgery, adjuvant therapy, or radiation), and 58% were seropositive for 
wild-type HSV-1 at baseline. 
 
A total of 436 patients were randomized to receive either IMLYGIC (n = 295) or GM-CSF (n = 
141). IMLYGIC was administered by intralesional injection at an initial concentration of 106 (1 
million) PFU per mL on Day 1, followed by a concentration of 108 (100 million) PFU per mL on 
Day 21 and every 2 weeks thereafter, at a dose of up to 4 mL per visit. GM-CSF was 
administered subcutaneously in 28-day cycles, i.e., 125 µg/m2 daily for 14 days followed by 14 
days without GM-CSF administration. 
 
Patients were to be treated for at least 6 months or until there were no injectable lesions. During 
this period, treatment could continue despite an increase in size in existing lesion(s) and/or 
development of new lesion(s), unless the patient developed intolerable toxicity or the 
investigator believed that it was in the best interest of the patient to stop treatment or to be given 
other therapy for melanoma. After 6 months of treatment, patients were to continue treatment 
until clinically relevant disease progression (i.e., disease progression associated with a decline in 
performance status and/or alternative therapy was required in the opinion of the investigator), up 
to 12 months. Patients experiencing a response at 12 months after the start of treatment could 
continue treatment for up to an additional 6 months, unless there were no remaining injectable 
lesions or disease progression. All patients were to be followed for survival status for at least 36 
months. 
 
The major efficacy outcome was durable response rate (DRR), defined as the percent of 
patients with complete response (CR) or partial response (PR) maintained continuously for a 
minimum of 6 months. Tumor responses were determined according to World Health 
Organization (WHO) response criteria modified to allow patients who developed new lesions 

 
MCC18621 
 
or disease progression of existing lesions to continue the treatment and be evaluated later for 
tumor response. 
 
The DRR was 16.3% in the IMLYGIC arm and 2.1% in the GM-CSF arm in the overall study 
population. The unadjusted relative risk was 7.6 (95% CI: 2.4, 24.1), with a p-value < 0.0001. 
The median time to response was 4.1 (range: 1.2 to 16.7) months in the IMLYGIC arm. 
 
There was no statistically significant difference in overall survival (OS) between the 
IMLYGIC and the GM-CSF arms. The median OS in the overall study population was 22.9 
months in the IMLYGIC arm and 19.0 months in the GM-CSF arm (p = 0.116). 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
 
How Supplied 
• 
IMLYGIC is provided as a sterile frozen suspension in a single-use, cyclic olefin 
polymer (COP) plastic resin vial with a chlorobutyl elastomer stopper, aluminum seal, and 
polypropylene cap. Each vial contains a retrievable minimal volume of 1 mL. 
• 
The vial cap is color coded: 
o 
106 (1 million) PFU per mL is light green (NDC 55513-078-01). 
o 
108 (100 million) PFU per mL is royal blue (NDC 55513-079-01). 
 
Storage and Handling 
• 
Store and transport IMLYGIC at −90°C to −70°C (−130°F to −94°F). 
• 
Protect IMLYGIC from light. 
• 
Store IMLYGIC in the carton until use. 
• 
Thaw IMLYGIC immediately prior to administration [see Dosage and Administration 
(2.2)]. 
• 
Do not draw IMLYGIC into a syringe until immediately prior to administration [see 
Dosage and Administration (2.2)]. 
 
17 
PATIENT COUNSELING INFORMATION 
 
Advise patients and/or close contacts to: 
• 
Read the FDA-approved patient labeling (Medication Guide). 
• 
Follow instructions below to prevent viral transmission [see Warnings and Precautions 
(5.1)]: 
o 
Avoid direct contact with injection sites, dressings, or body fluids of patients. 
o 
Wear gloves when changing dressing. 
o 
Avoid touching or scratching injection sites. 
o 
Keep injection sites covered for at least the first week after each treatment visit or 
longer if 
the injection site is weeping or oozing. Replace dressing if it falls off. 

 
MCC18621 
 
o 
Dispose of used dressings and cleaning materials in household waste in a sealed 
plastic bag. 
• 
Female patients of childbearing potential should use an effective method of contraception 
to prevent pregnancy during treatment with IMLYGIC [see Contraindications (4.2) and 
Use in Specific Populations (8.1)]. 
• 
Close contacts who are pregnant or immunocompromised should not change 
dressings or clean injection sites [see Warnings and Precautions (5.1)]. 
• 
In case of accidental exposure to IMLYGIC, clean the exposed area with soap and water 
and/or a disinfectant. Patients or close contacts with suspected herpetic infections should 
contact their healthcare provider to evaluate the lesions. Suspected herpetic lesions should be 
reported to Amgen at 1-855-IMLYGIC (1-855-465-9442); patients or close contacts have the 
option of follow-up testing for further characterization of the infection [see Warnings and 
Precautions (5.1) and (5.2)]. 
 
 
 
 
IMLYGICTM (talimogene laherparepvec) 
Manufactured by: 
BioVex, Inc., a subsidiary of Amgen 
Inc. One Amgen Center Drive 
Thousand Oaks, California 91320-1799 
 
Patent: http://pat.amgen.com/Imlygic/ 
 
© 2015 Amgen Inc. All rights 
reserved. v1