Clinical trial NCT03064763
Conditions: Unresectable Stage IIIB-IV Malignant Melanoma
Keywords: Unresectable Stage IIIB-IV Malignant Melanoma
Sponsor: Amgen
Start date: 2017-03-07; Completion date: 2023-01-12
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
There are 2 fold of purposes for this study. 1 is to evaluate safety and tolerability and the other is to study the anti-tumor effects of talimogene laherparepvec in Japanese participants with unresectable stage IIIB-IV malignant melanoma.

Detailed description:
This is a phase 1, multicenter, open-label study of talimogene laherparepvec in Japanese participants with unresectable stage IIIB-IVM1c malignant melanoma that are candidates for intralesional therapy. The Screening period is 28 days prior to study enrollment. There will be a Treatment period, Safety Follow-up period and a Long Term Follow-up period.

The Screening Period: Informed consent will be obtained prior to screening procedures. Screening procedures to determine eligibility include: medical history (including concomitant medications, prior therapy for melanoma and BRAF status (if known)), physical exam, vital signs, assessment of Eastern Cooperative Oncology Group (ECOG) performance level status, electrocardiogram (ECG), laboratory assessments (including hepatitis serology), baseline tumor assessments, and adverse events assessment.

Treatment Period: Initially, 6 Dose Limiting Toxicity (DLT)-evaluable participants will be enrolled and treated at 100% dose regimen of talimogene laherparepvec (Up to 4.0 mL of 10\_6 PFU/mL followed by a dose of up to 4.0 mL of 10\_8 PFU/mL). Upon demonstration of safety based on DLT incidence in the first 6 participants, an additional 12 participants will be enrolled and treated at Dose 1 to obtain additional safety data. If dose de-escalation is needed based on the DLT evaluation of first 6 participants, then additional 6 participants will be treated at lower dose (up to 4.0 mL of 10\_6 PFU/mL followed by a dose of up to 4.0 mL of 10\_7PFU/mL). The duration of treatment will vary for each participants. Participants will be treated until the participant has a DLT during the DLT evaluation period, participant has achieved a Complete Response, no injectable lesions, clinically relevant (resulting in clinical deterioration or requiring change in therapy) disease progression beyond 24-weeks of treatment, or safety concern, whichever occurs first. Maximum treatment duration will be 48 months. The total study duration for an individual participant can be up to 4 years.

Drug Administration: If the participants are found to be eligible to take part in this study, they will receive talimogene laherparepvec by intralesional injection only into injectable cutaneous, subcutaneous, and nodal tumors, with or without image ultrasound guidance. The first injection of talimogene laherparepvec will take place on day 1 (week 0). The second injection should be administered 3 weeks (+ 5 days) after the initial injection. Subsequent injections should be given every 2 weeks (± 3 days).

Study Visits: The participant will have a physical exam along with vital signs and ECOG. At any study visit blood may be collected to monitor health and safety, and effects of talimogene laherparepvec. Adverse events and medications taken will be reviewed at each study visit. The tumor assessment, physical exams, and ECOG performance status will be completed after 12 (± 1) weeks on treatment (ie, day 1 of week 11), and then every 12 (± 1) weeks (eg, weeks 23, 35, 47 etc.), or more frequently if clinically indicated, until Progressive disease beyond 6 months of treatment or until the start of a new anticancer therapy.

Central Lab tests: Blood for herpes simplex virus type-1 (HSV-1) Antibody Serostatus will collected within 3 days prior to dose at day 1 (week 0) and at week 5. Throughout the trial any participant developing a lesion of suspected herpetic origin will have a swab of the lesion for presence of talimogene laherparepvec DNA obtained within 3 days of the event.

Exposure to talimogene laherparepvec by the healthcare providers of the participant and/or close contacts will be assessed.

Safety Follow Visit: A safety follow-up visit will be performed 30 (+7) days after the last dose. The participant will have a physical exam, have vital signs taken, assessment of ECOG status and have weight measured. Adverse events will be assessed as well as the concomitant medications. Routine bloodwork and tumor response assessments will be performed.

Long-Term Follow-up Visits: Follow-up for survival status and, if applicable, commencement of any subsequent anticancer melanoma therapy will occur every 12 weeks (± 28 days) by phone or clinic visit for all participants who permanently discontinue talimogene laherparepvec for any reason other than withdrawal of full consent for up to 24 months after the last participant is enrolled in the study. For participants that discontinue talimogene laherparepvec for reason other than disease progression, the following additional procedures will be conducted during the long-term follow-up: radiographic tumor imaging, clinical tumor assessments, ECOG Performance Status assessments, reporting of pregnancy or lactation, assessment of swabs of lesions of suspected herpetic origin for presence of talimogene laherparepvec DNA, and tumor response assessments until documented disease progression beyond 24-weeks of treatment, until the start of a new anticancer therapy, or end of study, whichever is earliest. If a participant discontinues therapy more than 24 months after the last participant was enrolled in the study, when the long-term follow-up period ends, they will not enter long-term follow-up.

Arms: arm 1: Participants will receive talimogene laherparepvec administered by intralesional injection only into injectable cutaneous, subcutaneous, and nodal tumors, with or without image ultrasound guidance.

On Day 1 (Week 0), the initial dose of talimogene laherparepvec will be up to 4.0 mL of 10\^6 Plaque forming units per millilitre (PFU/mL). Subsequent doses of talimogene laherparepvec will be up to 4.0 mL of 10\^8 or 10\^7 PFU/mL. The second dose is to be administered 3 weeks (+ 5 days) after the initial dose, and subsequent doses were to be given every 2 weeks (+ 3 days).
Interventions: intervention 1: Talimogene laherparepvec
Intervention descriptions: intervention 1: Talimogene laherparepvec will be administered as an intralesional injection.

Protocol documents:
Prot_000.pdf: 
Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 1 of 98 
CONFIDENTIAL 
 
 
Title:  A phase 1, Multi-center, Open-label, Dose De-escalation Study to Evaluate 
the Safety and Efficacy of Talimogene Laherparepvec in Japanese Subjects With 
Unresectable Stage IIIB-IV Malignant Melanoma  
Amgen Protocol Number (Talimogene Laherparepvec) 20140270 
NCT number:  NCT03064763 
Clinical Study Sponsor: 
Amgen Inc. 
1 Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 1-805-447-1000 
 
Amgen K.K.  
9-7-1 Akasaka, Minato-ku, Tokyo Midtown Tower, Tokyo, 
TKYO 
107-6239, Japan 
Phone: 81-3-5293-9900; Fax: 81-3-6730-9645 
Key Sponsor Contact(s): 
, MD, PhD, 
Clinical Research Senior Medical Scientist 
1 Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone:
Email:
 
  
Global Clinical Trial Manager 
240 Cambridge Science Park 
Cambridge UK 
Telephone:
Email:
Original Protocol: 
28 October 2015 
Amendment 1: 
19 July 2016 
Amendment 2: 
08 August 2016 
Amendment 3: 
08 September 2016 
Amendment 4: 
05 December 2017 
Amendment 5 
01 September 2020 
To comply with local regulatory requirements, all uses of the term “clinical 
study” in the protocol, other study-related documents, and forms that have been 
issued or to be issued in future, is replaced with “post-marketing clinical study” 
after Talimogene Laherparepvec has been approved by regulatory authority. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 2 of 98 
CONFIDENTIAL 
 
 
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:  1-805-447-1000 or the local Key Sponsor Contact.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 3 of 98 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A phase 1, Multi-center, Open-label, Dose 
De-escalation Study to Evaluate the Safety and Efficacy of Talimogene Laherparepvec 
in Japanese Subjects with Unresectable Stage IIIB-IV Malignant Melanoma, dated 
01 September 2020, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
The study will be conducted in compliance with the Ministerial Ordinance on Good 
Clinical Practice for Drugs (Ministry of Health and Welfare Ordinance No. 28, 
27 March 1997).  
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 1 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:  20140270 
Date:  01 September 2020 
Page 4 of 98 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A phase 1, Multi-center, Open-label, Dose De-escalation Study to Evaluate the Safety and 
Efficacy of Talimogene Laherparepvec in Japanese Subjects with Unresectable Stage IIIB-IV 
Malignant Melanoma  
Study Phase:  phase 1 
Indication:  Melanoma 
Primary Objective(s):   
There are 2 fold of purposes for this study.  1 is to evaluate safety and tolerability and the other is 
to study the anti-tumor effects of talimogene laherparepvec in Japanese patients with 
unresectable stage IIIB-IV malignant melanoma. 
 
To evaluate the safety and tolerability of talimogene laherparepvec, subjects will be 
assessed by incidence of dose limiting toxicities (DLTs). 
 
These subjects will also be evaluated for the anti-tumor activity of talimogene 
laherparepvec as assessed by durable response rate (DRR) using modified World Health 
Organization (WHO) response criteria.  DRR is defined as the rate of objective response 
(Complete response [CR] or partial response [PR]) lasting continuously for  6 months 
and starting any time within 12 months of initiating therapy. 
Secondary Objective(s):   
 
To evaluate the anti-tumor activity of talimogene laherparepvec, as assessed by overall 
response rate (ORR), time to response (TTR), duration of response (DOR), progression free 
survival (PFS) using modified World Health Organization (WHO) response criteria by 
investigators 
 
To evaluate overall survival (OS) 
Safety Objective: 
 
To evaluate the safety of talimogene laherparepvec as determined by subject incidence of 
adverse events and clinically relevant laboratory abnormalities, where not defined as DLTs. 
Hypotheses: 
No formal statistical hypothesis will be tested for safety endpoints in this trial.  Based on the well 
tolerated safety profile from a global phase 3 study, it is hypothesized that talimogene 
laherparepvec will be safe and well tolerated in Japanese subjects with unresectable stage 
IIIB-IVM1c malignant melanoma.  A DRR is hypothesized to be consistent with results from the 
global phase 3 study. 
Primary Endpoint(s):   
 
Subject incidence of DLTs 
 
DRR using modified WHO response criteria by investigators 
Secondary Endpoint(s):  
 
ORR, TTR, DOR, and PFS using modified WHO response criteria by investigators 
 
OS 
Study Design:  
This is a phase 1, multicenter, open-label study of talimogene laherparepvec in Japanese 
subjects with unresectable stage IIIB-IV malignant melanoma who are candidates for intralesional 
therapy.  Up to approximately 18 subjects will be enrolled in the study.  Subjects may be included 
in the evaluation for both safety and efficacy.  The DLT evaluation period is 35 days from the 
initial administration of talimogene laherparepvec.  Initially, 6 DLT-evaluable subjects will be 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 5 of 98 
CONFIDENTIAL 
 
 
enrolled and treated at Dose 1 (up to 4.0 mL of 106 PFU/mL talimogene laherparepvec will be 
administered on day 1, followed by a dose of up to 4.0 mL of 108 PFU/mL 3 weeks [ 5 days] 
later and then up to 4.0 mL of 108 PFU/mL every 2 weeks [ 3 days] thereafter).  Upon 
demonstration of safety based on DLT rules, an additional 12 subjects will be enrolled and treated 
at Dose 1 to obtain additional safety data.  If dose de-escalation is needed based on the DLT 
evaluation of the first 6 DLT-evaluable subjects, then an additional 6 subjects will be treated at 
Dose -1 (up to 4.0 mL of 106 PFU/mL talimogene laherparepvec will be administered on day 1, 
followed by dose of up to 4.0 mL of 107 PFU/mL 3 weeks [ 5 days] later and then up to 4.0 mL of 
107 PFU/mL every 2 weeks [ 3 days] thereafter).  The same DLT rules will be used to evaluate 
safety based on the initial 6 DLT-evaluable subjects after dose de-escalation.  Upon 
demonstration of safety, additional subjects will be enrolled (up to a total of 18 subjects) at 
Dose-1 to obtain additional safety data.  The hypothesis test for DRR will include all subjects 
enrolled after dose de-escalation who received at least 1 dose of talimogene laherparepvec.  If no 
dose de-escalation is needed the DRR hypothesis test will include the first 18 subjects dosed.   
Treatment with talimogene laherparepvec will continue until the subject has a DLT during the DLT 
evaluation period, subject has achieved a CR, no injectable lesions, clinically relevant (resulting in 
clinical deterioration or requiring change in therapy) disease progression beyond 24 weeks of 
treatment per modified WHO response criteria, safety concern, a maximum treatment duration 
of 48 months, or the drug is commercially available in Japan,  whichever occurs first.  Due to 
the mechanism of action of talimogene laherparepvec, subjects may experience growth in 
existing tumors or the appearance of new tumors prior to maximal clinical benefit.  Therefore, 
treatment with talimogene laherparepvec should be continued for at least 6 months even in the 
presence of progression, including the appearance of new lesions to allow for 
delayed-immune-based antitumor effects to occur unless other therapy for melanoma is required. 
All subjects will complete a safety follow-up Visit 30 ( 7) days after the last dose of study 
treatment.  Subjects will be followed for survival, subsequent anticancer therapies and talimogene 
laherparepvec related adverse events every 12 weeks ( 28 days) for 24 months after the last 
subject is enrolled.  Subjects that are being treated beyond 24 months after the last subject 
enrolled will not enter long-term follow-up and their last visit will be safety follow-up. 
Sample Size:  Approximately 18 subjects will be enrolled.  Subjects may be included in the 
evaluation for both safety and efficacy. 
Summary of Subject Eligibility Criteria:  Key inclusion criteria include: male or female  
subjects,  18 years of age with histologically confirmed diagnosis of stage IIIB to IVM1c 
melanoma for whom surgery is not recommended.  Subject who is treatment naïve and is 
determined by the physician to be not suitable or eligible for the approved systemic anticancer 
drug therapy in Japan.  Subject may also have received prior systemic anticancer treatment 
consisting of chemotherapy, immunotherapy, or targeted therapy.  Subject must have measurable 
disease and must be a candidate for intralesional therapy with at least 1 injectable cutaneous, 
subcutaneous, or nodal melanoma lesion ( 10 mm in longest diameter) or with multiple 
injectable lesions that in aggregate have a longest diameter of  10 mm; to be classified as 
malignant, and measurable lymph nodes must be  15 mm in shortest diameter.  Also, subject 
must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and 
must have a serum lactate dehydrogenase (LDH)  1.5 X upper limit of normal and adequate 
hematologic, hepatic, and renal organ function.  Female subjects of childbearing potential must 
have a negative pregnancy test.  
Key exclusion criteria include: subject must not have clinically active cerebral metastases or 
 3 visceral metastases (this does not include lung or nodal metastases associated with visceral 
organs).  For subjects with  3 visceral metastases, no lesion  3 cm in longest dimension and 
liver lesions must be stable for at least 1 month prior to enrollment. In addition, subject must not 
have any bone metastases.  Subjects will be excluded if they have primary ocular or mucosal 
melanoma, history or evidence of symptomatic autoimmune disease (such as pneumonitis, 
glomerulonephritis, vasculitis, or other) or history of autoimmune disease that required systemic 
treatment (ie, use of corticosteroids, immunosuppressive drugs or biological agents used for 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 6 of 98 
CONFIDENTIAL 
 
 
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.  Subjects must not have active herpetic skin lesions or prior 
complications of herpetic infection (eg, herpetic keratitis or encephalitis) and must not require 
intermittent or chronic systemic treatment with an antiherpetic drug (eg, acyclovir), other than 
intermittent topical use.  Subjects known to have acute or chronic active hepatitis B, hepatitis C, 
or human immunodeficiency virus infection will also be excluded.  Subjects must not have been 
treated previously with talimogene laherparepvec.  For a full list of eligibility criteria, please refer 
to Section 4.1 and 4.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Talimogene laherparepvec will 
be manufactured and packaged by Amgen Inc.  Talimogene laherparepvec is supplied as a 
sterile frozen liquid in a single-use vial.  Each vial contains a minimum of 1.0 mL talimogene 
laherparepvec at either 106 plaque-forming unit (PFU)/mL or 108 PFU/ mL concentrations.  
Talimogene laherparepvec will be administered by intralesional injection only into injectable 
cutaneous, subcutaneous, and nodal tumors, with or without image ultrasound guidance.  On 
day 1 (week 0) 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 or 107 PFU/mL, should be administered 3 weeks 
( 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).  The dose of 108 PFU/mL will be diluted 1:10 to obtain a 
concentration of 107 PFU/mL immediately prior to injection.  Subsequent injections up to 4.0 mL 
of 108 or 107 PFU/mL should be given every 2 weeks ( 3) days.  The maximum volume of 
talimogene laherparepvec to be administered at each treatment visit is 4.0 mL.  Refer to 
Section 6.2.1. 
Procedures:  Written informed consent must be obtained from all subjects or legally acceptable 
representative before any study specific screening procedures are performed.  The following 
procedures will occur per the Schedule of Assessments: medical, surgical and medication history; 
physical examination, vital signs, body weight and height; ECOG performance status; 12-lead 
electrocardiogram (ECG); recording of concomitant medications; survival assessment; review of 
adverse events, disease related events and serious adverse events; and reporting of potential or 
known unintended exposure to talimogene laherparepvec by a household member, caregiver, or 
healthcare provider.  Blood will be collected for local laboratory testing including: chemistry, 
hematology, lactate dehydrogenase, coagulation, hepatitis  B surface antigen, hepatitis B core 
antibody, and hepatitis C virus antibody.  In females of childbearing potential. urine or serum 
pregnancy test will be performed locally.  Clinical and radiological tumor assessments will be 
performed.  Blood for herpes simplex virus type-1 (HSV-1) antibody serostatus will be collected 
and swabs of any cold sores, vesicles or lesions suspected to be of herpetic origin will be 
collected for qPCR testing of talimogene laherparepvec DNA .  Talimogene laherparepvec will be 
administered at day 1 (week 0), at week 3 ( 5 days) and every 2 weeks ( 3 days) thereafter.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 2).   
Statistical Considerations:   
Planned method of analyses: No formal interim efficacy analysis is planned for this study.  Interim 
safety analyses will be performed to support the evaluation of safety by a Dose Level Review 
Team (DLRT).  The primary efficacy analysis will occur when a durable response outcome has 
been assessed for all subjects included in the primary efficacy analysis. 
The DLT analysis set will be used to summarize the subject incidence of DLT for the study and 
the safety analysis set will be used for all other analyses of safety endpoints (including but not 
limited to all adverse events, grade  3 adverse events, serious adverse events, fatal adverse 
events, adverse events requiring discontinuation of study drug, and adverse events defined as 
events of interest).  A 1-sided 5 significance level exact binomial test will be performed to test 
the null hypothesis of a 2 DRR.  The expectation is that this test will be based on the first 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 7 of 98 
CONFIDENTIAL 
 
 
18 subjects that receive at least 1 dose of talimogene laherparepvec.  The null hypothesis will be 
rejected if at least 2 subjects achieve a durable response (DR).  Assuming a DRR of 
16.3 consistent with the global phase 3 study, this analysis will have 81 power.  DRR will be 
summarized with an associated exact 90 and 95 confidence interval.  DOR among 
responders, TTR, PFS and OS will be estimated using the Kaplan-Meier method.  
Treatment-emergent adverse events are defined as adverse events with an onset from the first 
dose of study therapy up to 30 days after the last dose of study therapy.  Subject incidences of 
treatment-emergent and treatment-related adverse events (including all adverse events, grade 
 3 adverse events, serious adverse events, fatal adverse events, adverse events of interest and 
events requiring the discontinuation of study therapy) will be summarized. Medical Dictionary for 
Regulatory Activities will be used to code adverse events to a system organ class and a preferred 
term within the system organ class.  Common Terminology Criteria for Adverse Events version 
4.0 will be used to grade severity of adverse events.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. and Amgen K.K. 
Data Element Standards 
Version(s)/Date(s):  
 
5: 20 March 2015 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 8 of 98 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
CR  complete response; PD disease progression; PFU plaque-forming unit; Q2W  every 2 weeks 
a Up to approximately 18 subjects will be enrolled in the study.  Subjects may be included in the evaluation for both safety and efficacy.  The DLT evaluation period is 
35 days from the initial administration of talimogene laherparepvec.  Initially, 6 DLT-evaluable subjects will be enrolled and treated at Dose 1.  Upon demonstration of 
safety based on DLT rules, an additional 12 subjects will be enrolled and treated at Dose 1 to obtain additional safety data.  However, if Dose 1 is declared unsafe 
based on DLT rules, then an additional  6 DLT-evaluable subjects will be enrolled at Dose -1.  
b Treatment will continue until subject experiences a DLT (during the DLT evaluation period), subject achieved a CR, no injectable lesions, clinically relevant (resulting 
in clinical deterioration or requiring change of therapy) disease progression beyond 24-weeks of treatment, per modified WHO response criteria, safety concern, a 
maximum treatment duration of 48 months, or the drug is commercially available in Japan, whichever occurs first. 
S
R
E
E
N
I
N
G
E
N
R
O
L
L
M
E
N
T
Talimogene
Laherparepvec a,b
Dose 1 
(Up to 4 mL 106 PFU/mL at day 1, 
108  PFU/mL 3 weeks later & then 108 PFU/mL 
Q2W) 
OR
Dose  -1
(Up to 4 mL 106 PFU/mL at day 1, 
107  PFU/mL 3 weeks later & then 107 PFU/mL 
Q2W)
N = 18
S
A
F
E
T
Y
F
O
L
L
O
W
U
P
L
O
N
G
T
E
R
M
F
O
L
L
O
W
U
P
E
N
D
O
F
S
T
U
D
Y
30 (+7)
days 
after
last dose
Screening 
28 days 
prior to 
enrollment
Every 12 weeks 
(± 28 days)  after 
safety follow- up 
for 24 months 
after the last 
subject is 
enrolled


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 9 of 98 
CONFIDENTIAL 
 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 10 of 98 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term Definition/Explanation 
ALT 
alanine aminotransferase  
AST  
aspartate aminotransferase   
BOR 
best overall response 
BRAFV600E/K 
serine/threonine protein kinase B-Raf V600E/K 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CRF  
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug-induced liver injury 
DLRT 
Dose Level Review Team 
DLT 
dose limiting toxicity 
DOR 
duration of response 
DR 
durable response 
DRR 
durable response rate 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
End of Study for 
Individual Subject 
The last day that protocol-specified procedures are conducted for an 
individual subject (ie, the date the subject withdraws full consent from 
the study, completes the safety follow-up visit or long-term follow-up 
[whichever is later] or death). 
End of Study (primary 
completion) 
The date when the last subject is assessed or receives an intervention 
for the final collection of data for the primary endpoint(s), for the purpose 
of conducting the primary efficacy analysis, whether the study concluded 
as planned in the protocol or was terminated early.  This will be the date 
when the last subject has been assessed for a durable response 
outcome. 
End of Study (end of 
trial) 
The date when the last subject is assessed or receives an intervention 
for evaluation in the study (ie, last subject last visit), following any 
additional parts in the study (eg, long-term follow-up), as applicable. 
End of Treatment 
The day of the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 11 of 98 
CONFIDENTIAL 
 
 
Abbreviation or Term Definition/Explanation 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HCP 
Health care professional 
Heart rate 
number of cardiac cycles per unit of time 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormonal replacement therapy 
HSV-1 
herpes simplex virus type-1 
ICH 
International Conference on Harmonisation 
ICP 
infected cell protein 
INR 
international normalization ratio 
IPIM 
Investigational Product Instruction Manual 
IEC/IRB 
independent ethics committee/institutional review board 
Interactive Voice 
Response (IVR) 
telecommunication technology that is linked to a central computer in real 
time as an interface to collect and process information.   
LDH 
lactate dehydrogenase 
MRI 
magnetic resonance imaging 
NA 
not applicable 
ND 
not done 
ORR 
overall response rate 
OS 
overall survival 
PD 
disease progression 
PD-1 
programmed death receptor 1 
PDn 
non-clinically relevant disease progression 
PDr 
clinically relevant disease progression 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFU 
plaque-forming unit 
PR 
partial response 
PR Interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
PT 
prothrombin time 
aPTT 
activated partial thromboplastin time 
qPCR 
real-time polymerase chain reaction 
QRS interval 
QRS interval is the interval between the Q wave and the S wave in the 
heart's electrical cycle as measured by ECG; represents the time it takes 
for the depolarization of the ventricles 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  01 September 2020 
Page 12 of 98 
CONFIDENTIAL 
 
 
Abbreviation or Term Definition/Explanation 
QT interval 
QT interval is a measure of the time between the start of the Q wave and 
the end of the T wave in the heart's electrical cycle as measured by 
ECG. 
QTc interval 
QT interval corrected for heart rate using accepted methodology  
SD 
stable disease 
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 
The first day that protocol-specified investigational product is  
administered to the subject 
TTR 
time to response 
ULN 
upper limit of normal 
UE 
unable to evaluate 
vs 
versus 
WHO 
World Health Organization 
 


Product:  Talimogene Laherparepvec 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 4 
Study Design and Treatment Schema ............................................................................. 8 
Study Glossary .............................................................................................................. 10 
1. 
OBJECTIVES ....................................................................................................... 18 
1.1 
Primary ..................................................................................................... 18 
1.2 
Secondary ................................................................................................. 18 
1.3 
Safety ........................................................................................................ 18 
2. 
BACKGROUND AND RATIONALE ...................................................................... 18 
2.1 
Disease ..................................................................................................... 18 
2.2 
Amgen Investigational Product Background:  Talimogene 
Laherparepvec .......................................................................................... 21 
2.3 
Rationale ................................................................................................... 24 
2.4 
Clinical Hypotheses ................................................................................... 24 
3. 
EXPERIMENTAL PLAN ........................................................................................ 25 
3.1 
Study Design ............................................................................................. 25 
3.2 
Number of Sites ........................................................................................ 26 
3.3 
Number of Subjects ................................................................................... 26 
3.4 
Replacement of Subjects .......................................................................... 26 
3.5 
Estimated Study Duration .......................................................................... 27 
3.5.1 
Study Duration for Subjects ....................................................... 27 
3.5.2 
End of Study .............................................................................. 27 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 28 
4.1 
Inclusion Criteria ....................................................................................... 28 
4.2 
Exclusion Criteria ...................................................................................... 29 
5. 
SUBJECT ENROLLMENT .................................................................................... 31 
5.1 
Treatment Assignment .............................................................................. 32 
6. 
TREATMENT PROCEDURES .............................................................................. 32 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 32 
6.2 
Investigational Product .............................................................................. 33 
6.2.1 
Amgen Investigational Product:  Talimogene 
Laherparepvec .......................................................................... 33 
6.2.1.1 
Dosage, Administration, and Schedule .................... 33 
6.2.1.2 
Dose-cohort Study De-escalation and 
Stopping Rules ........................................................ 35 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 37 
6.3 
Other Protocol-required Therapies ............................................................ 38 
6.4 
Concomitant Therapy ................................................................................ 38 


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6.5 
Other Treatment Procedures ..................................................................... 38 
6.6 
Medical Devices ........................................................................................ 39 
6.7 
Product Complaints ................................................................................... 39 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .................................................................................. 40 
6.9 
Contraceptive Requirements ..................................................................... 40 
6.9.1 
Female Subject ......................................................................... 41 
6.9.2 
Male Subjects ............................................................................ 42 
6.9.3 
Unacceptable Methods of Birth Control for Male and 
Female Subjects ....................................................................... 43 
7. 
STUDY PROCEDURES ....................................................................................... 43 
7.1 
Schedule of Assessments ......................................................................... 43 
7.2 
General Study Procedures ........................................................................ 47 
7.2.1 
Screening and Enrollment ......................................................... 47 
7.2.2 
Re-screening ............................................................................. 47 
7.2.3 
Treatment .................................................................................. 47 
7.2.4 
Follow-up ................................................................................... 48 
7.2.4.1 
Safety Follow-up ..................................................... 48 
7.2.4.2 
Long-term Follow-up ............................................... 48 
7.3 
Description of Study Procedures ............................................................... 48 
7.3.1 
Informed Consent ...................................................................... 49 
7.3.2 
Demographic Data..................................................................... 49 
7.3.3 
Medical History .......................................................................... 49 
7.3.4 
Prior Cancer Therapy ................................................................ 49 
7.3.5 
Concomitant Therapy ................................................................ 49 
7.3.6 
Adverse Events, Disease Related Events and Serious 
Adverse Events ......................................................................... 49 
7.3.7 
Physical Examination ................................................................ 49 
7.3.8 
Vital Signs ................................................................................. 49 
7.3.9 
Physical Measurements ............................................................ 50 
7.3.10 
ECG .......................................................................................... 50 
7.3.11 
BRAF V600E/K Status .................................................................... 50 
7.3.12 
ECOG........................................................................................ 50 
7.3.13 
Reporting of Exposure to Talimogene Laherparepvec ............... 50 
7.3.14 
Tumor Assessments .................................................................. 50 
7.3.14.1 
Clinical Tumor Assessment ..................................... 50 
7.3.14.2 
Radiological Tumor Assessment ............................. 51 
7.4 
Laboratory Assessments ........................................................................... 51 
7.4.1 
qPCR for Talimogene Laherparepvec ....................................... 52 
7.5 
Sample Storage and Destruction ............................................................... 52 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 54 
8.1 
Subjects’ Decision to Withdraw ................................................................. 54 


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8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 54 
8.3 
Reasons for Removal From Treatment or Study ....................................... 55 
8.3.1 
Reasons for Removal From Treatment ...................................... 55 
8.3.2 
Reasons for Removal From Study ............................................. 55 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 55 
9.1 
Definition of Safety Events ........................................................................ 55 
9.1.1 
Disease Related Events ............................................................ 55 
9.1.2 
Adverse Events ......................................................................... 56 
9.1.3 
Serious Adverse Events ............................................................ 56 
9.2 
Safety Event Reporting Procedures .......................................................... 57 
9.2.1 
Reporting Procedures for Disease Related Events .................... 57 
9.2.2 
Adverse Events ......................................................................... 58 
9.2.2.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 58 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 59 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 60 
9.3 
Pregnancy and Lactation Reporting .......................................................... 60 
9.4 
Reporting of Exposure to Talimogene Laherparepvec ............................... 61 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 62 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 62 
10.1.1 
Study Endpoints ........................................................................ 62 
10.1.1.1 
Primary Endpoints ................................................... 62 
10.1.1.2 
Secondary Endpoints .............................................. 62 
10.1.2 
Safety Endpoint ......................................................................... 62 
10.1.3 
Analysis Sets ............................................................................. 62 
10.1.3.1 
DLT Analysis Set ..................................................... 62 
10.1.3.2 
Safety Analysis Set ................................................. 62 
10.1.4 
Covariates and Subgroups ........................................................ 62 
10.2 
Sample Size Considerations ..................................................................... 63 
10.2.1 
Sample Size Considerations ...................................................... 63 
10.2.1.1 
Sample Size Considerations for Safety 
Evaluation ............................................................... 63 
10.2.1.2 
Sample Size Considerations for Efficacy ................. 64 
10.3 
Planned Analyses ..................................................................................... 65 
10.3.1 
Interim Analyses ........................................................................ 65 
10.3.2 
Dose Level Review Team .......................................................... 65 
10.3.3 
Primary Analysis ........................................................................ 66 
10.3.4 
Final Analysis ............................................................................ 66 
10.4 
Planned Methods of Analysis .................................................................... 66 


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10.4.1 
General Considerations ............................................................. 66 
10.4.2 
Primary Endpoint ....................................................................... 66 
10.4.3 
Secondary Endpoint .................................................................. 66 
10.4.4 
Safety Endpoints ....................................................................... 67 
10.5 
Handling of Missing and Incomplete Data ................................................. 67 
11. 
REGULATORY OBLIGATIONS ............................................................................ 68 
11.1 
Informed Consent ...................................................................................... 68 
11.2 
Independent Ethics Committee/Institutional Review Board ........................ 69 
11.3 
Subject Confidentiality ............................................................................... 69 
11.4 
Investigator Signatory Obligations ............................................................. 70 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 70 
12.1 
Protocol Amendments and Study Termination .......................................... 70 
12.2 
Study Documentation and Archive ............................................................ 70 
12.3 
Study Monitoring and Data Collection ....................................................... 71 
12.4 
Investigator Responsibilities for Data Collection ........................................ 73 
12.5 
Language .................................................................................................. 73 
12.6 
Publication Policy ...................................................................................... 73 
12.7 
Compensation ........................................................................................... 74 
13. 
REFERENCES ..................................................................................................... 75 
14. 
APPENDICES ...................................................................................................... 78 
List of Tables 
Table 1.  Talimogene Laherparepvec Injection Volume Guideline Based on 
Tumor Size ............................................................................................. 34 
Table 2.  Schedule of Assessments ............................................................................... 44 
Table 3.  Laboratory Analytes ........................................................................................ 52 
Table 4.  Probability of Declaring a Cohort Safe or Unsafe ............................................ 64 
Table 5.  Definition of Index Lesion Tumor Response Including New Lesions ............... 91 
Table 6.  Definition of Nonindex Lesion Tumor Response ............................................. 92 
Table 7.  Matrix for Determining the Overall Response at Each Assessment 
Point ....................................................................................................... 93 
List of Figures 
Figure 1.  Probability of Declaring a Cohort Safe (Unsafe)............................................. 64 


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List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 79 
Appendix B.  Sample Electronic Adverse Event Contingency Report Form ................... 80 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 83 
Appendix D.  Modified World Health Organization Response Criteria ............................ 85 
Appendix E.  Eastern Cooperative Oncology Group (ECOG) Performance 
Status ..................................................................................................... 94 
Appendix F.  Clinical Trial Report of Suspected Talimogene Laherparepvec 
Associated Adverse Event for HCP or Close Contact ............................. 95 


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1. 
OBJECTIVES 
1.1 
Primary 
There are 2 fold purposes for this study.  1 is to evaluate safety and tolerability and the 
other is to study the anti-tumor effects of talimogene laherparepvec in Japanese patients 
with unresectable stage IIIB-IV malignant melanoma.  
 
To evaluate the safety and tolerability of talimogene laherparepvec, subjects will be 
assessed by incidence of dose limiting toxicities (DLTs).   
 
These subjects will also be evaluated for the anti-tumor activity of talimogene 
laherparepvec as assessed by durable response rate (DRR) using modified World 
Health Organization (WHO) response criteria.  DRR is defined as the rate of 
objective response (Complete response [CR] or partial response [PR]) lasting 
continuously for 6 months and starting any time within 12 months of initiating 
therapy. 
1.2 
Secondary 
 
To evaluate the anti-tumor activity of talimogene laherparepvec, as assessed by 
overall response rate (ORR), time to response (TTR), duration of response (DOR), 
progression free survival (PFS) using modified World Health Organization (WHO) 
response criteria by investigators 
 
To evaluate overall survival (OS) 
1.3 
Safety 
To evaluate the safety of talimogene laherparepvec as determined by subject incidence 
of adverse events and clinically relevant laboratory abnormalities where not defined as 
DLTs. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Cutaneous melanoma is the fifth most common cancer in men and the seventh most 
common cancer in women in the United States of America (USA), with an estimated 
73,870 new cases and 9,940 deaths expected in 2015 (Siegel et al, 2015).  In Europe, 
the annual incidence of melanoma is somewhat lower than that in the USA, with a crude 
rate of approximately 14 per 100,000 as compared to 20 per 100,000 in the USA, but is 
the sixth most common cancer among women (Ferlay et al, 2013; Tannous et al, 2005; 
Siegel et al, 2015).  In Europe as a whole, approximately 100,442 new cases were 
diagnosed in 2012 (Ferlay et al, 2013).  The incidence of melanoma is increasing rapidly 
worldwide, with a 270 increase in the USA between 1973 and 2002.  This increase is 
the most rapid of any cancer with the exception of lung cancer in women 
(Jemal et al, 2006; Ries et al, 2000). 


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Melanoma that has spread to multiple regional nodal sites (stage III) is infrequently 
curable with standard therapy.  For those with multiple or clinically detectable nodal 
metastases or in-transit/satellite lesions (stages lllB and lllC), the 5-year survival rate 
ranges between 40 (for stage lllC disease) to 59 (for stage lllB disease) 
(Balch et al, 2009).  For patients with distant spread to skin, nodes, or visceral organs 
(stage IV disease), the 5-year survival rates are generally low, ranging from 20 for 
stage M1a disease (skin, subcutaneous, or nodes only), 5 to 10 for stage M1b 
disease (lung only), and  5 for stage M1c disease (other visceral lesions or high 
serum lactate dehydrogenase [LDH]); median survival is 12 months for stages M1a and 
M1b disease and 4 to 6 months for stage M1c disease (O'Day and Boasberg, 2006; 
Tannous et al, 2005). 
Melanoma is a relatively rare disease in Japan.  The estimated incidence rate of 
melanoma is 2/100,000 (Takata et al, 2007) and approximately 4000 patients were 
diagnosed with the disease in 2011 according to the Patient Survey by Ministry of 
Health, Labour, and Welfare (MHLW, 2011).  The prognosis of unresectable advanced 
melanoma is generally poor.  The 10-year survival rates of stage III and IV disease were 
reported as 54  and 7, respectively (Ishihara et al, 2008).  Although clinical data of 
chemotherapy in Japanese melanoma patients are limited, the reported 8-year survival 
rate of chemotherapy alone in stage M1b/M1c melanoma was 7.6 (Ishihara et al, 
2008).   
Until recently, traditional nonsurgical therapies for unresectable or advanced melanoma 
in adults included chemotherapy (dacarbazine, temozolomide, or other agents either 
alone or in combination), or interleukin-2.  Although some regimens produced objective 
responses, they were usually short-lived.  For example, dacarbazine or temozolomide 
achieved a 7 to 12 objective response rate, but an objective response did not appear 
to be associated with a prolongation in OS (Anderson et al, 1995; Chapman et al, 1999; 
Wagner et al, 2000; Middleton et al, 2000).  Response rates for interleukin-2 ranged 
from 10 to 20 (Rosenberg et al, 1994; Sparano et al, 1993; Atkins et al, 1999), with a 
small proportion achieving prolonged response, but its administration requires close 
patient monitoring in specialized facilities with well-trained staff based on the notable 
toxicity profile associated with its administration. 
In recent years, novel therapeutic agents such as nivolumab, ipilimumab, and 
vemurafenib have been approved for advanced melanoma in Japan.  In the phase 


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2 study of nivolumab in Japanese patients (n  35), the objective response rate and 
median OS were 22.9 and 473.0 days (90 [Cl]: 276.0, not reached), respectively 
(Yamazaki and Maeda, 2015).  Approval of Vemurafenib in December 2014 was based 
on the results from the global phase 3 trial (Chapman et al, 2011) along with the 
Japanese phase 1/2 clinical trial that demonstrated safety and efficacy of vemurafenib in 
melanoma patients from Japan (Yamazaki et al, 2015). 
The Food and Drug Administration (FDA), European Commission, and other regulatory 
agencies have approved 4 novel therapies for advanced melanoma in the last 5 years:  
an immune stimulatory agent, ipilimumab (Yervoy, 2013), and 3 agents for use in 
patients with BRAF mutant melanoma, a v-raf murine sarcoma viral oncogene homolog 
B1 (BRAF) inhibitor, vemurafenib (Zelboraf, 2013), the BRAF inhibitor dabrafenib 
(Tafinlar, 2014) and the MEK inhibitor trametinib (Mekinist, 2013).  The studies upon 
which approvals for ipilimumab and vemurafenib were based demonstrated improved 
survival compared to control treatments.  The pivotal study of ipilimumab showed an OS 
improvement in subjects with HLA-A2*0201 genotype previously treated metastatic 
melanoma as compared with a gp100 peptide vaccine (Hodi et al, 2010; Yervoy 2013).  
The median OS was 10.0 months in the group that received ipilimumab in combination 
with the gp100 peptide vaccine and 6.4 months in the group that received gp100 peptide 
vaccine alone (hazard ratio [HR]  0.68, p  0.001) (Hodi et al, 2010).  Approximately 8 
more patients survived 2 years in the ipilimumab arm than in the control arm 
(21.6 versus [vs] 13.7).  The objective response rate was 5.7 vs 1.5, respectively 
(p  0.04).  Similar results were reported for another study conducted in previously 
untreated subjects with metastatic melanoma who received ipilimumab and dacarbazine 
vs placebo and dacarbazine (Robert et al, 2011).  
The pivotal vemurafenib study showed improved OS and objective response rates in a 
substantial proportion of subjects with previously untreated metastatic melanoma with 
the BRAFV600E mutation who received vemurafenib vs standard dacarbazine 
(Chapman et al, 2011).  The median OS was 13.6 months in the vemurafenib group and 
9.4 months in the dacarbazine group (OS data for dacarbazine patients who crossed 
over to vemurafenib treatment were censored at the time of crossover) (Chapman et al, 
2012).  The hazard ratio for death was 0.62 (95 Confidence interval [Cl]: 0.49, 0.77).  
The objective response rate was 48 vs 5, respectively (p  0.001) (Chapman et al, 
2011).   


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In 2013, regulatory agencies also approved the BRAF inhibitor dabrafenib 
(Tafinlar, 2014) and the MEK inhibitor trametinib (Mekinist, 2013), both in BRAFV600 
mutant advanced melanoma.  Each agent showed a benefit in progression-free survival 
compared to dacarbazine in phase 3 trials (Hauschild et al, 2012; Flaherty et al, 2012a), 
though cross-over and short duration of follow-up to date limits interpretation of OS.  
Additionally, dabrafenib and trametinib were approved recently as a combination therapy 
for BRAF-mutant unresectable or metastatic melanoma. (Flaherty et al, 2012b). The 
combination of dabrafenib and trametinib has shown to improve overall survival when 
compared to BRAF inhibition (vemurafenib) alone in previously untreated patients with 
metatstatic melanoma with BRAF V600E or V600K mutations (Robert et al, 2015)  
In 2014, the FDA approved 2 programmed death receptor-1 (PD-1) blocking antibodies:  
pembrolizumab and nivolumab for the treatment of patients with unresectable or 
metastatic melanoma and disease progression following ipilimumab and, if BRAFV600 
mutation positive, a BRAF inhibitor (Keytruda, 2015; Opdivo, 2015).  Approval of these 
agents was based on response rates and duration of response.  Recently, phase 
3 studies reported OS benefit with the use of pembrolizumab (Robert et al, 2015) and 
nivolumab (Larkin et al, 2015). 
2.2 
Amgen Investigational Product Background:  Talimogene 
Laherparepvec 
Talimogene laherparepvec is an intralesionally delivered oncolytic immunotherapy 
comprised of a genetically engineered herpes simplex virus type-1 (HSV-1) that 
selectively replicates in tumor tissue.  The neurovirulence factor infected-cell protein 
(ICP) 34.5 and the ICP47-encoding gene are functionally deleted in the virus, while the 
gene for human granulocyte macrophage colony-stimulating factor (GM-CSF) is 
inserted.  The role of ICP47 is to block antigen presentation to major histocompatibility 
complex class I 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 


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production in CD4 and CD8 T-lymphocytes (Hart, 1997; Steinman, 2001; Ikeda et al, 
2004; Paul, 2007).  These Th1-type cytokines have the capacity to produce 
proinflammatory responses, eradicate tumors, and perpetuate autoimmune responses 
(Nishimura et al, 2000; Ikeda et al, 2004; Knutson and Disis, 2005).   
In the United States, talimogene laherparepvec (IMLYGIC) is indicated for the local 
treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with 
melanoma recurrent after initial surgery. 
The investigational product contains attenuated infectious herpes simplex virus-1.  Refer 
to the specific section of the Investigator’s Brochure for additional information related to 
the physical, chemical, and pharmaceutical properties and formulation(s). 
Talimogene Laherparepvec in Melanoma 
Efficacy: 
The efficacy of talimogene laherparepvec in subjects with regionally and distantly 
metastatic melanoma was evaluated in a pivotal, controlled, phase 3 study (Study 
005/05) and a supportive, single-arm, phase 2 study (Study 002/03).  Talimogene 
laherparepvec  up to 4.0 mL 106 PFU/mL was administered at day 1, followed by dose of 
up to 4.0 mL of 108 PFU/mL 3 weeks later and then every 2 weeks.  The phase 2 study 
was a single arm study conducted in 50 patients with unresectable late stage III or stage 
IV melanoma (Senzer et al, 2009).  The overall response rate was 28.  More than half 
of the responses were complete and many were durable, with the majority lasting longer 
than 6 months.  An important finding was that transient locoregional or distant 
progression, including new lesions, sometimes preceded response.  In the open-label, 
randomized, phase 3 study of talimogene laherparepvec versus subcutaneously 
administered GM-CSF in stages lllB, lllC, and IV unresectable melanoma, talimogene 
laherparepvec or GM-CSF was administered until CR, clinically significant disease 
progression, intolerable side effects, 12 months of therapy without an objective 
response, or withdrawal of consent (Study 20110263; OPTiM).  The primary endpoint of 
the study was durable response rate (objective response is maintained for at least 
6 months).  Primary analysis of the OPTiM Study showed a statistically significant 
difference between the rate of durable response among subjects treated with talimogene 
laherparepvec (16; 95 CI:  12, 21) versus those treated with GM-CSF 
(2; 95 CI:  0, 5) (p-value  0.0001).  Overall response rate was also improved 
from 6 with GM-CSF to 26 with talimogene laherparepvec (P  0.0001, descriptive).  


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Similarly, 11 of patients had a CR in the talimogene laherparepvec arm vs  1 in the 
GM-CSF arm.  In the event-driven primary OS analysis (secondary endpoint), median 
OS with talimogene laherparepvec treatment was 23.3 months compared with 
18.9 months with GM-CSF treatment (HR, 0.79 [95 CI, 0.62‒1.00]; p  0.051) 
(Andtbacka et al, 2015).  At the final planned analysis of OS which occurred when the 
last enrolled subject completed 3 years of follow-up, median OS was 23.3 months in the 
talimogene laherparepvec arm and 18.9 months in the GM-CSF arm (HR, 0.79; 95 CI, 
0.62‒1.00; p  0.049, [descriptive]). Survival at 12, 24, and 36 months in the talimogene 
laherparepvec arm was estimated to be 74, 50, and 41, respectively, and 69, 
41, and 28 in the GM-CSF arm, respectively.   
Safety: 
The overall safety evaluation of talimogene laherparepvec in melanoma is based on 
exposure of 292 patients in the phase 3 study and 50 patients in the phase 2 study.  In 
both the phase 2 and phase 3 studies, talimogene laherparepvec was administered at a 
dose of up to 4 mL of 108 PFU/mL every 2 weeks except for the second administration 
which was given 3 weeks after the 106 PFU/mL initial dose.  The safety profile was 
similar in the phase 2 and phase 3 studies with talimogene laherparepvec. 
In the phase 3 study (Study 005/05) the safety population consisted of 419 subjects 
(292 talimogene laherparepvec; 127 GM-CSF).  The median duration of treatment was 
23 weeks in the talimogene laherparepvec arm.  At least 1 adverse event was reported 
for 99.3 of talimogene laherparepvec treated subjects.  Most adverse events were mild 
or moderate in severity (63.4 talimogene laherparepvec) and generally resolved within 
72 hours.  The most common adverse drug reactions ( 25) in talimogene 
laherparepvec-treated patients were fatigue, chills, pyrexia, nausea, influenza-like 
illness, and injection site pain.  The most common grade 3 or higher adverse reaction 
was cellulitis in the talimogene laherparepvec arm.  Disease progression was the most 
frequently reported serious adverse event in 3.1 of talimogene laherparepvec treated 
subjects, followed by cellulitis (2.4), pyrexia (1.7), and tumor pain (1.4).  
In summary, talimogene laherparepvec has a favorable safety profile in subjects with 
stage IIIB-IVM1c melanoma at the dose evaluated (up to 4 mL of 108 PFU/mL ).  Most 
adverse events were mild to moderate with the most common being flu-like symptoms.  
Adverse events infrequently led to treatment discontinuation and deaths were usually in 
the setting of disease progression.  


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2.3 
Rationale 
While the approval of the newer agents represents a clear milestone in the treatment of 
advanced melanoma, limitations still exist.  The 2-year OS following ipilimumab remains 
only approximately 20 and the drug is associated with severe and potentially fatal 
immunological adverse effects (Hodi et al, 2010).  Vemurafenib, dabrafenib, and 
trametinib are indicated only in patients with BRAFV600 mutations, and are associated 
with early development of resistance in most cases, leading to short durations of 
response.  The safety profiles of vemurafenib and dabrafenib include increased 
incidence of cutaneous squamous cell carcinoma or high grade keratoacanthoma in 
almost 20 of patients treated with vemurafenib and  5 of patients treated with 
dabrafenib (Zelboraf, 2013; Tafinlar, 2014).  Additionally, grade 2 or higher 
dermatologic reactions including rash, pruritus, and hyperkeratosis are common with 
both agents.  Trametinib is associated with cuneiform dermatitis, peripheral edema, 
hypertension, decreased cardiac ejection fraction, and ocular events (Mekinist, 2013).  
Response rates are more modest with the PD-1 blocking antibodies, but can be durable.  
Their overall benefit-risk profiles have been determined primarily in patients with the 
most advanced stages of melanoma.   
An unmet medical need exists for additional treatment options that can provide patients 
with regionally or distantly metastatic melanoma an opportunity to achieve durable 
responses with a favorable safety profile.  A clear unmet need continues to exist for 
patients with advanced melanoma in Japan as well in spite of recent approvals of 
targeted and immunotherapy agents, for reasons described above.  The proposed 
phase 1 study will evaluate the safety and tolerability and efficacy of talimogene 
laherparepvec for the treatment of metastatic melanoma in Japanese patients, which will 
potentially help define a role for talimogene laherparepvec in the treatment landscape of 
melanoma in Japan. 
2.4 
Clinical Hypotheses 
No formal statistical hypothesis will be tested for safety endpoints in this trial.  Based on 
the well tolerated safety profile from a global phase 3 study, it is hypothesized that 
talimogene laherparepvec will be safe and well tolerated in Japanese subjects with 
unresectable Stage IIIB-IVM1c melanoma.  A DRR is hypothesized to be consistent with 
results from the global phase 3 study. 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 1, multicenter, open-label study of talimogene laherparepvec in 
Japanese subjects with unresectable stage IIIB-IVM1c malignant melanoma that are 
candidates for intralesional therapy.   
Approximately 18 subjects will be enrolled in the study.  Subjects may be included in the 
evaluation for both safety and efficacy.  The DLT evaluation period is 35 days from the 
initial administration of talimogene laherparepvec.  Initially, 6 DLT-evaluable subjects will 
be enrolled and treated at 100 of the dose regimen of talimogene laherparepvec 
(Dose 1) as described below.  The first dose administered will be up to 4.0 mL of 
106 PFU/mL (day 1, week 0) followed by dose of up to 4.0 mL of 108 PFU/mL 3 weeks 
( 5 days) later.  Subsequent doses of up to 4.0 mL of 108 PFU/mL will be administered 
every 2 weeks ( 3 days) thereafter (see Section 6.2.1.1).  A Dose Level Review Team 
(DLRT) meeting will be convened after 6 DLT-evaluable subjects are enrolled.  Further 
enrollment will be temporarily paused until the DLRT meeting is convened and a 
decision is made on the dose level.  Upon demonstration of safety based on DLT 
incidence  33  in the first 6 subjects, an additional 12 subjects will be enrolled and 
treated at Dose 1 to obtain additional safety data.  
However, if at any time there are 2 or more subjects with a DLT prior to enrollment of the 
first 6 DLT-evaluable subjects, an ad hoc DLRT meeting will be convened to determine if 
dose de-escalation is required. 
The safety data during the enrollment of the additional 12 subjects will be monitored on 
an going basis and an ad hoc DLRT meeting may be called, if needed, to determine the 
further course of the study.   
The hypothesis test for DRR will include all subjects enrolled after dose de-escalation 
who received at least 1 dose of talimogene laherparepvec. If no dose de-escalation is 
needed, the DRR hypothesis test will include the first 18 subjects dosed. 
Dose De-escalation 
If dose de-escalation is needed then the remaining subjects will be treated at the lower 
dose regimen of talimogene laherparepvec (Dose -1).  The initial dose administered will 
be up to 4.0 mL of 106 PFU/mL (day 1, week 0) followed by dose of up to 4.0 mL of 
107 PFU/mL 3 weeks ( 5 days) later.  Subsequent doses of up to 4.0 mL of 107 PFU/mL 
will be administered every 2 weeks ( 3 days) thereafter (see Section 6.2.1.2).  The 


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DLRT will review the safety data after the first 6 DLT-evaluable subjects at Dose -1 have 
been enrolled.  Enrollment will be temporarily paused during the DLT review period to 
evaluate the 6 DLT-evaluable subjects at Dose -1.  Upon demonstration of safety, 
additional subjects will be enrolled (up to a total of 18 subjects) at Dose -1 to obtain 
additional safety data.  
The safety data of the subjects enrolled at the Dose-1 level will be monitored on an 
going basis and an ad hoc DLRT meeting may be called, if needed, to determine the 
further course of the study.   
All subjects will complete a safety follow-up Visit 30 (7) days after the last dose of study 
treatment.  Adverse events and disease related events will be collected as described in 
Section 9.2.  After the safety follow-up visit, subjects will enter the long-term follow-up, 
unless they did not receive at least 1 dose of study treatment or received study 
treatment for more than 24 months after the last subject enrolled.  In long-term 
follow-up, subjects will be followed for survival and subsequent anticancer therapies 
every 12 weeks ( 28 days) until approximately 24 months after the last subject is 
enrolled.  In addition, talimogene laherparepvec related adverse events that occur 
through the end of the long-term follow-up will be reported. 
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 7 sites in Japan.  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 18 subjects will be enrolled.  Refer to Section 10.2 for sample size 
considerations. 
3.4 
Replacement of Subjects 
Subjects enrolled may be replaced if they are not evaluable for DLT (eg, a subject did 
not receive study treatment, or ended the study treatment before completion of DLT 
evaluation period for a reason other than experiencing a DLT).  


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3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The duration of screening for each subject will be approximately 28 days.  The duration 
of treatment will vary for each subject.  Subjects will be treated until the subject has a 
DLT during the DLT evaluation period, subject has achieved a CR, no injectable lesions, 
clinically relevant (resulting in clinical deterioration or requiring change in therapy) 
disease progression beyond 24-weeks of treatment per modified WHO response criteria 
(Appendix D), safety concern, a maximum treatment duration of 48 months, or until 
the drug is commercially available in Japan,  whichever occurs first.  Maximum 
treatment duration will be 48 months.  All subjects will complete a safety follow-up Visit 
30 (7) days after the last dose of study treatment.  After the safety follow-up visit 
subjects will enter long-term follow-up (not applicable for subjects treated longer 
than 24 months after the last subject is enrolled).  During this period, subjects will be 
followed for approximately 24 months after the last subject is enrolled.  The total study 
duration for an individual subject can be up to 4 years.  
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary efficacy analysis, 
whether the study concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when the last subject has been assessed for a 
durable response outcome. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject across 
all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, last safety follow-up 
visit), as applicable. 


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4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
1. 101 
Subject has provided informed consent prior to initiation of any study-
specific activities/procedures 
2. 102 
Subject’s legally acceptable representative has provided informed 
consent when the subject is legally too young (ie, subject age  20 years) to 
provide informed consent and the subject has provided written assent based on 
local regulations and/or guidelines prior to any study-specific 
activities/procedures being initiated 
3. 103 
Male or female age  18 years at the time of informed consent 
4. 104 
Histologically confirmed diagnosis of melanoma 
5. 105 
Subject with stage IIIB to IVM1c melanoma that is not surgically 
resectable 
6. 106 
Subject who is treatment naive and is determined by the physician to be 
not suitable or eligible for the approved systemic anticancer drug therapy in 
Japan.  Subject may also have received prior systemic anticancer treatment 
consisting of chemotherapy, immunotherapy, or targeted therapy.  Treatment for 
melanoma must have been completed at least 28 days prior to enrollment.  
7. 107 
Candidate for intralesional therapy (ie, disease is appropriate for direct 
injection or through the use of ultrasound guidance, where appropriate) defined 
as 1 or more of the following: 
 
at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion 
 10 mm in longest diameter, OR 
 
multiple injectable melanoma lesions that in aggregate have a longest 
diameter of  10 mm (see Appendix D for guidance on lesions that may be 
aggregated)  
8. 108 
Measurable disease defined as 1 or more of the following: 
 
at least 1 melanoma lesion that can be accurately and serially measured in at 
least 2 dimensions and for which the longest diameter is  10 mm as 
measured by contrast-enhanced or spiral computed tomography (CT) scan, 
magnetic resonance imaging (MRI), or ultrasound for nodal/soft tissue 
disease (excluding lymph nodes).  To be classified as malignant and 
measurable a lymph node must be  15 mm in shortest diameter. 
 
at least 1  10 mm longest diameter superficial cutaneous or subcutaneous 
melanoma lesion as measured by calipers 


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 
multiple superficial melanoma lesions which in aggregate have a longest total 
diameter of  10 mm (see Appendix D for guidance on lesions that may be 
aggregated; if the only measurable lesion is an aggregate, a photograph of 
the aggregate lesion must be provided and the case reviewed by the Amgen 
medical monitor for approval prior to enrollment) 
9. 
109 
Serum lactate dehydrogenase (LDH) levels  1.5 X upper limit of normal 
(ULN) within 28 days prior to enrollment 
10. 110 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 
1 
11. 
111 
Adequate organ function determined within 28 days prior to enrollment, 
defined as follows: 
 
absolute neutrophil count   1500/mm3 
 
platelet count  75,000/mm3 
 
hemoglobin  8 g/dL without need for hematopoietic growth factor or 
transfusion support 
 
serum creatinine  1.5 x ULN 
 
serum bilirubin  1.5 x ULN  
 
aspartate aminotransferase (AST)  2.5 x ULN 
 
alanine aminotransferase (ALT)  2.5 x ULN 
 
alkaline phosphatase  2.5 x ULN 
 
serum albumin  2.5 g/dL 
 
prothrombin time (PT)  1.5 x ULN (or international normalization ratio [INR] 
 1.3 x ULN) 
 
activated  partial thromboplastin time (aPTT)  1.5 x ULN  
Note: Prolongation of INR, PT, and aPTT when the results from therapeutic 
anticoagulation treatment are permitted for subjects whose injectable lesions are 
cutaneous and/or subcutaneous such that direct pressure could be applied in the 
event of excessive bleeding.  
12. 
112 
Female subjects of childbearing potential must have a negative urine or 
serum pregnancy test within 3 days prior to enrollment.  If urine pregnancy test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
4.2 
Exclusion Criteria 
13. 
201  
Clinically active cerebral metastases.  Subjects with up to 3 cerebral 
metastases may be enrolled, provided that all lesions have been adequately 
treated with stereotactic radiation therapy (including Gamma Knife) or 
craniotomy, with no evidence of progression and have not required steroids for at 
least 2 months prior to enrollment. 
14. 
202 
Greater than 3 visceral metastases (this does not include lung 
metastases or nodal metastases associated with visceral organs).  For subjects 
with  3 visceral metastases, no lesion  3 cm in longest dimension and liver 
lesions must be stable for at least 1 month prior to enrollment. 
15. 203 
Bone metastases  


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16. 204 
Primary ocular or mucosal melanoma 
17. 
205 
History or evidence of symptomatic autoimmune disease (eg, 
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) is not considered a form of 
systemic treatment for autoimmune disease. 
18. 206 
Evidence of clinically significant immunosuppression such as the 
following: 
 
Primary immunodeficiency state such as Severe Combined 
Immunodeficiency Disease 
 
concurrent opportunistic infection 
 
receiving systemic immunosuppressive therapy ( 2 weeks) including oral 
steroid doses  10 mg/day of prednisone or equivalent  within 2 months prior 
to enrollment. 
19. 
207 
Active herpetic skin lesions or prior complications of herpetic infection 
(eg, herpetic keratitis or encephalitis). 
20. 
208 
Requires intermittent or chronic systemic (intravenous or oral) treatment 
with an antiherpetic drug (eg, acyclovir), other than intermittent topical use. 
21. 209 
Previous treatment with talimogene laherparepvec  
22. 
210 
Currently receiving treatment with another investigational device or drug 
study, or  28 days since ending treatment with another investigational device or 
drug study(s) 
23. 211 
Other investigational procedures while participating in this study are 
excluded. 
24. 
212 
Known to have acute or chronic active hepatitis B infection, acute or 
chronic active hepatitis C infection or human immunodeficiency virus (HIV) 
infection 
25. 213 
History of other malignancy within the past 3 years with the following 
exceptions: 
 
Adequately treated mucosal gastric cancer 
 
malignancy treated with curative intent and with no known active disease 
present for  3 years before enrollment and felt to be at low risk for 
recurrence by the treating physician 
 
adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
 
adequately treated cervical carcinoma in situ without evidence of disease 
 
adequately treated breast ductal carcinoma in situ without evidence of 
disease 
 
prostatic intraepithelial neoplasia without evidence of prostate cancer 


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 
adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ 
26. 
214 
Subject has known sensitivity to bovine- or porcine-derived components 
or to any of the products or components to be administered during dosing. 
27. 
215 
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 and investigator’s knowledge. 
28. 
216 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen medical monitor, if consulted, would pose a risk to subject 
safety or interfere with the study evaluation, procedures, or completion 
29. 217 
Subject previously has entered this study 
30. 
218 
Female subject is pregnant or breast-feeding, or planning to become 
pregnant  during study treatment and through 3 months after the last dose of 
talimogene laherparepvec, or planning to breastfeed after starting treatment.  
Note:  Subjects who suspend breast-feeding prior to starting treatment with 
talimogene laherparepvec and do not intend to resume breast-feeding can be 
enrolled. 
31. 
219 
Female subject of childbearing potential who is unwilling to use 
acceptable method(s) of effective contraception during study treatment and 
through 3 months after the last dose of talimogene laherparepvec  
32. Note:  Acceptable methods of effective contraception are defined in 
Section 6.9 and the informed consent form.   
33. 
220. 
Sexually active subjects and their partners unwilling to use male or 
female latex condom to avoid potential viral transmission during sexual contact 
while on treatment and within 30 days after treatment with talimogene 
laherparepvec.  For those with latex allergies, polyurethane condoms may be 
used. 
34. 
221. 
Subject who is unwilling to minimize exposure with his/her blood or other 
body fluids to individuals who are at higher risks for HSV-1 induced complications 
such as immunosuppressed individuals, individuals known to have HIV infection, 
pregnant women, or children under the age of 1 year, during talimogene 
laherparepvec treatment and through 30 days after the last dose of talimogene 
laherparepvec. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written independent ethics committee/institutional review 
board (IEC/IRB) approval of the protocol, informed consent form, and all other subject 
information and/or recruitment material, if applicable (see Section 11.2).  All subjects or 
legally acceptable representatives must personally sign and date the IEC/IRB and 


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Amgen approved informed consent form before commencement of study-specific 
activities/procedures.   
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined 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 Interactive voice response (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 1 time at the discretion of the investigator.  Prior to rescreening, subjects 
may need to reconsent to the study to ensure that the IEC/IRB approved main informed 
consent form is signed within 28 days of enrollment.  Subjects who are determined not 
eligible after rescreen must be screen-failed in the IVR system and the reason for the 
screen-failure provided.  Subjects may only be enrolled 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.   
5.1 
Treatment Assignment  
All subjects enrolled will receive open-label talimogene laherparepvec.  The treatment 
assignment date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product (except if required by local regulation) used in this 
study includes: talimogene laherparepvec.   
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of talimogene laherparepvec.  


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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 
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.  As necessary, talimogene laherparepvec 108 PFU/mL will be diluted 
1:10 for a concentration of 107 PFU/mL immediately prior to injection. 
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 4.0 (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 (Table 2) and the results should be checked 
before each scheduled dose.  Dosing will occur only if these test values are acceptable 
per Section 6.2.1.2. 
Hospitalization for  24 hours may be allowed when subjects are administered the first 
dose of talimogene laherparepvec.  Need for hospitalization more than 1 day should be 
discussed between the treating physician and the Amgen medical monitor. 
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. 
On day 1 (week 0) 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 or 107 PFU/mL, should be 
administered 3 weeks ( 5) days after the initial injection (ie, no sooner than day 22 but 
should not be delayed more than 5 days after the 3-week time point).  Subsequent 
injections up to 4.0 mL of 108 or 107 PFU/mL should be given every 2 weeks ( 3) days. 


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The maximum volume of talimogene laherparepvec to be administered at each 
treatment visit  is 4.0 mL.  Investigators are encouraged to administer the maximum 
volume possible into each injected lesion based on lesion size, not to exceed 4.0 ml in 
any individual lesion.  Dose reduction for adverse events is not allowed.  However, if 
during the process of administering talimogene laherparepvec in the clinic, 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 volume of talimogene laherparepvec to be injected into the tumor(s) is dependent 
on the size of the tumor(s) and should be determined according to the injection volume 
guideline in Table 1.  The tumor size assessment should be done by clinical exam using 
ruler or caliper for cutaneous and palpable and protruding subcutaneous and nodal 
lesions, or by measurements under ultrasound of deep-seated subcutaneous and nodal 
lesions.  
Table 1.  Talimogene Laherparepvec Injection Volume Guideline 
Based on Tumor Size 
Tumor Size (longest dimension) 
Maximum Injection Volume 
 5.0 cm 
4.0 mL 
 2.5 cm to 5.0 cm 
2.0 mL 
 1.5 cm to 2.5 cm 
1.0 mL 
 0.5 cm to 1.5 cm 
0.5 mL 
 0.5 cm 
0.1 mL 
On each treatment day, prioritization of injections is should be as follows: 
 
any new injectable tumor that has appeared since the last injection 
 
by tumor size, beginning with the largest tumor  
The lesions injected and volume will be recorded on the CRF. 
A subject will be treated with talimogene laherparepvec until the subject has a DLT 
during the DLT evaluation period, subject has achieved a CR, no injectable lesions, 
clinically relevant (resulting in clinical deterioration or requiring change of therapy) 
disease progression beyond 24-week of treatment, per modified WHO response criteria 
(see Appendix D), or safety concern, a maximum treatment duration of 48 months, or 
the drug is commercially available in Japan, whichever occurs first.  Due to the 
mechanism of action, subjects may experience growth in existing tumors or the 


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appearance of new tumors prior to maximal clinical benefit of talimogene laherparepvec.  
Therefore, treatment with talimogene laherparepvec should be continued for at least 24-
weeks even in the presence of progression, including the appearance of new lesions to 
allow for delayed-immune-based anti tumor effects to occur unless other therapy for 
melanoma is required.  After 24 weeks, subjects will remain on treatment until clinically 
relevant disease progression occurs as defined in Appendix D. 
The dose, lesion site, start date, and lot number of talimogene laherparepvec are to be 
recorded on each subject’s CRF. 
6.2.1.2 
Dose-cohort Study De-escalation and Stopping Rules 
6.2.1.2.1 
Rules for DLT Evaluation 
The DLT evaluation period is 35 days from the first dose of talimogene laherparepvec.  
To be evaluable for a DLT, subjects must have received at least 1 dose of talimogene 
laherparepvec and had the opportunity to be followed for the entire DLT evaluation 
period or have experienced a DLT within the DLT evaluation period.  To obtain the first 
6 DLT-evaluable subjects, subjects will be replaced if they are not evaluable for DLT 
(eg, a subject did not receive study treatment, or ended the study treatment before 
completion of DLT evaluation period for a reason other than experiencing a DLT). 
A DLRT composed of the investigator(s), Amgen Medical Monitor, Amgen Global Safety 
Officer or designated safety scientist, Amgen Clinical Research Study Manager and 
Amgen Biostatistics representative will review data, monitor safety, and make dose and 
dose de-escalation decisions.  Additional members may be added to the DLRT as 
needed (eg, Global Development Leader) (see Section 10.3.2).  The DLRT will review 
the safety data after 6 DLT-evaluable subjects have been enrolled at Dose 
1 (see below).  Enrollment will be temporarily paused during the DLT review period to 
evaluate the 6 DLT-evaluable subjects.  The decision to continue to enroll 12 additional 
subjects at the Dose 1 will be based on observing  33 subject incidence of a DLT in 
the initial 6 subjects during the DLT evaluation period.  
If at any time there are 2 or more subjects with a DLTs prior to enrollment of the first 
6 DLT-evaluable subjects, an ad hoc DLRT meeting will be convened to determine if 
dose de-escalation (Dose -1) is required.  The safety data during the enrollment of the 
additional subjects will be monitored on an going basis and an ad hoc DLRT meeting 
may be called, if needed, to determine the further course of the study.   
Dose De-escalation 


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If dose de-escalation is needed, then the remaining subjects will be treated at the lower 
dose regimen of talimogene laherparepvec (Dose -1).   
Dose 
Initial dose 
Subsequent doses 
1 
106 PFU/mL (day 1, week 0) 
108 PFU/mL (3 weeks later and then every 
2 weeks thereafter) 
-1 
106 PFU/mL (day 1, week 0) 
107 PFU/mL (3 weeks later and then every 
2 weeks thereafter) 
Dose -1 will be administered as an initial dose up to 4.0 mL of 106 PFU/mL (day 1, 
week 0) followed by dose of up to 4.0 mL of 107 PFU/mL 3 weeks later ( 5 days). 
Subsequent doses of up to 4.0 mL of 107 PFU/mL will be administered every 2 weeks 
( 3 days) thereafter.  
The DLRT will review the safety data after the first 6 DLT-evaluable subjects at Dose -
1 have been enrolled.  Enrollment will be temporarily paused during the DLT review 
period to evaluate the 6 DLT-evaluable subjects at Dose -1.  Upon demonstration of 
safety, additional subjects will be enrolled (up to a total of 18 subjects) at Dose -1 to 
obtain additional safety data.  
The safety data of the subjects enrolled at the Dose-1 level will be monitored on an 
going basis and an ad hoc DLRT meeting may be called, if needed, to determine the 
further course of the study.   
6.2.1.2.2 
Definition of DLT 
All toxicities will be graded using the CTCAE version 4.0 (see Appendix A).  The 
occurrence of any of the following toxicities during the DLT evaluation period will be 
considered a DLT, if judged by the investigator to be related to the administration of 
talimogene laherparepvec: 
 
grade 4 non-hematologic toxicity 
 
grade 3 non-hematologic toxicity lasting  3 days despite optimal supportive care 
- 
grade 3 fatigue will not be classified as DLT, irrespective of duration 
 
Any grade 3 or higher non-hematologic laboratory value reported as an adverse 
event if: 
- 
medical intervention is required, or 
- 
the abnormality leads to hospitalization, or 
- 
the abnormality persists for  1 week (Laboratory values that persist for  1 week 
but are deemed not clinically important per both investigator and sponsor will not 
be considered DLTs) 
 
Febrile neutropenia grade 3 or grade 4 


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 
Thrombocytopenia  25 x 109/L associated with bleeding event requiring intervention 
 
Serious herpetic event (eg, herpetic encephalitis, encephalomyelitis, or disseminated 
herpetic infection) 
 
grade 5 toxicity (ie, death) 
 
Any other intolerable toxicity leading to permanent discontinuation of talimogene 
laherparepvec  
If a subject experiences a DLT during the DLT evaluation period, study treatment will be 
discontinued for that subject. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Dose reduction for adverse events is not allowed.  However, if during the process of 
administering talimogene laherparepvec in the clinic, 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. 
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 will be permanently discontinued if a subject has a DLT 
during the DLT evaluation period, subject achieved a CR, no injectable lesions, clinically 
relevant (resulting in clinical deterioration or requiring change of therapy) disease 
progression beyond 24-weeks of treatment, per modified WHO response criteria 
(Appendix D), or safety concern (refer to Section 8.1), reaches a maximum treatment 
duration of 48 months, or the drug becomes commercially available in Japan, 
whichever occurs first.   


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For additional information, related special warnings, and precautions for the use of 
talimogene laherparepvec please refer to the latest version of the talimogene 
laherparepvec Investigator’s Brochure. 
6.3 
Other Protocol-required Therapies 
All other protocol-required therapies including, topical anesthetic or injectable local 
anesthetic medications used for pretreatment of the talimogene laherparepvec injection 
site that are commercially available are not provided or reimbursed by Amgen (except if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these protocol-required therapies.  
Additional details regarding these protocol-required therapies are provided in the IPIM. 
6.4 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 
All prescription and non-prescription concomitant therapies are to be collected in the 
CRF from informed consent through 30 (7) days after the last dose of talimogene 
laherparepvec.  
For concomitant therapies collect therapy name, indication, dose, unit, frequency, route, 
start date, and stop date. 
6.5 
Other Treatment Procedures 
Treatment with talimogene laherparepvec may result in the reduction of tumor burden 
such that surgical resection of a previously unresected lesion becomes possible.  
Investigators may choose to resect lesions which become suitable for resection to 
render the subject free of macroscopic disease.  In the event of a complete response, 
residual visible cutaneous or subcutaneous index lesions must be documented by 
representative biopsy to not contain viable tumor.  If a subject undergoes resection of 
the lesion in the event other than CR the procedure should be recorded in the source 
document and CRF.  In these instances, if the response of other lesions is at least PR 
(if other lesions remain), the response should be designated PR with the date of surgery 
as the date of response.  If no residual disease remains following surgery, this should 
also be noted in the CRF, the response definition again being PR with the date of 
surgery as the date of response.  If no viable melanoma was found in the surgical 


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specimen and all other tumor lesions resolved completely (if present), the response 
definition will be CR with the date of surgery as the date of response. 
Local palliative radiation treatment for relief of various symptoms including, but not 
limited to, bleeding or pain associated with the underlying disease will be permitted at 
any time during the study.  Subjects with local symptoms suggestive of disease 
progression should be evaluated for tumor response per modified WHO response 
criteria (see Appendix D) prior to the administration of palliative radiotherapy.  If a 
subject undergoes local radiation, the investigator or designee should notify the sponsor 
medical monitor as soon as possible and the treatment should be recorded in the source 
document and CRF.  Best overall response (BOR) determination of such subjects who 
received palliative radiation should be done based on tumor assessments prior to 
radiation treatment.  
If a subject demonstrates evidence of recurrent or new central nervous system (CNS) 
metastases, talimogene laherparepvec should be withheld and the investigator or 
designee should notify the Amgen medical monitor as soon as possible.  Subjects may 
be allowed to remain on treatment after discussion between the Amgen medical monitor 
and the investigator to determine the appropriateness of treatment resumption provided 
CNS lesions can be treated with stereotactic radiotherapy (including GammaKnife) or 
resection and if there is no change in the baseline ECOG performance status.  Subjects 
may be allowed to reinitiate talimogene laherparepvec following treatment of CNS 
metastases while receiving dexamethasone or a similar corticosteroid at no more than 
1.5 mg dexamethasone (or 10 mg prednisone or equivalent) per day.  If higher doses of 
a steroid are used, talimogene laherparepvec must be held until that dose level is 
reached during the period of steroid tapering. 
6.6 
Medical Devices 
Medical devices (eg, sterile needles, alcohol prep pads) that are commercially available 
are not usually provided or reimbursed by the Sponsor (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 a drug(s) or device(s) after it is released for distribution to market or 


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clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s) or device(s) provisioned and/or repackaged/modified by 
Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) supplied by Amgen are to be reported according to the 
instructions provided in the IPIM. 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Subjects must not use any of the following therapies during screening or treatment 
period: 
 
other investigational agents or procedures   
 
concurrent experimental or approved anti-tumor therapies other than study drugs 
and radiation therapy required for palliation (as noted in Section 6.5).   
 
chronic oral or systemic steroid medication use at a dose of  10 mg/day of 
prednisone or equivalent (with the exception of treatment for adverse events 
[see Section 6.2.1.2] and CNS metastases [see Section 6.5]).  Steroids with low 
systemic absorption [eg, triamcinolone hexacetonide] injected into a joint space is 
allowed) 
 
antiherpetic drugs (eg, acyclovir), other than if topically administered  20 cm from a 
talimogene laherparepvec injection site.  If a subject requires treatment with a 
systemic antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir) talimogene 
laherparepvec should be withheld and the investigator or designee should notify the 
Amgen medical monitor as soon as possible.  Subject may be allowed to continue 
treatment after discussion between the Amgen medical monitor and the investigator 
to determine the appropriateness of treatment resumption. 
 
Subjects must not schedule any elective surgeries during the treatment period and 
for at least 30 days after the last administration of study drug.  If a subject undergoes 
any unexpected surgery during the course of the study, study treatment must be 
withheld and the investigator or designee should notify the sponsor medical monitor 
as soon as possible.  A subject may be allowed to resume study drug if both the 
investigator and sponsor medical monitor agree to restart study therapy. 
6.9 
Contraceptive Requirements 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Female in the following categories are not considered of child bearing potential: 
1. Premenopausal female with 1 of the following: 
a.  Documented hysterectomy 


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b.  Documented bilateral salpingectomy 
c.  Documented bilateral oophorectomy 
Note:  Site personnel documentation from the following sources is acceptable: 
1) review of subject medical records, 2) subject medical examination, or 3) subject 
medical history interview. 
2. Premenarchal female 
3. Postmenopausal female 
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
b. Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
The naturally occurring herpes simplex virus (HSV-1) can be transmitted through sexual 
contact.  It is not known if talimogene laherparepvec will behave the same way, thus you 
or your partner should use a latex condom during treatment and for up to 30 days after 
your last dose when engaging in sexual activity to prevent possible transmission of 
talimogene laherparepvec.  For those with latex allergies, polyurethane condoms may be 
used. 
6.9.1 
Female Subject 
Female subjects of childbearing potential must agree to use 1 acceptable method of 
effective contraception (as described in the table below) during treatment and for an 
additional 3 months after the last dose of talimogene laherparepvec.   


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Acceptable Methods of Effective Contraception for Female Subjects 
 
Combined (estrogen and progestogen) or Progestogen-only hormonal methods 
given orally 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
Bilateral tubal ligation 
 
Vasectomized partner (Provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (Defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject.) 
 
Double barrier method:  the male uses a condom and the female may choose either 
a cap, diaphragm, or sponge with spermicide.  (A female condom is not an option 
due to the risk of tearing when both partners use a condom.) 
If a female subject is suspected of being pregnant, the talimogene laherparepvec must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed.   
6.9.2 
Male Subjects 
If the male’s sole sexual partner is of non-childbearing potential or has had a bilateral 
tubal ligation, he is not required to use additional forms of contraception during the 
study.  The definition of non-childbearing potential is provided above. 
Male subjects with a partner of childbearing potential must agree to not father a child 
during treatment and for an additional 30 days after the last dose of talimogene 
laherparepvec.   


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Contraceptive options for male subjects include:   
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with talimogene laherparepvec).  The reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject. or  
 
Use a latex condom during treatment and for an additional 30 days after the last 
dose of talimogene laherparepvec.  For those with latex allergies, polyurethane 
condoms may be used. 
The female partner is to use an acceptable method of effective contraception such as: 
hormonal, IUD, IUS, female barrier method (diaphragm, cervical cap, contraceptive 
sponge [a female condom is not an option because there is a risk of tearing when both 
partners use a condom]).  Male subjects must not donate sperm during treatment and for 
an additional 30 days after the last dose of talimogene laherparepvec. 
Male subjects with a pregnant partner must practice sexual abstinence or wear a latex 
condom to prevent exposure of the unborn child to talimogene laherparepvec.  For those 
with latex allergies, polyurethane condoms may be used. 
6.9.3 
Unacceptable Methods of Birth Control for Male and Female 
Subjects 
Birth control methods that are considered unacceptable in clinical trials include:  periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to fetus if they become pregnant or father a child 
during treatment and for 3 months after the last dose of talimogene laherparepvec. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and for an increased length of time.  In addition, male subjects 
may also be required to use contraception.  The investigator must discuss these 
contraceptive changes with the subject. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
For Schedule of Assessments refer to Table 2 . 
 


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Table 2.  Schedule of Assessments 
  
Screening 
Treatment Perioda 
Follow-up Period 
Week 
 
0 (day 1) 
3 
5 
7 
9 
11 
13 
15 
15 and 
beyond 
Safety 
follow-up 
Long-term 
follow-upe 
GENERAL & SAFETY ASSESSMENTS  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of Medical History and Prior Cancer 
Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Recording of Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of Adverse events, Serious Adverse Events 
and Disease Related Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
 
 
 
 
Xh 
 
 
Every 
12 weeks
h 
X 
 
Vital Signs 
X 
X 
X 
 
X 
 
X 
 
X 
Every 
4 weeks 
X 
 
Weight 
 
X 
 
 
 
 
X 
 
 
Every 
12 weeks 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
BRAF status, if knownb 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
 
 
Xh 
 
 
Every 
12 weeks
h 
X 
Xg 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
X 
Reporting exposure of caregiver, close contact or 
health care provider 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Reporting of pregnancy or lactation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 1 of 2 
Footnotes defined on last page of the table 


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Table 2.  Schedule of Assessments 
  
Screening 
Treatment Perioda 
Follow-up Period 
Week 
 
0 (day 1) 
3 
5 
7 
9 
11 
13 
15 
15 and 
beyond 
Safety 
follow-up 
Long-term 
follow-upe 
LOCAL LABORATORY ASSESSMENTS 
 
Urine or Serum Pregnancy Testc 
X 
 
 
 
 
 
 
 
 
 
X 
 
Hematologyd  
X 
X 
X 
X 
 
 
 
X 
 
Every 
8 weeks 
X 
 
Chemistryd 
X 
X 
X 
X 
 
 
 
X 
 
Every 
8 weeks 
X 
 
Serum LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
PT (or INR) and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood for viral hepatitis testing f 
X 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Talimogene Laherparepvec 
 
X 
X 
X 
X 
X 
X 
X 
X 
Every 
2 weeks 
 
 
TUMOR ASSESSMENTS 
Clinical tumor assessment 
X 
 
 
 
 
 
 
Xh 
 
 
Every 
12 weeks
h 
Xg 
Xg 
Radiological tumor assessment 
X 
 
 
 
 
 
Xh 
 
 
Every 
12 weeks
h 
Xg 
Xg 
CENTRAL LABORATORY ASSESSMENTS 
 
Swab of Herpetic Lesion for qPCR 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
X 
Xg 
Blood for HSV-1 Antibody Serostatus 
 
Within 3 days prior to dose at day 1 (week  0) and then at week 5 
 
 
Page 2 of 2 
Footnotes defined on last page of the table 


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ECOG  Eastern Cooperative Oncology Group; ECG  electrocardiogram; PT  prothrombin time; INR  international normalization ratio; aPTT  activated partial 
thromboplastin time; qPCR  real-time polymerase chain reaction; BRAF  serine/threonine protein kinase B-Raf V600; LDH  lactate dehydrogenase; PDr  clinically 
relevant disease progression; WHO  World Health Organization  
a During the treatment period assessments and procedures can be performed  3 days of the planned visit. 
b BRAF V600E/K tumor status result, obtained from a local laboratory prior to screening for this study will be acceptable  
c Urine or serum pregnancy test must be performed on females of childbearing potential within 3 days prior to enrollment and at the safety follow-up visit. 
d  Blood samples for hematology and chemistry will be collected at screening, within 3 days prior to talimogene laherparepvec administration on day 1 (week 0), 
week 3, week 5, week 13 and then every 8 weeks until end of treatment, and at the safety follow-up visit.  
e For subjects that discontinue talimogene laherparepvec for reason other than disease progression or death, the following additional procedures will be conducted 
during the long-term follow-up: radiographic tumor imaging, clinical tumor assessments, ECOG Performance Status assessments, reporting of pregnancy or lactation, 
assessment of swabs of lesions of suspected herpetic origin for presence of talimogene laherparepvec DNA by qPCR test, and tumor response assessments until 
documented disease progression beyond 24-weeks of treatment, per modified WHO response criteria (Appendix D), until the start of a new anticancer therapy, or end 
of study, whichever the earliest.  Subjects treated for more than 24 months after the last subject is enrolled will not enter long-term follow-up (ie, their last 
visit will be the safety follow-up). 
f Baseline blood for viral hepatitis testing will be collected at screening for reactive testing as required during the course of the study.  Testing is not required for 
enrollment into the study. 
g If subject discontinues talimogene laherparepvec for a reason other than disease progression or death, tumor measurements are to be performed at the safety follow-
up visit (if not performed within previous 4 weeks [ 1 week]) and every 12 weeks ( 1 week) during the long-term follow-up period until PDr beyond 6 months of 
treatment (per modified WHO response criteria as described in Appendix D) or until the start of a new anticancer therapy.  Long-term follow-up is not applicable for 
subjects treated beyond 24 months after the last subject is enrolled. 
h The tumor assessment, physical exams, and ECOG performance status will be completed after 12 ( 1) weeks on treatment (ie, day 1 of week 11), and then every 
12 ( 1) weeks (eg, weeks 23, 35, 47 etc.), or more frequently if clinically indicated, until PDr beyond 6 months of treatment (per modified WHO response criteria [see 
Appendix D]) or until the start of a new anticancer therapy. 
 


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7.2 
General Study Procedures  
The procedures performed and timing of each study visit are outlined in the Schedule of 
Assessments (Table 2).  Details regarding each type of procedure are provided in 
subsequent sub-sections.  Procedures that are part of routine care are not considered 
study-specific procedures and may be used at screening to determine eligibility. 
Refer to the applicable supplemental central laboratory, IVR, IPIM, and study manuals 
for detailed collection and handling procedures.   
7.2.1 
Screening and Enrollment 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy or any disallowed therapy.  After signing the written 
informed consent form, the site will register the subject in IVR and screen the subject in 
order to assess eligibility for participation.  Screening procedures are to be completed 
during the screening period within 28 days prior to enrollment.  If a subject has not met 
all eligibility criteria at the end of the 28-day window, the subject will be registered as a 
screen fail.  Screen fail subjects may be eligible for re-screening once as described in 
Section 7.2.2  Prior to enrollment, subject eligibility must be confirmed with screening 
procedures.  Subjects satisfying eligibility requirements will be enrolled. 
7.2.2 
Re-screening 
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to re-screen once.  Re-screen subjects must first be registered as screen 
failed in IVR and subsequently registered as re-screened.  Subjects will retain the same 
subject identification number assigned at the original screening.  Once the subject is 
registered as re-screened, a new 28-day screening window will begin.  If the 
re-screening period begins more than 28-days after the original signing of the informed 
consent form, all screening procedures, including informed consent must be repeated.  If 
the re-screening occurs less than 28 days after the original signing of the informed 
consent, then only those criteria that were originally failed are required to be repeated. 
7.2.3 
Treatment 
Visits will occur per the Schedule of Assessments (Table 2) during the treatment period 
from day 1 (week 0).  On-study visits may be completed within  3 days of the planned 
visit date.  The date of the first dose of talimogene laherparepvec is defined as day 
1 (week 0).  All subsequent doses and study visits will be scheduled based on the day 
1 (week 0) date.  Study treatment should begin as soon as possible after enrollment via 
the IVR system but no later than 5 days after enrollment.  Administration of talimogene 


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laherparepvec is to be performed after all other procedures are completed during each 
visit that it is required, unless otherwise stated.  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).  A  5 day dosing window is allowed at 
week 3.  Subsequently a  3-day dosing and study procedure window is allowed.  
7.2.4 
Follow-up 
7.2.4.1 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, a safety 
follow-up visit will be performed 30 (7) days after the last dose of talimogene 
laherparepvec.  The safety follow-up visit is not required for those subjects who are 
enrolled, but did not receive any dose of investigational product.  
7.2.4.2 
Long-term Follow-up 
All subjects who permanently discontinue talimogene laherparepvec for any reason 
other than withdrawal of full consent or death will be contacted by telephone, or clinic 
visit, to assess survival status and, if applicable, commencement of any subsequent 
anticancer melanoma therapy.  Adverse events deemed by the investigator to be 
potentially related to talimogene laherparepvec and use of anti-cancer therapies for 
melanoma will also be recorded.  Follow-up will occur every 12 weeks ( 28 days) 
following the safety follow-up visit until death, subject withdraws full consent, or up to 
24 months after the last subject is enrolled in the study.  If a subject discontinues 
therapy more than 24 months after the last subject was enrolled in the study, 
when the long-term follow-up period ends, they will not enter long-term follow-up.  
If a subject has discontinued talimogene laherparepvec for reason other than disease 
progression or death, radiographic tumor imaging, clinical tumor assessments, ECOG 
Performance Status assessments, reporting of pregnancy or lactation, assessment of 
swabs of lesions of suspected herpetic origin for presence of talimogene laherparepvec 
DNA by qPCR test, and tumor response assessments will be performed until 
documented disease progression beyond 24-weeks of treatment, per modified WHO 
response criteria (Appendix D), until the start of a new anticancer therapy, or end of 
study, whichever the earliest.  
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures for required 
timepoints. 


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7.3.1 
Informed Consent 
All subjects or legally acceptable representative must sign and personally date the 
IEC/IRB approved informed consent  and if required the subject has provided assent 
before any study specific procedures are performed.  
7.3.2 
Demographic Data 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness. 
7.3.3 
Medical History 
Complete medical and surgical history will be collected.  Medical history will include 
information on the subject’s concurrent medical conditions.  The severity will be collected 
for each condition that has not resolved.  Melanoma history must date back to the 
original diagnosis.  Record all findings on the medical history CRF. 
7.3.4 
Prior Cancer Therapy 
Prior therapies (eg, surgery, radiation, systemic agents such as chemotherapy, targeted 
agents, immunotherapies)  that were being taken for current or prior malignancies. 
Collect therapy name, indication, dose, unit, frequency, and start and stop date. 
7.3.5 
Concomitant Therapy 
All concomitant medications that are administered after the subject has signed informed 
consent through 30 (7) days after the last administration of talimogene laherparepvec 
will be recorded in the case report form (refer to Section 6.4).  Concomitant medications 
should be assessed on an ongoing basis and recorded at each subject visit.  Only 
subsequent anticancer therapy will be recorded during the long-term follow-up period. 
7.3.6 
Adverse Events, Disease Related Events and Serious Adverse 
Events 
Safety event reporting procedures are described in Section 9.2.  
7.3.7 
Physical Examination 
Physical examination as per standard of care.  Physical examination findings should be 
recorded on the appropriate CRF (eg, medical history, event).  
7.3.8 
Vital Signs 
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 


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position selected and temperature location 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. 
7.3.9 
Physical Measurements 
Body weight in kilograms should be measured without shoes.  Height in centimeters 
should be measured without shoes. 
7.3.10 
ECG 
A 12-lead electrocardiogram (ECG) per standard of care:  The ECG must include the 
following measurements: heart rate, PR interval, QRS, QT and QTc intervals.  Subject 
must be in supine position in a rested and calm state for at least 5 minutes before ECG 
assessment is conducted.  If the subject is unable to be in the supine position, the 
subject should be in most recumbent position as possible.  The investigator or 
designated site physician will review all ECGs.  Once signed, the original ECG tracing 
will be retained with the subject’s source documents.  At the request of the sponsor, a 
copy of the original ECG will be made available to the Sponsor. 
7.3.11 
BRAF V600E/K Status 
BRAF V600E/K tumor status if available should be reported.  BRAF V600E/K obtained from a 
local laboratory prior to screening for this study will be acceptable 
7.3.12 
ECOG  
ECOG performance status will be collected as outlined in Appendix E. 
7.3.13 
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, the 
exposure must be reported to Amgen.  Refer to Section 9.4. 
7.3.14 
Tumor Assessments 
7.3.14.1 
Clinical Tumor Assessment 
Investigators will perform clinical measurement of cutaneous, subcutaneous, or nodal 
tumors by caliper at screening, 12 weeks ( 1 week) on treatment (ie, day 1 of week 11), 
and then every 12 weeks ( 1 week), or more frequently if clinically indicated, until PDr 
beyond 6 months of treatment (per modified WHO response criteria as described 


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in Appendix D) or until the start of a new anticancer therapy.  The screening 
measurement must be done within 28 days prior to enrollment and will be used as 
baseline.  If subject discontinues talimogene laherparepvec for a reason other than 
disease progression or death, clinical tumor measurements are to be performed at the 
safety follow-up visit (if not performed within previous 4 weeks [ 1 week]) and every 
12 weeks ( 1 week) during the long-term follow-up period until PDr beyond 6 months of 
treatment (per modified WHO response criteria as described in Appendix D) or until the 
start of a new anticancer therapy. 
7.3.14.2 
Radiological Tumor Assessment 
Radiographic imaging (CT, PET/CT, MRI, or US) of the chest, abdomen, and pelvis, and 
all other sites of disease, and CT scan or MRI of brain (only if symptoms or signs 
suggestive of CNS metastasis are present) at screening, 12 weeks ( 1 week) on 
treatment (ie, day 1 of week 11), and then every 12 weeks ( 1 week), or more 
frequently if clinically indicated, until PDr beyond 6 months of treatment (per modified 
WHO response criteria [see Appendix D]) or until the start of a new anticancer therapy.  
The screening assessment must be done within 28 days prior to enrollment and will be 
used as baseline.  If subject discontinues talimogene laherparepvec for reason other 
than disease progression or death, radiographic imaging is to be performed at safety 
follow-up visit (if not performed within previous 4 weeks [ 1 week]) and every 12 weeks 
( 1week) during the long-term follow-up period until PDr beyond 6 months of treatment 
(per modified WHO response criteria [see Appendix D]) or until the start of a new 
anticancer therapy. 
7.4 
Laboratory Assessments  
Screening laboratory values may be used for day 1 (week 0) assessment if completed 
within 10 days of study treatment initiation.  On-treatment tests should be performed 
within 3 days of the planned visit.  Results (with the exception of herpetic lesion 
polymerase chain reaction [qPCR] and HSV-1 antibody for serostatus) should be 
reviewed prior to the administration of talimogene laherparepvec.  All tests (except for 
herpetic lesion qPCR, and HSV-1 antibody) are to be performed at the local laboratory.  
Screening tests for hepatitis are acceptable within 6 weeks of study treatment initiation.  
Specific analytes for serum chemistry, coagulation, hematology, and other testing to be 
conducted on blood and swabs are below (Table 3).  


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Table 3.  Laboratory Analytes 
Serum Chemistry 
Coagulation 
Hematology 
Other Labs 
Sodium 
Potassium 
Chlorided 
Bicarbonate or CO2d 
Calcium 
Magnesium 
Phosphorus 
Uric acid 
Total protein 
Albumin 
Blood urea nitrogen 
Creatinine 
Total bilirubin 
Alkaline-phosphatase 
AST 
ALT 
Glucose 
PT or INR 
aPTT 
Red blood cell 
Hemoglobin 
Hematocrit 
Platelets 
White blood cell 
Differential a 
 
Neutrophils 
 
Eosinophils 
 
Basophils 
 
Lymphocytes 
 
Monocytes 
Urine or serum pregnancy test 
Hepatitis B surface antigenc and 
Hepatitis B core antibodyc 
Hepatitis C virus antibodyc 
qPCR for talimogene laherparepvec 
DNAb 
HSV-1 antibodyb 
Lactate dehydrogenase 
AST  aspartate aminotransferase; ALT  alanine aminotransferase ; CO2  carbon dioxide; 
PT  prothrombin time; INR  international normalization ratio; aPTT  activated partial thromboplastin 
time; qPCR  real-time polymerase chain reaction; HSV-1  herpes simplex virus type-1 
a 3-part differential (neutrophils, eosinophils, basophils) acceptable if 5-part unable to be performed 
b Performed by Central Laboratory 
c Baseline blood for viral hepatitis testing will be collected at screening for reactive testing as required during 
the course of the study.  Testing is not required for enrollment into the study. 
d If available as part of chemistry panel from venous blood draw 
7.4.1 
qPCR for Talimogene Laherparepvec 
Swab of cold sore, vesicles and other lesions suspected to be herpetic in origin (if any) 
for qPCR testing of talimogene laherparepvec DNA must be collected.  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 by 
the central laboratory to evaluate whether the talimogene laherparepvec DNA is 
detectable in the sample. 
7.5 
Sample Storage and Destruction  
Any blood or tumor sample collected according to the Schedule of Assessments 
(Table 2) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 


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also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  All samples obtained to perform central testing, such as 
HSV-1 serostatus and/or qPCR assays from swabs for the presence of talimogene 
laherparepvec will be sealed and shipped overseas to the central laboratory.  All other 
samples collected as per Table 2 will be used to run tests in the respective clinical trial 
site.   
If informed consent is provided by the subject or legally acceptable representative, 
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 and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
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 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, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 


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8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 2) and 
collection of data, including endpoints and adverse events.  The investigator must 
document the change to the Schedule of Assessments (Table 2) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
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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8.3 
Reasons for Removal From Treatment or Study  
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments 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, pregnancy) 
 
other protocol specified criteria see Section 6.2.2 (ie, DLT during the DLT evaluation 
period [ie, 35 days), subject achieved a CR, no injectable lesions). 
 
death 
 
lost to follow-up 
 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
 
disease progression 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease Related Events 
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  These could include  events such as 
pain or discomfort caused by growing tumors due to overall worsening of disease.  Such 
events do not meet the definition of an Adverse Event unless assessed to be more 
severe than expected for the subject’s condition and/or if the investigator believes that 
the event is related to the investigational product(s)/study treatment/protocol required 
therapies.  
Further, any disease related event which meets any of the seriousness criteria in 
Section 9.1.3 should be reported as a Serious Disease Related Event. 
Note:  For situations where disease related events are due to melanoma, the primary 
tumor type (eg, metastatic melanoma) should be used, rather than the term “disease 
progression.” 


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9.1.2 
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 or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) 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.   
Note:  For situations where adverse events are due to the subject’s primary melanoma, 
the primary tumor type (eg, metastatic melanoma) should be used, rather than the term 
“disease progression.” 
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.   
9.1.3 
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 
A disease related event (eg, PD or pain or discomfort caused by growing tumors) is to 
be reported as a serious adverse event if:   


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 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event,  
 
meets at least 1 of the serious criteria above. 
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.”   
9.2 
Safety Event Reporting Procedures  
9.2.1 
Reporting Procedures for Disease Related Events 
The investigator is responsible for ensuring that all Disease Related Events (serious or 
nonserious) observed by the investigator or reported by the subject that occur after the 
first dose of talimogene laherparepvec through the safety follow-up visit (ie, 30 [7] days 
after the last dose of talimogene laherparepvec), are reported using the Event CRF.  
Additionally, the investigator is required to report a fatal disease related event on 
the event CRF as a Disease Related Event.  
All serious disease related events will be recorded and reported to the sponsor or 
designee within 24 hours.  The investigator will submit any updated serious 
disease related event data to the sponsor within 24 hours of it being available. 
The investigator must assign the following attributes to each disease related event: 
 
disease related event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms), 
 
dates of onset and resolution (if resolved), 
 
severity (and/or toxicity per protocol), 
 
assessment of relatedness to talimogene laherparepvec, and 
 
action taken 
CTCAE version 4.0 will be used to grade a disease related event.  The grading scale 
used in this study is described in Appendix A. 
Note:  If the event is more severe than expected for the subject’s condition or if the 
investigator believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol required therapies and disease worsening, the event 
should be reported as an adverse event, not a disease related event. 


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The investigator is expected to follow reported disease related events (serious or non-
serious) until stabilization or reversibility.  
9.2.2 
Adverse Events 
9.2.2.1 
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 first dose of talimogene 
laherparepvec through the safety follow-up visit (ie, 30 [7] days after the last dose of 
talimogene laherparepvec) are reported using the Event CRF.  Additionally, 
talimogene laherparepvec related adverse events that occur after the safety 
follow-up visit through the end of the long-term follow-up will be reported. 
The investigator must assign the following attributes to each adverse event: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
 
Dates of onset and resolution (if resolved), 
 
Severity (and/or toxicity per protocol), 
 
Assessment of relatedness to talimogene laherparepvec and, 
 
Action taken. 
The adverse event grading scale used will be the CTCAE version 4.0.  The grading 
scale used in this study is described in Appendix A.  The investigator must assess 
whether the adverse event is possibly related to the talimogene laherparepvec.  This 
relationship is indicated by a “yes” or “no” response to the question:  Is there a 
reasonable possibility that the event may have been caused by the investigational 
product(s)? 
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, 
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.  


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9.2.2.2 
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 90 ( 7) days after the cessation of all study treatment, or 30 (7) days 
following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier, are recorded in the subject’s medical record and are submitted to 
Amgen/AABP.  Additionally, talimogene laherparepvec related serious adverse events 
that occur after the safety follow-up visit through the end of the long-term follow-up will 
be reported.  Any serious adverse event, or follow-up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (refer 
to Section 9.1.3 for additional details) that occurs to any subject must be reported within 
24 hours to Amgen/AABP including serious adverse events that cause the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment, or a 
procedure.  
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/AABP via an 
electronic Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the electronic 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 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
All new information relating to a previously reported serious adverse event must be 
submitted to Amgen/AABP 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 Event 
CRF. 


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If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen/AABP. 
Amgen/AABP will report serious adverse events and/or suspected unexpected serious 
adverse reactions as required to regulatory authorities, investigators/institutions, and 
IEC/IRBs in compliance with all reporting requirements according to local regulations 
and GCP.  
The investigator is to notify the appropriate IEC/IRB of serious adverse events occurring 
at the site and other adverse event reports received from Amgen/AABP, in accordance 
with local procedures and statutes. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen/AABP.  In some countries (eg, European 
Union [EU] member states), investigators are required to report serious adverse events 
that they become aware of after end of study.  If serious adverse events are reported, 
the investigator is to report them to Amgen/AABP 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.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking talimogene laherparepvec report the pregnancy to Amgen/AABP Global 
Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur after the last dose of talimogene laherparepvec through 
3 months after the last dose of talimogene laherparepvec.  
The pregnancy should be reported to Amgen’s 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).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested. 


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If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.  If a male 
subject's female partner becomes pregnant, the investigator should discuss obtaining 
information regarding the birth outcome and health of the infant from the pregnant 
partner.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event. 
If a female breastfeeds while taking talimogene laherparepvec report the lactation case 
to Amgen/AABP as specified below.  
In addition to reporting a lactation case during the study, investigators should report for 
lactation cases that occur after the last dose of protocol-required therapies through 
3 months after the last dose of talimogene laherparepvec.  
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
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/AABP as specified below.  In addition to reporting an unintended 
exposure case during the study treatment, investigators should monitor for potential 
exposure cases that occur after the last dose of talimogene laherparepvec through 
30 (7) days after the last dose of talimogene laherparepvec.  
Any potential or known unintended exposure should be reported to Amgen/AABP within 
24 hours of the investigator’s knowledge of the event of exposure.  Amgen/AABP 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 


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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 within 3-days of the 
symptoms or signs occurring. 
Report the herpes-related events on Clinical Trial Report of Suspected Talimogene 
Laherparepvec Associated Adverse Event for Health Care Professional (HCP) or Close 
Contact (Appendix F).  Amgen Global Patient Safety will follow-up with the investigator 
regarding additional information that may be requested. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoints 
 
Subject incidence of DLTs  
 
DRR using modified WHO response criteria by investigators 
10.1.1.2 
Secondary Endpoints 
 
ORR, TTR, DOR, and PFS using modified WHO response criteria by investigators 
 
OS 
10.1.2 
Safety Endpoint 
 
Subject incidence of all the following, where not defined as DLT: 
 
adverse events 
 
grade  3 adverse events 
 
serious adverse events 
 
clinically significant laboratory changes  
 
changes in vital signs 
10.1.3 
Analysis Sets 
10.1.3.1 
DLT Analysis Set 
The DLT analysis set will include DLT-evaluable subjects as defined in Section 6.2.1.2.2. 
10.1.3.2 
Safety Analysis Set 
The safety analysis set will include all subjects who received at least 1 dose of 
talimogene laherparepvec.   
10.1.4 
Covariates and Subgroups 
The following covariates will be used to examine efficacy and safety in subgroups or in 
multivariate analyses as appropriate: 


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 
Age at baseline:  50,  50;  65,  65;  75,  75 years 
 
Sex (female vs male) 
 
Disease stage at baseline:  IIIB and IIIC vs IVM1a vs IVM1b vs IVM1c 
 
Line of therapy for current disease 
 
Type of prior therapy 
 
Baseline HSV-1 serostatus 
 
Baseline LDH  ULN vs  ULN 
 
ECOG (0 vs 1) 
10.2 
Sample Size Considerations 
10.2.1 
Sample Size Considerations  
The total number of subjects that will participate in the study is approximately 18. 
10.2.1.1 
Sample Size Considerations for Safety Evaluation 
In the current study, a dose level will be considered safe if there are 0 to 1 DLTs 
observed in the initial 6 DLT evaluable subjects.  Table 4 and Figure 1 presents the 
probability of declaring a dose level safe (unsafe) for a range of true DLT rates for the 
protocol therapy for the 6 DLT-evaluable subjects (see triangle symbols).  As shown 
below in Table 4, the probability of declaring a dose level safe (unsafe) in the current 
study (based on only 6 DLT evaluable subjects) is 89 (11), 42 (58), and 11 
(89) if the true DLT rate is 10, 30, or 50, respectively.  Hypothetically, if the study 
were to enroll an additional 6 DLT-evaluable subjects after the initial 6 subjects (total of 
12 DLT evaluable subjects), the probability of observing a DLT rate  33 in the 
12 subjects following the observation of 0-1 DLTs in the first 6 DLT evaluable subjects 
would be 0.6, 8.6, and 6.7 if the true DLT rate is 10, 30, or 50, respectively. 


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Figure 1.  Probability of Declaring a Cohort Safe (Unsafe) 
DLT dose-limiting toxicity; Pr   probability 
Table 4.  Probability of Declaring a Cohort Safe or Unsafe 
True Cohort DLT Probability 
Probability Declare Cohort 
Safe 
Probability Declare Cohort 
Unsafe 
10 
89 
11 
20 
66 
34 
30 
42 
58 
40 
23 
77 
50 
11 
89 
DLT dose-limiting toxicity 
10.2.1.2 
Sample Size Considerations for Efficacy 
A 1-sided 5 significance level exact binomial test will be performed to test the null 
hypothesis of a 2 DRR.  The expectation is that this test will be based on the first 
18 subjects that receive at least 1 dose of talimogene laherparepvec.  The null 
hypothesis will be rejected if at least 2 subjects achieve a durable response 
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
Probability
Probability of DLT
Pr(Safe)
Pr(Unsafe)


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(DR).  Assuming a DRR of 16.3 consistent with the global phase 3 study, this analysis 
will have 81 power. 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
No formal interim efficacy analysis is planned for this study.  Interim safety analyses will 
be performed to support the evaluation of safety by the DLRT. 
10.3.2 
Dose Level Review Team 
DLRT meetings will be held to review data, monitor safety, and make dose and dose 
de-escalation decisions.  The review team will be composed of the investigator(s), 
Amgen Medical Monitor, Amgen Global Safety Officer or designated safety scientist, 
Amgen Clinical Research Study Manager and Amgen Biostatistics representative.  
Additional members may be added as needed (eg, Global Development Leader).  A 
quorum, defined as  50 of the participating investigators or their qualified designee 
[ie, sub-PI or research nurse or study coordinator possessing hard copy documentation 
(eg, email) of the PI’s vote regarding the dose level review], must be in attendance for 
DLRT.  The DLRT will be rescheduled if a quorum is not reached.  The DLRT members 
are responsible for dosing decisions, which may include dose de-escalation, 
continuation, delay, or termination of dosing.  All available study data, including 
demographics, investigational product administration, medical history, concomitant 
medications, adverse events, ECGs, vital signs, laboratory results will be reviewed.  In 
addition to DLTs, all  grade 3 toxicities not meeting DLT criteria will be reviewed by the 
team and can be considered in the DLRT’s decisions.  Data to be reviewed will be 
queried. 
The DLRT will review the safety data after the first 6 DLT-evaluable subjects have been 
enrolled.  The DLRT will recommend either to declare the current dose intolerable (if 2 or 
more DLTs observed among the first 6 subjects), or to declare the dose safe and 
enroll 12 additional subjects (if 0 to1 DLTs observed among first 6 subjects).   
The decision to enroll additional subjects at the same dose will be based on observing 
 33 subject incidence of a DLT.  
If at any time there are 2 or more subjects with a DLT prior to enrollment of the first 
6 DLT-evaluable subjects, an ad hoc DLRT meeting will be conveyed to determine if 
dose de-escalation is required. 


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If dose de-escalation is required, the DLRT will review the safety data after the first 
6 DLT-evaluable subjects at Dose -1 have been enrolled.  
The safety data of the subjects enrolled beyond the DLT evaluable period at the Dose-
1 level will be monitored on an ongoing basis and an ad hoc DLRT meeting may be 
called, if needed, to determine further course of the study.   
10.3.3 
Primary Analysis 
The primary analysis for safety will occur 3 months after the last subject is enrolled.  The 
primary analysis for efficacy will occur when a durable response outcome has been 
assessed for all subjects included in the primary efficacy analysis.  Safety will be 
re-analyzed at the primary efficacy analysis.   
10.3.4 
Final Analysis  
The final analysis will occur 24 months after the last subject is enrolled.  Safety and 
efficacy data collected after the final analysis will be summarized after the last 
subject completes safety follow-up.   
10.4 
Planned Methods of Analysis  
10.4.1 
General Considerations 
Descriptive statistics will be provided for demographic, safety and efficacy endpoints. 
10.4.2 
Primary Endpoint 
The DLT analysis set will be used to summarize the subject incidence of DLTs for the 
study and the safety analysis set will be used for all other analyses of safety endpoints.   
A 1-sided 5 significance level exact binomial test will be performed to test the null 
hypothesis of a 2 DRR.  The expectation is that this test will be based on the first 
18 subjects that receive at least 1 dose of talimogene laherparepvec.  The null 
hypothesis will be rejected if at least 2 subjects achieve a DR.  Assuming a DRR of 
16.3 consistent with the global phase 3 study, this analysis will have 81 power.  
Exact 90 and 95 CIs will be summarized for the DRR in the analysis set. 
10.4.3 
Secondary Endpoint 
ORR, DOR, TTR, PFS, and OS will be summarized in the overall population and by 
Dose level if applicable (Dose level 1 and Dose level -1).  ORR will be summarized with 
an associated exact 95 CI. DOR among responders, TTR, PFS and OS will be 
estimated using the Kaplan-Meier method.  


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10.4.4 
Safety Endpoints 
Subject incidence of treatment emergent adverse events will be tabulated by system 
organ class and preferred term.  Treatment-emergent adverse events are defined as 
adverse events with an onset from the first dose of study therapy up to 30 days after the 
last dose of study therapy.  Tables of fatal adverse events, serious adverse events, all 
adverse events, and adverse events leading to withdrawal from investigational product, 
will be provided. 
Subject incidence of disease- related events and fatal disease- related events will be 
tabulated by system organ class and preferred term.  
Medical Dictionary for Regulatory Activities will be used to code adverse events to a 
system organ class and a preferred term within the system organ class.  CTCAE 
version 4.0 will be used to grade severity of adverse events. 
Summary statistics over time will be provided for selected key safety laboratory 
endpoints.  Shifts in grades of these safety laboratory endpoints between the baseline 
and the worst on-study value will be tabulated by dose level group. 
The ECG measurements from this clinical study will be 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. Summaries 
and statistical analyses of ECG measurements are not planned, and these data would 
not be expected to be useful for meta-analysis with data from other trials. 
Subject incidence of suspected herpetic lesions along with data from qPCR analysis 
performed to detect talimogene laherparepvec DNA will be reported. 
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. 
Summary statistics will also be provided for concomitant medications, dose delay, study 
drug discontinuation, overall exposure, and ECOG performance status.  
Summary statistics will be provided for vital signs and other physical measurements.  
Details of the analysis will be provided in statistical analysis plan. 
10.5 
Handling of Missing and Incomplete Data 


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Partial or missing dates of adverse events and concomitant medications will be imputed.  
Adverse events with missing severity and/or possible relationship to talimogene 
laherparepvec will be included in the all adverse events analyses, except by severity 
grade and treatment-related.  Every effort will be made to obtain complete dates for 
deaths.  Details of the imputation algorithms will be specified in the study-specific 
statistical analysis plan. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject  or legally acceptable representative 
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.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
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 or a legally acceptable representative 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 or a legally acceptable representative. 


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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/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB 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 IEC/IRB 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IEC/IRB 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 IEC/IRB approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IEC/IRB continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 


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regulatory agency(s), and the IEC/IRB direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit such individuals to have access to his/her 
study-related records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
a recognized expert in the therapeutic area 
 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an Investigator contributing a high number of eligible subjects 
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 
IEC/IRB must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IEC/IRB 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 IEC/IRB in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 


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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 point and this is considered 
source data:  subject identification number. 
CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data).   
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
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 IEC/IRB 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
 
Non-investigational product(s) and or medical device(s) documentation, 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 


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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 
(or designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy 
storage areas, laboratories) and review of study-related records will occur to evaluate 
the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  
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, 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 EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the CRF, 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.   


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12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 2), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  CRFs must be 
completed in English.  TRADENAMES (if used) for concomitant medications may be 
entered in the local language.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which states 
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published (4) agreement to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.  Authors should meet conditions 1, 2, 3 and 4. 
When a large, multicenter group has conducted the work, the group should identify the 
individuals who accept direct responsibility for the manuscript.  These individuals should 


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fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors should qualify for authorship, and all those who qualify 
should be listed.  Each author should have participated sufficiently in the work to take 
public responsibility for appropriate portions of the content.  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. 
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Mekinist (trametnib) Prescribing Information. Research Triangle Park, NC, 
GlaxoSmithKline, USA, 2013. 
Middleton MR, Grob JJ, Aaronson N, et al,  Randomized phase 3 study of temozolomide 
versus dacarbazine in the treatment of patients with advanced metastatic malignant 
melanoma.  J Clin Oncol. 2000;18:158-166.  
Ministry of Health Labour and Welfare (MHLW). Patient Survey. 2011 
Nishimura T, Nakui M, Sato M, et al,  The critical role of Th1-dominant immunity in tumor 
immunology.  Cancer Chemother Pharmacol.  2000;46(suppl):S52-S61. 
O'Day S, Boasberg P.  Management of metastatic melanoma 2005.  Surg Oncol Clin N 
Am.  2006;15:419-437. 
Opdivo (Nivolumab) Prescribing Information. Princeton, NJ. Bristol-Myers Squibb 
Company, USA, 2015. 
Paul WE.  Dendritic cells bask in the limelight.  Cell.  2007;130:967-970. 
Ries LA, Wingo PA, Miller DS, et al,  The annual report to the nation on the status of 
cancer, 1973-1997, with a special section on colorectal cancer.  Cancer.  
2000;88:2398-2424. 
Robert C, Thomas L, Bondarenko I, et al,  Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma.  N Engl J Med.  2011;364:2517-2526. 
Robert C, Karaszewska B, Schachter J, et al, Improved Overall Survival in Melanoma 
with Combined Dabrafenib and Trametinib. N Engl J Med 2015; 372:30-39 
Robert C, Schachter J, Long GV, et al, Pembrolizumab versus Ipilimumab in Advanced 
Melanoma. N Engl J Med. 2015; 372:2521-2532. 
Rosenberg SA, Yang JC, Topalian SL, et al,  Treatment of 283 consecutive patients with 
metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2.  JAMA. 
1994;271:907-913. 
Senzer NN, Kaufman HL, Amatruda T, et al,  phase 2 clinical trial of a 
granulocyte-macrophage colony-stimulating factor-encoding, second-generation 
oncolytic herpesvirus in patients with unresectable metastatic melanoma.  J Clin Oncol. 
2009;27:5763-5771. 
Siegel RL, Miller KD,Jemal A. Cancer statistics, 2015. Cancer Clin J. 2015; 65:5-29. 


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Sparano JA, Fisher RI, Sunderland M, et al,  Randomized phase 3 trial of treatment with 
high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients 
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Steinman, RM. Dendritic cells and the control of immunity: enhancing the efficiency of 
antigen presentation.  Mt Sinai J Med.  2001;68:160-166. 
Tafinlar (dabrafenib) Prescribing Information. Research Triangle Park, NC, 
GlaxoSmithKline, USA, 2014. 
Talimogene Laherparepvec Investigator’s Brochure, Thousand Oaks, CA, Amgen Inc. 
USA. 
Takata M et al, Recent Advances in Melanoma Research. Shinshu Medical Journal. 
2007. 55(1); 3-9. 
Tannous ZS, Mihm MC, Jr., Sober AJ, Duncan LM.  Congenital melanocytic nevi: clinical 
and histopathologic features, risk of melanoma, and clinical management.  J Am Acad 
Dermatol.  2005;52:197-203. 
Wagner JD, Gordon MS, Chuang TY, Coleman JJ III.  Current therapy of cutaneous 
melanoma.  Plast Reconstr Surg.  2000;105:1774-1799. 
WHO Handbook for reporting results of cancer treatment. WHO, Geneva, Switzerland: 
1979. 
Yamazaki N and Maeda Y. Nivolumab for metastatic melanoma-basic knowledge and 
clinical data. Japan Journal of Cancer Chemotherapy Online. 2015;42:434-438. 
Yamazaki N, Kiyohara Y, Sugaya N, Uhara H. phase 1/II study of vemurafenib in 
patients with unresectable or recurrent melanoma with BRAF (V) (600) mutations. J. 
Dermatol. 2015;42:661-6. 
Yervoy (ipilimumab) Prescribing Information.  Princeton, NJ: Bristol-Myers Squibb, 
USA; 2013. 
Zelboraf (vemurafenib) Prescribing Information. South San Francisco, CA; Genentech, 
USA, Inc: 2013. 
 


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 is available 
at the following location: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


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Appendix B.  Sample Electronic Adverse Event Contingency Report Form 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
  


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


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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 study drug being 
administered), tumor lesions will be categorized as follows:  
 
measurable or  
 
nonmeasurable but evaluable  
Measurable Lesions 
Measurable lesions are defined at baseline as lesions that can be serially measured in 
2 dimensions and for which the longest diameter is: 
 
 10 mm as measured by CT scan, MRI, or ultrasound for nodal/soft tissue 
disease (excluding lymph nodes) 
 To be classified as malignant and measurable, a lymph node must be  15 mm in 
shortest diameter 
 
 10 mm caliper measurement by clinical exam for superficial cutaneous or 
subcutaneous melanoma lesion as measured by caliper 


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 
multiple superficial melanoma lesions which in aggregate have a longest total 
diameter of  10 mm 
 To be aggregated these lesions must be touching or abutting 1 another 
 An aggregated lesion should be recorded and followed according to its total 
(aggregated) measurement (ie, by the longest diameter and the longest 
perpendicular diameter of the aggregate) 
Nonmeasurable Lesions 
All other lesions, including small lesions (longest diameter  10 mm by 
CT/MRI/ultrasound for nodal/soft tissue disease 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.  If a subject has more than 20 non-measurable lesions at 
baseline, only 20 are required to be recorded.  (The investigator may choose to record 
more, but will subsequently need to follow all lesions recorded at baseline). 
Lymph Node Assesment Criteria 
If the short axis size is  15 mm, the lymph node can be designated as a malignant 
lymph node and thus be classified as a measurable lesion.   
If it is between  10 mm and  15 mm in short axis, the lymph node can be classified as 
pathological but not measureable.  As such it shall be designated as a non-measurable 
lesion.   
When a lymph node shrinks below 10 mm in short axis, the measurement is to be 
entered as 0 X 0 mm into the eCRF.  This will allow the lesion to be documented as no 
longer malignant.  
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 lesions (merging or fused) 
When 2 or more index or new measurable lesions merge without distinct borders 
between tumors, the smaller lesion should have 0 x 0 mm recorded for the current and 
all future assessments with a comment indicating that the lesion coalesced with the 
specified lesion, and the larger lesion should have the size of the merged lesion 


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recorded for the current assessment with a comment indicating that the lesion coalesced 
with the specified lesion and be followed for future assessments.  
If an index or new measurable lesion and a non-index or new non-measurable lesion 
merge, the non-index or new non-measurable lesion should be absent for the current 
and all future assessments while the index lesion or new measurable lesion should 
include both merged lesions for recording measurements with a comment indicating that 
the lesion coalesced with the specified lesion. 
When 2 or more nonindex or new non-measurable lesions merge, the smaller lesion 
should be recorded as absent for the current and all future assessments, and the larger 
lesion should be recorded as present for the current assessment (with a comment 
indicating that the lesion coalesced with the specified lesion) and followed for future 
assessments.  
Splitting lesions 
When an index or new measurable lesion splits into 2 or more lesions the largest 
measurable part of the split lesion should be considered to be the previously recorded 
index or new measurable lesion with measurements provided for the current assessment 
with the comment indicating that the lesion split from the specified lesion, and followed 
for future assessments.  The remaining lesions would be reported as a new measurable 
lesions or new non-measurable lesions depending on measurability with a comment 
indicating that the lesion split from the specified lesion. In this case, appearance of a 
new lesion from a previous lesion will not be considered a disease progression solely 
due to appearance of a new lesion (may be considered a disease progression due to  
25 increase in the sum of the products of the perpendicular diameters of all index 
tumors since baseline, or the unequivocal appearance of a new tumor, other than the 
product of the split tumor, since the last response assessment time point). 
Biopsy of Residual Lesions 
 
Biopsy and histological examination will be used to confirm or define responses (eg, 
after treatment to differentiate between residual benign lesions/pigmented areas and 
residual malignant lesions).  A needle biopsy is acceptable. 
 
Biopsies are mandatory (as far as is clinically feasible) under the following 
circumstances: 
 
If CR is suspected but residual pigmented areas or other residual masses 
suspected to no longer contain tumor remain – representative biopsies MUST be 
taken from these 


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 
If PR is suspected but residual pigmented areas or other residual masses 
suspected to no longer contain tumor remain which must be tumor free for the 
patient to meet the criteria for PR – representative biopsies MUST be taken from 
these 
 
If no injectable sites remain other than residual pigmented areas or other 
residual masses suspected to no longer contain tumor – representative biopsies 
MUST be taken from these 
 
Where biopsy has confirmed no tumor to be present, a measure of 0 x 0 mm should 
be entered for that tumor and all tumors of which the biopsied tumor is representative 
and these will be used for assessing the patient’s overall response status at each 
assessment 
Subjects who have had a procedure to completely/partially resect a lesion will be 
evaluated as follows: 
The procedure itself and all post-procedure lesion assessments should always be 
recorded in the CRF.  A completely resected lesion should be assigned a default code of 
0 mm (for target lesions) or “absent” (for non-target lesions).  If the resected lesion 
contained cancer or pathology results were unknown, the recorded tumor assessments 
post-procedure may be used for tumor burden calculations, but determination of 
response will be considered unevaluable (UE) for response except in the case of PD. 
Measureable Tumor Assessment/Burden 
Baseline Documentation of “Index Lesions” 
All baseline evaluations should be performed as close as possible to enrollment and 
never more than 4 weeks (ie, 28 days) prior to enrollment. 
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 longest diameter and the perpendicular diameter (SPD) 
of all index lesions will be calculated as the baseline total tumor burden. 
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. 


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Follow-up “Index Lesions” 
At each subsequent tumor assessment, the SPD of the index lesions are added together 
to provide the total tumor burden. 
Follow-up “Nonindex Lesions” 
Nonindex disease measurements are not required and these lesions should be followed 
as “present,” “absent,” or in rare cases “unequivocal progression.” 
Response Criteria 
Evaluation of Objective Response 
The subject response will be assessed based on the response of the index lesions and 
nonindex lesion, and presence or absence of new lesions.  Confirmation of complete or 
partial response is not required.  The overall response is derived from time point 
response assessments as described in Table 5, Table 6 and Table 7.  


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


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Table 6.  Definition of Nonindex Lesion Tumor Response 
Complete Response (CR): 
Disappearance of all nonindex lesions. 
Incomplete Response/Stable 
Disease (SD): 
Persistence of 1 or more nonindex tumor(s). 
Disease Progression (PD): 
Unequivocal  progression of 1 or more nonindex lesions 
There are 2 types of PD defined in this protocol: 
Non-clinically relevant disease progression (PDn): PD in subjects 
who do not suffer a decline in performance status and/or in the 
opinion of the investigator do not require alternative therapy.  
Subjects showing PDn as overall response will be allowed to 
continue study treatment. 
Clinically relevant disease progression (PDr): PD that is associated 
with a decline in performance status and/or in the opinion of the 
investigator the subject requires alternative therapy.  Subjects with 
PDr will be allowed to remain on study until 24 weeks of therapy 
unless, in the opinion of the investigator, other treatment is 
warranted. 
Unable to Evaluate (UE): 
Any nonindex lesion present at baseline which was not assessed, 
was unable to be evaluated leading to an inability to determine the 
status of that particular tumor for that time point, or was resected 
but on pathological review still contained melanoma.   
Not Applicable (NA) 
No nonindex lesions were identified at baseline 
Not Done (ND) 
Radiographic image or clinical measurement were not performed at 
this time point to evaluate the nonindex lesions 


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


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Appendix E.  Eastern Cooperative Oncology Group (ECOG) Performance Status  
Grade 
ECOG Performance Status 
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, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50 of waking hours 
3 
Capable of only limited selfcare; confined to a bed or chair more than 50 of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair 
5 
Dead 


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Appendix F.  Clinical Trial Report of Suspected Talimogene Laherparepvec 
Associated Adverse Event for HCP or Close Contact 
 


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Product:  Talimogene Laherparepvec 
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Amgen Proprietary - Confidential 
FORM-492529, Effective Date: 02 Mar 2020, Version:6.0 
Amendment #5 
Protocol Title: A phase 1, Multi-center, Open-label, Dose De-escalation Study to 
Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Japanese 
Subjects With Unresectable Stage IIIB-IV Malignant Melanoma 
 
Amgen Protocol Number Talimogene Laherparepvec 20140270 
 
Amendment Date: 
01 September 2020 
 
Rationale: 
This protocol is amended with the following: 
 
Administrative and editorial updates 
 
Subjects that are being treated beyond 24 months after the last subject enrolled 
will not enter long term follow up and their last visit will be safety follow up. 
 
A maximum treatment duration of 48 months, or the drug is commercially 
available in Japan. 
 
Removal of “Subjects that have discontinued investigational product and/or 
protocol-required therapies or procedures should not be automatically removed 
from the study.  Whenever safe and feasible, it is imperative that subjects remain 
on the study to undergo safety surveillance and/or collection of outcome data.” 
 
Addition of the following safety reporting requirements 
o The investigator is required to report a fatal disease related event on the 
event case report form as a Disease-Related Event.  All serious disease-
related events will be recorded and reported to the sponsor or designee 
within 24 hours. 
o The investigator will submit any updated serious disease related event 
data to the sponsor within 24 hours of it being available. 
o Talimogene laherparepvec related adverse events that occur after the 
safety follow-up visit through the end of the long-term follow-up will be 
reported. 


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Amendment 4 
Protocol Title:  A Phase 1, Multi-center, Open-label, Dose De-escalation Study to 
Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Japanese Subjects 
With Unresectable Stage IIIB-IV Malignant Melanoma 
 
Amgen Protocol Number (Talimogene Laherparepvec 20140270) 
NCT number:  NCT03064763 
Amendment 4 Date: 
05 December 2017 
Rationale: 
This protocol was amended to: 
x 
Update Appendix D – Modified World Health Organization Response Criteria for 
further clarification 
x 
Update Inclusion criteria #107 and #108 for further clarification 
x 
Update the Schedule of Assessments to: 
 
Add physical exams at Day 1 and every 12 weeks after the Week 15 visit 
 
Add Eastern Cooperative Oncology Group (ECOG) Performance Status at Day 1 
and every12 weeks after the Week 15 visit 
x 
Update laboratory assessments section to : 
 
Clarify which results needed prior to the administration of talimogene 
laherparepvec 
 
Which laboratory will be used for certain assessments (local or central) 
 
Clarify that Bicarbonate or Carbon Dioxide can be done if available as part of 
chemistry panel from venous blood draw 
x 
Update the following sections to align with current protocol template language; 
 
Section 3.5.2 - End of Study  
 
Section 12.6 - Publication Policy  
x 
Updated the following to align with other protocols within the talimogene 
laherparepvec program  
 
Section 9 – Safety Data Collection, Recording, and Reporting:  Updated 
language for disease-related events 
 
Section 6.2.2 – Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation:  Added clarification for talimogene 
laherparepvec if dosing is delayed by more than 4 weeks to align with other 
protocols within the talimogene laherparepvec program 
x 
Clarify Safety Follow-up information for subjects who do not receive treatment 
x 
Update Key Sponsor Contact 
$SSURYHG




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Amendment 3 
Protocol Title:  A Phase 1, Multi-center, Open-label, Dose De-escalation Study to 
Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Japanese 
Subjects with Unresectable Stage IIIB-IV Malignant Melanoma 
 
Amgen Protocol Number 20140270 
 
Amendment 3 Date: 
08 September 2016 
Rationale: 
This protocol is being amended to: 
• 
To meet the requests of the PMDA: 
o Additional information was provided to note that the investigational 
product contains attenuated infectious herpes simplex virus-1. 
o Inclusion criteria #106 was updated to add subjects who are determined 
by the physician to be not suitable or eligible for the approved systemic 
anticancer drug therapy in Japan. 
o Exclusion criteria #214 was updated to specifically note sensitivity to 
bovine- or porcine-derived components. 
o Exclusion criteria #218 was updated to clarify that subjects who suspend 
breast-feeding after starting treatment with talimogene laherparepvec 
should not intend to resume. 
o A new section (Section 6.9) was added to describe in detail the 
contraceptive requirements for male and female subjects.  As a result, 
exclusion criteria #219 was updated accordingly. 
o Details regarding samples shipped overseas to the central laboratory 
were added. 
• 
Correct the Schedule of Assessments to add assessments during the 
Long-term follow-up, and add additional rows to detail the investigational 
product (IP) dosing. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  08 August 2016  
Page 1 of 7 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 1, Multi-center, Open-label, Dose De-escalation Study to 
Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Japanese 
Subjects With Unresectable Stage IIIB-IV Malignant Melanoma 
 
Amgen Protocol Number 20140270 
EudraCT number N/A 
 
Amendment 2 Date: 
08 August 2016 
Rationale: 
This protocol is being amended to: 
• 
Add information on reporting herpes-related events 
o This includes adding Appendix F- Clinical Trial Report of Suspected 
Talimogene Laherparepvec Associated Adverse Event for HCP or Close 
Contact 
• 
Correct the reference date of Tafinlar™ 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140270 
Date:  19 July 2016  
Page 1 of 14 
CONFIDENTIAL  
 
 
Amendment 1 
Protocol Title:  A Phase 1, Multi-center, Open-label, Dose De-escalation Study to 
Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Japanese 
Subjects with Unresectable Stage IIIB-IV Malignant Melanoma 
 
Amgen Protocol Number 20140270 
EudraCT number N/A 
 
Amendment Date: 
19 July 2016 
Rationale: 
This protocol is being amended to: 
• 
Remove the assessment of DRR from the secondary objective as it is now a 
primary objective 
• 
Update the hypotheses to clarify that no formal hypothesis will be tested for 
safety endpoints, and added that a DRR is hypothesized to be consistent with 
results from the global phase 3 study 
o The hypothesis testing for DRR will be conducted on the first 18 treated 
subjects at dose level 1 if no dose de-escalation is required 
• 
Update the Statistical Considerations, which included: 
o The primary efficacy analysis will occur when a durable response 
outcome has been assessed for all subjects 
o The analysis set was defined for dose de-escalation and no dose 
de-escalation 
• 
Clarify that subjects may be included in the evaluation for both safety and 
efficacy 
• 
Update the primary completion definition 
• 
Update Table 2. Schedule of Assessments, Tumor Assessments, to match the 
text 
• 
Update the women not of childbearing definition to match other TVEC protocols 
• 
Definition of DLT (dose limiting toxicity) was updated to match 20140318 study 
• 
Section 9.3-Pregnancy and Lactation Reporting was updated to reflect new 
protocol template language 
• 
Update Key Sponsor Contact 

SAP_001.pdf: 
Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 1 
STATISTICAL ANALYSIS PLAN 
A Phase 1, Multi-center, Open-Label, Dose De-escalation Study to Evaluate the 
Safety and Efficacy of Talimogene Laherparepvec in Japanese Subject With 
Unresectable Stage IIIB-IV Malignant Melanoma 
Protocol Number: 
20140270 
Version: 
Version 3.0 
Date: 
04 November 2020 
Authors: 
NCT Number: NCT03064763
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 2 
 
Table of Contents 
Table of Abbreviations ..................................................................................................... 4 
1. 
Introduction ............................................................................................................. 6 
2. 
Objectives ............................................................................................................... 6 
2.1 
Primary ....................................................................................................... 6 
2.2 
Secondary ................................................................................................... 6 
2.3 
Safety .......................................................................................................... 6 
3. 
Study Overview ...................................................................................................... 6 
3.1 
Study Design ............................................................................................... 6 
3.2 
Sample Size ................................................................................................ 8 
4. 
Study Endpoints and Covariates ........................................................................... 10 
4.1 
Study Endpoints ........................................................................................ 10 
4.1.1 
Primary Endpoints ..................................................................... 10 
4.1.2 
Secondary Endpoints ................................................................ 10 
4.1.3 
Safety Endpoints ....................................................................... 10 
4.2 
Planned Covariates ................................................................................... 10 
5. 
Hypotheses and/or Estimations ............................................................................ 11 
6. 
Definitions ............................................................................................................. 11 
7. 
Analysis Subsets .................................................................................................. 14 
7.1 
DLT Analysis Set ....................................................................................... 14 
7.2 
Safety Analysis Set ................................................................................... 15 
7.3 
qPCR Analysis Set .................................................................................... 15 
7.4 
Subgroup Analyses ................................................................................... 15 
8. 
Interim Analysis and Early Stopping Guidelines .................................................... 15 
8.1 
Interim Analysis ......................................................................................... 15 
8.2 
Primary Analysis ....................................................................................... 15 
8.3 
Final Analysis ............................................................................................ 15 
9. 
Data Screening and Acceptance ........................................................................... 15 
9.1 
General Principles ..................................................................................... 15 
9.2 
Data Handling and Electronic Transfer of Data ......................................... 16 
9.3 
Handling of Missing and Incomplete Data ................................................. 16 
9.4 
Detection of Bias ....................................................................................... 16 
9.5 
Outliers ..................................................................................................... 16 
9.6 
Distributional Characteristics ..................................................................... 16 
9.7 
Validation of Statistical Analyses ............................................................... 16 
10. 
Statistical Methods of Analysis.............................................................................. 17 
10.1 
General Principles ..................................................................................... 17 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 3 
 
10.2 
Subject Accountability ............................................................................... 17 
10.3 
Important Protocol Deviations ................................................................... 17 
10.4 
Demographic and Baseline Characteristics ............................................... 18 
10.5 
Efficacy Analyses ...................................................................................... 18 
10.6 
Safety Analyses ........................................................................................ 18 
10.6.1 
DLT Analysis ............................................................................. 18 
10.6.2 
Adverse Events ......................................................................... 19 
10.6.3 
Laboratory Test Results ............................................................ 20 
10.6.4 
Vital Signs ................................................................................. 20 
10.6.5 
ECOG Performance Scores ...................................................... 20 
10.6.6 
Physical Measurements ............................................................ 20 
10.6.7 
Electrocardiogram (ECG) .......................................................... 20 
10.6.8 
Antibody Formation ................................................................... 20 
10.6.9 
Exposure to Investigational Product .......................................... 21 
10.6.10 
Exposure to Concomitant Medication ........................................ 21 
11. 
Literature Citations / References ........................................................................... 22 
12. 
Appendices ........................................................................................................... 23 
List of Tables 
Table 1.  Probability of Declaring a Cohort Safe or Unsafe .............................................. 9 
Table 2.  Potential Japanese Melanoma Phase 2 Single-Arm Designs to Test 
a Durable Response Rate Hypothesis Without Dose 
De-escalation ......................................................................................... 10 
List of Figures 
Figure 1.  Probability of Declaring a Cohort Safe (Unsafe)............................................... 9 
Figure 2.  The Definition of Analysis Sets ...................................................................... 14 
List of Appendices 
Appendix A.  Conventions for Clinical Data That Require Imputation for 
Partial or Missing Date ............................................................................ 24 
Appendix B.  Cutoff Values for qPCR Assay .................................................................. 26 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 4 
 
Table of Abbreviations 
Abbreviation or Term Definition/Explanation 
BRAF 
serine/threonine protein kinase B-Raf V600E/K 
CI  
confidence interval 
CR 
complete response 
CRF 
case report form 
CTCAE  
Common Terminology Criteria for Adverse Events 
DLRT 
Dose Level Review Team 
DLT 
DNA 
dose limiting toxicity 
deoxyribonucleic acid 
DOR 
DRE  
duration of response 
Disease-related events 
DRR 
durable resonse rate 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
End of Study for 
Individual Subject 
The last day that protocol-specified procedures are conducted for an 
individual subject (ie, the date the subject withdraws full consent from 
the study, completes the safety follow-up visit or long-term follow-up 
[whichever is later] or death). 
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 efficacy 
analysis. This will occur when a durable response outcome has been 
assessed for all subjects included in the primary efficacy analysis.  
End of Study (end of 
trial) 
The time when the last subject is assessed or receives an intervention 
for evaluation in the study. This is anticipated to occur when the last 
subject has had the opportunity to complete the safety follow-up visit or 
the last long term follow-up visit, whichever occurs later. 
End of Treatment 
The day of the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
HCP 
Health care providers 
Heart rate 
number of cardiac cycles per unit of time 
HSV-1 
herpes simplex virus type-1 
ICH 
IP 
IPD 
International Conference on Harmonisation 
Investigational product 
Important protocol deviations 
LDH 
LTFU 
lactate dehydrogenase 
Long term follow-up 
ORR 
overall response rate 
OS 
overall survival 
PD 
disease progression 
PFS 
progression-free survival 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 5 
 
Abbreviation or Term Definition/Explanation 
PFU 
plaque-forming unit 
PR 
partial response 
qPCR 
real-time polymerase chain reaction 
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 the clinical trial necessary for the 
reconstruction oand evaluation of the trial. Source data are contained in 
source documents(original records or certified copies). (ICH Guideline 
randomization identification, and stratification value. 
TEAE 
TESAE 
Treatment-emergent Adverse Events 
Treatment-emergent Serious Adverse Events 
TTR 
time to response 
ULN 
upper limit of normal 
UE 
unable to evaluate 
vs 
versus 
WHO 
World Health Organization 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
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 for talimogene laherparepvec Study 
20140270 (Amendment 5 dated 01 September 2020). The scope of this plan includes 
the primary analyses for safety and efficacy and the final analysis that are planned and 
will be executed by the Biostatistics department unless otherwise specified. 
2. 
Objectives 
2.1 
Primary 
 
To evaluate the safety and tolerability of talimogene laherparepvec, as assessed by 
incidence of dose limiting toxicities (DLTs), in subjects with unresectable stage 
IIIB-IV malignant melanoma  
 
These subjects will also be evaluated for the anti-tumor activity of talimogene 
laherparepvec as assessed by durable response rate (DRR) using modified World 
Health Organization (WHO) response criteria. DRR is defined as the rate of objective 
response (Complete response [CR] or partial response [PR]) lasting continuously for 
6 months or greater and starting any time within 12 months of initiating therapy.  
2.2 
Secondary 
 
To evaluate the anti-tumor activity of talimogene laherparepvec, as assessed by 
overall response rate (ORR), time to response (TTR), duration of response (DOR), 
progression free survival (PFS) using modified World Health Organization (WHO) 
response criteria by investigators 
 
To evaluate overall survival (OS) 
2.3 
Safety 
To evaluate the safety of talimogene laherparepvec as determined by subject incidence 
of adverse events and clinically relevant laboratory abnormalities where not defined as 
DLTs. 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1, multicenter, open-label study of talimogene laherparepvec in 
Japanese subjects with unresectable stage IIIB-IVM1c malignant melanoma that are 
candidates for intralesional therapy.  
Approximately 18 subjects will be enrolled in the study. The DLT evaluation period is 
35 days from the initial administration of talimogene laherparepvec. Initially, 
6 DLT-evaluable subjects will be enrolled and treated at 100 of the dose regimen of 
talimogene laherparepvec (Dose 1) as described below. The first dose administered will 
be up to 4.0 mL of 106 PFU/mL (day 1, week 0) followed by dose of up to 4.0 mL of 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 7 
 
108 PFU/mL 3 weeks ( 5 days) later. Subsequent doses of up to 4.0 mL of 108 PFU/mL 
will be administered every 2 weeks ( 3 days) thereafter (see Protocol Section 6.2.1.1). 
A Dose Level Review Team (DLRT) meeting will be convened after 6 DLT-evaluable 
subjects are enrolled. Further enrollment will be temporarily paused until the DLRT 
meeting is convened and a decision is made on the dose level. Upon demonstration of 
safety based on DLT incidence  33 in the first 6 subjects, an additional 12 subjects 
will be enrolled and treated at Dose 1 to obtain additional safety data.  
However, if at any time there are 2 or more subjects with a DLT prior to enrollment of the 
first 6 DLT-evaluable subjects, an ad hoc DLRT meeting will be convened to determine if 
dose de-escalation is required.  
The safety data during the enrollment of the additional 12 subjects will be monitored on 
an ongoing basis and an ad hoc DLRT meeting may be called, if needed, to determine 
the further course of the study.  
Dose De-escalation  
Following a decision to dose de-escalate, an additional 6 subjects will be treated at the 
lower dose regimen of talimogene laherparepvec (Dose -1). The initial dose 
administered will be up to 4.0 mL of 106 PFU/mL (day 1, week 0) followed by dose of up 
to 4.0 mL of 107 PFU/mL 3 weeks ( 5 days) later. Subsequent doses of up to 4.0 mL of 
107 PFU/mL will be administered every 2 weeks ( 3 days) thereafter (see Protocol 
Section 6.2.1.2). The DLRT will review the safety data after the first 6 DLT-evaluable 
subjects at Dose -1 have been enrolled. Subject treatment will continue, however, further 
enrollment will be temporarily paused during the DLT review period to evaluate the 
6 DLT-evaluable subjects at Dose -1. Upon demonstration of safety, additional subjects 
will be enrolled (up to a total of 18 subjects) at Dose -1 to obtain additional safety data.  
The safety data of the subjects enrolled at the Dose-1 level will be monitored on an 
ongoing basis and an ad hoc DLRT meeting may be called, if needed, to determine the 
further course of the study.  
All subjects will complete a safety follow-up visit approximately 30 (7) days after the last 
dose of study treatment. Adverse events and disease related events will be collected as 
described in Protocol Section 9.2. After the safety follow-up visit, all subjects will enter 
the long-term follow-up. If subjects receives therapy beyond 24 months after the last 
subject was enrolled in the study, when the LTFU period ends, they will not enter 
LTFU and their last vist will be safety follow-up visit. Otherwise, subjects will be 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 8 
 
followed for survival and subsequent anticancer therapies every 12 weeks ( 28 days) 
for approximately 24 months after the last subject is enrolled. In addition, talimogene 
laherparepvec related adverse events that occur after the safety follow-up visit 
through the end of the long-term follow-up will be reported. Maximum treatement 
duration is 48 months or until drug is commercially available in Japan, total study 
duration of an individual subject can be up to around 4 years plus enrollment duration. 
The hypothesis test for DRR will include all subjects enrolled after dose de-escalation 
who received at least 1 dose of talimogene laherparepvec. If no dose de-escalation is 
needed, the DRR hypothesis test will include the first 18 subjects dosed. 
3.2 
Sample Size 
Approximately 18 subjects will be enrolled. See protocol Section 10.2. The total number 
of subjects that will participate in the study and be used in the DLT analysis is 
approximately 18. The first 6 DLT-evaluable subjects will be used for the decision of 
dose de-escalation. If there is no dose de-escalation, the first 18 subjects in the safety 
analysis set will be used for the efficacy analysis of DRR, and the whole safety analysis 
set will be used for other efficacy analyses including ORR, TTR, DOR, PFS and OS. If 
dose de-escalation occurs, the efficacy analysis will be performed using the safety 
analysis set at Dose -1. In the current study design, a dose level will be considered safe 
if there are 0 to 1 DLTs observed in the initial 6 DLT evaluable subjects.  
Table 1 and Figure 1 presents the probability of declaring a dose level safe (unsafe) for 
a range of true DLT rates for the protocol therapy for the 6 DLT-evaluable subjects (see 
triangle symbols). As shown below in Table 1, the probability of declaring a dose level 
safe (unsafe) in the current study (based on only 6 DLT evaluable subjects) is 89 
(11), 42 (58), and 11 (89) if the true DLT rate is 10, 30, or 50, 
respectively. Hypothetically, if the study were to enroll an additional 6 DLT-evaluable 
subjects after the initial 6 subjects (total of 12 DLT evaluable subjects), the probability of 
observing a DLT rate  33 in the 12 subjects following the observation of 0-1 DLTs in 
the first 6 DLT evaluable subjects would be 0.6, 8.6, and 6.7 if the true DLT rate is 
10, 30, or 50, respectively. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 9 
 
Figure 1.  Probability of Declaring a Cohort Safe (Unsafe) 
 
Table 1.  Probability of Declaring a Cohort Safe or Unsafe 
True Cohort DLT 
Probability 
Probability Declare Cohort Safe 
Probability Declare Cohort 
Unsafe 
10 
89 
11 
20 
66 
34 
30 
42 
58 
40 
23 
77 
50 
11 
89 
DLT Dose Limiting Toxicity 
The total number of subjects that will participate in the study and be used in DLT 
analyses is approximately 18.  
As shown in Table 2, without dose de-escalation, 18 subjects provides maximum power 
to test the DRR null hypothesis in the range of 16 to 20 subjects, therefore only the first 
18 subjects in the safety analysis set will be used in the analysis. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 10 
 
Table 2.  Potential Japanese Melanoma Phase 2 Single-Arm Designs to Test a 
Durable Response Rate Hypothesis Without Dose De-escalation 
 
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
4.1.1 
Primary Endpoints 
 
Subject incidence of DLTs 
 
DRR using modified WHO response criteria by investigators 
4.1.2 
Secondary Endpoints 
 
ORR, TTR, DOR, and PFS using modified WHO response criteria by investigators  
 
OS  
4.1.3 
Safety Endpoints 
Subject incidence of all the following, where not defined as DLT: 
 
adverse events 
 
grade  3 adverse events 
 
serious adverse events 
 
clinically significant laboratory changes 
 
changes in vital signs 
4.2 
Planned Covariates 
The following covariates will be used to examine efficacy and safety in subgroups or in 
multivariate analyses as appropriate: 
 
Grouped disease stage at baseline: IIIB-IVM1a vs IVM1b-c  
 
Line of therapy for current disease: 1st line vs 2nd line or later  
 
Dose level (Dose 1 vs Dose -1, if applicable)  


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 11 
 
5. 
Hypotheses and/or Estimations 
No formal statistical hypothesis will be tested for safety endpoints in this trial. Based on 
the well tolerated safety profile from a global phase 3 study, it is hypothesized that 
talimogene laherparepvec will be safe and well tolerated in Japanese subjects with 
unresectable stage IIIB-IVM1c malignant melanoma.  
A DRR is hypothesized to be consistent with results from the global phase 3 study 
(Andtbacka et al., 2015). 
6. 
Definitions 
1-year, 2-year survival  
The Kaplan-Meier (K-M) estimate of the proportion of subjects alive at 1 year and 
2 years from the first dose, respectively.  
Actual Follow-up Time  
Actual follow-up time for a subject is calculated from the first dose to the last on-study 
date (ie, death date, or date last known to be alive for patients still alive).  
Baseline  
Baseline in general refers to study day 1. The baseline value of a parameter (eg, vital 
signs, laboratory tests, and tumor measurement) is considered to be the latest value 
prior to receiving any study drug. If a subject did not receive study drug, then the latest 
value on or prior to the enrollment date is to be used.  
Duration of Respose (DOR)  
DOR is defined as the time from the date of an initial response (CR or PR) to the earlier 
of PD or death. Subjects who have not ended their response at the time of analysis will 
be censored at their last evaluable tumor assessment.  
Durable Reponse Rate (DRR)  
DRR is the incidence of a durable response defined as an OR of CR or PR per modified 
WHO response criteria lasting continuously for  6 months and beginning at any point 
within 12 months of initiating therapy among a set of subjects analyzed. Subjects with an 
OR who do not have any follow-up tumor assessments will not be regarded as having a 
durable response.  
Evaluable tumor assessment  
An overall visit response other than UE. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 12 
 
Event of Interest (EOI)  
MedDRA dictionary preferred terms for each EOI search strategy are defined and 
maintained by Amgen Safety Medical Coding.  
Investigational product (IP)  
Investigational product refers to talimogene laherparepvec in this study.  
Objective Reponse (OR) per modified WHO criteria  
Objective response will be assessed based on the response of the index lesions and 
nonindex lesions, 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 Protocol Tables 5, 6, 7.  
Overall Response Rate (ORR)  
ORR is defined as the incidence of an OR of CR or PR per modified WHO response 
criteria among a set of subjects analyzed. Subjects who do not have any follow-up tumor 
assessments will be regarded as non-responders.  
Overall Survival (OS)  
OS is defined as the interval from the first dose to the event of death from any cause; 
otherwise, OS is censored at the date the subject was last known to be alive.  
Positive qPCR  
By performing qPCR analysis, the talimogene laheparepvec DNA is  cutoff in the 
sample. Details are provided in Appendix B, Section 12. 
Potential Follow-Up Time  
Potential follow-up time for a subject is calculated from the first dose to the analysis data 
cutoff date.  
Progression Free Survival (PFS)  
Progression-free survival (PFS) per modified WHO response criteria is defined as the 
interval from the first dose to the earlier of PD per modified WHO response criteria or 
death from any cause; otherwise, PFS is censored at the last evaluable tumor 
assessment.  


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 13 
 
Quantifiable qPCR  
By performing qPCR analysis, the talimogene laheparepvec DNA is  LLOQ in the 
sample. Details are provided in Appendix B, Section 12. 
Study day  
Study day is calculated from the first day when investigational product is administered to 
the subject; mathematically stated as Study day  (visit date – first dose date)  1.  
Study Day 1  
Study day 1 is defined as the first day of administration of the investigational product 
after enrollment. The day prior to Study Day 1 is considered Study Day -1.  
Study Week 0  
The start of investigational product administration to the subject is study week 0. Study 
day 1 corresponds to the first day of study week 0.  
Time to Response (TTR)  
This endpoint will only be calculated for those subjects in the safety analysis set with CR 
or PR. It is defined as the time from first dose to the date of the first CR or PR.  
Treatment period  
Study day 1 through 30 days after the last administration of investigational product.  
Treatment-emergent Adverse Events (TEAE)  
Treatment-emergent adverse events are defined as any adverse event during the 
treatment period. Adverse events that occur on the same day as the first dose date of IP 
will be treated as treatment emergent events unless indicated otherwise (for example, if 
an event occurs on the same date as the first administration of talimogene 
laherparepvec and the check box indicating prior to the first dose of IP is checked on 
CRF, then the event will not be counted as a treatment-emergent emergent AE). 
Additionally, if an event is identified as disease-related on the eCRF, it will not be 
counted as a treatment-emergent AE).  
Treatment-emergent Disease-related Events (TEDRE)  
Treatment-emergent Disease-Related Events (DREs) are defined as adverse events, 
determined by the investigator to be disease-related, with an onset during the treatment 
period. DREs that occur on the same day as the first dose of IP will be treated as 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 14 
 
treatment emergent events unless indicated otherwise (for example, if an event occurs 
on the same date as the first administration of talimogene laherparepvec and the check 
box indicating prior to the first dose of IP is checked on the eCRF, then the event will not 
be counted as a treatment-emergent DRE). 
Treatment-emergent Serious Adverse Events (TESAE)  
Treatment-emergent serious adverse events are defined as any serious adverse 
event with an onset date from first dose date to 90 days after the last dose of 
talimogene laherparepvec or 30 days following cessation of treatment if the 
subject initiates new anti-cancer therapy, whichever is earlier. 
7. 
Analysis Subsets 
The DLT analysis set will be used to summarize the subject incidence of DLTs for the 
study and the safety analysis set will be used for all other analyses of safety endpoints. 
The efficacy analysis will be conducted using the safety analysis set unless otherwise 
specified. 
Figure 2.  The Definition of Analysis Sets 
 
7.1 
DLT Analysis Set 
The DLT analysis set will include DLT-evaluable subjects defined as subjects who had 
the opportunity to be followed for at least 35 days on treatment from the initial dosing 
(unless discontinued due to DLT) and received at least one dose of talimogene 
laherparepvec. Subjects may be replaced in a cohort if they are not evaluable for DLT 
(eg, a subject did not receive study treatment, or ended the study treatment before 
completion of DLT evaluation period for a reason other than experiencing a DLT). 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 15 
 
7.2 
Safety Analysis Set 
The safety analysis set will include all subjects who received at least 1 dose of 
talimogene laherparepvec. The safety analysis set will be used for efficacy endpoints 
with the exception that only the first 18 subjects will be used to test the DRR null 
hypothesis for Dose 1. 
7.3 
qPCR Analysis Set 
The qPCR Analysis Set includes subjects in the Safety Analysis Set with a swab sample 
obtained for qPCR testing of talimogene laherparepvec DNA from any lesion suspected 
to be of herpetic origin. 
7.4 
Subgroup Analyses 
See Section 4.2. 
8. 
Interim Analysis and Early Stopping Guidelines 
8.1 
Interim Analysis 
No formal interim efficacy analysis is planned for this study.  Interim safety analyses will 
be performed to support the evaluation of safety by the DLRT (see protocol 
section 10.3.2). 
8.2 
Primary Analysis 
The primary analysis for safety will occur 3 months after the last subject is 
enrolled. The primary analysis for efficacy will occur when a durable response 
outcome has been assessed for all subjects included in the primary efficacy 
analysis. Safety will be re-analyzed at the primary efficacy analysis. 
8.3 
Final Analysis 
The final analysis will occur 24 months after the last subject is enrolled.  
If there are subjects who receive therapy beyond 24 months, a post final analysis 
of these subjects will occur after the last subject completes safety follow-up.  
Adverse events and tumor assessments evaluated after final analysis will be listed 
for these subjects. 
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. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
Page 16 
 
9.2 
Data Handling and Electronic Transfer of Data  
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE 
database. 
9.3 
Handling of Missing and Incomplete Data 
Every effort will be made to obtain complete data in the clinical study. Partial or missing 
dates of adverse events, disease-related events, and concomitant medications and 
incomplete death dates will be imputed. Details of the imputation algorithm are provided 
in Appendix A, Section 12. Adverse events with missing IP relatedness, seriousness, or 
CTCAE severity grades will be included in all analyses of TEAEs as long as the events 
qualify for the reporting period. Events with missing relatedness, seriousness, and 
severity grades will be excluded from corresponding analyses of TEAEs that are 
treatment-related, serious, and had a specific CTCAE grade. 
9.4 
Detection of Bias  
Lack of protocol compliance may introduce potential bias in the estimation of protocol 
endpoints. All important protocol deviations (IPDs) will be reported, documented and 
stored in eClinical (a clinical trial management system). IPD reports will be produced 
using Cognos by the study manager and will be regularly reviewed in the study team’s 
IPD review meetings as well as before analysis.  
Protocol compliance will be examined by tabulating subjects with IPDs. 
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.  
9.6 
Distributional Characteristics 
All binary endpoints will be assumed to follow a binomial distribution. The Kaplan-Meier 
estimates for the probability of time-to-event endpoints are non-parametric. 
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 9.2 or 
later.   
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
The DLT Analysis Set will be used to summarize the subject incidence of DLT and the 
Safety Analysis Set will be used for all other analyses of safety and efficacy endpoints. 
Descriptive statistics will be provided for efficacy and safety endpoints for all subjects. 
Summary statistics including mean, standard deviation, median, first and third quartiles, 
minimum and maximum will be provided for continuous variables.  Frequency and 
percentage will be summarized for binary and categorical variables.  Proportions and the 
corresponding exact 95 confidence intervals using F distributions will be calculated.  
Exact tests will be considered for subgroup analyses.  Time to-event endpoints will be 
estimated using the K-M method per Kalbfleisch and Prentice (1980) and confidence 
intervals for quartiles will be estimated per Brookmeyer & Crowley (1982). 
Separate reporting at a program-level may occur of close contact and HCP events with 
or without a known unintended exposure. 
10.2 
Subject Accountability 
The number of subjects enrolled will be tabulated by investigator sites. Subject 
disposition (including the number screened, enrolled, treated, ended treatment, that 
completed the safety follow-up visit, and that completed the study) will be summarized 
separately for all enrolled subjects. Reasons for not receiving treatment, for ending 
treatment, not completing the 30-day safety follow-up visit, and ending the study will 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, sub-category codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. Eligibility deviations that are defined as IPDs will be summarized in both 
the IPD and Eligibility Deviation table and IPD and Eligibility Deviation listings. 


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10.4 
Demographic and Baseline Characteristics 
Summary statistics of the following demographic and baseline characteristics will be 
tabulated using the Safety Analysis Set. 
 
Age at baseline:  50,  50;  65,  65;  75,  75 years 
 
Sex (female vs male) 
 
Disease stage at baseline: IIIB and IIIC vs IVM1a vs IVM1b vs IVM1c 
 
Line of therapy for current disease 
 
Type of prior therapy 
 
BRAF status 
 
Baseline HSV-1 serostatus 
 
Baseline LDH  ULN vs  ULN 
 
ECOG (0 vs 1) 
 
Other covariates reported in the literature or from other Amgen studies maybe 
considered in the analysis as appropriate and if feasible at the time of analysis. 
10.5 
Efficacy Analyses 
In general, the analysis of efficacy endpoints will be based on the Safety Analysis Set 
with the exception that only the first 18 subjects will be used to test the DRR null 
hypothesis for Dose 1.  
 
DRR and ORR (CRPR) will be summarized with associated exact 95 CIs for 
binomial proportions (Clopper & Pearson 1934). A 1-sided 5 significance level 
exact binomial test will be performed for a DRR  2. If there are more than 
18 subjects in the safety set for Dose Level 1, the test will be based on the first 
18 enrolled subjects; otherwise, it will be based on all subjects in the safety set 
for either Level 1 or -1). If there is no dose de-escalation, the DRR/ORR for Dose 
1 will be estimated using both the first 18 subjects and all treated.  
 
DRR/ORR will be summarized by planned covariates (grouped disease stage 
and lines of therapy) as in Section 4.2.  
 
DOR among responders, PFS and OS will be estimated using the Kaplan-Meier 
method and estimates of event time quartiles, event-free rates at selected times 
and the corresponding 95 CIs will be provided.  
 
Summary statistics will be estimated for TTR among responders.  
10.6 
Safety Analyses 
10.6.1 
DLT Analysis  
The subject incidence of DLT based on CRF will be summarized as a binary variable 
using the DLT Analysis Set by calculating the frequency, percentage, and exact 95 CI. 


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10.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 18.0 or later will be 
used to code all adverse events (AE) to a system organ class and a preferred term. The 
CTCAE version 4.0 will be used to grade severity of adverse events. In general, events 
with missing IP relatedness, seriousness, or CTCAE severity grades are included in the 
analysis of treatment emergent AE as long as the event meets the criteria for a TEAE. 
However, analyses of treatment-related, SAE, or grade 3 or higher, or combination 
thereof will exclude events with missing relatedness, seriousness, and severity grades, 
respectively. 
The analyses for AEs will include TEAEs (ie, occurring in the treatment period) unless 
otherwise specified. The subject incidence of TEAEs will be summarized for all AEs, 
serious AEs, AEs leading to withdrawal of investigational product, worst grade 3 or 
4 AEs, and fatal AEs. The subject incidence of all treatment-related AEs, serious AEs, 
AEs leading to withdrawal of investigational product, worst grade 3 or 4 AEs, and fatal 
AEs will be tabulated by system organ class (SOC) and preferred term in descending 
order of frequency.  
A listing of fatal AEs will be provided. A listing of all SAEs reported in the clinical 
database with an event onset from consent will be provided with onset reported relative 
to the first and most recent dose of study therapy and identification as a TEAE.  
Subject incidence of DREs (disease-related events) and fatal disease related events will 
be tabulated by system organ class and preferred term. Selected safety analyses may 
also be performed in which DREs are considered to be a TEAE.  
Treatment-related AEs reported in long term follow-up will be summarized in this study 
at the final analysis and also separately at a program-level.  
Potential or known unintended exposure to talimogene laherparepvec, related suspected 
herpetic signs or symptoms, and detection of talimogene laherparepvec in a subject’s 
household member, caregiver, or healthcare provider will be reported to Amgen. 
Exposures, signs or symptoms will be summarized and also analyzed separately at a 
program-level. 


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10.6.3 
Laboratory Test Results 
Shifts in grades of safety laboratory values between the baseline and the worst on-study 
value will be tabulated overall and by dose level group(if applicable). See Protocol 
Table 3 for list of laboratory analytes. 
A listing will be provided for subjects in the qPCR Analysis Set by assessed time point of 
qPCR analysis results (positive, and numeric value if quantifiable) for talimogene 
laherparepvec DNA in swab samples taken from cold sore, vesicles, and other lesions 
suspected to be herpetic in origin. 
10.6.4 
Vital Signs 
Descriptive statistics will be presented for systolic/diastolic blood pressure, heart rate, 
respiratory rate, temperature and temperature for baseline, each post-baseline visit, 
change from baseline, and percent change from baseline. 
10.6.5 
ECOG Performance Scores 
Shifts in scores for ECOG performance status scores between baseline and safety 
follow-up will be tabulated. 
10.6.6 
Physical Measurements 
Height and weight will be summarized at each assessed time point. The change in 
weight and percent change in weight from baseline to each assessed time point will also 
be summarized. 
10.6.7 
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.  Because 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. 
10.6.8 
Antibody Formation  
Baseline HSV-1 serostatus will be summarized. 
The incidence of HSV-1 seroconversion will be summarized for subjects that are 
baseline seronegative. 


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10.6.9 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational 
product. Summary statistics for exposure to talimogene laherparepvec, including total 
doses administered, total volume administered, duration from the first to the last 
administration of talimogene laherparepvec, and the average volume received by subject 
per visit will be provided and will be separated by the first (concentration of 106 PFU/mLl) 
and subsequent doses (concentration of 108 PFU/mL or 106 PFU/mL). Subject incidence 
rate and reasons for IP delay, dose change and withdrawal will be tabulated. 
10.6.10 
Exposure to Concomitant Medication  
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category overall and for each dose level as coded by 
the World Health Organization Drug (WHO DRUG) dictionary. 


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11. 
Literature Citations / References 
Clopper, C., et al (1934) “The Use of Confidence or Fiducial Limits Illustrated in the Case 
of the Binomial” Biometrika, 26, 404-413  
Kalbfleisch, J.D. and Prentice, R.L. (1980) The Statistical Analysis of Failure Time Data, 
New York: John Wiley & Sons  
Brookmeyer R. and Crowley J. (1982) “A Confidence Interval for the Median Survival 
Time” Biometrics; 38, 29-41  
Andtbacka R., et al (2015) “Talimogene Laherparepvec Improves Durable Response 
Rate in Patients With Advanced Melanoma.” Journal of Clinical Oncology; 33(25), 
2780-2788 


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Statistical Analysis Plan:  20140270 
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12. 
Appendices 


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Statistical Analysis Plan:  20140270 
Date:  04 November 2020 
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Appendix A.  Conventions for Clinical Data That Require Imputation for Partial or 
Missing Date   


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Statistical Analysis Plan:  20140270 
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Appendix B.  Cutoff Values for qPCR Assay 
The current assay cutoffvalues are as follows: 
For qPCR, the cutoff (LLOQ) is 0.6 (1.76) copies/μg for blood, 5.8 (24) copies/μg 
for urine, and 7.5 (18) copies/μg for swabs. 
For the most recent cutoff and LLOQ values and other details regarding their 
determination, refer to the following validation report: 
Validation Report to Establish the Performance Characteristics of the Talimogene 
Laherparepvec (T-VEC) Quantitative and Qualitative Real Time PCR (qPCR) 
assay in Whole Blood, Swabs and Urine qPCR (see table on page 6 in the 
validation report for qPCR LLOD and LLOQ values)  
Table B1.  Definition of qPCR Results 
 
Table B2.  Cutoff Values for qPCR Results Definition* 
 
* The analytical method has no upper limit of quantitation.