Clinical trial NCT02211131
Conditions: Completely Resectable Stage IIIB, IIIC, or IVM1a Melanoma
Sponsor: Amgen
Start date: 2015-02-03; Completion date: 2022-04-28
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.

Detailed description:
This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.

Arm 1: Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).

Arm 2: Immediate surgical resection of melanoma tumor lesion(s) Following surgery, adjuvant systemic therapy and/or radiotherapy may be administered at the investigator's discretion and per the institutional standard of care.

Subjects will be followed for safety approximately 30 (+15) days after surgery and for disease recurrence, subsequent anticancer therapy, and survival every 3 months (±30 days) for first 3 years after the end of the safety follow-up period and then every 6 months (±30 days) until death, subject withdraws full consent, or up to 5 years after the last subject is randomized.

Arms: arm 1: Surgical resection of melanoma tumor lesion(s) arm 2: Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).
Interventions: intervention 1: Talimogene Laherparepvec intervention 2: Immediate surgical resection of melanoma lesion(s)
Intervention descriptions: intervention 1: Talimogene laherparepvec will be administered by intralesional injection into the injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 10\^6 plaque forming units (PFU)/mL at day 1 of week 1 followed by a dose of 10\^8 PFU/mL at day 1 (±3 days) of week 4, 6, 8, 10 and 12 or until all injectable tumors have disappeared, or intolerance of study treatment or in the opinion of the investigator, immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first. intervention 2: Surgical resection of melanoma tumor lesion(s) will be performed after randomization any time during weeks 1 to 6.

Protocol documents:
Prot_000.pdf: 
Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 1 of 100
CONFIDENTIAL
Title:  A Phase 2, Multicenter, Randomized, Open-label Trial Assessing the 
Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus 
Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma
Amgen Protocol Number (Talimogene Laherparepvec) 20110266
EudraCT number 2014-001146-13
NCT02211131
Clinical Study Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Telephone: +1-805-447-1000
Key Sponsor Contacts:
 MD
Clinical Research Medical Director
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Telephone: 
Email address: 
 PhD
Senior Manager, Global Clinical Program 
Management
Amgen Limited
1 Sanderson Road (Uxbridge Business Park)
Uxbridge, UB8 1DH
Telephone:
Email: 
Date:
23 May 2014
Amendment 1 Date:
09 June 2014
Amendment 2 Date:
31 March 2016
Superseding Amendment 2 
Date:
Amendment 3 Date: 
22 April 2016
23 March 2018
Confidentiality Notice
This document contains confidential information of Amgen Inc.
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent.
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc.
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  USA sites, 1- 800-77-AMGEN, for all other 
countries, Amgen’s general number in the USA (1-805-447-1000). 
NCT Number: NCT02211131
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 2 of 100
CONFIDENTIAL
Investigator’s Agreement
I have read the attached protocol entitled A Phase 2, Multicenter, Randomized, 
Open-label Trial Assessing the Efficacy and Safety of Talimogene Laherparepvec 
Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Resectable, Stage IIIB to 
IVM1a Melanoma, dated 23 March 2018, 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:  20110266
Date:  23 March 2018
Page 3 of 100
CONFIDENTIAL
Protocol Synopsis
Title:  A Phase 2, Multicenter, Randomized, Open-label Trial Assessing the Efficacy and Safety 
of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for 
Resectable, Stage IIIB to IVM1a Melanoma
Study Phase:  2
Indication:  Neoadjuvant treatment of talimogene laherparepvec for resectable, stage IIIB to 
IVM1a melanoma.
Primary Objective:  To estimate the treatment effect of neoadjuvant talimogene laherparepvec 
plus surgery compared to surgery alone on recurrence-free survival (RFS).
Secondary Objectives:  The secondary objectives are:

To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery compared to 
surgery alone on 1-year, 2-year, 3-year, and 5-year RFS

To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery compared to 
surgery alone on rate of histopathological tumor-free margin (R0) surgical resection

To estimate the effect of neoadjuvant talimogene laherparepvec on rate of pathological 
complete response (pCR)

To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery compared to 
surgery alone on local recurrence-free survival (LRFS), regional recurrence-free survival 
(RRFS), and distant metastases-free survival (DMFS)

To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery compared to 
surgery alone on 1-year, 2-year, 3-year, 5-year, and overall survival (OS)

To estimate response to neoadjuvant talimogene laherparepvec overall and separately in 
injected and uninjected lesions during treatment (Arm 1 only)

To evaluate the safety of neoadjuvant talimogene laherparepvec plus surgery compared to 
surgery alone
Hypotheses:  Formal hypotheses will not be tested in this trial.  The study will provide an 
estimate of the treatment effect, as measured by the difference in RFS of talimogene 
laherparepvec neoadjuvant therapy followed by surgery compared to surgery alone in subjects 
with resectable, stage IIIB to IVM1a melanoma.
Primary Endpoint:  RFS.
Secondary Endpoints:  The secondary endpoints are:

1-year, 2-year, 3-year, and 5-year RFS

Rate of histopathology tumor-free margin (R0) surgical resection

Rate of pCR

LRFS

RRFS

DMFS

1-year, 2-year, 3-year, and 5-year, and overall survival

Overall tumor response and tumor response in injected and uninjected lesions (Arm 1 only)

Subject incidence of treatment-emergent and treatment-related adverse events


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 4 of 100
CONFIDENTIAL
Study Design: This is a phase 2, multicenter, randomized, open-label study to estimate the 
efficacy of talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared 
to surgery alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.  
Approximately 150 subjects will be randomized 1:1 to receive the following:

Arm 1:  Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma 
tumor lesion(s).

Talimogene Laherparepvec:
Talimogene laherparepvec will be administered by intralesional injection into the 
injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 106 plaque 
forming units (PFU)/mL at day 1 of week 1 followed by a dose of 108 PFU/mL at day 1 
(±3 days) of week 4, 6, 8, 10 and 12 or until all injectable tumors have disappeared, or 
intolerance of study treatment, whichever occurs first.  Due to the mechanism of action of 
talimogene laherparepvec, subjects may experience transient growth in existing tumors 
or the appearance of new tumors prior to maximal clinical benefit of talimogene 
laherparepvec.  Subjects who experience growth in existing tumors or the appearance of 
new tumors will be allowed to remain on talimogene laherparepvec treatment until 
week 12 of therapy unless, in the opinion of the investigator, immediate surgical resection 
or any other treatment for melanoma is warranted.  If talimogene laherparepvec 
treatment will end prior to week 12, the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.

Surgical Resection of Melanoma Tumor Lesions(s):
For subjects who complete 12 weeks of talimogene laherparepvec treatment, surgical 
resection of melanoma lesion(s) will be performed at any time during weeks 13 to 18.  
Refer to Appendix F for surgery guidelines. Subjects who stop talimogene laherparepvec 
prior to week 12 due to disappearance of all injectable tumor lesions, intolerance to 
talimogene laherparepvec, or any other reason will undergo surgical resection of 
melanoma lesion(s) or tissues where melanoma was present before achieving complete 
response (CR) within 1 to 6 weeks after the last dose of talimogene laherparepvec.  If 
surgery will be performed prior to week 12, the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.

Arm 2:  Immediate surgical resection of melanoma tumor lesion(s) 

Surgical resection of melanoma tumor lesion(s) will be performed after randomization any
time during weeks 1 to 6.  Refer to Appendix F for surgery guidelines.
Randomization will be stratified by disease stage (IIIB nodal versus IIIB in-transit versus IIIC 
nodal versus IIIC in-transit with nodal versus IVM1a), planned adjuvant therapy (adjuvant 
systemic therapy [eg, interferon alpha (INFα), ipilimumab] with or without radiotherapy versus
radiotherapy without adjuvant systemic therapy versus none).
Following surgery, adjuvant systemic therapy and/or radiotherapy may be administered at the 
investigator’s discretion and per the institutional standard of care.
Subjects will be followed for safety approximately 30 (+15) days after surgery and for disease 
recurrence (local, regional, or distant), subsequent anticancer therapy for melanoma, adverse 
events thought to be potentially related to talimogene laherparepvec (Arm 1 only), and survival 
every 3 months (±30 days) for first 3 years after the end of the safety follow-up period and then 
every 6 months (±30 days) until death, subject withdraws full consent, or up to 5 years after the 
last subject is randomized.  Thereafter, subjects randomized to Arm 1 who received at least a 
single dose of talimogene laherparepvec 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 subsequent anticancer 
therapy for melanoma. Subjects who after the long-term follow-up period of this study


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 5 of 100
CONFIDENTIAL
(Study 20110266) will elect to participate in the registry study must sign new informed consent 
form before any registry protocol-specific activities.
Sample Size:  150 subjects.
Summary of Subject Eligibility Criteria:
Key Inclusion Criteria:
Male or female ≥ 18 years of age with histologically confirmed diagnosis of stage IIIB, IIIC or 
IVM1a melanoma eligible for complete surgical resection.  Prior systemic, regional and radiation 
anticancer therapies for melanoma must have been completed at least 3 months prior to 
randomization.  Subject must have measurable disease and must be a candidate for intralesional 
therapy with at least one 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 (ULN) for stages IIIB/C melanoma and LDH ≤1.0 x ULN for stage IVM1a 
melanoma and adequate hematologic, hepatic, renal, and coagulation organ functions.
Key Exclusion Criteria:
Subject must not have primary ocular or mucosal melanoma, or history or evidence of melanoma 
associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or 
leukemia).  Subject must not have 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 herpes simplex type 1 (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.  Subject known to have acute or chronic active 
hepatitis B, hepatitis C, or human immunodeficiency virus infection will also be excluded.  Subject 
must not have been treated previously with talimogene laherparepvec.
For a full list of eligibility criteria, please refer to Section 4.1.
Investigational Product
Talimogene Laherparepvec Dosage and Administration (Arm 1 only):
Talimogene laherparepvec will be administered to subjects randomized to Arm 1 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 until 
week 12, all injectable tumors have disappeared, or intolerance of study treatment, whichever 
occurs first. 
Refer to Section 6.2.1.1 for additional information regarding the dosage and administration of 
talimogene laherparepvec.
Other Protocol-required Therapy
Surgical Resection of Melanoma Lesion(s):
Surgical radical resection of melanoma lesion(s) aimed to achieve negative margins will be 
performed at any time during weeks 13 to 18 (Arm 1) or week 1 to 6 (Arm 2).  Subjects
randomized to Arm 1 who ends talimogene laherparepvec prior to week 12 due to disappearance 
of all injectable tumor lesions, intolerance to talimogene laherparepvec, or any other reason will 


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 6 of 100
CONFIDENTIAL
undergo surgical resection of melanoma lesion(s) or tissue where melanoma was present before 
CR within 1 to 6 weeks after the last dose of talimogene laherparepvec.  Refer to Appendix F for 
surgery guidelines.
Refer to Section 6.3 for additional information regarding other protocol-required therapies.
Procedures:
Screening:
The following procedures will be performed during the screening period:

confirmation that the informed consent form has been signed 

review of medical and surgical history, physical examination

demographics, vital signs, and ECOG performance status assessment

local laboratory tests including, hematology panel, chemistry panel, serum LDH, prothrombin 
time (PT) (or international normalization ratio [INR]) and partial thromboplastin time (PTT) (or 
activated PTT), and serum or urine pregnancy test for female subjects of childbearing 
potential

clinical tumor assessment and radiographic tumor imaging

recording of concomitant medications, recording/reporting of any serious adverse events that 
occur after subject signs informed consent

review of inclusion criteria and randomization in Interactive Voice Response (IVR) system
For a full list of screening procedures, including the timing of each procedure, please 
refer to Section 7.2.1 and the Schedule of Assessments (Table 2 and Table 3).
Treatment:
The following procedures will be performed during the treatment period (Note: Some of the 
following procedures are not applicable to subjects randomized to Arm 2 [surgery alone]):

vital signs

ECOG performance status

physical examination

local laboratory tests including hematology panel and chemistry panel

central laboratory tests including blood samples for herpes simplex virus (HSV-1) antibody 
serostatus and biomarker analyses, tumor biopsy for biomarker analyses, swabs of cold sore, 
vesicles and other lesions suspected to be herpetic origin (if any) for real-time polymerase 
chain reaction (qPCR) analysis of talimogene laherparepvec DNA

archived tumor tissue for serine/threonine protein kinase B-Raf V600 (BRAFV600) mutation 
testing and biomarker analyses

radiographic tumor imaging, clinical tumor assessment, and tumor response assessment

histological tumor assessment of the surgical specimen, including assessment for tumor-free 
margins (R0 resection for negative margins, R1 or R2 resections for tumor positive margins) 
and pathological complete response (Arm 1 only), recording of concomitant medications, 
adverse events, at each visit, and reporting serious adverse events Amgen within 24 hours 
following the investigator’s knowledge of the event

reporting pregnancy or lactation in a female subject or a female partner of a male subject 

administration of talimogene laherparepvec at day 1 of each cycle and/or surgical resection of 
melanoma lesion based on the randomization arm
For a full list of applicable treatment procedures by treatment arm, including the timing of each 
procedure, please refer to Section 7.2.2 and the Schedule of Assessments (Table 2 and Table 3).


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 7 of 100
CONFIDENTIAL
Safety Follow-Up Visit:
The following will be performed during the safety follow-up visit (Note: Some of the following 
procedures are not applicable to subjects randomized to Arm 2 [surgery alone]):

physical examination, vital signs and ECOG performance status assessment

surgical safety evaluation

documentation of subsequent anticancer therapy for melanoma (including local, regional, or 
systemic therapy)

local laboratory tests including hematology panel, chemistry panel and serum or urine 
pregnancy test for female subjects of childbearing potential

central laboratory tests of swabs of cold sores, vesicles, and other lesions suspected to be 
herpetic in origin (if any) for qPCR testing of talimogene laherparepvec DNA within 24 hours 
following the investigator’s knowledge of the event

recording of concomitant medications, adverse events, and reporting serious adverse events

reporting pregnancy or lactation in a female subject or a female partner of a male subject 
For a full list of applicable safety procedures by treatment arm, including the timing of each 
procedure, please refer to Section 7.2.3 and the Schedule of Assessments (Table 2 and Table 3).
Long-term Follow-up:
All randomized subjects will be contacted by telephone, or clinic visit, to assess survival status, 
collect adverse events deemed by the investigator to be potentially related to talimogene 
laherparepvec (Arm 1 only), and, if applicable, commencement of any subsequent anticancer 
melanoma therapy (including local, regional, or systemic therapy).  Follow-up will occur every 
3 months (±30 days) for 3 years following the safety follow-up visit and then every 6 months 
(±30 days) until death, subject withdraws full consent, or up to 5 years after the last subject is 
randomized.
Radiographic tumor imaging, clinical tumor assessments, and tumor response assessments, will 
be performed as documented in Section 7.2.2 every 3 months (±30 days) for 3 years following the 
safety follow-up visit and then every 6 months (±30 days) until distant disease recurrence, death, 
subject withdraws full consent, or up to 5 years after the last subject is randomized, whichever is 
first.
After the long-term follow-up period of this study has ended, subjects randomized to Arm 1 who 
received at least a single dose of talimogene laherparepvec and 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 subsequent anticancer therapy for melanoma.  Subjects who after the 
long-term follow-up period of this study (Study 20110266) will elect to participate in the registry 
study must sign new informed consent form before any registry protocol-specific activities.
Reporting Exposure to Talimogene Laherparepvec (Arm 1 only):
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.
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 and Table 3).
Statistical Considerations:
The primary analysis for the primary endpoint will occur at the later time of either the occurrence 
of approximately 64 events (local, regional, or distant recurrence of melanoma or death) or 
approximately 2 years after the end of randomization.  An 80% confidence interval (CI) will be 


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 8 of 100
CONFIDENTIAL
estimated for the RFS hazard ratio (HR) and the between-arm difference (Arm 2 – Arm 1) in 
2-year RFS, ie, 2-year RFS.  It is assumed that: (i) RFS is exponential over the first 2 years, 
(ii) the 2-year RFS for Arm 1 is about 0.60 (Eggermont et al, 2008), and that there will be a 
10% exponential probability of drop-out by the primary analysis. The average width of the 
2-year RFS 80% CI was 0.20 based on the simulation with an approximately 150 subjects 
randomized 1:1 to the two arms.  
Two interim analyses with no formal stopping rules are planned to evaluate safety and some 
efficacy endpoints (eg, R0 resection rate, pCR rate, response to neoadjuvant treatment) when 
approximately 40 and 75 subjects randomized to talimogene laherparepvec have had the 
opportunity to complete the safety follow-up visit. The primary analysis for certain secondary 
endpoints (eg, response to neoadjuvant treatment, R0 resection rate, pCR rate, and safety) will 
be performed using the data from the second interim analysis.
An additional third interim analysis with no formal stopping rule is planned to evaluate 
RFS approximately 1 year after the end of randomization.  This analysis will be conducted 
by the Amgen study team.
The primary analyses for RFS will occur at the later time of either the occurrence of 
approximately 64 events (local, regional, or distant recurrence of melanoma or death) or 
approximately 2 years after end of randomization.
The final analyses will occur approximately 5 years after the end of randomization. An additional 
analysis will also occur approximately 3 years after the end of randomization.
Ad hoc analyses for safety or some efficacy endpoints (eg, response to neoadjuvant treatment, 
R0 resection rate, pCR rate) may be conducted before the planned primary and/or final analyses
if interim data are required for submission to regulatory authorities.
All efficacy analyses will be descriptive with no formal hypothesis testing. Kaplan-Meier (KM)
estimates and CI will be calculated for RFS, LRFS, RRFS, DMFS, OS landmarks (1-, 2-, 3- and 
5-year rates) and quartiles.  Estimates and CIs for between-group differences will also be 
calculated.  An overall between-group difference in RFS, LRFS, RRFS, DMFS, and OS will be 
evaluated with a log-rank test and corresponding proportional hazards model with or without two 
randomization stratification factors. Estimates and exact CIs for binary endpoints (eg, overall 
tumor response, response in injected and uninjected lesions, R0 rate, pCR) and their associated 
between-group differences will be calculated.
Subject incidence rates of treatment-emergent adverse events (including all adverse events, 
grade ≥ 3 adverse events, fatal adverse events, serious adverse events, adverse events of 
interest and events requiring the discontinuation of study drug, local effects on the tumor [ie, pain, 
inflammation and ulceration]) will be summarized.
The analyses of tumor tissue or serum biomarkers may be performed after collection of all 
samples during the conduct of the study and therefore may be reported after the primary analysis 
of efficacy endpoint.
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor:  Amgen Inc
Data Element Standards 
Version/Date: 
Version 4.0, 31 October 2013  


Product: Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 9 of 100
CONFIDENTIAL
Study Design and Treatment Schema


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 10 of 100
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Study Glossary
Abbreviation or Term
Definition/Explanation
AJCC
American Joint Committee on Cancer
ANC
absolute neutrophil count
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BRAF, BRAFV600
serine/threonine protein kinase B-Raf, serine/threonine protein 
kinase B-Raf V600
BUN
blood urea nitrogen
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic lymphocyte associated antigen 4 (CTLA-4)
DMFS
distant metastases-free survival
DRR
durable response rate
DRT
Data Review Team
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
End of Follow-up
defined as when the last subject completes the last 
protocol-specified long-term follow-up assessment in the study
End of Study for 
Individual Subject
defined as the last day that protocol-specified procedures are 
conducted for an individual subject
End of Study (primary 
completion)
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint (s).  The primary completion is anticipated to occur at the 
later time of either occurrence of approximately 64 events (local, 
regional, or distant recurrence of melanoma or death) or 
approximately 2 years after the end of randomization.
End of Study (end of trial) defined as when the last subject is assessed or receives an 
intervention for evaluation in the study.  The end of trial will occur 
when the last subject has had the opportunity to complete the 
long-term follow-up.  The end of trial is anticipated to occur 
approximately 5 years after the end of randomization.
End of Treatment
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject
eSAE
electronic serious adverse event
ESMO
European Society for Medical Oncology
GCP
Good Clinical Practice


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 11 of 100
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Abbreviation or Term
Definition/Explanation
GM-CSF
granulocyte macrophage colony-stimulating factor
HD
high-dose
HR
hazard ratio
HSV, HSV-1
herpes simplex virus, herpes simplex virus type 1
ICH
International Conference on Harmonisation
KM
Kaplan-Meier
IL
interleukin
INR
international normalization ratio
Interactive Voice 
Response (IVR)
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information. 
IFNα
interferon alpha
IPIM
Investigational Product Instruction Manual
IRB/IEC
institutional review board/independent ethics committee
LDH
lactate dehydrogenase
LRFS
local recurrence-free survival
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
OS
overall survival
pCR
pathological complete response
PD-1
program cell death-1
PD-L1
programmed cell death-1 ligand 1
PET
positron emission tomography
PFU
plaque forming unit
PKR
double-stranded RNA activated protein kinase
PR
partial response
PT
prothrombin time
PTT/aPTT
partial thromboplastin time/activated partial thromboplastin time
qPCR
real-time polymerase chain reaction
RBC
red blood cell
RFS
recurrence-free survival
RRFS
regional recurrence-free survival
SD
stable disease
SOC
system organ class


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
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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]).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value.
Study Day 1
defined as the first day that protocol-specified investigational 
product/protocol required therapies is/are administered to the subject
ULN
upper limit of normal
USA
United States of America
WBC
white blood cell
WHO
World Health Organization


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
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TABLE OF CONTENTS
Protocol Synopsis............................................................................................................3
Study Design and Treatment Schema .............................................................................9
Study Glossary..............................................................................................................10
1.
OBJECTIVES .......................................................................................................17
1.1
Primary .....................................................................................................17
1.2
Secondary.................................................................................................17
1.3
Exploratory................................................................................................17
2.
BACKGROUND AND RATIONALE ......................................................................17
2.1
Melanoma and Adjuvant and Neoadjuvant Therapy for 
Melanoma .................................................................................................17
2.2
Talimogene Laherparepvec Background...................................................22
2.3
Rationale...................................................................................................25
2.4
Clinical Hypotheses...................................................................................26
3.
EXPERIMENTAL PLAN........................................................................................26
3.1
Study Design.............................................................................................26
3.2
Number of Sites ........................................................................................28
3.3
Number of Subjects...................................................................................28
3.4
Replacement of Subjects ..........................................................................28
3.5
Estimated Study Duration..........................................................................28
3.5.1
Study Duration for Subjects.......................................................28
3.5.2
End of Study..............................................................................29
4.
SUBJECT ELIGIBILITY ........................................................................................29
4.1
Inclusion and Exclusion Criteria ................................................................29
4.1.1
Inclusion Criteria........................................................................29
4.1.2
Exclusion Criteria ......................................................................31
5.
SUBJECT ENROLLMENT....................................................................................32
5.1
Randomization/Treatment Assignment......................................................33
6.
TREATMENT PROCEDURES..............................................................................34
6.1
Classification of Product............................................................................34
6.2
Investigational Product..............................................................................34
6.2.1
Amgen Investigational Product Talimogene 
Laherparepvec ..........................................................................34
6.2.1.1
Dosage, Administration, and Schedule....................34
6.2.1.2
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation........................................................36
6.3
Other Protocol-required Therapies ............................................................38


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
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6.4
Concomitant Therapy................................................................................39
6.5
Other Treatment Procedures.....................................................................39
6.6
Medical Devices........................................................................................39
6.7
Product Complaints...................................................................................39
6.8
Excluded Treatments and/or Procedures During Study Period..................40
7.
STUDY PROCEDURES .......................................................................................40
7.1
Schedule of Assessments.........................................................................40
7.2
General Study Procedures ........................................................................46
7.2.1
Screening and Randomization...................................................47
7.2.2
Treatment..................................................................................48
7.2.3
Safety Follow-up Visit................................................................51
7.2.4
Long-term Follow-up..................................................................52
7.2.5
Reporting Exposure to Talimogene Laherparepvec...................53
7.3
Biomarker Development............................................................................53
7.3.1
Blood Samples ..........................................................................54
7.3.2
Tumor Tissue Samples..............................................................54
7.4
Pharmacogenetic Studies .........................................................................55
7.5
Sample Storage and Destruction...............................................................55
8.
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY..................57
8.1
Subjects’ Decision to Withdraw .................................................................57
8.2
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion......................................57
8.2.1
Reasons for Removal From Treatment......................................58
8.2.2
Reasons for Removal From Study.............................................58
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING.......................58
9.1
Adverse Events.........................................................................................58
9.1.1
Definition of Adverse Events......................................................58
9.1.2
Definition of Serious Adverse Events.........................................59
9.2
Reporting of Adverse Events.....................................................................60
9.2.1
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria.................................................................60
9.2.2
Reporting Procedures for Serious Adverse Events....................61
9.3
Pregnancy and Lactation Reporting ..........................................................62
9.4
Reporting of Exposure to Talimogene Laherparepvec...............................63
10.
STATISTICAL CONSIDERATIONS......................................................................63
10.1
Study Endpoints, Analysis Sets, and Covariates .......................................63
10.1.1
Study Endpoints ........................................................................63
10.1.1.1
Primary Endpoint.....................................................63
10.1.1.2
Secondary Endpoint................................................64
10.1.1.3
Exploratory Endpoints .............................................65
10.1.2
Analysis Sets.............................................................................65


Product:  Talimogene Laherparepvec
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10.1.3
Covariates and Subgroups ........................................................65
10.2
Sample Size Considerations .....................................................................66
10.3
Access to Individual Subject Treatment Assignments by Amgen 
or Designees.............................................................................................67
10.4
Planned Analyses .....................................................................................67
10.4.1
Interim Analyses........................................................................67
10.4.2
Data Review Team (DRT) .........................................................68
10.4.3
Primary Analysis........................................................................68
10.4.4
Final Analysis ............................................................................68
10.4.5
Additional Analysis ....................................................................68
10.5
Planned Methods of Analysis ....................................................................68
10.5.1
General Considerations.............................................................68
10.5.2
Primary Efficacy Endpoint..........................................................69
10.5.3
Secondary Efficacy Endpoints ...................................................69
10.5.4
Safety Endpoints .......................................................................70
11.
REGULATORY OBLIGATIONS............................................................................70
11.1
Informed Consent......................................................................................70
11.2
Independent Ethics Committee .................................................................71
11.3
Subject Confidentiality...............................................................................72
11.4
Investigator Signatory Obligations.............................................................73
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS..................................................73
12.1
Protocol Amendments and Study Termination ..........................................73
12.2
Study Documentation and Archive ............................................................73
12.3
Study Monitoring and Data Collection .......................................................74
12.4
Investigator Responsibilities for Data Collection........................................75
12.5
Language..................................................................................................75
12.6
Publication Policy......................................................................................76
12.7
Compensation...........................................................................................76
13.
REFERENCES.....................................................................................................77
14.
APPENDICES ......................................................................................................81
List of Tables
Table 1.  Talimogene Laherparepvec Injection Volume Guideline 
Based on Tumor Size .............................................................................35
Table 2.  Schedule of Assessments for Arm 1 (Talimogene Laherparepvec 
Plus Surgery)..........................................................................................41
Table 3.  Schedule of Assessment for Arm 2 (Surgery Alone) .......................................44
Table 4.  Laboratory Analytes........................................................................................46
Table 5.  Study Design Characteristics..........................................................................67


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
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List of Appendices
Appendix A. Additional Safety Assessment Information................................................82
Appendix B.  Sample Serious Adverse Event Report Form ...........................................83
Appendix C.  Pregnancy and Lactation Notification Worksheets....................................88
Appendix D.  Modified World Health Organization (WHO) Response Criteria................90
Appendix E.  Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................................97
Appendix F.  Surgery Guidelines ...................................................................................98


Product:  Talimogene Laherparepvec
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Date:  23 March 2018
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1.
OBJECTIVES
1.1
Primary
To estimate the treatment effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on recurrence-free survival (RFS).
1.2
Secondary
The secondary objectives are:

To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on 1-year, 2-year, 3-year, and 5-year RFS

To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on rate of histopathological tumor-free margin (R0) 
surgical resection

To estimate the effect of neoadjuvant talimogene laherparepvec on rate of 
pathological complete response (pCR)

To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on local recurrence-free survival (LRFS), regional 
recurrence-free survival (RRFS), and distant metastases-free survival (DMFS)

To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on 1-year, 2-year, 3-year, 5-year, and overall survival 
(OS)

To estimate response to neoadjuvant talimogene laherparepvec overall and 
separately in injected and uninjected lesions during treatment (Arm 1 only)

To evaluate the safety of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone
1.3
Exploratory
The exploratory objectives are:

To explore the correlation between baseline intratumoral CD8+ cell density and 
clinical outcomes

To explore the correlation between changes in an intratumoral CD8+ cell density
during talimogene laherparepvec treatment and clinical outcomes

To investigate the correlation between the changes in the population of 
tumor-specific cytotoxic T-cells during treatment and clinical outcomes

To assess blood and tumor for potential biomarkers which correlate with or predict 
clinical outcomes to talimogene laherparepvec
2.
BACKGROUND AND RATIONALE
2.1
Melanoma and Adjuvant and Neoadjuvant Therapy for 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 
76, 100 new cases and 9,710 deaths expected in 2014 (Siegel et al, 2014).  In Europe, 


Product:  Talimogene Laherparepvec
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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 
(Ferlay et al, 2013).  In Europe as a whole, 100, 442 new cases of skin melanoma and 
22, 212 deaths from melanoma were estimated in 2012 (Ferlay et al, 2013).  The 
incidence of melanoma in Australia is the highest in the world, with the age-standardized 
incidence rate of approximately 50 per 100,000 people in 2009 (Australian Institute of 
Health and Welfare, 2012).  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 thyroid cancer in women (Edwards et al, 2005; 
Siegel et al, 2014).  Median age for diagnosis of melanoma (59 years) is significantly 
lower than the median age of diagnosis for the more common solid tumors.  As such, 
melanoma is second only to adult leukemia in terms of loss of years of potential life per 
adult cancer-related death (Coit et al, 2013).
When discovered in earlier stages and fully excised, melanoma is highly curable with 
10-year overall survival (OS) approaching 95% for stage I and 45-77% for stage II 
(American Joint Committee on Cancer [AJCC], 7th edition) melanoma (Balch et al, 2009).  
It is estimated that about 10% of subjects with melanoma present with 
regionally-advanced disease (stage III) and approximately 30% will have nodal and/or 
in-transit metastasis as their first site of recurrence (Kirkwood et al, 2000; SEER, 2014).  
While radical resection is a cornerstone of treatment for subjects with stage III 
melanoma (Slingluff et al, 2011; Coit et al, 2013), the majority of subjects with clinically 
detectable nodal metastases and/or in-transit disease will experience recurrence, with 
5-year OS of 59% for subjects with stage IIIB disease and 40% for IIIC disease 
(Balch et al, 2009).  In one of the latest adjuvant trials utilizing pegylated interferon alpha
(IFNα)-2b, 4-year RFS and OS of all subjects with palpable nodal disease 
(N2-N3, AJCC, 7th edition) in the observation group were 33.9 ± 2.6% and 46.8 ± 2.6% 
respectively, dropping sharply with the amount of lymph nodes involved 
(Eggermont et al, 2008).
Approximately 20% of subjects with earlier stages of melanoma will develop distant 
cutaneous/subcutaneous or distant nodal metastasis in the absence of visceral disease 
or elevated lactate dehydrogenase (LDH) (stage IVM1a) (Kirkwood et al, 2000).  Stage 
IVM1a melanoma has better prognosis compared with metastases located in any other 
distant anatomic site, with 1-year OS of 62%, and 5-year OS approaching 30% 


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(Balch et al, 2009).  Resection, if feasible, is often recommended for this group of 
subjects (Slingluff et al, 2011; Coit et al, 2013).
High-dose (HD) IFNα (Intron® A, 2013) or pegylated IFNα (Sylatron, 2013) are the 
FDA-approved systemic therapies that can be considered in subjects after resection of 
stage III melanoma.  Other treatment options recommended by the National 
Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology 
(ESMO) Guidelines include participation in clinical trials, or observation 
(Dummer et al, 2012; Coit et al, 2013).  Even with a higher rate of relapse than stage III 
disease, there is little evidence to support adjuvant treatment with IFNα for resected 
IVM1a melanoma.
HD IFNα has shown a modest, but significant RFS benefit when given as adjuvant 
therapy to subjects with melanomas at high risk for recurrence (Kirkwood et al, 2000; 
Kirkwood et al, 1996).  A pooled analysis of three major adjuvant trials with HD IFNα 
found an improvement in RFS in subjects with melanomas that are 4 mm or thicker with 
no evidence of lymph node involvement, or stage III melanomas with either lymph node 
involvement and/or in-transit metastases (hazard ratio [HR] 0.77, two-sided p < 0.006, 
median follow-up of 7.2 years), but failed to demonstrate a significant improvement in 
OS (HR 0.93, two-sided p = 0.42) (Kirkwood et al, 2004).  Major toxicities of HD IFNα 
include flu-like symptoms, auto-immune disorders, hepatotoxicity, significant laboratory 
abnormalities, depression, and suicide (Slingluff et al, 2011).  As such, adjuvant HD 
IFNα after resection of stage III melanoma is decreasingly being utilized 
(Coit et al, 2013) and is not recommended as a standard of care for adjuvant therapy 
according to the guidelines of several professional societies (Marsden et al, 2010; 
Scottish Intercollegiate Guidelines Network, 2013).
Intermediate-dose regimens of pegylated IFNα, which are more convenient to 
administer and have been evaluated in several clinical trials, demonstrated improved 
RFS (HR 0.82, p = 0.011, 95% confidence interval [CI]: 0.71; 0.96), however there 
was no effect on DMFS or OS, and toxicity was significant with grade 3 adverse 
events in approximately 40% of subjects; leading to discontinuation of therapy in 
about one-third of subjects assigned to the treatment arm (Eggermont et al, 2008;
Eggermont et al, 2005).
A recently reported intergroup phase III trial compared a HD IFNα regimen to a 9-week 
“biochemotherapy” consisting of dacarbazine, vinblastine, cisplatin, intravenous 
interleukin (IL)-2, and subcutaneous IFNα as adjuvant treatment for patients after 


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resection of high-risk stage III melanoma. At a median follow-up of 6 years, 
biochemotherapy improved RFS (HR 0.77, p < 0.02; 90% CI: 0.62-0.96), however there 
was no difference in OS (HR 1.0, p = 0.49, 90% CI: 0.78-1.27) and same 56% of 
subjects were alive at 5 years in both arms of the trial. The biochemotherapy regimen 
was associated with substantial toxicity with grade 3 and 4 adverse events in 36% and 
40% of subjects, respectively (Flaherty et al, 2012).
Several meta-analyses have confirmed a significant effect of adjuvant IFNα on RFS 
and some demonstrated small but significant improvement in OS (Wheatley et al, 2007; 
Wheatley et al, 2003; Mocellin et al, 2013; Mocellin et al, 2010). In the latest Cochrane 
meta-analysis that included aggregate patient data from 17 randomized clinical trials 
comparing adjuvant IFNα to observation, adjuvant IFNα was associated with improved 
disease-free survival (HR 0.83, p<0.00001, 95% CI: 0.78-0.87) and improved OS 
(HR 0.91, p<0.003, 95% CI:  0.85-0.97) (Mocellin et al, 2013). The authors 
concluded that 35 participants needed to be treated in order to prevent 1 subject death 
of cutaneous stage II-III melanoma (95% CI: 21-108), confirming modest efficacy of 
adjuvant IFNα (Mocellin et al, 2013).
A variety of whole-cell based and defined antigen-based melanoma vaccines were 
explored in the adjuvant setting. However, the results of the trials either showed no 
benefit or could possibly be detrimental compared with observation 
(Eggermont et al, 2008; Blanchard et al, 2013).
Recently, ipilimumab, a cytotoxic lymphocyte associated antigen 4 (CTLA-4) inhibitor, 
was approved by the United States Food and Drug Administration for the adjuvant 
treatment of patients with cutaneous melanoma with pathologic involvement of regional 
lymph nodes of more than 1 mm who have undergone complete resection, including 
total lymphadenectomy (Yervoy, 2015). This approval was based on results of a 
randomized double-blind phase 3 trial conducted in 951 patients with completely 
resected stage IIIA (> 1 mm nodal involvement), IIIB, and IIIC melanoma 
(EORTC Study 18071). Patients with in-transit metastases were excluded. Ipilimumab 
improved recurrence-free survival (primary endpoint) in this trial from 17.1 months to 
26.1 months (HR 0.75; 95% CI 0.64–0.90; p=0.0013). Results of OS and distant
metastasis-free survival (secondary endpoints) are pending. Fifty-two percent of 
patients randomized to the ipilimumab arm discontinued treatment because of toxicity, 
5 patients (1%) died because of ipilimumab-related toxicities. Forty-six percent of 


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patients in the ipilimumab arm experienced grade 3 adverse events 
(37% immune-related), and 8% grade 4 (6% immune-related) (Eggermont et al, 2015).
Neoadjuvant therapy, the benefit of which has been demonstrated in several operable 
cancers (Bosset et al, 2006; Rastogi et al, 2008; Vergote et al, 2010), has potential 
advantages over adjuvant therapy in subjects with locally-advanced disease which 
include down-sizing of the primary tumor, consequently increasing the probability of 
negative margin resection, and early systemic exposure to potentially effective therapy 
through intact blood and lymphatic vessels.  Moreover, neoadjuvant therapy allows 
real-time assessment of antineoplastic effects of the therapy in vivo on tumor cells, 
tumor microenvironment and the immune system, and permits prospective and 
sequential collection of tissue samples for biomarker studies.
This investigational approach for preoperative treatment of subjects with 
locally-advanced melanoma was utilized in several phase 2 trials where the subjects 
were treated by intravenous high-dose IFNα (Moschos et al, 2006) or by 
biochemotherapy (Buzaid et al, 1998; Koyanagi et al, 2005; Lewis et al, 2006).  
Ninety-two subjects with histologically-proven stage III nodal melanoma were enrolled in 
the phase 2 study to receive 2 cycles of preoperative biochemotherapy followed by 
surgery and 2 postoperative cycles of biochemotherapy (Lewis et al, 2006).  Treatment, 
which included cisplatin, dacarbazine, vinblastine, and IL-2 and IFNα, was administered 
in the inpatient setting and included growth factors and blood pressure support.  
Common adverse events were hematological grade 3 and 4 toxicities, electrolytes 
grade 3 toxicities, and nausea and vomiting. Nearly 40% of subjects required dose 
reductions and 40% had treatment delays.  Among fifty subjects with measurable 
disease, complete response (CR) and partial response (PR) rates were 4% and 22%, 
respectively (assessed by World Health Organization [WHO] criteria [WHO handbook for 
reporting results of cancer treatment, 1979]).  Half of the subjects (50%) had stable 
disease (SD) and 8% had tumor progression.  At the time of surgery, 26% of subjects 
with measurable disease had pCR.  In another neoadjuvant trial, 20 subjects with 
palpable regional lymph node metastatic melanoma were treated by preoperative 
high-dose IFN for 4 weeks followed by surgery and postoperative subcutaneous IFN for 
48 weeks (Moschos et al, 2006).  CR was noted in 1 (5%) subject and 10 subjects (50%) 
had PR.  At the time of surgery, 15% of subjects had pCR.  Immunohistochemical 
analysis of pre-and post-treatment tumor biopsies revealed increases in peritumoral 
CD4+ T-lymphocytes and endotumoral monocyte-derived dendritic cells after the 


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treatment with high-dose IFNα.  Clinical responders compared with non-responders 
demonstrated a trend toward greater increases in endotumoral monocyte-derived 
dendritic cells (Moschos et al, 2006).
Limited clinical experience with neoadjuvant temozolomide administered for 6 weeks for 
two 8-week cycles to 19 patients, while well tolerated resulted in objective response in 
3 patients only (2 had CR and 1 had PR), stable disease in 4 patients, and tumor 
progression in 12 patients while on treatment (Shah et al, 2010).
2.2
Talimogene Laherparepvec Background
Talimogene laherparepvec is an intralesionally-delivered oncolytic immunotherapy 
comprised of a genetically engineered herpes simplex virus type 1 (HSV-1) that 
selectively replicates in tumors (Talimogene Laherparepvec Investigator’s 
Brochure, 2015).  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 ICP34.5 functional deletion allows 
the virus to replicate selectively in tumors.  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. 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).  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).
The postulated dual mechanism of action of talimogene laherparepvec comprises: 
1) 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 
2) enhancement of a systemic immune response by expression of GM-CSF in the tumor 
microenvironment to recruit and activate antigen presenting cells.  Clinical data currently 
available have provided evidence of talimogene laherparepvec’s efficacy in subjects with 


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unresectable metastatic melanoma (Talimogene Laherparepvec Investigator’s 
Brochure, 2015).  In particular, a high rate of 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 2015). 
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.
In the open-label, randomized, phase 3 study in 436 subjects with stages lllB, lllC, and 
IV unresectable melanoma, intralesional talimogene laherparepvec or subcutaneous 
GM-CSF were administered at least until week 24, or CR, clinically significant disease 
progression, intolerable side effects, 12 months of therapy without an objective 
response, or withdrawal of consent (Study 20110263; OPTiM).  If subjects were in 
response (CR or PR) at 12 months, they were treated in both arms up to 18 months or 
disease progression (PD), whichever was earlier. The primary endpoint of the OPTiM 
study was durable response rate (DRR), defined as the rate of subjects with an objective 
response (CR or PR) by central review lasting continuously for 6 months and starting 
any time within 12 months of initiating therapy. Secondary endpoints included OS, best 
response, modified PFS, tumor burden and safety.
Primary analysis of the OPTiM Study showed a statistically significant difference 
between the DRR 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) (Andtbacka et al, 2013). At the same analysis median modified PFS 
was 8.2 (95% CI, 6.5, 9.9) months in the talimogene laherparepvec arm versus 
2.9 (95% CI, 2.8, 4.0) months in the GM-CSF arm (HR=0.42; 95%CI=0.32, 0.54). An 
improvement that closely approached statistical significance was seen in the 
intent-to-treat population in the primary analysis of the secondary endpoint of OS with 
HR of 0.79 (95% CI: 0.62, 1.00), p = 0.051. Median OS of subjects treated with 
talimogene laherparepvec was 4.4 months longer than those treated with GM-CSF 
(23.3. months for talimogene laherparepvec versus 18.9 months for GM-CSF) 
(Kaufman et al, 2014). Survival at 12, 24, 36 and 48 months in the talimogene 
laherparepvec arm was estimated to be 74%, 50%, 39% and 33%, respectively, and 
69%, 40%, 30% and 21% in the GM-CSF arm, respectively. In exploratory subset 
analyses, the treatment effect was most pronounced among subjects receiving treatment 
as first-line therapy (HR=0.50; 95% CI=0.35, 0.73) compared with subjects receiving 


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Protocol Number:  20110266
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treatment as second-line or greater therapy (HR=1.13; 95% CI=0.82, 1.57), and subjects 
with stage lllB/C (HR for OS 0.48; 95% CI: 0.29, 0.80, log-rank p-value 0.004) and 
stage IVM1a (HR 0.67; 95% CI: 0.42, 1.07, log-rank p-value 0.09) melanoma
(Kaufman et al, 2014). Similarly, in exploratory subset analyses of DRR, the treatment 
effect was most pronounced among subjects with stage IIIB/C disease (DRR = 33% in 
talimogene laherparepvec arm versus 0% in GM-CSF arm), and stage IVM1a disease 
(DRR = 16% in talimogene laherparepvec arm versus 2% in GM-CSF arm), and these 
subjects represented > 55% of the study population.  DRR was also more pronounced in 
subjects receiving treatment as first-line therapy (24% versus 0%) than in those 
receiving treatment as second-line or greater therapy (10% versus 4%)
(Kaufman et al, 2013). Serine/threonine protein kinase B-Raf (BRAF) status was known 
in 31.4% of subjects; the DRR with talimogene laherparepvec was 11% in subjects with 
or without BRAF mutations.
Median (range) time to response among the 78 subjects in the talimogene 
laherparepvec arm with a response was 4.1 (1.2 to 16.7) months, whereas among the 
8 in the GM-CSF arm with a response, it was 3.7 (1.9 to 9.1) months.  Fifty-four percent 
of talimogene laherparepvec objective responders and 48% of talimogene laherparepvec 
durable responders exhibited “interval progression”, which is transient locoregional or 
distant progression including appearance of new lesions, before ultimately achieving 
response (Kaufman et al, 2013). When investigator-reported response rates (decrease 
in lesion area:  PR, 50 to <100%; CR, 100%) of 3,916 measurable lesions (average 13) 
in 285 subjects treated by talimogene laherparepvec in the OPTiM Study were analyzed
retrospectively, CR and PR rates in injected lesions were 47% and 17%, respectively. 
CR and PR in non-injected non-visceral lesions were 22% and 12%, respectively. CR 
and PR in visceral lesions, which were also non-injected, were 9% and 6%, respectively 
(Andtbacka et al, 2014).
The most common side effects in the OPTiM study were chills (talimogene 
laherparepvec, 49%; GM-CSF, 9%), pyrexia (43%; 9%), injection-site pain (28%; 6%), 
nausea (36%; 20%), influenza-like illness (30%; 15%), and fatigue (50%; 36%).  
Grade ≥3 adverse events occurred in 36% of subjects receiving talimogene 
laherparepvec and 21% of subjects receiving GM-CSF.  The only grade 3/4 adverse 
events occurring in ≥5 of subjects was cellulitis (talimogene laherparepvec, n=6 [2.1%]; 
GM-CSF, n=1 [<1%]).  Of 10 fatal adverse events in the talimogene laherparepvec 
arm, 8 were attributable to disease progression.  The remaining 2 fatal adverse events


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(sepsis in the setting of salmonella infection; myocardial infarction) were not considered 
treatment-related per investigator.
Recently, talimogene laherparepvec (Imlygic) was approved in the USA for the local
treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with 
melanoma recurrent after initial surgery (with limitation of use: Imlygic has not been 
shown to improve overall survival or have an effect on visceral metastases) 
(ImlygicPrescribing Information, 2015), in Europe for the treatment of adults with 
unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC, and 
IVM1a) with no bone, brain, lung or other visceral disease
(ImlygicSummary of Product Characteristics, 2015), and in Australia as monotherapy
for the treatment of melanoma in patients with unresectable cutaneous, subcutaneous, 
or nodal lesions after initial surgery (ImlygicPrescribing Information, 2015). 
Refer to the latest version of Talimogene Laherparepvec Investigator’s Brochure for 
additional information.
2.3
Rationale
The main purpose of the study is to estimate the ability of talimogene laherparepvec 
administered prior to surgery to increase RFS in subjects with resectable stage IIIB to 
IVM1a melanoma.
It is expected that neoadjuvant treatment with talimogene laherparepvec will improve 
both local and distant control by achieving higher rates of tumor-free (negative) margin 
surgical resection (R0), and will decrease distant metastasis rate through systemic 
effects on micrometastatic disease.
Since talimogene laherparepvec is assumed to work via activation of the immune system
and infiltrating T cells have also been shown to be prognostic for melanoma 
(Erdag et al, 2012), it is important to understand whether the number and type of tumor 
infiltrating and peripheral immune cells impact drug efficacy. Therefore, tumor and blood 
samples will be collected before and at the end of the talimogene laherparepvec 
treatment to investigate the relationship between the activities of the immune system, 
such as cytotoxic CD3+/CD8+ and CD8+/CD45R0 T-lymphocytes, tumor antigen 
specific T cells, regulatory T cells and myeloid-derived suppressor cells measured both 
in the tumor and/or in the peripheral blood, and response to the treatment.  Additionally, 
a number of immune-related biomarkers, such as antibodies to melanoma antigens and
expression of immune-stimulatory and immune-inhibitory molecules (eg CTLA-4, 


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program cell death-1 [PD-1], program cell death-1 ligand 1 [PD-L1] and others) in tumors 
or tumor infiltrating T-cells will be assessed to determine any association with clinical 
outcomes.
Moreover, tumor biopsy samples will be assessed for mutations effecting viral 
replication, such as double-stranded RNA-activated protein kinase (PKR) that cells 
activate to protect themselves from viral infection and whose activity may predict clinical 
response to treatment with talimogene laherparepvec.  Also, safety of talimogene 
laherparepvec, especially related to postoperative complications will be evaluated.
2.4
Clinical Hypotheses
Formal hypotheses will not be tested in this trial.  The study will provide an estimate of 
the treatment effect, as measured by the difference in RFS of talimogene laherparepvec 
neoadjuvant therapy followed by surgery compared to surgery alone in subjects with 
resectable, stage IIIB to IVM1a melanoma.
3.
EXPERIMENTAL PLAN
3.1
Study Design
This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of 
talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to 
surgery alone in subjects with resectable stage IIIB, IIIC, or IVM1a melanoma.  
Approximately 150 subjects with completely resectable melanoma and at least one 
injectable lesion will be randomized 1:1 to receive the following:

Arm 1: Talimogene laherparepvec for 6 doses followed by surgical resection of 
melanoma tumor lesion(s).

Talimogene Laherparepvec:
Talimogene laherparepvec will be administered by intralesional injection into the 
injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 
106 plaque forming units (PFU)/mL at day 1 of week 1 followed by a dose of 
108 PFU/mL at day 1 (±3 days) of weeks 4, 6, 8, 10 and 12 or until all injectable 
tumors have disappeared, or intolerance of study treatment, whichever occurs 
first.  Due to the mechanism of action of talimogene laherparepvec, subjects may 
experience transient growth in existing tumors or the appearance of new tumors 
prior to maximal clinical benefit of talimogene laherparepvec. Subjects who
experience growth in existing tumors or the appearance of new tumors will be 
allowed to remain on talimogene laherparepvec treatment until week 12 of 
therapy unless, in the opinion of the investigator, immediate surgical resection or 


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any other treatment for melanoma is warranted.  If talimogene laherparepvec 
treatment will end prior to week 12, the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.

Surgical Resection of Melanoma Tumor Lesions(s):
For subjects who complete 12 weeks of talimogene laherparepvec treatment, 
surgical resection of melanoma lesion(s) will be performed at any time during 
weeks 13 to 18. Subjects who stop talimogene laherparepvec prior to week 12 
due to disappearance of all injectable tumor lesions, intolerance to talimogene 
laherparepvec, or any other reason will undergo adequate surgical resection of 
melanoma lesion(s) or tissue where melanoma was present before achieving 
CR, within 1 to 6 weeks after the last dose of talimogene laherparepvec.  If 
surgery will be performed prior to week 12, the investigator or designee should 
notify the sponsor’s medical monitor as soon as possible.  Refer to Appendix F
for surgery guidelines.

Arm 2: Immediate surgical resection of melanoma tumor lesion(s) 

Surgical resection of melanoma tumor lesion(s) will be performed after enrolment
any time during weeks 1 to 6. Refer to Appendix F for surgery guidelines.
Randomization will be stratified by disease stage (IIIB nodal versus IIIB in-transit versus
IIIC nodal versus IIIC in-transit with nodal versus IVM1a), planned adjuvant therapy 
(adjuvant systemic therapy [eg, INFα, ipilimumab] with or without radiotherapy versus
radiotherapy without adjuvant systemic therapy versus none).
Following surgery, adjuvant systemic therapy and/or radiotherapy may be administered 
at the investigator’s discretion and per the institutional standard of care.
Subjects will be followed for safety approximately 30 (+15) days after surgery and for 
disease recurrence (local, regional, or distant), subsequent anticancer therapy for 
melanoma, adverse events thought to be potentially related to talimogene 
laherparepvec, and survival every 3 months (±30 days) for first 3 years after the end of 
the safety follow-up period and then every 6 months (±30 days) until death, subject 
withdraws full consent, or up to 5 years after the last subject is randomized, which is 
first.  Thereafter, subjects randomized to Arm 1 who received at least a single dose of 
talimogene laherparepvec 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 


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subsequent anticancer therapy for melanoma. Subjects who after the long-term 
follow-up period of this study (Study 20110266) will elect to participate in the registry 
study must sign new informed consent form before any registry protocol-specific
activities.
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
The study will be conducted at approximately 50 sites in Australia, Brazil, Europe,
Russia, and USA.  Additional sites and countries may be added.
Sites that do not enroll subjects within approximately 4 months of site initiation may be 
closed.
3.3
Number of Subjects
Participants in this clinical investigation shall be referred to as “subjects”.
Approximately 150 subjects will be randomized in this study. Refer to Section 10.2 for 
sample size considerations.
3.4
Replacement of Subjects
Subjects who are withdrawn or removed from treatment or the study will not be replaced.
3.5
Estimated Study Duration
3.5.1
Study Duration for Subjects
The duration for the study will be approximately 7 years. The duration of screening for 
each subject will be approximately 28 days. The subject accrual period is planned for 
approximately 18 months. The duration of treatment will vary by treatment arm.  
Subjects randomized to Arm 1 of the study will be treated with talimogene laherparepvec 
for approximately 12 weeks then followed by surgical resection of melanoma lesion(s) 
any time from week 13 to 18.  Subjects randomized to Arm 2 of the study will undergo 
immediate surgical resection of melanoma lesion(s) any time from week 1 to 6.  Subjects 
will be followed for safety approximately 30 (+15) days after surgery and for disease 
recurrence (local, regional, or distant), subsequent anticancer therapy for melanoma, 
adverse events thought to be potentially related to talimogene laherparepvec, and 
survival every 3 months (±30 days) for first 3 years after the end of the safety follow-up


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period and then every 6 months (±30 days) until death, subject withdraws full consent, or 
up to 5 years after the last subject is randomized, which is first.
The end of study for each subject is defined as the date the subject withdraws full 
consent from the study, completes the long-term survival follow-up, or death.
3.5.2
End of Study
Primary Completion:  the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis.  The 
primary completion is anticipated to occur at the later time of either the occurrence of 
approximately 64 events (local, regional, or distant recurrence of melanoma or death) or 
approximately 2 years after the end of randomization.
End of Trial:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study.  The end of trial will occur when the last subject has had the 
opportunity to complete the long-term follow-up. The end of trial is anticipated to occur 
approximately 5 years after the end of randomization.
4.
SUBJECT ELIGIBILITY
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about each 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
Disease stage:  Subject with histologically-proven stage IIIB, IIIC, or IVM1a 
eligible for complete surgical resection according to the surgery guidelines in 
Appendix F
104
Prior systemic, regional, and radiation anticancer therapies for melanoma must 
have been completed at least 3 months prior to randomization
105
Candidate for intralesional therapy (ie, disease is appropriate for direct injection 
or through the use of ultrasound guidance) defined as either one of the following:

at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion 
≥10 mm in longest diameter

multiple injectable melanoma lesions which in aggregate have a longest diameter 
of ≥10 mm


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106
Measurable disease defined as one or more of the following:

at least one melanoma lesion that can be accurately and serially measured in at 
least 2 dimensions and for which the diameter in at least 2 dimensions is 
≥10 mm as measured by contrast-enhanced or spiral computed tomography 
(CT) scan for nodal/soft tissue disease (including lymph nodes) or ultrasound for 
superficial lymph nodes and subcutaneous lesions

at least one superficial cutaneous or subcutaneous melanoma lesion as 
measured by calipers with diameter ≥ 10 mm in at least 2 dimensions

multiple superficial melanoma lesions which in aggregate have a total diameter of 
≥10 mm in at least 2 dimensions
107
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
108
Serum LDH level ≤ 1.5 x upper limit of normal (ULN) for stages IIIB and IIIC
melanoma and ≤ 1.0 x ULN for stage IVM1a melanoma within 28 days prior to 
randomization
109
Adequate organ function determined within 28 days prior to randomization,
defined as follows:

Hematological

white blood cell count ≥3000/mm3

absolute neutrophil count (ANC) ≥1500/mm3

platelet count ≥100,000/mm3

hemoglobin ≥ 10 g/dL without need for hematopoietic growth factor or 
transfusion support

Hepatic

serum bilirubin ≤ 2.0 x ULN

serum albumin ≥2.5 g/dL

aspartate aminotransferase (AST) ≤ 2.5 x ULN

alanine aminotransferase (ALT) ≤ 2.5 x ULN

alkaline phosphatase ≤ 2.5 x ULN

Renal

serum creatinine ≤ 1.5 x ULN

Coagulation

prothrombin time (PT) ≤ 1.5 x ULN (or international normalization ratio 
[INR] ≤1.5)

partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN


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4.1.2
Exclusion Criteria
201.
Primary ocular or mucosal melanoma
202.
History or evidence of melanoma associated with immunodeficiency states 
(eg, hereditary immune deficiency, organ transplant, or leukemia)
203.
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 
and has not received chemotherapy for 3 years before randomization and felt 
to be at low risk for recurrence by the treating physician

adequately treated non-melanoma skin cancer without evidence of disease at the 
time of randomization

adequately treated cervical carcinoma in situ without evidence of disease at the 
time of randomization

adequately treated breast ductal carcinoma in situ without evidence of disease at 
the time of randomization

prostatic intraepithelial neoplasia without evidence of prostate cancer at the time 
of randomization

adequately treated superficial or in situ carcinoma of the bladder without 
evidence of disease at the time of randomization
204
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.
205
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
206
Known to have acute or chronic active hepatitis B infection
207
Known to have acute of chronic active hepatitis C infection
208
Known to have human immunodeficiency virus infection
209
Active herpetic skin lesions or prior complications of HSV-1 infection (eg, herpetic 
keratitis or encephalitis)
210
Requires intermittent or chronic systemic (intravenous or oral) treatment with an 
antiherpetic drug (eg, acyclovir), other than intermittent topical use


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211
Prior therapy with talimogene laherparepvec
213
Currently receiving treatment in another investigational device or drug study, or 
less than 28 days since ending treatment on another investigational device or 
drug study
214
Other investigational procedures while participating in this study are excluded
215
Female subject is pregnant or breast-feeding, or planning to become pregnant 
during talimogene laherparepvec treatment and through 3 months after the last 
dose of talimogene laherparepvec
216
Female subject of childbearing potential who is unwilling to use acceptable 
method(s) of effective contraception during talimogene laherparepvec 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 less 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).
217
Subject has known sensitivity to talimogene laherparepvec 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 physician, 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
Sexually active subjects and their partners unwilling to use male or female latex 
condoms to avoid potential viral transmission during sexual contact while on 
treatment and within 30 days after treatment with talimogene laherparepvec.  For 
those with latex allergies, polyurethane condoms may be used.
5.
SUBJECT ENROLLMENT
Before subjects begin participation in any study-specific activities/procedures, 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 11.2). All
subjects must personally sign and date the informed consent form before 
commencement of study-specific activities/procedures.
Upon confirmation of eligibility, the site staff will use the Interactive Voice Response 
(IVR) system to randomize a subject.  The investigator is to document this decision and 


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date in the subject’s medical record and in/on the enrolment case report form (CRF). A 
subject is considered enrolled upon randomization in the IVR system.
Each subject who enters into the screening period for the study (defined as the point 
when the subject signs the informed consent) receives a unique subject identification 
number before any study-related activities/procedures are performed.  The subject 
identification number will be assigned by the IVR system. 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.
Subjects who are determined not eligible after screening must be screen-failed in the 
IVR 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 consent form is signed within 28 days of randomization. 
Subjects who are determined not eligible after rescreen must be screen-failed in the IVR 
system and the reason for the screen-failure provided. Subjects may be randomized 
only once into this study.
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. This number will not necessarily be the same as the randomization number 
assigned for the study.
5.1
Randomization/Treatment Assignment
Upon confirmation of eligibility, the site staff will use the IVR system to randomize a 
subject.
The IVR system will assign a randomization number. Approximately 150 subjects will be 
stratified by disease stage (IIIB nodal versus IIIB in-transit versus IIIC nodal versus IIIC 
in-transit with nodal versus IVM1a), planned adjuvant therapy (adjuvant systemic 
therapy [eg, INFα, ipilimumab] with or without radiotherapy versus radiotherapy without 
adjuvant systemic therapy versus none).
Subjects will be randomized with a 1:1 ratio to receive the following: 

Arm 1: Talimogene laherparepvec for 6 doses followed by surgical resection of 
melanoma tumor lesion(s).

Arm 2: Surgical resection of melanoma tumor lesion(s)


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Following randomization via the IVR system, talimogene laherparepvec treatment must 
commence within 5 days. 
Eligible subjects must be registered as randomized subjects in the IVR system before 
the administration of protocol specified therapy.
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.
6.
TREATMENT PROCEDURES
6.1
Classification of Product
The Amgen Investigational Product used in this study is talimogene laherparepvec. Only 
subjects randomized to Arm 1 will receive talimogene laherparepvec.
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the 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 
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 the 
106 PFU/mL concentration will be packaged separately from the supply for the 
108 PFU/mL concentration.
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 (ALT, AST, and total bilirubin) should be obtained 
according to the Schedule of Assessments (see Table 2) and the results should be 
checked before the administration of talimogene laherparepvec according to Schedule of 
Assessments.  Dosing will occur only if these test values are acceptable, per 
Section 6.2.1.2.


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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 until week 12, all injectable tumors have disappeared, or intolerance of 
study treatment, whichever occurs first.
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 
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 for the injection 
should be done by clinical exam using a ruler or caliper for cutaneous lesions 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


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All 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:

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
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.
A subject will be treated with talimogene laherparepvec until week 12, all injectable 
tumors have disappeared, or intolerance of study treatment, whichever occurs first.  Due 
to the mechanism of action, subjects may experience transient growth in existing tumors 
or the appearance of new tumors prior to maximal clinical benefit of talimogene 
laherparepvec.  Therefore, subjects will be allowed to remain on talimogene 
laherparepvec treatment until week 12 of therapy unless, in the opinion of the 
investigator, immediate surgical resection or any other treatment for melanoma is 
warranted.  If talimogene laherparepvec treatment will end prior to week 12, the 
investigator or designee should notify the sponsor’s medical monitor as soon as 
possible.
The dose, start date, and lot number of talimogene laherparepvec are to be recorded on 
the CRF.
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 


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
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Subjects who are receiving talimogene laherparepvec may not receive systemic 
antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir), but may receive a topically 
administered antiherpetic drug more than 20 cm from a talimogene laherparepvec 
injection site. Dosing should be permanently discontinued if, in the opinion of the 
investigator, the subject develops clinical evidence of any systemic herpes infection 
(such as encephalitis or disseminated infection).
If the subject requires corticosteroid dosing of >10 mg prednisone daily (or equivalent) 
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 therapies 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.

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 
alternative etiologies, however, immune-mediated adverse events can potentially 
involve any organ system.


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 38 of 100
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
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) while on talimogene 
laherparepvec treatment.

A female subject-breast feeds a child while on talimogene laherparepvec 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 to 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
Surgical radical resection of melanoma lesion(s) aimed to achieve both clinically and 
microscopically tumor-free margins will be performed at any time during weeks 13 to 
18 (Arm 1) or weeks 1 to 6 (Arm 2).  Subjects randomized to Arm 1 who stop talimogene 
laherparepvec prior to week 12 due to disappearance of all injectable tumor lesions, 
intolerance to talimogene laherparepvec, or any other reason will undergo surgical 
resection of melanoma lesion(s) or tissue where melanoma was present before 
achieving CR within 1 to 6 weeks after the last dose of talimogene laherparepvec. If 
surgery will be performed prior to week 12, the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible. Refer to Appendix F for surgery 
guidelines.  Details on handling surgical specimens are provided in the Laboratory 
Manual.
All other protocol-required therapies including topical anesthetics or 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.


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 39 of 100
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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 randomization, on an ongoing basis at randomization, 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 (+15) days after surgery.  The therapy name, indication, dose, unit, frequency, 
start date, and stop date will be collected. Concomitant medications administered 
30 (+15) days after surgery for serious adverse events should for recorded as defined in 
Section 9.2.
Investigators should use supportive care agents in compliance with their respective 
regional labels.  Investigators may not use supportive care agents as part of a separate 
clinical trial.
6.5
Other Treatment Procedures 
Following surgical resection of melanoma lesion(s), adjuvant systemic therapy and/or 
radiotherapy may be administered at the investigator’s discretion and per the institutional 
standard of care. If adjuvant therapy (systemic and/or radiation therapy; approved or 
investigational) is planned, this should be reported via IVR during randomization.
If a subject undergoes adjuvant therapy, the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible and the treatment should be recorded in 
the source document and CRF.
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, for example, 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).


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 40 of 100
CONFIDENTIAL
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 antitumor therapies other than study drug

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]). Steroids with low systemic absorption [eg, triamcinolone 
hexacetonide] injected into a joint space are allowed)

antiherpetic drugs (eg, acyclovir), other than if topically administered > 20 cm from a 
talimogene laherparepvec injection site

Subjects must not schedule any elective surgeries during the treatment period and 
for at least 30 days after surgical resection of melanoma lesion(s).  If a subject 
undergoes any unexpected surgery during the course of the study, talimogene 
laherparepvec must be withheld and the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.  A subject may be allowed to resume 
talimogene laherparepvec if both the investigator and the sponsor’s 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 postsurgery long-term 
follow-up period.
7.
STUDY PROCEDURES
7.1
Schedule of Assessments 
For Schedule of Assessments refer to Table 2 and Table 3, respectively.


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 41 of 100
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Table 2.  Schedule of Assessments for Arm 1 (Talimogene Laherparepvec Plus Surgery)
Screening a
Treatment Period b
Follow-up Period c
≤ 28 
days
≤ 3 
days
Week 
1
Week 
4
Week 
6
Week
8
Week
10
Week
12
Week
13 to 18
Safety
Follow-up
30 (+15)
days
Long-term
Follow-up
Every 3 months 
(± 30 days) for 
3 years then every 
6 months 
(± 30 days) until 
5 years after 
randomization
GENERAL & SAFETY ASSESSMENTS 
Informed Consent
X
  
Review of Medical/Surgical History
X
Demographic Data (sex, age or date of birth, race, 
and ethnicity)
X
Review of Eligibility Criteria
X
Concomitant Medications
X
X
Adverse and Serious Adverse Events
X
X
Adverse Events Potentially Related to Treatment 
with Talimogene Laherparepvec
X
Physical Exam
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Surgical Safety Evaluation (including wound 
closure, drain time, and post operation infection)
X
Subsequent Anticancer Therapy for Melanoma
X
X
Survival
X
LOCAL LABORATORY ASSESSMENTS 
Urine or Serum Pregnancy Test
X
X
Hematology
X
X
X
X
X
Chemistry
X
X
X
X
X
Serum LDH
X
PT, PTT or aPTT, INR
X
Page 1 of 3
Footnotes defined on last page of the table


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 42 of 100
CONFIDENTIAL
Table 2.  Schedule of Assessments for Arm 1 (Talimogene Laherparepvec Plus Surgery)
Screening a
Treatment Period b
Follow-up Period c
≤ 28 
days
≤ 3 
days
Week 
1
Week 
4
Week 
6
Week
8
Week
10
Week
12
Week
13 to 18
Safety
Follow-up
30 (+15) 
days
Long-term
Follow-up
Every 3 months 
(± 30 days) for
3 years then every 
6 months 
(± 30 days) until 
5 years after 
randomization
CENTRAL LABORATORY ASSESSMENTS
Blood for HSV-1 Antibody
Week 1 (prior to 1st dose)
Archived Tumor Tissue for Biomarker Analyses
Submit to central laboratory within 28 days after randomization
Archived Tumor Tissue for BRAFV600  Mutation 
Testing
Submit to central laboratory within 28 days after randomization if BRAFV600  
mutation status is unknown prior to screening and was not tested at local 
laboratory
Tumor Biopsy
X
X
Blood for Biomarker Development
X
X
X
Swab of Herpetic Lesion for qPCR
Within 3 days of occurrence of suspected lesion of herpetic origin
TREATMENT
Talimogene Laherparepvec Administration
X
X
X
X
X
X
Surgery
X
RADIOGRAPHIC IMAGING, CLINICAL, AND HISTOLOGICAL TUMOR ASSESSMENTS
Radiographic Imaging (CT, PET/CT, MRI)
X
X
X
Clinical Tumor Measurement and Response 
Assessment
X
X
X
Histological Tumor Assessment of Surgical 
Specimend
X
Page 2 of 3
Footnotes defined on next page of the table


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 43 of 100
CONFIDENTIAL
Table 2.  Schedule of Assessments for Arm 1 (Talimogene Laherparepvec Plus Surgery)
Screening a
Treatment Period b
Follow-up Period c
≤ 28 
days
≤ 3 
days
Week 
1
Week 
4
Week 
6
Week
8
Week
10
Week
12
Week
13 to 18
Safety
Follow-up
30 (+15) 
days
Long-term
Follow-up
Every 3 months 
(± 30 days) for 
3 years then every 
6 months 
(± 30 days) until 
5 years after 
randomization
REPORTING EXPOSURE TO TALIMOGENE LAHERPAREPVEC
Exposure of Subject’s Household member or 
Caregiver
X
X
Exposure of Subject’s Healthcare Provider
X
X
REPORTING PREGNANCY/LACTATION
Reporting of Pregnancy or Lactation e
X
Page 3 of 3
a For additional information regarding the procedures performed during screening procedures and the timing of the procedures please refer to Section 7.2.1.
b For additional information regarding the procedures performed during treatment and the timing of the procedures please refer to Section 7.2.2.
c For additional information regarding the procedures performed during safety follow-up and long-term follow-up and timing of the procedures please 
refer to Section 7.2.3 and Section 7.2.4, respectively.
d Surgical specimens will be assessed for presence of viable tumor and tumor margin status for cutaneous and subcutaneous tumor; please refer to Section 7.2.2.
e 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 in a female subject 
while the subject is taking talimogene laherparepvec and through 3 months after the last dose of talimogene laherparepvec, the case must be reported to Amgen as 
specified in Section 9.3.


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 44 of 100
CONFIDENTIAL
Table 3.  Schedule of Assessment for Arm 2 (Surgery Alone)
Screening a
Treatment Period b
Follow-up Period c
≤ 28 
days
≤ 3 
days
At time of Surgery
(Week 1 to 6)
Safety
Follow-up
30 (+15) days
Long-term
Follow-up
Every 3 months 
(± 30 days) for 
3 years then every 
6 months 
(± 30 days) until 
5 years after 
randomization
GENERAL & SAFETY ASSESSMENTS
Informed Consent
X
  
Review of Medical/Surgical History
X
Demographic Data (sex, age or date of birth, race, 
and ethnicity)
X
Review of Eligibility Criteria
X
Concomitant Medications
X
X
X
Adverse and Serious Adverse Events
X
X
X
Physical Exam
X
X
Vital Signs
X
X
X
ECOG Performance Status
X
X
Surgical Safety Evaluation (including wound 
closure, drain time, and post operation infection)
X
Subsequent Anticancer Therapy for Melanoma
X
X
Survival
X
LOCAL LABORATORY ASSESSMENTS 
Urine or Serum Pregnancy Test
X
X
Hematology
X
X
Chemistry
X
X
Serum LDH
X
PT, PTT or aPTT, INR
X
Page 1 of 2
Footnotes defined on next page of the table


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 45 of 100
CONFIDENTIAL
Table 3.  Schedule of Assessment for Arm 2 (Surgery Alone)
Screening a
Treatment Period b
Follow-up Period c
≤ 28 
days
≤ 3 
days
At time of Surgery
(Week 1 to 6)
Safety
Follow-up
30 (+15) days
Long-term
Follow-up
Every 3 months 
(± 30 days) for 
3 years then every 
6 months 
(± 30 days) until 
5 years after 
randomization
CENTRAL LABORATORY ASSESSMENTS 
Archived Tumor Tissue for Biomarker Analyses
Submit to central laboratory within 28 days after randomization
Archived Tumor Tissue for BRAFV600  Mutation 
Testing
Submit to central laboratory within 28 days after randomization if 
BRAFV600  mutation status is unknown prior to screening and was not 
tested at local laboratory
Tumor Biopsy
X
Blood for Biomarker Development
X
TREATMENT
Surgery
X
RADIOGRAPHIC IMAGING, CLINICAL, AND HISTOLOGICAL TUMOR ASSESSMENTS
Radiographic Imaging (CT, PET/CT, MRI)
X
X
Clinical Tumor Measurement and Response 
Assessment
X
X
Histological Tumor Assessment of Surgical 
Specimend
X
Page 2 of 2
a For additional information regarding the procedures performed during screening procedures and the timing of the procedures please refer to Section 7.2.1.
b For additional information regarding the procedures performed during treatment and the timing of the procedures please refer to Section 7.2.2.
c For additional information regarding the procedures performed during safety follow-up and long-term follow-up and timing of the procedures please 
refer to Section 7.2.3 and Section 7.2.4, respectively.
d Surgical specimens will be assessed for presence of viable tumor and tumor margin status for cutaneous and subcutaneous tumor; please refer to Section 7.2.2.


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 46 of 100
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7.2
General Study Procedures 
A signed and dated IRB-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 randomization.  Only eligible 
subjects will be randomized into the study.
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.
The following laboratory analytes in Table 4 will be assessed at various times throughout 
the study:
Table 4.  Laboratory Analytes
Chemistry
Coagulation
Hematology
Other Labs
Sodium
Potassium
Chloride
Calcium
Magnesium
Phosphorus
Uric acid
Total protein
Albumin
BUN
Creatinine
Total bilirubin
Alkaline-
phosphatase
AST
ALT
Glucose
PT or INR
PTT or aPTT
RBC
Hemoglobin
Hematocrit
Platelets
WBC
Differential*
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
LDH
Pregnancy
qPCR for 
talimogene 
laherparepvec 
DNA
HSV-1 antibody 
BRAFV600
Biomarkers
Blood
Archived tumor 
tissue
Fresh tumor 
biopsy tissue
* 3-part differential if 5-part unable to be performed
All tests (except for real-time polymerase chain reaction [qPCR], HSV-1 antibody and 
biomarkers) are to be performed at the local laboratory and test results are to be fully 
and routinely recorded on the CRFs. Serine/threonine protein kinase B-Raf V600
(BRAFV600) mutation analysis may be performed at a central laboratory. Missed tests 
that are not done must be reported as such on the CRFs. The qPCR, HSV-1 antibody


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 47 of 100
CONFIDENTIAL
and biomarker tests will be performed at a central laboratory and results will not be 
recorded on the CRFs.
7.2.1
Screening and Randomization
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments (Table 2 and Table 3):

Confirmation that the Informed Consent Form has been signed

Demographic data including sex, age or date of birth, race, and ethnicity will be 
collected in order to study their possible association with subject safety and 
treatment effectiveness.

Medical and surgical history:  The Investigator or designee will collect complete 
medical and surgical history. Medical history will include information on the subject’s 
concurrent medical conditions. Record all findings on the medical history CRF.

Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, 
temperature):  Subject must be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted. If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
as possible. The position selected for a subject should be the same that is used 
throughout the study and documented on the vital sign CRF. Record all 
measurements on the vital signs CRF.

Physical examination as per standard of care 

Documentation of concomitant medications

ECOG performance status assessment

Local Laboratory Assessments 

within ≤28 days prior to randomization
o
hematology panel: hemoglobin, hematocrit, white blood cell (WBC) count 
with 5-part differential (3-part differential if 5-part unable to be performed), red 
blood cell (RBC) count, platelets
o
chemistry panel: sodium, potassium, chloride, calcium, magnesium, 
phosphorous, uric acid, total protein, albumin, blood urea nitrogen (BUN), 
creatinine, total bilirubin, alkaline phosphatase, AST, ALT, glucose
o
LDH
o
coagulation: PT or INR and PTT or aPTT

within ≤3 days prior to randomization
o
serum or urine pregnancy test for female subjects of childbearing potential

Clinical tumor assessments, including clinical measurement of cutaneous, 
subcutaneous, and palpable nodal tumor lesions by caliper to be used as baseline 
assessment

Radiographic tumor imaging (including 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, MRI of the brain (required to be 
completed for all subjects), to be used as baseline imaging


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 48 of 100
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
Recording of serious adverse events that occur after subject signs informed consent.  
Serious adverse events will be reported to Amgen within 24 hours following the 
investigator’s knowledge of the event

Review of inclusion and exclusion criteria

Randomization in IVR system
Subjects who are determined not eligible after screening must be screen-failed in the 
IVR 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 consent form is signed within 28 days of randomization.  
Subjects who are determined not eligible after rescreen must be screen-failed in the IVR 
system and the reason for the screen-failure provided.  Subjects may only be 
randomized once into this study.
7.2.2
Treatment
Treatment begins when the first dose of protocol-required therapies is administered to a 
subject (Arm 1) or the subject undergoes surgery (Arm 2).
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 2 and Table 3).

Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, 
temperature):  Subject must be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted. If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
possible.  The position selected for a subject should be the same that is used 
throughout the study and be documented on the vital signs CRF.

Arm 1: prior to talimogene laherparepvec administration on day 1 of 
weeks 1, 4, 8, 12, and prior to surgery

Arm 2: within 3 days prior to surgery

Physical examination as per standard of care

Arm 1: within 3 days prior to talimogene laherparepvec administration on day 1 
of week 1 and within 3 days prior to surgery, and prior to talimogene 
laherparepvec administration on day 1 of weeks 4 and 8

ECOG performance status

Arm 1: prior to talimogene laherparepvec administration on day 1 of weeks 4 
and 8 and within 3 days prior to the surgery


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
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
Local laboratory assessments

Arm 1: prior to talimogene laherparepvec administration on day 1 of 
weeks 1, 6, 12. Screening laboratory values may be used for week 1 day 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 should be 
reviewed prior to the administration of study drug
o
Hematology panel: hemoglobin, hematocrit, WBC with 5-part differential 
(3-part differential if 5-part unable to be performed), RBC, platelet
o
Chemistry panel: sodium, potassium, chloride, calcium, magnesium, 
phosphorus, uric acid, total protein, albumin, BUN, creatinine, total bilirubin, 
alkaline phosphatase, AST, ALT, glucose

Central laboratory assessments:

Blood for HSV-1 antibody serostatus
o
Arm 1: within 3 days of day 1 of week 1 (prior to administration of talimogene 
laherparepvec) 

Blood for biomarker analysis 
o
Arm 1: within 3 days of day 1 of week 1 (prior to administration of talimogene 
laherparepvec) and week 6 (prior to administration of talimogene 
laherparepvec) and within 3 days prior to the day of surgery
o
Arm 2: within 3 days prior to the surgery

Tumor biopsy for biomarker analysis
o
Arm 1:  within 3 days of day 1 of week 1 (prior to talimogene laherparepvec 
administration) and at the time of surgery.  At the time of surgery the tumor 
biopsy should be marked as injected lesion or non-injected lesion.
o
Arm 2: at the time of surgery

Swab of cold sore, vesicles and other lesions suspected to be herpetic in origin 
(if any) for qPCR testing of talimogene laherparepvec DNA:
o
Arm 1 - Subject should return to the clinic within 3 days of the occurrence of a 
reportable lesion suspected to be herpetic in origin.  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.

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 randomization for biomarker analyses


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 50 of 100
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
BRAFV600 mutation testing/status may be obtained in a number of ways as listed 
below: 
o
previously known BRAFV600 tumor status:  BRAFV600 tumor status result, 
obtained from a local laboratory prior to screening for this study will be 
acceptable and should be available within 28 days after randomization
o
previously unknown BRAFV600 tumor status:  Archived formalin-fixed 
paraffin-embedded tumor tissue (block or unstained tumor slide) from either 
the primary tumor or a metastatic lesion (as described above) will be 
analyzed at a local laboratory or submitted to the central laboratory within 
28 days after randomization for BRAFV600 tumor status determination

Radiographic tumor imaging assessments 

Arm 1:  day 1 of week 12 (± 2 weeks) or within 2 weeks prior to surgery if a 
subject ends talimogene laherparepvec prior to week 12
o
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.

Clinical tumor assessments (clinical measurement of cutaneous, subcutaneous, or 
palpable nodal tumor measurement by caliper) 

Arm 1:  day 1 of week 12 (± 2 weeks) or within 1 week prior to surgery if a 
subject ends talimogene laherparepvec prior to week 12

Response assessment per modified WHO response criteria (Appendix D)

Arm 1:  day 1 of week 12 (± 2 weeks) or within 2 weeks prior to surgery if a 
subject ends talimogene laherparepvec prior to week 12

Histological tumor assessment of the surgical specimens. Surgical specimens will 
be assessed for presence of viable tumor and tumor margin status for cutaneous and 
subcutaneous tumor.

Tumor-free margins (negative margins, R0) resection is defined by 
pathologist as absence of ink on the tumor.  All other resections of viable 
tumor are described as tumor positive margins resections, and are defined as 
o
R1 resection - complete resection with no grossly visible tumor left 
behind as defined by the surgeon, or 
o
R2 resection - partial resection with grossly visible tumor left behind
as defined by the surgeon. 

A pathological complete response (pCR) in Arm 1 is defined as no evidence 
of viable tumor cells on complete pathological evaluation of the surgical 
specimen per institutional standards of care

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


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
Documentation of concomitant medications at each visit

Arm 1 - 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)

Arm 1 - 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)

Talimogene laherparepvec administration

Arm 1: day 1 of weeks 1, 4, 6, 8, 10, and 12 or until all injectable tumors have 
disappeared, intolerance of study treatment, whichever occurs first. Subjects 
who experience growth in existing tumors or the appearance of new tumors will 
be allowed to remain on talimogene laherparepvec treatment until week 12 of 
therapy unless, in the opinion of the investigator and in consultation with the 
sponsor’s medical monitor, immediate surgical resection or any other treatment 
for melanoma is warranted.

Surgery

Arm 1: For subjects who complete 12 weeks of talimogene laherparepvec 
treatment, surgical resection of melanoma lesion(s) will be performed at any time 
during weeks 13 to 18. Subjects who stop talimogene laherparepvec prior to 
week 12 due to disappearance of all injectable tumor lesions, intolerance to 
talimogene laherparepvec, or any other reason will undergo surgical resection of 
melanoma lesion(s) or tissue where melanoma was present before CR within 
1 to 6 weeks after the last dose of talimogene laherparepvec.  
Refer to Appendix F for surgery guidelines.

Arm 2: Surgical resection of melanoma tumor lesion(s) will be performed after 
randomization any time during weeks 1 to 6.  Refer to Appendix F for surgery 
guidelines.
7.2.3
Safety Follow-up Visit
Upon permanent discontinuation from the study treatment for any reason, the following 
procedures will be performed 30 (+15) days after the surgery:

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: 
-
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


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
Central laboratory assessments: 
-
Arm 1: 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.

Recording of adverse events

Recording of serious adverse events.  Serious adverse events will be reported to 
Amgen within 24 hours following the investigator’s knowledge of the event.

Documentation of concomitant medications

Documentation of subsequent anticancer therapy for melanoma (including local, 
regional, or systemic therapy)

Surgical safety evaluation (including wound closure, drain time and post operational 
infection)

Arm 1 - Reporting pregnancy in a female subject or a female partner of a male 
subject through 3 months after end of talimogene laherparepvec treatment 
(Section 9.3)

Arm 1 - Reporting lactation case in a female subject through 3 months after end of 
talimogene laherparepvec treatment (Section 9.3)
7.2.4
Long-term Follow-up
All randomized subjects will be contacted by telephone, or clinic visit, to assess survival 
status, collect adverse events deemed by the investigator to be potentially related to 
talimogene laherparepvec (Arm 1 only), and, if applicable, commencement of any 
subsequent anticancer melanoma therapy.  Follow-up will occur every 3 months 
(±30 days) for 3 years following the safety follow-up visit and then every 6 months 
(±30 days) until death, subject withdraws full consent, or up to 5 years after the last 
subject is randomized, which is first.
Radiographic tumor imaging, clinical tumor assessments, and tumor response 
assessments, will be performed as documented in Section 7.2.2 every 3 months 
(±30 days) for 3 years following the safety follow-up visit and then every 6 months 
(±30 days) until distant disease recurrence, death, subject withdraws full consent, or up 
to 5 years after the last subject is randomized, whichever is first.  Local and regional 
recurrences will be reported until appearance of distant recurrence, or end of study, 
whichever is first. Local recurrence is defined as histologically or cytologically confirmed 
reappearance of melanoma in the area of up to 2 cm from the scar from the surgical 


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excision or at the edge of the skin graft if that was used for closure. Regional recurrence
(excludes local recurrence) is defined as histologically, cytologically, or radiographically 
confirmed reappearance of melanoma in the regional lymph node basin. New in-transit 
melanoma metastases in the regional lymphatic drainage will be reported as regional 
recurrence. Histological or cytological confirmation of new in-transit metastases is 
recommended but is not required. Distant metastases exclude local and regional 
recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal 
metastases, or visceral, central nervous system, brain, or bone metastases.
After the long-term follow-up period of this study has ended, subjects randomized to 
Arm 1 who received at least a single dose of talimogene laherparepvec and 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 
subsequent anticancer therapy for melanoma. Subjects who after the long-term 
follow-up period of this study (20110266) will elect to participate in the registry study 
must sign new informed consent form before any registry protocol-specific activities. 
7.2.5
Reporting 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 was 
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.
7.3
Biomarker Development
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  In oncology, there is particular interest in the molecular changes underlying 
the oncogenic processes that may identify cancer subtypes, stage of disease, assess 
the amount of tumor growth, or predict disease progression, metastasis, and responses 
to investigational product.


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Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to talimogene laherparepvec.
7.3.1
Blood Samples
Blood samples are to be collected for biomarker development at time points designated 
in the Schedule of Assessments (Table 2 and Table 3) and as described in
Section 7.2.2.
Blood samples (both cells and plasma) will be analyzed for changes in the immune 
system before and during treatment that correlate with clinical response.  Tumor 
antigen-specific cytotoxic T cells will be enumerated in blood samples by assays which 
count T cells that bind or secrete cytokines in response to tumor antigen specific 
peptides such as the enzyme-linked immunosorbent spot (ELISPOT) or tetramer assay.  
Changes in circulating immune cells will be characterized by flow cytometry to 
enumerate the number of immune cell subsets such as T cells, B cells and NK cells.  
T cell subsets will also be characterized for activation markers such as HLA-DR and 
CD25.  Additional assays which may be performed on blood samples include measuring 
antibody responses to melanoma antigens, changes in circulating cytokine levels before 
and during treatment, and RNA transcript profiling of circulating blood cells.
Refer to the Laboratory Manual for detailed collection and handling procedures for blood 
samples for biomarker development.
7.3.2
Tumor Tissue Samples
Archived Tumor Tissue Sample:
A block of formalin-fixed paraffin-embedded tumor tissue collected prior to the study is to 
be sent to the central laboratory along with the corresponding pathology report as 
described in the Schedule of Assessments (Table 2 and Table 3) and in Section 7.2.2.
The tumor block is to be carefully selected by a pathologist or a skilled experienced 
histology associate to include generous tumor tissue using the Pathology Report as a 
guide.  In the event that multiple tumor blocks with generous tumor tissue are available, 
the most recent block should be submitted.  In lieu of a block, approximately 
20 unstained sections on charged slides from the same block can be submitted.  
Analyses of tumor-specific mutations or epigenetic changes may be performed 
(eg, somatic mutations) on tumor tissues.
Refer to Laboratory Manual for specific instructions on tumor block/slide preparation.  


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Tumor Biopsy Samples:
On-study biopsies will be collected, as described in the Schedule of Assessments 
(Table 2 and Table 3) and in Section 7.2.2, to characterize the mechanism of systemic
action of talimogene laherparepvec.  Refer to the Laboratory Manual for specific 
instructions on tumor biopsy procedures.
Immunohistochemistry at a central laboratory will be used to measure the number of 
infiltrating CD8+ T cells in tumor biopsy samples collected before and after treatment as 
well as in archival tumor samples. Tissue slides will be stained for CD8+ cells and 
scanned to create a digital image. Image analysis software will be used to exclude 
areas of adjacent normal tissue, necrotic tissue and large blood vessels and to define 
the region of interested which will be measured in square millimeters (mm2). Within the 
region of interest, the image analysis software will measure the number of CD8+ T cells 
and report the number of CD8+ T cells per square millimeter (#CD8+ cells/mm2).  In 
addition to CD8+ cells, a variety of other tumor infiltrating immune cell markers may be 
explored by immunohistochemistry such as CTLA-4, FoxP3, PD-1, PD-L1, IDO, 
granzyme, and others.  The tumor samples will also be analyzed for mutations or other 
changes within the PKR pathway, that could make tumor cells more susceptible to
talimogene laherparepvec viral replication.
7.4
Pharmacogenetic Studies
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses on blood samples may be performed.  These optional pharmacogenetic 
analyses focus on inherited genetic variations to evaluate their possible correlation to the 
disease and/or responsiveness to the therapies used in this study.  The goals of the 
optional studies include the use of genetic markers to help in the investigation of cancer 
and/or to identify subjects who may have positive or negative responses to talimogene 
laherparepvec.  No additional samples are collected for this part of the study.  DNA may 
be extracted from blood of subjects who consent to pharmacogenetic analyses,.
7.5
Sample Storage and Destruction
Any blood or tumor samples collected according to the Schedule of Assessments 
(Table 2 and Table 3) 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.


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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, 
characterization of antibody response, and characterization of 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.
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, 


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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 
Table 3) and collection of data, including endpoints and adverse events.  The 
investigator must document the change to the Schedule of Assessments (Table 2 and 
Table 3) 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, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.
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.


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8.2.1
Reasons for Removal From Treatment
Reasons for removal from protocol-required investigational product include any of the 
following:

subject request

safety concern (eg, due to an adverse event)

ineligibility determined

protocol deviation

non-compliance

requirement for alternative therapy

protocol-specified criteria (see Sections 6.2.1.2)

pregnancy

death

lost to follow-up

decision by sponsor (other than subject request, safety concern, lost to follow-up)

disease progression requiring immediate surgical resection
8.2.2
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.  
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.


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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 CRF.  The investigator is expected to follow reported adverse events 
until stabilization or reversibility.
For situations when an adverse event or serious adverse event is 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, metastatic 
pancreatic cancer).
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 
include allergic bronchospasm, convulsions, blood dyscrasias, or events that necessitate 
an emergency room visit, outpatient surgery, or urgent intervention.


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The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events. It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events.
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 randomization through the safety 
follow-up visit (ie, 30 [+15] days after surgery) are reported using the applicable CRF
(eg, Adverse Event Summary).
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 or surgery, and

Action taken.
The adverse event grading scale used will be the 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 or surgery.  
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 talimogene 
laherparepvec or surgery?
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity and/or procedure (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 
or adjustment in current therapy are considered adverse events.  Where applicable, 


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clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event.
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 the safety follow-up (ie, 30 [+15] days after surgery) 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 CRF.
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 /eSAE Contingency Report Form. For EDC studies where the 
first notification of a Serious Adverse Event is reported to Amgen via the eSerious 
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 or surgery.  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 talimogene laherparepvec or surgery?
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 


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“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 CRF).
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 talimogene laherparepvec, report the pregnancy to Amgen as specified 
below.
In addition to reporting any pregnancies occurring during the talimogene laherparepvec 
treatment, 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 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).  


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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 talimogene laherparepvec treatment, 
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 C).
9.4
Reporting of Exposure to Talimogene Laherparepvec
If a household member, caregiver, or healthcare provider who has had close contact 
with a subject treated with talimogene laherparepvec on this study 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 (+15) days after the last dose of talimogene laherparepvec.
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 sign 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.
10.
STATISTICAL CONSIDERATIONS
10.1
Study Endpoints, Analysis Sets, and Covariates
10.1.1
Study Endpoints
10.1.1.1
Primary Endpoint

Recurrence-free Survival (RFS): RFS is defined as time from randomization to the 
date of the first of local, regional, or distant recurrence of melanoma or death due to 
any cause.


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10.1.1.2
Secondary Endpoint
Efficacy Endpoints:

1-year, 2-year, 3-year, 5-year RFS: The Kaplan-Meier (K-M) estimate of RFS rate at 
1-year, 2 years, 3 years and 5 years

Rate of histopathology tumor-free margin (R0) surgical resection

Rate of pathological complete response (pCR)

Local recurrence-free survival (LRFS): Time from randomization to the date of the 
first of local disease recurrence or death due to any cause.  Local recurrence is 
defined as histologically or cytologically confirmed reappearance of melanoma in the 
in the area of up to 2 cm from the scar from the surgical excision or at the edge of 
the skin graft if that was used for closure

Regional recurrence-free survival (RRFS): Time from randomization to the date of 
the first of regional disease recurrence or death due to any cause.  Regional 
recurrence excludes local recurrence and is defined as histologically, cytologically, or 
radiographically confirmed reappearance of melanoma in the regional lymph node 
basin. New in-transit melanoma metastases in the regional lymphatic drainage will 
be reported as regional recurrence.  Histological or cytological confirmation of new 
in-transit metastases is recommended but is not required.

Distant metastases free survival (DMFS): Time from randomization to the date of the 
first of distant metastases or death due to any cause. Distant metastases exclude 
local and regional recurrence and will include distant cutaneous/subcutaneous 
metastases, distant nodal metastases, or visceral, central nervous system, brain, or
bone metastases.

Overall survival (OS): Time from randomization to death due to any cause

1-year, 2-year, 3-year and 5-year survival: The Kaplan-Meier (K-M) estimate of the 
survival rate at 1-year, 2 years, 3 years and 5 years

Overall tumor response and tumor response in injected and uninjected lesions 
(Arm 1 only):  The tumor response is evaluated up to the surgical resection.  The 
overall tumor response is per the modified WHO (Appendix D).  For tumor response 
in injected and uninjected lesions both subject-level and lesion-level response will be 
assessed.  The subject-level injected and uninjected responses will be based on the 
tumor burden of only injected index lesions including injected new measurable 
lesions, or the tumor burden of only uninjected index lesions including uninjected 
new measurable lesions, respectively.  The lesion-level response will evaluate the 
change of the area of each individual lesion.  For the tumor response based on the 
tumor burden of a subset of lesions (injected/uninjected lesions) or individual lesions, 
a response is achieved if the percentage of tumor burden reduction from baseline is 
at least 50%.  The related endpoints, such as time to response, may also be 
evaluated if appropriate.
Safety Endpoints:

Subject incidence of treatment-emergent and treatment-related adverse events


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10.1.1.3
Exploratory Endpoints

Correlation between baseline intratumoral CD8+ cell density and clinical outcomes

Correlation between changes in an intratumoral CD8+ cell density during talimogene 
laherparepvec treatment and clinical outcomes

Correlation between the changes in the population of tumor-specific cytotoxic T-cells 
during treatment and clinical outcomes

Assessment of blood and tumor for potential biomarkers which correlate with or 
predict clinical outcomes to talimogene laherparepvec
10.1.2
Analysis Sets
Intent to Treat Analysis Set
The primary analysis of all efficacy endpoints of the study will be conducted on the intent 
to treat analysis set defined as all randomized subjects who were randomized to either 
treatment arm.  All subjects will be analyzed according to their treatment randomization.
Safety Analysis Set
The safety analysis set will include all subjects who received talimogene laherparepvec
or surgical resection of melanoma tumor lesion(s).  The safety analyses will be 
performed by treatment received.
Efficacy Analysis Set
The efficacy analysis set will include all subjects in Arm 1 who received at least one 
dose of talimogene laherparepvec and surgical resection of melanoma tumor lesion(s)
and all the subjects in Arm 2 who received surgical resection of melanoma tumor
lesion(s).  In addition, all subjects in the efficacy analysis set must have achieved 
histopathologic tumor-free margin (R0) status after surgery and should not have any 
important protocol deviations which may affect the efficacy endpoints. The efficacy 
analysis set may be used for sensitivity analysis of efficacy endpoints if needed.
10.1.3
Covariates and Subgroups
Besides the stratification factors, the following covariates may be used to examine 
efficacy and safety in subgroups or in multivariate analyses:

Region, if applicable (USA or non-USA)

Age at baseline: < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years

Number of measurable tumors at baseline

Presence of uninjected tumors at baseline and during the treatment: yes vs no

The sum of the products of the two largest perpendicular diameters of baseline 
measurable lesions


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
Baseline absolute lymphocyte count: ≤1000 vs > 1000 

Recurrent disease ≥1 year from primary diagnosis vs recurrent disease <1 year from 
primary diagnosis vs no prior melanoma
10.2
Sample Size Considerations
All analyses will be descriptive with no formal hypothesis testing.  The primary objective 
of the study is to estimate the treatment effect, as measured by the hazard ratio of RFS, 
of talimogene laherparepvec neoadjuvant therapy followed by surgery (Arm 1) compared 
to surgery alone (Arm 2) in subjects with resectable, stage IIIB to IVM1a melanoma.
Approximately 150 subjects will be randomized 1:1 to receive Arm 1 vs Arm 2 stratified 
by: (i) disease stage (IIIB nodal vs IIIB in-transit vs IIIC nodal vs IIIC in-transit with nodal 
vs IVM1a), and (ii) planned adjuvant therapy (adjuvant systemic therapy [eg, INFα, 
ipilimumab] with or without radiotherapy vs radiotherapy without adjuvant systemic 
therapy vs none).
Primary efficacy analysis of RFS will be based on the Intent to Treat Analysis Set. An 
overall between-group difference in RFS will be evaluated with a log-rank test and 
corresponding proportional hazard model without stratification. The Kaplan-Meier (KM) 
method will be used to estimate 1-year, 2-year, 3-year, 5-year, and overall RFS.  
Subjects who are not confirmed to be disease-free post-surgery (ie, who do not have an 
R0 surgical outcome) or who withdraw prior to surgery will be considered a failure a day 
after randomization for RFS.
The primary analysis for the primary endpoint will occur at the later time of either the 
occurrence of approximately 64 events (local, regional, or distant recurrence of 
melanoma or death) or approximately 2 years after the end of randomization. An 
80% CI will be estimated for the hazard ratio of RFS.  In addition, an 80% CI will also be 
estimated for the between-arm difference (Arm 2 – Arm 1) in 2-year RFS, ie, 2-year 
RFS.  It is assumed that: (i) RFS is exponential over the first 2 years, (ii) the 2-year RFS 
for Arm 1 is about 0.60 (Eggermont et al, 2008), and that there will be a 10% exponential 
probability of drop-out by the primary analysis.  Simulations were used to evaluate the 
following parameters assuming possible true 2-year RFS values of 0.05, 0.10, 
and 0.15:  (i) the average 2-year RFS 80% CI and its width, (ii) the probability that the 
2-year RFS 80% CI is above 0, and (iii) the average number of events at the primary 
analysis.  The possible true 2-year RFS values were translated to a RFS hazard ratio 
(HR) (Arm 2 relative to Arm 1) and the HR 80% CI and the probability of it being


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< 1 were calculated based on the simulated average number of events.  The average 
width of the 2-year RFS 80% CI was 0.20 (Table 5).
Table 5.  Study Design Characteristics
2-year RFS
RFS 
HR
Ave. 80% CI
Prob. 
80%
CI > 0
Ave. HR 
80% CI
Prob. 
HR 80% 
CI < 1
Ave. 
Events
Arm 1
Arm 2

LL
UL
Width
LL
UL
0.70
0.60
0.100
0.70
0.00
0.20
0.20
0.51
0.51
0.96
0.56
64
0.725
0.125
0.63
0.02
0.22
0.20
0.62
0.45
0.87
0.71
62
0.750
0.150
0.56
0.05
0.25
0.20
0.74
0.40
0.78
0.83
60
RFS, Recurrence-free Survival; HR, Hazard Ratio; CI, Confidence Interval; LL, Lower Limit; UL, Upper Limit; 
Ave, Average; Prob., Probability; = Arm 2 – Arm 1 2-year RFS
10.3
Access to Individual Subject Treatment Assignments by Amgen or 
Designees
As this is an open-label study, the investigators/site personnel and the trial participating 
subjects will know the treatment assignments.
10.4
Planned Analyses
10.4.1
Interim Analyses
Two interim analyses with no formal stopping rules are planned to evaluate safety when 
approximately 40 and 75 subjects randomized to talimogene laherparepvec have had 
the opportunity to complete the safety follow-up visit. A Data Review Team (DRT) 
independent of the talimogene laherparepvec product team will review the first interim 
analysis (see Section 10.4.2).  The DRT will also review some efficacy endpoints 
(eg, R0 resection rate, pCR rate, response to neoadjuvant treatment).
The talimogene laherparepvec product team will review the second interim analysis 
because it will occur after all subjects have been already treated, have completed safety 
follow-up, and no additional interventions that may influence safety or efficacy of the 
investigational product are planned after this time point.  The talimogene laherparepvec 
product team will also review some efficacy endpoints (eg, R0 resection rate, pCR rate, 
response to neoadjuvant treatment).


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An additional third interim analysis with no formal stopping rule is planned to 
evaluate RFS approximately 1 year after the end of randomization.  This analysis 
will be conducted by the Amgen study team.
Ad hoc analyses for safety or some efficacy endpoints (eg, response to neoadjuvant 
treatment, R0 resection rate, pCR rate) may be conducted before the planned primary 
and/or final analyses if interim data are required for submission to regulatory authorities.
These ad hoc analyses will be executed by the talimogene laherparepvec product team.
10.4.2
Data Review Team (DRT)
The DRT will consist of one Amgen biostatistician and two Amgen clinicians (one from 
Clinical Development and one from Global Safety) who collectively have experience in 
oncology clinical research and in the conduct and monitoring of randomized clinical 
trials. In addition, the DRT may include one or more external clinical expert(s) (eg, a 
surgical oncologist in melanoma) not directly involved in the conduct of the study. The 
DRT will be supported by a statistician internal to Amgen but independent of the 
talimogene laherparepvec product team.  The DRT will review unblinded safety data at 
the first interim analysis. This independent DRT will be governed by a study-specific 
DRT charter.
10.4.3
Primary Analysis
The primary analyses for RFS will occur at the later time of either the occurrence of 
approximately 64 events (local, regional, or distant recurrence of melanoma or death) or 
approximately 2 years after end of randomization. The primary analysis for certain 
secondary endpoints will be performed using the data from the second interim analysis 
(eg, response to neoadjuvant treatment, R0 resection, pCR, exploratory correlative 
endpoints related to neoadjuvant treatment outcomes, and safety).
10.4.4
Final Analysis
The final analyses will occur approximately 5 years after end of randomization.
10.4.5
Additional Analysis 
An additional analysis will also occur approximately 3 years after end of randomization.
10.5
Planned Methods of Analysis
10.5.1
General Considerations
All analyses will be descriptive with no formal hypothesis testing.
In principle, mean, standard deviation, median, first and third quartiles, minimum and 
maximum will be calculated for continuous variables; frequency and percent will be 


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calculated for binary and categorical variables. Graphical summaries of the data may 
also be presented.
Analyses of tumor tissue or serum biomarkers may be performed after collection of all 
samples during the conduct of the study and therefore may be reported after the primary 
analysis of efficacy endpoint.
The primary analysis for efficacy endpoints will be performed on the Intent to Treat
Analysis Set by randomized treatment. Some of the analysis will be repeated on the
Efficacy Analysis Set by treatment actually received. Safety analyses will be conducted 
on the Safety Analysis Set.
10.5.2
Primary Efficacy Endpoint
An overall between-group difference in RFS will be evaluated with a log-rank test and 
corresponding proportional hazards model without stratification. A log-rank test and 
proportional hazards model with stratification by the two randomization factors will be 
also conducted. If warranted due to actual adjuvant therapy, these analyses will be 
repeated stratifying on actual rather than planned adjuvant therapy and/or adjuvant 
therapy containing selected types of immunotherapy. Multivariate proportional hazards 
models may be used to explore the prognostic and/or predictive value of baseline 
factors.
10.5.3
Secondary Efficacy Endpoints
KM estimates will be calculated for RFS, LRFS, RRFS, DMFS, OS landmarks 
(1-, 2-, 3- and 5-year rates) and quartiles.  Greenwood’s formula (Kalbfleisch and
Prentice, 1980) for standard error will be used to calculate CIs for each group and 
between-group differences in landmark KM rate estimates.  CIs for quartiles of each 
group will be estimated per Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) 
and bootstrap methods will be used to estimate CIs for between-group differences.  For 
each group the equal-precision band method will be used to calculate a simultaneous 
confidence band for RFS, LRFS, RRFS, and DMFS over the interval from 1 to 5 years 
(Nair, 1984).  An overall between-group difference in RFS, LRFS, RRFS, DMFS, and OS 
will be evaluated with a log-rank test and corresponding proportional hazard model with 
or without stratification by the two randomization factors.  If warranted due to actual 
adjuvant therapy, these analyses will be repeated stratifying on actual rather than 
planned adjuvant therapy and/or adjuvant therapy containing selected types of 
immunotherapy. Multivariate proportional hazards models may be used to explore the 
prognostic and/or predictive value of baseline factors.


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The Clopper-Pearson method (Clopper and Pearson, 1934) will be used to calculate 
exact CIs for binary endpoints (eg, overall tumor response, response in injected and 
uninjected lesions, R0 rate, pCR).  Wilson’s score method with continuity correction 
(Newcombe, 1998) will be used to calculate an approximate exact CI for between-group 
differences in binary rates. Multivariate logistic models may be used to explore the 
prognostic and/or predictive value of baseline factors.
10.5.4
Safety Endpoints
Subject incidence rates of treatment-emergent adverse events (including all adverse 
events, grade ≥ 3 adverse events, fatal adverse events, serious adverse events, adverse 
events of interest and events requiring the discontinuation of study drug, local effects on 
the tumor [ie, pain, inflammation and ulceration]) will be summarized.  The 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 and clinically significant changes in vital signs will be 
summarized with descriptive statistics. Summary statistics will also be provided for 
concomitant medications, adjuvant therapy, dose delay, study drug discontinuation, 
overall exposure, and changes in ECOG performance status.  Tables and/or narratives 
of deaths through 30 days after the latter of the last dose of talimogene laherparepvec or 
surgery will be provided.  The incidence of subjects with herpetic lesions found to be 
positive for talimogene laherparepvec DNA per qPCR in swab samples collected from 
lesions suspected to be herpetic in origin and the rate of positive lesions (if any) will be 
calculated.    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.
When appropriate, the safety data during the talimogene laherparepvec monotherapy 
period before surgical resection will be summarized separately from the safety data after 
surgical section, which will be summarized by treatment actually received.
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 


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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 
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
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 


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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.
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 randomization.

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) 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.


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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
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 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 and by what mechanism, after 
termination of the study and before the product is 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 CRFs will be included on the Amgen Delegation of Authority Form.
Source documents are original documents, data, and records from which the subject’s 
CRF 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 IVR system captures the following data points and these are 
considered source data:  subject identification number and randomization number.


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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.
Elements to include:

Subject files containing completed CRFs, 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 CRFs 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, CRFs and other 
pertinent data) provided that subject confidentiality is respected.
The Amgen clinical monitor is responsible for verifying the CRFs 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 CRFs.
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 CRFs, 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 


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the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.
Data capture for this study is planned to be electronic:

All source documentation supporting entries into the CRFs must be maintained and 
readily available.

Updates to CRFs 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, and/or data queries are created in the EDC system database for site 
resolution and subsequently closed by the EDC system or by an Amgen reviewer.

The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that investigator inspected or reviewed the 
data on the CRF, and the data queries, 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 visit-week 4 and early termination) 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 and Table 3), 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
CRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements.


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All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.
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 Recommendations for Conduct, Reporting, Editing, and Publication of Scholarly 
Work in Medical Journals (International Committee of Medical Journal Editors).
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
Andtbacka RHI, Roaa MI, Delman K, et al.  Responses of injected and uninjected 
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Andtbacka RH, Collichio FA, Amatruda T, et al.  OPTiM: a randomized phase III trial of 
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intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III  
melanoma (EORTC 18952), a randomised controlled trial.  Lancet.  
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Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo 
after complete resection of high-risk stage III melanoma (EORTC 18071): a randomized, 
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Hart DN.  Dendritic cells: unique leukocyte populations which control the primary 
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immunity in tumor immunotherapy.  Cancer Sci.  2004;95(9):697-703.
Imlygic(talimogene laherparepvec) Prescribing Information, Amgen Europe B.V, 2015.
Intron A® (interferon alfa-2b) Prescribing Information.  Merck, 2013
Kalbfleisch JD, Prentice RL.  The statistical analysis of failure time data. New York, 
NY:  John Wiley;1980.
Kaufman HL, Andtbacka HI, Collichio F, et al. Interim OS subset analyses in OPTiM, a 
randomized phase 3 trial of intralesional talimogene laherparepvec vs. subcutaneous 
granulocyte macrophage-colony stimulating factor in stage IIIB-IV melanoma. Society 
for Melanoma Research; 2013.
Kaufman HL, Andtbacka HI, Collichio F, et al.  Primary overall survival (OS) from 
OPTiM, a randomized phase 3 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.  American Society of Clinical 
Oncology Annual Meeting 2014. Abstract 9008a.
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oncology group and intergroup trials of adjuvant high-dose interferon for melanoma.  Clin 
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2000;18:2444-2458.
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of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group 
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immunotherapy.  Cancer Immunol Immunother.  2005;54(8):721-728.
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cells during neoadjuvant biochemotherapy for stage III melanoma: outcome prediction in 
a multicenter trial. J Clin Oncol. 2005,23:8057-8064.


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Lewis KD, Robinson WA, McCarter M, et al.  Phase II multicenter study of neoadjuvant 
biochemotherapy for patients with stage III malignant melanoma.  J Clin Oncol.  
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management of cutaneous melanoma 2010.  Brit J Dermatol.  2010;163:238–256 
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adjuvant treatment of cutaneous melanoma.  Cochrane Database Syst Rev.  
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with high-risk melanoma: A systematic review and meta-analysis. J Natl Cancer Inst. 
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melanoma with high-dose interferon alpfa-2b induces objective tumor regression in 
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National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin 
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Surveillance, Epidemiology, and End Results (SEER) Program Cancer Statistics Review 
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wholly owned subsidiary of Amgen); 2015.
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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) 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. Because cutaneous melanoma lesions may be irregularly shaped, WHO criteria 
using longest perpendicular diameters rather than Response Evaluation Criteria in Solid 
Tumors (RECIST) using single dimension measurement are preferred for evaluating 
tumor response.
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’s 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 


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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 
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 talimogene laherparepvec 
[Arm 1] or prior to surgery [Arm 2]), 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 in at least 
2 dimensions 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


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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 
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 lesions merge and at least one is an index 
lesion, the largest index lesion prior to merging should be measured and reported during 
the tumor response assessment. All other merged lesions should be reported as 
0 mm x 0 mm (for lesions previously reported as Index or New Measurable Lesions) or 
absent (for lesions previously reported as Non-Index or New Non-Measurable Lesions).
If two or more non-index lesions merge, the apparently larger lesion should be reported 
as present, and smaller lesion(-s) should be reported as absent. The indication that the 
lesion coalesced with the specified lesion(-s) should be provided for each merged lesion.
Splitting lesions:  When an index lesion splits into two or more lesions the largest 
measurable part of the split lesion will be measured for the current assessment with the 
indication that the lesion split from the specified lesion, and followed for future 
assessments. The remaining lesions will be measured as new lesions with an indication 
that the lesion split from the specified lesion. In this case, appearance of a new lesion 
from a previous lesion that split will not be considered disease progression solely due to 
appearance of a new lesion (may be considered 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).
When an non-index lesion splits into two or more lesions, the apparently larger lesion will 
be reported as a non-index lesion. All other smaller lesions will be reported as new 
non-index lesions with an indication that the lesion split from the specified lesion. In this 
case, appearance of a new lesion from a previous lesion that split will not be considered 


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disease progression solely due to appearance of a new lesion (may be considered 
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 randomization and 
never more than 4 weeks (ie, 28 days) prior to randomization.
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 largest perpendicular diameters of all index lesions will 
be calculated and reported.
If a subject has multiple small superficial cutaneous melanoma lesions at baseline (each 
lesions is less than 10 mm in at least 2 dimensions) which in aggregate have a total 
diameter of ≥ 10 mm in at least 2 dimensions, up to 10 largest lesions that were included 
in this measurement will be reported as ”Index Lesions”, and the sum of the products of 
the two largest perpendicular diameters 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 sum of the products of the two largest 
perpendicular diameters of the index lesions are added together to provide the total 
tumor burden.


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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”.
Follow-up “New Lesions”:
At tumor assessment, if new measurable lesions have appeared they should be added 
to sum of the products of the two largest perpendicular diameters of the index lesions to 
provide the total tumor burden. For nonmeasurable new lesion they should be followed 
as nonindex lesion as “present”, “absent”, or in rare cases “unequivocal progression”.  If 
a new lesion(s) that appears in between scheduled tumor response assessments 
disappear(s) before the next scheduled assessment, there is no need to include this 
lesion for tumor response evaluation. 
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 1, Table 2, and Table 3.


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Table 1.  Definition of Index Lesion Tumor Response Including
New Measurable Lesions
Complete Response (CR):
Complete disappearance of all index lesions, including any new 
measurable tumor lesions which might have appeared.
Partial Response (PR):
Achieving a 50% or greater reduction in the sum of the products 
of the two largest perpendicular diameters of all index lesions and 
new measurable lesions, if applicable, at the time of assessment 
as compared to the sum of the products of the perpendicular 
diameters of all index lesions at baseline.
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 measurable lesion since the last response 
assessment time point.
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
Table 2.  Definition of Nonindex Lesion Tumor Response Including 
New Nonmeasurable Lesions
Complete Response (CR):
Disappearance of all nonindex lesions, including any new 
nonmeasurable tumor lesions which might have appeared.
Incomplete 
Response/Stable Disease 
(SD):
Persistence of one or more nonindex tumor(s). 
Disease Progression (PD):
Unequivocal  progression of one or more nonindex lesions or the 
unequivocal appearance of a new nonmeasurable tumor lesion 
since the last response assessment time point
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
CR = complete response; SD = stable disease; PD = disease progression; UE = unable to evaluate; NA = 
not applicable; ND = not done.


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Table 3.  Matrix for Determining the Overall Response at Each Assessment Point 
Index Lesion Response 
Including New Measurable 
Lesions
Nonindex Lesion Response
Including New Nonmeasurable 
Lesions
Overall Response
CR
CR
CR
SD
PR
PD
PD
NA
CR
UE/ND
UE
PR
CR/SD
PR
PD
PD
NA
PR
UE/ND
UE
SD
CR
SD
SD
SD
PD
PD
NA
SD
UE/ND
UE
PD
Any
PD
UE/ND
CR/SD/ NA/UE/ND
UE
PD
PD
CR = complete response; PR = partial response; SD = stable disease; PD = 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 pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, 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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Appendix F.  Surgery Guidelines
The decision to perform surgery on subjects with stage IIIB, IIIC or IV M1a melanoma 
(dermal, subcutaneous or non-regional lymph node metastases) is a complex clinical 
decision making process that must be based on good clinical judgment that may include
consulting with other relevant medical specialities, and considering patient’s 
preferences. Eligible subjects for surgical resection must have metastatic disease that in 
the judgment of the investigator is deemed completely surgically resectable Eligible 
subjects may either present with a primary melanoma and evidence of concurrent 
dermal, subcutaneous or clinically palpable lymph node metastasis, or may have 
previously had a primary melanoma and subsequently develop recurrence. Subjects 
who present with metastasis from an unknown primary melanoma are also eligible to 
participate.  
1)
Definition of IIIB or IIIC Metastasis: Eligible subjects with stage IIIB or IIIC 
melanoma have histopathologically confirmed melanoma metastasis in:
a)
the dermis or subcutaneous tissue at, or close to the site of a primary 
cutaneous melanoma, and/or
b)
the lymphatic channels (satellite, in-transit, or intralymphatic metastasis) 
draining a primary cutaneous melanoma site, and/or
c)
the regional lymph nodes draining a primary cutaneous melanoma site
2)
Definition of IVM1a Metastasis: IVM1a means metastasis to distant skin, 
subcutaneous tissues, or lymph nodes. Subjects eligible for the protocol must 
have melanoma metastasis to a skin or soft tissue site beyond the potential 
lymph drainage basins of the primary site, or to lymph nodes beyond the 
potential lymph drainage pathways regional to the primary site.
3)
Surgical Margins: The goal of surgery is to completely resect all metastases with 
adequate margins to avoid local recurrence. The surgeon should always attempt 
to get negative margins and be well beyond the palpable tumor. In subjects with 
dermal or subcutaneous metastasis, wide margin resection beyond 2 cm is 
usually not indicated, but the surgeons should always consider appropriate 
margins of resection to achieve both a clinically and microscopically negative 
resection. If the metastasis is in the subcutaneous tissue, the underlying fascia 
should be excised with the specimen. If the margins are found to be positive on 
pathological examination during the surgery, an additional resection, if feasible,
of skin and subcutaneous tissue should be performed. Debulking surgery in 
which the tumor is shelled out invariably leads to prompt recurrence and is of 
little benefit to the subject.
4)
Handling of Surgical Specimen(s): It is recommended that surgeon will mark the 
lesion(s) (or the area if CR was achieved) with the suture that was injected with 
talimogene laherparepvec. Complete surgery report and surgical pathology 
report have to be recorded in CRF. For additional information on handling of 
surgical specimens refer to Laboratory Manual.


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 99 of 100
CONFIDENTIAL
Guidelines for Lymphadenectomy
1)
Axillary Dissection: A complete axillary lymph node dissection should include all 
three levels of node-bearing axillary tissue. The borders of dissection include 
superior along the axillary vein from the thoracic inlet (Halsted's ligament) to the 
latissimus dorsi tendon. The medial border is the intercostal and serratus 
anterior muscles on the chest wall. The lateral border is the edge of the 
latissimus dorsi muscle, and the inferior border is the fourth intercostal space. 
The dissection should extend to the subscapular muscle. All fat and lymphatic 
tissue should be resected from the axilla and the long thoracic and thoracodorsal 
neurovascular bundle should be preserved unless involved with tumor. The 
pectoral minor muscle may be transected or removed if necessary to assure 
complete dissection of Level III nodes. Drainage of the resection bed with a 
closed suction drain is recommended. The minimum number of nodes assessed 
from the axillary region is 15.
2)
Inguinal Dissection: Borders of dissection should be superior:  along the lower 
abdomen 5 cm above and parallel to the inguinal ligament, inferior to the apex of 
the femoral triangle, medially along the medial border of the adductor magnus 
muscle, and laterally along the lateral border of the sartorius muscle. The fatty 
tissue and lymphatic tissue overlying the femoral vessels and nerve are removed 
up to the inguinal ligament. Removal of the node of Cloquet is recommended. 
Drainage of the resection bed with a closed suction drain is recommended. The 
minimum number of nodes assessed from the superficial inguinal region is 8. A 
deep groin dissection is required if inguinal nodes are (a) clinically positive 
(palpable) and there are 3 or more positive inguinal nodes, (b) positive matted 
nodes or (c) the node of Cloquet is microscopically positive by either hematoxylin 
and eosin staining or immunohistochemistry. A deep groin dissection of the 
common and external iliac, hypogastric, and obturator nodes should be 
performed by entering the retroperitoneal space either through a separate 
incision through the abdominal musculature above and parallel to the inguinal 
ligament, or by transecting the inguinal ligament. Drainage of the resection bed 
with a closed suction drain is recommended. The minimum number of nodes 
assessed from the deep groin region is 4.
3)
Popliteal Region: The popliteal fossa lymph node dissection should contain the 
lymph nodes bordered laterally and superiorly by the biceps femoris muscle and 
medially and superiorly by the semimembranous and semitendinosus muscles.
The inferior margins are the lateral and medial heads of the gastrocnemius 
muscles. The roof of the fossa is bordered by the popliteal surface of the femur 
and popliteus muscle and the floor is bordered by the fascia lata, superficial 
fascia and skin. Usually ligation of the lesser saphenous vein is necessary for 
complete excision of the lymph nodes in this site. Drainage of the resection bed 
with a closed suction drain is recommended. The minimum number of nodes 
assessed from the popliteal region is 3.


Product:  Talimogene Laherparepvec
Protocol Number:  20110266
Date:  23 March 2018
Page 100 of 100
CONFIDENTIAL
4)
Neck Dissection: Either a classic radical or modified neck dissection preserving 
the spinal accessory nerve and sternocleidomastoid muscle are acceptable. In 
subjects who present with a primary melanoma on the anterior scalp, face or ear 
and concurrent palpable biopsy proven neck lymph node metastasis, a 
lymphoscintigraphy is recommended to assess possible drainage to the 
superficial parotid gland. If there is evidence of drainage to parotid lymph nodes, 
a superficial parotidectomy is required to remove the parotid nodes along with 
the neck lymph nodes. The borders of the neck dissection are inferior to the 
clavicle, superior to the mandible, mastoid and tail of the parotid gland, posterior 
to the anterior border of the of the trapezius muscle, and anterior to the strap 
muscles. Contents of the digastric triangles should be resected and the spinal 
accessory nerve preserved as long as there are no metastases in the upper 
jugular nodes. Drainage of the resection bed with a closed suction drain is 
recommended. The minimum numbers of nodes assessed from the neck region 
are as follows: (a) anterior cervical, including suprahyoid, jugulardigastric is
15; (b) posterior cervical, including supraclavicular is 15. Selected neck 
dissection could be considered in some circumstances, such as metastasis to 
submental nodes or very low cervical nodes from a medial shoulder primary 
melanoma.
For resected lymph nodes, refer to Table 4 below.
Table 4.  Quantitative/Qualitative Reporting of Fully Resected Lymph Nodes


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  23 March 2018 
Page 1 of 5 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase 2, Multicenter, Randomized, Open-label Trial Assessing 
the Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus 
Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma 
Amgen Protocol Number (Talimogene Laherparepvec) 20110266 
Amendment Date:  23 March 2018 
Rationale: 
This protocol is being amended to: 
• 
Add a third interim analysis to the protocol 1 year after the end of randomization in 
order to help inform Amgen regarding future potential clinical trials and data 
collection in this setting. 
• 
Update the time points for assessment of secondary objectives to start at first year. 
• 
Update the exclusion criteria for sexually active subjects and their partners with 
allergy by providing option for alternative condom type.  
• 
Provide guidance to sites on how to report data for fully resected lymph nodes after 
surgery with specific qualitative and quantitative features. 
• 
Make minor corrections and clarifications throughout the document, including 
administrative, typographical, and formatting errors. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  23 March 2018 
Page 2 of 5 
CONFIDENTIAL 
 
 
Description of Changes  
Section:  Global 
Change:  Update protocol amendment dates throughout document from 22 April 2016 to 
23 March 2018. 
Section:  Global 
Change:  Make editorial corrections (including typographical, grammatical, and 
formatting errors) throughout the document. 
Section:  Title page 
Add:  
Amgen Protocol Number (Talimogene Laherparepvec) 20110266 
EudraCT number 2014-001146-13 
NCT02211131 
Section:  Title page 
Replace: 
Key Sponsor Contacts: 
MD 
Clinical Research Medical Director 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 
 
Email address: 
 
 
 
Clinical Research Study Manager 
Amgen Limited 
1 Sanderson Road (Uxbridge Business Park) 
Uxbridge, UB8 1DH 
Telephone:
 
Email: 
 
Date: 
23 May 2014 
Amendment 1 Date: 
09 June 2014 
Amendment 2 Date: 
31 March 2016 
Superseding Amendment 2 
Date: 
22 April 2016 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  23 March 2018 
Page 3 of 5 
CONFIDENTIAL 
 
 
With:  
Key Sponsor Contacts: 
 MD 
Clinical Research Medical Director 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 
 
Email address: 
 
 
 PhD 
Senior Manager, Global Clinical Program 
Management 
Amgen Limited 
1 Sanderson Road (Uxbridge Business Park) 
Uxbridge, UB8 1DH 
Telephone: 
  
Email: 
 
Date: 
23 May 2014 
Amendment 1 Date: 
09 June 2014 
Amendment 2 Date: 
31 March 2016 
Superseding Amendment 2 
Date: 
Amendment 3 Date:  
22 April 2016 
23 March 2018 
Section:  Protocol Synopsis, Secondary Objectives, Bullet points 1 and 5. 
Add:  
• 
To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on 1-year, 2-year, 3-year, and 5-year RFS 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on 1-year, 2-year, 3-year, 5-year, and overall survival 
(OS) 
Section:  Protocol Synopsis, Secondary Endpoints, Bullet points 1 and 7. 
Add:  
• 
1-year, 2-year, 3-year, and 5-year RFS 
• 
1-year, 2-year, 3-year, and 5-year, and overall survival 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  23 March 2018 
Page 4 of 5 
CONFIDENTIAL 
 
 
Section:  Protocol Synopsis, Statistical Considerations, Paragraphs 3 and 7 
Add:  
An additional third interim analysis with no formal stopping rule is planned to 
evaluate RFS approximately 1 year after the end of randomization.  This analysis 
will be conducted by the Amgen study team. 
All efficacy analyses will be descriptive with no formal hypothesis testing.  Kaplan-Meier 
(KM) estimates and CI will be calculated for RFS, LRFS, RRFS, DMFS, OS landmarks 
(1-, 2-, 3- and 5-year rates) and quartiles.   
Section:  1.2.  Secondary, Bullet points 1 and 5. 
Add:  
• 
To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on 1-year, 2-year, 3-year, and 5-year RFS 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on 1-year, 2-year, 3-year, 5-year, and overall survival 
(OS) 
Section:  4.1.2.  Exclusion criteria, 221. 
Add:  
221 
Sexually active subjects and their partners unwilling to use male or female latex 
condoms to avoid potential viral transmission during sexual contact while on 
treatment and within 30 days after treatment with talimogene laherparepvec.  For 
those with latex allergies, polyurethane condoms may be used. 
Section:  10.1.1.2.  Secondary Endpoint, Efficacy Endpoints, Bullet points 1 and 8 
Add: 
• 
1-year, 2-year, 3-year, 5-year RFS:  The Kaplan-Meier (K-M) estimate of RFS rate at 
1-year, 2 years, 3 years and 5 years 
• 
1-year, 2-year, 3-year and 5-year survival:  The Kaplan-Meier (K-M) estimate of the 
survival rate at 1-year, 2 years, 3 years and 5 years 
Section:  10.2.  Sample Size Considerations, Paragraph 3 
Add:  
The Kaplan-Meier (KM) method will be used to estimate 1-year, 2-year, 3-year, 5-year, 
and overall RFS.   


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  23 March 2018 
Page 5 of 5 
CONFIDENTIAL 
 
 
Section:  10.4.1.  Interim Analyses, Paragraph 3 
Add:  
An additional third interim analysis with no formal stopping rule is planned to 
evaluate RFS approximately 1 year after the end of randomization.  This analysis 
will be conducted by the Amgen study team. 
Section:  10.5.3.  Secondary Efficacy Endpoints, Paragraph 1 
Add: 
KM estimates will be calculated for RFS, LRFS, RRFS, DMFS, OS landmarks  
(1-, 2-, 3- and 5-year rates) and quartiles.   
Section:  10.5.3.  Secondary Efficacy Endpoints, Paragraph 1 
Replace: 
For each group the equal precision band method will be used to calculate a 
simultaneous confidence band for RFS, LRFS, RRFS, and DMFS over the interval from 
2 to 5 years (Nair, 1984).   
With  
For each group the equal-precision band method will be used to calculate a 
simultaneous confidence band for RFS, LRFS, RRFS, and DMFS over the interval from 
1 to 5 years (Nair, 1984). 
Section:  Appendix F.  Surgery Guidelines 
Add: 
For resected lymph nodes, refer to Table 4 below. 
Table 4.  Quantitative/Qualitative Reporting of Fully Resected Lymph Nodes 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 1 of 25 
CONFIDENTIAL 
 
 
Superseding Amendment 2 
Protocol Title:  A Phase 2, Multicenter, Randomized, Open-label Trial Assessing 
the Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus 
Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma 
 
Amgen Protocol Number 20110266 
 
Amendment Date: 
22 April 2016 
 
Rationale: 
The Superseding Amendment 2 was written to: 
• 
Correct the numbering of the exclusion criteria in Amendment 2 
• 
Update sponsor contact 
The key protocol changes are:  
• 
Secondary objective 
An objective of regional recurrence-free survival (RRFS) was added to the following 
secondary objective “To estimate the effect of neoadjuvant talimogene laherparepvec 
plus surgery compared to surgery alone on local recurrence-free survival (LRFS) and 
distant metastases-free survival (DMFS)” to better characterize patterns of recurrences 
of melanoma, which include not only local and distant, but also regional recurrences.  
• 
Secondary endpoint 
Regional recurrence-free survival was added to the secondary endpoints in parallel to 
this addition to the secondary objective. 
• 
Distant metastases free survival  
The efficacy endpoint of DMFS was clarified by specifying what DMFS includes and 
excludes. 
• 
Adjuvant ipilimumab information 
Information on adjuvant ipilimumab use was added to the Introduction because 
ipilimumab was recently approved by the United States Food and Drug Administration 
(FDA) for the adjuvant treatment of patients with cutaneous melanoma with pathologic 
involvement of regional lymph nodes of more than 1 mm who have undergone complete 
resection, including total lymphadenectomy. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 2 of 25 
CONFIDENTIAL 
 
 
• 
Marketing information on talimogene laherparepvec 
Marketing information on talimogene laherparepvec (Imlygic) was added to the 
Introduction to update the background section because it was recently approved by 
regulatory authorities for specified indications in the US, Europe, and Australia. 
• 
Randomization stratification 
Stratification by adjuvant interferon use was replaced with adjuvant systemic therapy to 
include interferon alpha (INFα) and ipilimumab since ipilimumab has been FDA 
approved to reduce the risk of melanoma returning after surgery and other systemically 
active therapy may also be approved for this indication. 
• 
Number of sites 
The number of sites was changed from 40 to 50 to achieve the enrollment goal. 
• 
Safety follow-up 
The 30-day safety follow-up was modified to specify that subjects will be followed for 
local, regional, and distant disease recurrence and for melanoma and adverse events 
thought to be potentially related to talimogene laherparepvec to align with the schedule 
of assessment in the Registry Study 20120139.  The protocol was also changed to 
specify that subjects who participate in 20120139 must sign a new informed consent 
form. 
• 
Measurable disease inclusion criterion  
Inclusion criterion 106 was clarified to specify that the measurement of the lesion 
diameter “in at least 2 dimensions” is ≥ 10 mm to align with other talimogene 
laherparepvec studies.  Also, measurement using ultrasound for superficial lymph nodes 
and subcutaneous lesions was added. 
• 
Serum lactate dehydrogenase (LDH) level inclusion criterion 
Inclusion criterion 108 was changed as follows:  Serum LDH level ≤ 1.5 x upper limit of 
normal (ULN) for stages IIIB and IIIC melanoma and ≤ 1.0 x ULN for Stage IVM1a 
melanoma within 28 days prior to randomization, since LDH is not a staging component 
for Stage III melanoma. 
• 
Serum albumin inclusion criterion 
Inclusion criterion 109 was modified to include serum albumin ≥ 2.5 g/dL to align with 
other talimogene laherparepvec studies. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 3 of 25 
CONFIDENTIAL 
 
 
• 
Autoimmune disease exclusion criterion  
Exclusion criterion 204 was expanded to clarify symptomatic autoimmune disease to 
align with the same criterion in other talimogene laherparepvec monotherapy studies. 
• 
Clinically significant immunosuppression 
The definition of clinically significant immunosuppression was updated in exclusion 
criterion 205 to align with other talimogene laherparepvec monotherapy studies. 
• 
Tumor vaccine exclusion criterion 
Exclusion criterion 212 (prior therapy with tumor vaccine) was deleted to align with other 
talimogene laherparepvec monotherapy studies. 
• 
Viral transmission during sexual contact exclusion criterion 
The criterion (216) to exclude sexually active subjects and their partners unwilling to use 
male or female latex condoms to avoid potential viral transmission during sexual contact 
was added as a condition of marketing approval and to align with other talimogene 
laherparepvec studies. 
• 
Talimogene laherparepvec vials 
Each vial contains a minimum of 1.0 mL talimogene laherparepvec at either 106 PFU/mL 
or 108 PFU/mL concentrations.  The description of the two vial concentrations as green 
cap and blue cap, respectively, were deleted since they no longer apply.  
• 
Treatment procedures 
The following statement was added to stress the need to report adjuvant therapies, if 
planned, via Interactive Voice Response (IVR):  If adjuvant therapy (systemic and/or 
radiation therapy; approved or investigational) is planned, this should be reported via 
IVR at randomization. 
• 
Reporting of potentially talimogene laherparepvec related adverse events 
during long-term follow-up 
Adverse events deemed by the investigator to be potentially related to talimogene 
laherparepvec (Arm 1 only) and use of subsequent anticancer therapy for melanoma will 
be collected during long-term follow-up to align this protocol with all other talimogene 
laherparepvec studies. 
• 
Activated PTT  
Activated thromboplastin time was added as an alternative to PTT in screening 
laboratory tests because it may be an alternative test of choice for testing coagulation. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 4 of 25 
CONFIDENTIAL 
 
 
• 
Physical examination and ECOG performance status 
Required physical examination and ECOG performance status was added at weeks 4 
and 8 to report any change in a patient’s performance status. 
• 
Oral and genital swabbing after surgery 
Oral and genital swabbing for real-time polymerase chain reaction (qPCR) and 50% 
Tissue Culture Infective Dose (TCID50) assay testing was removed from the safety 
follow-up visit because identical information is currently being collected in 
Study 20120324.  
• 
Safety Follow-up procedures 
Surgical safety evaluation and recording of subsequent anticancer therapy for melanoma 
were added to safety follow-up procedures to align the schedule of assessment in the 
Registry Study 20120139. 
• 
Pregnancy and lactation reporting 
Reference to Amgen’s global Pregnancy and Lactation Surveillance Programs was 
deleted and replaced by Amgen Global Patient Safety to align with current company 
practice. 
• 
Statistical considerations 
RRFS analysis was added to meet the addition of RRFS to the secondary objectives. 
The protocol was modified to clarify that a DRT will review the first interim analysis and 
the talimogene laherparepvec product team will review the second interim analysis, 
since the second analysis will be performed after all subjects in Arm 1 have been 
enrolled.  The DRT and talimogene laherparepvec product team will also review some 
efficacy endpoints (eg, R0 resection rate, pCR rate, response to neoadjuvant treatment). 
Ad hoc analyses, executed by the talimogene laherparepvec product team, for safety or 
some efficacy endpoints may be conducted before the planned primary or final analyses 
if interim data are required for submission to regulatory authorities. 
• 
Sample size 
In the statement regarding subjects who are not confirmed to be disease-free 
post-surgery or who withdraw prior to surgery, failure was changed from at 
randomization to “a day after randomization” for RFS.  With this change, the number of 
subjects at risk at the earliest possible time (randomization +1 day) would not change 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 5 of 25 
CONFIDENTIAL 
 
 
due to non-melanoma subjects, and would reduce the impact on the Cox model, 
Kaplan-Meier, and log-rank test results. 
• 
Trial integrity document 
The mention of using a Trial Integrity Document was deleted to comply with current 
standard operating procedures.  
• 
Index lesions 
Language was added to Appendix D (documentation of index lesions) to clarify the 
recording of aggregate lesions and to align with other talimogene laherparepvec 
monotherapy studies. 
• 
Definition of progressive disease for measurable disease  
The definition of progressive disease (PD) was changed to clarify that PD includes the 
unequivocal appearance of a new measurable lesion since the last response 
assessment time point, to align with other talimogene laherparepvec studies. 
• 
Appendix F 
Appendix F was modified to state that the decision to perform surgery may include 
consulting with other relevant medical specialties and consideration of a patient’s 
preferences, to provide guidance on the decision making process of resection of 
melanoma. 
• 
Administrative 
Minor text clarifications, additions, and corrections as well as typographical and 
formatting changes were made throughout the protocol.  The key sponsor contact 
information was updated to align with current personnel and the talimogene 
laherparepvec Investigator Brochure reference was updated to the current version.  New 
references were added as needed for newly added text. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 6 of 25 
CONFIDENTIAL 
 
 
Description of Changes (all changes to the Protocol are indicated in bold text) 
 
Section: 
 
All applicable sections and header 
 
 
Replace:   
09 June 2014 
 
 
With: 
22 April 2016 
 
 
Replace: 
end point 
 
 
With: 
Endpoint 
 
 
Replace: 
arm 1, arm 2 
 
 
With: 
Arm 1, Arm 2 
 
 
Replace: 
(Talimogene Laherparepvec Investigator’s Brochure, 2014) 
 
 
With: 
(Talimogene Laherparepvec Investigator’s Brochure, 2015) 
 
 
Section 
Cover page 
 
Replace: 
PhD, MD 
Clinical Research Senior Medical Scientist 
Telephone:
Email address:
 
 
 
With: 
MD   
Clinical Research Medical Director 
Telephone:
Email address:
 
 
Replace: 
Clinical Research Study Manager 
Amgen Limited 
1 Sanderson Road (Uxbridge Business Park) 
Uxbridge, UB8 1DH 
Telephone:
Email:
 
 
With: 
Clinical Research Study Manager 
Amgen Limited 
1 Sanderson Road (Uxbridge Business Park) 
Uxbridge, UB8 1DH 
Telephone:
Email:
 
 
Add: 
Superseding Amendment 2 Date     22 April 2016 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 7 of 25 
CONFIDENTIAL 
 
 
Section: 
Protocol Synopsis, Secondary Objectives, bullet 4 
 
 
Add: 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec 
plus surgery compared to surgery alone on local recurrence-free 
survival (LRFS), regional recurrence-free survival (RRFS), and 
distant metastases-free survival (DMFS) 
 
 
Section: 
Protocol Synopsis, Secondary Endpoints, bullet 5 
 
 
Add: 
• 
RRFS 
 
 
Section: 
Synopsis, Study Design 
 
 
Replace: 
Randomization will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a), planned adjuvant therapy (interferon alpha [INFα] with or 
without radiotherapy versus radiotherapy without INFα versus
 
 none). 
 
With: 
Randomization will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a), planned adjuvant therapy (adjuvant systemic therapy [eg, 
interferon alpha (INFα), ipilimumab] with or without radiotherapy 
versus radiotherapy without adjuvant systemic therapy versus
 
 none). 
 
Add: 
Subjects will be followed for safety approximately 30 (+15) days after 
surgery and for disease recurrence (local, regional, or distant), 
subsequent anticancer therapy for melanoma, adverse events 
thought to be potentially related to talimogene laherparepvec 
(Arm 1 only), and survival every 3 months (±30 days) for first 3 years 
after the end of the safety follow-up period and then every 6 months 
(±30 days) until death, subject withdraws full consent, or up to 5 years 
after the last subject is randomized.  Thereafter, subjects randomized 
to Arm 1 who received at least a single dose of talimogene 
laherparepvec 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 
subsequent anticancer therapy for melanoma.  Subjects who after 
the long-term follow-up period of this study (Study 20110266) will 
elect to participate in the registry study must sign new informed 
consent form before any registry protocol-specific activities. 
 
 
Section: 
Synopsis, Key Inclusion Criteria 
 
 
Replace: 
Also, subject must have an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1 and must have a serum lactate 
dehydrogenase (LDH) ≤ 1.0 X upper limit of normal and adequate 
hematologic, hepatic, renal, and coagulation organ function. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 8 of 25 
CONFIDENTIAL 
 
 
With: 
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 (ULN) for stages 
IIIB/C melanoma and LDH ≤1.0 x ULN for stage IVM1a melanoma 
and adequate hematologic, hepatic, renal, and coagulation organ 
functions. 
 
 
Section: 
Synopsis, Key Exclusion Criteria 
 
 
Replace: 
Subject must not have history or evidence of symptomatic autoimmune 
pneumonitis, glomerulonephritis, vasculitis, or other symptomatic 
autoimmune disease.   
 
 
With: 
Subject must not have 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. 
 
 
Delete: 
Subject must not have been treated previously with talimogene 
laherparepvec or tumor vaccine. 
 
 
Section: 
Synopsis, Procedures, Screening, bullets 3 and 4 
 
 
Delete: 
demographics, physical examination, vital signs, and ECOG 
performance status assessment 
 
 
Add: 
local laboratory tests including, hematology panel, chemistry panel, 
serum LDH, prothrombin time (PT) (or international normalization ratio 
[INR]) and partial thromboplastin time (PTT) (or activated PTT), and 
serum or urine pregnancy test for female subjects of childbearing 
potential 
 
 
Section: 
Synopsis, Procedures, Treatment, bullets 2, 3, and 8 
 
 
Add: 
• 
ECOG performance status 
 
 
Add: 
• 
physical examination 
 
 
Add: 
histological tumor assessment of the surgical specimen, including 
assessment for tumor-free margins (R0 resection for negative 
margins, R1 or R2 resections for tumor positive margins) and 
pathological complete response (in Arm 1 only) 
 
 
Section: 
Synopsis, Procedures, Safety Follow-up Visit, bullets 2, 3, and 5 
 
 
Add: 
• 
surgical safety evaluation 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 9 of 25 
CONFIDENTIAL 
 
 
Add: 
• 
documentation of subsequent anticancer therapy for 
melanoma (including local, regional, or systemic therapy) 
 
 
Replace: 
• 
central laboratory tests including blood and urine for qPCR, oral 
mucosa swabs and genital swabs (if study drug is injected into a 
melanoma lesion below the waist) for qPCR and 50% Tissue 
Culture Infective Dose (TCID50) assay testing, and swabs of cold 
sores, vesicles, and other lesions suspected to be herpetic in origin 
(if any) for qPCR testing within 24 hours following the investigator’s 
knowledge of the event  
 
 
With: 
• 
central laboratory tests of swabs of cold sores, vesicles, and other 
lesions suspected to be herpetic in origin (if any) for qPCR testing 
of talimogene laherparepvec DNA within 24 hours following the 
investigator’s knowledge of the event  
 
 
Section: 
Synopsis, Procedures, Long-term Follow-up, paragraphs 1, 2, and 3 
 
 
Add: 
All randomized subjects will be contacted by telephone, or clinic visit, 
to assess survival status, collect adverse events deemed by the 
investigator to be potentially related to talimogene laherparepvec 
(Arm 1 only), and, if applicable, commencement of any subsequent 
anticancer melanoma therapy (including local, regional, or systemic 
therapy for melanoma). 
 
 
Add: 
every 3 months (±30 days) for 3 years following the safety follow-up 
visit and then every 6 months (±30 days) until distant disease 
recurrence, death, 
 
 
Add: 
After the long-term follow-up period of this study has ended, subjects 
randomized to Arm 1 who received at least a single dose of 
talimogene laherparepvec and who end the study for any reason 
other than death or withdrawal of full consent will be followed for 
survival under an 
 
 
Add: 
The registry protocol will also monitor for late and long-term adverse 
events thought to be potentially related to talimogene laherparepvec 
and use of subsequent anticancer therapy for melanoma.  
Subjects who after the long-term follow-up period of this study 
(Study 20110266) will elect to participate in the registry study 
must sign new informed consent form before any registry 
protocol-specific activities. 
 
 
Section: 
Synopsis, Statistical Considerations paragraphs 1, 2, 3, 5, and 6 
 
 
Add: 
The primary analysis for the primary endpoint will occur at the later 
time of either the occurrence of approximately 64 events (local, 
regional, or distant recurrence of melanoma or death) or 
approximately 2 years after the end of randomization. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 10 of 25 
CONFIDENTIAL 
 
 
Replace: 
Two interim analyses with no formal stopping rules are planned to 
evaluate safety when approximately 40 and 75 subjects randomized to 
talimogene laherparepvec have had the opportunity to complete the 
safety follow-up visit.  The primary analysis for certain secondary 
endpoints will be performed using the data from the second interim 
analysis. 
 
 
With: 
Two interim analyses with no formal stopping rules are planned to 
evaluate safety and some efficacy endpoints (eg, R0 resection 
rate, pCR rate, response to neoadjuvant treatment) when 
approximately 40 and 75 subjects randomized to talimogene 
laherparepvec have had the opportunity to complete the safety 
follow-up visit.  The primary analysis for certain secondary endpoints 
(eg, response to neoadjuvant treatment, R0 resection rate, pCR 
rate, and safety) will be performed using the data from the second 
interim analysis. 
 
 
Add: 
The primary analyses for RFS will occur at the later time of either 
the occurrence of approximately 64 events (local, regional, or 
distant recurrence of melanoma or death) or approximately 
2 years after end of randomization. 
 
 
Add: 
Ad hoc analyses for safety or some efficacy endpoints (eg, 
response to neoadjuvant treatment, R0 resection rate, pCR rate) 
may be conducted before the planned primary and/or final 
analyses if interim data are required for submission to regulatory 
authorities. 
 
 
Add: 
All efficacy analyses will be descriptive with no formal hypothesis 
testing.  Kaplan-Meier (KM) estimates and CI will be calculated for 
RFS, LRFS, RRFS, DMFS, OS landmarks (2-, 3- and 5-year rates) 
and quartiles.  Estimates and CIs for between-group differences will 
also be calculated.  An overall between-group difference in RFS, 
LRFS, RRFS, DMFS, and OS will be 
 
 
Section: 
Study Glossary, definition of end of study (primary completion) 
 
 
Add: 
The primary completion is anticipated to occur at the later time of 
either occurrence of approximately 64 events (local, regional, or 
distant recurrence of melanoma or death) or approximately 2 years 
after the end of randomization 
 
 
Add: 
RRFS - regional recurrence-free survival 
 
 
Delete: 
TCID50 - 50% Tissue Culture Infective Dose 
TID - Trial Integrity Document 
SPD - the sum of the products of the two largest perpendicular 
diameters 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 11 of 25 
CONFIDENTIAL 
 
 
Section: 
1.2  Secondary, bullet 4 
 
 
Add: 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec 
plus surgery compared to surgery alone on local recurrence-free 
survival (LRFS), regional recurrence-free survival (RRFS), and 
distant metastases-free survival (DMFS) 
 
 
Section: 
2.1  Melanoma and Adjuvant and Neoadjuvant Therapy for Melanoma, 
paragraphs 2, 7, and 10 
 
 
Delete: 
While radical resection is a cornerstone of treatment for subjects with 
stages III melanoma  
 
 
Add: 
The biochemotherapy regimen was associated with substantial toxicity 
with grade 3 and 4 adverse events in 36% and 40% of subjects, 
respectively (Flaherty et al, 2012). 
 
 
Add: 
Recently, ipilimumab, a a cytotoxic lymphocyte associated 
antigen 4 (CTLA-4 inhibitor), was approved by the United States 
Food and Drug Administration for the adjuvant treatment of 
patients with cutaneous melanoma with pathologic involvement 
of regional lymph nodes of more than 1 mm who have undergone 
complete resection, including total lymphadenectomy (Yervoy™, 
2015).  This approval was based on results of a randomized 
double-blind phase 3 trial conducted in 951 patients with 
completely resected stage IIIA (> 1 mm nodal involvement), IIIB, 
and IIIC melanoma (EORTC 18071).  Patients with in-transit 
metastases were excluded.  Ipilimumab improved recurrence-free 
survival (primary endpoint) in this trial from 17.1 months to 
26.1 months (HR 0.75; 95% CI 0.64–0.90; p=0.0013).  Results of OS 
and distant metastasis-free survival (secondary endpoints) are 
pending.  Fifty-two percent of patients randomized to the 
ipilimumab arm discontinued treatment because of toxicity, 
5 patients (1%) died because of ipilimumab-related toxicities.  
Forty-six percent of patients in the ipilimumab arm experienced 
grade 3 adverse events (37% immune-related), and 8% grade 4 
(6% immune-related) (Eggermont et al, 2015). 
 
 
Section: 
2.2  Talimogene Laherparepvec Background, paragraphs 8 and 9 
 
 
Replace: 
Clinical data currently available have provided evidence of talimogene 
laherparepvec’s efficacy in subjects with regionally and distantly 
metastatic melanoma 
 
 
With: 
Clinical data currently available have provided evidence of talimogene 
laherparepvec’s efficacy in subjects with unresectable metastatic 
melanoma 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 12 of 25 
CONFIDENTIAL 
 
 
Add: 
Recently, talimogene laherparepvec (Imlygic™) was approved in 
the USA for the local treatment of unresectable cutaneous, 
subcutaneous, and nodal lesions in patients with melanoma 
recurrent after initial surgery (with limitation of use:  Imlygic has 
not been shown to improve overall survival or have an effect on 
visceral metastases) (Imlygic™ Prescribing Information, 2015), in 
Europe for the treatment of adults with unresectable melanoma 
that is regionally or distantly metastatic (stage IIIB, IIIC, and 
IVM1a) with no bone, brain, lung or other visceral disease 
(Imlygic™ Summary of Product Characteristics, 2015), and in 
Australia as monotherapy for the treatment of melanoma in 
patients with unresectable cutaneous, subcutaneous, or nodal 
lesions after initial surgery (Imlygic™ Prescribing Information, 
2015).  
 
 
Add: 
Refer to the latest version of Talimogene Laherparepvec 
Investigator’s Brochure for additional information. 
 
 
Section: 
2.3  Rationale, paragraph 3 
 
 
Delete: 
Additionally, a number of immune-related biomarkers, such as 
antibodies to melanoma antigens and expression of immune-
stimulatory and immune-inhibitory molecules (eg cytotoxic lymphocyte 
associated antigen 4 [CTLA-4], program cell death-1 [PD-1], program 
cell death-1 ligand 1 [PD-L1] and others) in tumors or tumor infiltrating 
T-cells will be assessed to determine any association with clinical 
outcomes. 
 
 
Section: 
3.1  Study Design, paragraphs 5 and 7 
 
 
Replace: 
Randomization will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a) and planned adjuvant therapy (INFα with or without 
radiotherapy versus radiotherapy without INFα versus
 
 none). 
 
With: 
Randomization will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a), planned adjuvant therapy (adjuvant systemic therapy [eg, 
INFα, ipilimumab] with or without radiotherapy versus radiotherapy 
without adjuvant systemic therapy versus
 
 none).  
 
Add: 
Subjects will be followed for safety approximately 30 (+15) days after 
surgery and for disease recurrence (local, regional, or distant), 
subsequent anticancer therapy for melanoma, adverse events 
thought to be potentially related to talimogene laherparepvec, and 
survival every 3 months (±30 days) for first 3 years after the end of the 
safety follow-up 
 
 
Add: 
laherparepvec will be followed under an ongoing separate registry 
protocol (Study 20120139) for the long-term survival follow-up of 
subjects treated with talimogene 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 13 of 25 
CONFIDENTIAL 
 
 
Add: 
The registry protocol will also monitor for late and long-term adverse 
events thought to be potentially related to talimogene laherparepvec 
and use of subsequent anticancer therapy for melanoma.  
Subjects who after the long-term follow-up period of this study 
(Study 20110266) will elect to participate in the registry study 
must sign new informed consent form before any registry 
protocol-specific activities. 
 
 
Section: 
3.2  Number of Sites, paragraph 1 
 
 
Replace: 
The study will be conducted at approximately 40 sites in Australia, 
Brazil, United Kingdom, Russia, and USA.  Additional sites and 
countries may be added. 
 
 
With: 
The study will be conducted at approximately 50 sites in Australia, 
Brazil, Europe, Russia, and USA.  Additional sites and countries may 
be added. 
 
 
Section: 
3.5.1  Study Duration for Subjects 
 
 
Add: 
Subjects will be followed for safety approximately 30 (+15) days after 
surgery and for disease recurrence (local, regional, or distant), 
subsequent anticancer therapy for melanoma, adverse events 
thought to be potentially related to talimogene laherparepvec, and 
survival 
 
 
Section: 
3.5.2  End of Study 
 
 
Add: 
The primary completion is anticipated to occur at the later time of 
either the occurrence of approximately 64 events (local, regional, or 
distant recurrence of melanoma or death) or approximately 2 years 
after the end of randomization. 
 
 
Section: 
4.1.1  Inclusion Criterion, No. 106 
 
 
Replace: 
106      Measurable disease defined as one or more of the following: 
• 
at least one 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 
for nodal/soft tissue disease (including lymph nodes)  
• 
at least one ≥ 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 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 14 of 25 
CONFIDENTIAL 
 
 
With: 
106 
Measurable disease defined as one or more of the following: 
• 
at least one melanoma lesion that can be accurately and 
serially measured in at least 2 dimensions and for which the 
diameter in at least 2 dimensions is ≥ 10 mm as measured by 
contrast-enhanced or spiral computed tomography (CT) scan 
for nodal/soft tissue disease (including lymph nodes) or 
ultrasound for superficial lymph nodes and subcutaneous 
lesions 
• 
at least one superficial cutaneous or subcutaneous melanoma 
lesion as measured by calipers with diameter ≥ 10 mm in at 
least 2 dimensions 
• 
multiple superficial melanoma lesions which in aggregate have 
a total diameter of ≥ 10 mm in at least 2 dimensions 
 
 
Section: 
4.1.1  Inclusion Criterion, No. 108 
 
 
Replace: 
108  Serum LDH level ≤ 1.0 upper limit of normal (ULN) within 28 days 
prior to randomization 
 
 
With: 
108  Serum LDH level ≤ 1.5 x upper limit of normal (ULN) for stages 
IIIB and IIIC melanoma and ≤ 1.0 x ULN for stage IVM1a 
melanoma within 28 days prior to randomization  
 
 
Section: 
4.1.1  Inclusion Criterion, No. 109 
 
 
Add: 
• 
Hepatic 
− 
serum bilirubin ≤ 2.0 x ULN 
− 
serum albumin ≥ 2.5 g/dL 
− 
aspartate aminotransferase (AST) ≤ 2.5 x ULN 
 
• 
 
Section: 
4.1.2  Exclusion Criterion, No. 204 
 
 
Replace: 
204  History or evidence of symptomatic autoimmune pneumonitis, 
glomerulonephritis, vasculitis, or other symptomatic autoimmune 
disease 
 
 
With: 
204  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. 
 
 
Section: 
4.1.2  Exclusion Criterion, No. 205 
 
 
Replace: 
• 
receiving systemic immunosuppressive therapy (> 2 weeks 
prior to randomization), including oral steroid doses 
> 10 mg/day of prednisone or equivalent 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 15 of 25 
CONFIDENTIAL 
 
 
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 Criterion, No. 212 
 
 
Delete: 
212 
Prior therapy with tumor vaccine 
 
 
Section: 
4.1.2  Exclusion Criterion, No. 216 
 
 
Add: 
216  Sexually active subjects and their partners unwilling to use 
male or female latex condoms to avoid potential viral 
transmission during sexual contact while on treatment and within 
30 days after treatment with talimogene laherparepvec 
 
 
Section: 
5.1  Randomization/Treatment Assignment 
 
 
Replace: 
The IVR system will assign a randomization number.  Approximately 
150 subjects will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a) and planned adjuvant therapy (INFα with or without 
radiotherapy versus radiotherapy without INFα versus
 
 none). 
 
With: 
The IVR system will assign a randomization number.  Approximately 
150 subjects will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a) and planned adjuvant therapy (adjuvant systemic therapy 
[eg, INFα, ipilimumab] with or without radiotherapy versus 
radiotherapy without adjuvant systemic therapy versus
 
 none). 
 
Section: 
6.2.1  Amgen Investigational Product Talimogene Laherparepvec 
 
 
Delete: 
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. 
 
 
Section: 
6.5  Other Treatment Procedures 
 
 
Add: 
If adjuvant therapy (systemic and/or radiation therapy; approved 
or investigational) is planned, this should be reported via IVR at 
randomization. 
 
 
Section: 
7.1   Table 2.  Schedule of Assessments for Arm 1 (Talimogene 
Laherparepvec Plus Surgery) 
 
 
Add: 
Adverse Events Potentially Related to Treatment with Talimogene 
Laherparepvec 
X  under Long-term Follow-up 
 
 
Add: 
X under week 1, week 4, and week 8 for physical exam 
 
 
Add: 
X under week 4 and week 8 for ECOG performance status 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 16 of 25 
CONFIDENTIAL 
 
 
 
 
Add: 
Subsequent Anticancer Therapy for melanoma 
 
 
Delete: 
Blood and urine for qPCR 
 
 
Delete: 
Oral Mucosa Swab for qPCR and TCID50 Assay 
 
 
Delete: 
Genital Swab for qPCR and TCID50 Assay d 
 
 
Delete: 
dGenital swab sample is required if talimogene laherparepvec is 
injected into a melanoma lesion below the waist. 
 
 
Add: 
dSurgical specimens will be assessed for presence of viable 
tumor and tumor margin status for cutaneous and subcutaneous 
tumor; please refer to Section 7.2.2. 
 
 
Section: 
7.1  Table 3.  Schedule of Assessment for Arm 2 (Surgery Alone) 
 
 
Add: 
Subsequent Anticancer Therapy for Melanoma 
 
 
Add: 
d Surgical specimens will be assessed for presence of viable 
tumor and tumor margin status for cutaneous and subcutaneous 
tumor; please refer to Section 7.2.2.. 
 
 
Section: 
7.2  Table 4.  Laboratory Analytes 
 
 
Delete: 
TCID50 assay for talimogene laherparepvec viral infectivity 
 
 
Section: 
7.2.1  Screening and Randomization, bullet 10 
 
 
Delete: 
and CT scan or 
 
 
Section: 
7.2.2  Treatment 
 
 
Add: 
• 
Physical examination as per standard of care 
Arm 1:  within 3 days prior to talimogene laherparepvec administration 
on day 1 of week 1 and within 3 days prior to surgery, and prior to 
talimogene laherparepvec administration on day 1 of weeks 4 
and 8 
 
 
Add: 
• 
ECOG performance status 
− 
Arm 1:  prior to talimogene laherparepvec administration 
on day 1 of weeks 4 and 8 and within 3 days prior to the 
surgery  
 
 
Add: 
− 
A pathological complete response (pCR) in Arm 1 is 
defined as no evidence of viable tumor cells on complete 
pathological evaluation of the surgical specimen per 
institutional standards of care 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 17 of 25 
CONFIDENTIAL 
 
 
Section: 
7.2.3  Safety Follow-up Visit 
 
 
Delete: 
• 
Central laboratory assessments:  
- Arm 1:  blood and urine samples for qPCR analysis 
- Arm 1:  swab of oral mucosa for qPCR and 50% Tissue Culture 
Infective Dose (TCID50) assay testing: 
o Initially, a qPCR analysis will be performed on the swab 
sample to evaluate whether the talimogene laherparepvec 
DNA is detectable in the sample:  
i. 
If result of the qPCR testing is negative, TCID50 assay 
testing is not required 
ii. 
If the result of the qPCR testing is positive, then a 
TCID50 assay will be performed on the swab sample to 
assess viral infectivity 
- Arm 1:  genital swabs for qPCR and TCID50 assay testing is 
required if talimogene laherparepvec is injected into a 
melanoma lesion below the waist: 
o Initially, a qPCR analysis will be performed on the swab 
sample to evaluate whether the talimogene laherparepvec 
DNA is detectable in the sample:  
i. 
If result of the qPCR testing is negative, TCID50 assay 
testing is not required 
ii. 
If the result of the qPCR testing is positive, then a 
TCID50 assay will be performed on the swab sample to 
assess viral infectivity 
 
 
Add: 
• 
Documentation of subsequent anticancer therapy for melanoma 
(including local, regional, or systemic therapy) 
 
 
Section: 
7.2.4  Long-term Follow-up 
 
 
Add: 
All randomized subjects will be contacted by telephone, or clinic visit, 
to assess survival status, collect adverse events deemed by the 
investigator to be potentially related to talimogene laherparepvec 
(Arm 1 only), and, if applicable, commencement of any subsequent 
anticancer melanoma therapy. 
 
 
Add: 
Radiographic tumor imaging, clinical tumor assessments, and tumor 
response assessments, will be performed as documented in 
Section 7.2.2 every 3 months (±30 days) for 3 years following the 
safety follow-up visit and then every 6 months (±30 days) until distant 
disease recurrence, death, subject withdraws full consent, or up to 
5 years after the last subject is randomized, whichever is first.  Local 
and regional recurrences will be reported until appearance of 
distant recurrence, or end of study, whichever is first.  Local 
recurrence is defined as histologically or cytologically confirmed 
reappearance of melanoma in the area of up to 2 cm from the scar 
from the surgical excision or at the edge of the skin graft if that 
was used for closure.  Regional recurrence (excludes local 
recurrence) is defined as histologically, cytologically, or 
radiographically confirmed reappearance of melanoma in the 
regional lymph node basin.  New in-transit melanoma metastases 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 18 of 25 
CONFIDENTIAL 
 
 
in the regional lymphatic drainage will be reported as regional 
recurrence.  Histological or cytological confirmation of new 
in-transit metastases is recommended but is not required.  
Distant metastases exclude local and regional recurrence and will 
include distant cutaneous/subcutaneous metastases, distant 
nodal metastases, or visceral, central nervous system, brain, or 
bone metastases. 
 
 
Add: 
After the long-term follow-up period of this study has ended, subjects 
randomized to Arm 1 who received at least a single dose of 
talimogene laherparepvec and 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. 
 
 
Add: 
The registry protocol will also monitor for late and long-term adverse 
events thought to be potentially related to talimogene laherparepvec 
and use of subsequent anticancer therapy for melanoma.  
Subjects who after the long-term follow-up period of this study 
(20110266) will elect to participate in the registry study must sign 
new informed consent form before any registry protocol-specific 
activities.   
 
 
Section: 
7.3.1  Blood Samples 
 
 
Add: 
Blood samples are to be collected for biomarker development at time 
points designated in the Schedule of Assessments (Table 2 and 
Table 3) and as described in Section 7.2.2. 
 
 
Section: 
9.3  Pregnancy and Lactation Reporting 
 
 
Replace: 
The pregnancy should be reported to Amgen’s global Pregnancy 
Surveillance Program 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 Pregnancy Surveillance 
Program will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
 
 
With: 
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).   
 
 
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). 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 19 of 25 
CONFIDENTIAL 
 
 
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). 
 
 
Section: 
10.1.1.1  Primary Endpoint 
 
 
Add: 
• 
Recurrence-Free Survival (RFS):  RFS is defined as time from 
randomization to the date of the first of local, regional, or distant 
recurrence of melanoma or death due to any cause. 
 
 
Section: 
10.1.1.2  Secondary Endpoint, bullets 1, 4, 5, and 6 
 
 
Add: 
• 
2-year, 3-year, 5-year RFS:  The Kaplan-Meier (K-M) estimate of 
RFS rate at 2 years, 3 years and 5 years 
 
 
Add: 
Local recurrence is defined as histologically or cytologically confirmed 
reappearance of melanoma in the in the area of up to 2 cm from the 
scar from the surgical excision 
 
 
Add: 
• 
Regional recurrence-free survival (RRFS):  Time from 
randomization to the date of the first of regional disease 
recurrence or death due to any cause.  Regional recurrence 
excludes local recurrence and is defined as histologically, 
cytologically, or radiographically confirmed reappearance of 
melanoma in the regional lymph node basin.  New in-transit 
melanoma metastases in the regional lymphatic drainage will 
be reported as regional recurrence.  Histological or cytological 
confirmation of new in-transit metastases is recommended 
but is not required. 
 
 
Add: 
• 
Distant metastases free survival (DMFS):  Time from 
randomization to the date of the first of distant metastases or 
death due to any cause.  Distant metastases exclude local 
and regional recurrence and will include distant 
cutaneous/subcutaneous metastases, distant nodal 
metastases, or visceral, central nervous system, brain, or 
bone metastases. 
 
 
Section: 
10.1.3  Covariates and Subgroups, bullet 5 
 
 
Delete: 
• 
The sum of the products of the two largest perpendicular diameters 
of baseline measurable lesions (SPD) 
 
 
Section: 
10.2  Sample Size Considerations, paragraphs 2, 3, and 4 
 
 
Replace: 
Approximately 150 subjects will be randomized 1:1 to receive arm 1 vs 
arm 2 stratified by:  (i) disease stage (IIIB nodal vs IIIB in-transit vs IIIC 
nodal vs IIIC in-transit with nodal vs IVM1a), and (ii) planned adjuvant 
therapy (INFα with or without radiotherapy vs radiotherapy without 
INFα vs none).   


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 20 of 25 
CONFIDENTIAL 
 
 
 
 
With: 
Approximately 150 subjects will be randomized 1:1 to receive Arm 1 vs 
Arm 2 stratified by:  (i) disease stage (IIIB nodal vs IIIB in-transit vs IIIC 
nodal vs IIIC in-transit with nodal vs IVM1a), and (ii) planned adjuvant 
therapy (adjuvant systemic therapy [eg, INFα, ipilimumab] with or 
without radiotherapy vs radiotherapy without adjuvant systemic 
therapy vs none. 
 
 
Add: 
Subjects who are not confirmed to be disease-free post-surgery (ie, 
who do not have an R0 surgical outcome) or who withdraw prior to 
surgery will be considered a failure at day after randomization for 
RFS. 
 
 
Add: 
The primary analysis for the primary endpoint will occur at the later 
time of either the occurrence of approximately 64 events (local, 
regional, or distant recurrence of 
 
 
Section: 
Table 5.  Study Design Characteristics, 2-year RFS, Arm 1 
 
 
Replace: 
0.60 
 
 
With: 
0.70 
 
 
Add: 
0.725, 0.750 
 
 
Section: 
Table 5.  Study Design Characteristics, 2-year RFS, Arm 2 
 
 
Replace: 
0.70 
 
 
With: 
0.60 
 
 
Delete: 
0.725, 0.750 
 
 
Section: 
10.3  Access to Individual Subject Treatment Assignments by Amgen 
or Designees 
 
 
Delete: 
To guard against actual or perceived bias due to subjective decisions 
made by Amgen or designees in light of the treatment knowledge and 
data captured during the study, Amgen will implement a Trial Integrity 
Document (TID).  The TID will include study-specific guidelines to 
restrict access to aggregate postbaseline data by randomized or 
received treatment until the primary analysis.  Details of which sponsor 
staff or designees can access the data and their level of access will be 
provided in the TID.  Amgen will finalize the TID before the first subject 
is randomized in the study. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 21 of 25 
CONFIDENTIAL 
 
 
Section: 
10.4.1  Interim Analyses 
 
 
Add: 
A Data Review Team (DRT) independent of the talimogene 
laherparepvec product team will review the first interim analysis 
(see Section10.4.2).  The DRT will also review some efficacy 
endpoints (eg, R0 resection rate, pCR rate, response to 
neoadjuvant treatment). 
 
The talimogene laherparepvec product team will review the 
second interim analysis because it will occur after all subjects 
have been already treated, have completed safety follow-up, and 
no additional interventions that may influence safety or efficacy 
of the investigational product are planned after this time point.  
The talimogene laherparepvec product team will also review 
some efficacy endpoints (eg, R0 resection rate, pCR rate, 
response to neoadjuvant treatment). 
 
Ad hoc analyses for safety or some efficacy endpoints (eg, 
response to neoadjuvant treatment, R0 resection rate, pCR rate) 
may be conducted before the planned primary and/or final 
analyses if interim data are required for submission to regulatory 
authorities.  These ad hoc analyses will be executed by the 
talimogene laherparepvec product team. 
 
 
Section: 
10.4.2  Data Review Team (DRT) 
 
 
Delete: 
A Data Review Team (DRT) independent of the talimogene 
laherparepvec product team will be formed.   
 
 
Add: 
The DRT will be supported by a statistician internal to Amgen but 
independent of the talimogene laherparepvec product team.  This 
teamThe DRT will review unblinded safety data at the first interim 
analysis.   
 
 
Section: 
10.4.3  Primary Analysis 
 
 
Add: 
The primary analyses for RFS will occur at the later time of either the 
occurrence of approximately 64 events (local, regional, or distant 
recurrence of melanoma or death) or 
 
 
Section: 
10.5.3  Secondary Efficacy Endpoints 
 
 
Add: 
KM estimates will be calculated for RFS, LRFS, RRFS, DMFS, OS 
landmarks (2-, 3- and 5-year rates) and quartiles. 
 
 
Add: 
For each group the equal-precision band method will be used to 
calculate a simultaneous confidence band for RFS, LRFS, RRFS, and 
DMFS over the interval from 2 to 5 years (Nair, 1984).  An overall 
between-group difference in RFS, LRFS, RRFS, DMFS, and OS will 
be 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 22 of 25 
CONFIDENTIAL 
 
 
Section: 
10.5.4  Safety Endpoints 
 
 
Delete: 
The incidence of subjects with positive qPCR analysis result of 
talimogene laherparepvec DNA in blood and urine samples will be 
calculated.  The incidence of subjects with positive qPCR analysis 
result of talimogene laherparepvec DNA and positive TCID50 assay 
analysis result of talimogene laherparepvec viral infectivity in oral 
mucosa and genital swab samples, respectively, will be calculated. 
 
 
Section: 
13  References 
 
 
Add: 
Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al.  Adjuvant 
ipilimumab versus placebo after complete resection of high-risk 
stage III melanoma (EORTC 18071): a randomized, double-blind, 
phase 3 trial.  Lancet Oncol.  2015;16:522-530. 
 
 
Add: 
Imlygic™ (talimogene laherparepvec) Prescribing Information, 
Amgen Europe B.V, 2015. 
 
 
Add: 
Summary of Imlygic™ Product Characteristics, Amgen Europe 
B.V, 2015. 
 
 
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. 
Woburn, MA. BioVEX (a wholly owned subsidiary of Amgen); 2015. 
 
 
Add: 
Yervoy™ (ipilimumab) Prescribing Information, Bristol-Myers 
Squibb, 2015. 
 
 
Section: 
Appendix D  World Health Organization (WHO) Response Criteria 
 
 
Add: 
Modified World Health Organization (WHO) Response Criteria 
 
 
Replace: 
(Note:  When a lesion can be evaluated by both, clinical examination 
and imaging, radiographic imaging evaluations should be undertaken 
since it is more objective). 
 
 
With: 
(Note:  When a lesion can be evaluated by both, clinical examination 
and imaging, radiographic imaging evaluations should be preferred 
since it is more objective). 
 
 
Add: 
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 in at least 2 dimensions is: 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 23 of 25 
CONFIDENTIAL 
 
 
Add: 
Coalescing or Splitting Lesions: 
Coalescing lesions:  When two or more lesions merge and at 
least one is an index lesion, the largest index lesion prior to 
merging should be measured and reported during the tumor 
response assessment.  All other merged lesions should be 
reported as 0 mm x 0 mm (for lesions previously reported as 
Index or New Measurable Lesions) or absent (for lesions 
previously reported as Non-Index or New Non-Measurable 
Lesions).  If two or more non-index lesions merge, the apparently 
larger lesion should be reported as present, and smaller lesion(-s) 
should be reported as absent.  The indication that the lesion 
coalesced with the specified lesion(-s) should be provided for 
each merged lesion. 
Splitting lesions:  When an index lesion splits into two or more 
lesions the largest measurable part of the split lesion will be 
measured for the current assessment with the indication that the 
lesion split from the specified lesion, and followed for future 
assessments.  The remaining lesions will be measured as new 
lesions with an indication that the lesion split from the specified 
lesion.  In this case, appearance of a new lesion from a previous 
lesion that split will not
When an non-index lesion splits into two or more lesions, the 
apparently larger lesion will be reported as a non-index lesion.  
All other smaller lesions will be reported as new non-index 
lesions with an indication that the lesion split from the specified 
lesion.  In this case, appearance of a new lesion from a previous 
lesion that split 
 be considered disease progression solely 
due to appearance of a new lesion (may be considered 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). 
will not
 
 be considered disease progression solely 
due to appearance of a new lesion (may be considered 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). 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 24 of 25 
CONFIDENTIAL 
 
 
Section: 
Baseline Documentation of “Index Lesions”: 
 
Add: 
The sum of the products of the largest perpendicular diameters of 
all index lesions will be calculated and reported. 
 
If a subject has multiple small superficial cutaneous melanoma 
lesions at baseline (each lesions is less than 10 mm in at least 
2 dimensions) which in aggregate have a total diameter of 
≥ 10 mm in at least 2 dimensions, up to 10 largest lesions that 
were included in this measurement will be reported as ”Index 
Lesions”, and the sum of the products of the two largest 
perpendicular diameters of these lesions will be calculated and 
reported for tumor response assessments. 
 
 
Delete: 
The sum of the products of the two largest of perpendicular diameters 
(SPD) of all index lesions will be calculated and reported. 
 
 
Section: 
Follow-up “Index Lesions”: 
 
Replace: 
At each subsequent tumor assessment, the SPD of the index lesions 
are added together to provide the total tumor burden. 
 
 
With: 
At each subsequent tumor assessment, the sum of the products of 
the two largest perpendicular diameters of the index lesions are 
added together to provide the total tumor burden. 
 
 
Section: 
Follow-up “New Lesions”: 
 
Delete: 
At each subsequent tumor assessment, if new measurable lesions 
have appeared they 
 
 
Add: 
At tumor assessment, if new measurable lesions have appeared they 
should be added to sum of the products of the two largest 
perpendicular diameters SPD of the index lesions to provide the total 
tumor burden.  For nonmeasurable new lesion they should be followed 
as nonindex lesion as “present”, “absent”, or in rare cases 
“unequivocal progression”.  If a new lesion(s) that appears in 
between scheduled tumor response assessments disappear(s) 
before the next scheduled assessment, there is no need to 
include this lesion for tumor response evaluation.  
 
 
Section: 
Appendix D, Table 1 Definition of Index Lesion Tumor Response 
Including New Measurable Lesions 
 
 
Replace: 
Achieving a 50% or greater reduction in the SPD of the perpendicular 
diameters of all index lesions and new measurable lesions, if 
applicable, at the time of assessment as compared to the sum of the 
products of the perpendicular diameters of all index lesions at 
baseline. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  22 April 2016 
Page 25 of 25 
CONFIDENTIAL 
 
 
With: 
Achieving a 50% or greater reduction in the sum of the products of 
the two largest perpendicular diameters of all index lesions and 
new measurable lesions, if applicable, at the time of assessment as 
compared to the sum of the products of the perpendicular diameters of 
all index lesions at baseline. 
 
 
Replace: 
A > 25% increase in the sum of the products of the perpendicular 
diameters of all index tumors and new measurable lesions, if 
applicable, since baseline. 
 
 
With: 
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 measurable lesion since the last response 
assessment time point. 
 
 
Section: 
Appendix D, Table 2  Definition of Nonindex Lesion Tumor Response 
Including New Nonmeasurable Lesions, footnote 
 
 
Add: 
CR = complete response; SD = stable disease; PD = disease 
progression; UE = unable to evaluate; NA = not applicable;  
ND = not done. 
 
 
Section: 
Appendix D, Table 3 Matrix for Determining the Overall Response at 
Each Assessment Point, footnote 
 
 
Delete: 
PD = disease progression 
 
 
Section: 
Appendix F Surgery Guidelines 
 
 
Add: 
The decisions to perform surgery on subjects with stage IIIB, IIIC or IV 
M1a melanoma (dermal, subcutaneous or non-regional lymph node 
metastases) is a complex clinical decision making process that 
must be based on good clinical judgment that may include 
consulting with other relevant medical specialities, and 
considering patient’s preferences. 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 1 of 25 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 2, Multicenter, Randomized, Open-label Trial Assessing 
the Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus 
Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma 
 
Amgen Protocol Number 20110266 
 
Amendment Date: 
31 March 2016 
 
Rationale: 
The key protocol changes are:  
• 
Secondary objective 
An objective of regional recurrence-free survival (RRFS) was added to the following 
secondary objective “To estimate the effect of neoadjuvant talimogene laherparepvec 
plus surgery compared to surgery alone on local recurrence-free survival (LRFS) and 
distant metastases-free survival (DMFS)” to better characterize patterns of recurrences 
of melanoma, which include not only local and distant, but also regional recurrences.  
• 
Secondary endpoint 
Regional recurrence-free survival was added to the secondary endpoints in parallel to 
this addition to the secondary objective. 
• 
Distant metastases free survival  
The efficacy endpoint of DMFS was clarified by specifying what DMFS includes and 
excludes. 
• 
Adjuvant ipilimumab information 
Information on adjuvant ipilimumab use was added to the Introduction because 
ipilimumab was recently approved by the United States Food and Drug Administration 
(FDA) for the adjuvant treatment of patients with cutaneous melanoma with pathologic 
involvement of regional lymph nodes of more than 1 mm who have undergone complete 
resection, including total lymphadenectomy. 
• 
Marketing information on talimogene laherparepvec 
Marketing information on talimogene laherparepvec (Imlygic™) was added to the 
Introduction to update the background section because it was recently approved by 
regulatory authorities for specified indications in the US, Europe, and Australia. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 2 of 25 
CONFIDENTIAL 
 
 
• 
Randomization stratification 
Stratification by adjuvant interferon use was replaced with adjuvant systemic therapy to 
include interferon alpha (INFα) and ipilimumab since ipilimumab has been FDA 
approved to reduce the risk of melanoma returning after surgery and other systemically 
active therapy may also be approved for this indication. 
• 
Number of sites 
The number of sites was changed from 40 to 50 to achieve the enrollment goal. 
• 
Safety follow-up 
The 30-day safety follow-up was modified to specify that subjects will be followed for 
local, regional, and distant disease recurrence and for melanoma and adverse events 
thought to be potentially related to talimogene laherparepvec to align with the schedule 
of assessment in the Registry Study 20120139.  The protocol was also changed to 
specify that subjects who participate in 20120139 must sign a new informed consent 
form. 
• 
Measurable disease inclusion criterion  
Inclusion criterion 106 was clarified to specify that the measurement of the lesion 
diameter “in at least 2 dimensions” is ≥ 10 mm to align with other talimogene 
laherparepvec studies.  Also, measurement using ultrasound for superficial lymph nodes 
and subcutaneous lesions was added. 
• 
Serum lactate dehydrogenase (LDH) level inclusion criterion 
Inclusion criterion 108 was changed as follows:  Serum LDH level ≤ 1.5 x upper limit of 
normal (ULN) for stages IIIB and IIIC melanoma and ≤ 1.0 x ULN for Stage IVM1a 
melanoma within 28 days prior to randomization, since LDH is not a staging component 
for Stage III melanoma. 
• 
Serum albumin inclusion criterion 
Inclusion criterion 109 was modified to include serum albumin ≥ 2.5 g/dL to align with 
other talimogene laherparepvec studies. 
• 
Autoimmune disease exclusion criterion  
Exclusion criterion 204 was expanded to clarify symptomatic autoimmune disease to 
align with the same criterion in other talimogene laherparepvec monotherapy studies. 
• 
Clinically significant immunosuppression 
The definition of clinically significant immunosuppression was updated in exclusion 
criterion 205 to align with other talimogene laherparepvec monotherapy studies. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 3 of 25 
CONFIDENTIAL 
 
 
• 
Tumor vaccine exclusion criterion 
Exclusion criterion 212 (prior therapy with tumor vaccine) was deleted to align with other 
talimogene laherparepvec monotherapy studies. 
• 
Viral transmission during sexual contact exclusion criterion 
The criterion (216) to exclude sexually active subjects and their partners unwilling to use 
male or female latex condoms to avoid potential viral transmission during sexual contact 
was added as a condition of marketing approval and to align with other talimogene 
laherparepvec studies. 
• 
Talimogene laherparepvec vials 
Each vial contains a minimum of 1.0 mL talimogene laherparepvec at either 106 PFU/mL 
or 108 PFU/mL concentrations.  The description of the two vial concentrations as green 
cap and blue cap, respectively, were deleted since they no longer apply.  
• 
Treatment procedures 
The following statement was added to stress the need to report adjuvant therapies, if 
planned, via Interactive Voice Response (IVR):  If adjuvant therapy (systemic and/or 
radiation therapy; approved or investigational) is planned, this should be reported via 
IVR at randomization. 
• 
Reporting of potentially talimogene laherparepvec related adverse events 
during long-term follow-up 
Adverse events deemed by the investigator to be potentially related to talimogene 
laherparepvec (Arm 1 only) and use of subsequent anticancer therapy for melanoma will 
be collected during long-term follow-up to align this protocol with all other talimogene 
laherparepvec studies. 
• 
Activated PTT  
Activated thromboplastin time was added as an alternative to PTT in screening 
laboratory tests because it may be an alternative test of choice for testing coagulation. 
• 
Physical examination and ECOG performance status 
Required physical examination and ECOG performance status was added at weeks 4 
and 8 to report any change in a patient’s performance status. 
• 
Oral and genital swabbing after surgery 
Oral and genital swabbing for real-time polymerase chain reaction (qPCR) and 50% 
Tissue Culture Infective Dose (TCID50) assay testing was removed from the safety 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 4 of 25 
CONFIDENTIAL 
 
 
follow-up visit because identical information is currently being collected in 
Study 20120324.  
• 
Safety Follow-up procedures 
Surgical safety evaluation and recording of subsequent anticancer therapy for melanoma 
were added to safety follow-up procedures to align the schedule of assessment in the 
Registry Study 20120139. 
• 
Pregnancy and lactation reporting 
Reference to Amgen’s global Pregnancy and Lactation Surveillance Programs was 
deleted and replaced by Amgen Global Patient Safety to align with current company 
practice. 
• 
Statistical considerations 
RRFS analysis was added to meet the addition of RRFS to the secondary objectives. 
The protocol was modified to clarify that a DRT will review the first interim analysis and 
the talimogene laherparepvec product team will review the second interim analysis, 
since the second analysis will be performed after all subjects in Arm 1 have been 
enrolled.  The DRT and talimogene laherparepvec product team will also review some 
efficacy endpoints (eg, R0 resection rate, pCR rate, response to neoadjuvant treatment). 
Ad hoc analyses, executed by the talimogene laherparepvec product team, for safety or 
some efficacy endpoints may be conducted before the planned primary or final analyses 
if interim data are required for submission to regulatory authorities. 
• 
Sample size 
In the statement regarding subjects who are not confirmed to be disease-free 
post-surgery or who withdraw prior to surgery, failure was changed from at 
randomization to “a day after randomization” for RFS.  With this change, the number of 
subjects at risk at the earliest possible time (randomization +1 day) would not change 
due to non-melanoma subjects, and would reduce the impact on the Cox model, 
Kaplan-Meier, and log-rank test results. 
• 
Trial integrity document 
The mention of using a Trial Integrity Document was deleted to comply with current 
standard operating procedures.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 5 of 25 
CONFIDENTIAL 
 
 
• 
Index lesions 
Language was added to Appendix D (documentation of index lesions) to clarify the 
recording of aggregate lesions and to align with other talimogene laherparepvec 
monotherapy studies. 
• 
Definition of progressive disease for measurable disease  
The definition of progressive disease (PD) was changed to clarify that PD includes the 
unequivocal appearance of a new measurable lesion since the last response 
assessment time point, to align with other talimogene laherparepvec studies. 
• 
Appendix F 
Appendix F was modified to state that the decision to perform surgery may include 
consulting with other relevant medical specialties and consideration of a patient’s 
preferences, to provide guidance on the decision making process of resection of 
melanoma. 
• 
Administrative 
Minor text clarifications, additions, and corrections as well as typographical and 
formatting changes were made throughout the protocol.  The key sponsor contact 
information was updated to align with current personnel and the talimogene 
laherparepvec Investigator Brochure reference was updated to the current version.  New 
references were added as needed for newly added text. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 6 of 25 
CONFIDENTIAL 
 
 
Description of Changes (all changes to the Protocol are indicated in bold text) 
 
Section: 
 
All applicable sections and header 
 
 
Replace:   
09 June 2014 
 
 
With: 
31 March 2016 
 
 
Replace: 
end point 
 
 
With: 
endpoint 
 
 
Replace: 
arm 1, arm 2 
 
 
With: 
Arm 1, Arm 2 
 
 
Replace: 
(Talimogene Laherparepvec Investigator’s Brochure, 2014) 
 
 
With: 
(Talimogene Laherparepvec Investigator’s Brochure, 2015) 
 
 
Section 
Cover page 
 
Replace: 
PhD, MD 
Clinical Research Senior Medical Scientist 
 
With: 
 MD, PhD  
Clinical Research Medical Director 
 
Replace: 
Clinical Research Study Manager 
Amgen Limited 
1 Sanderson Road (Uxbridge Business Park) 
Uxbridge, UB8 1DH 
Telephone
Email:
 
 
With: 
Clinical Research Study Manager 
Amgen Limited 
1 Sanderson Road (Uxbridge Business Park) 
Uxbridge, UB8 1DH 
Telephone:
Email:
 
 
Add: 
Amendment 2 Date     31 March 2016 
 
 
Section: 
Protocol Synopsis, Secondary Objectives, bullet 4 
 
 
Add: 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec 
plus surgery compared to surgery alone on local recurrence-free 
survival (LRFS), regional recurrence-free survival (RRFS), and 
distant metastases-free survival (DMFS) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 7 of 25 
CONFIDENTIAL 
 
 
 
 
Section: 
Protocol Synopsis, Secondary Endpoints, bullet 5 
 
 
Add: 
• 
RRFS 
 
 
Section: 
Synopsis, Study Design 
 
 
Replace: 
Randomization will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a), planned adjuvant therapy (interferon alpha [INFα] with or 
without radiotherapy versus radiotherapy without INFα versus none). 
 
 
With: 
Randomization will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a), planned adjuvant therapy (adjuvant systemic therapy [eg, 
interferon alpha (INFα), ipilimumab] with or without radiotherapy 
versus radiotherapy without adjuvant systemic therapy versus none). 
 
 
Add: 
Subjects will be followed for safety approximately 30 (+15) days after 
surgery and for disease recurrence (local, regional, or distant), 
subsequent anticancer therapy for melanoma, adverse events 
thought to be potentially related to talimogene laherparepvec 
(Arm 1 only), and survival every 3 months (±30 days) for first 3 years 
after the end of the safety follow-up period and then every 6 months 
(±30 days) until death, subject withdraws full consent, or up to 5 years 
after the last subject is randomized.  Thereafter, subjects randomized 
to Arm 1 who received at least a single dose of talimogene 
laherparepvec 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 
subsequent anticancer therapy for melanoma.  Subjects who after 
the long-term follow-up period of this study (Study 20110266) will 
elect to participate in the registry study must sign new informed 
consent form before any registry protocol-specific activities. 
 
 
Section: 
Synopsis, Key Inclusion Criteria 
 
 
Replace: 
Also, subject must have an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1 and must have a serum lactate 
dehydrogenase (LDH) ≤ 1.0 X upper limit of normal and adequate 
hematologic, hepatic, renal, and coagulation organ function. 
 
 
With: 
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 (ULN) for stages 
IIIB/C melanoma and LDH ≤1.0 x ULN for stage IVM1a melanoma 
and adequate hematologic, hepatic, renal, and coagulation organ 
functions. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
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Page 8 of 25 
CONFIDENTIAL 
 
 
Section: 
Synopsis, Key Exclusion Criteria 
 
 
Replace: 
Subject must not have history or evidence of symptomatic autoimmune 
pneumonitis, glomerulonephritis, vasculitis, or other symptomatic 
autoimmune disease.   
 
 
With: 
Subject must not have 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. 
 
 
Delete: 
Subject must not have been treated previously with talimogene 
laherparepvec or tumor vaccine. 
 
 
Section: 
Synopsis, Procedures, Screening, bullets 3 and 4 
 
 
Delete: 
demographics, physical examination, vital signs, and ECOG 
performance status assessment 
 
 
Add: 
local laboratory tests including, hematology panel, chemistry panel, 
serum LDH, prothrombin time (PT) (or international normalization ratio 
[INR]) and partial thromboplastin time (PTT) (or activated PTT), and 
serum or urine pregnancy test for female subjects of childbearing 
potential 
 
 
Section: 
Synopsis, Procedures, Treatment, bullets 2, 3, and 8 
 
 
Add: 
• 
ECOG performance status 
 
 
Add: 
• 
physical examination 
 
 
Add: 
histological tumor assessment of the surgical specimen, including 
assessment for tumor-free margins (R0 resection for negative 
margins, R1 or R2 resections for tumor positive margins) and 
pathological complete response (in Arm 1 only) 
 
 
Section: 
Synopsis, Procedures, Safety Follow-up Visit, bullets 2, 3, and 5 
 
 
Add: 
• 
surgical safety evaluation 
 
 
Add: 
• 
documentation of subsequent anticancer therapy for 
melanoma (including local, regional, or systemic therapy) 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 9 of 25 
CONFIDENTIAL 
 
 
Replace: 
• 
central laboratory tests including blood and urine for qPCR, oral 
mucosa swabs and genital swabs (if study drug is injected into a 
melanoma lesion below the waist) for qPCR and 50% Tissue 
Culture Infective Dose (TCID50) assay testing, and swabs of cold 
sores, vesicles, and other lesions suspected to be herpetic in origin 
(if any) for qPCR testing within 24 hours following the investigator’s 
knowledge of the event  
 
 
With: 
• 
central laboratory tests of swabs of cold sores, vesicles, and other 
lesions suspected to be herpetic in origin (if any) for qPCR testing 
of talimogene laherparepvec DNA within 24 hours following the 
investigator’s knowledge of the event  
 
 
Section: 
Synopsis, Procedures, Long-term Follow-up, paragraphs 1, 2, and 3 
 
 
Add: 
All randomized subjects will be contacted by telephone, or clinic visit, 
to assess survival status, collect adverse events deemed by the 
investigator to be potentially related to talimogene laherparepvec 
(Arm 1 only), and, if applicable, commencement of any subsequent 
anticancer melanoma therapy (including local, regional, or systemic 
therapy for melanoma). 
 
 
Add: 
every 3 months (±30 days) for 3 years following the safety follow-up 
visit and then every 6 months (±30 days) until distant disease 
recurrence, death, 
 
 
Add: 
After the long-term follow-up period of this study has ended, subjects 
randomized to Arm 1 who received at least a single dose of 
talimogene laherparepvec and who end the study for any reason 
other than death or withdrawal of full consent will be followed for 
survival under an 
 
 
Add: 
The registry protocol will also monitor for late and long-term adverse 
events thought to be potentially related to talimogene laherparepvec 
and use of subsequent anticancer therapy for melanoma.  
Subjects who after the long-term follow-up period of this study 
(Study 20110266) will elect to participate in the registry study 
must sign new informed consent form before any registry 
protocol-specific activities. 
 
 
Section: 
Synopsis, Statistical Considerations paragraphs 1, 2, 3, 5, and 6 
 
 
Add: 
The primary analysis for the primary endpoint will occur at the later 
time of either the occurrence of approximately 64 events (local, 
regional, or distant recurrence of melanoma or death) or 
approximately 2 years after the end of randomization. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 10 of 25 
CONFIDENTIAL 
 
 
Replace: 
Two interim analyses with no formal stopping rules are planned to 
evaluate safety when approximately 40 and 75 subjects randomized to 
talimogene laherparepvec have had the opportunity to complete the 
safety follow-up visit.  The primary analysis for certain secondary 
endpoints will be performed using the data from the second interim 
analysis. 
 
 
With: 
Two interim analyses with no formal stopping rules are planned to 
evaluate safety and some efficacy endpoints (eg, R0 resection 
rate, pCR rate, response to neoadjuvant treatment) when 
approximately 40 and 75 subjects randomized to talimogene 
laherparepvec have had the opportunity to complete the safety follow-
up visit.  The primary analysis for certain secondary endpoints (eg, 
response to neoadjuvant treatment, R0 resection rate, pCR rate, 
and safety) will be performed using the data from the second interim 
analysis. 
 
 
Add: 
The primary analyses for RFS will occur at the later time of either 
the occurrence of approximately 64 events (local, regional, or 
distant recurrence of melanoma or death) or approximately 2 
years after end of randomization. 
 
 
Add: 
Ad hoc analyses for safety or some efficacy endpoints (eg, 
response to neoadjuvant treatment, R0 resection rate, pCR rate) 
may be conducted before the planned primary and/or final 
analyses if interim data are required for submission to regulatory 
authorities. 
 
 
Add: 
All efficacy analyses will be descriptive with no formal hypothesis 
testing.  Kaplan-Meier (KM) estimates and CI will be calculated for 
RFS, LRFS, RRFS, DMFS, OS landmarks (2-, 3- and 5-year rates) 
and quartiles.  Estimates and CIs for between-group differences will 
also be calculated.  An overall between-group difference in RFS, 
LRFS, RRFS, DMFS, and OS will be 
 
 
Section: 
Study Glossary, definition of end of study (primary completion) 
 
 
Add: 
The primary completion is anticipated to occur at the later time of 
either occurrence of approximately 64 events (local, regional, or 
distant recurrence of melanoma or death) or approximately 2 years 
after the end of randomization 
 
 
Add: 
RRFS - regional recurrence-free survival 
 
 
Delete: 
TCID50 - 50% Tissue Culture Infective Dose 
TID - Trial Integrity Document 
SPD - the sum of the products of the two largest perpendicular 
diameters 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 11 of 25 
CONFIDENTIAL 
 
 
Section: 
1.2  Secondary, bullet 4 
 
 
Add: 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec 
plus surgery compared to surgery alone on local recurrence-free 
survival (LRFS), regional recurrence-free survival (RRFS), and 
distant metastases-free survival (DMFS) 
 
 
Section: 
2.1  Melanoma and Adjuvant and Neoadjuvant Therapy for Melanoma, 
paragraphs 2, 7, and 10 
 
 
Delete: 
While radical resection is a cornerstone of treatment for subjects with 
stages III melanoma  
 
 
Add: 
The biochemotherapy regimen was associated with substantial toxicity 
with grade 3 and 4 adverse events in 36% and 40% of subjects, 
respectively (Flaherty et al, 2012). 
 
 
Add: 
Recently, ipilimumab, a a cytotoxic lymphocyte associated 
antigen 4 (CTLA-4 inhibitor), was approved by the United States 
Food and Drug Administration for the adjuvant treatment of 
patients with cutaneous melanoma with pathologic involvement 
of regional lymph nodes of more than 1 mm who have undergone 
complete resection, including total lymphadenectomy (Yervoy™, 
2015).  This approval was based on results of a randomized 
double-blind phase 3 trial conducted in 951 patients with 
completely resected stage IIIA (> 1 mm nodal involvement), IIIB, 
and IIIC melanoma (EORTC 18071).  Patients with in-transit 
metastases were excluded.  Ipilimumab improved recurrence-free 
survival (primary endpoint) in this trial from 17.1 months to 26.1 
months (HR 0.75; 95% CI 0.64–0.90; p=0.0013).  Results of OS and 
distant metastasis-free survival (secondary endpoints) are 
pending.  Fifty-two percent of patients randomized to the 
ipilimumab arm discontinued treatment because of toxicity, 5 
patients (1%) died because of ipilimumab-related toxicities.  
Forty-six percent of patients in the ipilimumab arm experienced 
grade 3 adverse events (37% immune-related), and 8% grade 4 
(6% immune-related) (Eggermont et al, 2015). 
 
 
Section: 
2.2  Talimogene Laherparepvec Background, paragraphs 8 and 9 
 
 
Replace: 
Clinical data currently available have provided evidence of talimogene 
laherparepvec’s efficacy in subjects with regionally and distantly 
metastatic melanoma 
 
 
With: 
Clinical data currently available have provided evidence of talimogene 
laherparepvec’s efficacy in subjects with unresectable metastatic 
melanoma 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 12 of 25 
CONFIDENTIAL 
 
 
Add: 
Recently, talimogene laherparepvec (Imlygic™) was approved in 
the USA for the local treatment of unresectable cutaneous, 
subcutaneous, and nodal lesions in patients with melanoma 
recurrent after initial surgery (with limitation of use:  Imlygic has 
not been shown to improve overall survival or have an effect on 
visceral metastases) (Imlygic™ Prescribing Information, 2015), in 
Europe for the treatment of adults with unresectable melanoma 
that is regionally or distantly metastatic (stage IIIB, IIIC, and 
IVM1a) with no bone, brain, lung or other visceral disease 
(Imlygic™ Summary of Product Characteristics, 2015), and in 
Australia as monotherapy for the treatment of melanoma in 
patients with unresectable cutaneous, subcutaneous, or nodal 
lesions after initial surgery (Imlygic™ Prescribing Information, 
2015).  
 
 
Add: 
Refer to the latest version of Talimogene Laherparepvec 
Investigator’s Brochure for additional information. 
 
 
Section: 
2.3  Rationale, paragraph 3 
 
 
Delete: 
Additionally, a number of immune-related biomarkers, such as 
antibodies to melanoma antigens and expression of immune-
stimulatory and immune-inhibitory molecules (eg cytotoxic lymphocyte 
associated antigen 4 [CTLA-4], program cell death-1 [PD-1], program 
cell death-1 ligand 1 [PD-L1] and others) in tumors or tumor infiltrating 
T-cells will be assessed to determine any association with clinical 
outcomes. 
 
 
Section: 
3.1  Study Design, paragraphs 5 and 7 
 
 
Replace: 
Randomization will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a) and planned adjuvant therapy (INFα with or without 
radiotherapy versus radiotherapy without INFα versus none). 
 
 
With: 
Randomization will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a), planned adjuvant therapy (adjuvant systemic therapy [eg, 
INFα, ipilimumab] with or without radiotherapy versus radiotherapy 
without adjuvant systemic therapy versus none).  
 
 
Add: 
Subjects will be followed for safety approximately 30 (+15) days after 
surgery and for disease recurrence (local, regional, or distant), 
subsequent anticancer therapy for melanoma, adverse events 
thought to be potentially related to talimogene laherparepvec, and 
survival every 3 months (±30 days) for first 3 years after the end of the 
safety follow-up 
 
 
Add: 
laherparepvec will be followed under an ongoing separate registry 
protocol (Study 20120139) for the long-term survival follow-up of 
subjects treated with talimogene 
 
 


Product:  Talimogene Laherparepvec 
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Date:  31 March 2016 
Page 13 of 25 
CONFIDENTIAL 
 
 
Add: 
The registry protocol will also monitor for late and long-term adverse 
events thought to be potentially related to talimogene laherparepvec 
and use of subsequent anticancer therapy for melanoma.  
Subjects who after the long-term follow-up period of this study 
(Study 20110266) will elect to participate in the registry study 
must sign new informed consent form before any registry 
protocol-specific activities. 
 
 
Section: 
3.2  Number of Sites, paragraph 1 
 
 
Replace: 
The study will be conducted at approximately 40 sites in Australia, 
Brazil, United Kingdom, Russia, and USA.  Additional sites and 
countries may be added. 
 
 
With: 
The study will be conducted at approximately 50 sites in Australia, 
Brazil, Europe, Russia, and USA.  Additional sites and countries may 
be added. 
 
 
Section: 
3.5.1  Study Duration for Subjects 
 
 
Add: 
Subjects will be followed for safety approximately 30 (+15) days after 
surgery and for disease recurrence (local, regional, or distant), 
subsequent anticancer therapy for melanoma, adverse events 
thought to be potentially related to talimogene laherparepvec, and 
survival 
 
 
Section: 
3.5.2  End of Study 
 
 
Add: 
The primary completion is anticipated to occur at the later time of 
either the occurrence of approximately 64 events (local, regional, or 
distant recurrence of melanoma or death) or approximately 2 years 
after the end of randomization. 
 
 
Section: 
4.1.1  Inclusion Criterion, No. 106 
 
 
Replace: 
106      Measurable disease defined as one or more of the following: 
• 
at least one 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 for 
nodal/soft tissue disease (including lymph nodes)  
• 
at least one ≥ 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 
 
 


Product:  Talimogene Laherparepvec 
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Date:  31 March 2016 
Page 14 of 25 
CONFIDENTIAL 
 
 
With: 
106 
Measurable disease defined as one or more of the following: 
• 
at least one melanoma lesion that can be accurately and 
serially measured in at least 2 dimensions and for which the 
diameter in at least 2 dimensions is ≥ 10 mm as measured by 
contrast-enhanced or spiral computed tomography (CT) scan 
for nodal/soft tissue disease (including lymph nodes) or 
ultrasound for superficial lymph nodes and subcutaneous 
lesions 
• 
at least one superficial cutaneous or subcutaneous melanoma 
lesion as measured by calipers with diameter ≥ 10 mm in at 
least 2 dimensions 
• 
multiple superficial melanoma lesions which in aggregate have 
a total diameter of ≥ 10 mm in at least 2 dimensions 
 
 
Section: 
4.1.1  Inclusion Criterion, No. 108 
 
 
Replace: 
108  Serum LDH level ≤ 1.0 upper limit of normal (ULN) within 28 days 
prior to randomization 
 
 
With: 
108  Serum LDH level ≤ 1.5 x upper limit of normal (ULN) for stages 
IIIB and IIIC melanoma and ≤ 1.0 x ULN for stage IVM1a 
melanoma within 28 days prior to randomization  
 
 
Section: 
4.1.1  Inclusion Criterion, No. 109 
 
 
Add: 
• 
Hepatic 
− 
serum bilirubin ≤ 2.0 x ULN 
− 
serum albumin ≥ 2.5 g/dL 
− 
aspartate aminotransferase (AST) ≤ 2.5 x ULN 
 
• 
 
Section: 
4.1.2  Exclusion Criterion, No. 204 
 
 
Replace: 
204  History or evidence of symptomatic autoimmune pneumonitis, 
glomerulonephritis, vasculitis, or other symptomatic autoimmune 
disease 
 
 
With: 
204  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. 
 
 
Section: 
4.1.2  Exclusion Criterion, No. 205 
 
 
Replace: 
• 
receiving systemic immunosuppressive therapy (> 2 weeks 
prior to randomization), including oral steroid doses 
> 10 mg/day of prednisone or equivalent 
 
 


Product:  Talimogene Laherparepvec 
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Page 15 of 25 
CONFIDENTIAL 
 
 
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 Criterion, No. 212 
 
 
Delete: 
212 
Prior therapy with tumor vaccine 
 
 
Section: 
4.1.2  Exclusion Criterion, No. 216 
 
 
Add: 
216  Sexually active subjects and their partners unwilling to use 
male or female latex condoms to avoid potential viral 
transmission during sexual contact while on treatment and within 
30 days after treatment with talimogene laherparepvec 
 
 
Section: 
5.1  Randomization/Treatment Assignment 
 
 
Replace: 
The IVR system will assign a randomization number.  Approximately 
150 subjects will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a) and planned adjuvant therapy (INFα with or without 
radiotherapy versus radiotherapy without INFα versus none). 
 
 
With: 
The IVR system will assign a randomization number.  Approximately 
150 subjects will be stratified by disease stage (IIIB nodal versus IIIB 
in-transit versus IIIC nodal versus IIIC in-transit with nodal versus 
IVM1a) and planned adjuvant therapy (adjuvant systemic therapy 
[eg, INFα, ipilimumab] with or without radiotherapy versus 
radiotherapy without adjuvant systemic therapy versus none). 
 
 
Section: 
6.2.1  Amgen Investigational Product Talimogene Laherparepvec 
 
 
Delete: 
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. 
 
 
Section: 
6.5  Other Treatment Procedures 
 
 
Add: 
If adjuvant therapy (systemic and/or radiation therapy; approved 
or investigational) is planned, this should be reported via IVR at 
randomization. 
 
 
Section: 
7.1   Table 2.  Schedule of Assessments for Arm 1 (Talimogene 
Laherparepvec Plus Surgery) 
 
 
Add: 
Adverse Events Potentially Related to Treatment with Talimogene 
Laherparepvec 
X  under Long-term Follow-up 
 
 
Add: 
X under week 1, week 4, and week 8 for physical exam 
 
 
Add: 
X under week 4 and week 8 for ECOG performance status 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 16 of 25 
CONFIDENTIAL 
 
 
 
 
Add: 
Subsequent Anticancer Therapy for melanoma 
 
 
Delete: 
Blood and urine for qPCR 
 
 
Delete: 
Oral Mucosa Swab for qPCR and TCID50 Assay 
 
 
Delete: 
Genital Swab for qPCR and TCID50 Assay d 
 
 
Delete: 
dGenital swab sample is required if talimogene laherparepvec is 
injected into a melanoma lesion below the waist. 
 
 
Add: 
dSurgical specimens will be assessed for presence of viable 
tumor and tumor margin status for cutaneous and subcutaneous 
tumor; please refer to Section 7.2.2. 
 
 
Section: 
7.1  Table 3.  Schedule of Assessment for Arm 2 (Surgery Alone) 
 
 
Add: 
Subsequent Anticancer Therapy for Melanoma 
 
 
Add: 
d Surgical specimens will be assessed for presence of viable 
tumor and tumor margin status for cutaneous and subcutaneous 
tumor; please refer to Section 7.2.2.. 
 
 
Section: 
7.2  Table 4.  Laboratory Analytes 
 
 
Delete: 
TCID50 assay for talimogene laherparepvec viral infectivity 
 
 
Section: 
7.2.1  Screening and Randomization, bullet 10 
 
 
Delete: 
and CT scan or 
 
 
Section: 
7.2.2  Treatment 
 
 
Add: 
• 
Physical examination as per standard of care 
Arm 1:  within 3 days prior to talimogene laherparepvec administration 
on day 1 of week 1 and within 3 days prior to surgery, and prior to 
talimogene laherparepvec administration on day 1 of weeks 4 and 
8 
 
 
Add: 
• 
ECOG performance status 
− 
Arm 1:  prior to talimogene laherparepvec administration 
on day 1 of weeks 4 and 8 and within 3 days prior to the 
surgery  
 
 
Add: 
− 
A pathological complete response (pCR) in Arm 1 is 
defined as no evidence of viable tumor cells on complete 
pathological evaluation of the surgical specimen per 
institutional standards of care 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
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Page 17 of 25 
CONFIDENTIAL 
 
 
Section: 
7.2.3  Safety Follow-up Visit 
 
 
Delete: 
• 
Central laboratory assessments:  
- Arm 1:  blood and urine samples for qPCR analysis 
- Arm 1:  swab of oral mucosa for qPCR and 50% Tissue Culture 
Infective Dose (TCID50) assay testing: 
o Initially, a qPCR analysis will be performed on the swab 
sample to evaluate whether the talimogene laherparepvec 
DNA is detectable in the sample:  
i. 
If result of the qPCR testing is negative, TCID50 assay 
testing is not required 
ii. 
If the result of the qPCR testing is positive, then a 
TCID50 assay will be performed on the swab sample to 
assess viral infectivity 
- Arm 1:  genital swabs for qPCR and TCID50 assay testing is 
required if talimogene laherparepvec is injected into a 
melanoma lesion below the waist: 
o Initially, a qPCR analysis will be performed on the swab 
sample to evaluate whether the talimogene laherparepvec 
DNA is detectable in the sample:  
i. 
If result of the qPCR testing is negative, TCID50 assay 
testing is not required 
ii. 
If the result of the qPCR testing is positive, then a 
TCID50 assay will be performed on the swab sample to 
assess viral infectivity 
 
 
Add: 
• 
Documentation of subsequent anticancer therapy for melanoma 
(including local, regional, or systemic therapy) 
 
 
Section: 
7.2.4  Long-term Follow-up 
 
 
Add: 
All randomized subjects will be contacted by telephone, or clinic visit, 
to assess survival status, collect adverse events deemed by the 
investigator to be potentially related to talimogene laherparepvec 
(Arm 1 only), and, if applicable, commencement of any subsequent 
anticancer melanoma therapy. 
 
 
Add: 
Radiographic tumor imaging, clinical tumor assessments, and tumor 
response assessments, will be performed as documented in 
Section 7.2.2 every 3 months (±30 days) for 3 years following the 
safety follow-up visit and then every 6 months (±30 days) until distant 
disease recurrence, death, subject withdraws full consent, or up to 
5 years after the last subject is randomized, whichever is first.  Local 
and regional recurrences will be reported until appearance of 
distant recurrence, or end of study, whichever is first.  Local 
recurrence is defined as histologically or cytologically confirmed 
reappearance of melanoma in the area of up to 2 cm from the scar 
from the surgical excision or at the edge of the skin graft if that 
was used for closure.  Regional recurrence (excludes local 
recurrence) is defined as histologically, cytologically, or 
radiographically confirmed reappearance of melanoma in the 
regional lymph node basin.  New in-transit melanoma metastases 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 18 of 25 
CONFIDENTIAL 
 
 
in the regional lymphatic drainage will be reported as regional 
recurrence.  Histological or cytological confirmation of new in-
transit metastases is recommended but is not required.  Distant 
metastases exclude local and regional recurrence and will include 
distant cutaneous/subcutaneous metastases, distant nodal 
metastases, or visceral, central nervous system, brain, or bone 
metastases. 
 
 
Add: 
After the long-term follow-up period of this study has ended, subjects 
randomized to Arm 1 who received at least a single dose of 
talimogene laherparepvec and 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. 
 
 
Add: 
The registry protocol will also monitor for late and long-term adverse 
events thought to be potentially related to talimogene laherparepvec 
and use of subsequent anticancer therapy for melanoma.  
Subjects who after the long-term follow-up period of this study 
(20110266) will elect to participate in the registry study must sign 
new informed consent form before any registry protocol-specific 
activities.   
 
 
Section: 
7.3.1  Blood Samples 
 
 
Add: 
Blood samples are to be collected for biomarker development at time 
points designated in the Schedule of Assessments (Table 2 and 
Table 3) and as described in Section 7.2.2. 
 
 
Section: 
9.3  Pregnancy and Lactation Reporting 
 
 
Replace: 
The pregnancy should be reported to Amgen’s global Pregnancy 
Surveillance Program 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 Pregnancy Surveillance 
Program will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
 
 
With: 
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).   
 
 
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). 
 
 


Product:  Talimogene Laherparepvec 
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Page 19 of 25 
CONFIDENTIAL 
 
 
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). 
 
 
Section: 
10.1.1.1  Primary Endpoint 
 
 
Add: 
• 
Recurrence-Free Survival (RFS):  RFS is defined as time from 
randomization to the date of the first of local, regional, or distant 
recurrence of melanoma or death due to any cause. 
 
 
Section: 
10.1.1.2  Secondary Endpoint, bullets 1, 4, 5, and 6 
 
 
Add: 
• 
2-year, 3-year, 5-year RFS:  The Kaplan-Meier (K-M) estimate of 
RFS rate at 2 years, 3 years and 5 years 
 
 
Add: 
Local recurrence is defined as histologically or cytologically confirmed 
reappearance of melanoma in the in the area of up to 2 cm from the 
scar from the surgical excision 
 
 
Add: 
• 
Regional recurrence-free survival (RRFS):  Time from 
randomization to the date of the first of regional disease 
recurrence or death due to any cause.  Regional recurrence 
excludes local recurrence and is defined as histologically, 
cytologically, or radiographically confirmed reappearance of 
melanoma in the regional lymph node basin.  New in-transit 
melanoma metastases in the regional lymphatic drainage will 
be reported as regional recurrence.  Histological or cytological 
confirmation of new in-transit metastases is recommended 
but is not required. 
 
 
Add: 
• 
Distant metastases free survival (DMFS):  Time from 
randomization to the date of the first of distant metastases or 
death due to any cause.  Distant metastases exclude local 
and regional recurrence and will include distant 
cutaneous/subcutaneous metastases, distant nodal 
metastases, or visceral, central nervous system, brain, or 
bone metastases. 
 
 
Section: 
10.1.3  Covariates and Subgroups, bullet 5 
 
 
Delete: 
• 
The sum of the products of the two largest perpendicular diameters 
of baseline measurable lesions (SPD) 
 
 
Section: 
10.2  Sample Size Considerations, paragraphs 2, 3, and 4 
 
 
Replace: 
Approximately 150 subjects will be randomized 1:1 to receive arm 1 vs 
arm 2 stratified by:  (i) disease stage (IIIB nodal vs IIIB in-transit vs IIIC 
nodal vs IIIC in-transit with nodal vs IVM1a), and (ii) planned adjuvant 
therapy (INFα with or without radiotherapy vs radiotherapy without 
INFα vs none).   


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
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Page 20 of 25 
CONFIDENTIAL 
 
 
 
 
With: 
Approximately 150 subjects will be randomized 1:1 to receive Arm 1 vs 
Arm 2 stratified by:  (i) disease stage (IIIB nodal vs IIIB in-transit vs IIIC 
nodal vs IIIC in-transit with nodal vs IVM1a), and (ii) planned adjuvant 
therapy (adjuvant systemic therapy [eg, INFα, ipilimumab] with or 
without radiotherapy vs radiotherapy without adjuvant systemic 
therapy vs none. 
 
 
Add: 
Subjects who are not confirmed to be disease-free post-surgery (ie, 
who do not have an R0 surgical outcome) or who withdraw prior to 
surgery will be considered a failure at day after randomization for 
RFS. 
 
 
Add: 
The primary analysis for the primary endpoint will occur at the later 
time of either the occurrence of approximately 64 events (local, 
regional, or distant recurrence of 
 
 
Section: 
Table 5.  Study Design Characteristics, 2-year RFS, Arm 1 
 
 
Replace: 
0.60 
 
 
With: 
0.70 
 
 
Add: 
0.725, 0.750 
 
 
Section: 
Table 5.  Study Design Characteristics, 2-year RFS, Arm 2 
 
 
Replace: 
0.70 
 
 
With: 
0.60 
 
 
Delete: 
0.725, 0.750 
 
 
Section: 
10.3  Access to Individual Subject Treatment Assignments by Amgen 
or Designees 
 
 
Delete: 
To guard against actual or perceived bias due to subjective decisions 
made by Amgen or designees in light of the treatment knowledge and 
data captured during the study, Amgen will implement a Trial Integrity 
Document (TID).  The TID will include study-specific guidelines to 
restrict access to aggregate postbaseline data by randomized or 
received treatment until the primary analysis.  Details of which sponsor 
staff or designees can access the data and their level of access will be 
provided in the TID.  Amgen will finalize the TID before the first subject 
is randomized in the study. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 21 of 25 
CONFIDENTIAL 
 
 
Section: 
10.4.1  Interim Analyses 
 
 
Add: 
A Data Review Team (DRT) independent of the talimogene 
laherparepvec product team will review the first interim analysis 
(see Section10.4.2).  The DRT will also review some efficacy 
endpoints (eg, R0 resection rate, pCR rate, response to 
neoadjuvant treatment). 
 
The talimogene laherparepvec product team will review the 
second interim analysis because it will occur after all subjects 
have been already treated, have completed safety follow-up, and 
no additional interventions that may influence safety or efficacy 
of the investigational product are planned after this time point.  
The talimogene laherparepvec product team will also review 
some efficacy endpoints (eg, R0 resection rate, pCR rate, 
response to neoadjuvant treatment). 
 
Ad hoc analyses for safety or some efficacy endpoints (eg, 
response to neoadjuvant treatment, R0 resection rate, pCR rate) 
may be conducted before the planned primary and/or final 
analyses if interim data are required for submission to regulatory 
authorities.  These ad hoc analyses will be executed by the 
talimogene laherparepvec product team. 
 
 
Section: 
10.4.2  Data Review Team (DRT) 
 
 
Delete: 
A Data Review Team (DRT) independent of the talimogene 
laherparepvec product team will be formed.   
 
 
Add: 
The DRT will be supported by a statistician internal to Amgen but 
independent of the talimogene laherparepvec product team.  This 
teamThe DRT will review unblinded safety data at the first interim 
analysis.   
 
 
Section: 
10.4.3  Primary Analysis 
 
 
Add: 
The primary analyses for RFS will occur at the later time of either the 
occurrence of approximately 64 events (local, regional, or distant 
recurrence of melanoma or death) or 
 
 
Section: 
10.5.3  Secondary Efficacy Endpoints 
 
 
Add: 
KM estimates will be calculated for RFS, LRFS, RRFS, DMFS, OS 
landmarks (2-, 3- and 5-year rates) and quartiles. 
 
 
Add: 
For each group the equal-precision band method will be used to 
calculate a simultaneous confidence band for RFS, LRFS, RRFS, and 
DMFS over the interval from 2 to 5 years (Nair, 1984).  An overall 
between-group difference in RFS, LRFS, RRFS, DMFS, and OS will 
be 
 
 


Product:  Talimogene Laherparepvec 
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Section: 
10.5.4  Safety Endpoints 
 
 
Delete: 
The incidence of subjects with positive qPCR analysis result of 
talimogene laherparepvec DNA in blood and urine samples will be 
calculated.  The incidence of subjects with positive qPCR analysis 
result of talimogene laherparepvec DNA and positive TCID50 assay 
analysis result of talimogene laherparepvec viral infectivity in oral 
mucosa and genital swab samples, respectively, will be calculated. 
 
 
Section: 
13  References 
 
 
Add: 
Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al.  Adjuvant 
ipilimumab versus placebo after complete resection of high-risk 
stage III melanoma (EORTC 18071): a randomized, double-blind, 
phase 3 trial.  Lancet Oncol.  2015;16:522-530. 
 
 
Add: 
Imlygic™ (talimogene laherparepvec) Prescribing Information, 
Amgen Europe B.V, 2015. 
 
 
Add: 
Summary of Imlygic™ Product Characteristics, Amgen Europe 
B.V, 2015. 
 
 
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. 
Woburn, MA. BioVEX (a wholly owned subsidiary of Amgen); 2015. 
 
 
Add: 
Yervoy™ (ipilimumab) Prescribing Information, Bristol-Myers 
Squibb, 2015. 
 
 
Section: 
Appendix D  World Health Organization (WHO) Response Criteria 
 
 
Add: 
Modified World Health Organization (WHO) Response Criteria 
 
 
Replace: 
(Note:  When a lesion can be evaluated by both, clinical examination 
and imaging, radiographic imaging evaluations should be undertaken 
since it is more objective). 
 
 
With: 
(Note:  When a lesion can be evaluated by both, clinical examination 
and imaging, radiographic imaging evaluations should be preferred 
since it is more objective). 
 
 
Add: 
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 in at least 2 dimensions is: 
 
 


Product:  Talimogene Laherparepvec 
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CONFIDENTIAL 
 
 
Add: 
Coalescing or Splitting Lesions: 
Coalescing lesions:  When two or more lesions merge and at 
least one is an index lesion, the largest index lesion prior to 
merging should be measured and reported during the tumor 
response assessment.  All other merged lesions should be 
reported as 0 mm x 0 mm (for lesions previously reported as 
Index or New Measurable Lesions) or absent (for lesions 
previously reported as Non-Index or New Non-Measurable 
Lesions).  If two or more non-index lesions merge, the apparently 
larger lesion should be reported as present, and smaller lesion(-s) 
should be reported as absent.  The indication that the lesion 
coalesced with the specified lesion(-s) should be provided for 
each merged lesion. 
Splitting lesions:  When an index lesion splits into two or more 
lesions the largest measurable part of the split lesion will be 
measured for the current assessment with the indication that the 
lesion split from the specified lesion, and followed for future 
assessments.  The remaining lesions will be measured as new 
lesions with an indication that the lesion split from the specified 
lesion.  In this case, appearance of a new lesion from a previous 
lesion that split will not be considered disease progression solely 
due to appearance of a new lesion (may be considered 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). 
When an non-index lesion splits into two or more lesions, the 
apparently larger lesion will be reported as a non-index lesion.  
All other smaller lesions will be reported as new non-index 
lesions with an indication that the lesion split from the specified 
lesion.  In this case, appearance of a new lesion from a previous 
lesion that split will not be considered disease progression solely 
due to appearance of a new lesion (may be considered 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). 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 24 of 25 
CONFIDENTIAL 
 
 
Section: 
Baseline Documentation of “Index Lesions”: 
 
Add: 
The sum of the products of the largest perpendicular diameters of 
all index lesions will be calculated and reported. 
 
If a subject has multiple small superficial cutaneous melanoma 
lesions at baseline (each lesions is less than 10 mm in at least 2 
dimensions) which in aggregate have a total diameter of ≥ 10 mm 
in at least 2 dimensions, up to 10 largest lesions that were 
included in this measurement will be reported as ”Index Lesions”, 
and the sum of the products of the two largest perpendicular 
diameters of these lesions will be calculated and reported for 
tumor response assessments. 
 
 
Delete: 
The sum of the products of the two largest of perpendicular diameters 
(SPD) of all index lesions will be calculated and reported. 
 
 
Section: 
Follow-up “Index Lesions”: 
 
Replace: 
At each subsequent tumor assessment, the SPD of the index lesions 
are added together to provide the total tumor burden. 
 
 
With: 
At each subsequent tumor assessment, the sum of the products of 
the two largest perpendicular diameters of the index lesions are 
added together to provide the total tumor burden. 
 
 
Section: 
Follow-up “New Lesions”: 
 
Delete: 
At each subsequent tumor assessment, if new measurable lesions 
have appeared they 
 
 
Add: 
At tumor assessment, if new measurable lesions have appeared they 
should be added to sum of the products of the two largest 
perpendicular diameters SPD of the index lesions to provide the total 
tumor burden.  For nonmeasurable new lesion they should be followed 
as nonindex lesion as “present”, “absent”, or in rare cases 
“unequivocal progression”.  If a new lesion(s) that appears in 
between scheduled tumor response assessments disappear(s) 
before the next scheduled assessment, there is no need to 
include this lesion for tumor response evaluation.  
 
 
Section: 
Appendix D, Table 1 Definition of Index Lesion Tumor Response 
Including New Measurable Lesions 
 
 
Replace: 
Achieving a 50% or greater reduction in the SPD of the perpendicular 
diameters of all index lesions and new measurable lesions, if 
applicable, at the time of assessment as compared to the sum of the 
products of the perpendicular diameters of all index lesions at 
baseline. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  31 March 2016 
Page 25 of 25 
CONFIDENTIAL 
 
 
With: 
Achieving a 50% or greater reduction in the sum of the products of 
the two largest perpendicular diameters of all index lesions and 
new measurable lesions, if applicable, at the time of assessment as 
compared to the sum of the products of the perpendicular diameters of 
all index lesions at baseline. 
 
 
Replace: 
A > 25% increase in the sum of the products of the perpendicular 
diameters of all index tumors and new measurable lesions, if 
applicable, since baseline. 
 
 
With: 
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 measurable lesion since the last response 
assessment time point. 
 
 
Section: 
Appendix D, Table 2  Definition of Nonindex Lesion Tumor Response 
Including New Nonmeasurable Lesions, footnote 
 
 
Add: 
CR = complete response; SD = stable disease; PD = disease 
progression; UE = unable to evaluate; NA = not applicable; ND = 
not done. 
 
 
Section: 
Appendix D, Table 3 Matrix for Determining the Overall Response at 
Each Assessment Point, footnote 
 
 
Delete: 
PD = disease progression 
 
 
Section: 
Appendix F Surgery Guidelines 
 
 
Add: 
The decisions to perform surgery on subjects with stage IIIB, IIIC or IV 
M1a melanoma (dermal, subcutaneous or non-regional lymph node 
metastases) is a complex clinical decision making process that 
must be based on good clinical judgment that may include 
consulting with other relevant medical specialities, and 
considering patient’s preferences. 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  09 June 2014 
Page 1 of 2 
 
Amendment 1 
Protocol Title:  A Phase 2, Multicenter, Randomized, Open-label Trial Assessing 
the Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus 
Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma 
 
Amgen Protocol Number (Talimogene Laherparepvec) 20110266 
 
Amendment Date: 
09 June 2014 
Rationale: The protocol was updated due to discrepancy noted in Section 10.4.2 (Data 
Review Team [DRT]) concerning the inclusion of external clinical expert to serve as a 
DRT member. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110266 
Date:  09 June 2014 
Page 2 of 2 
 
Description of Changes: 
Section:  Header 
Protocol date 
From:  
23 May 2014 
To: 
09 June 2014 
Section: Protocol Title Page 
Add: 
Amendment 1 Date: 
09 June 2014 
Section: Investigator’s Agreement 
From: 
I have read the attached protocol entitled A Phase 2, Multicenter, Randomized, 
Open-label Trial Assessing the Efficacy and Safety of Talimogene Laherparepvec 
Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Resectable, Stage IIIB to 
IVM1a Melanoma, dated 23 May 2014, and agree to abide by all provisions set forth 
therein. 
To: 
I have read the attached protocol entitled A Phase 2, Multicenter, Randomized, 
Open-label Trial Assessing the Efficacy and Safety of Talimogene Laherparepvec 
Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Resectable, Stage IIIB to 
IVM1a Melanoma, dated 09 June 2014, and agree to abide by all provisions set forth 
therein. 
Section 10.4.2:  Data Review Team (DRT) 
Sentence 3 
From: 
In addition the DRT will also include one or more external clinical expert(s) (a surgical 
oncologist in melanoma and a clinical virologist) who are not directly involved in the 
conduct of the study.  
To: 
In addition, the DRT may include one or more external clinical expert(s) (eg, a surgical 
oncologist in melanoma) not directly involved in the conduct of the study. 

SAP_001.pdf: 
Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 1 
STATISTICAL ANALYSIS PLAN 
Title:  A Phase 2, Multicenter, Randomized, Open-label Trial Assessing the 
Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus 
Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma 
Protocol Number: 
20110266 
NCT02211131 
Version: 
3.0 
Date: 
Amendment 1 Date: 
Amendment 2 Date：
Amendment 3 Date: 
19 September 2014 
23 September 2016 
23 March 2018 
14 May 2019 
Authors: 
NCT Number: NCT02211131
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 2 
 
Table of Contents 
Table of Abbreviations ...................................................................................................... 5 
1. 
Introduction .............................................................................................................. 6 
2. 
Objectives ................................................................................................................ 6 
2.1 
Primary ......................................................................................................... 6 
2.2 
Secondary .................................................................................................... 6 
2.3 
Exploratory ................................................................................................... 7 
3. 
Study Overview ........................................................................................................ 7 
3.1 
Study Design ................................................................................................ 7 
3.2 
Sample Size ................................................................................................. 9 
4. 
Study Endpoints and Covariates ............................................................................ 10 
4.1 
Study Endpoints ......................................................................................... 10 
4.1.1 
Primary Endpoint ........................................................................ 10 
4.1.2 
Secondary Endpoint ................................................................... 11 
4.1.2.1 
Efficacy Endpoints ................................................... 11 
4.1.2.2 
Safety Endpoints ...................................................... 13 
4.1.3 
Exploratory Endpoints ................................................................ 13 
4.2 
Planned Covariates .................................................................................... 13 
5. 
Hypotheses and/or Estimations .............................................................................. 14 
6. 
Definitions .............................................................................................................. 14 
7. 
Analysis Subsets .................................................................................................... 19 
7.1 
Intent to Treat Analysis Set ........................................................................ 19 
7.2 
Safety Analysis Set ..................................................................................... 20 
7.3 
Efficacy Analysis Set .................................................................................. 20 
7.4 
Subgroup Analyses .................................................................................... 20 
8. 
Planned Analyses .................................................................................................. 20 
8.1 
Interim Analysis and Early Stopping Rules ................................................. 20 
8.1.1 
Data Review Team (DRT) .......................................................... 21 
8.2 
Primary Analysis ......................................................................................... 21 
8.3 
Final Analysis ............................................................................................. 22 
8.4 
Additional Analysis ..................................................................................... 22 
9. 
Data Screening and Acceptance ............................................................................ 22 
9.1 
General Principles ...................................................................................... 22 
9.2 
Data Handling and Electronic Transfer of Data .......................................... 22 
9.3 
Handling of Missing and Incomplete Data .................................................. 22 
9.3.1 
Efficacy ....................................................................................... 22 
9.3.2 
Safety ......................................................................................... 22 
9.4 
Detection of Bias ........................................................................................ 22 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 3 
 
9.4.1 
Important Protocol Deviations (IPD) Impact ............................... 22 
9.4.2 
Timing Bias Impact ..................................................................... 23 
9.4.3 
Subsequent Anti-Cancer Therapy Impact .................................. 23 
9.5 
Outliers ....................................................................................................... 23 
9.6 
Distributional Characteristics ...................................................................... 24 
9.7 
Validation of Statistical Analyses ................................................................ 24 
10. 
Statistical Methods of Analysis ............................................................................... 25 
10.1 
General Principles ...................................................................................... 25 
10.2 
Subject Accountability ................................................................................ 26 
10.3 
Important Protocol Deviations .................................................................... 26 
10.4 
Demographic and Baseline Characteristics ................................................ 26 
10.5 
Efficacy Analyses ....................................................................................... 27 
10.5.1 
Analyses of Primary Efficacy Endpoint(s) ................................... 31 
10.5.2 
Analyses of Secondary Efficacy Endpoint(s) .............................. 31 
10.6 
Safety Analyses .......................................................................................... 33 
10.6.1 
Adverse Events .......................................................................... 33 
10.6.2 
Laboratory Test Results ............................................................. 34 
10.6.3 
Vital Signs ................................................................................... 34 
10.6.4 
ECOG Performance Status ........................................................ 35 
10.6.5 
Electrocardiogram (ECG) ........................................................... 35 
10.6.6 
Antibody Formation .................................................................... 35 
10.6.7 
Exposure to Investigational Product ........................................... 35 
10.6.8 
Exposure to Concomitant Medication/Adjuvant 
Therapy/Subsequent Anti-cancer Therapy................................. 36 
11. 
Changes From Protocol-specified Analyses .......................................................... 37 
12. 
Literature Citations / References ............................................................................ 38 
13. 
Data Not Covered by This Plan .............................................................................. 39 
14. 
Appendices ............................................................................................................ 40 
List of Tables 
Table 1.  Study Design Characteristics ........................................................................... 10 
Table 2.  Study Design Characteristics Example Endpoint Summary Table ................... 28 
List of Figures 
Figure 1.  Example of Treatment Period and T-VEC Monotherapy Period ..................... 15 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 4 
 
List of Appendices 
Appendix A.  Conventions for Clinical Data That Require Imputation for  
Partial or Missing Dates ........................................................................... 41 
Appendix B.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ....................................................... 43 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 5 
 
Table of Abbreviations 
In addition to the study glossaries and abbreviations defined in the protocol, here is a 
table of abbreviations used in this document: 
Abbreviation/Acronym 
Definition 
ADaM 
Analysis Data Model data sets 
BDSG 
Biomedical Data Stewardship Governance 
CRF 
Case Report Form 
IPCW 
IPD 
Inverse Probability Censoring Weighting 
Important Protocol Deviation 
ITT 
Intent to Treat 
SAP 
SDTM 
Statistical Analysis Plan 
Study Data Tabulation Model data sets 
SOA 
Schedule of Assessments 
TFL 
Table, Figure, Listing  


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 6 
 
1. 
Introduction 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 3 for the Talimogene 
Laherparepvec, Study 20110266 dated 23 March 2018. The scope of this plan includes 
the three interim analyses, the primary analysis, the final analysis, and one additional ad 
hoc analysis that may also be conducted before the planned primary and/or final 
analysis if interim data are required for submission to regulatory authorities. These 
analyses will be executed by the biostatistics department unless otherwise specified.   
This study will have data collected and analyzed in Amgen-owned databases and 
systems and will adhere to approved Data Element Standards and International Case 
Report Form (CRF) Standards, if available, established by Biomedical Data Stewardship 
Governance (BDSG).  Amgen-owned databases and systems include vendor and 
service provider databases built for Amgen-only use. 
2. 
Objectives 
2.1 
Primary 
To estimate the treatment effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on recurrence-free survival (RFS). 
2.2 
Secondary 
The secondary objectives are: 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on landmark RFS by year 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on rate of histopathological tumor-free margin (R0) 
surgical resection 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec on rate of 
pathological complete response (pCR) (Arm 1 only) 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 7 
 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on local recurrence-free survival (LRFS), regional 
recurrence-free survival (RRFS) and distant metastases-free survival (DMFS) 
• 
To estimate the effect of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone on landmark overall survival (OS) by year, and overall 
survival (OS) 
• 
To estimate response to neoadjuvant talimogene laherparepvec overall and 
separately in injected and uninjected lesions during treatment (Arm 1 only) 
• 
To evaluate the safety of neoadjuvant talimogene laherparepvec plus surgery 
compared to surgery alone 
2.3 
Exploratory 
The exploratory objectives are: 
• 
To explore the correlation between baseline intratumoral CD8+ cell density and 
clinical outcomes 
• 
To explore the correlation between changes in an intratumoral CD8+ cell density 
during talimogene laherparepvec treatment and clinical outcomes 
• 
To investigate the correlation between the changes in the population of 
tumor-specific cytotoxic T-cells during treatment and clinical outcomes 
• 
To assess blood and tumor for potential biomarkers which correlate with or predict 
clinical outcomes to talimogene laherparepvec 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of 
talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to 
surgery alone in subjects with resectable stage IIIB, IIIC, or IVM1a melanoma.  
Approximately 150 subjects with completely resectable melanoma and at least 
one injectable lesion will be randomized 1:1 to receive the following: 
• 
Arm 1:  Talimogene laherparepvec for 6 doses followed by surgical resection of 
melanoma tumor lesion(s). 
− 
Talimogene Laherparepvec: 
Talimogene laherparepvec will be administered by intralesional injection into the 
injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 106 plaque 
forming units (PFU)/mL at day 1 of week 1 followed by a dose of 108 PFU/mL at  
day 1 (± 3 days) of weeks 4, 6, 8, 10 and 12 or until all injectable tumors have 
disappeared, or intolerance of study treatment, whichever occurs first.  Due to the 
mechanism of action of talimogene laherparepvec, subjects may experience transient 
growth in existing tumors or the appearance of new tumors prior to maximal clinical 
benefit of talimogene laherparepvec.  Subjects who experience growth in existing tumors 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 8 
 
or the appearance of new tumors will be allowed to remain on talimogene laherparepvec 
treatment until week 12 of therapy unless, in the opinion of the investigator, immediate 
surgical resection or any other treatment for melanoma is warranted.  If talimogene 
laherparepvec treatment will end prior to week 12, the investigator or designee should 
notify the sponsor’s medical monitor as soon as possible. 
− 
Surgical Resection of Melanoma Tumor Lesions(s): 
For subjects who complete 12 weeks of talimogene laherparepvec treatment, 
surgical resection of melanoma lesion(s) will be performed at any time during 
weeks 13 to 18.  Subjects who stop talimogene laherparepvec prior to week 12 due 
to disappearance of all injectable tumor lesions, intolerance to talimogene 
laherparepvec, or any other reason will undergo adequate surgical resection of 
melanoma lesion(s) or tissue where melanoma was present before achieving CR, 
within 1 to 6 weeks after the last dose of talimogene laherparepvec.  If surgery will be 
performed prior to week 12, the investigator or designee should notify the sponsor’s 
medical monitor as soon as possible.  Refer to protocol Appendix F for surgery 
guidelines. 
• 
Arm 2:  Immediate surgical resection of melanoma tumor lesion(s) 
− 
Surgical resection of melanoma tumor lesion(s) will be performed after 
enrollment any time during weeks 1 to 6.   
Randomization will be stratified by disease stage (IIIB nodal versus IIIB in-transit 
versus IIIC nodal versus IIIC in-transit with nodal versus IVM1a) and planned 
adjuvant therapy (adjuvant systemic therapy [eg,INFα, ipilimumab] with or without 
radiotherapy versus radiotherapy without adjuvant systemic therapy versus none).  
Following surgery, adjuvant systemic therapy and/or radiotherapy may be 
administered at the investigator’s discretion and per the institutional standard of care.  
Subjects will be followed for safety approximately 30 (+ 15) days after surgery and 
for disease recurrence (local, regional, or distant), subsequent anticancer therapy for 
melanoma, adverse events thought to be potentially related to talimogene 
laherparepvec (Arm 1 only), and survival every 3 months (± 30 days) for first 3 years 
after the end of the safety follow-up period and then every 6 months (± 30 days) until 
death, subject withdraws full consent, or up to 5 years after the last subject is 
randomized, whichever is first.  Thereafter, subjects randomized to Arm 1 who 
received at least a single dose of talimogene laherparepvec will be followed under an 
ongoing separate registry protocol (study 20120139) for the long-term survival 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 9 
 
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 subsequent anticancer therapy for melanoma. 
Subjects who, after the long-term follow-up period of this study (Study 20110266), 
elect to participate in the registry study (Study 20120139) must sign new informed 
consent form before any registry protocol-specific activities. 
3.2 
Sample Size 
All analyses will be descriptive with no formal hypothesis testing.  The primary 
objective of the study is to estimate the treatment effect, as measured by the hazard 
ratio of RFS, of talimogene laherparepvec neoadjuvant therapy followed by surgery 
(Arm 1) compared to surgery alone (Arm 2) in subjects with resectable, stage IIIB to 
IVM1a melanoma.  Approximately 150 subjects will be randomized 1:1 to receive 
Arm 1 vs Arm 2 stratified by: (i) disease stage (IIIB nodal vs IIIB in-transit vs IIIC 
nodal vs IIIC in-transit with nodal vs IVM1a), and (ii) planned adjuvant therapy 
(adjuvant systemic therapy [eg, INFα, ipilimumab] with or without radiotherapy vs 
radiotherapy without adjuvant systemic therapy vs none).  Primary efficacy analysis 
of RFS will be based on the Intent to Treat Analysis Set.  An overall between-group 
difference in RFS will be evaluated with a log-rank test and corresponding 
proportional hazards model without stratification.  The Kaplan-Meier (KM) method 
will be used to estimate 1-year, 2-year, 3-year, 5-year, and overall RFS.  Subjects 
who are not confirmed to be disease-free post-surgery (i.e., who do not have an R0 
surgical outcome) or who withdraw prior to surgery will be considered a failure at 
randomization for RFS, RRFS, LRFS and DMFS.  The primary analysis for the 
primary endpoint will occur at the later time of either the occurrence of approximately 
64 events (local, regional, or distant recurrence of melanoma or death) or 
approximately 2 years after the end of randomization.  An 80% CI will be estimated 
for the hazard ratio of RFS.  In addition, an 80% CI will also be estimated for the 
between-arm difference (Arm 1 – Arm 2) in 2-year RFS, i.e., Δ 2-year RFS.  It is 
assumed that: (i) RFS is exponential over the first 2 years, (ii) the 2-year RFS for 
Arm 2 is about 0.60 (Eggermont et al, 2008), and that there will be a 10% 
exponential probability of drop-out by the primary analysis.  Simulations were 
performed for various scenarios from 0.05 to 0.15 to evaluate the following 
parameters assuming possible true Δ 2-year RFS values of 0.10, 0.125, and 0.15:  
(i) the average Δ 2-year RFS 80% CI and its width, (ii) the probability that the 
Δ 2-year RFS 80% CI is above 0, and (iii) the average number of events at the 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 10 
 
primary analysis.  The possible true Δ 2-year RFS values were translated to a RFS 
hazard ratio (HR) (Arm 1 relative to Arm 2) and the HR 80% CI and the probability of 
it being < 1 were calculated based on the simulated average number of events.  The 
average width of the Δ 2-year RFS 80% CI was 0.20 (Table 1). 
Table 1.  Study Design Characteristics 
2-year RFS 
RFS 
HR 
Ave. ∆ 80% CI 
Prob. 
∆ 
80% 
CI > 0 
Ave. HR 
80% CI 
Prob. 
HR 
80% 
CI < 1 
Ave. 
Events 
Arm 1 Arm 2 
∆ 
LL 
UL 
Width 
LL 
UL 
0.700 
 
0.100 
0.70 
0.00 
0.20 
0.20 
0.51 
0.51 
0.96 
0.56 
64 
0.725 
0.60 
0.125 
0.63 
0.02 
0.22 
0.20 
0.62 
0.45 
0.87 
0.71 
62 
0.750 
 
0.150 
0.56 
0.05 
0.25 
0.20 
0.74 
0.40 
0.78 
0.83 
60 
RFS, Recurrence-free Survival; HR, Hazard Ratio; CI, Confidence Interval; LL, Lower Limit; UL, Upper Limit; 
Ave, Average; Prob., Probability; ∆ = Arm 1 – Arm 2-year RFS  
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
4.1.1 
Primary Endpoint 
Recurrence-Free Survival (RFS):  The event for RFS is defined as the first of local, 
regional, or distant recurrence of melanoma or death due to any cause.  RFS is defined 
as time from randomization to the date of the event.  The following four rules will be 
used: 
1. For subjects having not experienced an event by the cutoff date, RFS will be 
censored at the last valid tumor evaluation (refer to Section 6 for the definition of last 
valid tumor evaluation). 
2. Subjects who are not confirmed to be disease-free post-surgery (i.e., who do not 
have an R0 surgical outcome) will be considered to have an event at randomization 
for RFS.   
3. Subjects who withdraw prior to surgery will be considered to have an event at 
randomization for RFS.   
4. Subjects with a non-melanoma tumor or a second malignancy identified before or at 
surgery will be censored at the day after randomization.  
Alternative RFS definitions will be evaluated in sensitivity analyses as follows. 
• 
RFS Sensitivity # 1: RFS is defined as the first of local, regional, or distant 
recurrence of melanoma or death due to any cause, regardless of surgical 
outcome, achieved by omitting rule 2. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 11 
 
Additional RFS rules related to death will be evaluated in sensitivity analyses as 
follows. 
• 
RFS Sensitivity # 2:  The primary analysis of RFS will be repeated with the 
consideration that in the absence of prior documented recurrence, death beyond 
90 days after the last valid tumor evaluation or randomization date (whichever is 
later) will not be considered an event, and instead will result in a censored RFS time.  
• 
RFS Sensitivity # 3: The primary analysis of RFS will be repeated with the 
consideration that in the absence of prior documented recurrence, deaths not 
determined to be related to melanoma will not be considered an event.  Deaths will 
be will considered as related to melanoma if the death reason is disease progression 
or unknown.   
RFS sensitivity analysis # 2 and/or # 3 will be conducted if RFS is revised for more 
than 10% of subjects in either arm due to revised specification, or if the absolute 
between-arm frequency difference is greater than 5%.   
4.1.2 
Secondary Endpoint 
4.1.2.1 
Efficacy Endpoints 
4.1.2.1.1 
Tumor Response (Arm 1 Only) 
The overall tumor response is evaluated up to the earlier of surgical resection or 
subsequent anti-cancer therapy. Lesion-level response is evaluated up to the earliest 
event of start of subsequent anti-cancer therapy, merge with another lesion, or resection. 
Subject-level response is evaluated up to the earliest event of start of subsequent 
anti-cancer therapy or a partial or complete lesion resection.   
Following endpoints will be analyzed for tumor response analysis,  
• 
The overall tumor response is per the modified WHO criteria of tumor.  
• 
Tumor response in injected/uninjected lesion(s) 
− 
The subject-level injected and uninjected responses will be based on the tumor 
burden of only injected index lesions including injected new measurable lesions, 
or the tumor burden of only uninjected index lesions including uninjected new 
measurable lesions, respectively.  
− 
The lesion-level injected and uninjected response will evaluate the change of the 
area of each individual lesion.  
• 
Similar to tumor response in injected/uninjected lesions, lesion-level and 
subject-level response may also be conducted for lesion subtypes, 
eg, cutaneous / subcutaneous, nodal. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 12 
 
For the subject-level tumor response by tumor burden type (injected, uninjected lesions), 
a response is achieved if the percentage of the specific tumor burden type reduction 
from baseline for both baseline and new measurable lesions (if applicable) is at 
least 50%. Overall tumor burden is calculated at a visit as the sum of tumor areas of all 
lesions of the same type.  The incidence of subject-level tumor response will be reported 
as the proportion of subjects with an evaluable tumor burden of the corresponding type 
that achieves a response.  
The incidence of lesion-level response will be reported as the proportion of evaluable 
lesions in response.  A lesion is in response if the decrease in tumor area is ≥ 50%.   
All overall tumor burden and lesion response analyses will be based on bi-dimensional 
lesion measurements reported at a tumor assessment and will not consider injected 
lesion longest diameters reported at the time of investigational product administration 
forms. 
4.1.2.1.2 
Other Endpoints 
• 
Landmark RFS by year:  The Kaplan-Meier (K-M) estimate of RFS rate at 1 year, 
2 years, 3 years, and 5 years  
• 
Rate of histopathology tumor-free margin (R0) surgical resection 
• 
Rate of pathological complete response (pCR) (Arm 1 only) 
• 
Local recurrence-free survival (LRFS):  Time from randomization to the earlier date 
of the first of local disease recurrence or death due to any cause.  Local recurrence 
is defined as histologically or cytologically confirmed reappearance of melanoma in 
the area of up to 2 cm from the scar from the surgical excision or at the edge of the 
skin graft if that was used for closure.  For subjects not having experienced an event 
by the cutoff date, LRFS will be censored at the last valid tumor evaluation before the 
data cutoff date.  An event will be imputed at randomization for subjects who do not 
have an R0 surgical outcome.  Subjects with a non-melanoma tumor identified at 
surgery will be censored at the day after randomization.   Sensitivity analyses as per 
RFS Sensitivity #1 (see Section 4.1.1) will be performed for LRFS.   
• 
Regional recurrence-free survival (RRFS): Time from randomization to the date of 
the first of regional disease recurrence or death due to any cause.  Regional 
recurrence excludes local recurrence and is defined as histologically, cytologically, or 
radiographically confirmed reappearance of melanoma in the regional lymph node 
basin. New in-transit melanoma metastases in the regional lymphatic drainage will 
be reported as regional recurrence. Histological or cytological confirmation of new 
in-transit metastases is recommended but is not required. For subjects not having 
experienced an event by the cutoff date, RRFS will be censored at the last valid 
tumor evaluation before the data cutoff date.  Subjects with a non-melanoma tumor 
identified at surgery will be censored a day after randomization. Sensitivity 
analyses as per RFS Sensitivity #1 (see Section 4.1.1) will be performed for 
RRFS.   


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• 
Distant metastases free survival (DMFS):  Time from randomization to the earlier 
date of the first of distant metastases or death due to any cause.  Distant metastases 
exclude local and regional recurrence and will include distant 
cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central 
nervous system, brain, or bone metastases. For subjects not having experienced an 
event by the cutoff date, DMFS will be censored at the last valid tumor evaluation 
before the data cutoff date.  Subjects with a non-melanoma tumor identified at 
surgery will be censored at the day after randomization.  Sensitivity analyses as per 
RFS Sensitivity #1 (see Section 4.1.1) will be performed for DMFS.   
• 
Overall survival (OS):  Time from randomization to death due to any cause 
• 
Landmark OS by year:  The Kaplan-Meier (K-M) estimate of the overall survival rate 
at 1 year, 2 years, 3 years and 5 years. 
4.1.2.2 
Safety Endpoints 
• 
Subject incidence of treatment-emergent and treatment-related adverse events 
• 
The incidence of subjects with herpetic lesions found to be positive for talimogene 
laherparepvec DNA per qPCR in swab samples collected from lesions suspected to 
be herpetic in origin and the rate of positive lesions (if any); 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 
4.1.3 
Exploratory Endpoints 
The following endpoints are included as exploratory endpoints and their analysis plan 
may be described in a separate supplemental SAP if appropriate and they may be 
reported separately from the primary CSR. 
• 
Correlation between baseline intratumoral CD8+ cell density in melanoma lesions 
and clinical outcomes  
• 
Correlation between changes in an intratumoral CD8+ cell density in melanoma 
lesions during talimogene laherparepvec treatment and clinical outcomes (for Arm 1 
only) 
• 
Correlation between the changes in the population of tumor-specific cytotoxic T-cells 
in blood samples during treatment and clinical outcomes (for Arm 1 only) 
• 
Assessment of blood and tumor for potential biomarkers which correlate with or 
predict clinical outcomes to talimogene laherparepvec 
4.2 
Planned Covariates 
The following covariates, including the stratification factors, will be used, with 
possible exceptions where associated subgroups are too small (eg, < 20 subjects) or 
have too few events (< 5 events), to examine efficacy individually and multivariately: 
• 
Region, if more than 10% subjects in ITT population are from non-USA countries 
(USA or non-USA) 
• 
Age at baseline:  < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 


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• 
Number of measurable tumors at baseline (will be dichotomized based on the 
median) 
• 
The sum of the products of the two largest perpendicular diameters of baseline 
measurable lesions (SPD) (will be dichotomized based on the median) 
• 
Baseline absolute lymphocyte count:  ≤ 1000 vs > 1000 
• 
Recurrent disease ≥1 year from primary diagnosis vs recurrent disease  
< 1 year from primary diagnosis vs no prior melanoma 
• 
Current disease stage (IVRS):  IIIB nodal vs IIIB in-transit vs IIC nodal vs IIIC 
in-transit with nodal vs IV M1a 
• 
Baseline ECOG performance status: 0 vs 1 
• 
BRAF mutation status:  mutation present vs mutation not present 
• 
Previous systemic anti-cancer therapy for melanoma: yes vs no 
• 
Previous systemic immune check-point inhibitor therapy for melanoma: yes vs no 
• 
Planned adjuvant therapy (IVRS): adjuvant systemic therapy with or without 
radiotherapy vs radiotherapy without adjuvant systemic therapy vs none 
5. 
Hypotheses and/or Estimations 
Formal hypotheses will not be tested in this trial.  The study will provide an estimate of 
the treatment effect, as measured by the difference in RFS of talimogene laherparepvec 
neoadjuvant therapy followed by surgery compared to surgery alone in subjects with 
resectable, stage IIIB to IVM1a melanoma. 
6. 
Definitions 
The definitions of efficacy endpoints are given in Section 4. 
• 
Investigational Product 
Investigational product refers to talimogene laherparepvec in this study. 
• 
Study Drug 
Study drug is defined as talimogene laherparepvec in this study. 
• 
Screening Phase 
The screening phase is the time period after signing the informed consent and before 
enrollment when study specific laboratory tests and procedures are performed, and 
medical history is reviewed to confirm subject eligibility for the study. 
• 
Study Day 1 
Study day 1 for a subject is defined as the first day that the study drug is 
administered to the subject or the surgical resection of melanoma tumor lesion(s), 
whichever is earlier.  Study day 1 is the date of randomization if a subject does not 


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receive talimogene laherparepvec or the surgical resection of melanoma tumor 
lesion(s). The day before the study day 1 is referred to as study day −1. 
• 
Baseline 
Baseline in general refers to study day 1.  The baseline value of a parameter 
(eg, vital signs, laboratory tests and efficacy endpoints) is considered to be the latest 
value prior to receiving talimogene laherparepvec or the onset of the surgical 
resection of melanoma tumor lesion(s), whichever is earlier. If subjects that do not 
receive study therapy or the surgical resection of melanoma tumor lesion(s), the 
baseline value will be the last record on or prior to the randomization date. 
• 
Treatment Period (also Study Treatment Period, Overall Treatment Period) 
Study day 1 through 30 days after the last administration of talimogene 
laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), 
whichever is later. 
• 
Talimogene Laherparepvec Monotherapy Period (Arm 1 Only) 
Talimogene laherparepvec monotherapy period starts at the initiation of the first 
talimogene laherparepvec dose administration and ends before the surgical 
resection of the melanoma tumor lesion(s), or 30 days after the last administration of 
talimogene laherparepvec, whichever is earlier.   
Figure 1.  Example of Treatment Period and T-VEC Monotherapy Period 
First T-VEC Dose 
Last T-VEC 
Dose 
30 Days After Last T-VEC Dose 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Onset of Surgery 
30 Days After Completion of 
Surgery 
  
Only 
T-VEC Talimogene Laherparepvec Monotherapy Period 
  
+ 
  
Treatment Period  
• 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events are events occurring during the Treatment 
Period.  Adverse events occurring on the same day of the start or end day of the 
treatment period will be counted as treatment-emergent adverse event unless there 
is evidence to indicate otherwise (eg, the checkbox in CRF, which indicates a AE 


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onset is prior to first dose of talimogene laherparepvec or surgical resection, is 
checked). 
• 
Treatment Emergent Death 
Treatment emergent death is defined as any death that occurs during the treatment 
period.  Any treatment emergent death will be reported as an SAE. 
• 
Safety Follow-Up 
Safety follow-up will be performed approximately 30 (+ 15) days after the last dose of 
talimogene laherparepvec or the completion of the surgical resection of melanoma 
tumor lesion(s), whichever is later. 
• 
End of Study 
Primary Completion:  the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis.  The 
primary completion is anticipated to occur at the later time of either the occurrence of 
approximately 64 events (local, regional or distant recurrence of melanoma or death) 
or approximately 2 years after the end of randomization. 
End of Trial:  the time when the last subject is assessed or receives an intervention 
for evaluation in the study.  The end of trial will occur when the last subject has had 
the opportunity to complete the long-term follow-up.  The end of trial is anticipated to 
occur approximately 5 years after the end of randomization. 
• 
Long-term Follow-up 
Long-term Follow-up will occur every 3 months (± 30 days) for 3 years following the 
safety follow-up visit and then every 6 months (± 30 days) until death, subject 
withdraws full consent, or up to 5 years after the last subject is randomized, 
whichever is first. 
• 
Concomitant Medications 
The concomitant medications include all non-anticancer medication during treatment 
period.  
• 
On-treatment Procedure/Surgery 
The on-treatment surgery includes all surgery subjects receive during treatment 
period except the protocol specified surgical resection of melanoma lesion(s)   


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• 
Prior Systemic Anti-cancer Therapies  
Prior systemic anti-cancer therapies for melanoma include chemotherapy, 
chemoradiotherapy, immunotherapy, targeted biologics, targeted small molecules, 
and chemo-embolization which are not in the setting for adjuvant or neoadjuvant 
treatment. 
• 
Previous Systemic Immune Check-Point Inhibitor Therapy for Melanoma 
Previous systemic immune check-point inhibitor anti-cancer therapies  
(eg, anti-CTLA4, anti-PD1) not in the setting for adjuvant or neoadjuvant treatment. 
• 
Subsequent Anti-Cancer Therapy for Melanoma after Recurrence 
Subsequent anti-cancer therapy for melanoma is defined as any anti-cancer therapy 
(or treatment) received for melanoma after recurrence. Subsequent anti-cancer 
therapy for melanoma will be collected from CRF form “Subsequent Anti-Cancer 
Therapies for Current Malignancy”. 
• 
Adjuvant therapy for Melanoma 
Adjuvant therapy is defined as anti-cancer therapy subjects receive after surgical 
resection of melanoma lesion(s) but before recurrence.  Adjuvant therapy will be 
collected from CRF form “Subsequent Anti-Cancer Therapies for Current 
Malignancy”. 
• 
Landmark OS by year  
Estimated proportion of subjects alive at each year by the Kaplan-Meier method. 
• 
Landmark RFS by year  
Estimated proportion of subjects experiencing overall recurrence (local, regional, 
distant) at each year by the Kaplan-Meier method. 
• 
Response (Arm 1 only) 
Refer to Section 4.1.2.1.1. 
• 
Best overall response (BOR) per investigator (Arm 1 only) 
Best response for a subject is the best overall response observed across all time 
points in the following order: CR, PR, SD, PD or UE. 


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• 
Histopathology Tumor-free margin (R0) Surgical Resection Rate 
Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as 
absence of ink on the tumor for all disease. R0 surgical resection rate is defined as 
proportion of subjects with R0 resection. For each subject, the R0 resection status 
(R0 or non-R0) will be derived from lesion level resection status collected from CRF. 
In order for a subject to count as an R0 resection event, all lesion observations will 
be R0 within the given subject.  Any observation of a non-R0 (R1, R2) for a subject 
will make the subject a non-R0 case for this endpoint.  
• 
Pathological Complete Response (pCR) Rate (Arm 1 Only) 
Pathological Complete Response (pCR) is defined as no evidence of viable tumor 
cells on complete pathological evaluation of the surgical specimen per institutional 
standards of care. pCR rate is defined as proportion of subjects which achieves a 
pCR. For each subject, the pCR status (pCR or non-pCR) will be determined based 
on whether or not viable tumor was detected in the surgical specimen.  
• 
Last Valid Tumor Evaluation 
For overall tumor response per modified WHO response criteria the last valid tumor 
evaluation refers to the last valid tumor response assessment (PR, CR, SD or PD) 
per investigator.  For the subject-level tumor response based on the tumor burden of 
a subset of lesions (injected, uninjected lesions, or other subtype) or the lesion-level 
response the last valid tumor evaluation refers to the assessment where the 
corresponding tumor burden or the corresponding individual tumor area is not 
missing.  
• 
Baseline Lesion 
Lesions measured at the most recent visit on or before receiving the first 
administration of talimogene laherparepvec (i.e., study day 1) will be flagged as 
baseline lesions.  Baseline lesions must have positive tumor area.  Lesions reported 
in the baseline measurable lesion CRF page but with a tumor area of zero or missing 
value at the last measurement on or before study day 1 will not be considered 
baseline lesions.   
• 
New Lesion 
New lesions are those that first appear after study day 1 with a positive tumor area or 
lesions without a positive lesion area in the last assessment on or before study day 1 


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but a positive lesion area from follow up tumor measurements.  Baseline tumor area 
of a new lesion is obtained from the earliest date with positive bi-dimensional tumor 
measurements after study day 1. If a new lesion(s) that appears in between 
scheduled tumor response assessments disappear(s) before the next scheduled 
assessment, there is no need to include this lesion for tumor response evaluation 
• 
Evaluable Lesion 
A baseline or new measurable lesion is defined as evaluable if it has an initial 
positive area followed by at least 1 assessment with a non-missing area.   
• 
Injected/Uninjected Lesion 
Baseline or new lesions that are reported as injected with talimogene laherparepvec 
at any time during the treatment period are considered injected lesions.  Baseline or 
new lesions that are not reported as injected with talimogene laherparepvec are 
considered uninjected lesions.   
• 
Baseline Tumor Burden 
The baseline tumor burden for a subject is the sum of the initial area of baseline 
lesions of the specific lesion type.   
• 
Tumor Burden 
The tumor burden for a subject at a visit is the sum of the area at that visit of 
baseline lesions of the specific lesion type.   
• 
Evaluable Tumor Burden 
A subject is defined as having an evaluable tumor burden of a specific type (injected, 
uninjected) if they have at least one evaluable tumor burden assessment of the 
specific type.  An evaluable assessment is one with a tumor burden that includes all 
lesions of the specific type with a non-missing area that were included in a baseline 
tumor burden assessment.  
7. 
Analysis Subsets 
7.1 
Intent to Treat Analysis Set 
The primary analysis of all efficacy endpoints of the study will be conducted on the intent 
to treat analysis set defined as all randomized subjects who were randomized to either 
treatment arm.  All subjects will be analyzed according to their treatment randomization.   


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7.2 
Safety Analysis Set 
The safety analysis set will include all randomized subjects who received talimogene 
laherparepvec or surgical resection of melanoma tumor lesion(s).  The safety analyses 
will be performed by treatment received (i.e., neoadjuvant talimogene laherparepvec  
+ surgical resection versus surgical resection alone).  Subjects will be classified in the 
talimogene laherparepvec arm for safety analyses if they received at least 
one administration of talimogene laherparepvec at any time during the treatment period. 
7.3 
Efficacy Analysis Set 
The efficacy analysis set will include all subjects in Arm 1 who received at least 
one dose of talimogene laherparepvec and surgical resection of melanoma tumor 
lesion(s) and all the subjects in Arm 2 who received surgical resection of melanoma 
tumor lesion(s).  In addition, all subjects in the efficacy analysis set must have achieved 
histopathologic tumor-free margin (R0) status after surgery and should not have any 
important protocol deviations considered to affect efficacy outcomes listed in 
Section 10.3.   
Subject with any of the following eligibility criteria IPDs will be removed from the 
Efficacy Analysis Set: 
• 
Subject does not have histologically proven stage IIIB, IIIC, or IVM1a 
melanoma eligible for complete surgical resection 
• 
Subject is not a candidate for intralesional therapy 
For purposes of the Efficacy Analysis Set sensitivity analysis, subjects who did 
not receive the assigned treatment arm will be excluded from the analysis.   
The Efficacy Analysis Set will be used for a sensitivity analysis of the primary efficacy 
endpoint. 
7.4 
Subgroup Analyses 
Efficacy analyses will be conducted utilizing the subgroups as defined in Section 4.2.   
Safety analyses will be conducted on the following subgroups:  age group  
(< 65, ≥ 65 and < 75, ≥ 75), sex, and race (white vs not white). 
8. 
Planned Analyses 
8.1 
Interim Analysis and Early Stopping Rules 
Two interim analyses with no formal stopping rules are planned to evaluate safety when 
approximately 40 and 75 subjects randomized to talimogene laherparepvec have had 
the opportunity to complete the safety follow-up visit.  The database will be cleaned 


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and a database snapshot will be used in each analysis. A Data Review Team (DRT) 
independent of the talimogene laherparepvec product team will review the first interim 
analysis (see Section 8.1.1). The DRT will also review some efficacy endpoints  
(eg, R0 resection rate, pCR rate, response to neoadjuvant treatment).   
The Amgen study team will review the second interim analysis because it will occur 
after all subjects have been already treated, have completed safety follow-up, and no 
additional interventions that may influence safety or efficacy of the investigational 
product are planned after this time point. The Amgen study team will also review some 
efficacy endpoints (eg, R0 resection rate, pCR rate, response to neoadjuvant treatment).   
An additional third interim analysis with no formal stopping rule is planned to evaluate 
RFS approximately 1 year after the end of randomization. This analysis will be 
conducted by the Amgen study team.  The database will be cleaned and a locked 
database will be used for this analysis. 
Ad hoc analyses for safety or some efficacy endpoints (eg, response to neoadjuvant 
treatment, R0 resection rate, pCR rate) may be conducted before the planned primary 
and/or final analyses if interim data are required for submission to regulatory authorities. 
These ad hoc analyses will be executed by the Amgen study team. 
8.1.1 
Data Review Team (DRT) 
A Data Review Team (DRT) independent of the talimogene laherparepvec product team 
will be formed.  The DRT will consist of one Amgen biostatistician and two Amgen 
clinicians (one from Clinical Development and one from Global Safety) who collectively 
have experience in oncology clinical research and in the conduct and monitoring of 
randomized clinical trials.  In addition, the DRT will include one external clinical expert 
(eg, a surgical oncologist in melanoma) not directly involved in the conduct of the study. 
The DRT will be supported by a statistician internal to Amgen but independent of the 
talimogene laherparepvec product team. This DRT will review unblinded safety data at 
the first interim analyses.  This independent DRT will be governed by a study-specific 
DRT charter. 
8.2 
Primary Analysis 
The primary analysis for RFS will occur at the later time of either the occurrence 
of approximately 64 events (local, regional, or distant recurrence of melanoma or 
death) or approximately 2 year after the end of the randomization.  The database 
will be cleaned and a locked database will be used in the analysis.   


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8.3 
Final Analysis 
The final analysis will occur approximately 5 year after the end of randomization.  
The database will be cleaned and a locked database will be used in analysis.   
8.4 
Additional Analysis 
An additional analysis will also occur approximately 3 years after the end of 
randomization.  The database will be cleaned and a locked database will be used 
in analysis. 
9. 
Data Screening and Acceptance 
9.1 
General Principles 
The objective of the data screening is to assess the quantity, quality and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
9.2 
Data Handling and Electronic Transfer of Data  
Amgen’s Clinical Data Management department will provide all data to be used in the 
planned analyses.  This study will use the RAVE database.  Antibody will be processed 
by vendor for Amgen BSM and then transferred to Amgen’s Medidata Rave database to 
be accessed for analysis.   
9.3 
Handling of Missing and Incomplete Data 
9.3.1 
Efficacy 
The method for handling missing data is described in the definition for each of the 
efficacy endpoints (Section 4).   
9.3.2 
Safety 
Partial or missing dates of adverse events and concomitant medications will be imputed.  
9.4 
Detection of Bias 
9.4.1 
Important Protocol Deviations (IPD) Impact 
All IPDs will be reported, documented, and stored in eClinical (Clinical Trial Management 
System).  An IPD report will be produced using Cognos by the Clinical Study Manager 
for regularly scheduled Study Team IPD Review meetings and before each analysis.  
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by tabulating subjects with important protocol violations by study arm.  A 


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listing of all IPDs will also be provided.  High rates of lack of compliance or differing rates 
between study arms could be an indication of bias.  A sensitivity analysis will be 
performed on the primary efficacy endpoint for the impact of important protocol 
deviations by repetition of analysis using the Efficacy Analysis Set (see Section 7.3). 
9.4.2 
Timing Bias Impact  
Differences between the arms in the Schedule of Assessments (SOA) may result in a 
possible bias in the detection of overall recurrence (local, regional, or distant 
recurrence).  
If 10% or more of the overall post-surgery recurrences (both arms combined), regardless 
of surgical outcome, occur within the first 6 months post-surgery, then a stratified 
piece-wise Cox model will be used to allow estimation of within interval treatment hazard 
ratios of talimogene laherparepvec plus surgery compared to surgery alone adjusting for 
the randomization factors for the overall ITT population (Collett 2003). The time intervals 
are defined as: ≤ 6 months post-surgery, then every 6 months thereafter. Please see 
Appendix B for code fragments. 
9.4.3 
Subsequent Anti-Cancer Therapy Impact 
To evaluate the potential bias introduced by the use of subsequent anti-cancer therapy 
on RFS, three separate sensitivity analyses will be performed based on the type of 
anti-cancer therapy received: (a) any subsequent anti-cancer therapy, (b) adjuvant 
anti-cancer therapy for melanoma, (c) non-adjuvant anti-cancer therapy for 
melanoma. For analyses (a) and (b), subjects who receive the respective 
subsequent anti-cancer therapy type prior to an RFS event will be censored at the 
last evaluable tumor assessment prior to receiving the respective subsequent 
anti-cancer therapy type. For analysis (c), subjects who receive non-adjuvant 
anti-cancer therapy for melanoma prior to an RFS event will be an event at the last 
evaluable tumor assessment prior to receiving the non-adjuvant anti-cancer 
therapy for melanoma. 
These sensitivity analyses will be repeated using the alternative definition for RFS 
as defined in RFS Sensitivity #1 (Section 4.1.1).  
9.5 
Outliers 
Descriptive statistics will be used to identify outliers in any key variables.  Suspected 
outliers will be included in all analyses unless there is sufficient scientific justification to 
exclude them. 


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9.6 
Distributional Characteristics 
Time to event endpoints will be evaluated with the non-parametric log-rank test.  The 
semi-parametric proportional hazards model will be used to estimate the treatment 
hazard ratio with and without stratification which assumes the hazard for events are 
proportional over time between the treatment arms within strata.   
Log-log curves will be plotted to assess the hazard proportionality between treatment 
arms.  The curves will be repeated by randomization stratum.  If the hazards are 
proportional between treatment arms, the curves must be parallel.  Also, KM curves 
should not cross (unless the hazards are similar which means no treatment difference). 
The assumption of proportional hazards will be investigated adding a treatment*log(time) 
interaction in the Cox model.  If the hazards are proportional between treatment arms, 
the treatment*log(time) interaction must be non-significant (see code fragment in 
Appendix B). 
A Kolmogorov-type supremum test will be used to test the proportional hazards 
assumption for treatment comparison based on an analysis of cumulative residuals 
overall and within the randomization strata (Lin, Wei, and Ying, 1993, see code fragment 
in Appendix B). 
The diagnostic approaches described before will be conducted by the study statistician 
and no official output will be provided unless necessary.  
If the proportional hazards assumption is strongly violated, then an alternative analysis 
will be considered.  A stratified piece-wise Cox model will be used to allow estimation of 
an overall weighted-average hazard ratio as well as within interval treatment hazard 
ratios (Collett 2003).  Three intervals will be used in the piecewise model, one from time 
0 to 12 months, one from time 12 to 24 months, and the other beyond 24 months  
(see code fragment in Appendix B), other intervals may be evaluated to assess 
sensitivity.   
9.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   


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The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System version 9.4 or 
later.   
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
All analyses will be descriptive with no formal hypothesis testing. 
In principle, mean, standard deviation, median, first and third quartiles, minimum and 
maximum will be calculated for continuous variables; frequency and percent will be 
calculated for binary and categorical variables.  Graphical summaries of the data may 
also be presented. 
Analyses of tumor tissue or serum biomarkers may be performed after collection of all 
samples during the conduct of the study and therefore may be reported after the primary 
analysis of efficacy endpoint. 
The primary analysis for efficacy endpoints will be performed on the Intent to Treat 
Analysis Set by randomized treatment. In addition, some of the analysis may be 
repeated on the Efficacy Analysis Set by treatment actually received.  Safety analyses 
will be conducted on the Safety Analysis Set. 
Data analysis is scheduled to occur at the following time points:  
• 
Two interim analyses with no formal stopping rules will be performed when 
approximately 40 and 75 subjects randomized to talimogene laherparepvec have 
had the opportunity to complete the safety follow-up visit. (Please refer to  
section 8.1 for details). 
• 
An additional third interim analysis with no formal stopping rule is planned to 
evaluate RFS approximately 1 year after the end of randomization. This analysis 
will be conducted by the Amgen study team. (Please refer to section 8.1 for 
details). 
• 
The primary analyses for RFS will occur at the later time of either the occurrence 
of approximately 64 events (local, regional, or distant recurrence of melanoma or 
death) or approximately 2 years after end of randomization. The primary analysis 
for certain secondary endpoints (eg, response to neoadjuvant treatment, R0 
resection rate, pCR rate, and safety) will be performed using the data from the 
second interim analysis. 
• 
The final analyses will occur approximately 5 years after the end of 
randomization. An additional analysis will also occur approximately 3 years after 
the end of randomization. 
• 
Ad hoc analyses for safety or some efficacy endpoints (eg, response to 
neoadjuvant treatment, R0 resection rate, pCR rate) may be conducted before 
the planned primary and/or final analyses if interim data are required for 
submission to regulatory authorities. These ad hoc analyses will be executed by 
the Amgen study team. 


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10.2 
Subject Accountability 
The number of subjects in each of the strata at randomization will be summarized by 
randomized treatment.   
A subject disposition summary table will be produced.  The number of subjects 
screened, randomized who are treated (talimogene laherparepvec or/and surgery) and 
not treated will be tabulated by randomized treatment.  Reasons for discontinuation of 
talimogene laherparepvec and not receiving surgery, end of study status (completed vs. 
did not complete), reason for not completing the study, the status of completing safety 
follow-up, and the reason for not completing safety follow-up will also be summarized by 
randomized treatment.  The number of screen failure subjects and screen failure 
reasons will also be provided.  
10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, deviation codes and descriptions will 
be used during the course of the study.  The final IPD list is used to produce the 
summary of IPDs table and the list of subjects with IPDs by deviation category, 
subcategory, and randomized treatment.  A separate summary table and listing will also 
be provided for inclusion/exclusion deviations.   
Subjects with the IPDs considered affecting efficacy outcomes will be excluded from the 
Efficacy Analysis Set (see Section 7.3).   
10.4 
Demographic and Baseline Characteristics 
Summary statistics of the following demographic and baseline disease 
characteristics will be tabulated by randomized treatment arm on the Intent To Treat 
Analysis Set:   
• 
Region: USA or non-USA 
• 
Age at baseline:  < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 
• 
Sex: male or female 
• 
Number of measurable tumors at baseline  
• 
Presence of uninjected tumors at baseline and during the treatment:  yes vs no 
(Arm 1 only) 
• 
The sum of the products of the two largest perpendicular diameters of baseline 
measurable lesions (SPD) 


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• 
Histogenetic subtype: acral lentiginous melanoma vs desmoplasitic vs lentigo 
maligna melanoma vs nodular melanoma vs superficial spreading melanoma 
vs unclassifiable vs missing 
• 
Current disease stage (IVRS):  IIIB nodal vs IIIB in transit vs IIC nodal vs IIIC 
in-transit with nodal vs IV M1a 
• 
Current disease stage (CRF): IIIB vs IIIC vs IV M1a   
• 
Time from initial histological diagnosis of melanoma to study entry 
• 
Baseline absolute lymphocyte count:  ≤ 1000 vs > 1000 
• 
Recurrent disease ≥ 1 year from primary diagnosis vs recurrent disease  
< 1 year from primary diagnosis vs no prior melanoma 
• 
Baseline ECOG performance status: 0 vs 1 
• 
BRAF mutation status:  mutation present vs mutation not present vs missing 
• 
Baseline HSV-1 status: negative vs positive vs equivocal vs unknown 
• 
Previous systemic anti-cancer therapy for melanoma: yes vs no 
• 
Previous systemic immune check-point inhibitor therapy for melanoma: yes vs 
no 
• 
Prior surgical procedures: yes vs no 
• 
Prior radiotherapy: yes vs no 
• 
Planned adjuvant therapy (IVRS): adjuvant systemic therapy with or without 
radiotherapy vs radiotherapy without adjuvant systemic therapy vs none 
10.5 
Efficacy Analyses  
The following table (Table 2) summarizes the efficacy endpoints and planned analysis 
methods. 
 


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Table 2.  Study Design Characteristics Example Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method 
Sensitivity Analysis 
Primary Endpoint 
• 
RFS 
• 
Log-rank test and 80% CI for the 
treatment hazard ratio from a 
proportional hazards model 
without stratification in the ITT 
analysis set. 
• 
Kaplan-Meier (K-M) estimation by 
randomized treatment arm.  
• 
Simultaneous 80% confidence 
band for each arm KM estimate 
from 1 to 5 years per equal-
precision band method. 
• 
80% CI for K-M quartiles by arm 
(where estimable) per 
Brookmeyer & Crowley. 
• 
80% CI for between-arm quartile 
difference in KM estimate via 
bootstrap. 
• 
Repeat with stratification by the two randomization factors  
• 
If 10% or more of the overall recurrence (both arms combined) occur within the first 
6 months post-surgery, the stratified analysis will be repeated with stratified piece-wise 
Cox model to estimate within interval hazard ratios adjusting for randomization factors. 
• 
Estimate the Cox model hazard ratio with Robins IPCW weighting censoring RFS at 
the start of all or selected adjuvant therapy for melanoma. 
• 
 If warranted (eg, the planned adjuvant therapy stratification factor is discordant with 
the actual for > 10% of all subjects), the stratified analysis will be repeated replacing 
planned adjuvant therapy with actual adjuvant therapy and/or adjuvant therapy 
containing selected types of systemic therapy, including immunotherapy.  
• 
Cox model and KM analysis of RFS according to randomized treatment and actual 
adjuvant systemic therapy (yes vs no) with 3 comparisons: all subjects, those with 
adjuvant systemic therapy, and those without adjuvant systemic therapy. 
• 
Repeat with and/or without stratification by the two randomization factors in the efficacy 
analysis set, if necessary. 
• 
Univariate and multivariate proportional hazards models without stratification may be 
used to explore the prognostic and/or predictive value of baseline covariates using 
primary endpoint definition and alternative endpoint definition #1 in Section 4.1.1.. 
• 
Subgroup analyses will be evaluated with a log-rank test and corresponding 
proportional hazard model without stratification using primary endpoint definition and 
alternative endpoint definition #1 in Section 4.1.1.  
• 
Repeat subgroup analyses with a log-rank test and proportional hazards model with 
stratification by two randomization factors. 
• 
Repeat using sensitivity analysis alternative endpoint definitions  (see Section 4.1.1). 
• 
Repeat based on the type of anti-cancer therapy received: any subsequent anti-cancer 
therapy, adjuvant anti-cancer therapy for melanoma, non-adjuvant anti-cancer therapy 
for melanoma using primary endpoint definition and alternative definition # 1 in  
Section 4.1.1. Subjects who receive the respective subsequent anti-cancer therapy 
type prior to an RFS event will be censored at the last evaluable tumor assessment 
prior to receiving the respective subsequent anti-cancer therapy type. 
Page 1 of 3 


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Table 2.  Study Design Characteristics Example Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method 
Sensitivity Analysis 
Key Secondary Endpoints 
• 
OS 
• 
DMFS 
• 
LRFS 
• 
RRFS 
• 
The same methods described for the primary 
endpoint. 
• 
Excluding OS, repeat with stratification by two 
randomization factors. 
• 
For LRFS, assess the equality between treatment 
groups using Gray's test, and estimate treatment HR 
with 95% CI stratified by the randomization factors 
using subdistribution proportional hazards model, with 
distant recurrence as competing risk. 
• 
DMFS will be compared with Gray’s test and the 
subdistribution proportional hazards model with 
censoring considered a competing risk if the subject 
has a primary reason for ending the study after a local 
or regional recurrence of withdrawal of consent or lost 
to follow-up. 
• 
RRFS will be compared with Gray’s test and the 
subdistribution proportional hazards model with 
censoring considered a competing risk if the subject 
has a primary reason for ending the study after a local 
recurrence of withdrawal of consent or lost to 
follow-up. 
• 
Landmark RFS, LRFS, 
RRFS, DMFS by year;  
• 
Landmark OS by year 
• 
80% CI for the K-M estimate in the ITT analysis set 
by randomized treatment arm with s.e. per 
Greenwood. 
• 
80% CI for the between-arm difference with s.e., 
per Greenwood. 
 
• 
Excluding OS, repeat using the alternative endpoint 
definition #1 in Section 4.1.1. 
Page 2 of 3 


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Table 2.  Study Design Characteristics Example Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method 
Sensitivity Analysis 
Key Secondary Endpoints 
• 
Rate of R0 surgical 
resection; 
• 
Rate of pCR 
• 
80% exact CI by randomized treatment arm in 
the ITT analysis set per Clopper-Pearson. 
• 
80% approximate exact CI for the between-arm 
difference per Wilson’s score method with 
continuity correction. 
• 
Repeat using the efficacy analysis set, if necessary.  
• 
Multivariate logistic models may be used to explore 
the prognostic and/or predictive value of baseline 
factors. 
 
Tumor response (Arm 1 Only): 
• 
Overall Tumor Response 
(per Investigator) 
• 
Individual injected lesion 
response overall and by 
subtype (cutaneous / 
subcutaneous vs lymph 
node) 
• 
Individual uninjected 
lesion response overall 
and by subtype 
(cutaneous / 
subcutaneous vs lymph 
node) 
• 
Subject response on 
overall injected lesions 
• 
Subject response on 
overall uninjected lesions 
• 
For response rate use the Clopper-Pearson 
method to calculate exact 80% CIs;  
• 
For time to response the Kaplan-Meier (K-M) 
estimate 
• 
The tumor response analysis is performed in the 
ITT analysis set. 
• 
Repeat using the efficacy analysis set, if necessary. 
Page 3 of 3 


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10.5.1 
Analyses of Primary Efficacy Endpoint(s) 
An overall between-group difference in RFS will be evaluated with a log-rank test and 
corresponding proportional hazards model without stratification.  Sensitivity analyses, 
using alternate definitions of RFS as defined in section 4.1.1, will be evaluated in the 
same manner. Additionally, for RFS, a log-rank test and proportional hazards model with 
stratification by the two randomization factors will also be conducted.   
A sensitivity analysis will be performed censoring RFS at the start of all or selected 
actual adjuvant therapy for melanoma. However, censoring at start of all or selected 
adjuvant therapy for melanoma may introduce dependent censoring as the ability to 
receive further adjuvant therapy will likely be correlated with RFS. An inverse probability 
censoring weighting (IPCW) method (Robins, et al) which may reduce the potential bias 
will also be used to obtain an estimate of the treatment effect on RFS and may include 
baseline covariates in Section 4.2.   
In order to assess the impact of imbalances in the type of adjuvant therapy, a stratified 
Cox model will be repeated stratifying actual adjuvant systemic therapy (yes vs no). A 
KM time to event plot for RFS will be generated by 4 groups (Arm 1 with adjuvant 
systemic therapy , Arm 1 without adjuvant systemic therapy, Arm 2 with adjuvant 
systemic therapy, Arm 2 without adjuvant systemic therapy), and 2 separate KM plots 
will be generated by randomized treatment group in subjects with and without adjuvant 
systemic therapy respectively. If warranted due to actual adjuvant therapy (eg, the 
planned adjuvant therapy stratification factor is discordant with the actual for > 10% of all 
subjects), the stratified Cox model analysis will be repeated stratifying on actual 
adjuvant therapy type (adjuvant systemic therapy with or without radiotherapy vs 
radiotherapy without adjuvant systemic therapy vs none). 
To explore the prognostic and/or predictive value of the covariates listed in 
Section 4.2, univariate and multivariate proportional hazards models without 
stratification will be used.  Subgroup analyses will be evaluated with a log-rank 
test and corresponding proportional hazards model without stratification.    
10.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
KM estimates will be calculated for RFS, LRFS, RRFS, DMFS, RFS landmarks by year, 
OS landmarks by year and quartiles.  Greenwood’s formula (Kalbfleisch and Prentice, 
1980) for standard error will be used to calculate CIs for each group and between-group 
differences in landmark KM rate estimates.  CIs for quartiles of each group will be 
estimated per Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) using a 


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log-log transformation and bootstrap methods will be used to estimate CIs for 
between-group differences (see Section B.3 for SAS code fragments).  For each group 
the equal-precision band method will be used to calculate a simultaneous confidence 
band for RFS, LRFS, RRFS and DMFS over the interval from 1 to 5 years (Nair, 1984) 
(see Section B.2 for SAS code fragments).   
An overall between-group difference in LRFS, RRFS, DMFS, and OS will be evaluated 
with a log-rank test and corresponding proportional hazard model with or without 
stratification by the two randomization factors.  
Informative censoring due to distant recurrence is expected for LRFS. For LRFS, after 
considering distant recurrence as competing event, Gray's test (Gray, 1988) will be 
performed to assess the equality of cumulative incidence functions between treatment 
groups, and the subdistribution proportional hazards model (Fine and Gray, 1999) will be 
used to calculate treatment HR with 95% CI with or without stratification by the 
randomization factors.  The same sensitivity analysis will be performed for DMFS with 
censoring considered a competing risk if the subject has a primary reason for ending the 
study after a local or regional recurrence withdrawal of consent or lost to follow-up.  The 
same analysis will be performed for RRFS with censoring considered a competing risk if 
the subject has a primary reason for ending the study after a local recurrence of 
withdrawal of consent or lost to follow-up.  Please see Appendix B for SAS code 
fragments.   
A sensitivity analysis will be performed for LRFS censoring at the start of all or selected 
actual adjuvant therapy (systemic therapy radiotherapy) for melanoma. However, 
censoring at start of selected adjuvant therapy (systemic therapy radiotherapy) for 
melanoma may introduce dependent censoring as the ability to receive further adjuvant 
therapy will likely be correlated with LRFS. An inverse probability censoring weighting 
(IPCW) method (Robins, et al) which may reduce the potential bias will also be used to 
obtain an estimate of the treatment effect on LRFS and may include baseline covariates 
in Section 4.2. Similar analyses will be performed on DMFS and RRFS. 
If warranted due to actual adjuvant therapy (eg, the planned adjuvant therapy 
stratification factor is discordant with the actual for > 10% of all subjects), the stratified 
Cox model analysis will be repeated stratifying on actual adjuvant therapy type 


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(adjuvant systemic therapy with or without radiotherapy vs radiotherapy without 
adjuvant systemic therapy vs none).  
Multivariate proportional hazards models may be used to explore the prognostic and/or 
predictive value of baseline factors. 
The Clopper-Pearson method (Clopper and Pearson, 1934) will be used to calculate 
exact CIs for binary endpoints (eg, overall tumor response, response in injected and 
uninjected lesions, R0 rate, pCR) (see Section B.1 for SAS code fragments).  Wilson’s 
score method with continuity correction (Newcombe, 1998) will be used to calculate an 
approximate exact CI for between-group differences in binary rates (see Section B.4 for 
SAS code fragments).  Multivariate logistic models may be used to explore the 
prognostic and/or predictive value of baseline factors. 
10.6 
Safety Analyses 
10.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.1 or later will be 
used to code AEs 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 AEs.    
Only treatment-emergent adverse events (see Section 6 for definition) will be 
summarized by treatment received.  Subject incidence rates of all treatment-emergent, 
grade ≥ 3, serious, non-serious, treatment related, serious treatment related, 
non-serious treatment related, events leading to talimogene laherparepvec 
withdrawal/delay/less than 4ml volume per administration, events leading to cancel the 
scheduled surgical removal of the melanoma tumor lesion(s), fatal adverse events and 
local effects on the lesion (i.e., pain, inflammation and ulceration) as well as adverse 
events of interest will be tabulated by SOC and PT in descending order of frequency 
within an SOC.  For all treatment-emergent adverse events additional summary tables 
will also be provided by (1) SOC, PT in descending order of frequency within an SOC 
and worst CTCAE grade, and (2) PT in descending order of frequency.   
In addition, certain categories of adverse events occurring within the talimogene 
laherparepvec monotherapy period and within the period after the start of the first dose 
of talimogene laherparepvec of 106 PFU/mL but before the first dose talimogene 
laherparepvec of 108 PFU/mL will be summarized separately by system organ class and 
preferred term in descending order of frequency.  These categories of adverse events 
include all treatment-emergent adverse events, serious treatment-emergent adverse 


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events, non-serious treatment-emergent adverse events, talimogene laherparepvec 
related treatment-emergent adverse events. 
Subgroups group analyses for age group (< 65, ≥ 65 and < 75, ≥ 75), sex, and race 
(white vs not white) will be presented for all treatment-emergent adverse events by 
system organ class and preferred term by treatment received in descending order of 
frequency.   
Narratives of deaths through either the 30 days after the last dose of talimogene 
laherparepvec or the surgical resection of melanoma tumor lesion(s), whichever is later, 
will be provided. 
Adverse events after the completion of the surgical resection of melanoma tumor 
lesion(s) through the 30 days after the last dose of talimogene laherparepvec or the 
completion of the surgical resection of melanoma tumor lesion(s), whichever is later, will 
be also be summarized. 
A listing of treatment-related AEs reported in long term follow-up will be provided for the 
final CSR and may be analyzed earlier as part of a program-wide analysis.  
10.6.2 
Laboratory Test Results 
Laboratory values will be summarized descriptively.  In addition, grade shifts in 
laboratory value from baseline to worst on-study value (according to NCI Common 
Toxicity Criteria (CTC) version 3.0 grading) and grade 3 or higher laboratory toxicities 
will be presented for selected laboratory tests with CTC grade.  Textbook lower and 
upper limits of the normal ranges will be used for CTC grading, where applicable.  For 
serum lactate dehydrogenase (LDH) local laboratory range will be used.  
10.6.3 
Vital Signs 
Descriptive statistics will be presented for systolic blood pressure, diastolic blood 
pressure, pulse, respiration rate and temperature for baseline, each post-baseline visit, 
and change from baseline. 


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10.6.4 
ECOG Performance Status 
ECOG performance status scores will be summarized for each treatment arm at each 
assessed time point.  The change in scores from baseline to each assessed time point 
will also be summarized.   
10.6.5 
Electrocardiogram (ECG) 
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; neither summaries nor 
statistical analyses will be provided, and these data would not be expected to be useful 
for meta-analysis with data from other trials. 
10.6.6 
Antibody Formation  
HSV-1 serostatus will be summarized for each visit for patients who receive talimogene 
laherparepvec.  IgG reactivity with HSV-1 will be determined.  The data summaries and 
baseline serostatus analyses will be performed for IgG.  Treatment-emergent adverse 
events will be summarized for subjects who receive talimogene laherparepvec by 
baseline HSV-1 serostatus by system organ class and preferred term.  In addition, 
treatment-emergent immune-related adverse events of interest will also be summarized 
by baseline HSV-1 serostatus and preferred term for patients treated with T-VEC.   
The incidence of subjects with herpetic lesions found to be positive for talimogene 
laherparepvec DNA per qPCR in swab samples collected from lesions suspected to be 
herpetic in origin and the rate of positive lesions (if any) will be calculated.   
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 in the final CSR.  Listings of 
reported cases with available qPCR testing results will be provided. Additionally, 
unintended exposures will be analyzed periodically as part of a program-wide analysis. 
10.6.7 
Exposure to Investigational Product 
Summary statistics for the total number of talimogene laherparepvec doses 
administered, total volume of talimogene laherparepvec administered, duration of first 
talimogene laherparepvec to last talimogene laherparepvec administration, and average 
volume of talimogene laherparepvec per visit will be provided for subjects who receive 
talimogene laherparepvec separately for the first dose of talimogene laherparepvec of 


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106 PFU/mL and the subsequent doses.  The incidence and reasons for drug withdrawal 
and injection less than 4 ml will be tabulated for subjects who receive talimogene 
laherparepvec.   
A listing of unique manufacturing lot number(s) for talimogene laherparepvec and 
subject listings of manufacturing lot number(s) of talimogene laherparepvec will be 
provided. 
The protocol specified surgical resection of melanoma tumor lesion(s) will be 
summarized.  For subjects who do not receive the surgery the reason why the surgery is 
not conducted will also be summarized. 
10.6.8 
Exposure to Concomitant Medication/Adjuvant Therapy/Subsequent 
Anti-cancer Therapy 
Prior systemic or regional anti-cancer therapies for current malignancy of melanoma, 
prior surgeries for current malignancy of melanoma and prior radiation therapy for 
current malignancy of melanoma will be summarized separately.   
The concomitant medications/on-treatment surgery include all /surgery except the 
protocol specified surgical resection of melanoma lesion(s) after randomization and all 
medications after randomization before receiving surgery except for talimogene 
laherparepvec.  The number and proportion of subjects receiving any concomitant 
medication during the treatment period will be summarized by preferred term as coded 
by the World Health Organization Drug (WHODRUG) dictionary.  
The subject incidence and duration of subsequent adjuvant therapy for melanoma will be 
summarized overall, by type (systemic therapy with radiotherapy, systemic therapy 
without radiotherapy, radiotherapy without systemic, no subsequent adjuvant therapy at 
all), and by specific therapy components. Time to first use of subsequent adjuvant 
anti-cancer therapy for melanoma will be summarized. 
The subject incidence and time to first use of subsequent non-adjuvant anti-cancer 
therapy for melanoma will be summarized. 


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11. 
Changes From Protocol-specified Analyses 
The changes from protocol-specified analyses are as following, 
• 
In the statement regarding subjects who are not confirmed to be disease-free 
post-surgery or who withdraw prior to surgery, failure was changed from “a day 
after randomization” to “at randomization” for RFS, RRFS, LRFS and DMFS in 
section 3.2. 
• 
Safety endpoints related to talimogene laherparepvec DNA shedding and 
potential or known unintended exposure to talimogene laherparepvec were 
added as safety endpoints.  The current protocol mentioned the analysis of these 
endpoints without specifically claiming them as safety endpoints.   


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12. 
Literature Citations / References 
Amgen, Protocol : “A Phase 2, Multicenter, Randomized, Open-label Trial Assessing the 
Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery 
Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma.” Amendment 1, 
09 June 2014  
Brookmeyer R, Crowley J. A confidence interval for median survival time. Biometrics. 
1982;38:29-41. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934:26:404-413. 
Fine, J. and Gray, R. A Proportional Hazards Model for the Subdistribution of a 
Competing Risk. Journal of the American Statistical Association. 1999;94: 496-509.  
Gray, R. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a 
Competing Risk. The Annals of Statistics. 1988;16: 1141–1154.  
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York, NY: 
John Wiley;1980. 
Nair VN. Confidence bands for survival functions with censored data: a comparative 
study. Technometrics. 1984;26:265-275. 
Newcombe RG. Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Statistics in Medicine. 1998;17:873-890. 
Robins R, Hernan M, and Brumback B. Marginal Structural Models and Causal Inference 
in Epidemiology. 2000; 11(5):550-560. 


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13. 
Data Not Covered by This Plan 
The analysis on exploratory endpoints described in Section 4.1.3 is not covered by this 
SAP. 


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14. 
Appendices 


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Appendix A.  Conventions for Clinical Data That Require Imputation for  
Partial or Missing Dates  


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Product:  Talimogene Laherparepvec 
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Appendix B.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs 
Code Fragments 
B.1 
Exact Confidence Interval 
proc freq data=dat1; 
   tables R0/ binomial(exact) alpha=.2; 
   by TRTGRP; 
run; 
B.2 
Nair Equal-Precision Band  
proc lifetest data=dat1 plots=survival(cb=ep test); 
   time OS * CENSOR(1); 
   strata TRTGRP; 
run; 
B.3 
Bootstrap for Confidence Interval of Quantile Difference per K-M Estimate 
%let rep = 100; 
proc surveyselect data= os out=bootsample 
     seed = 1347 method = urs 
 
 samprate = 1 outhits rep = &rep; 
run; 
ods listing close; 
 
ods output  Quartiles=TimeToDeath;  
proc lifetest data=bootsample alpha=0.2 ALPHAQT=0.2 plots=(s); 
  time OSM*CENSOR(1); 
  strata TRTGRP; 
  by Replicate; 
run; 
ods output close; 
B.4 
Wilson’s Score Method With Continuity Correction 
Macro and Sample Code for Wilson’s score method with continuity 
correction 
• 
S1 is the numerator and N1 is the denominator for T-VEC; S2 is the 
numerator and N2 is the denominator for GM-CSF 
• 
There are variables P1, P2 , LL and UL. 
• 
The percentage difference is the P1-P2 and 95% CI is (LL, UL) 
 
%macro method11(ds=,  
                dsout=, 
                by=, 
                cc=0.80); 
 
  data &dsout; 
    length s1 n1 p1 s2 n2 p2 LL UL cc 8; 
    set &ds; 
    retain cc &cc; 
    array nn{2} n1 n2; 
    array s{2} s1 s2; 
    array p{2} p1 p2; 
    array q{2} _temporary_; 


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    array np{2} _temporary_; 
    array nq{2} _temporary_; 
    array l{2} _temporary_; 
    array u{2} _temporary_; 
    ca2=probit(0.5 + cc/2); 
    ca2sq=ca2*ca2; 
    do i=1 to 2; 
      p{i}=s{i}/nn{i};; 
      q{i}=1-p{i};; 
      nq{i}=nn{i}*q{i}; 
      np{i}=nn{i}*p{i}; 
      if p{i}=0 then l{i}=0; 
      else l{i}=(((2*np{i})+(ca2sq-1))-(ca2*(sqrt((ca2sq-(2+(1/nn{i}))+ 
((4*p{i})*(nq{i}+1)))))))/(2*(nn{i}+ca2sq)) ; 
      if p{i}=1 then u{i}=1; 
      else u{i}=(((2*np{i})+(ca2sq+1))+(ca2*(sqrt((ca2sq+(2-(1/nn{i}))+ 
((4*p{i})*(nq{i}-1)))))))/(2*(nn{i}+ca2sq)) ; 
    end; 
    d=sqrt((p{1}-l{1})**2+(u{2}-p{2})**2); 
    e=sqrt((p{2}-l{2})**2+(u{1}-p{1})**2); 
    LL=p{1}-p{2}-d; 
    UL=p{1}-p{2}+e; 
  *  keep s1 n1 p1 s2 n2 p2 LL UL cc; 
    label s1='Number of Sample from Population 1' 
          n1='Number of Population 1' 
          p1='Proportion 1 = s1 / n1 ' 
          s2='Number of Sample from Population 2' 
          n2='Number of Population 2' 
          p2='Proportion 2 = s2 / n2' 
          ll='Lower limit of interval estimation for difference' 
          ul='Upper limit of interval estimation for difference' 
          cc='Confidence coefficient'; 
  run; 
 
  %if %length(&by)>0 %then %do; 
    proc sort data=&dsout; 
      by &by; 
    run; 
  %end; 
 
  title1 "Comparison of two independent proportions using continuity 
correction" ; 
  title2 'NEWCOMBER METHOD 11 : Example H '; 
  title3 "LL UL &cc% CI for Difference between Independent 
Proportions";  
  proc print data=&dsout label; 
    var &by n1 s1 p1 n2 s2 p2 LL UL cc; 
  run; 
%mend method11; 
 
 
data dsin; 
  input n1 n2 s1 s2; 
cards; 
25 50 5 4.25; 
run; 
%method11(ds=dsin, dsout=dsout, by=, cc=0.95); 


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B.5 
Assumption of non-proportional Hazard: Treatment*log (time) Interaction in 
the Cox Model 
proc phreg data=dat1; 
  model OS * CENSOR(1) = TRTGRP TRTGRP_T / ties=exact rl=pl; 
  TRTGRP_T = TRTGRP *log(OS); 
  strata randomization_strata; 
  proportionality_test: test TRTGRP_T; 
run;  
B.6 
Assumption of non-proportional Hazard: Kolmogorov-type Supremum Test 
ods select cumulativeresiduals scoreprocess; 
proc phreg data=dat1; 
  model OS*CENSOR(1) = TRTGRP / ties=exact rl=pl; 
* Delete strata statement to assess overall proportional hazards; 
  strata randomization_strata;      
  assess ph / resample seed=1234; 
run;  
B.7 
Piecewise Cox Model 
proc phreg data= dat1; 
  model OS*CENSOR(1) = TRTGRP1 TRTGRP2 TRTGRP3 / ties=exact rl=pl;  
  TRTGRP1 = TRTGRP *(OS lt 12);  
  TRTGRP2 = TRTGRP *(12 le OS lt 24);  
  TRTGRP3 = TRTGRP *(24 le OS); 
  strata randomization_strata; 
run; 
B.8 
Estimates Crude Cumulative Incidence Function and Test Equality of 
Cumulative Incidence (Gray’s Test)   
proc lifetest data=dat1; 
time LRFS*Status(0)/eventcode=1;  
strata TRTGRP / order=internal; 
*test for overall difference between groups; 
 
*strata randomization_strata/group=TRTGRP order=internal; 
* stratified test; 
run; 
  
/* The variable Status has three values: 0 for censored observations, 1 
for subjects with event of interest (e.g. local recurrence for LRFS), 
and 2 for patients who experienced competing risk .*/ 
B.9 
Fine-Gray Subdistribution Proportional Hazards Model 
Proc phreg data=dat1 ; 
   class TRTGRP (order=internal ref=first) param=galm; 
   model LRFS*Status(0)= TRTGRP x1 x2 / eventcode=1; 
   hazardratio 'Subdistribution Hazards' TRTGRP; 
   strata randomization_strata; 
* Delete strata statement to assess overall proportional hazards; 
* x1, x2 are covariates. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 46 
 
 
run; 
 
/* The variable Status has three values: 0 for censored observations, 1 
for subjects with event of interest (e.g. local recurrence for LRFS), 
and 2 for patients who experienced competing risk. */ 
B.10 
IPCW 
 
/*Model probability of not receiving all or selected actual adjuvant 
therapy for melanoma including time-independent covariate(s)*/ 
proc logistic data=time_indep; 
   class <categorical time-independent covariate(s)>; 
   model subther(event='0') = <time-independent covariate(s)>; 
   output out=out1 prob=num; 
run; 
 
proc sort data = time_dep; 
   by descending subther; 
run; 
 
/*Model probability of not receiving all or selected actual adjuvant 
therapy for melanoma including time-independent covariate(s) and time-
dependent covariate(s)*/ 
proc genmod data = time_dep descending order=data; 
   class <categorical time-independent covariate(s)> <categorical time-
dependent covariate(s)> usubjid; 
   model subther = <time-independent covariate(s)> <time-dependent 
covariate(s)> / d=binomial link=logit; 
   repeated subject=usubjid; 
   output out=out2 prob=den; 
run; 
 
proc sort data=out1;by usubjid;run; 
proc sort data=out2;by usubjid;run; 
 
/*Calculate weights*/ 
data dat1; 
   merge out1 out2; 
   by usubjid; 
run; 
 
data dat2; 
   set dat1; 
   by usubjid; 
   retain w_num w_den; 
   if first.usubjid then do; 
      w_num = 1; 
      w_den = 1; 
   end; 
   w_num = w_num*num; 
   w_den = w_den*den; 
 
   if subther = 1 then weights = (1-w_num)/(1-w_den); 
   else if subther = 0 then weights = w_num/w_denom; 
run; 
 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110266 
Date:  14 May 2019 
Page 47 
 
data dat3; 
   merge dat2(in=a) adam.adtte(in=b where=(paramcd=’RFSI’ keep=usubjid 
paramcd aval cnsr); 
   by usubjid; 
   if a and b; 
run; 
 
/*HR and corresponding CI using IPCW*/ 
proc phreg data = dat3; 
   class trt01p(ref="SURGERY"); 
   model aval*cnsr(1) = trt01p; 
   freq weights / notruncate; 
   hazardratio trt01p / alpha=0.05 cl=wald diff=ref; 
  strata <stratification factors>; 
run;