Clinical trial NCT02366195
Conditions: Unresected Stage IIIb to IVM1c Melanoma
Keywords: T-VEC CD8+ cell density objective response rate unresected Melanoma
Sponsor: Amgen
Start date: 2015-04-07; Completion date: 2020-12-25
Enrollment: 112 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study is a phase 2, multi centered, single arm study designed to evaluate the correlation between cluster of differentiation 8-positive (CD8+) cell density and objective response rate in adults with unresected stage IIIB to IVM1c melanoma. This study will also evaluate the safety and tolerability profile of talimogene laherparepvec.

Detailed description:
The study will explore the hypothesis that intratumoral CD8+ cell density at baseline correlates with objective response rate in adults with unresected stage IIIB to IVMIc melanoma treated with talimogene laherparepvec.

Arms: arm 1: Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 21 days after the initial dose and every 14 days thereafter. Participants were treated with talimogene laherparepvec until they achieved a complete response, all injectable tumors had disappeared, clinically significant (resulting in clinical deterioration or requiring change of therapy) disease progression beyond 6 months of treatment, per modified World Health Organization (WHO) response criteria, or intolerance of study treatment, whichever occurred first.
Interventions: intervention 1: Talimogene Laherparepvec
Intervention descriptions: intervention 1: The initial dose of talimogene laherparepvec is up to 4.0 mL of 10\^6 PFU/mL. Subsequent doses of talimogene laherparepvec are up to 4.0 mL of 10\^8 PFU/mL.

Protocol documents:
Prot_000.pdf: 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 2 of 90 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 2, Multicenter, Open-label, 
Single-arm Trial to Evaluate the Correlation Between Objective Response Rate and 
Baseline Intratumoral CD8+ Cell Density in Subjects With Unresected Stage IIIB to 
IVM1c Melanoma Treated with Talimogene Laherparepvec, dated 21 September 2015, 
and agree to abide by all provisions set forth therein.  
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by:   
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my Subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 3 of 90 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 2, Multicenter, Open-label, Single-arm Trial to Evaluate the Correlation Between 
Objective Response Rate and Baseline Intratumoral CD8+ Cell Density in Subjects With 
Unresected Stage IIIB to IVM1c Melanoma Treated with Talimogene Laherparepvec 
Study Phase:  2 
Indication:  Unresected stage IIIB to IVM1c melanoma 
Primary Objective:  The primary objective is to explore the correlation between baseline 
intratumoral CD8+ cell density and objective response rate (ORR) in subjects with unresected 
stage IIIB to IVM1c melanoma treated with talimogene laherparepvec. 
Secondary Objective(s):   
• 
to explore the correlation between baseline intratumoral CD8+ cell density and durable 
response rate (DRR), duration of response (DOR), and changes in tumor burden 
• 
to explore the correlation between changes in intratumoral CD8+ cell density during treatment 
and ORR, DRR, DOR, and changes in tumor burden 
• 
to evaluate ORR, DOR, time to treatment failure (TTF), DRR, OS, and change in tumor 
burden during treatment 
• 
to evaluate the safety and tolerability of talimogene laherparepvec  
Exploratory Objective(s):   
• 
to investigate the correlation between the changes in the population of tumor specific 
cytotoxic T cells and immunoscore during treatment and clinical response 
• 
to identify other potential blood and tissue biomarkers which correlate with or predict clinical 
outcome to talimogene laherparepvec 
Hypotheses:   
No formal statistical hypothesis will be tested in this trial.  The study will explore the hypothesis 
that intratumoral CD8+ cell density at baseline correlates with objective response rate in subjects 
with unresected stage IIIB to IVMIc melanoma treated with talimogene laherparepvec. 
Primary Endpoint:   
Correlation between baseline intratumoral CD8+ cell density and objective response rate 
Secondary Endpoint(s):  
• 
correlation between baseline intratumoral CD8+ cell density and DRR, DOR, and changes in 
tumor burden  
• 
correlation between changes in intratumoral CD8+ cell density during treatment and ORR, 
DRR, DOR, and changes in tumor burden  
• 
efficacy endpoints:  ORR, DOR, TTF,  DRR, OS, and change in tumor burden during 
treatment 
• 
safety endpoints:  subject incidence of treatment-emergent and treatment-related adverse 
events (including all adverse events, grade ≥ 3 adverse events, serious adverse events, fatal 
adverse events, events of interest, adverse events requiring the discontinuation of study 
drug), clinically significant laboratory changes, and incidence of symptomatic herpetic lesions 
that are positive for talimogene laherparepvec 
Exploratory Endpoint(s): 
• 
correlation between the changes in the population of tumor specific cytotoxic T cells and 
immunoscore during treatment and clinical response 
• 
identification of other potential blood and tumor biomarkers which correlate with or predict 
clinical outcomes to talimogene laherparepvec 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 4 of 90 
CONFIDENTIAL 
 
 
Study Design:   
This is a phase 2, multicenter, open-label, single-arm study to evaluate biomarkers in subjects 
with unresected stage IIIB to IVM1c melanoma who are treated with talimogene laherparepvec.  
Subjects will be treated with talimogene laherparepvec until the subject has achieved a complete 
response, all injectable tumors have disappeared, clinically significant (resulting in clinical 
deterioration or requiring change of therapy) disease progression beyond 6 months of treatment, 
per modified World Health Organization (WHO) response criteria (WHO handbook for reporting 
results of cancer treatment, 1979; refer to Appendix D), or intolerance of study treatment, 
whichever occurs first.   
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene laherparepvec 
and for survival every 12 weeks (± 28 days) for up to approximately 24 months after the last 
subject is enrolled in the study.  Thereafter, subjects will be followed under an ongoing separate 
registry protocol (Study 20120139) for the long-term survival follow-up of subjects treated with 
talimogene laherparepvec.  The registry protocol will also monitor for late and long-term adverse 
events thought to be potentially related to talimogene laherparepvec and use of anti-cancer 
therapy for melanoma. 
Blood and tumor tissue samples will be collected at timepoints outlined in the Schedule of 
Assessments (Table 2).  Tumor biopsies (taken from accessible cutaneous, subcutaneous or 
nodal lesions) will be performed on an uninjected lesion on day 1 of week 1, on a different 
uninjected lesion at week 6 (if available), and at disease progression that results in treatment 
discontinuation from the lesion responsible for progression as outlined in Section 7.2.2.  
Samples will be analyzed to explore if intratumoral CD8+ cell density at baseline and its change 
during treatment is correlated with the objective response rate in subjects with unresected stage 
IIIB-IVM1c melanoma treated with talimogene laherparepvec.   
For a full description of the study design, please refer to Section 3.1. 
Sample Size:  Approximately 110 subjects will be enrolled in the study. 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria: 
Male or female ≥ 18 years of age with histologically confirmed diagnosis of stage IIIB to IVMIc 
melanoma for whom surgery is not recommended.  Subject who is treatment naïve or had 
received prior treatment for melanoma.  Subject must have measurable disease and must be a 
candidate for intralesional therapy with at least 1 injectable cutaneous, subcutaneous, or nodal 
melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in 
aggregate have a longest diameter of ≥ 10 mm.  Also, subject must have an Eastern Cooperative 
Oncology Group (ECOG) performance status of 0 or 1 and must have a serum lactate 
dehydrogenase (LDH) ≤ 1.5 X upper limit of normal and adequate hematologic, hepatic, and renal 
organ function. 
Key Exclusion Criteria: 
Subject must not have clinically active cerebral metastases, greater than 3 visceral metastases 
(this does not include lung or nodal metastases associated with visceral organs), or any bone 
metastases, primary ocular or mucosal melanoma, history or evidence of symptomatic 
autoimmune disease (such as pneumonitis, glomerulonephritis, vasculitis, or other) or history 
of autoimmune disease that required systemic treatment (ie, use of corticosteroids, 
immunosuppressive drugs or biological agents used for treatment of autoimmune 
diseases) in past 2 months prior to enrollment.  Replacement therapy (eg, thyroxine for 
hypothyroidism, insulin for diabetes mellitus) is not considered a form of systemic 
treatment for autoimmune disease.  Subject must not have evidence of clinically significant 
immunosuppression or active herpetic skin lesions or prior complications of HSV-1 infection 
(eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic systemic 
treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.  Subjects 
known to have acute or chronic active hepatitis B, hepatitis C, or human immunodeficiency virus 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 5 of 90 
CONFIDENTIAL 
 
 
infection will also be excluded.  Subjects must not have been treated previously with talimogene 
laherparepvec. 
For a full list of eligibility criteria, please refer to Section 4. 
Investigational Product Dosage and Administration: 
Talimogene laherparepvec will be administered by intralesional injection into injectable 
cutaneous, subcutaneous, and nodal lesions with or without image ultrasound guidance. 
Talimogene laherparepvec must not be administered into visceral organ metastases.  The initial 
dose of talimogene laherparepvec is up to 4.0 mL of 106 PFU/mL.  Subsequent doses of 
talimogene laherparepvec are up to 4.0 mL of 108 PFU/mL.  The second dose up to 4.0 mL of 
108 PFU/mL should be administered 21 (+5) days after the initial dose (ie, no sooner than day 
22, but should not be delayed more than 5 days after the day 21 time point).  Subsequent doses 
up to 4.0 mL of 108 PFU/mL should be given every 14 (± 3) days.  
Procedures:   
Screening: 
The following will be performed during the screening period: 
• 
confirmation that the informed consent form has been signed  
• 
review of inclusion and exclusion criteria 
• 
review of medication and medical/surgical history 
• 
physical examination 
• 
vital signs and ECOG Performance Status assessment 
• 
local laboratory tests: 
- 
hematology panel 
- 
chemistry panel 
- 
serum lactate dehydrogenase (LDH) 
- 
prothrombin time (PT) (or international normalization ratio [INR]) and partial 
thromboplastin time (PTT) 
- 
serum or urine pregnancy test for female subjects of childbearing potential 
• 
radiographic tumor imaging and clinical tumor assessment 
• 
recording of concomitant medications  
• 
recording/reporting of any serious adverse events that occur after subject signs informed 
consent 
Treatment: 
The following will be performed during the treatment period: 
• 
vital signs 
• 
physical examination 
• 
ECOG Performance Status assessment  
• 
local laboratory tests 
- 
hematology panel 
- 
chemistry panel 
• 
archived tumor tissue for BRAFV600E/K mutation testing and biomarker analyses 
• 
central laboratory tests 
- 
swabs of cold sore, vesicles and other lesions suspected to be herpetic origin (if any) for 
qPCR analysis of talimogene laherparepvec DNA  
- 
blood samples for herpes simplex virus (HSV) serostatus  


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 6 of 90 
CONFIDENTIAL 
 
 
- 
blood samples for biomarker analysis  
- 
tumor biopsies for biomarker analyses 
• 
radiographic tumor imaging, clinical tumor assessment, and tumor response assessment  
• 
photographs of all visible cutaneous and subcutaneous tumor lesions (select sites only) 
always within 3 days of the treatment visit starting from the first treatment visit 
• 
recording of concomitant medications, adverse events, and serious adverse events at each 
visit 
• 
administration of talimogene laherparepvec at day 1 of each treatment cycle  
Safety Follow-Up Visit: 
The following will be performed during the safety follow-up visit: 
• 
physical examination 
• 
vital signs and ECOG Performance Status assessment 
• 
local laboratory tests: 
- 
hematology panel 
- 
chemistry panel 
- 
serum or urine pregnancy test for female subjects of childbearing potential  
• 
central laboratory tests: 
- 
swabs of cold sores, vesicles, and other lesions  suspected to be herpetic in origin 
(if any) for qPCR analysis of talimogene laherparepvec DNA  
• 
radiographic tumor imaging, clinical tumor assessment, and tumor response only if subject 
has discontinued study treatment for reason other than disease progression or death and if 
not performed within 4 weeks (+1 week) of the safety follow-up visit 
• 
recording of concomitant medications, adverse events, and serious adverse events 
Long-term Follow-up/End of Study:  
All subjects who permanently discontinue talimogene laherparepvec for any reason other than 
withdrawal of full consent or death will be contacted by telephone or clinic visit to assess survival, 
adverse events thought by the investigator to be potentially related to talimogene 
laherparepvec, and use of anti-cancer therapies for melanoma every 12 weeks (± 28 days) 
following the safety follow-up visit until death, subject withdraws full consent, or up to 24 months 
after the last subject is enrolled in the study. 
If subject has discontinued talimogene laherparepvec for reason other than disease progression 
or death, radiographic tumor imaging, clinical tumor assessments, ECOG Performance Status 
assessment, assessment of swabs of lesions of suspected herpetic origin by qPCR for 
talimogene laherparepvec DNA, and tumor response assessments will be performed until 
documented disease progression beyond 6 months of treatment, per modified WHO response 
criteria (Appendix D), or until the start of a new anticancer therapy or end of study, whichever 
the earliest. 
After the long term follow-up period of this study has ended, subjects who end the study for any 
reason other than death or withdrawal of full consent will be followed for survival under an 
ongoing separate registry protocol (Study 20120139) that is in place for the long-term follow-up of 
all subjects treated with talimogene laherparepvec in clinical trials.  The registry protocol will also 
monitor for late and long-term adverse events thought to be potentially related to talimogene 
laherparepvec and use of anti-cancer therapies for melanoma. 
Reporting Exposure to Talimogene Laherparepvec:  
Reporting potential or known unintended exposure to talimogene laherparepvec, suspected 
related signs or symptoms, and detection of talimogene laherparepvec in a subject’s household 
member, caregiver, or healthcare provider as specified in Section 9.4 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 7 of 90 
CONFIDENTIAL 
 
 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 2).   
Statistical Considerations:   
All analyses will be descriptive with no formal hypothesis testing.  The primary objective of the 
study is to explore the correlation between baseline intratumoral CD8+ cell density and objective 
response rate (ORR).  The sample size was selected based on practical considerations.  The 
adequacy of the sample size is discussed in Section 10.2.  
The main goals of the primary analysis are to evaluate the correlation between baseline 
intratumoral CD8+ cell density and ORR,DRR,DOR, and changes in tumor burden, in addition to 
the correlation between changes in intratumoral CD8+ cell density during treatment and 
ORR,DRR,DOR, and changes in tumor burden.  The timing of the primary analysis will be when 
all subjects have had the opportunity to complete 12 months of treatment with talimogene 
laherparepvec. 
An interim analysis to evaluate the study objectives will be conducted on approximately 
the first 50 subjects who received at least 1 dose of talimogene laherparepvec, with the 
biomarker recorded at baseline, and have had the opportunity to be in the study (treatment 
or follow-up) for 6 months.   
The final analysis will occur either 24 months after the last subject has been enrolled or when 
the last subject discontinues the study treatment and has had the opportunity to complete the 
safety follow-up, whichever is later.   
Descriptive statistics will be provided for demographic, safety, efficacy, and biomarkers as 
appropriate.  In general, the safety analysis set will be used for all safety analyses.  The safety 
analyses include incidence of treatment-emergent and treatment-related adverse events 
(all adverse events, ≥ grade 3 adverse events, serious adverse events, fatal adverse events and 
adverse events defined as events of interest). 
The efficacy analysis will be conducted using the safety analysis set as well, unless otherwise 
specified.  The ORR will be estimated with the associated 95% CI.  Descriptive statistics for DRR, 
time to treatment failure, changes in tumor burden, and OS will be provided.  In addition, DOR 
and changes in tumor burden for responders will also be summarized. 
The correlation between a baseline biomarker and response rate will be evaluated.  The 
functional manner in which the response rate may vary with the biomarker is unknown; therefore 
multiple functional relationships may be examined.  Pearson’s correlation coefficient (r) will be 
estimated between the biomarker change and the maximum decrease in index lesions to 
evaluate the correlation between changes in a biomarker post-treatment and the effect of 
treatment on measurable lesions, in addition to correlating biomarker changes with objective 
response using logistic regression. 
For further details on the statistical analysis, please refer to Section 10.  
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 4.0, 31 October 2013   


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 8 of 90 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S
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Talimogene 
Laherparepvec
Up to 4 mL
106 PFU/mL at Day 1  
followed by 
108 PFU/mL 21 (+5) days 
later,  then every 14 (±3) 
days 
N=110
30 (+7) 
days after 
last dose
Screening 
28 days 
prior to 
enrollment
Talimogene laherparepvec 
dosing until CR, all injectable 
lesions have disappeared, PD per 
modified WHO criteria, or 
intolerance for treatment, 
whichever occurs first.
L
O
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T
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M
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Every 12 
 (± 28 days)
weeks after 
safety follow-up for 
up to approximately 
24 months after the 
last subject is 
enrolled


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 9 of 90 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ALT 
alanine aminotransferase  
AST  
aspartate aminotransferase   
BRAF, BRAFV600, 
BRAFV600E/K 
v-raf murine sarcoma viral oncogene homolog B1, BRAF V600 
mutation, BRAF V600E/K mutations 
CI 
confidence interval 
CNS 
central nervous system 
CR  
complete response 
CRF 
case report form 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CZ  
Crystal Zenith 
DOR 
duration of response 
DRR 
durable response rate 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
End of Study for 
Individual Subject 
defined as the date the subject withdraws full consent from the 
study, completes the long-term follow-up, or dies, whichever is 
earlier 
End of Study (end of trial) defined as the time when the last subject is assessed or receives an 
intervention for evaluation in the study.  The end of study will occur 
when the last subject discontinues talimogene laherparepvec and 
has had the opportunity to complete the safety follow-up visit or the 
long term follow-up visit, whichever occurs later 
End of Treatment 
defined as the last dose of the protocol-specified treatment plus 
30 days after the last dose 
ETO system 
electronic trial operation system:  An electronic system that is used 
to facilitate the operations of a clinical trial through the collection of 
study related data.  
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HLA 
human leukocyte antigen 
HR 
hazard ratio 
HSV, HSV-1, HSV-2 
herpes simplex virus, herpes simplex virus type 1, herpes simplex 
virus type 2 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 10 of 90 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
INR 
international normalization ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
institutional review board 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NA 
not applicable 
ND 
not done 
NPV 
negative predictive value 
ORR 
objective response rate 
OS 
overall survival 
PD 
disease progression 
PDn 
nonclinically relevant disease progression 
PDr 
clinically relevant disease progression 
PET 
positron emission tomography 
PFU 
plaque-forming unit 
PPV 
positive predictive value 
PR 
partial response 
PSP 
Pregnancy Surveillance Program 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QC 
every cycle 
qPCR 
real-time polymerase chain reaction 
Q4C 
every fourth cycle 
RBC 
red blood cells 
ROC 
receiver operating characteristic 
SAE(s) 
serious adverse event(s) 
SOC 
system organ class 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 11 of 90 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  
(ICH Guideline [E6]).  Example of source data include:  subject 
identification. 
Study Day 1 
defined as the first day that protocol-specified investigational product 
is administered to the subject 
TTF 
time to treatment failure 
ULN 
upper limit of normal 
USA 
United States of America 
WBC 
white blood cells 
WHO 
World Health Organization 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 12 of 90 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 8 
Study Glossary .................................................................................................................. 9 
1. 
OBJECTIVES ......................................................................................................... 16 
1.1 
Primary ....................................................................................................... 16 
1.2 
Secondary .................................................................................................. 16 
1.3 
Exploratory ................................................................................................. 16 
2. 
BACKGROUND AND RATIONALE ........................................................................ 16 
2.1 
Melanoma ................................................................................................... 16 
2.2 
Talimogene Laherparepvec Investigational Product Background .............. 21 
2.3 
Rationale .................................................................................................... 23 
2.4 
Clinical Hypotheses .................................................................................... 23 
3. 
EXPERIMENTAL PLAN ......................................................................................... 23 
3.1 
Study Design .............................................................................................. 23 
3.2 
Number of Sites .......................................................................................... 25 
3.3 
Number of Subjects .................................................................................... 25 
3.4 
Replacement of Subjects ............................................................................ 25 
3.5 
Estimated Study Duration ........................................................................... 25 
3.5.1 
Study Duration for Subjects ........................................................ 25 
3.5.2 
End of Study ............................................................................... 26 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 26 
4.1 
Inclusion and Exclusion Criteria ................................................................. 26 
4.1.1 
Inclusion Criteria ......................................................................... 26 
4.1.2 
Exclusion Criteria ........................................................................ 28 
5. 
SUBJECT ENROLLMENT ..................................................................................... 29 
6. 
TREATMENT PROCEDURES ............................................................................... 30 
6.1 
Classification of Product ............................................................................. 30 
6.2 
Investigational Product ............................................................................... 30 
6.2.1 
Amgen Investigational Product Talimogene 
Laherparepvec ........................................................................... 30 
6.2.1.1 
Dosage, Administration, and Schedule .................... 31 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 33 
6.3 
Other Protocol-required Therapies ............................................................. 35 
6.4 
Concomitant Therapy ................................................................................. 35 
6.5 
Other Treatment Procedures ...................................................................... 36 


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6.6 
Medical Devices ......................................................................................... 37 
6.7 
Product Complaints .................................................................................... 37 
6.8 
Excluded Treatments and/or Procedures During Study Period .................. 37 
7. 
STUDY PROCEDURES ......................................................................................... 38 
7.1 
Schedule of Assessments .......................................................................... 38 
7.2 
General Study Procedures ......................................................................... 43 
7.2.1 
Screening and Enrollment .......................................................... 44 
7.2.2 
Treatment ................................................................................... 45 
7.2.3 
Safety Follow-up Visit ................................................................. 47 
7.2.4 
Long-term Follow-up/End of Study ............................................. 48 
7.2.5 
Reporting Exposure to Talimogene Laherparepvec ................... 49 
7.2.6 
Optional Photography Substudy (Select Sites Only) .................. 49 
7.3 
Biomarker Development ............................................................................. 49 
7.3.1 
Blood Samples ........................................................................... 50 
7.3.2 
Tumor Tissue Samples ............................................................... 50 
7.4 
Pharmacogenetic Studies ........................................................................... 51 
7.5 
Sample Storage and Destruction ................................................................ 52 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 53 
8.1 
Subjects’ Decision to Withdraw .................................................................. 53 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 53 
8.3 
Reasons for Removal From Treatment or Study ........................................ 54 
8.3.1 
Reasons for Removal From Treatment ...................................... 54 
8.3.2 
Reasons for Removal From Study ............................................. 54 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 54 
9.1 
Adverse Events .......................................................................................... 54 
9.1.1 
Definition of Adverse Events ...................................................... 54 
9.1.2 
Definition of Serious Adverse Events ......................................... 55 
9.2 
Reporting of Adverse Events ...................................................................... 56 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria .................................................................. 56 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 57 
9.3 
Pregnancy and Lactation Reporting ........................................................... 58 
9.4 
Reporting of Exposure to Talimogene Laherparepvec ............................... 59 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 59 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 59 
10.1.1 
Study Endpoints ......................................................................... 59 
10.1.1.1 
Primary Endpoint ..................................................... 59 
10.1.1.2 
Secondary Endpoints ............................................... 60 
10.1.1.3 
Exploratory Endpoints .............................................. 60 
10.1.2 
Analysis Sets .............................................................................. 60 


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10.1.3 
Covariates and Subgroups ......................................................... 61 
10.2 
Sample Size Considerations ...................................................................... 61 
10.3 
Planned Analyses ....................................................................................... 62 
10.3.1 
Interim Analyses ......................................................................... 62 
10.3.2 
Primary Analysis ......................................................................... 63 
10.3.3 
Final Analysis ............................................................................. 63 
10.4 
Planned Methods of Analysis ..................................................................... 63 
10.4.1 
Primary Endpoint ........................................................................ 63 
10.4.2 
Secondary Endpoint (s) .............................................................. 64 
10.4.3 
Safety Endpoints ........................................................................ 64 
10.4.4 
Exploratory Endpoints ................................................................ 65 
10.5 
Handling of Missing and Incomplete Data .................................................. 65 
11. 
REGULATORY OBLIGATIONS ............................................................................. 65 
11.1 
Informed Consent ....................................................................................... 65 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 66 
11.3 
Subject Confidentiality ................................................................................ 67 
11.4 
Investigator Signatory Obligations .............................................................. 67 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 68 
12.1 
Protocol Amendments and Study Termination ........................................... 68 
12.2 
Study Documentation and Archive ............................................................. 68 
12.3 
Study Monitoring and Data Collection ........................................................ 69 
12.4 
Investigator Responsibilities for Data Collection ........................................ 70 
12.5 
Language.................................................................................................... 70 
12.6 
Publication Policy ....................................................................................... 71 
12.7 
Compensation ............................................................................................ 71 
13. 
REFERENCES ....................................................................................................... 72 
14. 
APPENDICES ........................................................................................................ 76 
List of Tables 
Table 1.  Talimogene Laherparepvec Injection Volume Guideline 
Based on Tumor Size .............................................................................. 32 
Table 2.  Schedule of Assessments ................................................................................ 39 
Table 3.  Laboratory Analytes ......................................................................................... 43 
Table 4.  Expected 95% Confidence Intervals by Various True ORRs ........................... 62 
Table 5.  Definition of Index Lesion Tumor Response Including New Lesions ............... 87 
Table 6.  Definition of Nonindex Lesion Tumor Response .............................................. 88 
Table 7.  Matrix for Determining the Overall Response at Each Assessment 
Point ......................................................................................................... 89 


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List of Appendices  
Appendix A.  Additional Safety Assessment Information ................................................ 77 
Appendix B.  Sample Serious Adverse Event Report Form ............................................ 78 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 81 
Appendix D.  Modified World Health Organization (WHO) Response Criteria ................ 83 
Appendix E.  Eastern Cooperative Oncology Group Performance Status 
Scale ........................................................................................................ 90 
 


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1. 
OBJECTIVES 
1.1 
Primary 
The primary objective is to explore the correlation between baseline intratumoral 
CD8+ cell density and objective response rate (ORR) in subjects with unresected stage 
IIIB to IVM1c melanoma treated with talimogene laherparepvec. 
1.2 
Secondary 
The secondary objectives are as follows: 
• 
to explore the correlation between baseline intratumoral CD8+ cell density and 
durable response rate (DRR), duration of response (DOR), and changes in tumor 
burden 
• 
to explore the correlation between changes in intratumoral CD8+ cell density during 
treatment and ORR, DRR, DOR, and changes in tumor burden 
• 
to evaluate ORR, DOR, time to treatment failure (TTF), DRR, OS, and change in 
tumor burden during treatment 
• 
to evaluate the safety and tolerability of talimogene laherparepvec  
1.3 
Exploratory 
The exploratory objectives are as follows: 
• 
to investigate the correlation between the changes in the population of tumor specific 
cytotoxic T cells and immunoscore during treatment and clinical response 
• 
to identify other potential blood and tissue biomarkers which correlate with or predict 
clinical outcome to talimogene laherparepvec 
2. 
BACKGROUND AND RATIONALE 
2.1 
Melanoma 
Cutaneous melanoma is the fifth most common cancer in men and the seventh most 
common cancer in women in the United States of America (USA), with an estimated 
73,870 new cases and 9,940 deaths expected in 2015 (Siegel et al, 2015).  In Europe, 
the annual incidence of melanoma is somewhat lower than that in the USA, with a crude 
rate of approximately 14 per 100,000 as compared to 20 per 100,000 in the USA, but is 
the sixth most common cancer among women (Ferlay et al, 2013; Siegel et al, 2014).  In 
Europe as a whole, approximately 100,442 new cases were diagnosed in 2012 
(Ferlay et al, 2013).  The incidence of melanoma is increasing rapidly worldwide, with a 
270% increase in the USA between 1973 and 2002.  This increase is the most rapid of 
any cancer with the exception of lung cancer in women (Jemal et al, 2006; 
Ries et al, 2000). 


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Melanoma that has spread to multiple regional nodal sites (stage III) is infrequently 
curable with standard therapy.  For those with multiple or clinically detectable nodal 
metastases or in-transit/satellite lesions (stages lllB and lllC), the 5-year survival rate 
ranges between 40% (for stage lllC disease) to 59% (for stage lllB disease) 
(Balch et al, 2009).  For patients with distant spread to skin, nodes, or visceral organs 
(stage IV disease), the 5-year survival rates are generally low, ranging from 20% for 
stage M1a disease (skin, subcutaneous or nodes only), 5% to 10% for stage M1b 
disease (lung only), and < 5% for stage M1c disease (other visceral lesions or high 
serum lactate dehydrogenase [LDH]); median survival is 12 months for stages M1a and 
M1b disease and 4 to 6 months for stage M1c disease (O'Day and Boasberg, 2006; 
Tannous et al, 2005). 
Until recently, traditional nonsurgical therapies for unresectable or advanced melanoma 
in adults included chemotherapy (dacarbazine, temozolomide, or other agents either 
alone or in combination), or interleukin-2.  Although some regimens produced objective 
responses, they were usually short-lived (Anderson et al, 1995; Chapman et al, 1999; 
Wagner et al, 2000; Middleton et al, 2000).  Response rates for interleukin-2 ranged 
from 10% to 20% (Rosenberg et al, 1994; Sparano et al, 1993; Atkins et al, 1999), with a 
small proportion achieving prolonged response, but its administration requires close 
patient monitoring in specialized facilities with well-trained staff based on the notable 
toxicity profile associated with its administration. 
Recently, the Food and Drug Administration (FDA), European Commission, and other 
regulatory agencies have approved 6 novel therapies for advanced melanoma:  an 
immune stimulatory agent, ipilimumab (Yervoy®, 2015), pembrolizumab (Keytruda®, 
2015) and nivolumab (Opdivo®, 2015) and 3 agents for use in patients with BRAF 
mutant melanoma, a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor, 
vemurafenib (Zelboraf®, 2015), the BRAF inhibitor dabrafenib (Tafinlar™, 2013) and the 
MEK inhibitor trametinib (Mekinist™, 2014).  The studies upon which approvals for 
ipilimumab and vemurafenib were based demonstrated improved survival compared to 
control treatments.  The pivotal study of ipilimumab showed an overall survival (OS) 
improvement in subjects with human leukocyte antigen (HLA)-A2*0201 genotype 
previously treated metastatic melanoma as compared with a gp100 peptide vaccine 
(Hodi et al, 2010; Yervoy 2015).  The median overall survival (OS) was 10.0 months in 
the group that received ipilimumab in combination with the gp100 peptide vaccine and 
6.4 months in the group that received gp100 peptide vaccine alone (hazard ratio 


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[HR] = 0.68, p < 0.001) (Hodi et al, 2010).  Approximately 8% more patients survived 
2 years in the ipilimumab arm than in the control arm (21.6% vs 13.7%).  The objective 
response rate was 5.7% vs 1.5%, respectively (p = 0.04).  Similar results were reported 
for another study conducted in previously untreated subjects with metastatic melanoma 
who received ipilimumab and dacarbazine vs placebo and dacarbazine 
(Robert et al, 2011).  
The pivotal vemurafenib study showed improved OS and objective response rates in a 
substantial proportion of subjects with previously untreated metastatic melanoma with 
the BRAFV600E mutation who received vemurafenib vs standard dacarbazine 
(Chapman et al, 2011).  The median OS was 13.6 months in the vemurafenib group and 
9.4 months in the dacarbazine group (OS data for dacarbazine patients who crossed 
over to vemurafenib treatment were censored at the time of crossover) 
(Chapman et al, 2012).  The hazard ratio for death was 0.62 (95% Confidence interval 
[Cl]:  0.49, 0.77).  The objective response rate was 48% vs 5%, respectively (p < 0.001) 
(Chapman et al, 2011).   
In 2013, regulatory agencies also approved the BRAF inhibitor dabrafenib 
(Tafinlar™, 2013) and the MEK  inhibitor trametinib (Mekinist™, 2014), both in BRAFV600 
mutant advanced melanoma.  Each agent showed a benefit in progression-free survival 
compared to dacarbazine in Phase 3 trials (Hauschild et al, 2012; Flaherty et al, 2012a).  
Additionally, dabrafenib and trametinib were approved recently as a combination therapy 
for BRAF-mutant (V600 E/K) unresectable or metastatic melanoma. (Flaherty et al, 
2012b; Long et al, 2015; Robert et al, 2015).  
Nivolumab, an anti-PD-1 monoclonal antibody, demonstrated improvement in 
1-year OS in treatment naïve subjects with wild-type BRAF advanced melanoma 
compared  to dacarbazine (73% versus 42%; HR 0.42, 99.8% CI 0.25-0.73) 
(Robert et al, 2015); improved ORR  in subjects  previously treated with either 
ipilimumab or BRAF inhibitor versus dacarbazine or carboplatin with paclitaxel 
(32% vs 10%) (Weber et al, 2015), and improved PFS and ORR (either alone or in 
combination with ipilimumab) compared to  ipilimumab alone in treatment naïve 
subjects (Larkin et al, 2015). 
Pembrolizumab, is a monoclonal antibody that targets PD-1 protein, improved PFS 
and OS versus ipilimumab in subjects with advanced melanoma. Six-month 
progression-free rates were 47% and 46%, for pembrolizumab administered every 
2 and 3 weeks, versus 27% for ipilimumab (HR 0.58; P<0.001 for both 


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pembrolizumab regimens versus ipilimumab). Twelve-months OS rates were 74%, 
68%, and 58%, respectively (HR 0.63, P=0.0005 for pembrolizumab every 2  weeks 
and 0.69, P=0.004 for pembrolizumab every  3 weeks) (Robert et al, 2015) 
While the approval of these newer agents represents a clear milestone in the treatment 
of advanced melanoma, limitations still exist.  The two-year overall survival following 
ipilimumab remains only approximately 20%, and the drug is associated with severe and 
potentially fatal immunological adverse effects (Hodi et al, 2010).  Although not as 
common and severe as with ipilimumab, a wide range of immune related toxicities 
has been reported with permbrolizumab and nivolumab, which include 
pneumonitis, hepatitis, colitis, nephritis, thyroid dysfunction and others 
(Larkin et al, 2015; Robert et al, 2015; Weber et al, 2015).  Vemurafenib, dabrafenib, 
and trametinib are indicated only in patients with BRAFV600 mutations, and are 
associated with early development of resistance in most cases, leading to short 
durations of response.  The safety profiles of vemurafenib and dabrafenib include 
increased incidence of cutaneous squamous cell carcinoma or high grade 
keratoacanthoma in almost 20% of patients treated with vemurafenib and > 5% of 
patients treated with dabrafenib (Zelboraf®, 2015; Tafinlar™, 2013).  Additionally, 
grade 2 or higher dermatologic reactions including rash, pruritus, and hyperkeratosis are 
common with both agents.  Trametinib is associated with cuneiform dermatitis, 
peripheral edema, hypertension, decreased cardiac ejection fraction, and ocular events 
(Mekinist™, 2014).  Thus, the need remains for additional treatment options for patients 
with advanced melanoma (including those with regional and/or distant metastases). 
Biomarkers of melanoma prognosis and treatment effect and toxicity have been 
increasingly well studied in the past few years.  BRAF mutations have been identified 
that predict for response to BRAF inhibitors (Hoeflich et al, 2009).  Immunologic-based 
biomarkers are likely to be important for immunotherapies, including talimogene 
laherparepvec.  Many tumors, including melanoma, are heavily infiltrated by 
inflammatory and lymphoid cells which can be used as prognostic and predictive 
biomarkers and a variety of “immunoscores” have been employed in attempts to capture 
the maximal prognostic value of intratumoral immune cells (Galon et al, 2012).  These 
immunoscores are generally algorithms that combine the number of one or more types 
of immune cells observed in the tumor with information on the localization of the immune 
cells within the tumor (eg, proximity to blood vessels, invasive margin).  The most 
commonly used immunoscore is based on the density of cytotoxic CD8+ T-lymphocytes 


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in the center and in the invasive margins of tumor (Mlecnik et al, 2011).  The prognostic 
value of immunoscores composed of a combination of immunohistochemical staining 
densities for both intratumoral CD3+ / CD8+ T cells, combined with the location of the 
cells either in the invasive margin or central tumor, has been well documented in colon 
cancer and was shown to have a prognostic significance superior to that of the AJCC 
TNM classification system (Galon et al, 2006, Galon et al, 2012).  An international effort 
is underway to qualify an immunoscore as a predictive and prognostic biomarker for 
other cancers (Galon et al, 2014).   
Infiltrating T cells have also been shown to be prognostic for melanoma (Erdag et al, 
2012).  The authors’ primary analysis was performed using an immunoscore that 
counted CD45+ cells (lymphocytes) and combined the number of cells with the pattern of 
localization near blood vessels as detected by CD34+ staining.  They further showed 
that the single cell type most strongly correlated with survival was CD8+ cells which is 
why we have chosen to focus on CD8+ cells as the primary biomarker analysis in the 
current study.  Since talimogene laherparepvec is assumed to work via activation of 
tumor specific T cells, it is important to understand whether the number of infiltrating 
T cells at baseline impacts drug efficacy, especially since approximately one-third of 
melanomas have few or no infiltrating T cells (Erdag et al, 2012).  
The postulated dual mechanism of action of talimogene laherparepvec comprises a 
direct oncolytic effect achieved by infection and replication of the virus in tumor tissue 
resulting in tumor cell lysis and local release of tumor antigens, and enhancement of a 
systemic immune response by expression of GM-CSF in the tumor microenvironment to 
recruit and activate antigen presenting cells.  Activated antigen presenting cells initiate 
an adaptive antitumor immune response, ultimately leading to a persistent immunity.  In 
the current study we will measure tumor antigen-specific T cell responses induced by 
talimogene laherparepvec treatment in order to further explore mechanisms of action.   
Furthermore, baseline tumor mutational load and corresponding neoantigen 
signatures have been shown to correlate with responsiveness to immunotherapy 
(Rizvi et al, 2015; Snyder et al, 2014).  It will be important to understand if tumor 
mutational load can be predictive for response to talimogene laherparepvec as 
well. 
In addition, we will also explore the possibility that altered viral replication might affect 
response.  Deletion of the ICP34.5 gene is one of the means by which talimogene 
laherparepvec was engineered to limit replication to tumor cells.  ICP34.5 normally 


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interferes with the PKR (double-stranded RNA activated protein kinase) pathway which 
cells activate to protect themselves from viral infection.  This PKR pathway is typically 
inactivated in tumors, but the degree of residual PKR signaling in tumor cells may 
influence replication of talimogene laherparepvec.  Analysis of mutations in the PKR 
pathway and possibly other tumor cell pathways will be performed in this study in order 
to explore whether these mutations may affect response to treatment. 
2.2 
Talimogene Laherparepvec Investigational Product Background  
Talimogene laherparepvec is an intralesionally delivered oncolytic immunotherapy 
comprised of a genetically engineered HSV-1(herpes simplex virus type 1) that 
selectively replicates in tumor tissue (Talimogene Laherparepvec Investigator’s 
Brochure).  The neurovirulence factor ICP34.5 and the ICP47-encoding gene are 
functionally deleted in the virus, while the gene for human granulocyte macrophage 
colony-stimulating factor (GM-CSF) is inserted.  The role of ICP47 is to block antigen 
presentation to major histocompatibility complex class I molecules by blocking the 
transporter associated with antigen processing 1 and 2.  This deletion also allows the 
increased expression of the US11 gene.  This promotes virus growth in cancer cells 
without decreasing tumor selectivity. 
Additionally, the virus contains the coding sequence for human GM-CSF, a pleiotropic 
cytokine involved in the stimulation of cellular immune responses by promoting the 
generation of dendritic cells from blood monocytes (Demir et al, 2003; Lonial, 2004; 
Conti and Gessani, 2008).  Dendritic cells have the capacity to capture antigens, migrate 
in response to chemotactic stimuli, and induce proliferative responses and Th1 cytokine 
production in CD4+ and CD8+ T-lymphocytes (Hart, 1997; Steinman, 2001; Ikeda et al, 
2004; Paul, 2007).  These Th1-type cytokines have the capacity to produce 
proinflammatory responses, eradicate tumors, and perpetuate autoimmune responses 
(Nishimura et al, 2000; Ikeda et al, 2004; Knutson and Disis, 2005).   
Clinical data currently available has provided evidence of talimogene laherparepvec’s 
efficacy in patients with regionally and distantly metastatic melanoma (Talimogene 
Laherparepvec Investigator’s Brochure).  In particular, a high rate of complete response 
(CR) was achieved (16% in the phase 2 study with talimogene laherparepvec in stage 
lllC to IV melanoma) (Senzer et al, 2009; Talimogene Laherparepvec Investigator’s 
Brochure).  Moreover, responses were observed in both injected and uninjected sites, 
including visceral sites.  Responses were seen most often in earlier stage disease, 
including stage lllB/C and stage IVM1a, and in disease with lower visceral burden. 


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In the open-label, randomized, phase 3 study of talimogene laherparepvec versus 
subcutaneously administered GM-CSF in stages lllB, lllC, and IV unresectable 
melanoma, talimogene laherparepvec or GM-CSF was administered until CR, clinically 
significant disease progression, intolerable side effects, 12 months of therapy without an 
objective response, or withdrawal of consent (Study 20110263; OPTiM).  The primary 
endpoint of the study is durable response rate, defined as the rate of subjects with an 
objective response by central review (CR or partial response [PR]) lasting continuously 
for 6 months and starting any time within 12 months of initiating therapy. 
Primary analysis of the OPTiM Study showed a statistically significant difference 
between the rate of durable response among subjects treated with talimogene 
laherparepvec (16%; 95% CI:  12%, 21%) versus those treated with GM-CSF (2%; 95% 
CI:  0%, 5%) (p-value < 0.0001).  Overall response rate was also improved from 
6% with GM-CSF to 26% with talimogene laherparepvec (P < 0.0001, descriptive).  
Similarly, 11% of patients had a CR in the talimogene laherparepvec arm vs. 
< 1% in the GM-CSF arm.  In the event-driven primary OS analysis (secondary end 
point), median OS with talimogene laherparepvec treatment was 23.3 months 
compared with 18.9 months with GM-CSF treatment (HR, 0.79 [95% CI, 0.62‒1.00]; 
P = 0.051) (Andtbacka et al, 2015).  At the final planned analysis of OS which 
happened when last enrolled subject completed 3 years of follow-up, median OS 
was 23.3 months in the talimogene laherparepvec arm and 18.9 months in the 
GM-CSF arm (HR, 0.79; 95% CI, 0.62‒1.00; P=0.049), (descriptive) (Andtbacka et al, 
2015). 
The most common side effects were fatigue, chills, and pyrexia.  Serious adverse events 
occurred in 36% of the talimogene laherparepvec subjects and 21% of the GM-CSF 
subjects.  The only grade 3/4 adverse event occurring in ≥ 2% of patients was 
cellulitis (talimogene laherparepvec, n=6 [2.1%]; GM-CSF, n=1 [< 1%]).  Of 10 fatal 
events in the talimogene laherparepvec arm, none were considered 
treatment-related per investigator and most (80%) were associated with disease 
progression with the exception of sepsis in the setting of salmonella infection and 
myocardial infarction (Andtbacka et al, 2015). 
Refer to the latest version of the Talimogene Laherparepvec Investigator’s Brochure, 
for additional information. 


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CCI


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 24 of 90 
CONFIDENTIAL 
 
 
laherparepvec.  Subjects with unresected stage IIIB to IVM1c melanoma who meet the 
eligibility criteria outlined in Section 4 will be considered for participation in this study.  
Talimogene laherparepvec will be administered by intralesional injection into injectable 
cutaneous, subcutaneous, and nodal tumors initially at a dose of 106 Plaque-Forming 
Unit (PFU)/mL at study day 1 followed by a dose of 108 PFU/mL 21 (+5 ) days after the 
initial dose and every 14 (± 3) days thereafter.  Subjects will be treated with talimogene 
laherparepvec until the subject has achieved a CR, all injectable tumors have 
disappeared, clinically significant (resulting in clinical deterioration or requiring change of 
therapy) disease progression beyond 6 months of treatment, per modified World Health 
Organization (WHO) response criteria (WHO handbook for reporting results of cancer 
treatment, 1979; refer to Appendix D), or intolerance of study treatment, whichever 
occurs first.  Due to the mechanism of action, subjects may experience transient growth 
of existing tumors or the appearance of new tumors prior to achieving maximal clinical 
benefit of talimogene laherparepvec.  Therefore, dosing should be continued for at least 
6 months from the time of initial dose regardless of progression provided that the subject 
is able to tolerate the treatment and does not develop deterioration of health status 
requiring other treatment. 
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene 
laherparepvec for survival, adverse events thought by the investigator to be 
potentially related to talimogene laherparepvec, and use of anticancer therapies 
for melanoma every 12 weeks (± 28 days) for up to approximately 24 months after the 
last subject is enrolled  in the study.  Thereafter, subjects will be followed under an 
ongoing separate registry protocol (Study 20120139) for the long-term survival follow-up 
of subjects treated with talimogene laherparepvec.  The registry protocol will also 
monitor for late and long-term adverse events thought by the investigator to be 
potentially related to talimogene laherparepvec and use of anti-cancer therapies for 
melanoma. 
Blood and tumor tissue samples will be collected at timepoints outlined in the Schedule 
of Assessments (Table 2).  Tumor biopsies will be performed from an uninjected lesion 
on day 1 of week 1, from a different uninjected lesion at week 6 (if available), and from 
the lesion responsible for progression at the time of disease progression that 
results in treatment discontinuation as outlined in Section 7.2.2.  Samples will be 
analyzed to explore if intratumoral CD8+ cell density at baseline and its change during 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 25 of 90 
CONFIDENTIAL 
 
 
treatment is correlated with the objective response rate in subjects with unresected 
stage IIIB-IVM1c melanoma treated with talimogene laherparepvec.   
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 50 sites in Europe and the USA will participate in the study.  Additional 
sites and regions may be added to the study as necessary.  Sites that do not enroll 
subjects within 6 months of site initiation may be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  Approximately 
110 subjects will be enrolled in the study.  Refer to Section 10.2 for sample size 
considerations. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or from the study will not be 
replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The subject enrollment period is planned for approximately 17 months.   
The duration of the screening period for each subject will be up to 28 days.  The duration 
of treatment will vary for each subject.  Subjects will be treated with talimogene 
laherparepvec until the subject has achieved a CR, all injectable tumors have 
disappeared, clinically relevant (resulting in clinical deterioration or requiring change in 
therapy) disease progression beyond 6 months of treatment, per modified WHO 
response criteria (Appendix D), or intolerance of study treatment, whichever occurs first.  
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene 
laherparepvec and for survival, adverse events thought by the investigator to be 
potentially related to talimogene laherparepvec, and use of anti-cancer therapy for 
melanoma every 12 weeks (± 28 days) for up to approximately 24 months after the last 
subject is enrolled in the study.  The estimated average per-subject study duration is 
approximately 32 months. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 26 of 90 
CONFIDENTIAL 
 
 
After the end of the long term follow up subjects who end the study for any reason 
other than death or withdrawal of full consent will continue to be followed for 
survival under an ongoing separate registry protocol (Study 20120139).  The 
registry protocol will also monitor for adverse events thought by the investigator 
to be potentially related to talimogene laherparepvec and use of anti-cancer 
therapies for melanoma. 
3.5.2 
End of Study 
Primary Completion:  the time when the last subject is assessed or receives an 
intervention for the purpose of final collection of data for the primary analysis.  The 
primary completion is anticipated to occur when all subjects have had the opportunity to 
complete 12 months of treatment. 
End of Trial:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study.  The end of study will occur 24 months after the last subject 
has been enrolled or when the last subject discontinues talimogene laherparepvec and 
has had the opportunity to complete the safety follow-up visit, whichever occurs later. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.1).  
4.1 
Inclusion and Exclusion Criteria  
4.1.1 
Inclusion Criteria 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures  
102 
Male or female age ≥ 18 years at the time of informed consent 
103 
Histologically confirmed diagnosis of melanoma 
104 
Subject with stage IIIB to IVM1c melanoma for whom surgery is not 
recommended 
105 
Subject who is treatment naïve or had received prior treatment for melanoma. 
Any systemic treatment for melanoma must have been completed at least 
28 days prior to enrollment  


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 27 of 90 
CONFIDENTIAL 
 
 
106 
Candidate for intralesional therapy (ie, disease is appropriate for direct injection 
or through the use of ultrasound guidance) defined as one of the following:   
• 
at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion 
≥ 10 mm in longest diameter, or 
• 
multiple injectable melanoma lesions that in aggregate have a longest 
diameter of ≥ 10 mm 
107 
Measurable disease defined as one or more of the following: 
• 
at least 1 melanoma lesion that can be accurately and serially measured in at 
least 2 dimensions and for which the greatest diameter is ≥ 10 mm as 
measured by contrast-enhanced or spiral computed tomography (CT) scan, 
magnetic resonance imaging (MRI), or ultrasound for nodal/soft tissue 
disease (including lymph nodes) 
• 
at least 1 ≥ 10 mm superficial cutaneous or subcutaneous melanoma lesion 
as measured by calipers 
• 
multiple superficial melanoma lesions which in aggregate have a total 
diameter of ≥ 10 mm 
108 
Serum lactate dehydrogenase (LDH) levels ≤ 1.5 X upper limit of normal (ULN) 
within 28 days prior to enrollment  
109 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(see Appendix E) 
110 
Adequate organ function determined within 28 days prior to enrollment, defined 
as follows: 
• 
absolute neutrophil count ≥ 1500/mm3 
• 
platelet count ≥ 75,000/mm3 
• 
hemoglobin ≥ 8 g/dL without need for hematopoietic growth factor or 
transfusion support 
• 
serum creatinine ≤ 1.5 x ULN  
• 
serum bilirubin ≤ 1.5 x ULN 
• 
aspartate amino transferase (AST) ≤ 2.5 x ULN 
• 
alanine amino transferase (ALT) ≤ 2.5 x ULN 
• 
alkaline phosphatase ≤ 2.5 x ULN 
• 
serum albumin ≥ 2.5 g/dL 
• 
prothrombin time (PT) ≤ 1.5 x ULN (or international normalization ratio [INR] 
≤ 1.3)* 
• 
partial thromboplastin time (PTT) ≤ 1.5 x ULN* 
* Prolongation in INR, PT, and PTT when the result is from therapeutic 
anticoagulation treatment are permitted for subjects whose injectable lesions 
are cutaneous and/or subcutaneous such that direct pressure could be 
applied in the event of excessive bleeding. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 28 of 90 
CONFIDENTIAL 
 
 
4.1.2 
Exclusion Criteria 
201 
Clinically active cerebral metastases. Subjects with up to 3 cerebral metastases 
may be enrolled, provided that all lesions have been adequately treated with 
stereotactic radiation therapy (including Gamma Knife) or resection, with no 
evidence of progression and have not required steroids for at least two months 
prior to enrollment. 
202 
Greater than 3 visceral metastases (this does not include lung metastases or 
nodal metastases associated with visceral organs).  For subjects with ≤ 3 visceral 
metastases, no lesion > 3 cm and liver lesions must be stable for at least 
1 month prior to enrollment. 
203 
Bone metastases 
204 
Primary ocular or mucosal melanoma 
205 
History or evidence of symptomatic autoimmune disease (such as 
pneumonitis, glomerulonephritis, vasculitis, or other), or history of 
autoimmune disease that required systemic treatment (ie, use of 
corticosteroids, immunosuppressive drugs or biological agents used for 
treatment of autoimmune diseases) in past 2 months prior to enrollment.  
Replacement therapy (eg, thyroxine for hypothyroidism, insulin for 
diabetes mellitus) is not considered a form of systemic treatment for 
autoimmune disease. 
206 
Evidence of clinically significant immunosuppression such as the following: 
• 
primary immunodeficiency state such as Severe Combined 
Immunodeficiency Disease 
• 
concurrent opportunistic infection 
• 
receiving systemic immunosuppressive therapy (> 2 weeks), including oral  
steroid doses > 10 mg/day of prednisone or equivalent during the 2 months 
prior to enrollment 
207 
Active herpetic skin lesions or prior complications of HSV-1 infection (eg, herpetic 
keratitis or encephalitis) 
208 
Requires intermittent or chronic systemic (intravenous or oral) treatment with an 
antiherpetic drug (eg, acyclovir), other than intermittent topical use 
209 
Previous treatment with talimogene laherparepvec 
211 
Currently receiving treatment with another investigational device or drug study, or 
less than 28 days since ending treatment with another investigational device or 
drug study(s) 
212 
Other investigational procedures while participating in this study are excluded 
213 
Known to have acute or chronic active hepatitis B infection 
214 
Known to have acute or chronic active hepatitis C infection 
215 
Known to have human immunodeficiency virus infection 
216 
History of other malignancy within the past 3 years with the following exceptions: 
• 
malignancy treated with curative intent and with no known active disease 
present for ≥ 3 years before enrollment and felt to be at low risk for 
recurrence by the treating physician 
• 
adequately treated non-melanoma skin cancer without evidence of disease 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 29 of 90 
CONFIDENTIAL 
 
 
• 
adequately treated cervical carcinoma in situ without evidence of disease 
• 
adequately treated breast ductal carcinoma in situ without evidence of 
disease 
• 
prostatic intraepithelial neoplasia without evidence of prostate cancer 
• 
adequately treated urothelial papillary noninvasive carcinoma or carcinoma 
in situ 
217 
Subject has known sensitivity to any of the products or components to be 
administered during dosing 
218 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject’s and investigator’s knowledge 
219 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen medical monitor, if consulted, would pose a risk to subject 
safety or interfere with the study evaluation, procedures, or completion 
220 
Subject previously has entered this study 
221 
Female subject is pregnant or breast-feeding, or planning to become pregnant 
during study treatment and through 3 months after the last dose of talimogene 
laherparepvec 
222 
Female subject of childbearing potential who is unwilling to use acceptable 
method(s) of effective contraception during study treatment and through 
3 months after the last dose of talimogene laherparepvec 
Note:  Women not of childbearing potential are defined as:  Any female who is 
post-menopausal (age > 55 years with cessation of menses for 12 or more 
months or < than 55 years with postmenopausal status confirmed by 
follicle-stimulating hormone [FSH] in the postmenopausal range), or who have 
had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Note:  Acceptable methods of effective contraception are defined in the informed 
consent form.  Where required by local laws and regulations, additional 
country-specific requirements are outlined in a country-specific protocol 
supplement at the end of the Appendix Section of the protocol.  
223 
Sexually active subjects and their partners unwilling to use male or female 
latex condom to avoid potential viral transmission during sexual contact 
while on treatment and within 30 days after treatment with talimogene 
laherparepvec. 
5. 
SUBJECT ENROLLMENT 
Before subjects may be entered into the study, Amgen requires a copy of the site’s 
written institutional review board/independent ethics committee (IRB/IEC) approval of the 
protocol, informed consent form, and all other subject information and/or recruitment 
material, if applicable (see Section 11).  All subjects must personally sign and date the 
informed consent form before commencement of study-specific activities/procedures 
(ie, non-standard of care procedures). 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 30 of 90 
CONFIDENTIAL 
 
 
All subjects who enter into the screening period for the study (defined as the point when 
the subject signs the informed consent) must be registered as screened subjects in the 
electronic trial operation (ETO) system and will receive a unique subject identification 
number before any study-specific procedures are performed.  This number will be used 
to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.  The subject identification number must remain 
constant throughout the entire clinical study; it must not be changed at the time of 
rescreening or enrollment. 
Subjects who are determined not eligible after screening must be screen-failed in the 
ETO system and the reason for the screen-failure provided.  Subjects who do not meet 
all eligibility criteria may be rescreened once at the discretion of the investigator.  If a 
subject is being rescreened, he or she may need to reconsent to the study to ensure that 
the IRB/IEC-approved main informed consent form is signed within 28 days of 
enrollment.  Subjects who are determined not eligible after rescreen must be 
screen-failed in the ETO system and the reason for the screen-failure provided.  
Subjects may be enrolled only once into this study. 
Upon confirmation of eligibility, the site staff will use the ETO system to enroll a subject.  
A subject will be considered enrolled when the investigator confirms that the subject has 
met all eligibility criteria and the subject is registered as enrolled in the ETO system.  
The investigator is to document confirmation of eligibility in the subject’s medical record 
and in the case report form (CRF). 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product 
The Amgen Investigational Product used in this study is talimogene laherparepvec.  
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the description, storage, preparation, 
and administration of talimogene laherparepvec. 
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product Talimogene Laherparepvec 
Talimogene laherparepvec will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures.  Talimogene 
laherparepvec is supplied as a sterile frozen liquid in a single-use 2-cc Crystal Zenith 
(CZ resin) vial with a gray Fluorotec-coated chlorobutyl elastomer stopper, aluminum 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 31 of 90 
CONFIDENTIAL 
 
 
seal, and polypropylene cap.  Each vial contains a minimum of 1.0 mL talimogene 
laherparepvec at either 10⁶ PFU/mL  or 10⁸ PFU/mL concentrations.  The supply for 
10⁶ PFU/mL concentration will be packaged separately from the supply for 10⁸ PFU/mL 
concentration.  Additional details on talimogene laherparepvec packaging and 
formulation are provided in the Investigational Product Instruction Manual. 
6.2.1.1 
Dosage, Administration, and Schedule 
Talimogene laherparepvec must be prepared and administered by a qualified healthcare 
professional.  Subjects should be assessed clinically for adverse events/toxicity prior to 
each dose using the Common Terminology Criteria for Adverse Events (CTCAE) 
version 3.0 (Appendix A).  Complete blood count with differential and chemistry panels 
including liver function laboratory tests (such as ALT, AST, and total bilirubin) should be 
obtained according to the Schedule of Assessments (see Table 2) and the results should 
be checked before scheduled doses as per the requirements described in the 
Schedule of Assessments.  Dosing will occur only if these test values are acceptable, 
per Section 6.2.1.2. 
Talimogene laherparepvec will be administered by intralesional injection only into 
injectable cutaneous, subcutaneous, and nodal tumors, with or without image ultrasound 
guidance.  Talimogene laherparepvec must not be administered into visceral organ 
metastases.  The initial dose of talimogene laherparepvec is up to 4.0 mL of 
106 PFU/mL.  Subsequent doses of talimogene laherparepvec are up to 4.0 mL of 
108 PFU/mL. 
The first cycle of talimogene laherparepvec will be 21 (+ 5) days.  Subsequent cycles of 
talimogene laherparepvec will be 14 (± 3) days.  On day 1 of cycle 1 the first dose of 
talimogene laherparepvec will be up to 4.0 mL of 106 PFU/mL.  The second injection up 
to 4.0 mL of 108 PFU/mL, should be administered 21 (+ 5) days after the initial injection 
(ie, no sooner than day 22 but should not be delayed more than 5 days after the 21-day 
time point).  Subsequent injections up to 4.0 mL of 108 PFU/mL should be given every 
14 (± 3) days. 
The maximum volume of talimogene laherparepvec administered at any dose is 4.0 mL 
for any individual lesion.  The maximum dose in any treatment is 4.0 mL.  Investigators 
are encouraged to use the maximum amount whenever lesions allow.  Dose reduction 
for adverse events is not allowed.  However, if in the course of administration of 
talimogene laherparepvec the subject cannot tolerate the full dose due to an 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 32 of 90 
CONFIDENTIAL 
 
 
injection-related adverse event such as pain, the total volume given should be recorded, 
and the reason for intolerance should be documented as an adverse event. 
The recommended volume of talimogene laherparepvec to be injected into the tumor(s) 
is dependent on the size of the tumor(s) and should be determined according to the 
injection volume guideline in Table 1.  The tumor size assessment should be done by 
clinical exam using ruler or caliper for cutaneous and palpable and protruding 
subcutaneous and nodal lesions, or by measurements under ultrasound of deep-seated 
subcutaneous and nodal lesions. 
Table 1.  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 
At baseline, if there are ≥ 2 lesions, one cutaneous, subcutaneous or nodal lesion 
(ie, the lesion considered lowest priority for injection) should be left uninjected at least 
until it is biopsied at week 6  (see Section 7.2.2).  (No biopsy will be taken at week 6 
for subjects with 1 lesion present at baseline).  All other reasonably injectable lesions 
(cutaneous, subcutaneous, and nodal disease that can be injected with or without 
ultrasound guidance) should be injected with the maximum dosing volume available on 
an individual dosing occasion (Table 1).  On each treatment day, prioritization of 
injections is recommended as follows (aside from leaving one lesion uninjected until it is 
biopsied at week 6): 
• 
any new injectable tumor that has appeared since the last injection 
• 
by tumor size, beginning with the largest tumor  
• 
any previously uninjectable tumor(s) that is now injectable, including the previously 
uninjected lesion(s) after the biopsy at week 6 if now injectable 
It is recommended that each lesion should receive the maximum amount possible to 
inject due to tumor properties at each visit before moving on to the next lesion, using the 
prioritization model above and the injection volume guideline based on tumor size per  
Table 1.  Lesions should be injected until the maximum volume per day (4.0 mL) has 
been reached or there are no further injectable lesions, whichever comes first. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 33 of 90 
CONFIDENTIAL 
 
 
A subject will be treated with talimogene laherparepvec until the subject has achieved a 
CR, all injectable tumors have disappeared, clinically significant (resulting in clinical 
deterioration or requiring change of therapy) disease progression beyond 6 months of 
treatment, per modified World Health Organization (WHO) response criteria 
(Appendix D), or intolerance of study treatment, whichever occurs first.  Due to the 
mechanism of action, subjects may experience growth in existing tumors or the 
appearance of new tumors prior to maximal clinical benefit of talimogene laherparepvec.  
Therefore, dosing should be continued for at least 6 months from the time of initial dose, 
provided that the subject has no evidence of clinically significant deterioration of health 
status requiring discontinuation of treatment with talimogene laherparepvec and is able 
to tolerate the treatment. 
The dose, start date, and lot number of talimogene laherparepvec are to be recorded on 
the electronic case report form (eCRF). 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Dose reductions of talimogene laherparepvec are not permitted, other than with respect 
to a reduction in the volume injected due to a disease response. 
If a subject experiences any of the following treatment-related toxicities, talimogene 
laherparepvec administration should be delayed until the toxicity has resolved to at least 
CTCAE grade 1 or has returned to baseline: 
• 
grade 2 or greater immune-mediated adverse events, with the exception of vitiligo 
• 
grade 2 or greater allergic reactions 
• 
any other grade 3 or greater hematologic or non-hematologic toxicity  
Subjects who are receiving talimogene laherparepvec may not receive systemic 
antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir), but may receive a topically 
administered antiherpetic drug more than 20 cm from a talimogene laherparepvec 
injection site.  If a subject requires treatment with systemic antiherpetic drugs 
(eg, acyclovir, valacyclovir, famciclovir) talimogene laherparepvec should be 
witheld and the investigator or designee should notify the Amgen medical monitor 
as soon as possible.  Subject may be allowed to continue treatment after 
discussion between the Amgen medical monitor and the investigator to determine 
the appropriateness of treatment resumption. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 34 of 90 
CONFIDENTIAL 
 
 
Dosing should be permanently discontinued if, in the opinion of the investigator, the 
subject develops clinical evidence of any systemic herpes infection (such as encephalitis 
or disseminated infection).  
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) 
for related toxicities, talimogene laherparepvec dosing must be withheld until the 
corticosteroid dose has decreased to ≤ 10 mg prednisone daily (or equivalent). 
All necessary supportive care shall be available to subjects except for those listed in 
Section 6.8.  Talimogene laherparepvec treatment should be continued based on the 
potential benefit/risk assessment of the subject. 
If talimogene laherparepvec treatment is delayed by >1 week, that dose will be deemed 
to have been missed and the subject will proceed to the next scheduled treatment visit.  
If talimogene laherparepvec dosing is delayed by more than 4 weeks from the date of 
the planned dose (ie, approximately 6 weeks from the previous dose) due to the 
occurrence of an adverse event that is considered related to talimogene laherparepvec, 
the subject must be permanently withdrawn from talimogene laherparepvec treatment.  
If talimogene laherparepvec dosing is delayed by more than 4 weeks from the date of 
the planned dose (ie, approximately 6 weeks from the previous dose) for reasons other 
than treatment-related toxicity, the case must be reviewed by the Amgen medical 
monitor in conjunction with the investigator to determine if the subject can resume 
talimogene laherparepvec therapy. 
Talimogene laherparepvec is to be permanently discontinued for subjects meeting any of 
the following criteria: 
• 
The subject, for any reason, requires treatment with another anticancer therapeutic 
agent for treatment of the study disease (other than the exceptions noted in 
Section 6.5).  In this case, discontinuation from the treatment occurs immediately 
upon introduction of the new agent.  
• 
Clinically relevant disease progression beyond 6 months of treatment occurs as 
defined per the modified WHO response criteria (Appendix D).  
• 
A grade 2 or greater immune-mediated adverse event (with the exception of vitiligo) 
or allergic reactions attributed to talimogene laherparepvec that would require a dose 
delay of greater than 4 weeks from the date of the planned dose (ie, approximately 
6 weeks from the previous dose). 
Note:  immune-mediated glomerulonephritis, vasculitis, and pneumonitis and 
exacerbation of psoriasis have been observed in subjects receiving talimogene 
laherparepvec in clinical trials.  Most of these subjects had a history of other 
autoimmune disease and/or prior treatment with agents that offered plausible 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 35 of 90 
CONFIDENTIAL 
 
 
alternative etiologies, however, immune-mediated adverse events can potentially 
involve any organ system.  
• 
Any other talimogene laherparepvec-related non-hematologic or hematologic 
toxicities grade 3 or greater occur that, in the opinion of the investigator, would 
require a dose delay of greater than 4 weeks from the date of the planned dose 
(ie, approximately 6 weeks from the previous dose). 
• 
The subject develops clinical evidence of any systemic herpes infection (such as 
encephalitis or disseminated infection). 
• 
A female subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception (for those subjects who are able to conceive) including but not 
limited to male or female latex condom to avoid potential viral transmission 
during sexual contact. 
• 
A female subject breast feeds while on study treatment. 
• 
Concurrent medical illness that, in the judgment of the investigator, would make 
continued treatment with talimogene laherparepvec dangerous for the subject. 
For additional information related special warnings and precautions for the use of 
talimogene laherparepvec please refer to the latest version of the Talimogene 
Laherparepvec Investigator’s Brochure. 
6.3 
Other Protocol-required Therapies 
All other protocol-required therapies including topical anesthetic or an injectable local 
anesthetic medications used for pretreatment of the talimogene laherparepvec injection 
site that are commercially available are not provided or reimbursed by Amgen (except if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these protocol-required therapies. 
Additional details regarding these protocol-required therapies are provided in the IPIM. 
6.4 
Concomitant Therapy  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 
All prescription and nonprescription concomitant medication administered up to 28 days 
prior to enrollment, on an ongoing basis after enrollment, as well as changes in such 
concomitant medication, and any new concomitant medication taken while the subject is 
on study, should be recorded on the appropriate case report form (CRF) until 30 days 
(+ 7 days) after the last dose of talimogene laherparepvec.  The therapy name, 
indication, dose, unit, frequency, start date, and stop date will be collected. 


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Investigators should use supportive care agents in compliance with their respective 
regional label.  Investigators may not use supportive care agents as part of a separate 
clinical trial. 
6.5 
Other Treatment Procedures 
Treatment with talimogene laherparepvec may result in the reduction of tumor burden 
such that surgical resection of previously unresected lesion becomes possible.  
Investigators may choose to resect lesions which become suitable for resection to 
render the subject free of macroscopic disease.  Additionally, biopsies will be taken of 
cutaneous, subcutaneous or nodal lesions for tumor analysis during study.  In the event 
of a complete response, residual visible cutaneous or subcutaneous index lesions must 
be documented by representative biopsy to not contain viable tumor.  If a subject 
undergoes resection of the lesion in the event other than CR, the investigator or 
designee should notify the sponsor medical monitor as soon as possible and the 
procedure should be recorded in the source document and eCRF.  In these instances, if 
the response of other lesions is at least PR (if other lesions remain), the response 
should be designated PR with the date of surgery as the date of response.  If no residual 
disease remains following surgery, this should also be noted in the eCRF, the response 
definition again being PR with the date of surgery as the date of response.  If no 
viable melanoma was found in the surgical specimen and all other tumor lesions 
resolved completely (if were present), the response definition will be CR with the 
date of surgery as the date of response. 
Local palliative radiation treatment for relief of various symptoms including, but not 
limited to, bleeding or pain associated with the underlying disease will be permitted at 
any time during the study.  Subjects with local symptoms suggestive of disease 
progression should be evaluated for tumor response per modified WHO response 
criteria (see Appendix D) prior to the administration of palliative radiotherapy.  If a 
subject undergoes local radiation, the investigator or designee should notify the sponsor 
medical monitor as soon as possible and the treatment should be recorded in the source 
document and eCRF.  
If a subject demonstrates evidence of recurrent or new central nervous system (CNS) 
metastases, talimogene laherparepvec should be withheld and the investigator or 
designee should notify the Amgen medical monitor as soon as possible.  Subjects may 
be allowed to remain on protocol after discussion between the Amgen medical monitor 
and the investigator to determine the appropriateness of treatment resumption provided 


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Protocol Number:  20120325 
Date:  21 September 2015 
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CNS lesions can be treated with stereotactic radiotherapy (including GammaKnife) or 
resection and if there is no change in the baseline ECOG performance status.  Subjects 
may be allowed to reinitiate talimogene laherparepvec following treatment of CNS 
metastases while receiving dexamethasone or a similar corticosteroid at no more than 
1.5 mg dexamethasone (or 10 mg prednisone or equivalent) per day.  If higher doses of 
a steroid are used, talimogene laherparepvec must be held until that dose level is 
reached during the period of steroid tapering. 
6.6 
Medical Devices 
Medical devices (eg, syringes, sterile needles, alcohol prep pads), that are commercially 
available are not usually provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these devices.   
6.7 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of any investigational or non-investigational product(s) or device(s). 
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.8 
Excluded Treatments and/or Procedures During Study Period  
Subjects must not use any of the following therapies during screening or treatment 
period: 
• 
other investigational agents or procedures   
• 
concurrent experimental or approved anti-tumor therapies other than study drug and 
radiation therapy required for palliation (as noted in Section 6.5)  
• 
chronic oral or systemic steroid medication use at a dose of >10 mg/day of 
prednisone or equivalent (with the exception of treatment for adverse events 
[see Section 6.2.1.2] and CNS metastases [see Section 6.5]).  Steroids with low 
systemic absorption [eg, triamcinolone hexacetonide] injected into a joint space is 
allowed) 
• 
antiherpetic drugs (eg, acyclovir), other than if topically administered > 20 cm from a 
talimogene laherparepvec injection site.  If a subject requires treatment with a 
systemic antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir) 
talimogene laherparepvec should be witheld and the investigator or designee 
should notify the Amgen medical monitor as soon as possible.  Subject may 
be allowed to continue treatment after discussion between the Amgen medical 
monitor and the investigator to determine the appropriateness of treatment 
resumption. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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• 
Subjects must not schedule any elective surgeries during the treatment period and 
for at least 30 days after the last administration of study drug.  If a subject undergoes 
any unexpected surgery during the course of the study, study treatment must be 
withheld and the investigator or designee should notify the sponsor medical monitor 
as soon as possible.  A subject may be allowed to resume study drug if both the 
investigator and sponsor medical monitor agree to restart study therapy. 
The exclusion criteria describe other medications and procedures which are prohibited in 
this study (refer to Sections 4.1.2). 
There are no prohibited therapies and procedures during the post treatment long-term 
follow-up period. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
The schedule of assessments for the study is summarized in Table 2 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 39 of 90 
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Table 2.  Schedule of Assessments 
  
Screening
a 
Treatment Period
b 
Follow-up Period 
Cycle
t 
≤ 28 days 
1 
2 
3 
4 
5 
6 
7 
8 
Cycle 8 and 
Beyond
t 
Safety
c 
Survival
d 
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
30 (+7) Days 
Every 12 
(±28 days) 
Weeks 
GENERAL & SAFETY ASSESSMENTS  
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications
e 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse and Serious Adverse Events
f 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Thought to Be Related 
to Talimogene Laherprepvec
f 
 
X 
 
 
 
 
 
 
 
 
 
X 
Physical Exam
g 
X 
X 
 
 
 
 
X 
 
 
Q6C 
X 
 
Vital Signs
h 
X 
X 
X 
 
X 
 
X 
 
X 
Q2C 
X 
 
ECOG Performance Status
w 
X 
X 
 
 
 
 
X 
 
 
Q6C 
X 
 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
X 
Anti-cancer therapy for melanoma
x 
 
 
 
 
 
 
 
 
 
 
X 
X 
LOCAL LABORATORY ASSESSMENTS  
 
Urine or Serum Pregnancy Test
i 
X 
  
 
  
 
  
  
 
  
 
X 
 
Hematology
j 
 
X 
X 
X 
X 
 
 
 
X 
 
Q4C 
X 
 
Chemistry
k 
X 
X 
X 
X 
 
 
 
X 
 
Q4C 
X 
 
Serum LDH 
X 
 
 
 
 
 
 
 
 
 
  
 
PT (or INR) and PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
CENTRAL LABORATORY ASSESSMENTS  
 
Archived Tumor Tissue for  Biomarker 
Analysis and BRAF
 V600E/K l 
 
Within 28 days after enrollment 
 
 
Swab of Herpetic Lesion for qPCR
m 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
X 
X 
Blood for HSV Serostatus
n 
 
Within 3 days prior to dose at day 1 of week 1, week 6, and week 12 
 
 
Page 1 of 2 
Footnotes defined on next page. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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Table 2.  Schedule of Assessments 
  
Screening
a 
Treatment Period
b 
Follow-up Period 
Cycle
t 
≤ 28 days 
1 
2 
3 
4 
5 
6 
7 
8 
Cycle 8 and 
Beyond 
Safety
c 
Survival
d 
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
30 (+7) Days 
 
12 (±28 days) 
Weeks 
Blood for Biomarker Analysis
o 
 
Within 3 days prior to dose at day 1 of week 1, week 6, week 12, week 24 
 
 
Tumor Biopsy for Biomarker Analysis
p 
 
Within 5 days prior to dose at day 1 of week 1, within 7 days prior to dose at 
week 6 and within 7 days after the documentation of disease progression 
followed by treatment discontinuation  
 
 
TUMOR/RESPONSE ASSESSMENTS 
 
Clinical Tumor Assessments
q 
X 
Day 1 of week 12 and then every 12 weeks until PD or start of new anticancer 
therapy  
X 
X 
Radiological Tumor Assessments
r 
X 
Day 1 of week 12 and then every 12 weeks until PD or start of new anticancer 
therapy 
X 
X 
Photographs of all Visible Tumor Lesions
s 
(Select Sites Only) 
 
X 
X 
 
X 
 
X 
 
X 
Q2C 
 
 
DOSING 
 
Talimogene Laherparepvec 
Administration
t 
 
X 
X 
X 
X 
X 
X 
X 
X 
QC 
 
 
REPORTING EXPOSURE TO TALIMOGENE LAHERPAREPVEC  
 
Exposure of Household member, 
Healthcare provider, or close contact
u 
 
X 
 
 
 
 
 
 
 
 
 
 
REPORTING PREGNANCY/LACTATION 
 
Reporting of Pregnancy or Lactation
v 
 
X 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
a  Screening assessments to be performed within 28 days prior to enrollment, unless otherwise indicated. 
b  During the treatment period assessments and procedures can be performed within 3 days of the planned visit unless otherwise specified. 
c  Safety follow-up will be performed 30 (+7) days after the last dose of talimogene laherparepvec. 
d  All subjects who permanently discontinue talimogene laherparepvec for any reason other than withdraw of full consent or death will be contacted by telephone, or 
clinic visit, to assess survival.  Adverse events deemed by the investigator to be potentially related to talimogene laherparepvec will also be recorded. 
Follow-up will occur every 12 weeks (± 28 days) following the safety follow-up visit until death, subject withdraws full consent, or up to 24 months after the last subject 
is enrolled in the study.  After the long term follow-up period has ended, subjects who end the study for any reason other than death or withdrawal of full consent will 
be followed for survival under an ongoing separate registry protocol (Study 20120139) that is in place for the long-term follow-up of subjects treated with talimogene 
laherparepvec in clinical trials. 
e  All concomitant medications that are administered after the subject has signed informed consent through 30 (+7) days after the last administration of talimogene 
laherparepvec will be recorded in the case report form.  Concomitant medications should be assessed on an ongoing basis and recorded at each subject visit.  Only 
subsequent anticancer therapy for melanoma will be recorded during the long term follow-up survival assessment period.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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f  All nonserious adverse events (related or not related to talimogene laherparepvec) that occur after the first dose through 30 (+7) days after the last 
administration of talimogene laherparepvec will be recorded in the case report form.  In addition, all adverse events deemed by the investigator to be potentially 
related to talimogene laherparepvec will be recorded in the case report form through the survival follow-up.  Adverse events should be assessed on an 
ongoing basis and recorded at each subject visit.  All serious adverse events that occur after the subject has signed the informed consent through 30 (+7) days after 
the last administration of talimogene laherparepvec will be reported to Amgen and recorded in the case report form.  Serious adverse events must be reported to 
Amgen within 24 hours of discovery. 
g  Physical examination as per standard of care. 
h  Vital signs (blood pressure, heart rate, and temperature) must be performed at screening, prior to talimogene laherparepvec administration on day 1 of cycle 
1, 2, and 4, then every other cycle (Q2C) until end of treatment, and at the safety follow-up visit. 
i  Urine or serum pregnancy test must be performed on females of childbearing potential within 3 days prior to enrollment and at the safety follow-up visit.  Note:  
Additional on-treatment pregnancy testing may be performed at the investigator’s discretion or as defined in a country-specific protocol supplement at the end of the 
Appendix Section of the protocol as required per local laws and regulations. 
j  Blood samples for hematology will be collected at screening, within 3 days prior to talimogene laherparepvec administration on day 1 of cycles 1, 2, and 3,then every 
4th cycle (Q4C) until end of treatment, and at the safety follow-up visit.  Results must be reviewed prior to scheduled dose of study treatment. 
k  Blood samples for chemistry will be collected at screening, within 3 days prior to talimogene laherparepvec administration on day 1 of cycles 1, 2, and 3, then every 
4th cycle (Q4C) until end of treatment, and at the safety follow-up visit.  Results must be reviewed prior to scheduled dose of study treatment. 
l   Archived formalin-fixed paraffin-embedded tumor tissue (block or unstained tumor slide) from either the primary tumor or a metastatic lesion, and the associated 
pathology reports should be submitted to the central laboratory within 28 days after enrollment for biomarker analyses.  BRAF V600E/K mutation status may be obtained 
in a number of ways.  For previously Known BRAF V600E/K Tumor Status,  BRAF V600E/K tumor status result, obtained from a local laboratory prior to screening for this 
study will be acceptable.  For previously Unknown BRAF V600E/K Tumor Status, archived formalin-fixed paraffin-embedded tumor tissue (block or unstained tumor 
slide) from either the primary tumor or a metastatic lesion should be analyzed at a local laboratory or submitted to the central laboratory within 28 days after 
enrollment. 
m  Swabs of any lesion suspected to be herpetic in origin will be collected as follows:  Subject should return to clinic within 3 days of the occurrence of reportable lesion 
suspected to be herpetic in origin, such as cold sores or vesicles.  The lesion should be evaluated by the investigator and swabbed if herpetic infection is suspected.  
A qPCR analysis will be performed at a central lab on the swab to evaluate whether the talimogene laherparepvec DNA is detectable in the sample. 
n  Blood sample for HSV serostatus will be collected (within 3 days prior to talimogene laherparepvec administration) at day 1 of week 1 [Cycle 1], week 6 [Cycle 3], 
and week 12 [Cycle 6].   
o  Blood sample for biomarker analysis will be collected (within 3 days prior to talimogene laherparepvec administration) at day 1 of week 1 [Cycle 1], week 6 [Cycle 3], 
week 12 [Cycle 6], and week 24 [Cycle 12]. 
p  Tumor biopsy from cutaneous, subcutaneous or nodal lesions for biomarker analysis should not be collected prior to the subject being enrolled.  Tumor 
biopsy should be collected (within 5 days prior to first talimogene laherparepvec administration) from one lesion at day 1 of week 1 [Cycle 1] and, if there are 
≥ 2 lesions at baseline and one is left uninjected as described in Section 6.2.1.1, from an uninjected lesion within 7 days prior to dose at day 1 of week 6 [Cycle 3].  
Also within 7 days after documentation of disease progression followed by treatment discontinuation from the available cutaneous, subcutaneous or nodal 
lesion responsible for PD and easily accessible for biopsy with or without unltrasound guidance.  Note:  uninjected lesion biopsied at day 1 of week 6 [Cycle 3] 
must be different lesion from the lesion biopsied at day 1 of week 1 [Cycle 1]. 
q  Investigator’s clinical measurement of cutaneous, subcutaneous, or nodal tumor by caliper at screening, day 1 of week 12 (± 1 week) [Cycle 6] and then every 
12 weeks (± 1 week), or more frequently if clinically indicated, until clinically relevant disease progression beyond 6 months of treatment (per modified WHO response 
criteria, Appendix D) or until the start of a new anticancer therapy.  The screening measurement must be done within 28 days prior to enrollment and will be used as 
baseline.  If subject discontinues talimogene laherparepvec for reason other than disease progression or death, clinical tumor measurements are to be performed at 
safety follow-up visit (if not performed within previous 4 weeks [+ 1 week]) and every 12 weeks (±1week) during the long term follow-up period until clinically relevant 
disease progression beyond 6 months of treatment (per modified WHO response criteria, Appendix D) or until the start of a new anticancer therapy. 


Product:  Talimogene Laherparepvec 
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r  Radiographic imaging (CT, PET/CT, MRI, or US) of the chest, abdomen, and pelvis, and all other sites of disease, and CT scan or MRI of brain (only if symptoms or 
signs suggestive of CNS metastasis are present) at screening, day 1 of week 12 (± 1 week) [Cycle 6] and then every 12 weeks (± 1 week), or more frequently if 
clinically indicated, until clinically relevant disease progression beyond 6 months of treatment (per modified WHO response criteria, Appendix D or until the start of a 
new anticancer therapy.  The screening assessment must be done within 28 days prior to enrollment and will be used as baseline.  If subject discontinues talimogene 
laherparepvec for reason other than disease progression or death, radiographic imaging is to be performed at safety follow-up visit (if not performed within previous 
4 weeks [+ 1 week]) and every 12 weeks (±1week) during the long term follow-up period until clinically relevant disease progression beyond 6 months of treatment 
(per modified WHO response criteria, Appendix D) or until the start of a new anticancer therapy. 
s  At select sites only, photographs of all visible cutaneous and subcutaneous tumor lesions at Cycle 1, Cycle 2, and every second subsequent cycle until end of 
treatment (always within 3 days prior to investigational product administration).  See Section 7.2.6  
t  The first cycle of talimogene laherparepvec will be 21 (+ 5) days.  Subsequent cycles of talimogene laherparepvec will be 14 (± 3) days (QC).  On day 1 of cycle 1, 
the first dose of talimogene laherparepvec will be up to 4.0 mL of 106 PFU/mL.  The second injection up to 4.0 mL of 108 PFU/mL should be administered 21 (+ 5) 
days after the initial injection (ie, no sooner than day 22 but should not be delayed more than 5 days after the 21-day time point).  Subsequent injections up to 4.0 mL 
of 108 PFU/mL should be given every 14 (± 3) days.  Subjects will be treated with talimogene laherparepvec until the subject has achieved a complete response, all 
injectable tumors have disappeared, clinically significant (resulting in clinical deterioration or requiring change of therapy) disease progression beyond 6 months of 
treatment, per modified WHO response criteria (Appendix D), or intolerance of study treatment, whichever occurs first. 
u  Reporting potential or known unintended exposure to talimogene laherparepvec:  If a household member, caregiver, or healthcare provider who has had close 
contact with the subject is suspected to have been exposed to talimogene laherparepvec (eg,  have or who have had signs or symptoms suspected to be herpetic 
origin or accidentally exposed to talimogene laherparepvec), report the potential or known unintended exposure to talimogene laherparepvec, suspected related 
signs or symptoms, and detection of talimogene laherparepvec in a subject’s household member, caregiver, or healthcare provider as specified in Section 9.4 
V  Reporting of pregnancy or lactation:  If a pregnancy occurs in a female subject, or female partner of a male subject, or a lactation case occurs while the subject is 
taking talimogene laherparepvec, the case must be reported to Amgen Global Patient Safety through 3 months after the last dose of talimogene laherparepvec as 
specified in Section 9.3 
w  ECOG Performance Status will be assessed at screening, day 1 of Cycle 1, then every 12 weeks (ie, every sixth cycle) alongside the tumor response 
assessments until the end of tumor response assessments per study protocol. 
x  Anti-cancer therapy may include any systemic, regional, and local therapies for melanoma disease. 
 


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Protocol Number:  20120325 
Date:  21 September 2015 
Page 43 of 90 
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Refer to the applicable supplemental laboratory manuals for detailed collection and 
handling procedures for laboratory samples. 
7.2 
General Study Procedures  
A signed and dated IRB/IEC-approved informed consent must be obtained before any 
study specific procedures are performed.  Procedures that are part of routine care are 
not considered study specific procedures and may be used at screening to determine 
eligibility.  All subjects will be screened for eligibility before enrollment.  Only eligible 
subjects will be enrolled into the study. 
During treatment, assessments and procedures can be performed within 3 days of the 
planned visit unless specified otherwise.  It is recommended that dosing occur on the 
same day of the week (eg, if first dose is administered on Monday, all subsequent doses 
should be administered on a Monday), however a ± 3 day dosing and study procedure 
window is allowed. 
The following laboratory analytes in Table 3 will be assessed at various times throughout 
the study: 
Table 3.  Laboratory Analytes 
Chemistry 
Hematology 
Biomarkers 
Other Labs 
Sodium 
Potassium 
Chloride 
Total protein 
Albumin 
Calcium 
Creatinine 
Total bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differentiala 
 Bands/Neutrophils 
 Eosinophils 
 Basophils 
 Lymphocytes 
 Monocytes  
HSV Serostatus 
Blood for 
biomarker 
analysis 
Archived tumor 
tissue for 
biomarker 
analysis 
Tumor biopsy for 
biomarker 
analysis 
Pregnancy 
LDH 
qPCR for 
talimogene 
laherparepvec DNA
PT (or INR), PTT 
a 3-part differential if 5-part is unable to be performed 
The chemistry, hematology, PT( or INR), PTT and pregnancy tests are to be performed 
at a local laboratory and test results are to be fully and routinely recorded on the 
electronic CRFs (eCRFs).  Missed tests that are not done must be reported as such on 
the eCRFs and should not be completed as unscheduled tests between cycles.  
The real-time quantitative polymerase chain reaction (qPCR) and biomarker/antibody 
tests will be performed at a central laboratory and tests results will not be reported on 
the eCRFs. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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Procedures deemed necessary as part of standard of care or as required by local laws 
and regulations may be performed at the Investigator’s discretion. 
Where required by local laws and regulations additional assessments are defined in a 
country-specific protocol supplement at the end of the Appendix Section of the protocol. 
7.2.1 
Screening and Enrollment 
The following procedures are to be completed during the screening period within 
28 days of enrollment (unless otherwise noted) at time points designated in the 
Schedule of Assessments (Table 2): 
• 
Confirmation that the Informed Consent Form has been signed  
• 
Review of inclusion and exclusion criteria 
• 
Demographic data including sex, date of birth, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment 
effectiveness 
• 
Review of medications and medical/surgical history 
• 
Physical Examination as per standard of care  
• 
Vital signs (eg, systolic/diastolic blood pressure, heart rate, and temperature) 
• 
Determination of ECOG performance status (Appendix E) 
• 
Local laboratory assessments 
- within ≤ 28 days prior to enrollment: 
o hematology panel:  hemoglobin, hematocrit, white blood cells (WBC) with 
5-part differential (3-part differential if 5-part unable to be performed), red 
blood cells (RBC), platelets 
o chemistry panel:  sodium, potassium, chloride, total protein, albumin, calcium, 
creatinine, total bilirubin, alkaline phosphatase, AST, ALT 
o serum LDH 
o PT (or INR), PTT 
- within ≤ 3 days prior to enrollment: 
o serum or urine pregnancy test for female subjects of childbearing potential.  
Note:  Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion or as defined in a country-specific protocol 
supplement at the end of the Appendix Section of the protocol as required per 
local laws and regulations. 
• 
Clinical tumor assessments, including clinical measurement of cutaneous, 
subcutaneous, or nodal tumor lesions by caliper (to be used as baseline) 
• 
Radiographic tumor imaging (including computed tomography [CT] scan, positron 
emission tomography[PET]/CT scan, magnetic resonance imaging[MRI], 
or ultrasound) of the chest, abdomen, pelvis and all other sites of disease (to be 
used as baseline).  Also, CT scan or MRI of the brain if symptoms or signs 
suggestive of CNS metastasis are present. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 45 of 90 
CONFIDENTIAL 
 
 
• 
Documentation of concomitant medications 
• 
Reporting of serious adverse events (SAEs) that occur after subject signs informed 
consent form.  SAEs will be reported to Amgen within 24 hours following the 
investigator’s knowledge of the event 
• 
Registration in Electronic Trial Operation (ETO) system (see Section 5) 
7.2.2 
Treatment  
Treatment begins when the first dose of talimogene laherparepvec is administered to a 
subject.  Study treatment should begin as soon as possible after enrollment via ETO but 
no later than 5 days after enrollment.  Study treatment is to be administered after all 
other procedures are completed during each visit, unless otherwise stated. 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 2):  
• 
Vital signs (eg, systolic/diastolic blood pressure, heart rate, and temperature) at day 
1 of cycles 1, 2, and 4, then every other cycle until end of study treatment 
• 
Determination of ECOG Performance Status at day 1 of Cycle 1, and then every 
12 weeks (ie, every sixth cycle) in parallel with tumor response assessment 
and until the end of tumor assessment per study protocol (Appendix E) 
• 
Physical exams as per standard of care at day 1 of Cycle 1,  and then every 
12 weeks (ie, every sixth cycle) until the end of study treatment 
• 
Local laboratory assessments:  Screening laboratory values may be used for day 1 
cycle 1 assessment if completed within 3 days of study treatment initiation.  On 
treatment tests can be performed within 3 days of the planned visit.  Results must be 
reviewed prior to the administration of study treatment. 
- hematology panel:  hemoglobin, hematocrit, WBC with 5-part differential 
(3-part differential if 5-part is unable to be performed),RBC, platelets  
o day 1 of cycles 1, 2, and 3, then every fourth (4th) cycle until end of study 
treatment 
- chemistry panel:  sodium, potassium, chloride, total protein, albumin, calcium, 
creatinine, total bilirubin, alkaline phosphatase, AST, ALT 
o day 1 of cycles 1, 2, and 3, then every fourth (4th) cycle until end of study 
treatment  
- Note:  Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion or as defined in a country-specific protocol supplement at 
the end of the Appendix Section of the protocol as required per local laws and 
regulations. 
• 
Central laboratory assessments: 
- Archived formalin-fixed paraffin-embedded tumor tissue (block or unstained 
tumor slide) from either the primary tumor or a metastatic lesion, and the 
associated pathology reports, must be submitted to the central laboratory within 
28 days after enrollment for biomarker analyses 


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Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 47 of 90 
CONFIDENTIAL 
 
 
(eg, CT or MRI) should remain constant throughout the study for any individual 
subject. 
• 
Clinical tumor assessments (clinical measurement of cutaneous, subcutaneous, or 
nodal tumor measurement by caliper) at day 1 of week 12 (± 1 week) and then every 
12 (± 1 week) weeks or more frequently if clinically indicated, until clinically relevant 
disease progression beyond 6 months of treatment, per modified WHO response 
criteria (Appendix D), or until the start of a new anticancer therapy 
• 
Tumor response assessments at day 1 of week 12 (± 1 week) and then every 
12 (± 1 week) weeks or more frequently if clinically indicated, until clinically relevant 
disease progression beyond 6 months of treatment, per modified WHO response 
criteria (Appendix D), or until the start of a new anticancer therapy  
• 
Photographs of all visible cutaneous and subcutaneous tumor lesions at day 1 
Cycle 1, day 1 Cycle 2, and day 1 of every second subsequent cycle until end of 
tumor response assessment per protocol, always within 3 days prior to 
investigational product administration. (Select Sites Only:  see Section 7.2.6) 
• 
Recording of adverse events at each visit 
• 
Recording of serious adverse events at each visit.  Serious adverse events will be 
reported to Amgen within 24 hours following the investigator’s knowledge of the 
event 
• 
Documentation of concomitant medications at each visit 
• 
Reporting pregnancy in a female subject or a female partner of a male subject while 
the subject is taking talimogene laherparepvec treatment and through 3 months after 
end of treatment (Section 9.3) 
• 
Reporting lactation case in a female subject while the subject is taking talimogene 
laherparepvec treatment and through 3 months after end of treatment (Section 9.3) 
• 
Administration of talimogene laherparepvec treatment at day 1 of each cycle 
(Section 6.2.1.1) 
7.2.3 
Safety Follow-up Visit 
Upon permanent discontinuation from the study treatment for any reason, the following 
procedures will be performed 30 (+ 7) days after the last dose of talimogene 
laherparepvec:   
• 
Physical examination as per standard of care  
• 
Vital signs (eg, systolic/diastolic blood pressure, heart rate, and temperature) 
• 
Determination of ECOG Performance Status alongside the tumor response 
assessments until the end of tumor response assessments per study protocol 
(Appendix E) 
• 
Local laboratory assessments:  
- hematology panel:  hemoglobin, hematocrit, WBC with 5-part differential (3-part 
differential if 5-part is unable to be performed), RBC, platelets  
- chemistry panel:  sodium, potassium, chloride, total protein, albumin, calcium, 
creatinine, total bilirubin, alkaline phosphatase, AST, ALT 
- serum or urine pregnancy test for female subjects of childbearing potential 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 48 of 90 
CONFIDENTIAL 
 
 
• 
Central laboratory assessments:  
- swabs of cold sores, vesicles, and other lesions suspected to be herpetic in 
origin (if any) for qPCR testing:  
o subject should return to clinic within 3 days of the occurrence of a reportable 
lesion suspected to be herpetic in origin such as cold sores or vesicles.  The 
lesion should be evaluated by the investigator and swabbed if HSV infection 
is suspected.  A qPCR analysis will be performed on the swab sample to 
evaluate whether the talimogene laherparepvec DNA is detectable in the 
sample. 
• 
Radiographic tumor imaging, clinical tumor assessments, and tumor response 
assessments, will be performed as documented in Section 7.2.2 until documented 
clinically relevant disease progression beyond 6 months of treatment, per modified 
WHO response criteria (Appendix D), or until the start of a new anticancer therapy.  
(Only if subject has discontinued study treatment for reason other than disease 
progression or death and if not performed within 4 weeks [+1 week] of the safety 
visit.)   
• 
Recording of adverse events 
• 
Recording of serious adverse events.  SAEs will be reported to Amgen within 
24 hours following the investigator’s knowledge of the event. 
• 
Documentation of concomitant medications 
7.2.4 
Long-term Follow-up/End of Study 
All subjects who permanently discontinue talimogene laherparepvec for any reason 
other than withdrawal of full consent or death will be contacted by telephone, or clinic 
visit, to assess survival status and, if applicable, commencement of any subsequent 
anticancer melanoma therapy.  Adverse events deemed by the investigator to be 
potentially related to talimogene laherparepvec and use of anti-cancer therapies 
for melanoma will also be recorded.  Follow-up will occur every 12 weeks (± 28 days) 
following the safety follow-up visit until death, subject withdraws full consent, or up to 
24 months after the last subject is enrolled in the study. 
If subject has discontinued talimogene laherparepvec for reason other than disease 
progression or death, radiographic tumor imaging, clinical tumor assessments, ECOG 
Performance Status assessments, reporting of pregnancy or lactation, 
assessment of swabs of lesions of suspected herpetic origin for presence of 
talimogene laherparepvec DNA by qPCR test, and tumor response assessments will 
be performed as documented in Section 7.2.2 until documented disease progression 
beyond 6 months of treatment, per modified WHO response criteria (Appendix D), until 
the start of a new anticancer therapy, or end of study, whichever the earliest. 
After the long term follow-up period of this study has ended, subjects who end the study 
for any reason other than death or withdrawal of full consent will be followed for survival 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 49 of 90 
CONFIDENTIAL 
 
 
under an ongoing separate registry protocol (Study 20120139) that is in place for the 
long-term follow-up of all subjects treated with talimogene laherparepvec in clinical trials.  
The registry protocol will also monitor for late and long-term adverse events thought to 
be potentially related to talimogene laherparepvec and use of anti-cancer therapies 
for melanoma. 
7.2.5 
Reporting Exposure to Talimogene Laherparepvec  
If a household member, caregiver, or healthcare provider who have had close contact 
with the subject is suspected to have been exposed to talimogene laherparepvec 
(eg, have or who have had signs or symptoms suspected to be herpetic in origin or 
accidentally exposed to talimogene laherparepvec), report the potential or known 
unintended exposure to talimogene laherparepvec, suspected related signs or 
symptoms, and detection of talimogene laherparepvec in a subject’s household member, 
caregiver, or healthcare provider as specified Section 9.4.   
7.2.6 
Optional Photography Substudy (Select Sites Only)  
For sites selected to participate in the photography substudy, photographs of all visible 
(ie, visible protrusion from skin surface) cutaneous and subcutaneous tumor lesions will 
be performed as detailed in Section 7.2.2 until end of treatment (always within 3 days 
prior to investigational product administration).  Amgen may use, copy, and/or 
distribute the photographs for educational purposes, in scientific lectures, journal 
articles, and textbooks.  Amgen may also use the photographs for general commercial 
purposes and may have the photographs published, circulated or presented in any way 
either alone or with other written, printed, graphic, or audio matter to members of the 
medical, nursing, pharmaceutical and related professions, as well as to the public at 
large.  The subjects’ identity will not be disclosed in any photographs.  Amgen would 
only show the photographs of subjects from the neck down excluding face or scalp 
without identifying the subject facial characteristics.  Any tattoos or other body marks 
that may identify the subjects will be covered.  Amgen may edit, reduce, enlarge or 
otherwise change the photographs.  The photographs may have commercial value to 
Amgen.  Neither Amgen nor the investigator will compensate the subject for the 
photographs or the use of the photographs.  Refer to the Photography Manual for further 
instructions.  
7.3 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 


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Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 52 of 90 
CONFIDENTIAL 
 
 
7.5 
Sample Storage and Destruction  
Any blood or tumor samples collected according to the Schedule of Assessments 
(Table 2) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
cancer, the dose response and/or prediction of response to talimogene laherparepvec, 
characterize antibody response, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to be available in time to benefit the subject 
directly or to alter the treatment course, the results of qPCR testing from swabs of cold 
sores, vesicles, and other lesions suspected to be herpetic in origin will not be provided 
unless requested by the investigator or the subject.  Results may not be available until 
the end of the study.  Results of biomarker development or other exploratory studies are 
not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood or tumor samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 


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The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 2) and 
collection of data, including endpoints and adverse events.  The investigator must 
document the change to the Schedule of Assessments (Table 2) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  


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8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.  
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study  
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from the protocol-required investigational product or procedural 
assessments may include any of the following: 
 
subject request  
 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance (eg, procedural or dosing as defined in Section 6.2.1.1), 
requirement for alternative therapy, pregnancy) 
 
decision by sponsor (other than subject request or safety concern) 
 
death 
 
lost to follow-up 
 
clinically relevant disease progression beyond 6 months of treatment, per modified 
WHO response criteria (Appendix D) 
 
other protocol-specified criteria (Section 6.2.1.2) 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  


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The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened during the study or involves an intervention such as elective cosmetic surgery 
or a medical procedure while on study, is not considered an adverse event.   
For situations when an adverse event or serious adverse event is considered to be due 
to melanoma, report all known signs and symptoms.  Death due to disease progression 
in the absence of signs and symptoms should be reported as the primary tumor type 
(eg, worsening of melanoma).  
Note:  The term “disease progression” should not be used to describe the adverse event.   
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.2 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 


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include allergic bronchospasm, convulsions, blood dyscrasias, or events that necessitate 
an emergency room visit, outpatient surgery, or urgent intervention. 
9.2 
Reporting of Adverse Events 
9.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of talimogene 
laherparepvec through 30 (+ 7) days after the last dose of talimogene laherparepvec are 
reported using the applicable eCRF (eg, Adverse Event Summary).  Adverse events 
deemed by the investigator to be potentially related to talimogene laherparepvec 
that occur during and after the first dose of talimogene laherparepvec and through 
the survival follow-up are to be reported.  
The investigator must assign the following adverse event attributes: 
 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
 
dates of onset and resolution (if resolved), 
 
severity (and/or toxicity per protocol), 
 
assessment of relatedness to talimogene laherparepvec and 
 
action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE), version 3.0.  The grading scale used in this study is described 
in Appendix A.  The investigator must assess whether the adverse event is possibly 
related to talimogene laherparepvec.  This relationship is indicated by a “yes” or “no” 
response to the question:  Is there a reasonable possibility that the event may have been 
caused by administration of investigational product?   
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity and/or procedure (eg, including any screening procedures).  
This relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity and/or 
procedure”?  
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 


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or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
If the severity of an adverse event worsens from the date of onset to the date of 
resolution, record a single event for each increased level of severity on the Adverse 
Event Summary eCRF.  The investigator is expected to follow reported adverse events 
until stabilization or reversibility.  
9.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 (+ 7) days after the last dose of  talimogene laherparepvec are 
recorded in the subject’s medical record and are submitted to Amgen.  All serious 
adverse events must be submitted to Amgen within 24 hours following the investigator’s 
knowledge of the event via the applicable eCRF.  
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours following 
the investigator’s knowledge of the event.  Serious adverse events reported outside of 
the protocol-required reporting period will be captured within the safety database as 
clinical trial cases for the purposes of expedited reporting.  
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet /electronic Serious Adverse Event Contingency Report Form.  
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the electronic Serious Adverse Event Contingency Report Form, the data 
must be entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
talimogene laherparepvec.  This relationship is indicated by a “yes” or “no” response to 
the question:  “Is there a reasonable possibility that the event may have been caused by 
the investigational product”?   


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The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable CRF (eg, Adverse 
Event Summary eCRF). 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and Good 
Clinical Practice (GCP).  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies, report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur after the last dose of talimogene laherparepvec through 
3 months after the last dose of talimogene laherparepvec.  The pregnancy should be 
reported to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of the event of a pregnancy.  Report a pregnancy on the Pregnancy 
Notification Worksheet (Appendix B).   


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If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of talimogene laherparepvec through 
3 months after the last dose of talimogene laherparepvec. 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix B). 
9.4 
Reporting of Exposure to Talimogene Laherparepvec 
If a household member, caregiver, or healthcare provider who has had close contact 
with the subject is suspected to have been exposed to talimogene laherparepvec 
(eg, have or who have had signs or symptoms suspected to be herpetic in origin or who 
have been accidentally exposed to talimogene laherparepvec), while the subject is 
taking talimogene laherparepvec, report the exposure to Amgen as specified below.  In 
addition to reporting an unintended exposure case during the study treatment, 
investigators should monitor for potential exposure cases that occur after the last dose of 
talimogene laherparepvec through 30 (+ 7) days after the last dose of talimogene 
laherparepvec.  Please refer to your study specific documents for reporting details. 
Any potential or known unintended exposure should be reported to Amgen within 
24 hours of the investigator’s knowledge of the event of exposure.  Amgen will seek to 
follow-up with the exposed individual, if necessary, to collect more information about the 
exposed individual contact with clinical trial subject, signs and/or symptoms related to 
the exposure, medical history, and/or outcome of the exposure.  If the exposed individual 
is reporting signs or symptoms suspected to be related to talimogene laherparepvec 
exposure, the exposed individual may be asked to have a swab taken to evaluate for the 
presence of talimogene laherparepvec in the lesion, within 3 days of the symptoms or 
signs occurring. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
Correlation between baseline intratumoral CD8+ cell density and objective response 
rate (ORR)   


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10.1.1.2 
Secondary Endpoints  
• 
Correlation between baseline intratumoral CD8+ cell density and durable response 
rate (DRR), and duration of response (DOR), and changes in tumor burden 
• 
Correlation between changes in intratumoral CD8+ cell density during treatment and 
ORR, DRR, DOR, and changes in tumor burden  
• 
Efficacy Endpoints:  ORR, DOR, time to treatment failure (TTF), DRR, OS, and 
change in tumor burden during treatment 
• 
Safety Endpoints:  subject incidence of treatment-emergent and treatment-related 
adverse events (including all adverse events, grade ≥ 3 adverse events, serious 
adverse events, fatal adverse events, events of interest, adverse events requiring the 
discontinuation of study drug), clinically significant laboratory changes, and incidence 
of symptomatic herpetic lesions that are positive for talimogene laherparepvec 
10.1.1.3 
Exploratory Endpoints 
• 
Correlation between the changes in the population of tumor specific cytotoxic T cells 
and immunoscore during treatment and clinical response 
• 
Identification of other potential blood and tumor biomarkers which correlate with or 
predict clinical outcomes to talimogene laherparepvec 
10.1.2 
Analysis Sets 
Safety Analysis Set:  The safety analysis set will include all subjects who have received 
at least 1 dose of talimogene laherparepvec.  The efficacy analysis and safety analysis 
will be performed on the safety analysis set.  
Baseline Biomarker Analysis Set:  The baseline biomarker analysis set will be defined 
separately for each baseline biomarker.  The baseline biomarker analysis set includes all 
subjects who received at least 1 dose of talimogene laherparepvec and have the 
biomarker recorded at baseline.  The correlation between a baseline biomarker and 
objective response rate, durable response rate, and duration of response will be 
conducted on the baseline biomarker analysis set. 
Biomarker Evaluable Analysis Set:  The biomarker evaluable analysis set will be 
defined separately for each biomarker.  Lesions will be analyzed by injection status.  The 
biomarker evaluable analysis set includes all subjects who received at least 1 dose of 
talimogene laherparepvec and have the biomarker recorded both at baseline and 
week 6.  The correlation between biomarker changes during treatment and objective 
response rate, durable response rate, and duration of response will be conducted on the 
biomarker evaluable analysis set. 


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10.1.3 
Covariates and Subgroups 
The following covariates may be used to examine efficacy and safety in subgroups or in 
multivariate analyses: 
• 
Region, if applicable 
• 
Age at baseline:  < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 
• 
Disease stage at baseline:  IIIB and IIIC vs IVM1a vs IVM1b vs IVM1c 
• 
Baseline LDH ≤ ULN vs > ULN 
• 
Sex (Female vs Male) 
• 
ECOG Performance Status (0 vs 1) 
10.2 
Sample Size Considerations 
All analyses will be descriptive with no formal hypothesis testing.  The sample size was 
selected based on practical considerations.  The primary objective of the study is to 
assess whether baseline intratumoral CD8+ cell density is correlated with the likelihood 
of response to talimogene laherparepvec.  Analyses for the objective will focus on 
whether the response rate varies with baseline intratumoral CD8+ cell density.  The 
functional manner in which the response rate may vary with the biomarker is unknown, 
therefore multiple functional relationships may be examined.  It is assumed that 
100 subjects (approximately 91% of the enrolled) will have an evaluable baseline 
intratumoral CD8+ cell density.  The adequacy of the sample size was evaluated for one 
of several possible analyses that evaluates whether the response rate is positively 
correlated with a high baseline intratumoral CD8+ cell density where a low and high 
biomarker is defined as a value below versus at or above the sample median, 
respectively.  A one-sided Fisher’s Exact test will be performed at a 5% nominal level to 
explore the hypothesis that the response rate is equal regardless of baseline 
intratumoral CD8+ cell density.  The overall ORR is assumed to be 26.4%.  The power 
for the test will depend on the true response rates in the biomarker subgroups.  
Assuming the true response rate is 13.2% in the biomarker low subgroup, and 39.6% in 
the biomarker high subgroup, the power will be 88% to detect a positive association.  
A secondary objective of this study is to estimate the objective response rate.  Based on 
the analysis of the OPTiM study, the overall response rate for stage IIIB/C and IVM1c is 
assumed to be around 26.4% where, among responders, the probability of response 
onset after 12 months was < 5%.  The expected exact 95% CIs for various true ORRs 
are listed in Table 4.  The expected width of the 95% CI is around 18% under these 
scenarios. 


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Table 4.  Expected 95% Confidence Intervals by Various True ORRs 
Subjects enrolled (N) 
True 
Expected 
95% CI (width) 
110 
20% 
13% - 29% (16%) 
 
30% 
22% - 39% (18%) 
 
40% 
31% - 50% (19%) 
 
50% 
40% - 60% (19%) 
Another secondary objective is to explore the correlation between changes in 
intratumoral CD8+ cell density during treatment and objective response rate.  The 
primary focus will be on changes in tumor cell CD8+ density.  It is assumed that 
55 subjects (approximately 50% of all enrolled) will be evaluable with a pre- and 
on-treatment lesion biopsy that is sufficient to evaluate biomarker changes in uninjected 
lesions.  In addition to correlating biomarker changes with objective response, Pearson’s 
correlation coefficient (r) will also be estimated between the biomarker change and the 
maximum decrease in index lesions.  With 55 evaluable subjects, a value of r ≤ 0.30 will 
be rejected at a nominal 1-sided 5% significance level with an observed r > 0.49 for 
which the power will be > 80% given a true value for r ≥ 0.60. 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
An interim analysis to evaluate the study objectives of correlation between the 
biomarker (ie baseline intratumoral CD8+ cell density changes in intratumoral 
CD8+ cell density and other biomarkers) and ORR will be conducted on 
approximately the first 50 subjects only who received at least 1 dose of 
talimogene laherparepvec, with the biomarker recorded at baseline, and have had 
the opportunity to be on study (treatment or follow-up phase) for at least 
6 months.  The study will not be discontinued due to the results of this interim 
analyses; however, predictive hypotheses generated from the interim analysis 
may lead to subsequent changes to study conduct. For example, if the interim 
analysis suggests an enhanced effect in a biomarker-defined subgroup, then the 
protocol and statistical analysis plan may be revised to ensure the study can 
adequately evaluate the subgroup effect.  Revisions may also happen due to 
obtaining new relevant data from external sources, such as scientific publications 
and communications.  


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10.3.2 
Primary Analysis 
The clinical study report (CSR) will be written based on the results of the primary 
analysis.  The main goals of the primary analysis are to evaluate the ORR and 
correlation of baseline intratumoral CD8+ cell density and the likelihood of response to 
talimogene laherparepvec, in addition to the correlation between changes in intratumoral 
CD8+ cell density during treatment and objective response.  The timing of the primary 
analysis will be when all subjects have had the opportunity to complete 12 months of 
treatment of talimogene laherparepvec. 
10.3.3 
Final Analysis 
The final analysis will occur either 24 months after the last subject has been enrolled 
or when the last subject discontinues the study treatment and has had the opportunity to 
complete the safety follow–up, whichever is later.  The CSR will be amended with the 
updated results from the final analysis at the completion of the study. 
10.4 
Planned Methods of Analysis 
Descriptive statistics will be provided for demographic, safety, efficacy, and biomarkers 
as appropriate.  In general, the safety analysis set will be used for all safety analyses.  
The safety analyses include incidence of treatment-emergent and treatment related 
adverse events (all adverse events, ≥ grade 3 adverse events, serious adverse events, 
fatal adverse events and adverse events defined as events of interest). 
The efficacy analysis will be conducted using the safety analysis set as well unless 
otherwise specified.  The ORR will be estimated with the associated 95% CI.  
Descriptive statistics for DRR, time to treatment failure and OS will be provided.  In 
addition, DOR and changes in tumor burden for responders will also be summarized. 
The correlation between a baseline biomarker and response rate will be evaluated.  The 
functional manner in which the response rate may vary with the biomarker is unknown; 
therefore multiple functional relationships may be examined.  Pearson’s correlation 
coefficient (r) will be estimated between the biomarker change and the maximum 
decrease in index lesions to evaluate the correlation between changes in a biomarker 
post-treatment and the effect of treatment on measurable lesions, in addition to 
correlating biomarker changes with objective response using logistic regression. 
10.4.1 
Primary Endpoint 
The primary endpoint of the study is the correlation between baseline intratumoral 
CD8+ cell density and objective response rate (ORR).  The correlation of intratumoral 


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CD8+ cell density and other biomarkers with ORR will be evaluated as described in 
Section 10.4 for ORR and DRR. 
10.4.2 
Secondary Endpoint (s) 
Multiple biomarkers will be examined to assess the correlation between their baseline 
value and DRR, DOR, and changes in tumor burden as well as the changes in their 
value during treatment with ORR, DRR, DOR, and changes in tumor burden.  The 
functional manner in which the ORR, DRR, DOR, and change in tumor burden may vary 
with each biomarker is unknown, therefore multiple functional relationships will be 
examined to assess overall evidence of an association.  Combinations of biomarkers 
may be explored to assess their predictive value for patient selection.  Example analyses 
include, but are not limited to:  (a) the correlation of baseline value as a continuous 
variable with the odds of OR, DR or the hazard of ending response; (b) a trend test for 
an increasing ORR, DRR with pre-specified, ordered biomarker categories, (c) a test that 
the ORR, DRR or hazard of ending response is greater between subgroups of subjects 
with a high vs. low baseline biomarker value for all possible cut-points for a minimum 
high biomarker value, (d) a receiver operating characteristic (ROC) analysis (categorical 
and continuous biomarker values), and (e) calculation of negative predictive value (NPV) 
and positive predictive value (PPV) for each candidate cut-point for ORR and DRR.   
In order to evaluate the correlation between changes in biomarkers during treatment and 
the effect of treatment on measurable lesions, Pearson’s correlation coefficient (r) will be 
estimated between the biomarker change and the maximum decrease in index lesions, 
in addition to correlating biomarker changes with ORR/DRR using logistic regression, 
and duration of response using Cox model regression. 
Overall survival (OS), duration of response and time to treatment failure will be 
summarized by K-M methods.  Durable response rate and objective response rate will 
be presented with 95% CI. 
10.4.3 
Safety Endpoints 
Subject incidence rates of treatment-emergent adverse events (including all adverse 
events, grade ≥ 3 adverse events, serious adverse events, adverse events of interest 
and events requiring the discontinuation of study drug, and local effects on the tumor 
[ie, pain, inflammation and ulceration]) will be summarized.  Medical Dictionary for 
Regulatory Activities (MedDRA) will be used to code adverse events to a system organ 
class (SOC) and a preferred term within the SOC.  The CTCAE version 3.0 will be used 
to grade severity of adverse events.  In addition clinically significant laboratory changes 


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and clinically significant changes in vital signs will be summarized with descriptive 
statistics.  Summary statistics will also be provided for concomitant medications, dose 
delay, study drug discontinuation, overall exposure, and changes in ECOG performance 
status.  Tables and/or narratives of deaths after initiation of the study through 30 days 
since the last dose of talimogene laherparepvec will be provided. 
The qPCR analysis result of talimogene laherparepvec DNA in swab samples taken from 
cold sore, vesicles, and other lesions suspected to be herpetic in origin (if any) will be 
summarized descriptively. 
Potential or known unintended exposure to talimogene laherparepvec, related suspected 
signs or symptoms, and detection of talimogene laherparepvec in a subject’s household 
member, caregiver, or healthcare provider will be reported. 
10.4.4 
Exploratory Endpoints 
Correlation between the changes in the population of tumor specific cytotoxic T-cells and 
immunoscore during treatment and clinical response will be assessed by the same 
methods described in Section 10.4.  In addition, other potential blood and tumor 
biomarkers which predict ORR will be explored similarly.  
10.5 
Handling of Missing and Incomplete Data 
Partial or missing dates of adverse events and concomitant medications will be imputed.  
Adverse events with missing severity and/or possible relationship to talimogene 
laherparepvec will be included in the all adverse events analyses, except by severity 
grade and treatment-related.  Every effort will be made to obtain complete dates for 
deaths.  Details of the imputation algorithms will be specified in the study-specific 
statistical analysis plan. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 


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protocol-specific screening procedures or any investigational product(s) is/are 
administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 


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The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/International Conference on Harmonisation 
(ICH)/ Good Clinical Practice (GCP) Guidelines, it is required that the investigator and 
institution permit authorized representatives of the company, of the regulatory agency(s), 
and the IRB/IEC direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit such individuals to have access to his/her study-related records, 
including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator.  The coordinating investigator, 
identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the ETO system captures the following data points and these are 
considered source data:  subject identification.  
eCRF entries may be considered source data if the eCRF is the site of the original 
recording (ie, there is no other written or electronic record of data). 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   


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Elements to include the following: 
• 
subject files containing completed eCRFs, informed consent forms, and subject 
identification list 
• 
study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen clinical monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The clinical monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global R&D Compliance and Audit function 
(or designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy 
storage areas, laboratories) and review of study-related records will occur to evaluate 
the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 


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Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the eCRFs must be maintained and 
readily available. 
• 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen (or designee) 
reviewer. 
• 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that the investigator inspected or reviewed 
the data on the eCRF, the data queries, and the site notifications, and agrees with 
the content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visits) and clarifying “other, specify” if data are provided (eg, race, 
physical examination).  Each investigative site will be provided a list of the types of 
corrections applied to study data at the initiation of the trial and at study closeout.   
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 2), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   


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12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors Guidelines). 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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13. 
REFERENCES 
Anderson CM, Buzaid AC, Legha SS.  Systemic treatments for advanced cutaneous 
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Andtbacka RHIA, Kaufman H, Collichio FA, et al.  Talimogene laherparepvec 
improves durable response rate in patients with advanced melanoma. J Clin Oncol 
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Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for 
patients with metastatic melanoma:  analysis of 270 patients treated between 1985 and 
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Balch CM, Gershenwald JE, Soong S-J, et al.  Final version of 2009 AJCC melanoma 
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Chapman PB, Hauschild A, Robert C, et al.  Updated overall survival (OS) results for 
BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor 
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Chapman PB, Hauschild A, Robert C, et al.  Improved survival with vemurafenib in 
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Conti L, Gessani S.  GM-CSF in the generation of dendritic cells from human blood 
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Demir G, Klein HO, Tuzuner N.  Low dose daily rhGM-CSF application activates 
monocytes and dendritic cells in vivo.  Leuk Res.  2003;27(12):1105-1108. 
Erdag G, Schaefer JT, Smolkin ME, et al.  Immunotype and immunohistologic 
characteristics of tumor-infiltrating immune cells are associated with clinical outcome in 
metastatic melanoma.  Cancer Res.  2012;72(5):1070-1080. 
Ferlay J, Soerjomataram I, Ervik M, et al.  GLOBOCAN 2012 v1.0, Cancer Incidence 
and Mortality Worldwide:  IARC CancerBase No. 11 [Internet]. Lyon, France:  
International Agency for Research on Cancer; 2013. http://globocan.iarc.fr 
Flaherty KT, Robert C, Hersey P, et al.  Improved survival with MEK inhibition in 
BRAF-mutated melanoma.  N Engl J Med.  2012a; 367:107-114. 
Flaherty KT, Infante, JR, Daud, A, et al.  Combined BRAF and MEK inhibition in 
melanoma with BRAFV600 mutations.  N Engl J Med.  2012b, 367:  1694-1703 
Galon J, Costes A, Snachez-Cabo F, et al. Type, density, and location of immune cells 
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Galon J, Pages F, Marincola FM, et al.  The immune score as a new possible approach 
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the classification of malignant tumors. J Pathol 2014;232:199-209. 
Hart DN.  Dendritic cells:  unique leukocyte populations which control the primary 
immune response.  Blood.  1997;90(9):3245-3287. 


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Hauschild A, Grob JJ, Demidov LV, et al.  Dabrafenib in BRAF-mutated metastatic 
melanoma:  a multicentre, open-label, phase 3 randomised controlled trial.  Lancet. 
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Hodi FS, O'Day SJ, McDermott DF, et al.  Improved survival with ipilimumab in patients 
with metastatic melanoma.  N Engl J Med.  2010;363:711-723. 
Hoeflich KP, Herter S, Tien J,et al.  Antitumor efficacy of the novel RAF inhibitor 
GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular 
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Ikeda H, Chamoto K, Tsuji T, et al.  The critical role of type-1 innate and acquired 
immunity in tumor immunotherapy.  Cancer Sci.  2004;95(9):697-703. 
Jemal A, Siegel R, Ward E, et al.  Cancer statistics, 2006.  CA Cancer J Clin.  
2006;56:106-130. 
Keytruda® (Pembrolizumab) Prescribing Information.  Merck & Co, Whitehouse 
Station, USA; 2015. 
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. 
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immunotherapy.  Cancer Immunol Immunother.  2005;54(8):721-728. 
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or monotherapy in untreated Melanoma. N Engl J Med. 2015;373:23-34 
Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus 
dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-
blind, phase 3 randomised controlled trial. Lancet 2015, 386:444-451 
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GlaxoSmithKline, USA, 2014. https://www.gsksource.com/pharma/content/dam/ 
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temozolomide versus dacarbazine in the treatment of patients with advanced metastatic 
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Ries LA, Wingo PA, Miller DS, et al.  The annual report to the nation on the status of 
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Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in 
advanced melanoma. N Engl J Med. 2015;372:2521-2532. 
Robert C, Thomas L, Bondarenko I, et al.  Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma.  N Engl J Med.  2011;364:2517-2526. 
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Senzer NN, Kaufman HL, Amatruda T, et al.  Phase II clinical trial of a 
granulocyte-macrophage colony-stimulating factor-encoding, second-generation 
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2009;27(34):5763-5771. 
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65:5-29. 
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Steinman, RM. Dendritic cells and the control of immunity:  enhancing the efficiency of 
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CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-2199. 
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Tannous ZS, Mihm MC, Jr., Sober AJ, Duncan LM.  Congenital melanocytic nevi:  
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Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in 
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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information  
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be used 
for adverse event grading.  The CTCAE version 3.0 is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


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Appendix B.  Sample Serious Adverse Event Report Form 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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Appendix D.  Modified World Health Organization (WHO) Response Criteria 
A modified version of the World Health Organization (WHO) response criteria 
(WHO handbook for reporting results of cancer treatment, 1979) will be employed in this 
study. 
Method of Measurement of Melanoma Tumor Lesions 
Clinical Examination Using Caliper:  All measurements will be determined using a 
ruler or calipers and reported in metric notation (mm) and will be recorded 
bi-dimensionally.  Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm in at least 2 dimensions as assessed using calipers 
(eg, superficial cutaneous melanoma lesion).  (Note:  When a lesion can be evaluated by 
both, clinical examination and imaging, radiographic imaging evaluations should be 
preferred since it is more objective).  
CT scans (or MRI):  Computed tomography (CT) scans by contrast-enhanced or spiral 
scan (or magnetic resonance imaging [MRI] scan) will be performed to evaluate tumor 
response for nodal/soft tissue disease (including lymph nodes).  Measurability of lesions 
on CT scans is based on the assumption that CT slice thickness is 5 mm or less.  When 
CT scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be the greater of either at least 10 mm or twice the slice thickness.  MRI is 
acceptable to assess disease extent if used throughout the study. 
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.  A 
switch from contrast enhanced CT to noncontract CT or to MRI (or vice versa) should 
not preclude response assessment if, in the judgment of the site radiologist, there is no 
significant difference in the assessment by changing modalities.  This may occur if a 
subject has developed a medical contraindication to intravenous contrast for CT scans 
while on trial.  This change would require the preapproval of the sponsor medical 
monitor. 
Positron Emission Tomography (PET)/CT Scans:  If a combined PET/CT scan is 
performed at the discretion of the investigator, the CT portion of that exam should not be 
substituted for the dedicated CT exams required by this protocol.  The PET portion of the 
CT may introduce additional data which may bias the investigator assessment of 
response if it is not routinely or serially performed.  However, if the investigator or the 
site radiologist can document that the CT performed as part of a PET/CT is of identical 


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diagnostic quality to a diagnostic CT (with intravenous and oral contrast) then the CT 
portion of the PET/CT can be used for tumor measurements.  
Ultrasound:  Ultrasound may be used to assess superficial palpable lymph nodes and 
subcutaneous lesions where ultrasound provides a more accurate measure than clinical 
measurement, CT or MRI.  In addition, ultrasound can be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.  However, 
if ultrasound is not useful in assessment of lesion size it must not be used as a method 
of measurement.  If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. 
Measureable Disease  
Measurability is defined by the ability to measure a lesion bi-dimensionally with surface 
area determined by multiplying the longest diameter by the diameter perpendicular to the 
longest diameter as defined below.  An individual lesion measure is therefore provided 
by the product of a tumor’s longest diameter and the diameter perpendicular to that. 
All measurements will be determined using a ruler or calipers and reported in metric 
notation (mm) and will be recorded bi-dimensionally.  
Definitions of Measurable and Nonmeasurable: 
At baseline (the last assessment on or prior to the first dose of study drug being 
administered), tumor lesions will be categorized as follows:   
• 
measurable or  
• 
nonmeasurable but evaluable  
Measurable Lesions: 
Measurable lesions are defined at baseline as lesions that can be accurately and serially 
measured in at least 2 dimensions and for which the longest diameter is: 
• 
≥ 10 mm as measured by CT scan, MRI, or ultrasound for nodal/soft tissue disease 
(including lymph nodes) 
• 
≥ 10 mm caliper measurement by clinical exam for superficial cutaneous or 
subcutaneous melanoma lesion as measured by caliper 
• 
multiple superficial melanoma lesions which in aggregate have a total diameter of 
≥ 10 mm 
Nonmeasurable Lesions: 
All other lesions, including small lesions (longest diameter < 10 mm by 
CT/MRI/ultrasound for nodal/soft tissue disease [including lymph nodes] or < 10 mm 
caliper measurement by clinical exam for superficial cutaneous melanoma lesion) and 


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other truly nonmeasurable lesions are considered nonmeasurable and characterized as 
nonindex lesions.  This will include any measurable lesions beyond the maximum 
number of 10 lesions that were not chosen as index lesions.   
Lesions with Prior Local Treatment: 
Tumor lesions situated in a previously irradiate area, or an area subject to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Coalescing or splitting lesions: 
• 
Coalescing lesions:  When two or more index or new measurable lesions 
merge without distinct borders between tumors, the smaller lesion should 
have 0 x 0 mm recorded for the current and all future assessments with a 
comment indicating that the lesion coalesced with the specified lesion, and the 
larger lesion should have the size of the merged lesion recorded for the 
current assessment with a comment indicating that the lesion coalesced with 
the specified lesion and be followed for future assessments.  When two or 
more nonindex or new non-measurable lesions merge, the smaller lesion 
should be recorded as absent for the current and all future assessments, and 
the larger lesion should be recorded as present for the current assessment 
(with a comment indicating that the lesion coalesced with the specified lesion) 
and followed for future assessments.  If an index or new measurable lesion 
and a non-index or new non-measurable lesion merge, the non-index or new 
non-measurable lesion should be absent for the current and all future 
assessments while the index lesion or new measurable lesion should include 
both merged lesions for recording measurements with a comment indicating 
that the lesion coalesced with the specified lesion. 
• 
Splitting lesions:  When an index or new measurable lesion splits into two or 
more lesions the largest measurable part of the split lesion should be 
considered to be the previously recorded index or new measurable lesion with 
measurements provided for the current assessment with the comment 
indicating that the lesion split from the specified lesion, and followed for future 
assessments. The remaining lesions would be reported as a new measurable 
lesions or new non-measurable lesions depending on measurability with a 
comment indicating that the lesion split from the specified lesion. In this case, 
appearance of a new lesion from a previous lesion will not be considered a 
disease progression solely due to appearance of a new lesion (may be 
considered a disease progression due to > 25% increase in the sum of the 
products of the perpendicular diameters of all index tumors since baseline, or 
the unequivocal appearance of a new tumor, other than the product of the split 
tumor, since the last response assessment time point). 
Measureable Tumor Assessment/Burden: 
Baseline Documentation of “Index Lesions”: 
All baseline evaluations should be performed as close as possible to enrollment and 
never more than 4 weeks (ie, 28 days) prior to enrollment. 


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At baseline, up to 10 measurable cutaneous, nodal, or soft tissue lesions will be chosen 
to measure over the course of therapy.  The distribution of these index lesions should be 
representative of the subject’s overall disease status.  Index lesions should be selected 
on the basis of their size (lesions with longest bi-dimensionally perpendicular diameters) 
and suitability for accurate repeated measurements by imaging techniques (CT, MRI or 
ultrasound) and/or other method such as clinical exam. 
The sum of the products of the two largest of perpendicular diameters (SPD) of all index 
lesions will be calculated and reported. 
If subject has multiple small superficial melanoma lesions at baseline (less than 
10 mm in longest diameter) which  in aggregate have a total diameter of ≥ 10 mm, 
up to 10 largest lesions that were included in this measurement will be reported as 
”Index Lesions”, and sum of the products of the two largest of perpendicular SPD 
of these lesions will be calculated and reported for tumor response assessments.  
Baseline Documentation of “Nonindex Lesions”:   
All other lesions (or sites of disease), including any measurable lesions that were not 
chosen as index lesions will be identified as nonindex lesions.  Nonindex lesions should 
be recorded and assessed qualitatively over the course of therapy. 
Follow-up “Index Lesions”: 
At each subsequent tumor assessment, the SPD of the index lesions are added together 
to provide the total tumor burden. 
Follow-up “Nonindex Lesions”: 
Nonindex disease measurements are not required and these lesions should be followed 
as “present,” “absent,” or in rare cases “unequivocal progression”. 
Response Criteria 
Evaluation of Objective Response: 
The subject response will be assessed based on the response of the index lesions and 
nonindex lesion, and presence or absence of new lesions.  Confirmation of complete or 
partial response is not required.  The overall response is derived from time point 
response assessments as described in Table 5, Table 6, and Table 7.  


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Table 5.  Definition of Index Lesion Tumor Response Including New Lesions 
Complete Response (CR): 
Complete disappearance of all index lesions, including any new 
tumors which might have appeared.  Any residual cutaneous or 
subcutaneous index lesions must be documented by 
representative biopsy to not contain viable tumor. 
Partial Response (PR): 
Achieving a 50% or greater reduction in the SPD of the 
perpendicular diameters of all index lesions at the time of 
assessment as compared to the sum of the products of the 
perpendicular diameters of all index lesions at baseline.  If any 
new lesions have appeared, the sum of products of the 
perpendicular diameters of new measurable lesions must have 
reduced by 50% or more from when first documented.   
Disease Progression (PD): 
A > 25% increase in the sum of the products of the perpendicular 
diameters of all index tumors since baseline, or the unequivocal 
appearance of a new tumor since the last response assessment 
time point.  
There are 2 types of PD defined in this protocol: 
Non-clinically relevant disease progression (PDn):  PD in 
subjects who do not suffer a decline in performance status and/or 
in the opinion of the investigator do not require alternative therapy.  
Subjects showing overall response as PDn will be allowed to 
continue study treatment.  
Clinically relevant disease progression (PDr):  PD that is 
associated with a decline in performance status and/or in the 
opinion of the investigator the subject requires alternative therapy.  
Subjects with PDr will be allowed to remain on study until 
24 weeks of therapy unless, in the opinion of the investigator, other 
treatment is warranted.  
Stable Disease (SD): 
Neither sufficient tumor shrinkage of index lesion to qualify for 
response (PR or CR) nor sufficient tumor increase of index lesion 
to qualify for PD. 
Unable to Evaluate (UE): 
Any index lesion present at baseline which was not assessed or 
was unable to be evaluated leading to an inability to determine the 
status of that particular tumor for that time point. 
Not Done (ND) 
Radiographic image or clinical measurement were not performed 
at this time point to evaluate the index lesions 


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Table 6.  Definition of Nonindex Lesion Tumor Response 
Complete Response (CR): 
Disappearance of all nonindex lesions. 
Incomplete 
Response/Stable Disease 
(SD): 
Persistence of one or more nonindex tumor(s).  
Disease Progression (PD): 
Unequivocal  progression of one or more nonindex lesions  
There are 2 types of PD defined in this protocol: 
Non-clinically relevant disease progression (PDn):  PD in 
subjects who do not suffer a decline in performance status and/or 
in the opinion of the investigator do not require alternative therapy.  
Subjects showing PDn as overall response will be allowed to 
continue study treatment.  
Clinically relevant disease progression (PDr):  PD that is 
associated with a decline in performance status and/or in the 
opinion of the investigator the subject requires alternative therapy.  
Subjects with PDr will be allowed to remain on study until 
24 weeks of therapy unless, in the opinion of the investigator, 
other treatment is warranted. 
Unable to Evaluate (UE): 
Any nonindex lesion present at baseline which was not assessed 
or was unable to be evaluated leading to an inability to determine 
the status of that particular tumor for that time point. 
Not Applicable (NA) 
No nonindex lesions were identified at baseline 
Not Done (ND) 
Radiographic image or clinical measurement were not performed 
at this time point to evaluate the nonindex lesions 


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Protocol Number:  20120325 
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Table 7.  Matrix for Determining the Overall Response at Each Assessment Point  
Index Lesion Response 
Including New Lesions 
Nonindex Lesion Response 
Overall Response 
CR 
CR 
CR 
SD 
PR 
PDn 
PDn 
PDr 
PDr 
NA 
CR 
UE/ND 
UE 
PR 
CR/SD 
PR 
PDn 
PDn 
PDr 
PDr 
NA 
PR 
UE/ND 
UE 
SD 
CR 
SD 
SD 
SD 
PDn 
PDn 
PDr 
PDr 
NA 
SD 
UE/ND 
UE 
PDn 
CR/SD/PDn/NA/UE/ND 
PDn 
PDr 
PDr 
PDr 
Any 
PDr 
UE/ND 
CR/SD/ NA/UE/ND 
UE 
PDn 
PDn 
PDr 
PDr 
Subjects with PDn as overall response will be allowed to continue study treatment.  
Subjects with PDr will be allowed to remain on study until 24 weeks of therapy unless, in the opinion of the 
investigator, other treatment is warranted. 
CR = complete response; PR = partial response; SD = stable disease; PD = disease progression;  
PDn = nonclinically disease progression; PDr = clinically relevant disease progression; UE = unable to 
evaluate; NA = not applicable; ND = not done. 


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Appendix E.  Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, ie, light housework or office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about > 50% of waking hours. 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of waking 
hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead 
 


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Amendment 1 
Protocol Title:  A Phase 2, Multicenter, Open-label, Single-arm Trial to Evaluate the 
Correlation Between Objective Response Rate and Baseline Intratumoral 
CD8+ Cell Density in Subjects With Unresected Stage IIIB to IVM1c Melanoma 
Treated with Talimogene Laherparepvec 
 
Talimogene Laherparepvec 
Amgen Protocol Number (Talimogene Laherparepvec) 20120325 
 
Amendment 1 Date: 
31 August 2015 
Superseding Date: 
21 September 2015 
This document summarizes the changes made to the protocol in both Amendment 1 and 
the superseding version. 
Rationale: 
 
Removed Inclusion Criterion 105 to allow subjects to join the study after having 
received first-line therapy. 
 
Removed exclusion of subjects receiving any non-oncology vaccine therapies used 
for the prevention of infectious disease within 28 days prior to enrollment and during 
treatment period (Exclusion criterion 210). 
 
Clarified that if no viable cells were found following surgery, the response definition 
will be complete response (CR). 
 
Added testing for herpes simplex virus type 2 (HSV-2) within 3 days prior to dose at 
day 1 of week 1 [Cycle 1], week 6 [Cycle 3], and week 12 [Cycle 6]. 
 
Increased the window to 5 days for tumor biopsy for biomarker analysis for the 
Week 1 biopsy, 7 days for the Week 6 biopsy, and to 7 days after documentation of 
disease progression at PD. 
 
Added assessment of Eastern Cooperative Oncology Group (ECOG) performance 
status every 3 months during treatment period. 
 
Revised photography assessments in the schedule of assessments to remove 
requirement at screening, update cycles, and removed the word “measurable.” 
 
In Schedule of Assessments, clarified that the week 1 biopsy should not be collected 
prior to the subject being enrolled. 
 
Removed word “uninjected” from the correlation between changes in intratumoral 
CD8+ cell density during treatment and objective response rate in the study 
endpoints. 
 
Revised the number of planned sites to be 50. 
 
Added exclusion criterion to avoid potential viral transmission during sexual contact. 
 
Specified how lesions that separate or merging are to be assessed. 


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• 
Added an interim analysis. 
• 
Added reporting of treatment related adverse events during the long-term follow-up. 
• 
Added addition of anti-cancer therapy for melanoma during long term period 
follow-up. 
• 
In Table 5: Definition of Index Lesion Tumor Response Including New Lesions, 
removed the following text from the definition of partial response, “Any residual 
cutaneous or subcutaneous index or new lesions that must be tumor free for the 
subject to meet the criteria for partial response (PR) must be documented as such by 
representative biopsy”.  
• 
Updated text throughout document to specify cycle number corresponding to study 
week. 
• 
Implemented minor administrative and formatting changes. 
• 
Added references in Section 2.2 and in the reference list. 
• 
Added ECOG and physical examination during treatment period and follow-up 
period. 
• 
Defined the final analysis after 24 months from LSE rather than keeping it open 
ended. 
• 
Clarified that unless patient dies or withdraws full consent after they have completed 
the LTFU portion of the study they will then be transferred to the registry protocol 
where they will continue to be followed up, until death or full consent withdraw. 


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Description of Changes: 
Section:  Global 
Replace: 
5 December 2014 
With: 
21 September 2015 
Section:  Synopsis, Secondary Objective(s) 
Bullet 2 
Replace: 
to explore the correlation between changes in intratumoral CD8+ cell density during 
treatment (in injected and uninjected lesions) and ORR, DRR, DOR, and changes in 
tumor burden 
With: 
to explore the correlation between changes in intratumoral CD8+ cell density during 
treatment and ORR, DRR, DOR, and changes in tumor burden 
Section:  Synopsis, Secondary Endpoints 
Bullet 1 
Replace: 
correlation between changes in intratumoral CD8+ cell density during treatment 
(in injected and uninjected lesions) and ORR, DRR, DOR, and changes in tumor burden 
With: 
correlation between changes in intratumoral CD8+ cell density during treatment and 
ORR, DRR, DOR, and changes in tumor burden 
Section:  Synopsis, Study Design 
Paragraph 3 
Replace: 
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene 
laherparepvec and for survival every 12 weeks (± 28 days) for up to approximately 


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Protocol Number:  20120325 
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24 months after the last subject is enrolled. Thereafter, subjects will be followed under 
an ongoing separate registry protocol (Study 20120139) for the long-term survival 
follow-up of subjects treated with talimogene laherparepvec.  The registry protocol will 
also monitor for late and long-term adverse events thought to be potentially related to 
talimogene laherparepvec. 
With: 
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene 
laherparepvec and for survival every 12 weeks (± 28 days) for up to approximately 
24 months after the last subject is enrolled in the study. Thereafter, subjects will be 
followed under an ongoing separate registry protocol (Study 20120139) for the long-term 
survival follow-up of subjects treated with talimogene laherparepvec.  The registry 
protocol will also monitor for late and long-term adverse events thought to be potentially 
related to talimogene laherparepvec and use of anti-cancer therapy for melanoma. 
Section:  Synopsis, Study Design 
Paragraph 4 
Replace: 
Blood and tumor tissue samples will be collected at timepoints outlined in the Schedule 
of Assessments (Table 2). Tumor biopsies will be performed on an uninjected lesion on 
day 1 of week 1, on a different uninjected lesion at week 6 (if available), and at disease 
progression (PDn or PDr beyond 6 months of treatment) on the lesion responsible for 
PD as outlined in Section 7.2.2.  Samples will be analyzed to explore if intratumoral 
CD8+ cell density at baseline and its change during treatment is correlated with the 
objective response rate in subjects with unresected stage IIIB-IVM1c melanoma treated 
with talimogene laherparepvec.  
With: 
Blood and tumor tissue samples will be collected at timepoints outlined in the Schedule 
of Assessments (Table 2). Tumor biopsies (taken from accessible cutaneous, 
subcutaneous or nodal lesions) will be performed on an uninjected lesion on day 1 of 
week 1, on a different uninjected lesion at week 6 (if available), and at disease 
progression that results in treatment discontinuation from the lesion responsible for 
progression as outlined in Section 7.2.2. Samples will be analyzed to explore if 
intratumoral CD8+ cell density at baseline and its change during treatment is correlated 


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Protocol Number:  20120325 
Date:  21 September 2015 
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with the objective response rate in subjects with unresected stage IIIB-IVM1c melanoma 
treated with talimogene laherparepvec.  
Section:  Synopsis, Key Inclusion Criteria 
Replace: 
Male or female ≥ 18 years of age with histologically confirmed diagnosis of stage IIIB to 
IVMIc melanoma for whom surgery is not recommended.  Subject must be treatment 
naïve with no prior systemic anticancer treatment for melanoma.  Subject must have 
measurable disease and must be a candidate for intralesional therapy with at least 
1 injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest 
diameter) or with multiple injectable lesions that in aggregate have a longest diameter of 
≥ 10 mm.  Also, subject must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 and must have a serum lactate dehydrogenase (LDH) 
≤ 1.5 X upper limit of normal and adequate hematologic, hepatic, and renal organ 
function. 
With: 
Male or female ≥ 18 years of age with histologically confirmed diagnosis of stage IIIB to 
IVMIc melanoma for whom surgery is not recommended.  Subject who is treatment 
naïve or had received prior treatment for melanoma.  Subject must have measurable 
disease and must be a candidate for intralesional therapy with at least 1 injectable 
cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or 
with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.  
Also, subject must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 and must have a serum lactate dehydrogenase (LDH) ≤ 1.5 X upper limit 
of normal and adequate hematologic, hepatic, and renal organ function. 
Section:  Synopsis, Key Exclusion Criteria 
Replace: 
Subject must not have clinically active cerebral metastases, greater than 3 visceral 
metastases (this does not include lung or nodal metastases associated with visceral 
organs), or any bone metastases, primary ocular or mucosal melanoma, or history or 
evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or 
other symptomatic autoimmune disease.  Subject must not have evidence of clinically 
significant immunosuppression or active herpetic skin lesions or prior complications of 


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HSV-1 infection (eg, herpetic keratitis or encephalitis) and must not require intermittent 
or chronic systemic treatment with an antiherpetic drug (eg, acyclovir), other than 
intermittent topical use.  Subjects known to have acute or chronic active hepatitis B, 
hepatitis C, or human immunodeficiency virus infection will also be excluded.  Subjects 
must not have any nononcology vaccine therapies used for the prevention of infectious 
disease within 28 days prior to enrollment and must not have been treated previously 
with talimogene laherparepvec. 
With: 
Subject must not have clinically active cerebral metastases, greater than 3 visceral 
metastases (this does not include lung or nodal metastases associated with visceral 
organs), or any bone metastases, primary ocular or mucosal melanoma, history or 
evidence of symptomatic autoimmune disease (such as pneumonitis, 
glomerulonephritis, vasculitis, or other) or history of autoimmune disease that 
required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs 
or biological agents used for treatment of autoimmune diseases) in past 2 months 
prior to enrollment.  Replacement therapy (eg, thyroxine for hypothyroidism, 
insulin for diabetes mellitus) is not considered a form of systemic treatment for 
autoimmune disease.  Subject must not have evidence of clinically significant 
immunosuppression or active herpetic skin lesions or prior complications of HSV-1 
infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or 
chronic systemic treatment with an antiherpetic drug (eg, acyclovir), other than 
intermittent topical use.  Subjects known to have acute or chronic active hepatitis B, 
hepatitis C, or human immunodeficiency virus infection will also be excluded.  Subjects 
must not have been treated previously with talimogene laherparepvec. 
Section:  Synopsis, Screening 
Bullet 8 
Delete: 
photographs of visible cutaneous and subcutaneous tumor lesions (select sites only) 


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Section:  Synopsis, Treatment  
Bullet 2 
Add: 
physical examination 
Section:  Synopsis, Treatment 
Bullet 3 
Add: 
ECOG Performance Status assessment 
Section:  Synopsis, Treatment  
Bullet 6, subbullet 2 
Replace: 
blood samples for herpes simplex virus (HSV-1) antibody serostatus 
With: 
blood samples for herpes simplex virus (HSV) serostatus 
Section:  Synopsis, Treatment 
Bullet 8 
Replace: 
photographs of visible cutaneous and subcutaneous tumor lesions (select sites only) 
With: 
photographs of all visible cutaneous and subcutaneous tumor lesions (select sites only) 
always within 3 days of the treatment visit starting from the first treatment visit 
Section:  Synopsis, Treatment 
Bullet 10 
Replace: 
administration of talimogene laherparepvec at day 1 of each cycle 


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With: 
administration of talimogene laherparepvec at day 1 of each treatment cycle 
Section:  Synopsis, Long-term Follow-up/End of Study 
Paragraph 1 
Replace: 
All subjects who permanently discontinue talimogene laherparepvec for any reason 
other than withdrawal of full consent or death will be contacted by telephone or clinic visit 
to assess survival every 12 weeks (± 28 days) following the safety follow-up visit until 
death, subject withdraws full consent, or up to 24 months after the last subject is 
enrolled.   
With: 
All subjects who permanently discontinue talimogene laherparepvec for any reason 
other than withdrawal of full consent or death will be contacted by telephone or clinic visit 
to assess survival, adverse events thought by the investigator to be potentially 
related to talimogene laherparepvec, and use of anti-cancer therapies for 
melanoma every 12 weeks (± 28 days) following the safety follow-up visit until death, 
subject withdraws full consent, or up to 24 months after the last subject is enrolled in the 
study.   
Section:  Synopsis, Long-term Follow-up/End of Study 
Paragraph 2 
Replace: 
If subject has discontinued talimogene laherparepvec for reason other than disease 
progression or death, radiographic tumor imaging, clinical tumor assessments, and 
tumor response assessments will be performed until documented disease progression 
beyond 6 months of treatment, per modified WHO response criteria (Appendix D), or 
until the start of a new anticancer therapy. 
With: 
If subject has discontinued talimogene laherparepvec for reason other than disease 
progression or death, radiographic tumor imaging, clinical tumor assessments, ECOG 
Performance Status assessment, assessment of swabs of lesions of suspected 


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herpetic origin by qPCR for talimogene laherparepvec DNA, and tumor response 
assessments will be performed until documented disease progression beyond 6 months 
of treatment, per modified WHO response criteria (Appendix D), or until the start of a 
new anticancer therapy or end of study, whichever the earliest. 
Section:  Synopsis, Long-term Follow-up/End of Study 
Paragraph 3 
Replace: 
After the long term follow-up period of this study has ended, subjects who end the study 
for any reason other than death or withdrawal of full consent will be followed for survival 
under an ongoing separate registry protocol (Study 20120139) that is in place for the 
long-term follow-up of all subjects treated with talimogene laherparepvec in clinical trials.  
The registry protocol will also monitor for late and long-term adverse events thought to 
be potentially related to talimogene laherparepvec. 
With: 
After the long term follow-up period of this study has ended, subjects who end the study 
for any reason other than death or withdrawal of full consent will be followed for survival 
under an ongoing separate registry protocol (Study 20120139) that is in place for the 
long-term follow-up of all subjects treated with talimogene laherparepvec in clinical trials.  
The registry protocol will also monitor for late and long-term adverse events thought to 
be potentially related to talimogene laherparepvec and use of anti-cancer therapies 
for melanoma. 
Section:  Synopsis, Statistical Consideration 
Paragraph 2 
Replace: 
The main goals of the primary analysis are to evaluate the correlation between baseline 
intratumoral CD8+ cell density and ORR,DRR,DOR, and changes in tumor burden, in 
addition to the correlation between changes in CD8+ cell density during treatment (in 
injected and uninjected lesions) and ORR,DRR,DOR, and changes in tumor burden. The 
timing of the primary analysis will be when all subjects have had the opportunity to 
complete 12 months of treatment with talimogene laherparepvec. The final analysis will 


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occur when the last subject discontinues the study treatment and has had the 
opportunity to complete the long term follow-up. 
With: 
The main goals of the primary analysis are to evaluate the correlation between baseline 
intratumoral CD8+ cell density and ORR,DRR,DOR, and changes in tumor burden, in 
addition to the correlation between changes in intratumoral CD8+ cell density during 
treatment and ORR,DRR,DOR, and changes in tumor burden. The timing of the primary 
analysis will be when all subjects have had the opportunity to complete 12 months of 
treatment with talimogene laherparepvec. The final analysis will occur when the last 
subject discontinues the study treatment and has had the opportunity to complete the 
long term follow-up. 
Section:  Synopsis, Statistical Consideration 
Paragraph 3 
Add: 
An interim analysis to evaluate the study objectives will be conducted on 
approximately the first 50 subjects who received at least 1 dose of talimogene 
laherparepvec, with the biomarker recorded at baseline, and have had the 
opportunity to be in the study (treatment or follow-up) for 6 months. 
Section:  Synopsis, Statistical Consideration 
Paragraph 4 
Replace: 
The final analysis will occur when the last subject discontinues the study treatment and 
has had the opportunity to complete the long term follow-up. 
With: 
The final analysis will occur either 24 months after the last subject has been enrolled 
or when the last subject discontinues the study treatment and has had the opportunity to 
complete the safety follow-up, whichever is later. 


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Section:  Study Glossary 
Delete: 
AE(s) 
adverse event(s) 
Section:  Study Glossary 
Add: 
HLA 
human leukocyte antigen 
Section:  1.2 Secondary 
Bullet 2 
Replace: 
to explore the correlation between changes in intratumoral CD8+ cell density during 
treatment (in injected and uninjected lesions) and ORR, DRR, DOR, and changes in 
tumor burden 
With: 
to explore the correlation between changes in intratumoral CD8+ cell density during 
treatment and ORR, DRR, DOR, and changes in tumor burden 
Section:  2.1 Melanoma 
Paragraph 1, sentence 1 
Replace: 
Cutaneous melanoma is the fifth most common cancer in men and the seventh most 
common cancer in women in the United States of America (USA), with an estimated 
76,100 new cases and 9,710 deaths expected in 2014 (Siegel et al, 2014). 
With: 
Cutaneous melanoma is the fifth most common cancer in men and the seventh most 
common cancer in women in the United States of America (USA), with an estimated 
73,870 new cases and 9,940 deaths expected in 2015 (Siegel et al, 2015). 


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Section:  2.1 Melanoma 
Paragraph 3, sentence 3 
Delete: 
For example, dacarbazine or temozolomide achieved a 7% to 12% objective response 
rate (ORR), but an objective response did not appear to be associated with a 
prolongation in overall survival 
Section:  2.1 Melanoma 
Paragraph 4, sentence 1 
Replace: 
Recently, the Food and Drug Administration (FDA), European Commission, and other 
regulatory agencies have approved 4 novel therapies for advanced melanoma:  an 
immune stimulatory agent, ipilimumab (Yervoy®, 2013), and 3 agents for use in patients 
with BRAF mutant melanoma, a v-raf murine sarcoma viral oncogene homolog 
B1 (BRAF) inhibitor, vemurafenib (Zelboraf®, 2013), the BRAF inhibitor dabrafenib 
(Tafinlar™, 2013) and the MEK inhibitor trametinib (Mekinist™, 2013). 
With: 
Recently, the Food and Drug Administration (FDA), European Commission, and other 
regulatory agencies have approved 6 novel therapies for advanced melanoma:  an 
immune stimulatory agent, ipilimumab (Yervoy®, 2015), pembrolizumab (Keytruda®, 
2015) and nivolumab (Opdivo®, 2015) and 3 agents for use in patients with BRAF 
mutant melanoma, a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor, 
vemurafenib (Zelboraf®, 2015), the BRAF inhibitor dabrafenib (Tafinlar™, 2013) and the 
MEK inhibitor trametinib (Mekinist™, 2014). 
Section:  2.1 Melanoma 
Paragraph 4, sentence 3 
Replace: 
The pivotal study of ipilimumab showed an overall survival (OS) improvement in subjects 
with HLA-A2*0201 genotype previously treated metastatic melanoma as compared with 
a gp100 peptide vaccine (Hodi et al, 2010; Yervoy 2013). 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 13 of 69 
CONFIDENTIAL 
 
 
With: 
The pivotal study of ipilimumab showed an overall survival (OS) improvement in subjects 
with human leukocyte antigen (HLA)-A2*0201 genotype previously treated metastatic 
melanoma as compared with a gp100 peptide vaccine (Hodi et al, 2010; Yervoy 2015). 
Section:  2.1 Melanoma 
Paragraph 6 
Replace: 
In 2013, regulatory agencies also approved the BRAF inhibitor dabrafenib 
(Tafinlar™, 2013) and the MEK  inhibitor trametinib (Mekinist™, 2013), both in BRAFV600 
mutant advanced melanoma.  Each agent showed a benefit in progression-free survival 
compared to dacarbazine in Phase 3 trials (Hauschild et al, 2012; Flaherty et al, 2012a), 
though cross-over and short duration of follow-up to date limits interpretation of overall 
survival.  Additionally, dabrafenib and trametinib were approved recently as a 
combination therapy for BRAF-mutant unresectable or metastatic melanoma. 
(Flaherty et al, 2012b). 
With: 
In 2013, regulatory agencies also approved the BRAF inhibitor dabrafenib 
(Tafinlar™, 2013) and the MEK  inhibitor trametinib (Mekinist™, 2014), both in BRAFV600 
mutant advanced melanoma.  Each agent showed a benefit in progression-free survival 
compared to dacarbazine in Phase 3 trials (Hauschild et al, 2012; Flaherty et al, 2012a).  
Additionally, dabrafenib and trametinib were approved recently as a combination therapy 
for BRAF-mutant (V600 E/K) unresectable or metastatic melanoma. (Flaherty et al, 
2012b; Long et al, 2015; Robert et al, 2015). 
Section:  2.1 Melanoma 
Paragraph 7 
Add: 
Nivolumab, an anti-PD-1 monoclonal antibody, demonstrated improvement in 
1-year OS in treatment naïve subjects with wild-type BRAF advanced melanoma 
compared  to dacarbazine (73% versus 42%; HR 0.42, 99.8% CI 0.25-0.73) (Robert 
et al, 2015); improved ORR  in subjects  previously treated with either ipilimumab 
or BRAF inhibitor versus dacarbazine or carboplatin with paclitaxel (32% vs 10%) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 14 of 69 
CONFIDENTIAL 
 
 
(Weber et al, 2015), and improved PFS and ORR (either alone or in combination 
with ipilimumab) compared to  ipilimumab alone in treatment naïve subjects 
(Larkin et al, 2015). 
Section:  2.1 Melanoma 
Paragraph 8 
Add: 
Pembrolizumab, is a monoclonal antibody that targets PD-1 protein, improved PFS 
and OS versus ipilimumab in subjects with advanced melanoma. Six-month 
progression-free rates were 47% and 46%, for pembrolizumab administered every 
2 and 3 weeks, versus 27% for ipilimumab (HR 0.58; P<0.001 for both 
pembrolizumab regimens versus ipilimumab). Twelve-months OS rates were 74%, 
68%, and 58%, respectively (HR 0.63, P=0.0005 for pembrolizumab every 2  weeks 
and 0.69, P=0.004 for pembrolizumab every  3 weeks) (Robert et al, 2015) 
Section:  2.1 Melanoma 
Paragraph 9, sentence 3 
Add: 
Although not as common and severe as with ipilimumab, a wide range of immune 
related toxicities has been reported with permbrolizumab and nivolumab, which 
include pneumonitis, hepatitis, colitis, nephritis, thyroid dysfunction and others 
(Larkin et al, 2015; Robert et al, 2015; Weber et al, 2015). 
Section:  2.1 Melanoma 
Paragraph 9, sentence 3 
Replace: 
The safety profiles of vemurafenib and dabrafenib include increased incidence of 
cutaneous squamous cell carcinoma or high grade keratoacanthoma in almost 20% of 
patients treated with vemurafenib and > 5% of patients treated with dabrafenib 
(Zelboraf®, 2013; Tafinlar™, 2013). 
With: 
The safety profiles of vemurafenib and dabrafenib include increased incidence of 
cutaneous squamous cell carcinoma or high grade keratoacanthoma in almost 20% of 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 15 of 69 
CONFIDENTIAL 
 
 
patients treated with vemurafenib and > 5% of patients treated with dabrafenib 
(Zelboraf®, 2015; Tafinlar™, 2013). 
Section:  2.1 Melanoma 
Paragraph 9, sentence 7 
Replace: 
Trametinib is associated with cuneiform dermatitis, peripheral edema, hypertension, 
decreased cardiac ejection fraction, and ocular events (Mekinist™, 2013). 
With:  
Trametinib is associated with cuneiform dermatitis, peripheral edema, hypertension, 
decreased cardiac ejection fraction, and ocular events (Mekinist™, 2014). 
Section:  2.1 Melanoma 
Paragraph 10, sentence 7 
Replace: 
The prognostic value of immunoscores composed of a combination of 
immunohistochemical staining densities for both intratumoral CD3+ and CD8+ T cells, 
combined with the location of the cells either in the invasive margin or central tumor, has 
been well documented in colon cancer and was shown to have a prognostic significance 
superior to that of the AJCC TNM classification system (Galon et al, 2006, Galon et al, 
2012). 
With: 
The prognostic value of immunoscores composed of a combination of 
immunohistochemical staining densities for both intratumoral CD3+ / CD8+ T cells, 
combined with the location of the cells either in the invasive margin or central tumor, has 
been well documented in colon cancer and was shown to have a prognostic significance 
superior to that of the AJCC TNM classification system (Galon et al, 2006, 
Galon et al, 2012). 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 16 of 69 
CONFIDENTIAL 
 
 
Section:  2.1 Melanoma 
Paragraph 10, sentence 3 
Replace: 
In the current study we will measure tumor antigen-specific T cell responses induced by 
talimogene laherparepvec treatment in order to explore the association between the 
cytotoxic T cell response and response to treatment. 
With: 
In the current study we will measure tumor antigen-specific T cell responses induced by 
talimogene laherparepvec treatment in order to further explore mechanisms of action. 
Section:  2.1 Melanoma 
Paragraph 11 
Add: 
Furthermore, baseline tumor mutational load and corresponding neoantigen 
signatures have been shown to correlate with responsiveness to immunotherapy 
(Rizvi et al, 2015; Snyder et al, 2014).  It will be important to understand if tumor 
mutational load can be predictive for response to talimogene laherparepvec as 
well. 
Section:  2.2  Talimogene Laherparepvec Investigational Product Background 
Paragraph 1, sentence 1 
Replace: 
Talimogene laherparepvec is an intralesionally delivered oncolytic immunotherapy 
comprised of a genetically engineered HSV-1(herpes simplex virus type 1) that 
selectively replicates in tumor tissue (Talimogene Laherparepvec Investigator’s 
Brochure, 2014). 
With: 
Talimogene laherparepvec is an intralesionally delivered oncolytic immunotherapy 
comprised of a genetically engineered HSV-1(herpes simplex virus type 1) that 
selectively replicates in tumor tissue (Talimogene Laherparepvec Investigator’s 
Brochure). 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 17 of 69 
CONFIDENTIAL 
 
 
Section:  2.2  Talimogene Laherparepvec Investigational Product Background 
Paragraph 3, sentences 1 and 2 
Replace: 
Clinical data currently available has provided evidence of talimogene laherparepvec’s 
efficacy in patients with regionally and distantly metastatic melanoma (Talimogene 
Laherparepvec Investigator’s Brochure, 2014).  In particular, a high rate of complete 
response (CR) was achieved (16% in the phase 2 study with talimogene laherparepvec 
in stage lllC to IV melanoma) (Senzer et al, 2009; Talimogene Laherparepvec 
Investigator’s Brochure, 2014). 
With: 
Clinical data currently available has provided evidence of talimogene laherparepvec’s 
efficacy in patients with regionally and distantly metastatic melanoma (Talimogene 
Laherparepvec Investigator’s Brochure).  In particular, a high rate of complete response 
(CR) was achieved (16% in the phase 2 study with talimogene laherparepvec in stage 
lllC to IV melanoma) (Senzer et al, 2009; Talimogene Laherparepvec Investigator’s 
Brochure). 
Section:  2.2 Talimogene Laherparepvec Investigational Product Background 
Paragraph 1, sentence 3 
Replace: 
The role of ICP47 is to block antigen presentation to major histocompatibility complex 
class I and II molecules by blocking the transporter associated with antigen processing 
1 and 2. 
With: 
The role of ICP47 is to block antigen presentation to major histocompatibility complex 
class I molecules by blocking the transporter associated with antigen processing 
1 and 2. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 18 of 69 
CONFIDENTIAL 
 
 
Section:  2.2 Talimogene Laherparepvec Investigational Product Background 
Paragraph 5 
Replace: 
Primary analysis of the OPTiM Study showed a statistically significant difference 
between the rate of durable response among subjects treated with talimogene 
laherparepvec (16%; 95% CI:  12%, 21%) versus those treated with GM-CSF (2%; 95% 
CI:  0%, 5%) (p-value < 0.0001).  A trend toward improved OS was also seen in a 
preplanned interim analysis (HR 0.79; 95% CI:  0.61, 1.02; p-value = 0.07) 
(Andtbacka et al, 2013).  Survival at 12, 24, and 36 months in the talimogene 
laherparepvec arm was estimated to be 74%, 50%, and 41%, respectively, and 69%, 
41%, and 28% in the GM-CSF arm, respectively.  The most common side effects were 
fatigue, chills, and pyrexia.  Serious adverse events occurred in 26% of the talimogene 
laherparepvec subjects and 13% of the GM-CSF subjects.  No grade 3/4 adverse events 
occurred in ≥ 3% of subjects in either arm. 
With: 
Primary analysis of the OPTiM Study showed a statistically significant difference 
between the rate of durable response among subjects treated with talimogene 
laherparepvec (16%; 95% CI:  12%, 21%) versus those treated with GM-CSF (2%; 95% 
CI:  0%, 5%) (p-value < 0.0001).  Overall response rate was also improved from 
6% with GM-CSF to 26% with talimogene laherparepvec (P < 0.0001, descriptive).  
Similarly, 11% of patients had a CR in the talimogene laherparepvec arm versus 
< 1% in the GM-CSF arm.  In the event-driven primary OS analysis (secondary end 
point), median OS with talimogene laherparepvec treatment was 23.3 months 
compared with 18.9 months with GM-CSF treatment (HR, 0.79 [95% CI, 0.62‒1.00]; 
P=0.051) (Andtbacka et al, 2015).  At the final planned analysis of OS which 
happened when last enrolled subject completed 3 years of follow-up, median OS 
was 23.3 months in the talimogene laherparepvec arm and 18.9 months in the 
GM-CSF arm (HR, 0.79; 95% CI, 0.62‒1.00; P=0.049, (descriptive) (Andtbacka et al, 
2015).   
The most common side effects were fatigue, chills, and pyrexia.  Serious adverse events 
occurred in 36% of the talimogene laherparepvec subjects and 21% of the GM-CSF 
subjects.  The only grade 3/4 adverse event occurring in ≥ 2% of patients was 
cellulitis (talimogene laherparepvec, n=6 [2.1%]; GM CSF, n=1 [< 1%]).  Of 10 fatal 


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Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 20 of 69 
CONFIDENTIAL 
 
 
Section:  3.1 Study Design 
Paragraph 2, sentence 3 
Replace: 
Due to the mechanism of action, subjects may experience growth in existing tumors or 
the appearance of new tumors prior to maximal clinical benefit of talimogene 
laherparepvec. 
With: 
Due to the mechanism of action, subjects may experience transient growth of existing 
tumors or the appearance of new tumors prior to achieving maximal clinical benefit of 
talimogene laherparepvec. 
Section:  3.1 Study Design 
Paragraph 3 
Replace: 
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene 
laherparepvec and for survival every 12 weeks (± 28 days) for up to approximately 
24 months after the last subject is enrolled. Thereafter, subjects will be followed under 
an ongoing separate registry protocol (Study 20120139) for the long-term survival 
follow-up of subjects treated with talimogene laherparepvec. The registry protocol will 
also monitor for late and long-term adverse events thought to be potentially related to 
talimogene laherparepvec. 
With: 
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene 
laherparepvec for survival,  adverse events thought by the investigator to be 
potentially related to talimogene laherparepvec, and use of anticancer therapies 
for melanoma every 12 weeks (± 28 days) for up to approximately 24 months after the 
last subject is enrolled in the study.  Thereafter, subjects will be followed under an 
ongoing separate registry protocol (Study 20120139) for the long-term survival follow-up 
of subjects treated with talimogene laherparepvec.  The registry protocol will also 
monitor for late and long-term adverse events thought by the investigator to be 
potentially related to talimogene laherparepvec and use of anti-cancer therapies for 
melanoma. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 21 of 69 
CONFIDENTIAL 
 
 
Section:  3.1 Study Design 
Paragraph 4 
Replace: 
Blood and tumor tissue samples will be collected at timepoints outlined in the Schedule 
of Assessments (Table 2).  Tumor biopsies will be performed on an uninjected lesion on 
day 1 of week 1, on a different uninjected lesion at week 6 (if available), and at disease 
progression (PDn or PDr beyond 6 months of treatment) on the lesion responsible for 
PD as outlined in Section 7.2.2.  Samples will be analyzed to explore if intratumoral 
CD8+ cell density at baseline and its change during treatment is correlated with the 
objective response rate in subjects with unresected stage IIIB-IVM1c melanoma treated 
with talimogene laherparepvec.  
With: 
Blood and tumor tissue samples will be collected at timepoints outlined in the Schedule 
of Assessments (Table 2). Tumor biopsies will be performed from an uninjected lesion 
on day 1 of week 1, from a different uninjected lesion at week 6 (if available), and from 
the lesion responsible for progression at the time of disease progression that 
results in treatment discontinuation as outlined in Section 7.2.2.  Samples will be 
analyzed to explore if intratumoral CD8+ cell density at baseline and its change during 
treatment is correlated with the objective response rate in subjects with unresected 
stage IIIB-IVM1c melanoma treated with talimogene laherparepvec.  
Section:  3.2 Number of Sites 
Replace: 
Approximately 35 sites in Europe and the USA will participate in the study. Additional 
sites and regions may be added to the study as necessary.  Sites that do not enroll 
subjects within 4 months of site initiation may be closed. 
With: 
Approximately 50 sites in Europe and the USA will participate in the study.  Additional 
sites and regions may be added to the study as necessary.  Sites that do not enroll 
subjects within 6 months of site initiation may be closed. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 22 of 69 
CONFIDENTIAL 
 
 
Section:  3.5.1 Study Duration for Subjects 
Paragraph 2 
Replace: 
The duration of the screening period for each subject will be up to 28 days.  The duration 
of treatment will vary for each subject.  Subjects will be treated with talimogene 
laherparepvec until the subject has achieved a CR, all injectable tumors have 
disappeared, clinically relevant (resulting in clinical deterioration or requiring change in 
therapy) disease progression beyond 6 months of treatment, per modified WHO 
response criteria (Appendix D), or intolerance of study treatment, whichever occurs first.  
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene 
laherparepvec and for survival every 12 weeks (± 28 days) for up to approximately 
24 months after the last subject is enrolled.  The estimated average per-subject study 
duration is approximately 32 months. 
With: 
The duration of the screening period for each subject will be up to 28 days.  The duration 
of treatment will vary for each subject.  Subjects will be treated with talimogene 
laherparepvec until the subject has achieved a CR, all injectable tumors have 
disappeared, clinically relevant (resulting in clinical deterioration or requiring change in 
therapy) disease progression beyond 6 months of treatment, per modified WHO 
response criteria (Appendix D), or intolerance of study treatment, whichever occurs first.  
Subjects will be followed for safety 30 (+ 7) days after the last dose of talimogene 
laherparepvec and for survival, adverse events thought by the investigator to be 
potentially related to talimogene laherparepvec, and use of anti-cancer therapy for 
melanoma every 12 weeks (± 28 days) for up to approximately 24 months after the last 
subject is enrolled in the study.  The estimated average per-subject study duration is 
approximately 32 months. 
Section:  3.5.1 Study Duration for Subjects 
Paragraph 3 
Add: 
After the end of the long term follow up subjects who end the study for any reason 
other than death or withdrawal of full consent will continue to be followed for 
survival under an ongoing separate registry protocol (Study 20120139).  The 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 23 of 69 
CONFIDENTIAL 
 
 
registry protocol will also monitor for adverse events thought by the investigator 
to be potentially related to talimogene laherparepvec and use of anti-cancer 
therapies for melanoma. 
Section:  3.5.2 End of Study 
Paragraph 2 
Replace: 
End of Trial
With: 
:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study.  The end of study will occur when the last subject discontinues 
talimogene laherparepvec and has had the opportunity to complete the safety follow-up 
visit or the last long term follow-up visit, whichever occurs later. 
End of Trial
Section:  4.1.1 Inclusion Criteria 
:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study.  The end of study will occur 24 months after the last subject 
has been enrolled or when the last subject discontinues talimogene laherparepvec and 
has had the opportunity to complete the safety follow-up visit, whichever occurs later. 
Criterion 105 
Replace: 
Subject who is treatment naïve:  must not have received any prior systemic anticancer 
treatment consisting of chemotherapy, immunotherapy, or targeted therapy for 
unresected stage IIIB to IVM1c melanoma 
• 
subjects who received prior adjuvant therapy for melanoma may be eligible as long 
as prior adjuvant therapy was completed at least 6 months prior to enrollment 
With: 
Subject who is treatment naïve or had received prior treatment for melanoma. Any 
systemic treatment for melanoma must have been completed at least 28 days 
prior to enrollment 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 24 of 69 
CONFIDENTIAL 
 
 
Section:  4.1.2 Exclusion Criteria 
Criterion 201 
Replace: 
Clinically active cerebral metastases.  Subjects with up to 3 (neurological performance 
status of 0) cerebral metastases may be enrolled, provided that all lesions have been 
adequately treated with stereotactic radiation therapy (including Gamma Knife) or 
craniotomy, with no evidence of progression and have not required steroids for at least 
two months prior to enrollment. 
With: 
Clinically active cerebral metastases. Subjects with up to 3 cerebral metastases may be 
enrolled, provided that all lesions have been adequately treated with stereotactic 
radiation therapy (including Gamma Knife) or resection, with no evidence of progression 
and have not required steroids for at least two months prior to enrollment. 
Section:  4.1.2 Exclusion Criteria 
Criterion 205 
Replace: 
History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, 
vasculitis, or other symptomatic autoimmune disease 
With: 
History or evidence of symptomatic autoimmune disease (such as pneumonitis, 
glomerulonephritis, vasculitis, or other), or history of autoimmune disease that 
required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs 
or biological agents used for treatment of autoimmune diseases) in past 2 months 
prior to enrollment.  Replacement therapy (eg, thyroxine for hypothyroidism, 
insulin for diabetes mellitus) is not considered a form of systemic treatment for 
autoimmune disease. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 25 of 69 
CONFIDENTIAL 
 
 
Section:  4.1.2 Exclusion Criteria 
Criterion 206, bullet 3 
Replace: 
 
receiving systemic immunosuppressive therapy (> 2 weeks), including oral steroid 
doses > 10 mg/day of prednisone or equivalent 
With: 
 
receiving systemic immunosuppressive therapy (> 2 weeks), including oral  steroid 
doses > 10 mg/day of prednisone or equivalent during the 2 months prior to 
enrollment 
Section:  4.1.2 Exclusion Criteria 
Criterion 210 
Delete: 
Any nononcology vaccine therapies used for the prevention of infectious disease within 
28 days prior to enrollment and during treatment period 
Section:  4.1.2 Exclusion Criteria 
Criterion 216, bullet 2 
Replace: 
adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease 
With: 
adequately treated non-melanoma skin cancer without evidence of disease 
Section:  4.1.2 Exclusion Criteria 
Criterion 223 
Add: 
Sexually active subjects and their partners unwilling to use male or female latex 
condom to avoid potential viral transmission during sexual contact while on 
treatment and within 30 days after treatment with talimogene laherparepvec. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 26 of 69 
CONFIDENTIAL 
 
 
Section:  6.1 Classification of Product 
Paragraph 2 
Replace: 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, and 
administration of talimogene laherparepvec. 
With: 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the description, storage, preparation, 
and administration of talimogene laherparepvec. 
Section:  6.2.1 Amgen Investigational Product Talimogene Laherparepvec 
Paragraph 1, sentence 3 
Replace: 
Each vial contains a minimum of 1.0 mL talimogene laherparepvec at either 10⁶ PFU/mL 
(green cap) or 10⁸ PFU/mL (blue cap) concentrations. 
With: 
Each vial contains a minimum of 1.0 mL talimogene laherparepvec at either 10⁶ PFU/mL  
or 10⁸ PFU/mL  concentrations. 
Section:  6.2.1 Amgen Investigational Product Talimogene Laherparepvec 
Paragraph 1, sentence 5 
Add: 
Additional details on talimogene laherparepvec packaging and formulation are 
provided in the Investigational Product Instruction Manual. 
Section:  6.2.1.1 Dosage, Administration, and Schedule 
Paragraph 1 
Replace: 
Talimogene laherparepvec must be prepared and administered by a qualified healthcare 
professional.  Subjects should be assessed clinically for adverse events/toxicity prior to 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 27 of 69 
CONFIDENTIAL 
 
 
each dose using the Common Terminology Criteria for Adverse Events (CTCAE) 
version 3.0 (Appendix A).  Complete blood count with differential and chemistry panels 
including liver function laboratory tests (such as ALT, AST, and total bilirubin) should be 
obtained according to the Schedule of Assessments (see Table 2) and the results should 
be checked before each scheduled dose.  Dosing will occur only if these test values are 
acceptable, per Section 6.2.1.2. 
With: 
Talimogene laherparepvec must be prepared and administered by a qualified healthcare 
professional.  Subjects should be assessed clinically for adverse events/toxicity prior to 
each dose using the Common Terminology Criteria for Adverse Events (CTCAE) 
version 3.0 (Appendix A).  Complete blood count with differential and chemistry panels 
including liver function laboratory tests (such as ALT, AST, and total bilirubin) should be 
obtained according to the Schedule of Assessments (see Table 2) and the results should 
be checked before scheduled doses as per the requirements described in the 
Schedule of Assessments.  Dosing will occur only if these test values are acceptable, 
per Section 6.2.1.2. 
Section:  6.2.1.1 Dosage, Administration, and Schedule 
Paragraph 6, sentence 1 
Replace: 
At baseline, if there are ≥ 2 lesions, one lesion (ie, the lesion considered lowest priority 
for injection) should be left uninjected at least until it is biopsied at week 6  
(see Section 7.2.2). 
With: 
At baseline, if there are ≥ 2 lesions, one cutaneous, subcutaneous or nodal lesion (ie, 
the lesion considered lowest priority for injection) should be left uninjected at least until it 
is biopsied at week 6  (see Section 7.2.2). 
Section:  6.2.1.1 Dosage, Administration, and Schedule 
Paragraph 6, sentence 2 
Add: 
(No biopsy will be taken at week 6 for subjects with 1 lesion present at baseline).   


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 28 of 69 
CONFIDENTIAL 
 
 
Section:  6.2.1.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Paragraph 3 
Replace: 
Subjects who are receiving talimogene laherparepvec may not receive systemic 
antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir), but may receive a topically 
administered antiherpetic drug more than 20 cm from a talimogene laherparepvec 
injection site.  Dosing should be permanently discontinued if, in the opinion of the 
investigator, the subject develops clinical evidence of any systemic herpes infection 
(such as encephalitis or disseminated infection).  
With: 
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.  If a subject requires treatment with systemic antiherpetic drugs 
(eg, acyclovir, valacyclovir, famciclovir) talimogene laherparepvec should be 
witheld and the investigator or designee should notify the Amgen medical monitor 
as soon as possible.  Subject may be allowed to continue treatment after 
discussion between the Amgen medical monitor and the investigator to determine 
the appropriateness of treatment resumption. 
Dosing should be permanently discontinued if, in the opinion of the investigator, the 
subject develops clinical evidence of any systemic herpes infection (such as encephalitis 
or disseminated infection).  
Section:  6.2.1.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Paragraph 5 
Replace: 
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) 
for related toxicities, talimogene laherparepvec dosing must be withheld until the 
corticosteroid dose has decreased to < 10 mg prednisone daily (or equivalent). 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 29 of 69 
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With: 
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) 
for related toxicities, talimogene laherparepvec dosing must be withheld until the 
corticosteroid dose has decreased to ≤ 10 mg prednisone daily (or equivalent). 
Section:  6.2.1.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Paragraph 10, bullet 6 
Replace: 
A female subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception (for those subjects who are able to conceive).  
With: 
A female subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception (for those subjects who are able to conceive) including but not limited to 
male or female latex condom to avoid potential viral transmission during sexual 
contact. 
Section:  6.2.1.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Paragraph 11 
Replace: 
For additional information related special warnings and precautions for the use of 
talimogene laherparepvec please refer to the latest version of the Talimogene 
Laherparepvec Investigator’s Brochure, 2014. 
With: 
For additional information related special warnings and precautions for the use of 
talimogene laherparepvec please refer to the latest version of the Talimogene 
Laherparepvec Investigator’s Brochure. 


Product:  Talimogene Laherparepvec 
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Section:  6.4 Concomitant Therapy 
Paragraph 2 
Replace: 
All prescription and nonprescription concomitant medication administered up to 28 days 
prior to enrollment, on an ongoing basis at enrollment, as well as changes in such 
concomitant medication, and any new concomitant medication taken while the subject is 
on study, should be recorded on the appropriate case report form (CRF) until 30 days 
(+ 7 days) after the last dose of talimogene laherparepvec.  The therapy name, 
indication, dose, unit, frequency, start date, and stop date will be collected. 
With: 
All prescription and nonprescription concomitant medication administered up to 28 days 
prior to enrollment, on an ongoing basis after enrollment, as well as changes in such 
concomitant medication, and any new concomitant medication taken while the subject is 
on study, should be recorded on the appropriate case report form (CRF) until 30 days 
(+ 7 days) after the last dose of talimogene laherparepvec.  The therapy name, 
indication, dose, unit, frequency, start date, and stop date will be collected. 
Section:  6.5 Other Treatment Procedures 
Paragraph 1, sentence 3 
Replace: 
Additionally, biopsies will be taken of cutaneous or subcutaneous lesions for tumor 
analysis during study. 
With: 
Additionally, biopsies will be taken of cutaneous, subcutaneous or nodal lesions for 
tumor analysis during study. 
Section:  6.5 Other Treatment Procedures 
Paragraph 1, sentence 4 
Replace: 
In the event of a complete response, any residual cutaneous or subcutaneous index 
lesions must be documented by representative biopsy to not contain viable tumor. 


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With: 
In the event of a complete response, residual visible cutaneous or subcutaneous index 
lesions must be documented by representative biopsy to not contain viable tumor. 
Section:  6.5 Other Treatment Procedures 
Paragraph 1, sentence 7 
Replace: 
If no residual disease remains following surgery, this should also be noted in the eCRF, 
the response definition again being PR. 
With: 
If no residual disease remains following surgery, this should also be noted in the eCRF, 
the response definition again being PR with the date of surgery as the date of 
response. 
Section:  6.5 Other Treatment Procedures 
Paragraph 1, sentence 8 
Add: 
If no viable melanoma was found in the surgical specimen, and all other tumor 
lesions resolved completely (if were present), the response definition will be CR 
with the date of surgery as the date of response. 
Section:  6.5 Other Treatment Procedures 
Paragraph 3, sentences 2 and 3 
Replace: 
Subjects may be allowed to remain on protocol after discussion between the Amgen 
medical monitor and the investigator to determine the appropriateness of treatment 
resumption provided CNS lesions can be treated with stereotactic radiotherapy 
(including GammaKnife) or craniotomy and if there is no change in the baseline ECOG 
performance status.  Subjects may be allowed to reinitiate talimogene laherparepvec 
following treatment of CNS metastases while receiving dexamethasone or a similar 
corticosteroid at no more than 1.5 mg dexamethasone (or 10 mg prednisone) per day. 


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Protocol Number:  20120325 
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With: 
Subjects may be allowed to remain on protocol after discussion between the Amgen 
medical monitor and the investigator to determine the appropriateness of treatment 
resumption provided CNS lesions can be treated with stereotactic radiotherapy 
(including GammaKnife) or resection and if there is no change in the baseline ECOG 
performance status.  Subjects may be allowed to reinitiate talimogene laherparepvec 
following treatment of CNS metastases while receiving dexamethasone or a similar 
corticosteroid at no more than 1.5 mg dexamethasone (or 10 mg prednisone, or 
equivalent) per day. 
Section:  6.8 Excluded Treatments and/or Procedures During Study Period 
Bullet 4 
Replace: 
antiherpetic drugs (eg, acyclovir), other than if topically administered > 20 cm from a 
talimogene laherparepvec injection site. 
With: 
antiherpetic drugs (eg, acyclovir), other than if topically administered > 20 cm from a 
talimogene laherparepvec injection site.  If a subject requires treatment with a 
systemic antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir) talimogene 
laherparepvec should be witheld and the investigator or designee should notify 
the Amgen medical monitor as soon as possible.  Subject may be allowed to 
continue treatment after discussion between the Amgen medical monitor and the 
investigator to determine the appropriateness of treatment resumption. 
Section:  6.8 Excluded Treatments and/or Procedures During Study Period 
Bullet 5  
Delete: 
any nononcology vaccine therapies used for the prevention of infectious disease within 
28 days prior to enrollment or randomization and during treatment period 


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Protocol Number:  20120325 
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Section:  6.8 Excluded Treatments and/or Procedures During Study Period 
Bullet 6  
Delete: 
any surgery for melanoma (other than the exceptions noted in Section 6.5 
 


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Section:  7.1 Schedule of Assessments 
Replace: 
  
Screeninga 
Treatment Periodb 
Follow-up Period 
Cyclet 
≤ 28 days 
1 
2 
3 
4 
5 
6 
7 
8 
Cycle 8 and 
Beyond 
Safetyc 
 
Survivald 
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
30 (+7) Days 
 
12 (±28 days) 
Weeks 
GENERAL & SAFETY ASSESSMENTS  
 
 
Concomitant Medicationse 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical Examg 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Swab of Herpetic Lesion for qPCRm 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
X 
 
Blood for HSV-1 Antibody Serostatusn 
 
Within 3 days prior to dose at day 1 of week 1, week 6, and week 12 
 
 
 
Tumor Biopsy for Biomarker Analysisp 
 
Within 3 days prior to dose at day 1 of week 1 and week 6 and at disease 
progression (beyond 6 months of treatment) 
 
 
 
Photographs of Visible Tumor Lesionss 
(Select Sites Only)  
X 
Monthly until End of Treatment 
 
 


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Protocol Number:  20120325 
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With: 
  
Screeninga 
Treatment Periodb 
Follow-up Period 
Cyclet 
≤ 28 days 
1 
2 
3 
4 
5 
6 
7 
8 
Cycle 8 and 
Beyondt 
Safetyc 
 
Survivald 
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
30 (+7) Days 
 
Every 12 (±28 
days) Weeks 
GENERAL & SAFETY ASSESSMENTS  
 
 
Concomitant Medicationse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Thought to Be Related 
to Talimogene Laherprepvecf 
 
X 
 
 
 
 
 
 
 
 
 
X 
Physical Examg 
X 
X 
 
 
 
 
X 
 
 
Q6C 
X 
 
 
ECOG Performance Statusw 
X 
X 
 
 
 
 
X 
 
 
Q6C 
X 
 
 
Anti-cancer therapy for melanomax 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Swab of Herpetic Lesion for qPCRm 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
X 
X 
Blood for HSV Serostatusn 
 
Within 3 days prior to dose at day 1 of week 1, week 6, and week 12 
 
 
 
Tumor Biopsy for Biomarker Analysisp 
 
Within 5 days prior to dose at day 1 of week 1, within 7 days prior to dose at 
week 6 and within 7 days after the documentation of disease progression 
followed by treatment discontinuation 
 
 
 
Photographs of all Visible Tumor Lesionss 
(Select Sites Only) 
 
X 
X 
 
X 
 
X 
 
X 
Q2C 
 
 
 


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Protocol Number:  20120325 
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Section:  7.1 Schedule of Assessments 
Footnote b 
Replace: 
During the treatment period assessments and procedures can be performed within 
3 days of the planned visit. 
With: 
During the treatment period assessments and procedures can be performed within 
3 days of the planned visit unless otherwise specified. 
Section:  7.1 Schedule of Assessments 
Footnote d 
Replace: 
All subjects who permanently discontinue talimogene laherparepvec for any reason 
other than withdraw of full consent or death will be contacted by telephone, or clinic visit, 
to assess survival.  Follow-up will occur every 12 weeks (± 28 days) following the safety 
follow-up visit until death, subject withdraws full consent, or up to 24 months after the 
last subject is enrolled.  After the long term follow-up period has ended, subjects who 
end the study for any reason other than death or withdrawal of full consent will be 
followed for survival under an ongoing separate registry protocol (Study 20120139) that 
is in place for the long-term follow-up of subjects treated with talimogene laherparepvec 
in clinical trials. 
With: 
All subjects who permanently discontinue talimogene laherparepvec for any reason 
other than withdraw of full consent or death will be contacted by telephone, or clinic visit, 
to assess survival.  Adverse events deemed by the investigator to be potentially 
related to talimogene laherparepvec will also be recorded. Follow-up will occur 
every 12 weeks (± 28 days) following the safety follow-up visit until death, subject 
withdraws full consent, or up to 24 months after the last subject is enrolled in the study.  
After the long term follow-up period has ended, subjects who end the study for any 
reason other than death or withdrawal of full consent will be followed for survival under 
an ongoing separate registry protocol (Study 20120139) that is in place for the long-term 
follow-up of subjects treated with talimogene laherparepvec in clinical trials. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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Section:  7.1 Schedule of Assessments 
Footnote e 
Replace: 
All concomitant medications that are administered after the subject has signed informed 
consent through 30 (+7) days after the last administration of talimogene laherparepvec 
will be recorded in the case report form.  Concomitant medications should be assessed 
on an ongoing basis and recorded at each subject visit.  Only subsequent anticancer 
therapy will be recorded during the long term follow-up survival assessment period. 
With: 
All concomitant medications that are administered after the subject has signed informed 
consent through 30 (+7) days after the last administration of talimogene laherparepvec 
will be recorded in the case report form.  Concomitant medications should be assessed 
on an ongoing basis and recorded at each subject visit.  Only subsequent anticancer 
therapy for melanoma will be recorded during the long term follow-up survival 
assessment period. 
Section:  7.1 Schedule of Assessments 
Footnote f 
Replace: 
All nonserious adverse events that occur after enrollment through 30 (+7) days after the 
last administration of talimogene laherparepvec will be recorded in the case report form.  
Adverse events should be assessed on an ongoing basis and recorded at each subject 
visit.  All serious adverse events that occur after the subject has signed the informed 
consent through 30 (+7) days after the last administration of talimogene laherparepvec 
will be reported to Amgen and recorded in the case report form.  Serious adverse events 
must be reported to Amgen within 24 hours of discovery. 
With: 
All nonserious adverse events (related or not related to talimogene laherparepvec) 
that occur after the first dose through 30 (+7) days after the last administration of 
talimogene laherparepvec will be recorded in the case report form.  In addition, all 
adverse events deemed by the investigator to be potentially related to talimogene 
laherparepvec will be recorded in the case report form through the survival 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
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follow-up.  Adverse events should be assessed on an ongoing basis and recorded at 
each subject visit.  All serious adverse events that occur after the subject has signed the 
informed consent through 30 (+7) days after the last administration of talimogene 
laherparepvec will be reported to Amgen and recorded in the case report form.  Serious 
adverse events must be reported to Amgen within 24 hours of discovery. 
Section:  7.1 Schedule of Assessments 
Footnote m 
Replace: 
Swabs of any lesion suspected to be herpetic in origin will be collected as follows:  
Subject should return to clinic within 3 days of the occurrence of reportable lesion 
suspected to be herpetic in origin, such as cold sores or vesicles.  The lesion should be 
evaluated by the investigator and swabbed if HSV infection is suspected.  A qPCR 
analysis will be performed at a central lab on the swab to evaluate whether the 
talimogene laherparepvec DNA is detectable in the sample. 
With: 
Swabs of any lesion suspected to be herpetic in origin will be collected as follows:  
Subject should return to clinic within 3 days of the occurrence of reportable lesion 
suspected to be herpetic in origin, such as cold sores or vesicles.  The lesion should be 
evaluated by the investigator and swabbed if herpetic infection is suspected.  A qPCR 
analysis will be performed at a central lab on the swab to evaluate whether the 
talimogene laherparepvec DNA is detectable in the sample. 
Section:  7.1 Schedule of Assessments 
Footnote n 
Replace: 
Blood sample for HSV-1 antibody serostatus will be collected (within 3 days prior to 
talimogene laherparepvec administration) at day 1 of week 1, week 6, and week 12.  
With: 
Blood sample for HSV serostatus will be collected (within 3 days prior to talimogene 
laherparepvec administration) at day 1 of week 1 [Cycle 1], week 6 [Cycle 3], and 
week 12 [Cycle 6].  


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Section:  7.1 Schedule of Assessments 
Footnote o 
Replace: 
Blood sample for biomarker analysis will be collected (within 3 days prior to talimogene 
laherparepvec administration) at day 1 of week 1, week 6, week 12, and week 24. 
With: 
Blood sample for biomarker analysis will be collected (within 3 days prior to talimogene 
laherparepvec administration) at day 1 of week 1 [Cycle 1], week 6 [Cycle 3], week 12 
[Cycle 6], and week 24 [Cycle 12]. 
Section:  7.1 Schedule of Assessments 
Footnote p 
Replace: 
Tumor biopsy for biomarker analysis (within 3 days prior to talimogene laherparepvec 
administration). from one lesion at day 1 of week 1  and, if there are ≥ 2 lesions at 
baseline and one is left uninjected as described in Section 6.2.1.1, from an uninjected 
lesion at day 1 of week 6. Also at disease progression (beyond 6 months of treatment) 
from the lesion responsible for PD. Note:  uninjected lesion biopsied at day 1 of week 6 
must be different lesion from the lesion biopsied at day 1 of week 1. 
With: 
Tumor biopsy from cutaneous, subcutaneous or nodal lesions for biomarker analysis 
should not be collected prior to the subject being enrolled.  Tumor biopsy should 
be collected (within 5 days prior to first talimogene laherparepvec administration) from 
one lesion at day 1 of week 1 [Cycle 1] and, if there are ≥ 2 lesions at baseline and one 
is left uninjected as described in Section 6.2.1.1, from an uninjected lesion within 
7 days prior to dose at day 1 of week 6 [Cycle 3]. Also within 7 days after 
documentation of disease progression followed by treatment discontinuation from 
the available cutaneous, subcutaneous or nodal lesion responsible for PD and easily 
accessible for biopsy with or without unltrasound guidance. Note:  uninjected lesion 
biopsied at day 1 of week 6 [Cycle 3] must be different lesion from the lesion biopsied at 
day 1 of week 1 [Cycle 1]. 


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Protocol Number:  20120325 
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Section:  7.1 Schedule of Assessments 
Footnote q, sentence 1 
Replace: 
Investigator’s clinical measurement of cutaneous, subcutaneous, or nodal tumor by 
caliper at screening, day 1 of week 12 (± 1 week) and then every 12 weeks (± 1 week), 
or more frequently if clinically indicated, until clinically relevant disease progression 
beyond 6 months of treatment (per modified WHO response criteria, Appendix D) or until 
the start of a new anticancer therapy.  
With: 
Investigator’s clinical measurement of cutaneous, subcutaneous, or nodal tumor by 
caliper at screening, day 1 of week 12 (± 1 week) [Cycle 6] and then every 12 weeks 
(± 1 week), or more frequently if clinically indicated, until clinically relevant disease 
progression beyond 6 months of treatment (per modified WHO response criteria, 
Appendix D) or until the start of a new anticancer therapy.  
Section:  7.1 Schedule of Assessments 
Footnote r, sentence 1 
Replace: 
Radiographic imaging (CT, PET/CT, MRI, or US) of the chest, abdomen, and pelvis, and 
all other sites of disease, and CT scan or MRI of brain (only if symptoms or signs 
suggestive of CNS metastasis are present) at screening, day 1 of week 12 (± 1 week) 
and then every 12 weeks (± 1 week), or more frequently if clinically indicated, until 
clinically relevant disease progression beyond 6 months of treatment (per modified WHO 
response criteria, Appendix D or until the start of a new anticancer therapy. 
With: 
Radiographic imaging (CT, PET/CT, MRI, or US) of the chest, abdomen, and pelvis, and 
all other sites of disease, and CT scan or MRI of brain (only if symptoms or signs 
suggestive of CNS metastasis are present) at screening, day 1 of week 12 (± 1 week) 
[Cycle 6] and then every 12 weeks (± 1 week), or more frequently if clinically indicated, 
until clinically relevant disease progression beyond 6 months of treatment (per modified 
WHO response criteria, Appendix D or until the start of a new anticancer therapy. 


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Section:  7.1 Schedule of Assessments 
Footnote s 
Replace: 
At select sites only, photographs of visible cutaneous and subcutaneous tumor lesions at 
screening and then monthly until end of treatment. See Section 7.2.6 
With: 
At select sites only, photographs of all visible cutaneous and subcutaneous tumor 
lesions at Cycle 1, Cycle 2, and every second subsequent cycle until end of 
treatment (always within 3 days prior to investigational product administration). 
See Section 7.2.6. 
Section:  7.1 Schedule of Assessments 
Footnote v 
Replace: 
Reporting of pregnancy or lactation:  If a pregnancy occurs in a female subject, or 
female partner of a male subject, or a lactation case occurs while the subject is taking 
talimogene laherparepvec, the case must be reported to Amgen through 3 months after 
the last dose of talimogene laherparepvec as specified in Section 9.3 
With: 
Reporting of pregnancy or lactation:  If a pregnancy occurs in a female subject, or 
female partner of a male subject, or a lactation case occurs while the subject is taking 
talimogene laherparepvec, the case must be reported to Amgen Global Patient Safety 
through 3 months after the last dose of talimogene laherparepvec as specified in 
Section 9.3. 
Section:  7.1 Schedule of Assessments 
Footnote w 
Add: 
ECOG Performance Status will be assessed at screening, day 1 of Cycle 1, then 
every 12 weeks (ie, every sixth cycle) alongside the tumor response assessments 
until the end of tumor response assessments per study protocol. 


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Section:  7.1 Schedule of Assessments 
Footnote x 
Add: 
Anti-cancer therapy may include any systemic, regional, and local therapies for 
melanoma disease. 
Section:  7.2 General Study Procedures 
Paragraph 2 
Replace: 
During treatment, assessments and procedures can be performed within 3 days of the 
planned visit.  It is recommended that dosing occur on the same day of the week (eg, if 
first dose is administered on Monday, all subsequent doses should be administered on a 
Monday), however a ± 3 day dosing and study procedure window is allowed. 
With: 
During treatment, assessments and procedures can be performed within 3 days of the 
planned visit unless specified otherwise.  It is recommended that dosing occur on the 
same day of the week (eg, if first dose is administered on Monday, all subsequent doses 
should be administered on a Monday), however a ± 3 day dosing and study procedure 
window is allowed. 
Section:  7.2 General Study Procedures, Table 3, Biomarkers 
Replace: 
HSV-1 Antibody 
With: 
HSV Serostatus 
Section:  7.2 General Study Procedures 
Paragraph 4 
Replace: 
The chemistry, hematology, PT( or INR), PTT and pregnancy tests are to be performed 
at a local laboratory and test results are to be fully and routinely recorded on the 


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electronic CRFs (eCRFs). Missed tests that are not done must be reported as such on 
the eCRFs. The real-time polymerase chain reaction (qPCR) and biomarker tests will be 
performed at a central laboratory and tests results will not be reported on the eCRFs. 
With: 
The chemistry, hematology, PT( or INR), PTT and pregnancy tests are to be performed 
at a local laboratory and test results are to be fully and routinely recorded on the 
electronic CRFs (eCRFs). Missed tests that are not done must be reported as such on 
the eCRFs and should not be completed as unscheduled tests between cycles. 
The real-time quantitative polymerase chain reaction (qPCR) and biomarker/antibody 
tests will be performed at a central laboratory and tests results will not be reported on 
the eCRFs. 
Section:  7.2.1 Screening and Enrollment 
Bullet 11 
Delete: 
Photographs of visible (ie, visible protrusion from skin surface) cutaneous and 
subcutaneous tumor lesions (Select Sites Only:  see Section 7.2.6) 
Section:  7.2.2 Treatment 
Paragraph 2, bullet 2 
Add: 
Determination of ECOG Performance Status at Day 1 of Cycle 1 and then every 
12 weeks (ie every sixth cycle) in parallel with tumor response assessment and 
until the end of study treatment (Appendix E) 
Section:  7.2.2 Treatment 
Paragraph 2, bullet 3 
Add: 
Physical exams as per standard of care at day 1 of Cycle 1, and then every 
12 weeks (ie, every sixth cycle) until the end of tumor assessment per study 
protocol  


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Section:  7.2.2 Treatment 
Paragraph 2, bullet 5, subbullets 3, 4, 5, and 6 
Replace: 
swabs of cold sores, vesicles, and other lesions suspected to be herpetic in origin (if 
any) for qPCR testing:  
o subject should return to clinic within 3 days of the occurrence of a reportable 
lesion suspected to be herpetic in origin, such as cold sores or vesicles.  The 
lesion should be evaluated by the investigator and swabbed if HSV infection is 
suspected.  A qPCR analysis will be performed on the swab sample to evaluate 
whether the talimogene laherparepvec DNA is detectable in the sample.  
blood sample for HSV-1 antibody serostatus (within 3 days prior to talimogene 
laherparepvec administration) at day 1 of week 1, week 6, and week 12. 
blood sample for biomarker analysis (within 3 days prior to talimogene laherparepvec 
administration) at day 1 of week 1, week 6, week 12, and week 24. Note:  Lymphocyte 
subsets will be measured by flow cytometric determination of the following markers 
including but not limited to:  T cells:  CD3, CD4, CD8; B cells; CD19; activation markers:  
HLA-DR; T-regs:  CD25, CD127.  
tumor biopsy for biomarker analysis (within 3 days prior to talimogene laherparepvec 
administration) from one lesion at day 1 of week 1 and, if there are ≥ 2 lesions at 
baseline and one is left uninjected as described in Section 6.2.1.1, from an uninjected 
lesion at day 1 of week 6. Also at disease progression (PDn or PDr) beyond 6 months of 
treatment, from the lesion responsible for PD 
With: 
swabs of cold sores, vesicles, and other lesions suspected to be herpetic in origin (if 
any) for qPCR testing:  
o subject should return to clinic within 3 days of the occurrence of a reportable 
lesion suspected to be herpetic in origin, such as cold sores or vesicles.  The 
lesion should be evaluated by the investigator and swabbed if herpetic infection 
is suspected.  A qPCR analysis will be performed on the swab sample to 
evaluate whether the talimogene laherparepvec DNA is detectable in the sample.  
blood sample for HSV serostatus (within 3 days prior to talimogene laherparepvec 
administration) at day 1 of week 1, week 6, and week 12. 
blood sample for biomarker analysis (within 3 days prior to talimogene laherparepvec 
administration) at day 1 of week 1, week 6, week 12 and week 24. Note:  Lymphocyte 


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Protocol Number:  20120325 
Date:  21 September 2015 
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subsets will be measured by flow cytometric determination of the following markers 
including but not limited to:  T cells:  CD3, CD4, CD8; B cells; CD19; activation markers:  
HLA-DR; T-regs:  CD25, CD127.  
all tumor biopsies in the study should be performed from easily accessible with or 
without ultrasound guidance cutaneous, subcutaneous or nodal  lesions.  Tumor 
biopsy for biomarker analysis should not be collected prior to the subject being 
enrolled.  Tumor biopsy should be collected (within 5 days prior to first talimogene 
laherparepvec administration) from one lesion at day 1 of week 1 and, if there are 
≥ 2 lesions at baseline and one is left uninjected as described in Section 6.2.1.1, from an 
uninjected lesion within 7 days prior to talimogene laherparepvec injection at day 1 
of week 6.  Also within 7 days after documentation of disease progression (PDn or 
PDr) that resulted in treatment discontinuation, from the available and easily 
accessible for biopsy with or without ultrasound guidance cutaneous, 
subcutaneous or nodal lesion responsible for progression 
Section:  7.2.2 Treatment 
Bullet 6, subbullet 1 
Replace: 
radiographic imaging must include CT scan, PET/CT, MRI, or ultrasound of the chest, 
abdomen, and pelvis and all other sites of disease.  In addition, CT scan or MRI of the 
brain will only be performed if symptoms or signs suggestive of CNS metastasis are 
present.  The imaging modality selected (eg, CT or MRI) should remain constant for any 
individual subject. 
With: 
radiographic imaging must include CT scan, PET/CT, MRI, or ultrasound (if applicable) 
of the chest, abdomen, and pelvis and all other sites of disease.  In addition, CT scan or 
MRI of the brain will only be performed if symptoms or signs suggestive of CNS 
metastasis are present.  The imaging modality selected (eg, CT or MRI) should remain 
constant throughout the study for any individual subject. 


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Protocol Number:  20120325 
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Section:  7.2.2 Treatment 
Bullet 9 
Replace: 
• 
Photographs of visible cutaneous and subcutaneous measurable tumor lesions 
monthly until end of treatment. (Select Sites Only:  see Section 7.2.6) 
With: 
• 
Photographs of all visible cutaneous and subcutaneous tumor lesions at day 1 
Cycle 1, day 1 Cycle 2, and day 1 of every second subsequent cycle until 
end of tumor response assessment per protocol, always within 3 days prior 
to investigational product administration.  (Select Sites Only:  see Section 
7.2.6) 
Section:  7.2.3 Safety Follow-up Visit 
Bullet 3 
Replace: 
• 
Determination of ECOG performance status (Appendix E) 
With: 
• 
Determination of ECOG Performance Status alongside the tumor response 
assessments until the end of tumor response assessments per study 
protocol (Appendix E) 
Section:  7.2.3 Safety Follow-up Visit 
Bullet 8 
Replace: 
• 
Recording of serious adverse events at each visit.  SAEs will be reported to 
Amgen within 24 hours following the investigator’s knowledge of the event. 
With: 
• 
Recording of serious adverse events.  SAEs will be reported to Amgen within 
24 hours following the investigator’s knowledge of the event 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 47 of 69 
CONFIDENTIAL 
 
 
Section:  7.2.4 Long-term Follow-up/End of Study 
Paragraph 1 
Replace: 
All subjects who permanently discontinue talimogene laherparepvec for any reason 
other than withdrawal of full consent or death will be contacted by telephone, or clinic 
visit, to assess survival status and, if applicable, commencement of any subsequent 
anticancer melanoma therapy.  Follow-up will occur every 12 weeks (± 28 days) 
following the safety follow-up visit until death, subject withdraws full consent, or up to 
24 months after the last subject is enrolled. 
With: 
All subjects who permanently discontinue talimogene laherparepvec for any reason 
other than withdrawal of full consent or death will be contacted by telephone, or clinic 
visit, to assess survival status and, if applicable, commencement of any subsequent 
anticancer melanoma therapy.  Adverse events deemed by the investigator to be 
potentially related to talimogene laherparepvec and use of anti-cancer therapies 
for melanoma will also be recorded.  Follow-up will occur every 12 weeks (± 28 days) 
following the safety follow-up visit until death, subject withdraws full consent, or up to 
24 months after the last subject is enrolled in the study. 
Section:  7.2.4 Long-term Follow-up/End of Study 
Paragraph 2 
Replace: 
If subject has discontinued talimogene laherparepvec for reason other than disease 
progression or death, radiographic tumor imaging, clinical tumor assessments, and 
tumor response assessments will be performed as documented in Section 7.2.2 until 
documented disease progression beyond 6 months of treatment, per modified WHO 
response criteria (Appendix D), or until the start of a new anticancer therapy. 
With: 
If subject has discontinued talimogene laherparepvec for reason other than disease 
progression or death, radiographic tumor imaging, clinical tumor assessments, ECOG 
Performance Status assessments, reporting of pregnancy or lactation, 
assessment of swabs of lesions of suspected herpetic origin for presence of 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 48 of 69 
CONFIDENTIAL 
 
 
talimogene laherparepvec DNA by qPCR test, and tumor response assessments will 
be performed as documented in Section 7.2.2 until documented disease progression 
beyond 6 months of treatment, per modified WHO response criteria (Appendix D), until 
the start of a new anticancer therapy, or end of study, whichever the earliest. 
Section:  7.2.4 Long-term Follow-up/End of Study 
Paragraph 3 
Replace: 
After the long term follow-up period of this study has ended, subjects who end the study 
for any reason other than death or withdrawal of full consent will be followed for survival 
under an ongoing separate registry protocol (Study 20120139) that is in place for the 
long-term follow-up of all subjects treated with talimogene laherparepvec in clinical trials.  
The registry protocol will also monitor for late and long-term adverse events thought to 
be potentially related to talimogene laherparepvec. 
With: 
After the long term follow-up period of this study has ended, subjects who end the study 
for any reason other than death or withdrawal of full consent will be followed for survival 
under an ongoing separate registry protocol (Study 20120139) that is in place for the 
long-term follow-up of all subjects treated with talimogene laherparepvec in clinical trials.  
The registry protocol will also monitor for late and long-term adverse events thought to 
be potentially related to talimogene laherparepvec and use of anti-cancer therapies 
for melanoma. 
Section:  7.2.6 Optional Photography Substudy (Select Sites Only) 
Paragraph 1, sentence 1 
Replace: 
For sites selected to participate in the photography substudy, photographs of visible 
(ie, visible protrusion from skin surface) cutaneous and subcutaneous measurable tumor 
lesions will be performed as detailed in Section 7.2.1 and Section 7.2.2 until end of 
treatment. 
With: 
For sites selected to participate in the photography substudy, photographs of all visible 
(ie, visible protrusion from skin surface) cutaneous and subcutaneous tumor lesions will 


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CCI


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 50 of 69 
CONFIDENTIAL 
 
 
talimogene laherparepvec. Collecting a biopsy from an uninjected lesion during the 
treatment period (eg, at week 6) is critical for identifying the changes in intratumoral 
CD8+ cell density that occur following talimogene laherparepvec treatment and that may 
be associated with clinical benefit. Refer to the Laboratory Manual for specific 
instructions on tumor biopsy procedures. 
With: 
On study biopsies will be collected, as described in the Schedule of Assessments 
(Table 2) and in Section 7.2.2, to characterize the mechanism of systemic action of 
talimogene laherparepvec. Collecting a biopsy from an uninjected lesion during the 
treatment period (eg, within 7 days prior to dosing at week 6) is critical for identifying 
the changes in intratumoral CD8+ cell density that occur following talimogene 
laherparepvec treatment and that may be associated with clinical benefit. Refer to the 
Laboratory Manual for specific instructions on tumor biopsy procedures. 
Section:  9.2.1 Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
Paragraph 1 
Replace: 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of talimogene 
laherparepvec through 30 (+ 7) days after the last dose of talimogene laherparepvec are 
reported using the applicable eCRF (eg, Adverse Event Summary). 
With: 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of talimogene 
laherparepvec through 30 (+ 7) days after the last dose of talimogene laherparepvec are 
reported using the applicable eCRF (eg, Adverse Event Summary).  Adverse events 
deemed by the investigator to be potentially related to talimogene laherparepvec 
that occur during and after the first dose of talimogene laherparepvec and through 
the survival follow-up are to be reported.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 51 of 69 
CONFIDENTIAL 
 
 
Section:  9.3 Pregnancy and Lactation Reporting 
Paragraph 2 
Replace: 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of talimogene laherparepvec 
through 3 months after the last dose of talimogene laherparepvec.  The pregnancy 
should be reported to Amgen’s global Pregnancy Surveillance Program (PSP) within 
24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet (Appendix C).  The PSP will seek to 
follow the pregnant woman throughout her pregnancy and her baby up to 12 months 
after birth. 
With: 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur after the last dose of talimogene laherparepvec through 
3 months after the last dose of talimogene laherparepvec.  The pregnancy should be 
reported to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of the event of a pregnancy.  Report a pregnancy on the Pregnancy 
Notification Worksheet (Appendix C). 
Section:  9.3 Pregnancy and Lactation Reporting 
Paragraph 5 
Replace: 
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
within 24 hours of the investigator’s knowledge of event.  Report a lactation case on the 
Lactation Notification Worksheet (Appendix C). 
With: 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C). 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 52 of 69 
CONFIDENTIAL 
 
 
Section:  9.4 Reporting of Exposure to Talimogene Laherparepvec 
Paragraph 1, sentence 3 
Add: 
Please refer to your study specific documents for reporting details. 
Section:  9.4 Reporting of Exposure to Talimogene Laherparepvec 
Paragraph 2, sentence 3 
Replace: 
If the exposed individual is reporting signs or symptoms suspected to be related to 
talimogene laherparepvec exposure, the exposed individual may be asked to have a 
swab taken to evaluate for the presence of talimogene laherparepvec in the lesion. 
With: 
If the exposed individual is reporting signs or symptoms suspected to be related to 
talimogene laherparepvec exposure, the exposed individual may be asked to have a 
swab taken to evaluate for the presence of talimogene laherparepvec in the lesion, 
within 3 days of the symptoms or signs occurring. 
Section:  10.1.1.2 Secondary Endpoints 
Bullet 2 
Replace: 
Correlation between changes in intratumoral CD8+ cell density during treatment (in 
injected and uninjected lesions) and ORR, DRR, DOR, and changes in tumor burden 
With: 
Correlation between changes in intratumoral CD8+ cell density during treatment and 
ORR, DRR, DOR, and changes in tumor burden  


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 53 of 69 
CONFIDENTIAL 
 
 
Section:  10.1.2 Analysis Sets 
Paragraph 3, sentence 4 
Replace: 
The correlation between biomarker changes during treatment (in injected and uninjected 
lesions) and objective response rate, durable response rate, and duration of response 
will be conducted on the biomarker evaluable analysis set. 
With: 
The correlation between biomarker changes during treatment and objective response 
rate, durable response rate, and duration of response will be conducted on the 
biomarker evaluable analysis set. 
Section:  10.1.3 Covariates and Subgroups 
Bullet 1 
Replace: 
Region, if applicable (USA or non-USA) 
With: 
Region, if applicable  
Section:  10.1.3 Covariates and Subgroups 
Bullet 6 
Replace: 
ECOG (0 vs 1) 
With: 
ECOG Performance Status (0 vs 1) 
Section:  10.3.1 Interim Analyses 
Replace: 
No interim analysis is planned. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 54 of 69 
CONFIDENTIAL 
 
 
With: 
An interim analysis to evaluate the study objectives of correlation between the 
biomarker (ie baseline intratumoral CD8+ cell density changes in intratumoral 
CD8+ cell density and other biomarkers) and ORR will be conducted on 
approximately the first 50 subjects only who received at least 1 dose of 
talimogene laherparepvec, with the biomarker recorded at baseline, and have had 
the opportunity to be on study (treatment or follow-up phase) for at least 
6 months.  The study will not be discontinued due to the results of this interim 
analyses; however, predictive hypotheses generated from the interim analysis 
may lead to subsequent changes to study conduct. For example, if the interim 
analysis suggests an enhanced effect in a biomarker-defined subgroup, then the 
protocol and statistical analysis plan may be revised to ensure the study can 
adequately evaluate the subgroup effect.  Revisions may also happen due to 
obtaining new relevant data from external sources, such as scientific publications 
and communications.  
Section:  10.3.3 Final Analysis 
Replace: 
The final analysis will occur when the last subject discontinues the study treatment and 
has had the opportunity to complete the long term follow -up.  The CSR will be amended 
with the updated results from the final analysis at the completion of the study. 
With: 
The final analysis will occur either 24 months after the last subject has been enrolled 
or when the last subject discontinues the study treatment and has had the opportunity to 
complete the safety follow–up, whichever is later.  The CSR will be amended with the 
updated results from the final analysis at the completion of the study. 
Section:  13 References 
Delete: 
Andtbacka RHIA, Collichio FA, Amatruda T, et al.  OPTiM:  a randomized phase III trial 
of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-
macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected 
stage IIIB/C and IV melanoma.  J Clin Oncol.  2013;31(suppl). Abstract LBA9008. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 55 of 69 
CONFIDENTIAL 
 
 
Section:  13 References 
Add: 
Andtbacka RHIA, Kaufman H, Collichio FA, et al.  Talimogene laherparepvec 
improves durable response rate in patients with advanced melanoma. J Clin Oncol 
2015[Epub ahead of print]. 
Section:  13 References 
Add: 
Keytruda® (Pembrolizumab) Prescribing Information.  Merck & Co, Whitehouse 
Station, USA; 2015. 
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. 
Accessed on 27 August 2015. 
Section:  13 References 
Add: 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab 
or monotherapy in untreated Melanoma. N Engl J Med. 2015;373:23-34 
Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus 
dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, 
double-blind, phase 3 randomised controlled trial. Lancet 2015, 386:444-451 
Section:  13 References 
Replace: 
Mekinist™ (trametnib) Prescribing Information. Research Triangle Park, NC, 
GlaxoSmithKline, USA, 2013. 
With: 
Mekinist™ (trametnib) Prescribing Information. Research Triangle Park, NC, 
GlaxoSmithKline, USA, 2014. https://www.gsksource.com/pharma/content/dam/ 
GlaxoSmithKline/US/en/Prescribing_Information/Mekinist/pdf/MEKINIST-PI-
PIL.PDF. Accessed on 27 August 2015. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 56 of 69 
CONFIDENTIAL 
 
 
Section:  13 References 
Add: 
Opdivo® (Nivolumab) Prescribing Information.  Princeton, NJ:  Bristol-Myers 
Squibb, USA; 2015. http://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed on 
27 August 2015. 
Section:  13 References 
Add: 
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational 
landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. 
Science. 2015;348:124-128. 
Robert C, Karaszewska B, Schachter J, et al. Improved Overall Survival in 
Melanoma with Combined Dabrafenib and Trametinib. New Engl J Med 2015, 372, 
30-39 
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma 
without BRAF mutation. N Engl J Med. 2015;372:320-330. 
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in 
advanced melanoma. N Engl J Med. 2015;372:2521-2532. 
Section:  13 References 
Add: 
Siegel RL, Miller KD, and Jemal A. Cancer statistics, 2015. Cancer Clin J 2015; 
65:5-29. 
Section:  13 References 
Add: 
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to 
CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-2199. 
Section:  13 References 
Replace: 
Talimogene Laherparepvec Investigator’s Brochure, Edition 10.0. Woburn, MA. BioVEX 
(a wholly owned subsidiary of Amgen); 17 January 2014. 
With: 
Talimogene Laherparepvec Investigator’s Brochure, Edition 13.0. Amgen; 2015. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 57 of 69 
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Section:  13 References 
Add: 
Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in 
patients with advanced melanoma who progressed after anti-CTLA-4 treatment 
(CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet 
Oncol. 2015;16:375-384. 
Section:  13 References 
Replace: 
Yervoy® (ipilimumab) Prescribing Information.  Princeton, NJ:  Bristol-Myers Squibb, 
USA; 2013. 
Zelboraf® (vemurafenib) Prescribing Information. South San Francisco, CA; Genentech 
USA, Inc:  2013. 
With: 
Yervoy® (ipilimumab) Prescribing Information.  Princeton, NJ:  Bristol-Myers Squibb, 
USA; 2015. http://packageinserts.bms.com/pi/pi_yervoy.pdf . Accessed on 27 
August 2015. 
Zelboraf® (vemurafenib) Prescribing Information. South San Francisco, CA; Genentech 
USA, Inc:  2015. http://www.gene.com/download/pdf/zelboraf_prescribing.pdf. 
Accessed on 27 August 2015. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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Section:  14 Appendices, Appendix B 
Replace: 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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CONFIDENTIAL 
 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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CONFIDENTIAL 
 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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CONFIDENTIAL 
 
 
With: 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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CONFIDENTIAL 
 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
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Section:  14 Appendices, Appendix C 
Replace: 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 67 of 69 
CONFIDENTIAL 
 
 
With: 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 68 of 69 
CONFIDENTIAL 
 
 
Section:  14 Appendices, Appendix D 
paragraph 2 
Replace: 
Clinical Examination Using Caliper:  All measurements will be determined using a ruler 
or calipers and reported in metric notation (mm) and will be recorded bi dimensionally.  
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in at least 2 dimensions as assessed using calipers (eg, superficial cutaneous 
melanoma lesion).  (Note:  When a lesion can be evaluated by both, clinical examination 
and imaging, radiographic imaging evaluations should be undertaken preferred since it is 
more objective). 
With: 
Clinical Examination Using Caliper:  All measurements will be determined using a ruler 
or calipers and reported in metric notation (mm) and will be recorded bi-dimensionally.  
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in at least 2 dimensions as assessed using calipers (eg, superficial cutaneous 
melanoma lesion).  (Note:  When a lesion can be evaluated by both, clinical examination 
and imaging, radiographic imaging evaluations should be preferred since it is more 
objective). 
Section:  14 Appendices, Appendix D 
Add: 
Coalescing or splitting lesions: 
• 
Coalescing lesions:  When two or more index or new measurable lesions 
merge without distinct borders between tumors, the smaller lesion should 
have 0 x 0 mm recorded for the current and all future assessments with a 
comment indicating that the lesion coalesced with the specified lesion, and the 
larger lesion should have the size of the merged lesion recorded for the 
current assessment with a comment indicating that the lesion coalesced with 
the specified lesion and be followed for future assessments.  When two or 
more non-index or new non-measurable lesions merge, the smaller lesion 
should be recorded as absent for the current and all future assessments, and 
the larger lesion should be recorded as present for the current assessment 
(with a comment indicating that the lesion coalesced with the specified lesion) 
and followed for future assessments. If an index or new measurable lesion and 
a non-index or new non-measurable lesion merge, the non-index or new 
non-measurable lesion should be absent for the current and all future 
assessments while the index lesion or new measurable lesion should include 


Product:  Talimogene Laherparepvec 
Protocol Number:  20120325 
Date:  21 September 2015 
Page 69 of 69 
CONFIDENTIAL 
 
 
both merged lesions for recording measurements with a comment indicating 
that the lesion coalesced with the specified lesion. 
 
Splitting lesions:  When an index or new measurable lesion splits into two or 
more lesions the largest measurable part of the split lesion should be 
considered to be the previously recorded index or new measurable lesion with 
measurements provided for the current assessment with the comment 
indicating that the lesion split from the specified lesion, and followed for future 
assessments. The remaining lesions would be reported as a new measurable 
lesions or new non-measurable lesions depending on measurability with a 
comment indicating that the lesion split from the specified lesion. In this case, 
appearance of a new lesion from a previous lesion will not be considered a 
disease progression solely due to appearance of a new lesion (may be 
considered a disease progression due to > 25% increase in the sum of the 
products of the perpendicular diameters of all index tumors since baseline, or 
the unequivocal appearance of a new tumor, other than the product of the split 
tumor, since the last response assessment time point) 
Section:  14 Appendices, Appendix D 
Add: 
If subject has multiple small superficial melanoma lesions at baseline (less than 
10 mm in longest diameter) which  in aggregate have a total diameter of ≥ 10 mm, 
up to 10 largest lesions that were included in this measurement will be reported as 
”Index Lesions”, and sum of the products of the two largest of perpendicular SPD 
of these lesions will be calculated and reported for tumor response assessments.  
Section:  14 Appendices , Appendix D 
Replace: 
Partial Response (PR): 
Achieving a 50% or greater reduction in the SPD of the perpendicular 
diameters of all index lesions at the time of assessment as compared 
to the sum of the products of the perpendicular diameters of all index 
lesions at baseline. If any new lesions have appeared, the sum of 
products of the perpendicular diameters of new measurable lesions 
must have reduced by 50% or more from when first documented. Any 
residual cutaneous or subcutaneous index or new lesions that must 
be tumor free for the subject to meet the criteria for PR must be 
documented as such by representative biopsy. 
With: 
Partial Response (PR): 
Achieving a 50% or greater reduction in the SPD of the perpendicular 
diameters of all index lesions at the time of assessment as compared 
to the sum of the products of the perpendicular diameters of all index 
lesions at baseline. If any new lesions have appeared, the sum of 
products of the perpendicular diameters of new measurable lesions 
must have reduced by 50% or more from when first documented.  
 

SAP_001.pdf: 
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