Conditions: Advanced Non CNS Tumors
Keywords: Non CNS Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
This is a phase 1 study to evaluate the safety of intralesional talimogene laherparepvec administration in pediatric subjects with advanced non-CNS tumors that are amenable to direct injection

Detailed description:
This is a phase 1, multicenter, open-label study of talimogene laherparepvec in pediatric subjects with advanced non-CNS tumors that are amenable to direct injection in the clinical setting. Approximately 18 - 24 pediatric subjects are expected to be enrolled and treated with at least 1 dose of talimogene laherparepvec into 2 cohorts stratified by age. DLT will be evaluated based on at least 9 DLT-evaluable subjects in cohort A1. The DLT evaluation period is 35 days from the initial administration of talimogene laherparepvec.

Arms:
arm 1: The first dose of talimogene laherparepvec will be administered at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (+3 days) later. Subsequent doses of up to 4.0 mL of 10ᶺ8 PFU/mL will be administered every 14 days (± 3 days) thereafter. Cohorts will be assigned as follows: Cohort A1 (age 12 to ≤ 21 years). Cohort B1 (age 2 to \< 12 years). The DLRT will review the safety data of the first 3 subjects in the older age cohort A1 to decide if the younger age cohort B1 can be opened for enrollment. If dose de-escalation is needed and if permissible based on the incidence of DLTs, additional DLT-evaluable subjects will be enrolled and treated at a lower dose level of talimogene laherparepvec. Dose de-escalation cohorts will be assigned as follows and the same DLT rules will be applied: Cohort A2 (age 12 to ≤ 21 years), Cohort B2 (age 2 to \< 12 years).

Interventions: intervention 1: Talimogene Laherparepvec
Intervention descriptions: intervention 1: Talimogene laherparepvec will be administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance. The first dose of talimogene laherparepvec will be up to 4.0 mL of 10\^6 PFU/mL administered on day 1. The second injection, up to 4.0 mL of 10\^8 PFU/mL (or up to 4.0 mL of 10\^6 PFU/mL for a dose de-escalated cohort), will be administered 21 (+3) days after the initial injection. All subsequent injections, up to 4.0 mL of 10\^8 PFU/mL (or up to 4.0 mL of 10\^6 PFU/mL for a dose de-escalated cohort), will be administered every 14 (± 3) days. The treatment cycle interval may be increased due to toxicity.

Protocol document:
Prot_000.pdf: 
Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 1 of 99 
CONFIDENTIAL 
 
 
Title:  A Phase 1, Multi-center, Open-label, Dose De-escalation Study to Evaluate 
the Safety and Efficacy of Talimogene Laherparepvec in Pediatric Subjects With 
Advanced Non-central Nervous System Tumors That are Amenable to Direct 
Injection 
Amgen Protocol Number (Talimogene Laherparepvec) 20110261 
 
EudraCT number 2015-003645-25 
NCT number NCT02756845 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone:  +1-805-447-1000 
Key Sponsor Contact(s): 
, MD 
Clinical Research Medical Director 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 
Email:  
 
Date: 
15 September 2015 
Amendment 1 Date: 
04 April 2017 
Amendment 2 Date: 
10 October 2018 
Amendment 3 Date: 
12 June 2020 
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:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN, for all other countries,1-805-447-1000.  
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 2 of 99 
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 Pediatric Subjects With Advanced Non-central Nervous System Tumors That are 
Amenable to Direct Injection, dated 12 June 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.  
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) 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 3 of 99 
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 Pediatric Subjects With Advanced Non-central Nervous 
System Tumors That are Amenable to Direct Injection 
Study Phase:  Phase 1 
Indication:  Non-central nervous system (CNS) tumors 
Primary Objective:  To determine the safety and tolerability of talimogene laherparepvec, as 
assessed by incidence of dose-limiting toxicities (DLT), in pediatric subjects with advanced 
non-central nervous system tumors that are amenable to direct injection. 
Secondary Objectives:   
• 
To evaluate the anti-tumor activity of talimogene laherparepvec, as assessed by overall 
response rate (ORR), duration of response (DOR), time to response (TTR), time to 
progression (TTP), progression-free survival (PFS) using immune-related response criteria 
simulating Response Evaluation Criteria in Solid Tumor (RECIST 1.1) (modified 
immune-related response criteria simulating Response Evaluation Criteria in Solid Tumors 
[irRC-RECIST]), and overall survival (OS). 
Safety Objective: 
• 
To evaluate the safety and tolerability of talimogene laherparepvec. 
Hypotheses:  Talimogene laherparepvec injected in pediatric subjects with advanced non-CNS 
tumors that are amenable to direct injection will be safe as assessed by subject incidence of 
DLTs and the safety profile. 
Primary Endpoint:  Subject incidence of DLTs 
Secondary Endpoints:   
• 
ORR, DOR, TTR, TTP, and PFS using modified irRC-RECIST 
• 
OS  
Safety Endpoint: 
• 
Subject incidence of adverse events and significant laboratory abnormalities  
Study Design:  This is a phase 1, multicenter, open-label study of talimogene laherparepvec in 
pediatric subjects with advanced non-CNS tumors that are amenable to direct injection in the 
clinical setting.   
Approximately 18 to 24 pediatric subjects are expected to be enrolled and treated with at least 
1 dose of talimogene laherparepvec into 2 cohorts stratified by age (permissible based on the 
incidence of DLTs, a minimum of 18 dosed subjects total for the primary analysis).   
• 
Cohort A1 (12 to ≤ 21 years of age) 
• 
Cohort B1 (2 to < 12 years of age) 
Initially, 3 subjects 12 to ≤ 21 years of age are to be enrolled and treated at 100% of the 
recommended adult dose regimen of talimogene laherparepvec (cohort A1).  The first dose 
administered will be up to 4.0 mL of 106 plaque-forming unit (PFU)/mL followed by a dose of up to 
4.0 mL of 108 PFU/mL 21 days (+ 3 days) later.  Subsequent doses of up to 4.0 mL of 
108 PFU/mL will be administered approximately every 14 days (± 3 days) thereafter.  The DLT 
evaluation period is 35 days from the initial administration of talimogene laherparepvec.  The 
dose level review team (DLRT) will review the safety data of the first 3 subjects in the older age 
cohort A1 to decide if the younger age cohort B1 can be opened for enrollment.  If none of the 
first 3 DLT-evaluable subjects in cohort A1 experiences a DLT, then cohort B1 will be opened for 
enrollment and treatment at the same dose level per the Study Design and Treatment Schema.  If 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 4 of 99 
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a DLT occurs in the first 3 DLT-evaluable subjects in the older age cohort (A1 or A2), the younger 
age cohort will not open until a DLT rate < 33% is observed with at least 6 DLT-evaluable 
subjects in the older age cohort (A1 or A2). 
Cohort A1 or B1 can enroll up to a maximum of 18 subjects treated with at least 1 dose of 
talimogene laherparepvec with at least 9 DLT-evaluable subjects in cohort A1.  In the case 
of dose de-escalation, the minimum number of DLT-evaluable subjects at the de-escalated dose 
will be 6 (permissible based on the incidence of DLTs).  After an age cohort is closed for further 
enrollment, if < 33% of all DLT-evaluable subjects in the cohort experiences a DLT at a dose level 
(minimum of 6 DLT-evaluable subjects), the dose will be declared safe for the cohort. 
If dose de-escalation is needed and if permissible based on the incidence of DLTs, a minimum of 
6 DLT-evaluable subjects will be enrolled and treated at a lower dose level of talimogene 
laherparepvec (Dose Level -1).  Dose de-escalation cohorts will obey the following naming 
convention, based on age at baseline, and the same DLT rules will be applied to the de-escalated 
cohorts: 
• 
Cohort A2 (12 to ≤ 21 years of age) 
• 
Cohort B2 (2 to < 12 years of age) 
Sample Size:  If permissible based on the incidence of DLTs, approximately 18 to 24 dosed 
subjects will be enrolled into cohorts, stratified by age. 
Summary of Subject Eligibility Criteria:  Subjects must be 2 to ≤ 21 years of age at the time of 
informed consent/assent.  Subjects must have local HSV-1 serostatus with measurable or 
non-measurable disease.  Subject must have histologically or cytologically confirmed non-CNS 
solid tumor that recurred after standard/frontline therapy (or for which there is no 
standard/frontline therapy available).  The subject must be a candidate for intralesional therapy 
and have Karnofsky performance status of ≥ 70% for subjects 12 to ≤ 21 years of age or Lansky 
play scale of ≥ 70% for children 2 to < 12 years of age.  Subjects must have a life expectancy of 
> 4 months from date of enrollment and adequate organ function.  Female subjects of 
childbearing potential must have a negative pregnancy test.  For a full list of eligibility criteria, 
please refer to Section 4.1 and Section 4.2.   
Investigational Product 
Amgen Investigational Product Dosage and Administration:  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 vial.  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. 
The first dose of talimogene laherparepvec will be up to 4.0 mL of 106 PFU/mL administered on 
Day 1.  The second injection, up to 4.0 mL of 108 PFU/mL, will be administered 21 days (+3 days) 
after the initial injection (ie, no sooner than day 22 but should not be delayed more than 3 days 
after the 21-day time point).  All subsequent injections, up to 4.0 mL of 108 PFU/mL will be 
administered approximately every 14 days (± 3 days).  The treatment cycle interval may be 
increased due to toxicity.  See Section 6.2.1.2 for dose-cohort study de-escalation and stopping 
rules.   
Procedures:  Written informed consent/assent must be obtained from all subjects or legally 
acceptable representatives before any study specific screening procedures are performed.  The 
following procedures will occur per the Table 3: review of eligibility criteria, demographics, 
medical, surgical and medication history, physical examination and vital signs, body weight, 
height, performance status, recording of concomitant medications, 12-lead electrocardiogram 
(ECG), review of adverse events, disease-related events and serious adverse events as well as 
reporting of potential or known unintended exposure to talimogene laherparepvec by a household 
member, caregiver, or healthcare provider, and survival assessment.   
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
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CONFIDENTIAL 
 
 
Blood will be collected for local laboratory testing including: hematology, serum chemistry, 
hepatitis B surface antigen and core antibody and hepatitis C virus antibody, prothrombin time 
(PT) or international normalization ratio (INR), and partial thromboplastin time (PTT) or activated 
PTT (aPTT), and blood for herpes simplex virus (HSV) serostatus at screening.  In females of 
childbearing potential, urine pregnancy test will be performed locally.  Central laboratory tests 
include:  blood for HSV serostatus (with the exception of the screening test which will be done 
locally), 
 
 
 
 
 
 
Radiographic scans (as appropriate for tumor), clinical tumor assessments, and tumor marker 
assessments will also be performed.  Talimogene laherparepvec will be administered at day 1 
and 21 days (+3 days) after the initial injection.  All subsequent injections will be administered 
approximately every 14 days (±3 days).   
Subjects will have a safety follow-up visit approximately 30 (+ 7) days after the last dose of study 
treatment.  Subjects will be followed for survival and use of subsequent anticancer therapies 
every 12 weeks (± 28 days) from the safety follow-up visit until death, subject or legally 
acceptable representative withdraws full consent/assent, or up to approximately 24 months after 
the last subject is enrolled in the study (whichever comes first).   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 3).   
Statistical Considerations:   
Sample size consideration: 
The sample size of 18 to 24 subjects will be enrolled and treated with at least 1 dose of 
talimogene laherparepvec with at least 9 DLT-evaluable subjects in cohort A1.  For age 
cohort opening and dose de-escalation, criteria from 3+3 phase 1 designs assuming a true 
DLT incidence rate < 33% is used.  Sample size for cohorts with age between 2 and 12 years 
are not required. 
A dose level will be considered safe for a cohort if < 33% of all DLT-evaluable subjects in a given 
cohort experiences a DLT (minimum of 6 DLT-evaluable subjects).  Table 5 and Figure 1 
presents the probability of declaring a dose level safe (unsafe) for a range of true DLT rates for 
the protocol therapy based on 6 DLT-evaluable subjects (see triangle symbols).  For example, 
the probability of declaring a dose level safe (unsafe) is 89% (11%), 42% (58%), and 11% (89%) 
if the true DLT rate is 10%, 30%, or 50%, respectively. 
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. 
Planned methods of analysis: 
The data will be analyzed by cohort and in the overall population.  Descriptive statistics will be 
provided for demographic, safety, efficacy and exploratory endpoints. 
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. 
ORR, DOR, TTR, TTP, PFS, OS will be summarized in the overall population.  ORR will be 
summarized with an associated exact 95% CI.  DOR among responders, TTR, TTP, PFS and OS 
will be estimated using the Kaplan-Meier method.   
Subject incidence of treatment-emergent and treatment-related adverse events will be 
summarized.  Medical Dictionary for Regulatory Activities (MedDRA) will be used to code adverse 
events to a system organ class (SOC) and a preferred term within the SOC.  The Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used to grade severity of 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 6 of 99 
CONFIDENTIAL 
 
 
adverse events.   In addition, clinically significant laboratory changes and clinically significant 
changes in vital signs will be summarized with descriptive statistics.  A summary of deaths after 
initiation of the study through 30 days since the last dose of talimogene laherparepvec will be 
provided.   
Summary statistics will also be provided for concomitant medications, dose delay, study drug 
discontinuation, overall exposure, and Karnofsky performance status and Lansky play scale.  
Potential or known unintended exposure to talimogene laherparepvec, related suspected signs or 
symptoms, and detection of exposure to talimogene laherparepvec in a subject’s household 
member, caregiver, or healthcare provider will be reported. 
Summary statistics will be provided for vital signs, physical measurements and laboratory data.  
Details of the analysis will be provided in statistical analysis plan. 
 
 
  
 
 
 
 
 
  
 
 
 
 
  For a full description of 
statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version(s) 5: 20 March 2015   
 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 7 of 99 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
Screening 
Screening 
 D21 (+ 3d) 
 D21 (+ 3d) D35 (± 3d) 
EOT
e 
Q2W 
Dose Level 1 (PFU/mL)
b           10
6        10
8           10
8                10
8 
EOT
e 
Q2W 
EOS 
Cohort A1
a, b 12 to ≤ 21 yr 
(A1 + B1 ≥18)f 
 
Safety FU 
30 (+ 7) days 
Long-term FU 
≈ 24 monthsg 
DLRT 
 D-28 
D1 
EOS 
D35 (± 3d) 
< 33% DLTa 
Cohort B1b 2 to < 12 yr 
 D-28 
D1 
Dose Level 1 (PFU/mL)
b        10
6              10
8              10
8                 10
8 
Safety FU 
30 (+ 7) days 
Long-term FU 
≈ 24 monthsg 
DLRT 
If ≥ 33% DLT 
Dose de-escalate (next page)c, d 
If ≥33% DLT 
Dose de-escalate (next page) c, d 
 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
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D = day; DLRT = dose level review team; DLT = dose-limiting toxicity; EOS = end of study; EOT = end of treatment; irRC-RECIST = immune-related response criteria 
simulating Response Evaluation Criteria in Solid Tumors; FU = follow-up; PFU = plaque-forming unit; yr = years of age 
a Enrollment will begin with cohort A1.  The DLT evaluation period is 35 days from the first dose of talimogene laherparepvec.  The DLRT will review the safety data of 
the first 3 subjects in the older age cohort A1 to decide if the younger age cohort B1 can be opened for enrollment.  If none of the first 3 DLT-evaluable subjects in 
cohort A1 experiences a DLT, then cohort B1 will be opened for enrollment and treatment at the same dose level.  If a DLT occurs in the first 3 DLT-evaluable 
subjects in the older age cohort (A1 or A2), the younger age cohort will not open until a DLT rate < 33% is observed with at least 6 DLT-evaluable subjects in the 
older age cohort (A1 or A2).   
b The initial dose administered (Dose Level 1) will be up to 4.0 mL of 106 PFU/mL followed by dose of up to 4.0 mL of 108 PFU/mL 21 (+ 3) days later.  Subsequent 
doses of up to 4.0 mL of 108 PFU/mL will be administered every 14 (± 3) days thereafter.  For additional details refer to Section 6.2.1.2. 
c If the observed DLT rate is ≥ 33% in a cohort (eg, ≥ 33% DLT-evaluable subjects experience DLT after receiving either 106 or 108 PFU/mL dose) or if the DLRT deem 
the dose intolerable in a cohort in the DLT evaluation period, then dose de-escalation or discontinuation of treatment with subsequent enrollment stop for that cohort 
will occur. 
Cohort A1
a, b 12 to ≤ 21 yr 
 (A1 + B1 ≥ 18)f 
Cohort B1a, b 2 to < 12 yr 
 
Cohort A2
a, b 12 to ≤ 21 yr 
 
Cohort B2a, b 2 to < 12 yr 
 
If ≥ 33% DLT 
Dose de-escalate to  
Dose Level -1c, d 
If ≥ 33% DLT 
Dose de-escalate to  
Dose Level -1c, d 
< 33% DLTa 
< 33% DLTa  
Dose De-escalation Rules 
 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
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d If dose de-escalation is needed and if permissible based on the incidence of DLTs, a minimum of 6 DLT-evaluable subjects will be enrolled and treated at a lower 
dose level of talimogene laherparepvec (Dose Level -1).  The initial dose administered will be up to 4.0 mL of 106 PFU/mL followed by dose of up to 4.0 mL of 
106 PFU/mL 21 days (+3 days) later.  Subsequent doses of up to 4.0 mL of 106 PFU/mL will be administered 14 days (± 3 days) thereafter. 
e Treatment visits continue until the subject has achieved a complete response, all injectable tumors have disappeared, confirmed progressive disease per modified 
irRC RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or need for alternative anticancer therapy, 
whichever occurs first.  
f If permissible based on the incidence of DLTs. 
g Subjects will be followed for survival and use of subsequent anticancer therapies every 12 weeks (± 28 days) from the safety follow-up visit until death, 
subject or legally acceptable representative withdraws full consent/assent, or up to approximately 24 months after the last subject is enrolled in the 
study, whichever occurs first. 
 
 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 10 of 99 
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Study Glossary 
Abbreviation or Term Definition/Explanation 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
ASR 
age-standardized incidence rates 
AST  
aspartate aminotransferase   
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 
ECG 
electrocardiogram 
EDC 
electronic data capture 
End of Study for 
Individual Subject 
Defined as the last day that protocol-specified procedures are conducted 
for an individual subject (ie, the date the subject withdraws full 
consent/assent 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 primary completion date is defined as the date when the last subject 
is assessed or received an intervention for the final collection of data for 
the primary endpoint(s), whether the study concluded as planned in the 
protocol or was terminated early. 
The primary completion date is anticipated to occur 35 days after the 
last subject has enrolled and received at least 1 dose of talimogene 
laherparepvec. 
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, long-term follow-up), as applicable. 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EU 
European Union 
FCBP 
female of childbearing potential 
GCP 
Good Clinical Practice 
Approved 
 
 


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Abbreviation or Term Definition/Explanation 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HIV 
human immunodeficiency virus 
HSV, HSV-1 
herpes simplex virus, herpes simplex virus type-1 
ICH 
International Council for Harmonisation 
ICP 
infected cell protein 
INR 
international normalization ratio 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
irRC-RECIST 
immune-related response criteria simulating Response Evaluation 
Criteria in Solid Tumors (RECIST) 
IRT 
interactive response technology that is linked to a central computer 
in real time as an interface to collect and process information 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
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 
PTT/aPTT 
partial thromboplastin time/activated partial thromboplastin time 
qPCR 
real-time polymerase chain reaction 
QRS interval 
QRS interval 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 
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  
RECIST 
Response Evaluation Criteria in Solid Tumor 
SCCHN 
squamous cell cancer of the head and neck 
SD 
stable disease 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
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CONFIDENTIAL 
 
 
Abbreviation or Term Definition/Explanation 
SOC 
system organ class 
Source Data 
information from an original record or certified copy of the original record 
containing patient information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in 
source documents (original records or certified copies) (ICH Guideline 
[E6]).  Examples of source data include subject identification, 
randomization identification, and stratification value. 
Study day 1 
defined as the first day that protocol-specified investigational products 
are administered to the subject 
TTP 
time to progression 
TTR 
time to response 
ULN 
upper limit of normal 
Approved 
 
 


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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 7 
Study Glossary .............................................................................................................. 10 
1. 
OBJECTIVES ....................................................................................................... 18 
1.1 
Primary ..................................................................................................... 18 
1.2 
Secondary ................................................................................................. 18 
1.3 
Safety ........................................................................................................ 18 
1.4 
Exploratory ................................................................................................ 18 
2. 
BACKGROUND AND RATIONALE ...................................................................... 18 
2.1 
Childhood Cancers .................................................................................... 18 
2.1.1 
Oncolytic Virotherapy in Pediatric Oncology .............................. 19 
2.2 
Amgen Investigational Product Background: Talimogene 
Laherparepvec .......................................................................................... 21 
2.2.1 
Preclinical Data ......................................................................... 21 
2.2.2 
Clinical Data .............................................................................. 22 
2.3 
Pediatric Risk Assessment ........................................................................ 24 
2.4 
Rationale ................................................................................................... 24 
2.5 
Clinical Hypotheses ................................................................................... 25 
3. 
EXPERIMENTAL PLAN ........................................................................................ 26 
3.1 
Study Design ............................................................................................. 26 
3.1.1 
Follow-Up .................................................................................. 27 
3.1.1.1 
Safety Follow-up ..................................................... 27 
3.1.1.2 
Long-term Follow-up ............................................... 27 
3.2 
Number of Sites ........................................................................................ 28 
3.3 
Number of Subjects ................................................................................... 28 
3.4 
Replacement of Subjects .......................................................................... 28 
3.5 
Estimated Study Duration .......................................................................... 28 
3.5.1 
Study Duration for Subjects ....................................................... 28 
3.5.2 
End of Study .............................................................................. 28 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 30 
4.1 
Inclusion Criteria ....................................................................................... 30 
4.2 
Exclusion Criteria ...................................................................................... 31 
5. 
SUBJECT ENROLLMENT .................................................................................... 34 
5.1 
Treatment Assignment .............................................................................. 35 
6. 
TREATMENT PROCEDURES .............................................................................. 35 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 35 
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6.2 
Investigational Product .............................................................................. 35 
6.2.1 
Amgen Investigational Product (Talimogene 
Laherparepvec) ......................................................................... 35 
6.2.1.1 
Dosage, Administration, and Schedule .................... 35 
6.2.1.2 
Dose-cohort Study De-escalation and 
Stopping Rules ........................................................ 37 
6.2.1.3 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 40 
6.3 
Other Protocol-required Therapies/Medications ........................................ 42 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 42 
6.4.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product Due to Potential Hepatotoxicity ............. 43 
6.4.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 43 
6.4.3 
Criteria for Rechallenge of Amgen Investigational 
Product After Potential Hepatotoxicity ....................................... 44 
6.5 
Concomitant Therapy ................................................................................ 44 
6.6 
Other Treatment Procedures ..................................................................... 45 
6.7 
Medical Devices ........................................................................................ 45 
6.8 
Product Complaints ................................................................................... 45 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .................................................................................. 45 
7. 
STUDY PROCEDURES ....................................................................................... 46 
7.1 
Schedule of Assessments ......................................................................... 46 
7.2 
General Study Procedures ........................................................................ 52 
7.2.1 
Screening and Enrollment ......................................................... 52 
7.2.2 
Treatment .................................................................................. 52 
7.2.3 
Follow-Up .................................................................................. 52 
7.2.3.1 
Safety Follow-up Visit .............................................. 52 
7.2.3.2 
Long-term Follow-up ............................................... 53 
7.3 
Description of Study Procedures ............................................................... 53 
7.3.1 
Informed Consent/Assent .......................................................... 53 
7.3.2 
Demographic Data..................................................................... 53 
7.3.3 
Medical and Surgical History ..................................................... 53 
7.3.4 
Medication History ..................................................................... 53 
7.3.5 
Physical Examination ................................................................ 53 
7.3.6 
Physical Measurement .............................................................. 54 
7.3.7 
Electrocardiogram ..................................................................... 54 
7.3.8 
Vital Signs ................................................................................. 54 
7.3.9 
Performance Status ................................................................... 54 
7.3.10 
Adverse Events and Disease-related Events ............................. 54 
7.3.11 
Concomitant Medications .......................................................... 54 
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........................................... 55 
7.3.13 
Radiographic Assessment ......................................................... 55 
7.3.14 
Clinical Tumor Assessment ....................................................... 55 
........... 56 
7.3.16 
Reporting Potential or Known Unintended Exposure to 
Talimogene Laherparepvec ....................................................... 56 
7.4 
Laboratory Assessments ........................................................................... 56 
7.5 
Sample Storage and Destruction ............................................................... 57 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 58 
8.1 
Subjects’ Decision to Withdraw ................................................................. 58 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 59 
8.3 
Reasons for Removal From Treatment or Study ....................................... 59 
8.3.1 
Reasons for Removal From Treatment ...................................... 59 
8.3.2 
Reasons for Removal From Study ............................................. 60 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 60 
9.1 
Definition of Safety Events ........................................................................ 60 
9.1.1 
Disease-related Events ............................................................. 60 
9.1.2 
Adverse Events ......................................................................... 60 
9.1.3 
Serious Adverse Events ............................................................ 61 
9.2 
Safety Event Reporting Procedures .......................................................... 62 
9.2.1 
Reporting Procedures for Disease-related Events ..................... 62 
9.2.2 
Adverse Events ......................................................................... 63 
9.2.2.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 63 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 64 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 65 
9.3 
Pregnancy and Lactation Reporting .......................................................... 65 
9.4 
Reporting of Exposure to Talimogene Laherparepvec ............................... 66 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 66 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 66 
10.1.1 
Study Endpoints ........................................................................ 66 
10.1.1.1 
Primary Endpoint ..................................................... 66 
10.1.1.2 
Secondary Endpoints .............................................. 66 
10.1.1.3 
Safety Endpoint ....................................................... 67 
10.1.1.4 
Exploratory Endpoints ............................................. 67 
10.1.2 
Analysis Sets ............................................................................. 67 
10.1.2.1 
DLT Analysis Set ..................................................... 67 
10.1.2.2 
Safety Analysis Set ................................................. 67 
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10.1.3 
Covariates ................................................................................. 67 
10.2 
Sample Size Considerations ..................................................................... 68 
10.3 
Planned Analyses ..................................................................................... 69 
10.3.1 
Interim Analyses ........................................................................ 69 
10.3.2 
Dose Level Review Team (DLRT) ............................................. 69 
10.3.3 
Primary Analysis ........................................................................ 70 
10.3.4 
Final Analysis ............................................................................ 70 
10.4 
Planned Methods of Analysis .................................................................... 70 
10.4.1 
Primary Endpoint ....................................................................... 70 
10.4.2 
Secondary Endpoints ................................................................ 70 
10.4.3 
Exploratory Endpoints ............................................................... 71 
10.5 
Handling of Missing and Incomplete Data ................................................. 72 
11. 
REGULATORY OBLIGATIONS ............................................................................ 72 
11.1 
Informed Consent/Assent .......................................................................... 72 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 73 
11.3 
Subject Confidentiality ............................................................................... 73 
11.4 
Investigator Signatory Obligations ............................................................. 74 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 74 
12.1 
Protocol Amendments and Study Termination .......................................... 74 
12.2 
Study Documentation and Archive ............................................................ 75 
12.3 
Study Monitoring and Data Collection ....................................................... 76 
12.4 
Investigator Responsibilities for Data Collection ........................................ 77 
12.5 
Language .................................................................................................. 77 
12.6 
Publication Policy ...................................................................................... 77 
12.7 
Compensation ........................................................................................... 78 
13. 
REFERENCES ..................................................................................................... 79 
14. 
APPENDICES ...................................................................................................... 81 
List of Tables 
Table 1.  Dose De-escalation ........................................................................................ 27 
Table 2.  Talimogene Laherparepvec Injection Volume Guideline Based on 
Tumor Size ............................................................................................. 37 
Table 3.  Schedule of Assessments ............................................................................... 47 
Table 4.  Laboratory Analytes ........................................................................................ 57 
Table 5.  Probability of Declaring a Cohort Safe or Unsafe ............................................ 68 
Table 6.  Definition of Measurable Tumor Response (Baseline Target and 
New, Measurable Lesions) ..................................................................... 94 
Table 7.  Matrix for Determining the Overall Response at Each Assessment 
Point ....................................................................................................... 95 
 
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List of Figures 
Figure 1.  Probability of Declaring a Cohort Safe (Unsafe)............................................. 69 
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 82 
Appendix B.  Electronic Adverse Event Contingency Report Form ................................ 84 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 87 
Appendix D.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response ............................................................................................... 89 
Appendix E.  Karnofsky Performance Status and Lansky Play Scale ............................ 99 
 
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1. 
OBJECTIVES 
1.1 
Primary 
To determine the safety and tolerability of talimogene laherparepvec, as assessed by 
incidence of dose-limiting toxicities (DLT), in pediatric subjects with advanced 
non-central nervous system (CNS) tumors that are amenable to direct injection. 
1.2 
Secondary 
• 
To evaluate the anti-tumor activity of talimogene laherparepvec, as assessed by 
overall response rate (ORR), duration of response (DOR), time to response (TTR), 
time to progression (TTP), progression-free survival (PFS) using immune-related 
response criteria simulating Response Evaluation Criteria in Solid Tumor 
(RECIST 1.1) (modified immune-related response criteria simulating Response 
Evaluation Criteria in Solid Tumors [irRC-RECIST]), and overall survival (OS). 
1.3 
Safety  
• 
To evaluate the safety and tolerability of talimogene laherparepvec. 
1.4 
Exploratory 
2. 
BACKGROUND AND RATIONALE 
2.1 
Childhood Cancers 
The incidence of childhood cancer is approximately 13 to 17 per 100 000 in both the 
United States (Siegel et al, 2014) and across Europe (Gatta et al, 2014).  Across 
Europe, the incidence of childhood cancer varies widely, ranging from 9.1 to 
17.8 per 100 000 (Gatta et al, 2014) and is generally higher in boys than in girls  
(Steliarova-Foucher et al, 2004).  Among developing countries, limited data suggest a 
cancer incidence in the range of 8 to 10 per 100 000 (Magrath et al, 2013).  
Most common cancer types in children are leukemia (age-standardized incidence rates 
[ASR], 44.8 per million), CNS tumors (ASR = 29.8 per million) and lymphomas 
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(ASR = 15.5 per million).  According to age, the most common cancer type was 
neuroblastoma for infants (28%), leukemia for those aged 1 to 4 (41%), and CNS tumors 
for those aged 5 to 9.  After age 10, lymphomas, carcinomas, germ-cell tumors, and 
bone tumors are more common, whereas embryonic tumors (ie, retinoblastoma, 
nephroblastoma [mainly renal tumors]) and hepatoblastoma (ie, mainly hepatic tumors) 
are rare.  Childhood cancer represents 5% of all childhood deaths and 15% of all deaths 
amongst those age 5 to 14 (Steliarova-Foucher et al, 2004).  Overall 1-year survival for 
all childhood cancers is 91%, 81% at 3-years, and 78% at 5-years (Gatta et al, 2014).  
Compared to the general population, children survivors are 8- to 11-times at greater risk 
of death, and their risk remains 3-times higher amongst those who survived 45 years 
after diagnosis (Steliarova-Foucher et al, 2004).  Despite improvements in survival due 
to the implementation of multimodal therapy, survival for children with high risk solid 
tumors (comprising those with metastases, relapse or poor prognosis genomic features) 
is still poor and there is an unmet need to develop new drugs and therapies for this 
group of patients (Pui et al, 2011). 
2.1.1 
Oncolytic Virotherapy in Pediatric Oncology 
Oncolytic viruses are attractive cancer therapies because of their potential to target and 
kill cancer cells and create an antitumor immune response while sparing normal cells 
with theoretically less toxicity than conventional therapies.  Oncolytic viruses can be 
administered either via intratumoral injection or intravenously.  Intratumoral injection of 
an oncolytic virus can be a difficult procedure to perform in children, particularly when 
targeting tumors that reside deep in the chest or abdomen.  However, intratumoral 
injection has the advantage of delivering higher viral loads to the tumor, expediting 
delivery and potentially allowing to avoid rapid immune clearance. 
Recently, Children’s Oncology Group reported data from 2 oncolytic virus studies 
(Seneca Valley virus and reovirus).  Both trials proved the feasibility and safety of this 
approach in children.  The Seneca Valley virus (NTX-010) is a single-stranded RNA 
virus in the Picornaviridae family which showed efficacy in preclinical studies.  The drug 
was safely administered intravenously at multiple dose levels, combined with oral and 
intravenous cyclophosphamide, and given in 2 doses (21 days apart) in 22 patients with 
recurrent refractory solid tumors.  Diagnoses included neuroblastoma (n = 12), 
rhabdomyosarcoma (n = 3), carcinoid tumor (n = 4), and adrenocorticocarcinoma (n = 3).  
There was a single DLT (grade 3 pain) at the lowest dose level.  All patients cleared the 
virus from blood and stool within 3 weeks and nearly all developed neutralizing 
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antibodies in spite of adding cyclophosphamide as immunomodulatory therapy, which 
appeared to limit efficacy as there were no objective responses.  However, 10 of 
16 patients had stable disease (SD) at the time of disease assessment 
(Burke et al, 2015).  Reolysin is a double-stranded RNA virus in the Reoviridae family 
which selectively replicates in RAS-activated pediatric cancer cells in preclinical studies.  
Reovirus was safely administered intravenously alone for 5 consecutive days of a 
28-day cycle or combined with oral cyclophosphamide in 24 patients with 
relapsed/refractory extracranial solid tumors, where the majority were 
rhabdomyosarcoma (n = 6), and osteosarcoma (n = 4).  There were no DLTs; although 
grade 5 respiratory failure and a thromboembolic event were reported in the setting of 
disease progression.  No virus was detected in the saliva or stool, and the average time 
of viremia clearance was 6.5 days with no virus noted in blood after 17 days.  No 
objective responses were seen; although there were 3 patients with SD who received a 
second cycle.  The authors concluded that the low incidence of tumor responses 
observed suggests that the utility of reovirus will likely require combination therapies 
which are currently being evaluated in adults (Kolb et al, 2015). 
In addition to these trials, several other pediatric oncolytic virotherapy trials are being 
conducted.  JX-594 (Pexa-Vec) is a double-stranded vaccinia virus in the Poxviridae 
family designed to destroy cancer cells through viral lysis and induce granulocyte 
macrophage colony stimulating factor (GM-CSF) driven tumor-specific immunity.  
Pexa-Vec was safely intratumorally injected into 6 pediatric patients; hepatocellular 
carcinoma (n = 3), neuroblastoma (n = 2), and Ewing’s sarcoma (n = 1).  All toxicities 
were ≤ grade 3.  The most common side effects were fever, tachycardia and 
asymptomatic grade 1 treatment-related pustules that resolved within 3 to 4 weeks.  No 
objective responses were noted; however, there was evidence of necrotic changes in 
1 patient’s necrotic injected tumor on magnetic resonance imaging (MRI) and a 
decrease in standard uptake value on positron emission testing 22 days following the 
first injection suggestive of a potential antitumor response (Cripe et al, 2015).  Two trials 
of intratumoral oncolytic herpes simplex virus (HSV) (HSV 1716), a double-stranded 
DNA cytolytic virus with deletion of the virulence gene (ICP34.5) are ongoing in patients 
with recurrent non-CNS solid tumors (clinicaltrials.gov; NCT 00931931) and CNS tumors 
(clinicaltrials.gov; NCT02031965).  An intravenous cohort has been added to the 
non-CNS trial for subjects not suitable for direct injections. 
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2.2 
Amgen Investigational Product Background: Talimogene 
Laherparepvec 
Talimogene laherparepvec is a virus-based oncolytic immunotherapy consisting of an 
immune-enhanced herpes simplex virus type-1 (HSV-1) that selectively replicates in 
solid tumors.  In this genetically modified strain, the HSV-1 viral genes encoding ICP34.5 
(a neurovirulence factor) and ICP47 (which blocks viral antigen presentation to major 
histocompatibility complex class 1 and 2 molecules) have been functionally deleted.  The 
coding sequence for human GM-CSF have been inserted in place of ICP34.5 and is 
intended to enhance the immune response to tumor antigens released after virus 
replication.  Talimogene laherparepvec enables both direct tumor lysis at the site of 
injection as well as enhancement of a systemic immune response by expression of 
GM-CSF in the tumor microenvironment to recruit and activate antigen presenting cells 
required for a T cell mediated antitumor response.  In the pivotal study in which adult 
patients with injectable melanoma that was not surgically resectable were randomly 
assigned at a 2:1 ratio to intralesional talimogene laherparepvec or subcutaneous 
GM-CSF, systemic immune effects of talimogene laherparepvec were demonstrated with 
the finding that 15% of measureable visceral (uninjected) metastases reduced in size by 
> 50% among talimogene laherparepvec treated patients.  Median duration of treatment 
in the talimogene laherparepvec and GM-CSF arms was 23.0 weeks (range, 0.1 to 
78.9 weeks) and 10.0 weeks (range, 0.6 to 72.0 weeks), respectively.  Median potential 
follow-up (time from random assignment to analysis) was 44.4 months (range, 32.4 to 
58.7 months) at the primary analysis of OS.  Additionally, development of vitiligo in 
talimogene laherparepvec treatment patients was seen in some patients indicating that 
an immune response to melanocyte antigens was induced (Andtbacka et al, 2015). 
2.2.1 
Preclinical Data  
No dedicated juvenile toxicity studies have been conducted with talimogene 
laherparepvec in the clinical setting.  A review of the literature, using the search terms 
“juvenile” or “adolescent”, “HSV-1”, and “infection” [PubMed (US National Library of 
Medicine, National Institutes of Health), 8 November 2016] does not identify a particular 
risk of juvenile HSV-1 infection compared to risks in adults.  The toxicology program 
evaluated the safety of talimogene laherparepvec following repeated subcutaneous 
dosing for up to 13 weeks in the BALB/c mouse (Studies 4648-00027, 4648-00028, 
4648-00029).  Additional studies evaluated the safety of talimogene laherparepvec 
following a single intra-arterial dose in the rat (Study 4648-00031), a single intraprostatic 
dose in the dog (Study 4648-00032), and the repeated intravenous dosing in an 
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embryo-fetal developmental toxicity study in the BALB/c mouse (Study-117250).  
Supplemental studies evaluated neurovirulence with talimogene laherparepvec following 
direct intracerebral injection (Study 4648-00004) or intranasal instillation in the BALB/c 
mouse (Study 4648-00014).  Additionally, the safety of a surrogate HSV-1 construct 
expressing murine GM-CSF administered as a repeated SC injection was evaluated in 
BALB/c mice (Studies 4648-00052 and 4648-00029).  The mice used in toxicology 
studies were approximately 13- to 15-weeks old when studies commenced, whereas 
mice used in the pharmacology studies were generally 4- to 6-weeks old at study start.  
High and multiple doses of talimogene laherparepvec were well tolerated in 
immunocompetent mice following subcutaneous, intravenous, or intralesional injection 
across this age range, which spans adolescence in mice, with no noted difference in 
sensitivity by age, and with hematological and histological effects consistent with a 
normal response to viral infection (Amgen data on file). 
The invitro therapeutic effect of talimogene laherparepvec was tested on a number of 
National Cancer Institute relevant cell lines.  The solid tumors cell lines 
(rhabdomyosarcoma, rhabdoid tumors, Ewing’s sarcoma, and neuroblastoma) were 
found to be sensitive, while leukemia and lymphoma cell lines showed resistance to 
talimogene laherparepvec.  Talimogene laherparepvec was further tested in mouse 
xenograft models of Ewing’s sarcoma (A-673), neuroblastoma (SK-N-AS), osteosarcoma 
(SJSA-1), rhabdoid tumor (G-401), and rhabdomyosarcoma (SJCRH30).  Across these 
models, 65% to 100% of tumor growth inhibition was seen, and 10% to 30% of animals 
showed complete tumor regression (Amgen data on file).  These data are consistent with 
reports in the literature of the efficacy of other HSV-1 oncolytic viruses (Waters et al, 
2016). 
2.2.2 
Clinical Data 
As of 26 October 2016, 15 clinical studies (including 2 extension studies) have been or 
are being conducted in several advanced tumor types (advanced solid tumors, 
melanoma, squamous cell cancer of the head and neck, and pancreatic cancer), with an 
estimate of 893 subjects treated with talimogene laherparepvec. 
In the first-in-human study, 001/01, talimogene laherparepvec was administered in single 
ascending doses of 106, 107, or 108 plaque-forming unit (PFU)/mL (up to 4 mL).  In the 
first 2 single-dose cohorts, subjects who were HSV-1 seronegative at study entry 
experienced more adverse events, including febrile influenza-like syndromes associated 
with symptoms of fatigue, rigors, erythematous skin rashes and small vesicles in the 
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skin.  At the highest dose (108 PFU/mL), only HSV-1 seropositive subjects received 
talimogene laherparepvec and no rashes or rigors were observed.  In the subsequent 
multidose part of the study, talimogene laherparepvec was well tolerated in HSV-1 
seronegative as well as seropositive subjects who received a first dose of 106 PFU/mL, 
followed by 2 doses of 108PFU/mL.  Febrile responses were minimal.  Of the 
17 subjects, 7 subjects were HSV-1 seronegative at baseline but within 21 days 
(3 weeks) after the initial dose of 106 PFU/mL was administered, 6 of the 7 subjects 
seroconverted.  Based on these findings, to facilitate tolerance, enable seroconversion, 
and ensure consistency in dosing, the recommended dose in adults (both HSV-1 
seropositive and seronegative groups) was established to be 106 PFU/mL followed by 
108 PFU/mL 21 days (3 weeks) later.  Subsequent dosing could safely be administered 
every 14 days (2 weeks).  
The pivotal study (Study 005-05) was a phase 3, multinational, randomized, open-label 
study to assess the efficacy and safety of talimogene laherparepvec monotherapy 
versus GM-CSF in subjects with unresectable stage 3b, 3c or 4 melanoma.  Among 
436 patients randomized, the primary endpoint of durable response (objective response 
lasting continuously for ≥ 6 months) rate was significantly higher with talimogene 
laherparepvec than GM-CSF (16.3% vs 2.1% odds ratio = 8.9; p < 0.0001).  ORR was 
also higher in the talimogene laherparepvec arm (26.4% vs 5.7%).  Median OS was 
23.3 months in the talimogene laherparepvec group versus 18.9 months in the GM-CSF 
group (hazard ratio 0.79, p = 0.051).  The 3 most frequent adverse events observed in 
the talimogene laherparepvec group compared with the GM-CSF group, respectively, 
were fatigue (50.3%, 36.2%), chills (48.6%, 8.7%), and pyrexia (42.8%, 8.7%).  Common 
(> 20%) treatment-emergent adverse events that occurred with a higher incidence 
(> 5%) in the talimogene laherparepvec group compared with the GM-CSF group, 
respectively, included chills (48.6% and 8.7%), pyrexia (42.8%, 8.7%), injection site pain 
(27.7%, 6.3%), nausea (35.6%, 19.7%), influenza like illness (30.5%, 15.0%), fatigue 
(50.3%, 36.2%), myalgia and vomiting (21.2%, 9.4%).  The only grade 3 or 4 adverse 
events occurring in ≥ 2% of talimogene laherparepvec patients was cellulitis (2.1%).  No 
fatal treatment-related adverse events occurred (Andtbacka et al, 2015).  
In the earlier clinical studies, (001/01, 002/03 and 004/04), viral shedding was observed 
in only 11% of subjects across all 3 studies.  The longest time that infectious virus was 
detected in the injection site swabs was 8 days post-injection.  All swabs of the exterior 
of the dressing were negative for the infectious virus at all time points tested across all 
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studies.  Thus, it appeared that the dressings were used effectively and prevented 
shedding of any virus from the tumors into the environment.  Additional biodistribution 
and shedding data have been collected in study 20120324.  Interim analysis of this 
ongoing study included 2447 samples from 30 subjects treated with talimogene 
laherparepvec.  Talimogene laherparepvec DNA was detected with the greatest 
frequency in swabs of injected lesions, but the incidence of viral infectivity was low.  No 
blood or urine samples have tested positive at 30 days after the last dose of talimogene 
laherparepvec.  For additional information, refer to the talimogene laherparepvec 
Investigator’s Brochure. 
2.3 
Pediatric Risk Assessment 
The level of risk associated with talimogene laherparepvec in pediatric subjects with 
advanced solid tumors is expected to be similar to that experienced by the adult 
population; however, the incidence and severity of adverse events in the pediatric 
population is unknown.  Based on data from preclinical studies, it seems unlikely that 
talimogene laherparepvec would have specific safety concerns in the juvenile patient 
population.  The risk of viral therapy in neonates (0 to 3 months old) who have an 
immature immune system is not defined, but this population will not be included in the 
study due to the lack of eligible tumor types.  This study is the first to use talimogene 
laherparepvec in pediatric subjects with non-CNS solid tumors and no/limited other 
therapeutic options.  There is a possibility of no direct treatment benefit to the subjects.  
The results of this study are likely to define safe doses to be tested in a pediatric 
phase 2 study. 
2.4 
Rationale 
Talimogene laherparepvec has demonstrated improved outcomes in advanced adult 
melanoma.  Since there is no information to suggest that the mechanisms of action of 
talimogene laherparepvec (including virus replication in injected tumors and immune 
response against tumor antigens) would differ in children and adolescents compared to 
adults, it is expected that talimogene laherparepvec might have a similar beneficial effect 
on tumor response in children and adolescents as it had in adults.  Preclinical 
experiments have demonstrated that talimogene laherparepvec is active in a number of 
pediatric tumors supporting further investigation of talimogene laherparepvec in 
refractory pediatric solid tumors such as rhabdomyosarcoma, Ewing’s sarcoma and 
neuroblastoma (Amgen data on file).  As talimogene laherparepvec has not been 
evaluated in a pediatric population, the first step to the evaluation is determination of 
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safety.  Hence, a phase 1 dose de-escalation study is proposed starting with the 
recommended adult dose.  Only pediatric subjects with advanced non-CNS tumors 
amenable to direct injection (excluding visceral organ injection) will be enrolled.   
Enrollment will start with the oldest age cohort from 12 to ≤ 21 years of age.  Because of 
the protocol-specified requirement for intratumoral injection of a nonvisceral lesion, the 
most likely eligible tumor types in this cohort will be Ewing’s sarcoma, osteosarcoma, 
non-rhabdomyosarcomatous soft tissue sarcoma or rhabdomyosarcoma.  This prediction 
is based on the relative incidence of the most common cancers in this age group 
(Bleyer et al, 2008).  As the average age of diagnosis of these cancers is around 
15 years old (Daw et al, 2015; Brasme et al, 2014; Spunt et al, 2002) and the time to 
tumor recurrence from diagnosis could vary from 1 to 5 years from the initial diagnosis 
(Daw et al, 2015; Chisholm et al, 2011; McTiernan et al, 2006; Spunt et al, 2002), the 
age when these patients might become eligible for this study could be up to 21 year old.  
Thus, the upper age limit for the oldest cohort was set at 21 years of age.   
After review of the safety data in the oldest cohort, recruitment will open for the younger 
patients (2 to < 12 years of age).  Subjects younger than 2 years of age are not included 
in this study due to the lack of eligible tumor types amendable for direct intratumoral 
injection and availability of effective treatment options. 
The recommended adult talimogene laherparepvec dose of 106 PFU/mL followed by 
108 PFU/mL 3 weeks later has been shown to be well tolerated in HSV-1 seropositive 
and seronegative adult subjects.  Symptoms of pyrexia, chills and influenza-like illness 
occurred more frequently during the first 3 months of treatment, particularly in patients 
who were HSV-1 negative at baseline (Andtbacka et al, 2015).  Given this finding, 
preemptive measures are strongly recommended prior to each talimogene 
laherparepvec dose to prevent the occurrence of the influenza-like symptoms in the 
pediatric subjects who might be more susceptible for developing these adverse events.  
2.5 
Clinical Hypotheses 
Talimogene laherparepvec injected in pediatric subjects with advanced non-CNS tumors 
that are amenable to direct injection will be safe as assessed by subject incidence of 
DLTs and the safety profile. 
Approved 
 
 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 1, multicenter, open-label study of talimogene laherparepvec in pediatric 
subjects with advanced non-CNS tumors that are amenable to direct injection in the 
clinical setting.  The overall study design is described by the Study Design and 
Treatment Schema. 
Approximately 18 to 24 pediatric subjects are expected to be enrolled and treated with 
at least 1 dose of talimogene laherparepvec into 2 cohorts stratified by age 
(permissible based on the incidence of DLTs, a minimum of 18 dosed subjects total for 
the primary analysis) as follows: 
• 
Cohort A1 (12 to ≤ 21 years of age) 
• 
Cohort B1 (2 to < 12 years of age) 
Initially, 3 subjects 12 to ≤ 21 years of age are to be enrolled and treated at 100% of the 
recommended adult dose regimen of talimogene laherparepvec (cohort A1).  The first 
dose administered will be up to 4.0 mL of 106 PFU/mL followed by a dose of up to 
4.0 mL of 108 PFU/mL 21 days (+ 3 days) later.  Subsequent doses of up to 4.0 mL of 
108 PFU/mL will be administered approximately every 14 days (± 3 days) thereafter  
(see Section 6.2.1.1).  The DLT evaluation period is 35 days from the initial 
administration of talimogene laherparepvec.  Rules for DLT evaluation are described in 
Section 6.2.1.2.1.  The dose level review team (DLRT) will review the safety data of the 
first 3 subjects in the older age cohort A1 to decide if the younger age cohort B1 can be 
opened for enrollment.  If none of the first 3 DLT-evaluable subjects in cohort A1 
experiences a DLT, then cohort B1 will be opened for enrollment and treatment at the 
same dose level per the Study Design and Treatment Schema.  If a DLT occurs in the 
first 3 DLT-evaluable subjects in the older age cohort (A1 or A2), the younger age cohort 
will not open until a DLT rate < 33% is observed with at least 6 DLT-evaluable subjects 
in the older age cohort (A1 or A2).  If any of the first 3 subjects in cohort A1 experiences 
a DLT, the DLRT will make a recommendation on whether an additional 3 subjects 
should be enrolled in cohort A1. 
Cohort A1 or B1 can enroll up to a maximum of 18 dosed subjects with at least 
9 DLT-evaluable subjects in cohort A1.  In the case of dose de-escalation, the 
minimum number of DLT-evaluable subjects at the de-escalated dose will be 
6 (permissible based on the incidence of DLTs).  After an age cohort is closed for further 
enrollment, if < 33% of all DLT-evaluable subjects in the cohort experiences a DLT at a 
Approved 
 
 


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dose level (minimum of 6 DLT-evaluable subjects), the dose will be declared safe for 
the cohort. 
If dose de-escalation is needed and if permissible based on the incidence of DLTs, a 
minimum of 6 additional DLT-evaluable subjects will be enrolled and treated at a lower 
dose level of talimogene laherparepvec (Dose Level -1).   The initial dose administered 
will be up to 4.0 mL of 106 PFU/mL followed by dose of up to 4.0 mL of 106 PFU/mL 
21 days (+3 days) later.  Subsequent doses of up to 4.0 mL of 106 PFU/mL will be 
administered approximately every 14 days (± 3 days) thereafter (see Table 1).  Dose 
de-escalation cohorts will obey the following naming convention, based on age at 
baseline, and the same DLT rules will be applied to the de-escalated cohorts: 
• 
Cohort A2 (12 to ≤ 21 years of age) 
• 
Cohort B2 (2 to < 12 years of age) 
Table 1.  Dose De-escalation 
Dose Level 
Initial Dose 
Subsequent Doses 
1 
106 PFU/mL 
108 PFU/mL 
-1 
106 PFU/mL 
106 PFU/mL 
PFU = plaque-forming unit 
3.1.1 
Follow-Up 
3.1.1.1 
Safety Follow-up 
Adverse events will be collected as described in Section 9.2.  All subjects will complete a 
safety follow-up visit approximately 30 (+ 7) days after the last dose of study treatment.  
Adverse events and any concomitant medications associated with adverse events that 
occur 30 (+ 7) days following cessation of treatment will be reported, followed, and 
recorded in the case report form (CRF). 
3.1.1.2 
Long-term Follow-up 
After the safety follow-up visit, all subjects will enter the long-term follow-up.  Subjects 
will be followed for survival and use of subsequent anticancer therapies every 12 weeks 
(± 28 days) from the safety follow-up until death, subject or legally acceptable 
representative withdraws full consent/assent, or up to approximately 24 months after the 
last subject is enrolled in the study.  In addition, talimogene laherparepvec-related 
adverse events that occur through the end of the long term follow-up will be reported. 
Approved 
 
 


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3.2 
Number of Sites 
The study will be conducted at approximately 22 sites in Europe and North America.  
Additional sites and countries may be added.  Sites that do not enroll subjects within 
approximately 18 months of site initiation may be closed.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
If permissible based on the incidence of DLTs, approximately 18 to 24 subjects will be 
enrolled into cohorts stratified by age (a minimum of 18 dosed subjects for the 
primary analysis). 
Refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects enrolled 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).  The 
decision to replace subjects will depend on the totality of reasons for subjects not 
completing the DLT evaluation. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The duration of screening for each subject will be approximately 28 days (1 month).  The 
duration of treatment is anticipated to be 9 months.  All subjects will complete a safety 
follow-up visit approximately 30 (+ 7) days after the last dose of study treatment.  After 
the safety follow-up visit subjects will enter the long-term follow-up.  During this period, 
subjects will be followed for survival for and use of subsequent anticancer therapies 
every 12 weeks (± 28 days) from the safety follow-up visit until death, subject or 
legally acceptable representative withdraws full consent/assent, or up to 
approximately 24 months after the last subject is enrolled in the study, whichever 
occurs first.  The study duration for an individual subject is expected to be 
approximately 35 months.   
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or received an intervention for the final collection of data for the 
primary endpoint(s), whether the study concluded as planned in the protocol or was 
terminated early. 
Approved 
 
 


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The primary completion date is anticipated to occur 35 days after the last subject has 
enrolled and received at least 1 dose of talimogene laherparepvec.  
Approved 
 
 


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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, long-term follow-up), as applicable. 
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/assent must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
101 
Subject’s legally acceptable representative has provided informed 
consent/assent when the subject is legally too young to provide informed 
consent/assent and the subject has provided written assent based on local 
regulations and/or guidelines prior to any study-specific activities/procedures 
being initiated. 
103 
Should be willing to submit local HSV-1 serostatus within 28 days prior to 
enrollment. 
106 
Subject must be a candidate for intralesional injection, defined as one or more of 
the following: 
• 
at least 1 injectable lesion ≥ 10 mm in longest diameter  
• 
multiple injectable lesions that in aggregate have a longest diameter of 
≥ 10 mm  
NOTE:  visceral lesions are not eligible for injection.  Additionally, bone lesions 
are not eligible for injection unless there is a soft tissue component that is 
amenable to injection.  
108 
Life expectancy > 4 months from the date of enrollment.  
111. 
Male or female subjects 2 to ≤ 21 years of age at the time of informed 
consent/assent. 
112. 
Histologically or cytologically confirmed non-CNS solid tumor that recurred after 
standard/frontline therapy, or for which there is no standard/frontline therapy 
available. 
113. 
Presence of measurable or non-measurable lesions as defined by irRC-RECIST 
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114. 
Performance status:  
• 
Karnofsky ≥ 70% for 12 to ≤ 21 years of age.  
• 
Lansky play scale ≥ 70% for children 2 to < 12 years of age.  
116. 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to dosing.  If urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.  A female is 
considered of childbearing potential (FCBP), ie, fertile, following menarche and 
until becoming post-menopausal unless permanently sterile.  Permanent 
sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 
117. 
 
 
118. 
Adequate organ function as defined as follows:  
• 
Hematological (without need of hematopoietic growth factor and/or 
transfusion support within 7 days from screening assessment)  
− 
absolute neutrophil count (ANC) ≥ 1.0 x 109/L  
− 
platelet count ≥ 75 x 109/L  
− 
hemoglobin ≥ 8 g/dL  
• 
Renal  
− 
serum creatinine ≤ 1.5x upper limit of normal (ULN) for age, OR 
creatinine clearance ≥ 60 mL/min/1.73 m2 for a subject with creatinine 
levels > 1.5x ULN for age. (Note: creatinine clearance need not be 
determined if the baseline serum creatinine is ≤ 1.5x ULN for age.  
Creatinine clearance should be determined per institutional standards).  
• 
Hepatic  
− 
serum bilirubin ≤ 1.5× ULN for age or ≤ 1.5× baseline value if baseline 
value was abnormal for a subject with Gilbert’s syndrome or direct 
bilirubin ≤ ULN for age for a subject with total bilirubin level > 1.5× ULN 
for age 
− 
aspartate aminotransferase (AST) ≤ 2.5x ULN for age or ≤ 5x ULN for age 
for subject with liver metastases  
− 
alanine aminotransferase (ALT) ≤ 2.5x ULN for age or ≤ 5x ULN for age 
for subject with liver metastases  
• 
Coagulation  
− 
international normalization ratio (INR) or prothrombin time (PT) 
≤ 1.5x ULN for age 
− 
partial thromboplastin time (PTT) or activated partial thromboplastin time 
(aPTT) ≤ 1.5x ULN for age 
4.2 
Exclusion Criteria 
201. 
Diagnosis of leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, or other 
hematologic malignancy.  
202. 
Radiotherapy to the bone marrow within 6 weeks prior to enrollment OR within  
3 months prior to enrollment if prior radiotherapy to the craniospinal axis or to at 
Approved 
 
 


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least 60% of the pelvis was received; within 2 weeks prior to enrollment if local 
palliative radiotherapy was received.  
203. 
 
204. 
Primary ocular or mucosal melanoma.  
206. 
History of other malignancy within the past 5 years with the following exception:  
• 
malignancy treated with curative intent and with no known active disease 
present and has not received chemotherapy for > 5 years before enrollment 
and felt to be at low risk for recurrence by the treating physician.  
207. 
History or evidence of active autoimmune disease that requires systemic 
treatment (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs).  Replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.  
209. 
Active herpetic skin lesions or prior complications of herpetic infection 
(eg, herpetic keratitis or encephalitis).  
210. 
Prior treatment with talimogene laherparepvec or any other oncolytic virus. 
211. 
Prior treatment with a tumor vaccine. 
212. 
Requires intermittent or chronic treatment with an antiherpetic drug 
(eg, acyclovir), other than intermittent topical use.  
214. 
 
215. 
 
216. 
Expected to require other cancer therapy while on study with the exception of 
local palliative radiation treatment.  
217. 
Has acute or chronic active hepatitis B virus or hepatitis C virus infection or 
received treatment with nucleotide analogs such as those used in the treatment 
of hepatitis B virus (eg, lamivudine, adefovir, tenofovir, telbivudine, and 
entecavir), ribavirin, or interferon alpha within 12 weeks of initiation of study 
treatment.  
218. 
Known or suspected human immunodeficiency virus (HIV) infection.  
219. 
Received live vaccine within 28 days prior to enrollment.  
220. 
No antiplatelet or anticoagulation medications allowed within 7 days prior to 
talimogene laherparepvec injection except low-dose heparin needed to maintain 
venous catheter patency.  
221. 
Female subject is pregnant or breast-feeding, or planning to become pregnant 
during study treatment and through 3 months after the last dose of talimogene 
laherparepvec.  
222. 
Female subject of childbearing potential who is unwilling to use acceptable 
method(s) of effective contraception during study treatment and through 
3 months after the last dose of talimogene laherparepvec.  Note:  Acceptable 
methods of effective contraception are defined in the informed consent/assent 
form.  Where required by local laws and regulations, additional country-specific 
contraception requirements may be outlined in a country-specific protocol 
supplement at the end of the Appendix Section of protocol.  
Approved 
 
 


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224. 
Subject has known sensitivity to any of the products or components to be 
administered during dosing.  
225. 
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.  
226. 
History or evidence of any psychiatric disorder, substance abuse or any other 
clinically significant disorder, condition or disease (with the exception of those 
outlined above) that, in the opinion of the investigator or Amgen physician, if 
consulted, would pose a risk to subject safety or interfere with the study 
evaluation, procedures or completion.  
227. 
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 
(immunosuppressed individuals, HIV-positive individuals, pregnant women, or 
children under the age of 1 year) during talimogene laherparepvec treatment and 
through 28 days after the last dose of talimogene laherparepvec. 
228. 
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 prior to 
enrollment), including oral steroid doses (with the exception of maintenance 
physiologic replacement).  Subjects who require intermittent use of steroids 
for inhalation or local steroid injection will not be excluded from the study 
• 
less than 6 months from autologous bone marrow transplant or stem cell 
infusion 
• 
history of allogeneic bone marrow transplant 
230. 
History or evidence of xeroderma pigmentosum. 
231. 
Sexually active subjects and their partners unwilling to use a 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. 
232. 
Prior chemotherapy, treatment dose radiotherapy, or biological cancer therapy 
within 14 days prior to enrollment or has not recovered to Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE) grade 1 or better from adverse 
event due to cancer therapy administered more than 14 days prior to enrollment.  
233. 
CNS tumor or clinically active brain metastases (patient with a history of 
treated brain metastases are eligible if there is radiographic evidence of 
improvement upon the completion of CNS-directed therapy and no 
evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study). 
234. 
Currently receiving treatment in another investigational device or drug study, or 
less than 14 days since ending treatment on another investigational device or 
drug study(ies) or has not recovered to CTCAE version 4.0 grade 1 or better 
from adverse event due to other investigational device or drug study 
administered more than 14 days prior to enrollment.  Other investigational 
procedures while participating in this study are excluded. 
Approved 
 
 


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235. 
Major surgery ≤ 14 days prior to enrollment or has not recovered to CTCAE 
version 4.0 grade 1 or better from adverse event due to surgery performed 
more than 14 days prior to enrollment. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent/assent form, and all 
other subject information and/or recruitment material, if applicable (see Section 11.2).  
All subjects or legally acceptable representatives must sign and date the IRB/IEC and 
Amgen approved informed consent (and assent, if appropriate) 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 CRF. 
Each subject who enters into the screening period for the study (defined when the 
subject or legally acceptable representative signs the informed consent/assent) receives 
a unique subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned by the interactive 
response technology (IRT).  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 
IRT 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.  If a 
subject is being rescreened, he or she may need to reconsent to the study to ensure that 
the IRB/IEC approved main informed consent/assent form is signed within 28 days of 
enrollment.  Subjects who are determined not eligible after rescreen must be 
screen-failed in the IRT 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.   
Approved 
 
 


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5.1 
Treatment Assignment 
All subjects enrolled in the study will be assigned 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 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.  
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. 
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 CTCAE version 4 (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 3) 
and the results should be checked before each treatment.  Dosing will occur only if these 
test values are acceptable per Section 6.2.1.2 and 6.2.1.3.  Sedation can be used and 
the type and dose is up to the discretion of the investigator taking into consideration the 
subject’s medical history, age, and site of disease.  Additionally, use of pain medication 
(eg, acetaminophen/paracetamol/narcotic) or anti-anxiety medication 
(eg, benzodiazepine) as premedication to help decrease the pain or anxiety associated 
with the injection is acceptable and left to the discretion of the investigator.  Because 
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flu-like symptoms are common adverse events experienced by HSV-seronegative 
subjects after talimogene laherparepvec treatment, premedication with the appropriate 
antipyretic and/or antiemetic medications prior to each talimogene laherparepvec 
treatment is strongly recommended to prevent the occurrence of these symptoms in the 
HSV-seronegative subjects.  The type and dose will be up to the discretion of the 
investigator taking into consideration the subject’s medical history and age. 
Talimogene laherparepvec will be administered by intralesional injection only into 
injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or 
without image guidance.  Talimogene laherparepvec must not be administered into 
tumor lesions in visceral organs. 
The first dose of talimogene laherparepvec will be up to 4.0 mL of 106 PFU/mL 
administered on day 1.  The second injection, up to 4.0 mL of 108 PFU/mL (or up to 
4.0 mL of 106 PFU/mL for a dose de-escalated cohort), will be administered 
21 (+ 3) days after the initial injection (ie, no sooner than day 22 but should not be 
delayed more than 3 days after the 21-day time point).  All subsequent injections, up to 
4.0 mL of 108 PFU/mL (or up to 4.0 mL of 106 PFU/mL for a dose de-escalated cohort), 
will be administered every 14 (± 3) days.  The treatment cycle interval may be increased 
due to toxicity.   
The maximum volume of talimogene laherparepvec administered at any dose is 4.0 mL 
for any individual lesion and in any treatment.   
The recommended volume of talimogene laherparepvec to be injected into the tumor(s) 
is dependent on the size of the tumor(s) and should be determined according to the 
injection volume guideline in Table 2.  It is recommended that each lesion should receive 
the maximum amount possible to inject due to tumor properties at each visit before 
moving on to the next lesion, using the prioritization model below and the injection 
volume guideline based on tumor size per Table 2.  The lesion site injected will be 
recorded on the CRF. 
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Table 2.  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 recommended as follows: 
1. any new injectable tumor that appeared since the last injection 
2. by tumor size, beginning with the largest tumor  
3. any tumor previously seen on tumor assessment that was too small to inject that has 
now become large enough to inject 
Subjects will be treated with talimogene laherparepvec until subjects have achieved a 
complete response (CR), all injectable tumors have disappeared, confirmed progressive 
disease (PD) per modified irRC-RECIST, intolerance of study treatment, 24 months from 
the date of the first dose of talimogene laherparepvec, or need for alternative anti-cancer 
therapy, whichever occurs first.  Due to the mechanism of action, subjects may 
experience growth in existing tumors or the appearance of new tumors prior to maximal 
clinical benefit of talimogene laherparepvec.  Therefore, modified irRC-RECIST will be 
used instead of standard RECIST 1.1 (Nishino et al, 2014).  Details can be found in 
Appendix D.   
The dose (total volume and concentration), lesion site, treatment start date, and lot 
number of talimogene laherparepvec are to be recorded on the CRF. 
6.2.1.2 
Dose-cohort Study De-escalation and Stopping Rules 
Unlike conventional treatments, talimogene laherparepvec is administered directly into 
tumors and the dose is dependent on tumor size rather than subject’s age, weight or 
body surface area.  As the adult doses were safe and well-tolerated, this phase 1 study 
is designed with a dose de-escalation schema, which is described in detail in Section 3.1 
Study Design. 
If the DLT is a serious herpetic event (eg, encephalitis, encephalomyelitis, or 
disseminated herpetic-like infection) caused by talimogene laherparepvec as 
Approved 
 
 


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demonstrated by real-time polymerase chain reaction (qPCR) analysis, then the study 
will be terminated. 
6.2.1.2.1 
Rules for DLT Evaluation 
The DLT evaluation period is 35 days from the initial administration of talimogene 
laherparepvec.  For a subject to be considered DLT-evaluable, subjects must receive 
2 doses of talimogene laherparepvec (one dose of up to 4.0 mL of 106 PFU/mL followed 
by a dose of up to 4.0 mL of 108 PFU/mL for Dose Level 1, or 2 doses of up to 4.0 mL of 
106 PFU/mL for Dose Level -1) during the 35 day DLT evaluation period, with the 
exception when a DLT occurs after the first dose.  Subjects may be replaced in a cohort 
if they are not evaluable for DLT (ie, a subject did not receive at least 2 treatments of 
talimogene laherparepvec, or ended the study treatment before completion of DLT 
evaluation period for a reason other than experiencing a DLT).   
A DLRT will review the safety data to evaluate possible drug effects and DLT.  The 
DLRT will review the safety data of the first 3 DLT-evaluable subjects in the older age 
cohort (A1 or A2) to decide if the younger age cohort can be opened for enrollment.  The 
decision to open the younger age cohort for subject enrollment will be based on < 33% 
DLT rate of the first 3 DLT-evaluable subjects in the older age cohort (A1 or A2) during 
the DLT evaluation period. 
If a DLT occurs in the first 3 DLT-evaluable subjects in the older age cohort (A1 or A2), 
the younger age cohort will not open until a DLT rate < 33% is observed with at least 
6 DLT-evaluable subjects in the older age cohort (A1 or A2).  The starting dose for the 
younger age cohort will be Dose Level 1 (if the DLT rate in the older age cohort at Dose 
Level 1 is < 33%) or Dose Level -1 (if Dose Level 1 is intolerable for the older age 
cohort).  After both cohorts are open, the DLRT will review the safety data after the 
earlier of the following events: (a) the addition of 3 new DLT-evaluable subjects in a 
cohort until there’re 9 DLT-evaluable subjects in the cohort; (b) a DLT rate ≥ 33% 
considering all DLT-evaluable subjects in a cohort; (c) at the occurrence of the first DLT 
in either cohort.  If deemed necessary, ad-hoc meetings to review the safety data 
can be convened anytime by the DLRT.  
After an age cohort is closed for further enrollment, the dose will be declared safe for the 
cohort if the DLT rate at the dose level is < 33% (minimum of 6 DLT-evaluable 
subjects).  If a DLT rate ≥ 33% is observed at any time in a cohort or if it is deemed 
unsafe by the DLRT to continue enrollment in the cohort, the dose will be declared 
intolerable for the cohort.  If permissible based on the incidence of DLTs, enrollment will 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 39 of 99 
CONFIDENTIAL 
 
 
stop when 18 dosed subjects evaluable for the primary analysis have been confirmed 
across cohorts A1 and B1 except in the case of dose de-escalation when 6 additional 
DLT-evaluable subjects at Dose Level -1 will be needed (permissible based on the 
incidence of DLTs).  Enrollment will not be halted while the DLT-evaluation period is still 
ongoing.  During this time, investigators should contact the medical monitor to discuss 
the screening and enrollment of any potential subjects.  However, enrollment may be 
halted for the following: 
• 
if a DLT occurs in the older age cohort while both cohorts are enrolling subjects and 
before the younger age cohort reaches the first safety review, then further enrollment 
will be halted in the younger age cohort until a DLT rate < 33% is observed with at 
least 6 DLT-evaluable subjects in the older age cohort; 
• 
if dose de-escalation occurs in any cohort while both cohorts are enrolling subjects. 
The DLRT will consider the totality of available data across all cohorts in coming to any 
recommendation, including dose de-escalation, enrollment halt, opening or re-opening of 
cohort(s) for enrollment and/or the starting dose for the cohorts.  
6.2.1.2.2 
Rules for Dose De-escalation 
• 
If the observed DLT rate is ≥ 33% in a cohort (eg, ≥ 33% DLT-evaluable subjects 
experience DLT after receiving either 106 or 108 PFU/mL dose) or if the DLRT deem 
the dose intolerable in a cohort in the DLT evaluation period, then dose de-escalation 
or discontinuation of treatment with subsequent enrollment stop for that cohort will 
occur.  
• 
In the case that dose de-escalation is needed, a minimum of 6 additional 
DLT-evaluable subjects will be enrolled at Dose Level -1 (permissible based on the 
incidence of DLTs) 
• 
If the younger age cohort starts at Dose Level -1, no dose re-escalation will be 
considered. 
6.2.1.2.3 
Definition of DLT  
All toxicities will be graded using the CTCAE version 4.0 (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 if: 
− 
medical intervention is required, or 
− 
the abnormality leads to hospitalization, or 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 40 of 99 
CONFIDENTIAL 
 
 
− 
the abnormality persists for > 1 week unless deemed not clinically important 
per both investigator and sponsor.  
• 
Febrile neutropenia grade 3 or grade 4 
• 
Thrombocytopenia < 25 x 109/L associated with bleeding event requiring intervention  
• 
Serious herpetic event: 
− 
herpetic encephalitis 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 treatments will 
be discontinued for that subject.   
Subjects who are in CR and no longer have injectable lesions will enter the 30-day 
safety follow-up and continue to have tumor assessments every 12 weeks for up to 
24 months.  Subjects who develop a new injectable lesion(s) within 12 months from the 
start date of treatment, but after all other injectable lesions have responded such that 
they are no longer injectable are eligible to restart treatment with talimogene 
laherparepvec under this protocol for up to a further 12 months.  This includes subjects 
that achieve a CR and then develop a new injectable lesion. 
6.2.1.3 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Talimogene laherparepvec treatment should be continued based on the potential 
benefit/risk assessment of the subject. 
Dose reduction within a cohort for an individual subject who experience adverse events 
is not allowed.  If in the course of administration of talimogene laherparepvec the subject 
cannot tolerate the full dose due to an injection-related adverse event, the total volume 
given should be recorded, and the reason for intolerance should be documented as an 
adverse event. 
If a subject experiences any of the following treatment-related toxicities, administration 
should be delayed until the toxicity has resolved to at least CTCAE grade 1 or baseline: 
• 
grade 2 or greater immune-mediated adverse events, with the exception of vitiligo 
• 
grade 2 or greater allergic reactions 
• 
any other grade 3 or greater hematologic or non-hematologic toxicity  
If the subject requires corticosteroid dosing greater than that required for maintenance 
physiologic replacement therapy, talimogene laherparepvec dosing should be withheld. 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 41 of 99 
CONFIDENTIAL 
 
 
If a subject demonstrates evidence of new or worsening CNS metastases, all study 
treatments should be withheld.  Resumption of talimogene laherparepvec dosing should 
be left to the discretion of the investigator and discussed with the Amgen medical 
monitor. 
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 6 weeks from the date of 
the planned 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 
6 weeks from the date of the planned 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.  Reason for dose change of talimogene laherparepvec is to be recorded on 
CRF.   
Talimogene laherparepvec will be permanently discontinued for subjects meeting any of 
the following criteria: 
• 
Subject developed DLT during the DLT evaluation period. 
• 
The subject, for any reason, requires treatment with another anticancer therapeutic 
agent for the study disease (other than the exceptions noted in Section 6.4).  In this 
case, discontinuation from the study treatment occurs immediately upon introduction 
of the new agent.  
• 
Confirmed PD occurs as defined per modified irRC-RECIST or clinical progression 
per the investigator. 
• 
A grade 2 or greater immune-mediated adverse event (with the exception of vitiligo) 
or allergic reactions attributed to talimogene laherparepvec that would require a dose 
delay of greater than 6 weeks from the date of the planned dose. 
− 
NOTE:  immune-mediated glomerulonephritis, vasculitis, and pneumonitis and 
exacerbation of psoriasis have been observed in subjects receiving talimogene 
laherparepvec in clinical trials.  Most of these subjects had a history of other 
autoimmune disease and/or prior treatment with agents that offered plausible 
alternative etiologies; however, immune-mediated adverse events can potentially 
involve any organ system.   
• 
Any other talimogene laherparepvec-related non-hematologic or hematologic 
toxicities grade 3 or greater that, in the opinion of the investigator, would require a 
dose delay of greater than 6 weeks from the date of the planned dose. 
• 
The subject develops clinical evidence of any systemic herpetic infection (such as 
encephalitis or disseminated infection). 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 42 of 99 
CONFIDENTIAL 
 
 
• 
An FCBP subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception.  
• 
A female subject breastfeeds while on study treatment. 
• 
Concurrent medical illness that, in the judgment of the investigator, would make 
continued treatment with talimogene laherparepvec dangerous for the subject. 
• 
Subject or legally acceptable representative withdraws consent/assent or wishes to 
stop the study treatment. 
For additional information related to special warnings and precautions for the use of 
talimogene laherparepvec please refer to the latest version of the talimogene 
laherparepvec Investigator’s Brochure. 
6.3 
Other Protocol-required Therapies/Medications 
All other protocol-required/recommended therapies/medications, including topical 
anesthetic or an injectable local anesthetics 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/recommended therapies.  
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin and/or INR and/or signs/symptoms of hepatitis (as described in 
Sections 6.4.1 and 6.4.2) may meet the criteria for withholding or permanent 
discontinuation of Amgen investigational product  or other protocol-specified therapies 
as specified in the United States Food and Drug Administration Guidance for Industry 
Drug-induced Liver Injury (DILI):  Premarketing Clinical Evaluation, July 2009. 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 43 of 99 
CONFIDENTIAL 
 
 
6.4.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product Due to Potential Hepatotoxicity 
Amgen investigational product should be discontinued permanently and the subject 
should be followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information and Drug-induced Liver Injury Reporting & Additional 
Assessments) for possible DILI, if ALL of the criteria below are met:  
• 
Current total bilirubin > 2x ULN for age following baseline total bilirubin < ULN or INR 
> 1.5 
• 
AND current AST or ALT > 3x ULN for age following baseline AST or ALT < ULN 
respectively 
• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
total bilirubin values include, but are not limited to: 
− 
Hepatobiliary tract disease 
− 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
HSV, varicella, toxoplasmosis, and parvovirus) 
− 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia   
− 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms  
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation  
(eg, indinavir, atazanavir) 
− 
Alpha-one antitrypsin deficiency 
− 
Alcoholic hepatitis 
− 
Autoimmune hepatitis  
− 
Wilson’s disease and hemochromatosis 
− 
Nonalcoholic fatty liver disease including steatohepatitis  
− 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on subject population and/or 
severity of the hepatotoxicity or event) if Amgen investigational product should be 
withheld or permanently discontinued, as deemed appropriate for the safety of the 
subject. 
6.4.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen 
investigational product outlined above and have no underlying liver disease, and 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 44 of 99 
CONFIDENTIAL 
 
 
eligibility criteria requiring normal transaminases and total bilirubin at baseline or 
subjects with underlying liver disease and baseline abnormal transaminases, the 
following rules are recommended for withholding of Amgen investigational product and 
other protocol-required therapies:  
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
≤ 3x ULN for age 
> 5x ULN for ≥ 2 weeks 
≤ 3x ULN for age 
> 5x ULN and unable to adhere to enhanced monitoring 
schedule 
≤ 5x ULN for age 
> 8x ULN at any time 
• 
OR:  total bilirubin > 3x ULN for age at any time 
• 
OR:  ALP > 8x ULN for age at any time 
Amgen investigational product should be withheld pending investigation into alternative 
causes of DILI.  If investigational product(s) is withheld, the subject is to be followed 
according to recommendations in Appendix A for possible DILI.  Rechallenge may be 
considered if an alternative cause for impaired liver tests (ALT, AST, ALP) and/or 
elevated total bilirubin, is discovered and the laboratory abnormalities resolve to normal 
or baseline (Section 6.4.3). 
6.4.3 
Criteria for Rechallenge of Amgen Investigational Product After 
Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject or legally acceptable representative, investigator, and 
Amgen medical monitor. 
If signs or symptoms recur with rechallenge, then Amgen investigational product, as 
appropriate should be permanently discontinued.  Subjects who clearly meet the criteria 
for permanent discontinuation (as described in Section 6.4.1) should never be 
rechallenged without consulting with the Amgen medical monitor. 
6.5 
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 6.9. 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 45 of 99 
CONFIDENTIAL 
 
 
6.6 
Other Treatment Procedures 
Local radiation treatment to the site of bone and other metastasis will be permitted for 
palliative pain management at any time during the study.  If a subject undergoes local 
radiation, the investigator or designee should notify the sponsor’s medical monitor as 
soon as possible. 
If a subject demonstrates evidence of new or worsening CNS metastases, all study 
treatments should be withheld and the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.  Subjects may be allowed to remain on 
study after discussion between the sponsor’s medical monitor and the investigator to 
determine the appropriateness of treatment resumption provided CNS lesions are 
adequately treated and corticosteroid dose does not exceed levels typically required for 
maintenance physiologic replacement.  Re-exposure to talimogene laherparepvec may 
occur only if the investigator and sponsor agree that the subject safety will not be 
compromised.  
6.7 
Medical Devices 
Medical devices (eg, syringes, sterile needles, alcohol prep pads) that are commercially 
available are not usually provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these devices. 
6.8 
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 
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. 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Subjects must not use any of the following therapies during screening or treatment 
period, unless indicated otherwise: 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 46 of 99 
CONFIDENTIAL 
 
 
• 
other investigational agents or procedures   
• 
concurrent experimental or approved anticancer therapies other than study drug and 
radiation therapy required for palliation.   
In addition, the following are not permitted during the treatment period: 
• 
Immunosuppressive agents with the exception of treatment for adverse events  
• 
If the subject requires corticosteroid dosing for related toxicities, talimogene 
laherparepvec treatment must be withheld until the corticosteroid dose has 
decreased to doses acceptable for maintenance physiologic replacement 
• 
Subjects who are receiving talimogene laherparepvec may not receive systemic 
antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir), but may receive a 
topically administered antiherpetic drug more than 20 cm from a talimogene 
laherparepvec injection site with the exception of treatment for adverse events.  
• 
Childhood vaccinations that contain live attenuated virus 
If a subject undergoes any unexpected surgery during the course of the study, all study 
treatments must be withheld and the investigator or designee should notify the sponsor’s 
medical monitor as soon as possible.  Re-exposure to talimogene laherparepvec may 
occur only if the investigator and sponsor agree that the subject safety will not be 
compromised.  
Subjects in the safety follow-up period who have not demonstrated confirmed disease 
progression, rapid clinical deterioration, clinical progression, or intolerance to 
talimogene laherparepvec may not receive any experimental or approved antitumor 
therapies unless the sponsor’s medical monitor is consulted and approved. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
For Schedule of Assessments please refer to Table 3. 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 47 of 99 
CONFIDENTIAL 
 
 
Table 3.  Schedule of Assessments 
Period 
Screening  
(≤ 28 days) 
Treatmenta, d 
Safety 
Follow-upb 
Long-term 
Follow-upc 
Week 
 
1 
2 
4 
5 
6 
8 
10 
12 14 
16 
18 
20 
22 
24 
26 
28 
30 
32d 
 
Every 12 
weeks 
Talimogene 
Laherparepvec Cycle 
 
1 
1 
1 
2 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Day 
 
1 
2 
8 
22 
23 
29 
36 
50 
64 
78 92 106 
120 134 148 162 176 190 
204 218 
 
 
General Assessmentsd 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical, 
surgical and medication 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Vital signse 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance statusf 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Recording of 
concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of adverse 
events, disease-related 
events and serious 
adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
Survival assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 1 of 3 
Footnotes defined on last page of the table. 
 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 48 of 99 
CONFIDENTIAL 
 
 
Table 3.  Schedule of Assessments 
Period 
Screening 
(≤ 28 days) 
Treatmenta 
Safety 
Follow-upb 
Long-term 
Follow-upc 
Week 
 
1 
2 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32d 
 
Every 12 
weeks 
Treatment Cycle 
 
1 
1 
1 
2 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Day 
 
1 
2 
8 
22 
23 
29 
36 
50 
64 
78 
92 
106 120 
134 
148 162 
176 190 
204 
218 
 
 
Local Laboratory Tests 
Chemistryd 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematologyd 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hepatitis B surface 
antigen and Hepatitis 
B core antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C virus 
antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT or INR and PTT 
or aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testi 
 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Central Laboratory Tests 
Blood for HSV 
serostatusk 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Page 2 of 3 
Footnotes defined on last page of the table. 
 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 49 of 99 
CONFIDENTIAL 
 
 
Table 3.  Schedule of Assessments 
Period 
Screening 
(≤ 28 days) 
Treatmenta 
Safety 
Follow-upb 
Long-term 
Follow-upc 
Week 
 
1 
2 
4 
5 
6 
8 
10 12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32d 
 
Every 12 
weeks 
Talimogene 
Laherparepvec Cycle 
 
1 
1 
1 
2 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Day 
 
1 
2 
8 
22 
23 
29 
36 
50 
64 78 
92 106 120 
134 148 162 
176 190 
204 
218 
 
 
Radiographic Tumor/Response Assessmentsd 
Radiographic scans 
(± 7 days; appropriate to 
tumor)s  
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Xt 
Clinical tumor assessmentu 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Tumor markers (if clinically 
applicable)v 
X 
To be performed to confirm a suspected complete response, if elevated at baseline 
 X 
X 
Treatment Administration 
Talimogene laherparepvec 
administration 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xw 
 
 
Reporting Exposure to Talimogene Laherparepvec 
Exposure of subject's 
household member or 
caregiverd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Exposure of subject's 
healthcare providerx, d 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Page 3 of 3 
Footnotes defined on next page. 
 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 50 of 99 
CONFIDENTIAL 
 
 
ECG = electrocardiogram; HSV = herpes simplex virus; qPCR = real-time polymerase chain reaction; aPTT = activated partial thromboplastin time; CR = complete 
response; INR = international normalization ratio; irRC-RECIST = immune-related response criteria simulating Response Evaluation Criteria in Solid Tumors; PT = 
prothrombin time; PTT = partial thromboplastin time; 
; ULN = upper limit of normal  
a Treatment visits continue until the subject has achieved a complete response, all injectable tumors have disappeared, confirmed progressive disease per modified 
irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or need for alternative anticancer therapy, 
whichever occurs first.  
b Approximately 30 (+ 7) days after the last dose of study treatment. 
c Subjects will be followed for survival and use of subsequent anticancer therapies every 12 weeks (± 28 days) from the safety follow-up visit until death, subject or 
legally acceptable representative withdraws full consent/assent, or up to approximately 24 months after the last subject is enrolled in the study, whichever occurs first. 
d Subjects undergoing talimogene laherparepvec treatment beyond week 32 should continue general study assessments and local laboratory tests until the end of 
treatment (vital signs, recording of concomitant medications and review of adverse events, disease-related events and serious adverse events, 
 
, physical exam, body weight and performance status every fourth cycle and chemistry and hematology every second cycle).  Exposure of 
subject's household member or caregiver and healthcare provider should continue to be checked at every cycle. 
e Vital signs (blood pressure, heart rate, respiration rate, and temperature) to be collected predose. 
f Karnofsky performance status will be used for subjects aged 12 to ≤ 21 years; Lansky play scale will be used for subjects aged 2 to < 12 years.  
g Only anticancer therapies will be collected/recorded every 12 weeks during the long-term follow-up.   
h Talimogene laherparepvec related adverse events. 
i Female subjects of childbearing potential only.  A female is considered of childbearing potential (ie, fertile), following menarche and until becoming post-menopausal 
unless permanently sterilized.  Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
j To be performed within 72 hours prior to dosing.   
k Blood sample for HSV serostatus will be performed at a local laboratory at screening and at a central laboratory thereafter. 
 
 
 
m Blood draw for real-time polymerase chain reaction (qPCR) testing of talimogene laherparepvec DNA will be performed at the following time points:   
• 
day 1 (prior to and approximately 1 hour [± 15 minutes] and 4 hours [± 30 minutes] after talimogene laherparepvec administration), day 2 approximately 
24 hours [± 30 minutes] after talimogene laherparepvec administration, day 8 (± 2 days), day 22 (prior to and approximately 1 hour [± 15 minutes] and 4 hours 
[± 30 minutes] after talimogene laherparepvec administration), day 23 approximately 24 hours [± 30 minutes] after talimogene laherparepvec administration, 
day 29 (± 2 days), day 36 (± 2 days) prior to dosing, and day 50 (± 2 days) prior to dosing.  
 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020 
Page 51 of 99 
CONFIDENTIAL 
 
 
s Radiologic imaging of all sites of disease must be performed (including imaging of the brain when clinically indicated).  For subjects remaining on treatment with 
talimogene laherparepvec beyond week 32, radiologic imaging should continue every 12 weeks until confirmed progressive disease per modified irRC-RECIST or start 
of new anticancer treatment.  All study imaging should be performed according to the calendar and not adjusted for any cycle initiation delays.  
t Subjects who are in complete response and no longer have injectable lesions will enter the 30-day safety follow-up and continue to have tumor assessments every 
12 weeks for up to 24 months.   
u For subjects with metastatic melanoma, clinical tumor assessments, including clinical measurements of cutaneous, subcutaneous, or nodal measurement by caliper 
should be measured at baseline assessment, as well as subsequent scheduled tumor assessments.  Measurements should continue every 12 weeks until confirmed 
progressive disease per modified irRC-RECIST or start of new anticancer treatment.   
v Clinically applicable tumor markers appropriate for the tumor type include, but are not limited to, serum alpha fetoprotein, serum beta human chorionic gonadotropin 
and urine for homovanillic acid/vanillylmandelic acid.  Tumor marker measurement is required to confirm CR if screening level of tumor marker was above the ULN and 
criteria for CR per modified irRC-RECIST guidelines are met.  
w Treatment may continue for up to 24 months depending on response to and tolerance of talimogene laherparepvec. 
x If applicable. 
 
 
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Refer to the applicable supplemental (eg, laboratory, imaging) manuals for detailed 
collection and handling procedures. 
7.2 
General Study Procedures  
A signed and dated IRB/IEC-approved informed consent/assent must be obtained before 
any study-specific procedures are performed.  
Procedures that are part of routine care are not considered study-specific procedures 
and may be used at screening to determine eligibility.  All subjects will be screened for 
eligibility before enrollment.  Only eligible subjects will be enrolled into the study.  During 
treatment, assessments and procedures can be performed within 3 days of the planned 
visit unless specified in the study procedures.  It is recommended that dosing occur on 
the same day of the week when possible (eg, if first dose is administered on Monday, all 
subsequent doses should be administered on a Monday).  
7.2.1 
Screening and Enrollment  
Screening procedures are to be completed during the screening period within 28 days 
prior to enrollment.  Subjects who do not meet all eligibility criteria may be rescreened 
once at the discretion of the investigator. 
The time points for the procedures to be completed during the screening period are 
designated in the Schedule of Assessments (Table 3). 
7.2.2 
Treatment  
Treatment begins when the first dose of protocol-required therapy is administered to a 
subject.  Study treatment should begin as soon as possible after enrollment via the IRT 
system but no later than 5 days after enrollment.   
Administration of protocol-required therapies is to be performed after all other required 
procedures are completed during each visit, unless otherwise stated.  Upon permanent 
discontinuation from study treatment for any reason, a safety follow-up visit will be 
performed approximately 30 (+ 7) days after the last dose of talimogene laherparepvec.  
The time points for the procedures to be completed during the treatment period are 
designated in the Schedule of Assessments (Table 3).   
7.2.3 
Follow-Up 
7.2.3.1 
Safety Follow-up Visit 
All subjects will complete a safety follow-up visit approximately 30 (+ 7) days after the 
last dose of study treatment.  The time points for the procedures to be completed during 
the safety follow-up period are designated in the Schedule of Assessments (Table 3).   
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7.2.3.2 
Long-term Follow-up 
After the safety follow-up visit all subjects will enter the long-term follow-up.  Subjects will 
be asked to come for a clinic visit or contacted by telephone to assess survival and 
initiation of additional anticancer therapy.   
Contact for all subjects will be attempted every 12 weeks (± 28 days) following the safety 
follow-up visit until death, subject or legally acceptable representative withdraws full 
consent/assent, or up to approximately 24 months after the last subject is enrolled in the 
study, whichever comes first.  During long-term follow-up concomitant medications 
recording is to be restricted to anticancer therapy and safety reporting will be limited to 
talimogene laherparepvec related adverse events.  
For subjects who discontinued treatment for any reason other than confirmed PD, every 
effort should be made to perform radiographic scan for tumor assessments every 
12 weeks until documentation of confirmed PD per modified irRC-RECIST, start of new 
anticancer therapy, or end of study, whichever occurs first. 
7.3 
Description of Study Procedures 
7.3.1 
Informed Consent/Assent 
All subjects or legally acceptable representative must sign and personally date the 
IRB/IEC approved informed consent/assent and provide subject assent if appropriate 
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’s safety and treatment effectiveness.  
7.3.3 
Medical and Surgical History 
Complete medical and surgical history will be collected.  Medical history will include 
information on the subject’s concurrent medical conditions.  The current toxicity grade 
and severity will be collected for each condition that has not resolved.  Record all 
findings on the medical history CRF. 
7.3.4 
Medication History 
Therapy name, indication, dose, unit, frequency, and start and stop date will be collected 
for prior therapies taken for current or prior malignancies. 
7.3.5 
Physical Examination 
A physical examination per standard of care will be performed.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
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7.3.6 
Physical Measurement 
Height in centimeters and weight in kilograms should be measured. 
7.3.7 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed per standard of care.  The ECG 
must include the following measurements: heart rate, PR interval, QRS, QT and QT 
interval corrected for heart rate using accepted methodology (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. 
7.3.8 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, temperature.  Subject must be in a supine position in a rested and 
calm state for at least 5 minutes before blood pressure assessments are conducted.  If 
the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF.  Record all 
measurements on the vital signs CRF. 
7.3.9 
Performance Status 
Karnofsky performance status will be used for subjects 12 to ≤ 21 years of age and 
Lansky play scale will be used for subjects 2 to < 12 years of age (Appendix E). 
7.3.10 
Adverse Events and Disease-related Events 
Adverse events and disease-related events observed by the investigator or reported by 
the subject will be collected as per Section 9. 
7.3.11 
Concomitant Medications 
Concomitant therapies are to be collected from informed consent to 30 (+7) days 
following cessation of treatment.  For all concomitant therapies (including those being 
taken for the current malignancy) therapy name, indication, dose, unit, frequency and 
start and stop date will be collected (see Section 6.5).  Only anticancer therapies will be 
collected/recorded every 12 weeks during the long term follow up. 
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7.3.13 
Radiographic Assessment 
Radiologic imaging of all sites of disease must be performed (including imaging of the 
brain when clinically indicated).  The choice of imaging modality(ies) for tumor 
assessment should be tailored according to what is appropriate for the tumor type being 
assessed (eg, computed tomography [CT] or MRI of the primary tumor and CT of the 
chest may be sufficient for subjects with primary osteosarcoma whereas CT/MRI of the 
primary tumor as well as metastatic site[s], bone scan, and metaiodobenzylguanidine 
scan may be appropriate in subjects with neuroblastoma).  All subsequent tumor 
assessments should include at least the same imaging modality(ies) and equipment as 
in baseline.  Assessment of tumor response will be performed according to modified 
irRC-RECIST (Appendix D).  Response (CR or partial response [PR]) or PD is to be 
confirmed by a second consecutive clinical and radiographic assessment no less than 
4 weeks from the date of the first documented response or PD. 
7.3.14 
Clinical Tumor Assessment 
For subjects with metastatic melanoma, clinical tumor assessments, including clinical 
measurements of cutaneous, subcutaneous, or nodal measurement by caliper should be 
measured at baseline assessment, as well as subsequent scheduled tumor 
assessments. 
Clinically applicable tumor markers appropriate for the tumor type include, but are not 
limited to, serum alpha fetoprotein and serum beta human chorionic gonadotropin and 
urine for homovanillic acid/vanillylmandelic acid.  Tumor marker measurement is 
required to confirm CR if screening level of tumor marker was above the ULN and 
criteria for CR per modified irRC-RECIST guidelines are met. 
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7.3.16 
Reporting Potential or Known Unintended Exposure to Talimogene 
Laherparepvec 
If a household member, caregiver, or healthcare provider who has had close contact 
with the subject is suspected to have been exposed to talimogene laherparepvec 
(eg, has signs or symptoms suspected to be herpetic in origin or is accidentally exposed 
to talimogene laherparepvec), report to Amgen the potential or known unintended 
exposure to talimogene laherparepvec, suspected related signs or symptoms, and 
detection of talimogene laherparepvec DNA by qPCR testing in a swab taken from a 
lesion, if any, in subject’s household member, caregiver, or healthcare provider. 
7.4 
Laboratory Assessments 
The following screening and on-study laboratory samples will be processed in local lab: 
hematology panel, chemistry panel, screening hepatitis B surface antigen and hepatitis 
B core antibody, screening hepatitis C virus antibody, screening coagulation tests, urine 
pregnancy test, clinically applicable tumor markers, and the screening HSV serostatus.   
The central laboratory will be responsible for on-study testing of HSV serostatus (week 6 
and safety follow-up), 
 
 
 
 
 
 
.   
Specific analytes for serum chemistry, coagulation hematology, and other labs to be 
conducted on blood and urine samples are presented in Table 4. 
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Table 4.  Laboratory Analytes 
Chemistry 
Coagulation 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium 
Magnesium 
Phosphorus 
Total protein 
Albumin 
Blood urea nitrogen or 
urea 
Creatininea 
Total bilirubinb 
ALP 
AST 
ALT 
Glucose 
PT or INR 
PTT or aPTT 
Red blood cell 
Hemoglobin 
Hematocrit 
Platelets 
White blood cell 
differential 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Pregnancy test (urine) 
qPCR for talimogene 
laherparepvec DNA 
 
Hepatitis C virus antibody 
Hepatitis B surface antigen 
and hepatitis B core antibody 
 
Blood for HSV serostatus 
Applicable tumor markersc 
ALP = alkaline phosphatase; AST = aspartate aminotransferase; ALT = alanine aminotransferase; 
HSV = herpes simplex virus; INR = international normalization ratio; PT = prothrombin time; 
PTT/aPTT = partial thromboplastin time/activated partial thromboplastin time; qPCR = real time polymerase 
chain reaction; 
; ULN = upper limit of normal  
a Creatinine clearance should be determined per institutional standard.  Creatinine clearance need not be 
determined if the baseline serum creatinine is within normal limits per protocol.  
b Direct bilirubin should be measured at screening if total bilirubin is > 1.5x ULN for age. 
c Clinically applicable tumor markers appropriate for the tumor type include, but are not limited to, serum 
alpha fetoprotein, serum beta human chorionic gonadotropin and urine for homovanillic acid/vanillylmandelic 
acid. 
7.5 
Sample Storage and Destruction  
Any blood or tumor sample collected according to the Schedule of Assessments 
(Table 3) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
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. 
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If informed consent/assent 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.  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of biomarker development or other exploratory studies are 
not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent/assent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood or tumor samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects (or a legally acceptable representative) 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. 
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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 (or a legally acceptable representative) the 
appropriate processes for discontinuation from investigational product or other 
protocol-required therapies and must discuss with the subject (or a legally acceptable 
representative) the options for continuation of the Schedule of Assessments (Table 3) 
and collection of data, including endpoints and adverse events.  The investigator must 
document the change to the Schedule of Assessments (Table 3) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, 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. 
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 (or a legally acceptable representative) request 
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy, other 
protocol-specified criteria) 
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• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
• 
disease progression (confirmed PD per modified irRC-RECIST or clinical 
progression) 
• 
other protocol-specified criteria (Section 6.2.1.2.3)  
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent/assent 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 or if the investigator believes that the 
event is related to the investigational product(s), study treatment, or protocol required 
therapies.  Further, any disease-related event which meets any of the seriousness 
criteria in Section 9.1.3 should be recorded as a Serious Disease-related Event and 
reported to the sponsor or designee within 24 hours.  
Note:  For situations where disease-related events are due to squamous cell cancer of 
the head and neck (SCCHN), the primary tumor type (eg, metastatic SCCHN) should be 
used, rather than the term “disease progression”. 
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 
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(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.  For situations when an adverse event or serious 
adverse event is due to advanced non-CNS tumors, report all known signs and 
symptoms.  Death due to disease progression in the absence of signs and symptoms 
should be reported as the primary tumor type (eg, metastatic sarcoma).  
Note:  The term “disease progression” should not be used to describe the 
disease-related event or adverse event.   
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative, requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.3 
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  
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a subject 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,  
• 
and the event meets at least 1 of the serious criteria above. 
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An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include a new cancer that is not a condition of the study, events associated with an 
overdose, allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A 
for DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
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 recorded using 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 
• 
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.  The investigator is 
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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 adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity (and/or toxicity per protocol), 
• 
Assessment of relatedness to talimogene laherparepvec and, 
• 
Action taken. 
The adverse event grading scale used will be the 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/assent through 30 (+7) days after the last dose of talimogene laherparepvec are 
recorded in the subject’s medical record and are submitted to Amgen.  All serious 
adverse events must be submitted to Amgen within 24 hours following the investigator’s 
knowledge of the event via the Event CRF.  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. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet /electronic Serious Adverse Event Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the eSerious Adverse Event Contingency Report Form, the data must be entered into 
the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
any study mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
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Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and Good 
Clinical Practice (GCP).  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes.  
9.2.2.3 
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.  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 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 pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies, report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
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).   
If a lactation case occurs while the female subject is taking protocol-required therapies, 
report the lactation case to Amgen as specified below.  
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In addition to reporting a lactation case during the study, investigators should monitor 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). 
9.4 
Reporting of Exposure to Talimogene Laherparepvec 
If a household member, caregiver, or healthcare provider who has had close contact 
with a subject treated with talimogene laherparepvec on this study is suspected to have 
been exposed to talimogene laherparepvec (eg, have or who have had signs or 
symptoms suspected to be herpetic in origin or who have been accidentally exposed to 
talimogene laherparepvec), while the subject is taking talimogene laherparepvec, report 
the exposure to Amgen as specified below.  In addition to reporting an unintended 
exposure case during the study treatment, investigators should monitor for potential 
exposure cases that occur after the last dose of talimogene laherparepvec through 
30 (+ 7) days after the last dose of talimogene laherparepvec.  
Any potential or known unintended exposure should be reported to Amgen within 
24 hours of the investigator’s knowledge of the event of exposure.  Amgen will seek to 
follow-up with the exposed individual, if necessary, to collect more information about the 
exposed individual contact with clinical trial subject, signs and/or symptoms related to 
the exposure, medical history, and/or outcome of the exposure.  If the exposed individual 
is reporting sign or symptoms suspected to be related to talimogene laherparepvec 
exposure, the exposed individual may be asked to have a swab taken to evaluate for the 
presence of talimogene laherparepvec DNA in the lesion. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
Subject incidence of DLTs 
10.1.1.2 
Secondary Endpoints 
• 
ORR, DOR, TTR, TTP, and PFS using modified irRC-RECIST 
• 
OS 
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10.1.1.3 
Safety Endpoint 
• 
Subject incidence of adverse events and significant laboratory abnormalities 
10.1.1.4 
Exploratory Endpoints 
10.1.2 
Analysis Sets 
10.1.2.1 
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 
and received at least 2 treatments of talimogene laherparepvec (except subjects who 
had a DLT after the first dose).  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). 
10.1.2.2 
Safety Analysis Set 
The safety analysis set will include all subjects who received at least 1 dose of 
talimogene laherparepvec.   
10.1.3 
Covariates  
The following covariates may be used to examine clinical activity in subgroups or in 
multivariate analysis.   
• 
Age at baseline (12 to ≤ 21 versus 2 to < 12 years of age) 
• 
Sex (female versus male) 
• 
HSV-1 baseline serostatus (positive versus negative) 
• 
Baseline sum of largest diameter of target lesions 
• 
Extent of disease (localized versus metastatic) 
• 
Performance status (Karnofsky/Lansky play scale [70% versus > 70%])  
• 
Prior lines of therapy in the recurrent/metastatic setting (0,1, 2, > 2) 
• 
Prior surgery for current malignancy (yes versus no) 
• 
Prior radiotherapy for current malignancy (yes versus no) 
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• 
Complete surgical resection of all gross diseases (yes versus no) 
• 
Other covariates reported in the literature or from other Amgen studies maybe 
considered in the analysis as appropriate at the time of analysis. 
10.2 
Sample Size Considerations 
The sample size of 18 to 24 subjects will be enrolled and treated with at least 
1 dose of talimogene laherparepvec including at least 9 DLT-evaluable subjects in 
cohort A1.  For age cohort opening and dose de-escalation, criteria from 3+3 
phase 1 design assuming a true DLT incidence rate < 33% is used.  Sample size for 
cohorts with age between 2 and 12 years are not required. 
A dose level will be considered safe for a cohort if < 33% of all DLT-evaluable subjects in 
a given cohort experiences a DLT (minimum 6 DLT-evaluable subjects).  Table 5 and 
Figure 1 presents the probability of declaring a dose level safe (unsafe) for a range of 
true DLT rates for the protocol therapy based on 6 DLT-evaluable subject (see triangle 
symbols in Figure 1).  For example, the probability of declaring a dose level safe 
(unsafe) is 89% (11%), 42% (58%), and 11% (89%) if the true DLT rate is 10%, 30%, or 
50%, respectively.  
Table 5.  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% 
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Figure 1.  Probability of Declaring a Cohort Safe (Unsafe) 
 
DLT = dose-limiting toxicity 
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.  Subjects may continue 
treatment during the interim safety analyses. 
10.3.2 
Dose Level Review Team (DLRT) 
An interim safety analysis is planned after the first 3 DLT-evaluable subjects for each 
cohort.  A DLRT consisting of the Amgen study team, including at least 1 medical 
monitor, 1 safety representative, and 1 biostatistician, and at least 1 participating 
investigator who has recruited subjects into this study, will review the safety data to 
evaluate possible DLTs. 
Based on the DLT evaluation rules in Section 6.2.1.2, the DLRT will recommend whether 
to continue the dose for 3 additional DLT-evaluable subjects in the cohort and if 
applicable, whether the younger age cohort can be opened for enrollment.  Subsequent 
safety analyses are planned for: (a) every addition of 3 new DLT-evaluable subjects in a 
cohort until there are 9 DLT-evaluable subjects in the cohort; (b) if there have been 
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≥ 33% DLT rate in the cohort since the last safety analysis; (c) at the occurrence of the 
first DLT in either cohort.  Based on the DLT evaluation rules and safety analyses, the 
DLRT will make recommendation on dose de-escalation, enrollment halt, the opening or 
re-opening of the cohort(s) for enrollment and/or the starting dose for the cohort(s).  If 
deemed necessary, ad-hoc meetings to review the safety data can be convened 
anytime by the DLRT.   
10.3.3 
Primary Analysis 
The clinical study report will be written based on the results of the primary analysis.  The 
primary analysis will occur 35 days after the last subject has enrolled and received at 
least 1 dose of talimogene laherparepvec.  
10.3.4 
Final Analysis  
The final analysis will occur when all the subjects have discontinued the study treatment 
and have had the opportunity to complete the long-term follow-up visit.  A separate 
clinical study report will be written with the updated results from the final analysis at the 
completion of the study. 
10.4 
Planned Methods of Analysis  
The data will be analyzed by cohort and in the overall population.  Descriptive statistics 
will be provided for demographic, safety, efficacy and exploratory endpoints.  
10.4.1 
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.  
The efficacy analysis will be conducted using the safety analysis set unless otherwise 
specified. 
10.4.2 
Secondary Endpoints 
Efficacy Endpoints: 
ORR, DOR, TTR, TTP, PFS, and OS will be summarized in the overall population.  ORR 
will be summarized with an associated exact 95% CI using the safety analysis set and 
excluding subjects without baseline measurable disease, if applicable.  DOR among 
responders, TTR, TTP, PFS and OS will be estimated using the Kaplan-Meier method.   
Safety Endpoints 
Subject incidence of treatment-emergent and treatment-related adverse events will be 
summarized.  Treatment-emergent adverse events are defined as any adverse 
event occurring after first dose through 30 days after last dose of talimogene 
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laherparepvec.  Treatment-related adverse events are defined as 
treatment-emergent adverse events which are considered to be related to the 
treatment of talimogene laherparepvec, as determined by the investigator.  Medical 
Dictionary for Regulatory Activities (MedDRA) will be used to code adverse events to a 
system organ class (SOC) and a preferred term within the SOC.  The CTCAE version 
4.0 will be used to grade severity of adverse events.  In addition, clinically significant 
laboratory changes and clinically significant changes in vital signs will be summarized 
with descriptive statistics.   
Subject incidence of all disease-related events, fatal disease-related events, serious 
disease-related events, and disease-related events leading to withdrawal from study 
drug will be provided. 
A summary of deaths after initiation of the study through 30 days since the last dose of 
talimogene laherparepvec will be provided.   
Summary statistics will also be provided for concomitant medications, dose delay, study 
drug discontinuation, overall exposure, and Karnofsky performance status and Lansky 
play scale.  
Potential or known unintended exposure to talimogene laherparepvec, related suspected 
signs or symptoms, and detection of exposure to talimogene laherparepvec in a 
subject’s household member, caregiver, or healthcare provider will be reported. 
Summary statistics will be provided for vital signs, physical measurements and 
laboratory data.  Details of the analysis will be provided in statistical analysis plan. 
10.4.3 
Exploratory Endpoints 
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10.5 
Handling of Missing and Incomplete Data 
Partial or missing dates of adverse events and concomitant medications will be imputed.  
Adverse events with missing severity and/or possible relationship to talimogene 
laherparepvec will be included in the all adverse events analyses, except by severity 
grade and treatment-related.  Every effort will be made to obtain complete dates for 
deaths.  Details of the imputation algorithms will be specified in the study-specific 
statistical analysis plan. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent/Assent 
An initial sample informed consent/assent form is provided for the investigator to prepare 
the informed consent/assent 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/assent 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/assent from the subject or legally authorized 
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.   
The investigator is also responsible for asking the subject (or a legally acceptable 
representative) 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.   
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The acquisition of informed consent/assent and the subject’s or legally acceptable 
representative 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/assent 
form is to be signed and personally dated by the subject or legally acceptable 
representative by the person who conducted the informed consent/assent discussion.  
The original signed informed consent/assent form is to be retained in accordance with 
institutional policy, and a copy of the signed consent/assent form is to be provided to the 
subject or legally acceptable representative. 
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/assent form to the subject and must allow for questions.  Thereafter, 
both the subject and the witness must sign the informed consent/assent form to attest 
that informed consent/assent was freely given and understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent/assent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed 
consent/assent form must be received by Amgen before recruitment of subjects into the 
study and shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent/assent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
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• 
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/assent 
forms) are to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/ International Council for Harmonisation (ICH) 
GCP Guidelines, it is required that the investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and the IRB/IEC direct 
access to review the subject’s original medical records for verification of study-related 
procedures and data.  Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  
The investigator is obligated to inform and obtain the consent/assent 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 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.   
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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. 
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 IRT system captures the following data points and these are 
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/assent forms, and 
subject identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
• 
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. 
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Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen Clinical Monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global R&D Compliance Auditing Function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  
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. 
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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 3), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
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 encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Recommendations for the Conduct, Reporting, Editing, and Publication of  
Scholarly Work in Medical Journals (International Committee of Medical Journal Editors, 
2013, updated 2014), which states: 
• 
Authorship credit should 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, 
and 3. 
• 
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 fully meet the criteria for authorship defined above. 
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• 
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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Daw NC, Chou AJ, Jaffe N, et al. Recurrent osteosarcoma with a single pulmonary 
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of EUROCARE-5--a population-based study.  Lancet Oncol. 2014;15(1):35-47. 
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McTiernan AM, Cassoni AM, Driver D, et al. Improving Outcomes After Relapse in 
Ewing's Sarcoma: Analysis of 114 Patients From a Single Institution.  Sarcoma 2006; 
83548.  Epub 2006 Nov 6. 
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR.  The measurement of 
performance in childhood cancer patients.  Cancer. 1987 Oct 1;60(7):1651-1656. 
Magrath I, Steliarova-Foucher E, Epelman S, et al.  Paediatric cancer in low-income and 
middle-income countries.  Lancet Oncol.  2013 Mar;14(3):e104-16. 
Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS.  Optimizing immune-related 
tumor response assessment:  does reducing the number of lesions impact response 
assessment in melanoma patients treated with ipilimumab.  J Immunother Cancer.  
2014;2(17);1-12. 
Pui C, Gajjar AJ, Kane, JR, et al.  Challenging issues in pediatric oncology.  Nat Rev 
Clin Oncol.  2011;8(9):540-549. 
Schag CC, Heinrich RL, Ganz PA.  Karnofsky performance status revisited: reliability, 
validity, and guidelines.  J Clin Oncol. 1984 Mar;2(3):187-93. 
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Siegel DA, King J, Tai E, Buchanan N, Ajani UA, Li J.  Cancer incidence rates and 
trends among children and adolescents in the United States, 2001-2009.  Pediatrics. 
2014 Oct;134(4):e945-55. 
Spunt SL, Hill A, Motosue AM, et al. Clinical Features and Outcome of Initially 
Unresected Nonmetastatic Pediatric Nonrhabdomyosarcoma Soft Tissue Sarcoma.  
J Clin Oncol 2002;20(15):3225-3235. 
Steliarova-Foucher E, Stiller C, Kaatsch P, et al. Geographical patterns and time trends 
of cancer incidence and survival among children and adolescents in Europe since the 
1970s (the ACCISproject): an epidemiological study.  Lancet. 2004;364(9451):2097-
2105. 
Talimogene laherparepvec Investigator’s Brochure.  Woburn, MA. BioVEX (a wholly 
owned subsidiary of Amgen). 
Waters AM, Friedman GK, Ring EK, Beierle EA.  Oncolytic virotherapy for pediatric 
malignancies: future prospects.  Oncolytic Virother.  2016;5:73-80.  
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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 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of Drug-Induced Liver Injury (DILI), cases 
of concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and 
total bilirubin and/or international normalization ratio (INR) elevation according to the 
criteria specified in Section 6.4 require the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate case report form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) is/are withheld (either permanently or 
conditionally) due to potential DILI as specified in Section 6.4.1 and Section 6.4.2 or who 
experience AST or ALT elevations > 3 x upper limit of normal (ULN) for age are to 
undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include:  
• 
Repeat AST, ALT, alkaline phosphatase (ALP), bilirubin (total and direct), and INR 
within 24 hours  
• 
In cases of total bilirubin > 2x ULN for age or INR > 1.5, retesting of liver tests, 
bilirubin (total and direct), and INR is to be performed every 24 hours until laboratory 
abnormalities improve 
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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
total bilirubin: 
− 
Obtain complete blood count with differential to assess for eosinophilia 
− 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody, Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 to assess for 
autoimmune hepatitis 
− 
Obtain serum acetaminophen (paracetamol) levels 
− 
Obtain a more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special 
diets 
o Concomitant use of medications (including non-prescription medicines 
and herbal and dietary supplements), plants, and mushrooms 
− 
Obtain viral serologies 
− 
Obtain creatine phosphokinase, haptoglobin, lactate dehydrogenase, and 
peripheral blood smear 
− 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, total bilirubin, INR) until all 
laboratory abnormalities return to baseline or normal.  The “close observation period” 
is to continue for a minimum of 30 [+7] days (4 weeks) after discontinuation of all 
investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
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Appendix B.  Electronic Adverse Event Contingency Report Form 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Appendix D.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response 
Note:  Immune-related Response Criteria (irRC) simulating Response Evaluation Criteria 
in Solid Tumors version (RECIST) version 1.1 [irRC-RECIST] defined by Nishino et al, 
2014, with modification will be employed to account for unique tumor response 
characteristics observed with immunotherapies to enable treatment beyond progression, 
if the subject is clinically stable. 
Method of Measurement of Tumor Lesions: 
Computed tomography scans (or magnetic resonance imaging [MRI]):  
Computed tomography (CT) scans by contrast-enhanced or spiral scan (or magnetic 
resonance imaging [MRI] scan) will be performed to evaluate tumor response for visceral 
or nodal/soft tissue disease (including lymph nodes).  Measurability of lesions on CT 
scan is based on the assumption that CT slice thickness is 5 mm or less.  Scan slices 
should ideally be 3 to 5 mm.  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 noncontrast CT or to MRI (or vice versa) should 
not preclude response assessment if, in the judgment of the site radiologist, there is no 
significant difference in the assessment by changing modalities.  This may occur if a 
subject has developed a medical contraindication to intravenous contrast for CT scans 
while on trial.  This change would require the preapproval of the sponsor medical 
monitor. 
Positron Emission Tomography (PET)/CT Scans:   
If a combined PET/CT scan is performed at the discretion of the investigator, the CT 
portion of that exam should not be substituted for the dedicated CT exams required by 
this protocol.  The PET portion of the CT may introduce additional data which may bias 
the investigator assessment of response if it is not routinely or serially performed.  
However, if the investigator or the site radiologist can document that the CT performed 
as part of a PET/CT is of identical 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.  
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Clinical lesion measurements: 
Clinical lesions will only be considered measurable when they are superficial and 
> 10 mm diameter as assessed using calipers (eg, skin nodules).  For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the 
lesion is suggested.  As noted above, when lesions can be evaluated by both clinical 
exam and imaging, imaging evaluation should be undertaken since it is more objective 
and may also be reviewed at the end of the study 
Ultrasound:  
Ultrasound should not be used as a primary method to assess lesion measurements in 
response to treatment.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. 
At baseline, lesions are categorized as measurable or non-measurable according to the 
following definitions: 
Measurable Lesions: 
Measurable lesions are defined at baseline as lesions that can be accurately measured 
in at least one dimension (ie, longest diameter for non-nodal lesions and short axis for 
lymph nodes will be measured and followed) with a minimum size of: 
• 
≥ 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI  
• 
≥ 10 mm caliper measurement by clinical exam for superficial cutaneous or 
subcutaneous melanoma lesion as measured by caliper  
• 
A lymph node must be ≥ 15 mm in short axis when assessed by CT scan or MRI. 
Target lesions must not be chosen from a previously irradiated field unless there has 
been documented tumor progression in that field prior to enrollment.  The distribution of 
the target lesions should be representative of the subject’s overall disease (eg, largest 
lesions per organ). 
Non-Measurable Lesions: 
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 mm but < 15 mm short axis) and other truly non-measurable 
lesions are considered non-measurable and characterized as non-target lesions.  This 
will include any measurable lesions beyond the maximum number of 10 total or 5 per 
organ at each time point that were not chosen as target lesions.  Only cancerous lesions 
should be selected as non-measurable lesions and not indeterminate lesions and lesions 
that could be cancer.  Other examples of non-measurable lesions include some bone 
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lesions*, leptomeningeal disease, inflammatory breast disease, lymphangitic 
involvement of the skin or (lymphangitis cutis/pulmonis), and groups of lesions that are 
small and numerous. 
Fluid Collections 
Ascites, pleural effusion, or pericardial effusion should not be selected as 
non-measurable disease at baseline or, if new or increased, as evidence of progressive 
disease (PD).  These collections may occur with both benign and malignant conditions, 
and their etiology is often not clear.  These collections may be removed via 
interventional procedures, which can lead to a false interpretation of disease response.  
These fluid collections should not be used as a baseline non-target lesions or as 
evidence of disease response. 
* Bone Lesions: 
• 
Bone scans, PET scans or plain films are not considered adequate imaging 
techniques to measures bone lesions.  However, these techniques can be used 
to confirm the presence or absence of bone lesions. 
• 
Osteolytic (lytic) bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross-sectional imaging technique 
such as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above.  Only the soft 
tissue component of the bone lesion should be measured. 
• 
Many osteoblastic (blastic) bone abnormalities can be benign and should not be 
selected as baseline lesions.  An isolated new small blastic lesion should not be 
selected as a new lesion unless there is demonstrated growth on subsequent 
scans.  Multiple new blastic lesions that are clearly cancerous may be considered 
for new lesions. 
Cystic Lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable or non-measurable) 
since they are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same subject, these are 
preferred for selection as target lesions.  If a cystic lesion is clearly cancerous 
and has both cystic and solid components, then the complete lesion should be 
measured including both components without excluding the cystic portion of a 
cystic tumor lesion when measuring. 
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Lesions with Prior Local Treatment: 
Tumor lesions situated in a previously irradiated area, or an area subject to other 
loco-regional therapy, should not be considered measurable unless there has been 
demonstrated progression in the lesion. 
Baseline Documentation of “Target” and “Non-Target” Lesions: 
Baseline evaluations will be used to prospectively identify all sites of disease present as 
close as possible to the enrollment and never more than 4 weeks before the enrollment 
date.  Sites of disease will be characterized as either target or non-target lesions. 
Baseline Documentation of Target Lesions: 
Up to 10 target lesions (a maximum of 5 per organ) will be chosen to measure over the 
course of therapy.  Pathological lymph nodes that are defined as measurable must meet 
the criterion of a short axis of ≥ 15 mm by CT scan in order to be identified as target 
lesions.  
The distribution of these target lesions should be representative of the subject’s overall 
disease status.  Target lesions should be selected on the basis of their size (lesions with 
longest diameter) and suitability for accurate repeated measurements by imaging 
techniques.  In situations where larger lesions cannot be accurately measured 
repeatedly (eg, near the diaphragm where respiratory changes may affect 
measurements), smaller lesions that meet criteria for measurability may be selected 
instead. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  The 
baseline sum of diameters will be used as reference by which to characterize the 
objective tumor response.   
Baseline Documentation of Non-Target Lesions:  
All other lesions (or sites of disease), including any measurable lesions that were not 
chosen as target lesions and pathological lymph node with short axis ≥ 10 mm but 
< 15 mm, should be identified as non-target lesions.  Measurable non-target lesions 
(ie, lesions in an organ beyond the allowed maximum number of targets that would 
otherwise qualify as target lesions) should also be recorded and assessed qualitatively 
over the course of therapy.  Non-measurable non-target disease measurements are not 
required, but these lesions are evaluated at each timepoint and will be evaluated as 
‘present’, ‘absent’, or in rare cases ‘unequivocal progression’.   
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Follow-up Assessment of Tumor Lesions: 
At each subsequent tumor assessment, the sum of diameters of target lesions identified 
at baseline plus the sum of diameters of up to 10 (maximum 5 per organ) new 
measurable lesions per timepoint (for which the longest diameter is ≥ 10 mm for 
non-nodal lesions or the short axis is ≥ 15 mm for non-nodal lesions) are added together 
to provide the total tumor burden.  If more than 10 new measurable lesions total (or 5 per 
organ) at a given timepoint are present, the new measurable lesions should be selected 
on the basis of their size and suitability for accurate repeated measurements by imaging 
techniques (CT or MRI).  If there are lesions beyond the new measurable lesion limit 
during the course of the study for one subject, the additional lesions would be 
considered new non-measurable lesions. 
Tumor Burden = sum of diameter of target lesions + sum of diameter of new measurable 
lesions. 
Non-target disease measurements are not required and these lesions should be 
followed as “present”, “absent”, or “unequivocal progression”. 
For non-nodal target lesions that become too small to measure, a value of 5 mm will be 
assigned.  If the non-nodal lesion subsequently increases in size to greater than or equal 
to 5 mm in one dimension, its true size will be recorded.  If an actual measurement is 
able to be provided, this should be recorded even if it is <5 mm.  If it is in the opinion of 
the radiologist that the non-nodal lesion has likely disappeared, the measurement should 
be recorded as “0 mm”.  Nodal disease should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study.  
Response Evaluation: 
Evaluation of Objective Response: 
The subject response will be assessed based on tumor burden (the sum of diameters of 
target lesions plus the sum of up to 10 [maximum 5 per organ] new measurable lesions 
per timepoint), and, in the case of complete response (CR), the presence of any 
non-target and/or new non-measurable lesions.  The overall response is derived from 
timepoint response assessments as described in Table 6 and Table 7. 
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Table 6.  Definition of Measurable Tumor Response (Baseline Target and New, 
Measurable Lesions) 
Complete Response (CR): 
Disappearance of all lesions (whether measurable or not 
and whether baseline or new) and confirmation by a repeat, 
consecutive assessment no less than 4 weeks (28 days) 
from the date first documented.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm. 
Partial Response (PR): 
Decrease in tumor burdena ≥ 30% relative to baseline 
confirmed by a consecutive assessment at least 4 weeks 
(28 days) after first documentation  
Progressive Disease (PD): 
Increase in tumor burdena ≥ 20% and at least 5 mm absolute 
increase relative to nadir (minimum recorded tumor burden) 
confirmation by a repeat, consecutive assessment no less 
than 4 weeks (28 days) from the date first documented PD.  
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD. 
Unable to Evaluate (UE): 
Any lesion present at baseline which was not assessed or 
was unable to be evaluated leading to an inability to 
determine the status of that particular tumor for that time 
point. 
Not Applicable (NA) 
No target lesions were identified at baseline 
Not Done (ND) 
Radiographic imaging was not performed at this time point to 
evaluate the response of measurable lesions 
a Tumor Burden = sum of diameter of target lesions + sum of diameter of new measurable lesions.  
Diameters used: 
• 
For nodal disease, shortest axis 
• 
For non-nodal disease, longest diameters 
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Table 7.  Matrix for Determining the Overall Response at Each Assessment Point 
Measurable Response 
Non-measurable Response 
Overall 
Response 
Target and new, 
measurable lesions 
(tumor burden)a, % 
Non-target 
New, nonmeasurable 
lesions 
Using 
irRC-RECIST 
↓100b 
Absent/NAc 
Absent 
CRd 
↓100 
Present/ND/UE 
Any 
PRd 
↓100 
Unequivocal progression 
Any 
PRd 
↓≥ 30 
Absent/Present NAc/ND/UE 
Any 
PRd 
↓≥ 30 
Unequivocal progression 
Any 
PRd 
↓< 30 to ↑< 20 
Absent/Present/NAc/ND/UE 
Any 
SD 
↓< 30 to ↑< 20 
Unequivocal progression 
Any 
SD 
↑≥ 20e 
Any 
Any 
PD 
UEg 
Any 
Any 
UE 
NDg 
Any 
Any 
UE 
NAf 
Any 
Any 
UE 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; 
UE = unevaluable; ND = not done; NA = not applicable; irRC-RECIST = immune-related response criteria 
simulating Response Evaluation Criteria in Solid Tumors (RECIST) 
a Disease relative to baseline, including new measurable lesions only (> 10 mm). 
b Disappearance of all non-lymph node lesions and all lymph nodes < 10 mm in short axis would also be CR 
even if lymph node measurements prevent 100% tumor burden reduction. 
c No non-target lesions identified at baseline. 
d Assuming response (CR or PR) or progression are confirmed by a second, consecutive assessment at 
least 4 weeks (28 days) apart. 
e In addition to relative increase of ≥ 20%, the tumor burden must also demonstrate an absolute increase 
of ≥ 5 mm from nadir for PD. 
f No target lesions identified at baseline.  When a subject has only nonmeasurable disease (ie, no target 
lesions identified at baseline) the response will be (UE) unevaluable. 
g If one or more target/new measurable lesions are unevaluable or not measured but the sum of all 
evaluable target/new lesions measured show a ≥ 20% and at least 5 mm absolute increase relative to 
nadir, then the visit overall Target Response will be PD. 
Determination of best overall response is based on changes in total tumor burden from 
the baseline (nadir, for PD) tumor assessment, regardless of any initial increase in 
baseline lesions or the appearance of new lesions. 
Subjects are considered to have partial response (PR) or stable disease (SD) even if 
new lesions were present, as long as they met the respective thresholds of response as 
described in Table 7. 
A best overall response of SD requires a visit response of SD or better no earlier than 
49 days after the date of enrollment; otherwise the overall response will be UE. 
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Confirmation of Response (CR or PR): 
To be assigned a status of CR or PR changes in tumor measurements must be 
confirmed by consecutive repeat assessments performed no less than 4 weeks 
(28 days) after the criteria for response are first met. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of CR depends on this determination, it is recommended 
that the residual lesion be investigated (ie, biopsy) to confirm the CR status. 
Confirmation of Disease Progression: 
If a subject is classified as having PD at a post baseline tumor assessment, then 
confirmation of PD by a second assessment ≥ 4 weeks (28 days) later in the absence of 
rapid clinical deterioration (ie, rapid decline in performance status) or symptomatic 
disease requiring rapid initiation of alternative systemic anti-cancer therapy is required.  
The definition of confirmation of progression represents a ≥ 20% and at least 5 mm 
absolute increase in the total tumor burden (ie, the sum of diameters of target lesions 
plus new measurable lesions) compared to the nadir at 2 consecutive time-points at 
least 4 weeks (28 days) apart (with the date of progression considered to be the time of 
the initial evaluation showing PD).   
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of PD at the time should have the reason for 
treatment discontinuation specified.  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
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 case report form (CRF).  A completely resected lesion should be 
assigned a default code of 0 mm (for target lesions) or “absent” (for non-target lesions), 
except as described below for lymph nodes.  A partially resected lesion should be 
assigned its measurement post-procedure (for target lesions) or “present” (for non-target 
lesions).  If the resected lesion contained no cancer under pathology evaluation, 
subsequent tumor assessments post-procedure may be used for tumor burden 
calculations and/or determination of response.  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.  
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If the new tumor burden post-procedure is lower than the nadir before the procedure, 
then the new nadir will be set to the post-procedure tumor burden.  Otherwise, the 
previous pre-procedure nadir will be retained as the nadir.  Subsequent assessments for 
PD will be determined from the nadir. 
Target lymph node previously present 
For any target lymph node that is fully resected (and previously present ≥ 15 mm) and 
contained cancer or pathology results were unknown, 0 mm should not be recorded.  In 
the event a measurement is not available, a 10 mm short axis should be reported. 
For any target lymph node that is fully resected (and previously present ≥ 15 mm) and 
contained no cancer under pathology evaluation, 0 mm should not be recorded.  In the 
event a measurement is not available, a 9 mm short axis should be reported. 
Non-target lymph node previously present 
For any non-target lymph node that is fully resected and contained cancer or pathology 
results were unknown, “present” should always be reported. 
For any non-target lymph node that is fully resected and contained no cancer under 
pathology evaluation, “absent” should always be reported. 
Lymph node not previously present 
If a new lymph node was fully resected, measured and contained cancer or pathology 
results were unknown, it should be reported as a new non-measurable lymph node if its 
short axis was < 15 mm or, if it was ≥ 15 mm, it should be reported as a new measurable 
lymph node with a short axis of 10 mm. 
If a new lymph node was fully resected, not measured and contained cancer or 
pathology results were unknown, it should be reported as a new non-measurable lymph 
node.   
The initial dimension of a new measurable lymph node or presence of a new 
non-measurable lymph node should be reported at all subsequent assessments. 
For any new lymph node that is fully resected and contained no cancer under pathology 
evaluation, it should not be recorded as either a target or non-target lesion.  The full 
resection should only be reported on the Procedures eCRF. 
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Merging Lesions 
When two or more target/new measurable lesions merge, the smaller lesion should have 
0 (zero) mm recorded for the current and all future assessments, and the larger lesion 
should have the longest diameter of the merged lesion recorded for the current 
assessment and be followed for future assessments.  When two or more non-target/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 and followed for future assessments.   
If a target/new measurable lesion and a non-target/new non-measurable lesion merge, 
the non-target/new non-measurable lesion should be recorded as “absent” for the 
current and all future assessments while the target lesion/new measurable lesion should 
include both merged lesions for recording measurements. 
Separating Lesions 
When a target/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 
target/new measurable lesion with measurements provided for the current assessment 
and followed for future assessments.  The dimensions of the split parts would still be 
considered measurable.  Any new lesions that result from separating should be 
documented and followed for future assessments as new measurable or 
non-measurable lesions that were generated by separating and not truly new lesions. 
When a non-target/new non-measurable lesions splits into 2 or more lesions, the largest 
part of the split lesion should be considered to be the previously recorded 
non-target/new non-measurable lesion and followed as “present” for the current 
assessment and followed for future assessments.  Any new lesions that result from 
separating should be documented and followed for future assessments as new 
non-measurable lesions that were generated by separating and not truly new lesions. 
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Appendix E.  Karnofsky Performance Status and Lansky Play Scale 
 
Source: Schag et al, 1984; Lansky et al, 1987 
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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 Pediatric 
Subjects With Advanced Non-central Nervous System Tumors That are Amenable 
to Direct Injection 
 
Amgen Protocol Number (Talimogene Laherparepvec) 20110261 
EudraCT number 2015-003645-25 
 
Amendment Date: 
12 June 2020 
 
Rationale: 
This protocol is being amended to: 
• 
Updated  
− 
(1) the number of pediatric subjects to be enrolled for the study from 18 to 27 to 
18 to 24;  
− 
(2) the number of dose-limiting toxicities (DLT) evaluable subjects from 9 to 6 jn 
the event of a dose de-escalation; and  
− 
(3) the maximum of 18 subjects treated with at least 1 dose of talimogene 
laherparepvec with at least 9 DLT-evaluable subjects in cohort A1.  
Based on the current enrolment pattern of the study (a total of 11 subjects enrolled 
with 10 in cohort A1 and 1 in cohort B1), it’s anticipated that the majority of the 
subjects enrolled going forward will be in cohort A1 (12 to ≤ 21 years).  Thus, the 
sample size and the minimum number of DLT evaluable subjects for each cohort 
were adjusted for feasibility and evaluability for the primary endpoint. 
• 
Update sample size considerations and DLT evaluation:  
− 
From 6 to 12 DLT-evaluable subjects to 18 to 24 subjects enrolled and treated 
with at least 1 dose of talimogene laherparepvec with at least 9 DLT-evaluable 
subjects in cohort A1 
− 
Clarify the 3+3 phase 1 design is for age cohort opening and dose de-escalation, 
assuming a true DLT incidence rate < 33% is used (with a minimum of 6 
DLT-evaluable subjects) 
− 
Sample size for cohorts with age between 2 and 12 years are not required. 
− 
Clarified that after both cohorts are open, the Dose Level Review Team (DLRT) 
can review the safety data after the addition of 3 new DLT-evaluable subjects in 
a cohort until there’re 9 DLT-evaluable subjects in the cohort.  Additionally, 
ad-hoc meetings to review the safety data can be convened anytime, if deemed 
necessary.  These changes were made to maximize the efficiency of the DLRT 
meeting based on safety need.  
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  12 June 2020  
Page 2 of 25 
Confidential 
 
• 
Updated the definition for primary completion date to occur 35 days after the last 
subject has enrolled and received at least 1 dose of talimogene laherparepvec.  The 
definition is modified based on the changes in the minimum number of DLT 
evaluable subjects for each cohort. 
• 
Update objectives/endpoints: 
− 
− 
Added exploratory objective and endpoint to assess 
 
 
 
 
 
 
 
 
 
• 
Inclusion criteria definition for adequate organ function is updated for  
− 
(1) hematological: no transfusion/growth factor support within 7 days from 
screening assessment instead of 4 weeks from screening blood count; and  
− 
(2) hepatic: serum bilirubin ≤ 1.5× baseline value if baseline value was abnormal 
for a subject with Gilbert’s syndrome.  
These changes were made to ease restriction on the eligibility criteria since 
talimogene laherparepvec is not known to have serious adverse effects on bone 
marrow and liver function. 
• 
Exclusion criteria updated: 
− 
for central nervous system (CNS) tumor or clinically active brain metastases 
updated with the clarification that subjects with a history of treated brain 
metastases shall be eligible if they fulfill the following criteria: radiographic 
evidence of improvement with CNS-directed therapy, and no interim progression 
is observed.  This change was made to clarify the definition of clinically active 
brain metastases.  
− 
for receiving treatment in another investigational study device or study drug and 
major surgery updated to 14 days since ending treatment.  These changes were 
made to align the wash out/waiting period from prior therapies with exclusion 
criteria 232, which was amended at the last protocol amendment. 
− 
Major surgery ≤ 14 days prior to enrollment or has not recovered to CTCAE 
version 4.0 grade 1 or better from adverse event due to surgery performed more 
than 14 days prior to enrollment. 
• 
Updated language for reporting the serious disease-related events as all events to 
be reported to sponsor or designee within 24 hours. 
• 
Make editorial and administrative changes throughout the document. 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  10 October 2018 
Page 1 of 14 
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 Pediatric 
Subjects With Advanced Non-central Nervous System Tumors That are Amenable 
to Direct Injection 
 
Amgen Protocol Number 20110261 
EudraCT number 2015-003645-25 
NCT number NCT02756845 
 
Amendment Date: 
10 October 2018 
Rationale: 
This protocol is being amended to: 
 
Clarify that if 
 
 
 
 
 
Update end of study language to align with the current protocol template language 
 
Update contraception language to align with the current risk and discomforts 
language 
 
Clarify transfusion timeframe in Inclusion Criterion 115 to ensure that adequate 
hematologic function is not confounded by a recent transfusion or growth factor 
support 
 
Clarify that subjects with history or evidence of giant congenital melanocytic nevi or 
dysplastic nevis syndrome are not excluded from the study (Exclusion Criterion 205) 
because such subjects are at risk of developing advanced melanoma with injectable 
disease and will therefore be eligible for the study 
 
Shorten the washout period for prior chemotherapy, treatment dose radiotherapy, or 
biological cancer therapy from 28 days to14 days prior to enrollment (Exclusion 
Criterion 229).  The reason for this change is to ensure that subjects who are being 
considered for the study do not wait too long without treatment when they have 
already recovered from adverse event(s) due to prior therapy 
 
 
 
 
Clarify that coagulation tests are only required at screening 
 
Update the number of sites participating in the study 
 
Update disease-related events language 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  10 October 2018 
Page 2 of 14 
CONFIDENTIAL 
 
 
 
Remove ‘Reporting a Safety Endpoint as a Study Endpoint’ section as this section is 
not applicable to this study 
 
Update the matrix for determining the overall response to account for when nontarget 
lesion assessment was not done 
 
Remove self-evident corrections language 
 
Make editorial, typographical, and formatting changes throughout the document 
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  04 April 2017 
Page 1 of 86 
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 Pediatric 
Subjects With Advanced Non-central Nervous System Tumors That are Amenable 
to Direct Injection 
 
Amgen Protocol Number (Talimogene laherparepvec) 20110261 
EudraCT number 2015-003645-25 
 
Amendment 1 Date: 
04 April 2017 
 
Rationale: 
The rationale for the major changes in the study design is provided below: 
 
• 
The upper age limit of eligible subjects has been changed from 18 to 21 years of age 
to facilitate the enrollment of young adults with an advanced/recurrent/refractory 
pediatric tumor who might benefit from talimogene laherparepvec treatment.  
• 
The lowest age cohort (0 to < 2 years of age) has been removed because of the 
following reasons: 
− 
the perceived toxicity risk of treating these pediatric patients, who have an 
immature immune system, with talimogene laherparepvec  
− 
the anticipated low benefit of talimogene laherparepvec treatment for this 
population for which standard of care and other proven salvage regimens are 
available for the type of advanced/recurrent/refractory pediatric tumor(s) seen in 
this age subset 
• 
The requirement to enroll subjects according to herpes simplex virus type 1 (HSV-1) 
serostatus has been removed because of the following reasons: 
− 
low prevalence of HSV-1 positivity in the pediatric population  
− 
the addition of a recommendation to use premedication to mitigate the side 
effects of talimogene laherparepvec in HSV-1 negative subjects 
• 
Maximum number of subjects enrolled was changed from 36 to 27 subjects because 
of the changes in the age cohorts. 
Other changes to the protocol: 
• 
Section 2 Background and Rationale was updated with background information that 
supports changes to the study design. 
• 
Eligibility criteria were clarified and updated to reflect changes in the study design. 
• 
Recommendation to use premedication with the appropriate antipyretic and/or 
antiemetic medications prior to each talimogene laherparepvec treatment was added 
to Section 6.2.1.1 Dosage, Administration, and Schedule. 
CONFIDENTIAL 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110261 
Date:  04 April 2017 
Page 2 of 86 
• 
Rules for DLT evaluation were clarified and stopping rules were updated. 
• 
Rules for opening younger age cohort were updated. 
• 
Rules for dose de-escalation were updated. 
• 
Childhood vaccinations that contain live attenuated virus were added to the list of 
excluded treatments. 
• 
Schedule of Assessments table was updated to: 
− 
clarify the timing of procedures. 
− 
add an additional pregnancy test and performance status assessments 
• 
Section 7.4 Laboratory Assessments was updated to clarify which tests will be done 
locally versus centrally. 
• 
Text describing reporting procedures for serious adverse events was moved from 
Section 9.2.2.3 Reporting Serious Adverse Events After the Protocol-required 
Reporting Period to Section 9.2.2.2 Reporting Procedures for Serious Adverse 
Events. 
• 
Exploratory endpoints were updated. 
• 
Section 10 Statistical Considerations was updated to reflect changes in the study 
design. 
• 
Appendix D was updated to clarify assessments for tumor response. 
• 
Administration, typographical and formatting changes were made throughout the 
protocol. 
CONFIDENTIAL 
 

SAP_001.pdf: 
Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 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 Pediatric Subjects With 
Advanced Non Central Nervous System Tumors That are Amenable to Direct 
Injection 
Protocol Number: 
(Talimogene Laherparepvec) 20110261 
EudraCT number 2015-003645-25 
Version: 
Version 3.0 
Date: 
August 19, 2020 
Authors: 
  
  
 
 
 
 
NCT Number: NCT02756845
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 2 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
19JAN2016 
Not applicable 
Amendment 1 (v2.0) 
18APR2017 
The summary of changes document is 
saved in RIM with file name “AMG 678 
20110261 Statistical Analysis Plan version 
2 changes Memo” 
Amendment 2 (v3.0) 
19AUG2020 
Rationale 
Changes (as per protocol amendment 3) in 
this version are primarily focus on sample 
size change (due to enrollment challenge). 
Minimum enrollment number for younger 
cohorts is removed and changed total 
sample size to 18 dosed subjects from 18 
DLT evaluable subjects. In current version, 
sample size 18-24 was used in protocol and 
SAP description which includes all possible 
cohorts (current cohorts at 2 different age 
ranges  de-escalated cohorts at 2 different 
age ranges). 
  
All changes are noted in this version of the 
statistical analysis plan by the use of bold 
letters.  
 
Description of Changes 
Section 2.2. Secondary Objectives 
Rewrite: 
 
To evaluate the anti-tumor activity of 
talimogene laherparepvec, as assessed 
by overall response rate (ORR), 
duration of response (DOR), time to 
response (TTR), time to progression 
(TTP), progression-free survival (PFS) 
using immune related Response Criteria 
Simulating Response Evaluation 
Criteria in Solid Tumors(RECIST 1.1) 
[Modified irRC RECIST], and overall 
survival (OS). 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 3 
 
 
 
As: 
 
To evaluate the anti-tumor activity of 
talimogene laherparepvec, as assessed 
by overall response rate (ORR), 
duration of response (DOR), time to 
response (TTR), time to progression 
(TTP), progression-free survival (PFS) 
using immune related Response Criteria 
Simulating Response Evaluation 
Criteria in Solid Tumors(RECIST 1.1) 
[Modified irRC RECIST], and overall 
survival (OS). 
Section 2.4. Exploratory 
Rewrite: 
As: 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 4 
 
Section 3.1. Study Design 
Rewrite: 
This is a phase 1, multicenter, open label 
study of talimogene laherparepvec in 
pediatric subjects with advanced non-CNS 
tumors that are amenable to direct injection 
in the clinical setting. 
Approximately 18 treated pediatric subjects 
are expected to be enrolled  into – 2 
cohorts stratified by age (permissible based 
on the incidence of DLTs, a minimum of 
6 subjects/cohort and a minimum of 
18 subjects total) as follows: 
 
Cohort A1 (12 to  21 years of age) 
 
Cohort B1 (2 to  12 years of age) 
Initially, 3 subjects 12 to   21 years of age 
are to be enrolled and treated at 100 of 
the recommended adult dose regimen of 
talimogene laherparepvec (Cohort A1).  
The first dose administered will be up to 4.0 
mL of 106 PFU/mL followed by a dose of up 
to 4.0 mL of 108 PFU/mL 21 days (3 days) 
later.  Subsequent doses of up to 4.0 mL of 
108 PFU/mL will be administered  
approximately every 14 days ( 3 days) 
thereafter (see protocol Section 6.2.1.1).  
The DLT evaluation period is 35 days from 
the initial administration of talimogene 
laherparepvec. Rules for DLT evaluation 
are described in Section 6.2.1.2.1.of the 
protocol.The dose level review team 
(DLRT) will review the safety data of the 
first 3 subjects in the older age cohort A1 to 
decide if the younger age cohort B1 can be 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 5 
 
opened for enrollment.  If none of the first 
3 DLT-evaluable subjects in cohort A1 
experiences a DLT  then cohort B1 will be 
opened for enrollment and treatment at the 
same dose level per the section Study 
Design and Treatment Schema of the 
protocol.  If a DLT occurs in the first 3 
DLT-evaluable subjects in the older age 
cohort (A1 or A2), the younger age cohort 
will not open until a DLT rate  33 is 
observed with at least 6 DLT-evaluable 
subjects in the older age cohort (A1 or A2).  
If any of the first 3 subjects in cohort A1 
experiences a DLT, the DLRT will make a 
recommendation on whether an  additional 
3 subjects should be enrolled in cohort A1.  
Cohort A1 or B1 can enroll up to a 
maximum of 12 DLT-evaluable subjects.  If 
permissible based on the incidence of 
DLTs, the minimum number of 
DLT-evaluable subjects per cohort will be 6 
and the minimum number of DLT-evaluable 
subjects across cohorts A1 and B1 for the 
study will be 18.  In the case of dose 
de-escalation, the minimum number of 
DLT-evaluable subjects at the de-escalated 
dose will be 9 (permissible based on the 
incidence of DLTs).  After an age cohort is 
closed for further enrollment, if  33 of all 
DLT-evaluable subjects in the cohort 
experiences a DLT at a dose level, the 
dose will be declared safe for the cohort. 
If dose de-escalation is needed and if 
permissible based on the incidence of 
DLTs, a minimum of 9 additional DLT 
evaluable subjects will be enrolled and 
treated at a lower dose level of talimogene 
laherparepvec (Dose Level -1).  The initial 
dose administered will be up to 4.0 mL of 
106 PFU/mL followed by dose of up to 4.0 
mL of 106 PFU/mL 21 days (3 days) later.  
Subsequent doses of up to 4.0 mL of 106 
PFU/mL will be administered approximately 
every 14 days ( 3 days) thereafter (see 
Table 1). Dose de-escalation cohorts will 
obey the following naming convention, 
based on age at baseline, and the same 
DLT rules will be applied to the 
de-escalated cohorts: 
 
Cohort A2 (12 to  21 years of age) 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 6 
 
 
Cohort B2 (2 to  12 years of age) 
As: 
This is a phase 1, multicenter, open label 
study of talimogene laherparepvec in 
pediatric subjects with advanced non-CNS 
tumors that are amenable to direct injection 
in the clinical setting. 
Approximately 18 to 24 pediatric subjects 
are expected to be enrolled  and treated 
with at least 1 dose of talimogene 
laherparepvec into 2 cohorts stratified by 
age (permissible based on the incidence of 
DLTs, a minimum of 18 dosed subjects 
total for the primary analysis) as follows: 
 
Cohort A1 (12 to  21 years of age) 
 
Cohort B1 (2 to  12 years of age) 
Initially, 3 subjects 12 to   21 years of age 
are to be enrolled and treated at 100 of 
the recommended adult dose regimen of 
talimogene laherparepvec (Cohort A1).  
The first dose administered will be up to 
4.0 mL of 106 PFU/mL followed by a dose 
of up to 4.0 mL of 108 PFU/mL 21 days 
(3 days) later.  Subsequent doses of up to 
4.0 mL of 108 PFU/mL will be administered  
approximately every 14 days ( 3 days) 
thereafter (see protocol Section 6.2.1.1).  
The DLT evaluation period is 35 days from 
the initial administration of talimogene 
laherparepvec. Rules for DLT evaluation 
are described in Section 6.2.1.2.1.of the 
protocol.The dose level review team 
(DLRT) will review the safety data of the 
first 3 subjects in the older age cohort A1 to 
decide if the younger age cohort B1 can be 
opened for enrollment.  If none of the first 
3 DLT-evaluable subjects in cohort A1 
experiences a DLT  then cohort B1 will be 
opened for enrollment and treatment at the 
same dose level per the section Study 
Design and Treatment Schema of the 
protocol.  If a DLT occurs in the first 3 
DLT-evaluable subjects in the older age 
cohort (A1 or A2), the younger age cohort 
will not open until a DLT rate  33 is 
observed with at least 6 DLT-evaluable 
subjects in the older age cohort (A1 or A2).  
If any of the first 3 subjects in cohort A1 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 7 
 
experiences a DLT, the DLRT will make a 
recommendation on whether an  additional 
3 subjects should be enrolled in cohort A1.  
Cohort A1 or B1 can enroll up to a 
maximum of 18 subjects treated with at 
least 1 dose of talimogene 
laherparepvec with at least 9 
DLT-evaluable subjects in cohort A1. In 
the case of dose de-escalation, the 
minimum number of DLT-evaluable 
subjects at the de-escalated dose will be 6 
(permissible based on the incidence of 
DLTs).  After an age cohort is closed for 
further enrollment, if  33 of all 
DLT-evaluable subjects in the cohort 
experiences a DLT at a dose level, the 
dose will be declared safe for the cohort. 
If dose de-escalation is needed and if 
permissible based on the incidence of 
DLTs, a minimum of 6 additional DLT 
evaluable subjects will be enrolled and 
treated at a lower dose level of talimogene 
laherparepvec (Dose Level -1).  The initial 
dose administered will be up to 4.0 mL of 
106 PFU/mL followed by dose of up to 4.0 
mL of 106 PFU/mL 21 days (3 days) later.  
Subsequent doses of up to 4.0 mL of 106 
PFU/mL will be administered approximately 
every 14 days ( 3 days) thereafter (see 
Table 1). Dose de-escalation cohorts will 
obey the following naming convention, 
based on age at baseline, and the same 
DLT rules will be applied to the 
de-escalated cohorts: 
 
Cohort A2 (12 to  21 years of age) 
 
Cohort B2 (2 to  12 years of age) 
 
Section.3.1.1.2 Long-term Follow-up 
Rewrite: 
After the safety follow up visit, all subjects 
will enter the long term follow up. Subjects 
will be followed for survival and use of 
subsequent anticancer therapies every 
12 weeks ( 28 days) from the safety 
follow-up until death, subject or legally 
acceptable representatives withdraws full 
consent/ assent, or up to approximately 
24 months after the last subject is enrolled 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 8 
 
in the study. In addition, talimogene 
laherparepvec related adverse events that 
occur through the end of the long term 
follow up will be reported. 
As: 
After the safety follow up visit, all subjects 
will enter the long term follow up. Subjects 
will be followed for survival and use of 
subsequent anticancer therapies every 
12 weeks ( 28 days) from the safety 
follow-up visit until death, subject or legally 
acceptable representative withdraws full 
consent/ assent, or up to approximately 
24 months after the last subject is enrolled 
in the study whichever occurs first.  In 
addition, talimogene laherparepvec related 
adverse events that occur through the end 
of the long term follow up will be reported. 
 
Section 3.2.  Sample Size 
Rewrite:  
The sample size of 6 to 12 DLT-evaluable 
subjects for each age cohort is determined 
empirically and is consistent with those 
used in 33 phase 1 designs assuming a 
true DLT incidence rate  33.  
A dose level will be considered safe for a 
cohort if  33 of all DLT-evaluable 
subjects in a given cohort experiences a 
DLT.  
Table 2. presents the probability of 
declaring a dose level safe (unsafe) for a 
range of true DLT rates for the protocol 
therapy in the “33” phase. For example, 
the probability of declaring a dose level safe 
(unsafe) is 89 (11), 42 (58), and 
11 (89) if the true DLT rate is 10, 30, 
or 50, respectively. 
As: 
The sample size of 18 to 24 subjects will 
be enrolled and treated with at least 
1 dose of talimogene laherparepvec with 
at least 9 DLT-evaluable subjects in 
cohort A1. For age cohort opening and 
dose de-escalation, criteria from 33 
phase 1 designs assuming a true DLT 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 9 
 
incidence rate  33 is used. Minimum 
sample size with age between 2 and 
12 years cohort is not required.  
A dose level will be considered safe for a 
cohort if  33 of all DLT evaluable 
subjects in a given cohort experiences a 
DLT (minimum of 6 DLT evaluable 
subjects). Table 2.  and Figure 1. 
presents the probability of declaring a dose 
level safe (unsafe) for a range of true DLT 
rates for the protocol therapy based on 6 
DLT evaluable subjects (see the triangle 
symbols). For example, the probability of 
declaring a dose level safe (unsafe) is 89 
(11), 42 (58), and 11 (89) if the 
true DLT rate is 10, 30, or 50, 
respectively. 
 
Section 4.2.  Planned Covariates 
Delition: 
 GM-CSF receptors / subunits in archival 
tumor tissue  
 
Section 6.  Definitions 
Treatment-emergent Adverse Events 
(TEAE) 
 
Rewrite: 
Treatment-emergent adverse events 
(TEAE) are defined as any adverse event 
with an onset date 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 
eCRF, then the event will not be counted as 
a treatment-emergent AE. Additionally, if an 
event is identified as disease-related on the 
eCRF, it will not be counted as a 
treatment-emergent AE). 
 
As: 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 10 
 
Treatment-emergent adverse events 
(TEAE) are defined as any adverse event 
occurring after first dose through 
30 days after last dose of talimogene 
laherparepvec. 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 eCRF, then the event will not 
be counted as a treatment-emergent AE. 
Additionally, if an event is identified as 
disease-related on the eCRF, it will not be 
counted as a treatment-emergent AE). 
Addition: 
Treatment-emergent Serious Adverse 
Events (TESAE) 
Treatment-emergent serious adverse 
events are defined as any serious 
adverse event occurring after initiation 
of the first dose of study therapy 
through 30 days after the last 
administration of study therapy. 
Treatment-related emergent Adverse 
Events  
Treatment-related adverse events are 
defined as treatment-emergent adverse 
events which are considered to be 
related to the treatment of talimogene 
laherparepvec, as determined by the 
investigator.  
Treatment-related Adverse Events in 
Long Term Follow-up 
Treatment -related adverse events in 
long term follow-up are collected after 
the safety follow-up visit through the 
end of the long-term follow-up. 
 
Section 7.1.  DLT Analysis Set 
Rewrite: 
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 and received at least two treatments 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 11 
 
of talimogene laherparepvec (except 
subjects who had a DLT after the first  
dose) 
. 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). 
As: 
The DLT analysis set will include DLT 
evaluable subjects defined as subjects 
who had the opportunity to be followed 
for at least 35 days from the initial 
dosing of talimogene laherparepvec and 
received at least  two treatments of 
talimogene laherparepvec (except subjects 
who had a DLT after the first dose). 
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).  
Delition: 
Section 7.3.  GM-CSF Receptors/Subunits 
Analysis Set 
 
The GM-CSF receptors/subunits analysis 
set will include all treated subjects with 
available baseline result of GM-CSF 
receptors/subunits. 
 
Addition: 
8.1 Primary Analysis 
The primary analysis will occur 35 days 
after the last subject has enrolled and 
received at least 1 dose of talimogene 
laherparepvec. 
8.2 Final Analysis 
The final analysis will occur when all the 
subjects have discontinued the study 
treatment and have had the opportunity 
to complete the long-term follow-up 
visit. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 12 
 
Deleted the below text at Section 10.4 : 
 
GM-CSF receptors / subunits in 
archival tumor tissue 
Deleted the below text at Section 10.5.2 : 
Analysis of GM-CSF receptors/subunits will 
be based on GM-CSF Receptors/Subunits 
Analysis Set. 
 
If adequate sasmples are received, the 
association between GM-CSF 
receptors/subunits in archival tumor tissue 
and efficacy endpoints (such as ORR, 
DOR, TTR, TTP, PFS, and OS) may be 
examined by multiple functional 
relationships, for example:  
(a) The correlation of baseline value as a 
continuous variable with the odds of OR, or 
the hazard of ending 
response/death/progression;  
(b) A test that the ORR, or hazard of ending 
response/death/progression is greater in 
subgroups of subjects with a baseline value 
at or above a cutoff versus below.  
Association between GM-CSF 
receptors/subunits in archival tumor tissue 
and safety endpoints may be examined by 
multiple functional relationships as 
described in above. 
 
Section 10.5.3. Analyses of Exploratory 
Endpoints 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 13 
 
Section 10.6.2. Adverse Events 
MedDRA version is updated to 23.0 
Addition: 
Section 11.  Changes From 
Protocol-specified Analyses 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 14 
 
In order to define DLT evaluable 
subjects consistently with protocol 
section 6.2.1.2.1, definition of DLT 
analysis set is updated in statistical 
analysis plan section 7.1 from protocol 
section 10.1.2.1. Subjects who had the 
opportunity to be followed for at least 
35 days from the initial administration of 
talimogene laherparepvec and received 
at least two treatment of talimogene 
laherparepvec, with the exception when 
a DLT occurs after the first dose, will be 
considered DLT evaluable. 
 
 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
Date:  19 August 2020 
Page 15 
 
Table of Contents 
Table of Abbreviations or Term...................................................................................... 18 
1. 
Introduction ........................................................................................................... 21 
2. 
Objectives ............................................................................................................. 21 
2.1 
Primary ..................................................................................................... 21 
2.2 
Secondary ................................................................................................. 21 
2.3 
Safety ........................................................................................................ 21 
2.4 
Exploratory ................................................................................................ 21 
3. 
Study Overview .................................................................................................... 22 
3.1 
Study Design ............................................................................................. 22 
3.1.1 
Tumor Response Assessment ................................................... 23 
3.1.1.1 
Safety Follow-up ..................................................... 23 
3.1.1.2 
Long-term Follow-up ............................................... 23 
3.2 
Sample Size .............................................................................................. 24 
4. 
Study Endpoints and Covariates ........................................................................... 25 
4.1 
Study Endpoints ........................................................................................ 25 
4.1.1 
Primary Endpoints ..................................................................... 25 
4.1.2 
Secondary Endpoints ................................................................ 25 
4.1.3 
Safety Endpoints ....................................................................... 25 
4.1.4 
Exploratory Endpoints ............................................................... 25 
4.2 
Planned Covariates ................................................................................... 26 
5. 
Hypotheses and/or Estimations ............................................................................ 26 
6. 
Definitions ............................................................................................................. 26 
7. 
Analysis Subsets .................................................................................................. 33 
7.1 
DLT Analysis Set ....................................................................................... 33 
7.2 
Safety Analysis Set ................................................................................... 33 
.... 33 
.... 34 
.... 34 
.... 34 
7.7 
Subgroup Analyses ................................................................................... 34 
8. 
Interim Analysis and Early Stopping Guidelines .................................................... 35 
8.1 
Primary Analysis ....................................................................................... 35 
8.2 
Final Analysis ............................................................................................ 35 
9. 
Data Screening and Acceptance ........................................................................... 35 
9.1 
General Principles ..................................................................................... 35 
9.2 
Data Handling and Electronic Transfer of Data ......................................... 35 
9.3 
Handling of Missing and Incomplete Data ................................................. 35 


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9.4 
Detection of Bias ....................................................................................... 35 
9.5 
Outliers ..................................................................................................... 36 
9.6 
Distributional Characteristics ..................................................................... 36 
9.7 
Validation of Statistical Analyses ............................................................... 36 
10. 
Statistical Methods of Analysis.............................................................................. 36 
10.1 
General Principles ..................................................................................... 36 
10.2 
Subject Accountability ............................................................................... 36 
10.3 
Important Protocol Deviations ................................................................... 37 
10.4 
Demographic and Baseline Characteristics ............................................... 37 
10.5 
Efficacy Analyses ...................................................................................... 37 
10.5.1 
Analyses of Secondary Endpoints - ORR, DOR, TTR, 
TTP, PFS, OS ........................................................................... 37 
10.5.2 
Analyses of Exploratory Endpoints ............................................ 38 
10.6 
Safety Analyses ........................................................................................ 39 
10.6.1 
Analyses of Primary Endpoints .................................................. 39 
10.6.2 
Adverse Events ......................................................................... 39 
10.6.3 
Laboratory Test Results ............................................................ 40 
10.6.4 
Vital Signs ................................................................................. 40 
10.6.5 
Lansky Play Scale and Karnofsky Performance Status ............. 40 
10.6.6 
Physical Measurements ............................................................ 41 
10.6.7 
Electrocardiogram (ECG) .......................................................... 41 
10.6.8 
Exposure to Investigational Product .......................................... 41 
10.6.9 
Exposure to Concomitant Medication/On-study 
Surgery or Procedure/Subsequent Anti-cancer 
Therapy ..................................................................................... 41 
11. 
Changes From Protocol-specified Analyses.......................................................... 41 
12. 
Literature Citations / References ........................................................................... 42 
13. 
Appendices ........................................................................................................... 43 
List of Tables 
Table 1.  Dose De-escalation ........................................................................................ 23 
Table 2.  Probability of Declaring a Cohort Safe or Unsafe ............................................ 24 
Table 3.  Matrix of Determining BOR per Modified irRC-RECIST ................................... 28 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
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List of Figures 
Figure 1.  Probability of Declaring a Cohort Safe (Unsafe)............................................. 25 
List of Appendices 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
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Table of Abbreviations or Term 
Abbreviation or Term Definition/Explanation 
AE 
adverse event 
BDSG 
Biomedical Data Stewardship Governance  
BOR 
best overall response 
CI 
confidence interval 
CRF  
case report form 
CNS 
central nervous system 
CR 
complete response 
CSR 
clinical study report 
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 
DRE 
Disease-related events 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
End of Study for 
Individual Subject 
Defined as the last day that protocol-specified procedures are conducted 
for an individual subject (ie, the date the subject withdraws full 
consent/assent 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 primary completion date is defined as the date when the last subject 
is assessed or received an intervention for the final collection of data for 
the primary endpoint(s), whether the study concluded as planned in the 
protocol or was terminated early. 
The primary completion date is anticipated to occur 35 days after the 
last subject has enrolled and received at least 1 dose of talimogene 
laherparepvec.  
 
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, long-term follow-up), as applicable. 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
FDA 
Food and Drug Administration 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HSV, HSV-1 
herpes simplex virus, herpes simplex virus type 1 


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Abbreviation or Term Definition/Explanation 
HCP 
Health Care Professional 
IP 
Investigational Product 
IPD 
Important Protocol Deviations 
irRC-RECIST 
Immune-related Response Criteria (irRC) simulating Response 
Evaluation Criteria in Solid Tumors (RECIST)  
L-CR 
L-DOR 
Lesion complete response 
Lesion duration of response 
LLOQ 
Lower Limit of Quantification 
L-ORR 
Lesions objective response rate 
L-PR 
L-TTR 
Lesion partial response 
Lesion time to response 
MedDRA 
Medical Dictionary for Regulatory Activities 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PFU 
plaque-forming unit 
PR 
partial response 
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 
QT interval corrected for heart rate using accepted methodology 
RECIST 
Response Evaluation Criteria in Solid Tumor 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
System organ class 
Source Data 
Information from an original record or certified copy of the original record 
containing patient information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in 
source documents (original records or certified copies).  (ICH Guideline 
[E6]).  Examples of source data include subject identification, 
randomization identification, and stratification value. 
Study Day 1 
defined as the first day that Talimogene laherparepvec administered to 
the subject 
TEAE 
 
TESAE 
Treatment-Emergent Adverse Event 
 
Treatment-Emergent Serious Adverse Event 


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Statistical Analysis Plan:  20110261 
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Abbreviation or Term Definition/Explanation 
ULN 
Upper Limit of Normal 


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Statistical Analysis Plan:  20110261 
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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 3 for talimogene 
laherparepvec  Study 20110261 dated 12 June 2020.  The scope of this plan includes 
the primary analysis and the final analysis that are planned and will be executed by the 
Biostatistics department unless otherwise specified. 
The clinical study report (CSR) will be written based on the results of the primary 
analysis. Data collected and analyzed in Amgen-owned databases and systems will 
adhere to approved Data Element Standards and International Case Report Form (CRF) 
Standards established by Biomedical Data Stewardship Governance (BDSG). 
2. 
Objectives 
2.1 
Primary 
To  evaluate the safety and tolerability of talimogene laherparepvec, as assessed by 
incidence of dose-limiting toxicities (DLT), in pediatric subjects with advanced 
non-central nervous system (CNS) tumors that are amenable to direct injection. 
2.2 
Secondary 
 
To evaluate the anti-tumor activity of talimogene laherparepvec, as assessed by 
overall response rate (ORR), duration of response (DOR), time to response (TTR), 
time to progression (TTP), progression-free survival (PFS) using immune related 
Response Criteria Simulating Response Evaluation Criteria in Solid Tumors(RECIST 
1.1) [Modified irRC RECIST], and overall survival (OS). 
2.3 
Safety 
To evaluate the safety and tolerability of talimogene laherparepvec 
2.4 
Exploratory 


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3. 
Study Overview 
3.1 
Study Design 
This is a phase 1, multicenter, open label study of talimogene laherparepvec in pediatric 
subjects with advanced non-CNS tumors that are amenable to direct injection in the 
clinical setting. 
Approximately 18 to 24 pediatric subjects are expected to be enrolled  and treated with 
at least 1 dose of talimogene laherparepvec into 2 cohorts stratified by age 
(permissible based on the incidence of DLTs, a minimum of 18 dosed subjects total for 
the primary analysis) as follows: 
 
Cohort A1 (12 to  21 years of age) 
 
Cohort B1 (2 to  12 years of age) 
Initially, 3 subjects 12 to   21 years of age are to be enrolled and treated at 100 of the 
recommended adult dose regimen of talimogene laherparepvec (Cohort A1).  The first 
dose administered will be up to 4.0 mL of 106 PFU/mL followed by a dose of up to 
4.0 mL of 108 PFU/mL 21 days (3 days) later.  Subsequent doses of up to 4.0 mL of 
108 PFU/mL will be administered  approximately every 14 days ( 3 days) thereafter (see 
protocol Section 6.2.1.1).  The DLT evaluation period is 35 days from the initial 
administration of talimogene laherparepvec. Rules for DLT evaluation are described in 
Section 6.2.1.2.1.of the protocol.The dose level review team (DLRT) will review the 
safety data of the first 3 subjects in the older age cohort A1 to decide if the younger age 
cohort B1 can be opened for enrollment.  If none of the first 3 DLT-evaluable subjects in 
cohort A1 experiences a DLT  then cohort B1 will be opened for enrollment and 
treatment at the same dose level per the section Study Design and Treatment Schema 
of the protocol.  If a DLT occurs in the first 3 DLT-evaluable subjects in the older age 
cohort (A1 or A2), the younger age cohort will not open until a DLT rate  33 is 
observed with at least 6 DLT-evaluable subjects in the older age cohort (A1 or A2).  If 
any of the first 3 subjects in cohort A1 experiences a DLT, the DLRT will make a 
recommendation on whether an  additional 3 subjects should be enrolled in cohort A1.  
Cohort A1 or B1 can enroll up to a maximum of 18 subjects treated with at least 1 
dose of talimogene laherparepvec with at least 9 DLT-evaluable subjects in cohort 
A1. In the case of dose de-escalation, the minimum number of DLT-evaluable subjects 
at the de-escalated dose will be 6 (permissible based on the incidence of DLTs).  After 
an age cohort is closed for further enrollment, if  33 of all DLT-evaluable subjects in 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
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the cohort experiences a DLT at a dose level, the dose will be declared safe for the 
cohort. 
If dose de-escalation is needed and if permissible based on the incidence of DLTs, a 
minimum of 6 additional DLT evaluable subjects will be enrolled and treated at a lower 
dose level of talimogene laherparepvec (Dose Level -1).  The initial dose administered 
will be up to 4.0 mL of 106 PFU/mL followed by dose of up to 4.0 mL of 106 PFU/mL 
21 days ( 3 days) later.  Subsequent doses of up to 4.0 mL of 106 PFU/mL will be 
administered approximately every 14 days ( 3 days) thereafter (see Table 1). Dose 
de-escalation cohorts will obey the following naming convention, based on age at 
baseline, and the same DLT rules will be applied to the de-escalated cohorts: 
 
Cohort A2 (12 to  21 years of age) 
 
Cohort B2 (2 to  12 years of age) 
Table 1.  Dose De-escalation 
Dose Level 
Initial Dose 
Subsequent Doses 
1 
106 PFU/mL 
108 PFU/mL 
-1 
106 PFU/mL 
106 PFU/mL 
3.1.1 
Tumor Response Assessment 
Assessment of tumor response will be performed according to modified irRC-RECIST 
(Nishino et al, 2013 and Nishino et al, 2014). Details can be found in protocol 
Appendix D.  
3.1.1.1 
Safety Follow-up 
Adverse events will be collected as described in protocol Section 9.2.  All subjects will 
complete a safety follow up visit approximately 30 ( 7) days after the last dose of study 
treatment.  Adverse events and any concomitant medications associated with adverse 
events that occur 30 ( 7) days following cessation of treatment will be reported, 
followed, and recorded in the case report form (CRF). 
3.1.1.2 
Long-term Follow-up 
After the safety follow up visit, all subjects will enter the long term follow up. Subjects will 
be followed for survival and use of subsequent anticancer therapies every 12 weeks 
( 28 days) from the safety follow-up visit until death, subject or legally acceptable 
representative withdraws full consent/ assent, or up to approximately 24 months after the 
last subject is enrolled in the study whichever occurs first.  In addition, talimogene 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110261 
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laherparepvec related adverse events that occur through the end of the long term follow 
up will be reported. 
3.2 
Sample Size 
The sample size of 18 to 24 subjects will be enrolled and treated with at least 1 dose 
of talimogene laherparepvec with at least 9 DLT-evaluable subjects in cohort A1. 
For age cohort opening and dose de-escalation, criteria from 33 phase 1 designs 
assuming a true DLT incidence rate  33 is used. Minimum sample size with age 
between 2 and 12 years cohort is not required.  
A dose level will be considered safe for a cohort if  33 of all DLT evaluable subjects in 
a given cohort experiences a DLT (minimum of 6 DLT evaluable subjects). Table 2.  
and Figure 1. presents the probability of declaring a dose level safe (unsafe) for a range 
of true DLT rates for the protocol therapy based on 6 DLT evaluable subjects (see the 
triangle symbols). For example, the probability of declaring a dose level safe (unsafe) 
is 89 (11), 42 (58), and 11 (89) if the true DLT rate is 10, 30, or 50, 
respectively.  
Table 2.  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 


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Figure 1.  Probability of Declaring a Cohort Safe (Unsafe) 
 
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
4.1.1 
Primary Endpoints 
 
Subject incidence of DLTs 
4.1.2 
Secondary Endpoints 
 
ORR, DOR, TTR, TTP, and PFS using modified irRC-RECIST 
 
OS 
4.1.3 
Safety Endpoints 
 
Subject incidence of adverse events and clinical significant laboratory abnormalities 
4.1.4 
Exploratory Endpoints 


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4.2 
Planned Covariates 
The following covariates may be used to examine clinical activity  in subgroups or in 
multivariate analysis.   
 
Age at baseline: (2 to  12 years, 12 to  21 years)   
 
Sex (female versus male) 
 
HSV-1 baseline serostatus (positive versus negative) 
 
Baseline sum of largest diameter of target lesions 
 
Extent of disease (localised versus metastatic) 
 
Performance status (Karnofsky/Lansky play scale (70 versus  70))  
 
Prior lines of therapy in the recurrent/metastatic setting (0,1, 2,  2) 
 
Prior surgery for current malignancy (yes versus no) 
 
Prior radiotherapy for current malignancy (yes versus no) 
 
Complete surgical resection of all gross diseases (yes versus no) 
 
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. 
5. 
Hypotheses and/or Estimations 
Talimogene laherparepvec injected in pediatric subjects with advanced non-CNS tumors 
that are amenable to direct injection will be safe as assessed by subject incidence of 
DLTs and the safety profile. 
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, 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. 
Best overall response (BOR) per Modified irRC-RECIST 
Best overall response (BOR) of complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD) or un-evaluable (UE) will be derived based on 


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Statistical Analysis Plan:  20110261 
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investigator assessment using modified irRC-RECIST as defined in protocol Appendix D.  
Any baseline tumor markers above the ULN must normalize for an overall visit response 
of CR.    
Overall visit response assessments occurring after the start of the first subsequent 
anticancer therapy, including complete or partial removal/reduction of any target lesion, 
will not be included. Consecutive confirmation of CR, PR, and PD is required where the 
second overall response must be at least 28 days from the first, the only exception being 
when the investigator reports that an initial PD cannot be confirmed due to rapid clinical 
deterioration. The following will be considered a confirmed PR: CR followed by PR or PR 
followed by CR.  
BOR is defined as the best visit response in the following order:  CR, PR, SD, PD, or UE 
(see Table 3 ).  BOR  is defined as SD if the best overall visit response is an 
unconfirmed CR or PR, and UE if it is either SD earlier than 49 days after the date of first 
dosing or an unconfirmed PD when confirmation of PD is required (ie, initial PD without 
rapid clinical deterioration).    


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Table 3.  Matrix of Determining BOR per Modified irRC-RECIST 
Visit Overall Response 
Sequence 
Examples 
Best 
Overall 
Response 
Confirmation specifications 
*, CR, CR,* 
PR, CR, CR 
CR, CR, PD 
CR 
The confirmatory CR must be at least 
4 weeks (28 days) later; a subsequent 
CR within 28 days will not be valid for 
confirmation and will be ignored; the CR 
will also not be confirmed if there is a 
subsequent PR/SD/PD at any time prior 
to the next CR. 
*, PR, PR, * 
 
*, PR, CR/PR, non-CR, * 
 
*,CR, PR,* 
PR, PR, PD 
PR, CR, PD 
CR, PR, PD 
PR 
Criteria for BORCR not met. 
The confirmatory PR/CR   must be no 
less than 4 weeks (28 days) later; a 
subsequent PR/CR  within 28 days will 
not be valid for confirmation and will be 
ignored; the PR will also not be 
confirmed if there is a subsequent  
SD/PD at any time prior to the next 
PR/CR . 
*, SD, * 
 
*,CR, non-PR/CR, * 
 
*,PR, non-PR/CR, * 
CR 
PD, CR 
PR 
PD, PR, SD 
SD 
PD,SD,PD 
SD 
Criteria for BORCR or PR not met. 
SD must be  49 days from first dose; 
however, this is not required for an 
unconfirmed CR/PR. 
Page 1 of 2 


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Table 3.  Matrix of Determining BOR per Modified irRC-RECIST 
Visit Overall Response 
Sequence 
Examples 
Best 
Overall 
Response 
Confirmation 
specifications 
*,PD, PD, * 
 
*, PDr, * 
 
 
PDr  PD with 
concurrent or 
subsequent rapid clinical 
deterioration as the 
reason for ending 
radiographic follow-up. 
PD, PD 
PD, SD, PD, 
PD 
PDr 
PD 
Criteria for BOR CR, 
PR, or SD not met. 
The confirmatory 
PD  must be no less than 
4 weeks (28 days) later 
unless there is rapid 
clinical deterioration;  PDr 
does not require 
confirmation; a 
subsequent PD within 
28 days will not be valid 
for confirmation and will 
be ignored. 
*, SD, * 
 
PD 
SD 
UE, SD 
PD 
UE, PD 
UE 
Criteria for BORCR, PR, 
SD, or PD not met. 
SD must be  49 days 
from first dose (or 
randomization if not 
treated). 
Page 2 of 2 
Duration of response (DOR) per Modified irRC-RECIST 
Duration of response (DOR) is defined as the time from the date of an initial response 
that is subsequently confirmed to the earlier of PD (see definition of BOR per Modified 
irRC-RECIST) or death.  Subjects who have not ended their response at the time of 
analysis will be censored at their last evaluable tumor assessment.  
Evaluable tumor assessment 
An overall visit response other than UE. 
Event of Interest (EOI) 
MedDRA dictionary preferred terms for each EOI search strategy is defined and 
maintained by Amgen Safety Medical Coding. 
Investigational product (IP) 
Investigational product refers to talimogene laherparepvec in this study. 


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Objective response rate (ORR) per Modified irRC-RECIST 
ORR is defined as the incidence of a BOR of CR or PR per Modified irRC-RECIST 
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 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. 
Potential Follow-Up Time 


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Potential follow-up time for a subject is calculated from the first dose to the analysis data 
cutoff date.  
Progression-free survival (PFS) per Modified irRC-RECIST 
Progression-free survival (PFS) per Modified irRC-RECIST is defined as the interval 
from first dose to the earlier of PD per Modified irRC-RECIST or death from any cause; 
otherwise, PFS is censored at the last evaluable tumor assessment. The initial date of 
PD will be the PFS date when it is consecutively confirmed. 
Study day 
Study day is calculated from the first day when investigational product is administered to 
the subject.  
That is, Study day  visit date – first dose date  1, if visit date is after first dose date 
Study Day  first dose date – visit date, if visit date is prior to first dose date 
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 1 
The start of Investigational product administration to the subject is study week 1. Study 
day 1 is corresponding to the first day of study week 1. 


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Time to progression (TTP): defined as the interval from first dose to the date of the first 
PD per Modified irRC-RECIST; otherwise, TTP is censored at the last evaluable tumor 
assessment.  
Time to response (TTR): (calculated only for those subjects in the safety analysis set 
with confirmed CR or PR) time from first dose to the date of the first confirmed 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 (TEAE) are defined as any adverse event 
occurring after first dose through 30 days after last dose of talimogene 
laherparepvec. 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 
eCRF, then the event will not be counted as a treatment-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 Serious Adverse Events (TESAE) 
Treatment-emergent serious adverse events are defined as any serious adverse 
event occurring after initiation of the first dose of study therapy through 30 days 
after the last administration of study therapy. 
Treatment-related emergent Adverse Events  
Treatment-related adverse events are defined as treatment-emergent adverse 
events which are considered to be related to the treatment of talimogene 
laherparepvec, as determined by the investigator.  
Treatment-related Adverse Events in Long Term Follow-up 
Treatment -related adverse events in long term follow-up are collected after the 
safety follow-up visit through the end of the long-term follow-up. 
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 


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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). 
7. 
Analysis Subsets 
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 from the initial dosing of 
talimogene laherparepvec and received at least  two treatments of talimogene 
laherparepvec (except subjects who had a DLT after the first dose). 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).  
7.2 
Safety Analysis Set 
The safety analysis set will include all subjects who received at least 1 dose of 
talimogene laherparepvec.  


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7.7 
Subgroup Analyses 
See  Section 4.2. 


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8. 
Interim Analysis and Early Stopping Guidelines 
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).  
8.1 
Primary Analysis 
The primary analysis will occur 35 days after the last subject has enrolled and 
received at least 1 dose of talimogene laherparepvec. 
8.2 
Final Analysis 
The final analysis will occur when all the subjects have discontinued the study 
treatment and have had the opportunity to complete the long-term follow-up visit. 
9. 
Data Screening and Acceptance 
9.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
9.2 
Data Handling and Electronic Transfer of Data  
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 and concomitant medications and incomplete death dates will 
be imputed. Details of the imputation algorithm are provided in Appendix A, section 13.  
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). IPDs 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. 


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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.   
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, safety, talimogene laherparepvec 
DNA, and other exploratory endpoints for all subjects and by cohort. 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 (Clopper & 
Pearson 1934).  Exact tests will be considered for subgroup analyses.  Time to-event 
endpoints will be estimated using the K-M method.   
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 countries and investigator sites 
overall and by cohort (based on age). Subject disposition (including the number 


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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. 
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:  (2 to  12 years, 12 to  21 years)  
 
Sex (female versus male) 
 
HSV-1 baseline serostatus (positive versus negative) 
 
Baseline sum of largest diameter of target lesions 
 
Extent of disease (localized versus metastatic) 
 
Performance status (Karnofsky/Lansky play scale (70 versus  70)  
 
Prior lines of therapy in the recurrent/metastatic setting (0,1, 2,  2) 
 
Prior surgery for current malignancy (yes versus no) 
 
Prior radiotherapy for current malignancy (yes versus no) 
 
Complete surgical resection of all gross diseases (yes versus no) 
 
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  
10.5.1 
Analyses of Secondary Endpoints - ORR, DOR, TTR, TTP, PFS, OS 
Analysis of secondary endpoints such as ORR, DOR, TTR, TTP, PFS, OS will be based 
on Safety Analysis Set and excluding subjects without baseline measurable disease, if 
applicable.  
 
ORR (CRPR) will be summarized with associated exact 95 CIs for binomial 
proportions (Clopper & Pearson 1934).  


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 
DOR among responders, TTP, 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. 
10.5.2 
Analyses of Exploratory Endpoints 


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10.6 
Safety Analyses 
10.6.1 
Analyses of Primary Endpoints 
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. 
10.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 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. 


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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, 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, 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), fatal disease related events, 
serious disease-related events, and disease-related events leading to withdrawal from 
study will be tabulated by system organ class and preferred term. 
Treatment-related AEs reported in long term follow-up will be summarized in this study 
and analyzed at a program-level.  
Potential or known unintended exposure to talimogene laherparepvec, related suspected 
signs or symptoms, and detection of exposure to talimogene laherparepvec in a 
subject’s household member, caregiver, or healthcare provider will be reported to 
Amgen. Exposures, signs or symptoms will be summarized in this study and analyzed at 
a program-level. 
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. For a list of laboratory measurements see protocol Section 7.4 
Table 3. Subject incidence of potential hepatoxicity as identified by the Hy’s Law criteria 
(FDA guidance for Industry Drug Induced Liver Injury: pre-marketing evaluation, 
July 2009) as well as confirmed DILI events as reported by investigators will be 
presented. 
10.6.4 
Vital Signs 
Descriptive statistics will be presented for systolic/diastolic blood pressure, heart rate, 
respiratory rate, and temperature for baseline, each post-baseline visit, and change from 
baseline. 
10.6.5 
Lansky Play Scale and Karnofsky Performance Status  
Performance status scores will be summarized at each assessed time point. The change 
in scores from baseline to each assessed time point will also be summarized. 


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10.6.6 
Physical Measurements 
Height and weight will be summarized at each assessed time point. The change in 
weight from baseline to each assessed time point will also be summarized as a 
difference in original units of measurement and as percentage difference. 
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. Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; neither summaries nor 
statistical analyses will be provided, and these data would not be expected to be useful 
for meta-analysis with data from other trials. 
10.6.8 
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/mL) and 
subsequent doses (concentration of 108 PFU/mL or 106 PFU/mL). Subject incidence rate 
and reasons for IP delay, dose change, withdrawal and/or injections with  4 mL will be 
tabulated. 
10.6.9 
Exposure to Concomitant Medication/On-study Surgery or 
Procedure/Subsequent Anti-cancer Therapy  
The concomitant medications include all medications during the treatment period except 
for planned study drugs. The number and proportion of subjects receiving therapies of 
interest will be summarized by preferred term or cohort as coded by the World Health 
Organization Drug (WHO DRUG) dictionary.  
11. 
Changes From Protocol-specified Analyses 
In order to define DLT evaluable subjects consistently with protocol 
section 6.2.1.2.1, definition of DLT analysis set is updated in statistical analysis 
plan section 7.1 from protocol section 10.1.2.1. Subjects who had the opportunity 
to be followed for at least 35 days from the initial administration of talimogene 
laherparepvec and received at least two treatment of talimogene laherparepvec, 
with the exception when a DLT occurs after the first dose, will be considered DLT 
evaluable. 


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12. 
Literature Citations / References 
Agresti, A. (2002) Categorical Data Analysis, 2nd Edition, New York: John Wiley & Sons.  
Brookmeyer, R., et al (1982) “A Confidence Interval for the Median Survival Time.” 
Biometrics, 38, 29-41 Clopper, C., et al (1934) “The Use of Confidence or Fiducial Limits 
Illustrated in the Case of the Binomial,” Biometrika, 26, 404-413  
Eisenhauer, A., et al (2009) “New Response Evaluation in Solid Tumors: Revised 
RECIST Guideline (version 1.1)”, EJC, 45, 228-247.  
Kalbfleisch, J.D., et al (1980) The Statistical Analysis of Failure Time Data, New York: 
John Wiley & Sons.  
Nishino, M., et al (2014) “Optimizing immune-related tumor response assessment: does 
reducing the number of lesions impact response assessment in melanoma patients 
treated with ipilimumab?” J Immunother Cancer. 2014; 2: 17. 
Nishino, M., et al (2013) “Developing a common language for tumor response to 
immunotherapy: Immune-related response criteria using unidimensional measurements”. 
Clin Cancer Res; 19(14); 3936-43.  
Wolchok, J.D., et al. (2009) “Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria.” Clin Cancer Res, 15(23), 7412-7420. 


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13. 
Appendices 


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