Conditions: Carcinoma of the Head and Neck
Keywords: Recurrent Metastatic Squamous Cell Carcinoma Head and Neck
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
The primary objective of this study was to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in adults with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Detailed description:
This is a phase 1b/3, multicenter, clinical trial conducted in 2 parts (phase 1b and phase 3). In phase 1b talimogene laherparepvec is to be administered in combination with pembrolizumab to adults with recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). Dose limiting toxicity (DLT) is to be evaluated based on the first 18 DLT-evaluable participants. An expansion cohort of up to an additional 22 treated patients could be enrolled to further evaluate the safety and to estimate the efficacy of the combination of talimogene laherparepvec with pembrolizumab and to support a decision to initiate the phase 3 part of the study. The phase 3 part of the study was designed as a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, as assessed by overall survival, of treatment with talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab in adults with recurrent or metastatic SCCHN, however, a decision was made not to proceed to the phase 3 part of the study.

Arms:
arm 1: Talimogene laherparepvec is administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 3 weeks after the initial dose and every 3 weeks (Q3W) thereafter. Pembrolizumab is administered by intravenous infusion at a dose of 200 mg Q3W after the initial dose. Participants are treated until complete response, no injectable lesions, confirmed disease progression, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first.

Interventions: intervention 1: Talimogene Laherparepvec intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: The initial dose of talimogene laherparepvec is up to 8.0 mL of 10⁶ PFU/mL. Subsequent doses of talimogene laherparepvec are up to 8.0 mL of 10⁸ PFU/mL. intervention 2: Administered as a 30-minute intravenous infusion at a dose of 200 mg Q3W

Protocol document:
SAP_002.pdf: 
Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
Page 1 
STATISTICAL ANALYSIS PLAN 
A Phase 1b/3 Multicenter, Randomized Trial of Talimogene Laherparepvec in 
Combination With Pembrolizumab for the Treatment of Subjects With Recurrent or 
Metastatic Squamous Cell Carcinoma of the Head and Neck 
Protocol Number: 
(Talimogene Laherparepvec) 20130232 
EudraCT number 2015-003011-38 
Version: 
Version 4.0 
Date: 
15 July 2020 
Authors: 
NCT Number: NCT02626000
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
Page 2 
Table of Contents 
Table of Abbreviations ..................................................................................................... 5
1.
Introduction ............................................................................................................. 8
2.
Objectives ............................................................................................................... 8
2.1
Primary ....................................................................................................... 8
2.2
Secondary ................................................................................................... 8
2.3
Exploratory .................................................................................................. 8
3.
Study Overview ...................................................................................................... 9
3.1
Study Design ............................................................................................... 9
3.1.1 
Phase 1b Study Design ............................................................... 9
3.1.1.1
Rules for DLT Evaluation in Phase 1b ....................... 9
3.1.2
Tumor Response Assessment ..................................................... 9
3.1.3
Follow-Up .................................................................................. 10
3.1.3.1
Follow-Up Analysis for Phase 1b ............................. 10
3.1.3.2
Safety Follow-up ..................................................... 10
3.1.3.3
Long-term Follow-up ............................................... 10
3.2 
Sample Size .............................................................................................. 10
3.2.1
Sample Size Considerations for Phase 1b ................................. 10
4.
Study Endpoints and Covariates ........................................................................... 11
4.1 
Study Endpoints ........................................................................................ 11
4.1.1
Primary Endpoints ..................................................................... 11
4.1.2
Secondary Endpoints ................................................................ 11
4.1.3
Exploratory Endpoints ............................................................... 11
4.2 
Planned Covariates ................................................................................... 11
5.
Hypotheses and/or Estimations ............................................................................ 12
6.
Definitions ............................................................................................................. 12
7.
Analysis Subsets .................................................................................................. 20
7.1
DLT Analysis Set ....................................................................................... 20
7.2
Efficacy Analysis Set ................................................................................. 21
7.3
Full Analysis Set........................................................................................ 21
7.4
Safety Analysis Set ................................................................................... 21
7.5
Biomarker Analysis Set ............................................................................. 21
7.6
qPCR Suspicious Lesion Swab Analysis Set ............................................. 21
7.7
qPCR Blood Analysis Set .......................................................................... 21
7.8
qPCR Urine Analysis Set .......................................................................... 22
7.9
qPCR Exterior Occlusive Dressing Analysis Set........................................ 22
7.10
qPCR Injected Lesion Analysis Set ........................................................... 22
7.11
qPCR Oral Mucosa Analysis Set ............................................................... 22
7.12
qPCR Blood Clearance Analysis Set ......................................................... 22


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
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7.13 
qPCR Urine Clearance Analysis Set ......................................................... 22 
7.14 
Lesion Analysis Sets ................................................................................. 22 
8. 
Interim Analysis and Early Stopping Guidelines .................................................... 23 
8.1 
Interim Analyses........................................................................................ 23 
8.1.1 
DLT Safety Analysis (Phase 1b) ................................................ 23 
9. 
Data Screening and Acceptance ........................................................................... 23 
9.1 
General Principles ..................................................................................... 23 
9.2 
Data Handling and Electronic Transfer of Data ......................................... 23 
9.3 
Handling of Missing and Incomplete Data ................................................. 23 
9.4 
Detection of Bias ....................................................................................... 24 
9.5 
Outliers ..................................................................................................... 24 
9.6 
Distributional Characteristics ..................................................................... 24 
9.7 
Validation of Statistical Analyses ............................................................... 24 
10. 
Statistical Methods of Analysis.............................................................................. 24 
10.1 
General Principles ..................................................................................... 24 
10.2 
Subject Accountability ............................................................................... 25 
10.3 
Important Protocol Deviations ................................................................... 25 
10.4 
Demographic and Baseline Characteristics ............................................... 25 
10.5 
Efficacy Analyses ...................................................................................... 26 
10.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 26 
10.5.1.1 
Phase 1b ................................................................. 26 
10.5.2 
Analyses of Secondary Efficacy Endpoints ................................ 26 
10.5.2.1 
Phase 1b ................................................................. 26 
10.5.3 
Analyses of Exploratory Endpoints ............................................ 27 
10.5.3.1 
Phase 1b ................................................................. 27 
10.5.4 
Biomarker Endpoints ................................................................. 27 
10.5.5 
Sensitivity Analyses ................................................................... 27 
10.6 
Safety Analyses ........................................................................................ 27 
10.6.1 
Adverse Events and Disease-Related Events ............................ 27 
10.6.2 
Laboratory Test Results ............................................................ 29 
10.6.3 
Vital Signs ................................................................................. 29 
10.6.4 
Electrocardiogram (ECG) .......................................................... 29 
10.6.5 
Antibody Formation ................................................................... 29 
10.6.6 
Exposure to Investigational Product .......................................... 29 
10.6.7 
Exposure to Concomitant Medication ........................................ 30 
10.6.8 
Talimogene Laherparepvec DNA ............................................... 30 
10.6.8.1 
Incidence of Detection of Talimogene 
Laherparepvec DNA in Lesions Suspected 
to be Herpetic in Origin ............................................ 30 
10.6.8.2 
Incidence of Clearance of Talimogene 
Laherparepvec DNA From Blood and 
Urine ....................................................................... 30 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
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10.6.8.3 
Rate of Detection and Subject Incidence of 
Talimogene laherparepvec DNA and Virus 
From Blood, Urine, Exterior of Occlusive 
Dressing, Surface of Injected Lesions, and 
Oral Mucosa ............................................................ 31 
10.7 
Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Analysis .................................................................................................... 31 
11. 
Changes From Protocol-specified Analyses.......................................................... 32 
12. 
Literature Citations / References ........................................................................... 33 
13. 
Appendices ........................................................................................................... 34 
List of Tables 
Table 1.  Matrix of Determining iBOR per irRECIST ...................................................... 14 
List of Appendices 
 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
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Table of Abbreviations 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event 
AEOSI 
adverse events of specific interest 
BDSG 
Biomedical Data Stewardship Governance 
BOR 
best overall response (per RECIST v1.1) 
CI 
confidence interval 
CR 
complete response (per RECIST v1.1) 
CRF  
case report form 
CRR 
complete response rate (per RECIST v1.1) 
CSR 
Clinical Study Report 
CST 
Clinical Study Team 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate (per RECIST v1.1) 
DILI 
drug-induced liver injury 
DLRT 
Dose Level Review Team 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response (per RECIST v1.1) 
DRE 
disease-related event 
EAS 
Efficacy Analysis Set 
ECG 
electrocardiogram 
ECI 
event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOI 
event of interest 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GSO-DM 
Amgen Global Study Operations-Data Management 
HPV 
Human papillomavirus 
HR 
hazard ratio 
HSV, HSV-1 
herpes simplex virus, herpes simplex virus type 1 
IP 
Investigational product 
IPD 
Important protocol deviation 
iBOR 
best overall response (per irRECIST) 
iCR 
complete response (per irRECIST) 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
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Abbreviation or Term 
Definition/Explanation 
iCRR 
complete response rate (per irRECIST) 
iDCR 
disease control rate (per irRECIST) 
iDOR 
duration of response (per irRECIST) 
iORR 
objective response rate (per irRECIST) 
iPD 
progressive disease (per irRECIST) 
iPFS 
progression-free survival (per irRECIST) 
iPR 
partial response (per irRECIST) 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
(RECIST)  
iSD 
stable disease (per irRECIST) 
iUE 
unable to evaluate (per irRECIST) 
IV 
intravenous 
IVR 
Interactive Voice Response 
KM 
Kaplan-Meier 
L-CR 
lesion complete response 
L-ORR 
lesion objective response rate 
L-PR 
lesion partial response 
LSE(G) 
global last subject enrolled 
MRI 
magnetic resonance imaging 
ND 
not done 
ORR 
objective response rate (per RECIST v1.1) 
OS 
overall survival 
PD 
progressive disease (per RECIST v1.1) 
PD-L1 
programmed cell death-1 ligand 1 
PFS 
progression-free survival (per RECIST v1.1) 
PFU 
plaque-forming unit 
PK 
pharmacokinetics 
PR 
partial response 
qPCR 
quantitative polymerase chain reaction 
rcd 
rapid clinical deterioration 
RECIST 
Response Evaluation Criteria in Solid Tumor 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease (per RECIST v1.1) 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
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Abbreviation or Term 
Definition/Explanation 
UE 
unable to evaluate (per RECIST v1.1) 
WHO DRUG 
World Health Organization Drug 
 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
Page 8 
 
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 #4 for Talimogene 
Laherparepvec Study 20130232 dated 11 May 2018.  The scope of this plan includes 
the primary analysis, follow-up analysis, and final analysis of the phase 1b part of the 
study 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 
completion analysis, follow-up analysis, and final analysis of phase 1b.  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 
Phase 1b 
 
To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), 
of talimogene laherparepvec in combination with pembrolizumab in subjects with 
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) 
2.2 
Secondary 
Phase 1b 
 
To evaluate the efficacy of talimogene laherparepvec in combination with 
pembrolizumab as assessed by: 
 
Objective response rate (iORR), complete response rate (iCRR), and best 
overall response (iBOR); duration of response (iDOR), disease control 
rate (iDCR), and progression free survival (iPFS) (response evaluation by 
investigator using immune-related RECIST [irRECIST]) 
 
OS  
 
To evaluate the safety of talimogene laherparepvec in combination with 
pembrolizumab as assessed by incidence of adverse events and laboratory 
abnormalities 
2.3 
Exploratory 
Phase 1b 
 
To evaluate ORR, CRR, BOR, DCR, and DOR (response by investigator using 
modified RECIST v1.1) 
 
To evaluate responses in injected and uninjected tumors by investigator 
assessment  
 
To estimate the incidence of detection of talimogene laherparepvec DNA in 
lesions suspected to be herpetic in origin 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
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 
To estimate the incidence of clearance of talimogene laherparepvec DNA from 
blood and urine 
 
To estimate the rate of detection and subject incidence of talimogene 
laherparepvec DNA and virus from blood, urine exterior of occlusive dressing, 
surface of injected lesions and oral mucosa 
 
To assess blood and tumor tissue for potential biomarkers which predict and/or 
are correlated with clinical outcomes to talimogene laherparepvec with 
pembrolizumab 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1b/3, multicenter clinical trial. The study will be conducted in 2 parts 
(phase 1b and phase 3).  Only phase 1b is described below.  
3.1.1 
Phase 1b Study Design 
Phase 1b is a multicenter single-arm study.  Talimogene laherparepvec will be 
administered in combination with pembrolizumab to approximately 40 subjects with 
recurrent or metastatic SCCHN.  DLT will be evaluated based on the first 
18 DLT-evaluable subjects.  An expansion cohort of up to an additional 22 treated 
subjects will be enrolled to obtain a total of approximately 40 treated subjects to further 
evaluate the safety and to estimate the efficacy of the combination of talimogene 
laherparepvec with pembrolizumab to support a decision to initiate the phase 3 study.    
3.1.1.1 
Rules for DLT Evaluation in Phase 1b 
Safety will be evaluated considering the incidence of DLTs among all DLT-evaluable 
subjects in the phase 1b.  See protocol Section 3.1.1.1 for rules for DLT evaluation and 
Section 3.1.1.2 for the definition of DLT.   
3.1.2 
Tumor Response Assessment 
For Phase 1b, conventional RECIST 1.1 (Eisenhauer et al., 2009), with the following 
modification, will be used by the investigator to determine eligibility: 
 
Increased total target lesions to a maximum of 10 (up to a maximum of 5 per 
organ) 
A variation of RECIST 1.1, irRECIST, will be used by the investigator to assess tumor 
response and make treatment decisions, and to assess the secondary tumor response 
related endpoints in the phase 1b portion of the study.    


Product:  Talimogene Laherparepvec 
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Date:  15 July 2020 
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3.1.3 
Follow-Up 
3.1.3.1 
Follow-Up Analysis for Phase 1b 
For the phase 1b part of the study, the primary analysis will be repeated 1 year after the 
last subject enrolled. 
3.1.3.2 
Safety Follow-up 
All subjects who receive investigational product will complete a safety follow-up visit 
approximately 30 (+7) days after the last dose of study treatment.  Adverse events and 
disease related events (DRE) will be collected as described in protocol Section 9.2. 
Serious adverse events and any concomitant medications associated with serious 
adverse events observed by the investigators or reported by the subjects that occur 
through 90 (+7) days after the cessation of all study treatment or 30 (+7) days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier, will be reported to Amgen and recorded in the CRF. 
3.1.3.3 
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 subsequent anticancer therapies every 12 weeks 
(± 28 days) from safety follow-up for approximately 36 months after the last subject is 
enrolled (see section 7.3). In addition, talimogene laherparepvec/placebo related 
adverse events that occur through the end of the long-term follow-up will be reported.  
The phase 1b subjects will be followed for approximately 36 months after the last subject 
is enrolled.   
For subjects who discontinue study treatment without documented iPD and have not 
initiated a new anticancer therapy, every effort should be made to continue monitoring 
tumor response status by clinical and radiographic tumor assessments. 
3.2 
Sample Size 
3.2.1 
Sample Size Considerations for Phase 1b 
See protocol Section 10.2.1. 


Product:  Talimogene Laherparepvec 
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Date:  15 July 2020 
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4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
4.1.1 
Primary Endpoints 
Phase 1b 
 
Subject incidence of DLT 
4.1.2 
Secondary Endpoints 
Phase 1b 
 
iORR (iCR+iPR), iCRR, iBOR, iDOR, iDCR, and iPFS (response evaluation by 
investigator using irRECIST) 
 
OS 
 
Subject incidence of treatment-emergent and treatment-related adverse events 
(all adverse events, grade ≥ 3 adverse events, serious adverse events, fatal 
adverse events, adverse events and serious adverse events leading to 
discontinuation of treatment, and adverse events defined as events of interest) 
and laboratory abnormalities. 
4.1.3 
Exploratory Endpoints 
 
Phase 1b 
 
ORR, CRR, BOR, DCR, and DOR (response evaluation by investigator using 
modified RECIST v1.1) 
 
Incidence of clearance of talimogene laherparepvec DNA from blood and urine 
 
Rate of detection and subject incidence of talimogene laherparepvec DNA and 
virus from blood, urine, exterior of occlusive dressing, surface of injected lesions, 
and oral mucosa 
 
Response rates in injected and uninjected lesions: evaluable lesion incidence of 
a ≥ 30% decrease in lesion length for ≥ 4 weeks 
 
Incidence of detection of talimogene laherparepvec DNA in lesions suspected to 
be herpetic in origin 
 
Potential biomarkers which predict and/or are correlated with clinical outcomes to 
talimogene laherparepvec and pembrolizumab 
4.2 
Planned Covariates 
To explore the robustness of efficacy signal in phase 1b, iORR may also be estimated 
separately by PD-L1 status (positive/not positive) or other covariates listed below. 
 
Region (South America vs North America vs EU vs Asia vs Other for phase 1b) 
 
Age at baseline: < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 
 
Sex (female vs male) 
 
Prior smoking (never vs former vs current) 
 
HSV-1 serostatus (positive vs negative) 


Product:  Talimogene Laherparepvec 
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 
HPV status (positive vs negative vs unknown) (phase 1b) 
 
The sum of diameters of target lesions 
 
Weight loss >5% in the previous 6 months 
 
Primary tumor site (oral cavity vs oropharynx vs hypopharynx vs larynx) 
 
Brain metastasis status (baseline brain metastasis vs no baseline brain 
metastasis) 
 
Prior radiotherapy for the treatment of SCCHN 
 
Extent of disease (metastatic vs locoregionally recurrent) 
 
Prior lines of therapy in recurrent/metastatic setting (0, 1 or 2) 
 
PD-L1 status at baseline (PD-L1 positive vs PD-L1 not positive) 
 
CD8+ T cell density 
 
Maximum blinded investigational product total volume per treatment 
administration > 4 mL at highest concentration (yes, no)  
Other covariates reported in the literature or from other Amgen studies maybe 
considered as appropriate at the time of analysis. 
5. 
Hypotheses and/or Estimations 
Phase 1b:  
Talimogene laherparepvec in combination with pembrolizumab will be safe and well 
tolerated in subjects with recurrent or metastatic SCCHN. 
6. 
Definitions 
1-year, 2-year, and 3-year survival 
The Kaplan-Meier (KM) estimate of the overall survival (OS) at 1 year, 2 years, and 
3 years. 
Actual Follow-Up Time 
Actual follow-up time for a subject is calculated from the enrollment (phase 1b) date to 
the last on-study date (ie, death date, or date last known to be alive for subjects 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 (ie, on or prior to the first date of dosing) in the 
respective phase of the study.  Parameters that are obtained on the same day as the 
first date of dosing are assuming to be pre-dose. For subjects who are not dosed, the 


Product:  Talimogene Laherparepvec 
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Date:  15 July 2020 
Page 13 
 
baseline value of a parameter is considered to be the latest value prior to the enrollment 
date. 
Best overall response (iBOR) per irRECIST 
Best overall response (iBOR) of complete response (iCR), partial response (iPR), stable 
disease (iSD), progressive disease (iPD) or unevaluable (iUE) will be derived based on 
investigator assessment using immune-related RECIST [irRECIST]) (see protocol 
Appendix D).  The visit overall response assessments occurring after initiation of 
non-study anticancer therapy will not be included. The visit overall response 
assessments occurring on or after a complete or partial removal/reduction of any 
target or non-target lesion containing cancer or with unknown pathology results will not 
be included except an iPD observation.   
Confirmation of iCR, iPR, and iPD is required as noted in the individual definitions for 
iCR, iPR and iPD per irRECIST. For the derivation of iBOR, the overall visit response will 
be considered iSD if it is an unconfirmed iCR or iPR, and iUE if it is either iSD earlier 
than 56 days after the date of first dose (phase 1b) or an unconfirmed iPD when 
confirmation of iPD is required (eg, initial iPD without clinical deterioration). As indicated 
in Table 1, iBOR is defined as the best overall visit response in the following order: iCR, 
iPR, iSD, iPD, or iUE.   


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Table 1.  Matrix of Determining iBOR per irRECIST 
Visit Overall 
Response Sequence Examples 
Best 
Overall 
Response Specifications 
*, iCR, iCR,* 
iPR, iCR, iCR 
iCR, iCR, iPD 
iCR 
A confirmatory iCR must be at least 
4 weeks (28 days) later; a subsequent 
iCR within 28 days will not be valid for 
confirmation and will be ignored; the iCR 
will also not be confirmed if there is a 
subsequent iPR/iSD/iPD at any time prior 
to the next iCR. 
*, iPR, iPR, * 
 
*, iPR, iCR/iPR, 
non-iCR, * 
 
*,iCR, iPR,* 
iPR, iPR, iPD 
iPR, iCR, iPD 
 
iCR, iPR, iPD 
iPR 
Criteria for iBOR=iCR not met. 
A confirmatory iPR/iCR   must be no less 
than 4 weeks (28 days) later; a 
subsequent iPR/iCR within 28 days will 
not be valid for confirmation and will be 
ignored; the iPR will also not be confirmed 
if there is a subsequent iSD/iPD at any 
time prior to the next iPR/iCR. 
*, iSD, * 
 
*, iCR, non-iPR/iCR, 
* 
 
*, iPR, non-iPR/iCR, * 
iCR 
iPD, iCR 
iPR 
iPD, iPR, iSD 
iSD 
iPD, iSD, iPD 
iSD 
Criteria for iBOR=iCR or iPR not met. 
iSD must be ≥ 56 days from first dose 
(phase 1b); however, this is not required 
for an unconfirmed iCR/iPR. 
*, iPD, iPD, * 
 
*, iPDrcd, * 
 
 
*, iPD, non-iPD, iPD,* 
iPDrcd = iPD from 
rapid clinical 
deterioration as the 
reason for ending 
radiographic 
follow-up. 
iPD, iPD 
iPD,iSD,iPD,iPD 
iPD, iUE, iPD 
iPDrcd 
iPD 
Criteria for iBOR=iCR, iPR, or iSD not 
met. 
A consecutive confirmatory iPD must be 
no less than 4 weeks (28 days) later 
unless there is rapid clinical 
deterioration; iPDrcd does not require 
confirmation.  If an initial visit overall 
response of iPD is not confirmed, then a 
subsequent iPD does not need to be 
confirmed for a subject overall response 
of iPD. 
*, iSD, * 
 
iPD 
iSD 
iUE, iSD 
iPD 
iUE, iPD 
iUE 
Criteria for iBOR=iCR, iPR, iSD, or iPD 
not met. 
iSD must be < 56 days from first dose 
(phase 1b). 


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Best overall response (BOR) per RECIST v1.1 
Best overall response (BOR) of complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD) or unevaluable (UE) will be derived based on 
investigator assessment using RECIST v1.1 (see protocol Appendix E).  The visit overall 
response assessments occurring after initiation of non-study anticancer therapy will not 
be included. The visit overall response assessments occurring on or after a 
complete or partial removal/reduction of any target or non-target lesion containing 
cancer or with unknown pathology results will not be included except a PD observation.   
Confirmation of CR and PR is not required. For the derivation of BOR, the overall visit 
response will be UE if SD is earlier than 56 days after the date of first dose. As 
indicated in protocol Table 15, BOR is defined as the best overall visit response in the 
following order: CR, PR, PD, SD, or UE.   
BOR per modified RECIST v1.1 for Phase 1b subjects will follow the same derivation. 
Disease control rate (iDCR) per irRECIST 
Disease control rate (iDCR) per irRECIST is defined as the incidence of an iBOR of iCR 
or iPR or iSD among the set of subjects analyzed.  
Disease control rate (DCR) per RECIST v1.1 
Disease control rate (DCR) per RECIST v1.1 is defined as the incidence of a BOR of CR 
or PR or SD among the set of subjects analyzed.  
Duration of response (iDOR) per irRECIST 
Duration of response (iDOR) per irRECIST is defined as the time from the date of an 
initial response of iCR or iPR that is subsequently confirmed to the earlier of a subject 
overall response of iPD (see protocol Table 14) or death. Subjects who have not ended 
their response at the time of analysis will have iDOR censored at their last evaluable 
tumor assessment. This endpoint only applies to subjects with an iCR or iPR per 
irRECIST. 
Duration of response (DOR) per RECIST v1.1 
Duration of response (DOR) per RECIST v1.1 is defined as the time from the date of an 
initial response of CR or PR to the earlier of a subject overall response of PD (see 
protocol Table 16) or death.  Subjects who have not ended their response at the time of 


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analysis will have DOR censored at their last evaluable tumor assessment. This 
endpoint only applies to subjects with a CR or PR per RECIST v1.1. 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the purposes of final collection of data 
for the primary endpoint(s), for the purposes of conducting the primary analysis, whether 
the study concluded as planned in the protocol or was terminated early. 
If a 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). 
Primary Completion Phase 1b only:  The time when the last phase 1b subject is 
assessed or receives an intervention for the purposes of final collection of data for the 
primary endpoint of phase 1b.  The primary completion is anticipated to occur when the 
last phase 1b subject completes the week 9 tumor response assessment. 
End of Study (end of trial):  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.  This is anticipated to occur 36 months after the last subject is 
enrolled. 
Evaluable tumor assessment 
A visit overall response other than unevaluable (iUE) for irRECIST (see protocol 
Table 14) or not evaluable (NE) for RECIST v1.1 (see protocol Table 16).   
Event of Interest (EOI) for Talimogene Laherparepvec 
An event of interest (EOI) is a noteworthy treatment-emergent adverse event for 
talimogene laherparepvec that may warrant careful monitoring. It could be serious or 
non-serious, and could include events that might be potential precursors or prodromes 
for more serious medical conditions in susceptible individuals (Council for International 
Organizations of Medical Sciences (CIOMS) VI, 2005).  
 
 
. The 
set of EOIs to be evaluated will be identified at the time of analysis based on the current 


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product-specific standard MedDRA queries or Amgen MedDRA Queries maintained by 
Amgen Pharmacovigilance Operations. 
 
Investigational product (IP) 
Investigational product (IP) refers to talimogene laherparepvec (also known as “Amgen 
IP”) and pembrolizumab (also known as “non-Amgen IP”). 
Lesion complete response (L-CR) 
Lesion complete response (L-CR) applies only to measurable lesions (baseline) and is 
defined as complete disappearance of a lesion with confirmation by a repeat consecutive 
assessment no less than 4 weeks (28 days) from the date first documented.  A lesion 
will be censored for L-CR after the start of non-study anticancer therapy, if it merges with 
another lesion or it is resected (except if it is completely resected and pathology 
indicates absence of malignant cells). 
Lesion objective response rate (L-ORR) 
Lesion objective response rate (L-ORR) is defined as the incidence among a set of 
lesions analyzed of L-CR or L-PR.  Lesions without a follow-up assessment will be 
regarded as a non-responding lesion. 
Lesion partial response (L-PR) 
Lesion partial response applies only to measurable lesions (baseline) and is defined as 
≥ 30% decrease in lesion length (ie, longest diameter for non-nodal, shortest axis for 
nodal) relative to baseline with confirmation by a repeat consecutive assessment no less 
than 4 weeks (28 days) from the date first documented.  A lesion will be censored for 
L-PR after the start of non-study anticancer therapy, if it merges with another lesion or it 
is resected (except if it is completely resected and pathology indicates absence of 
malignant cells). 
Objective response rate (iORR) per irRECIST 
iORR is defined as the incidence of an iBOR of iCR or iPR per irRECIST among a set of 
subjects analyzed.  Subjects with an iCR or iPR will be defined as responders.  Subjects 
who do not have any follow-up tumor assessments will be regarded as non-responders 
per irRECIST. 


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Objective response rate (ORR) per RECIST v1.1 
ORR is defined as the incidence of a BOR of CR or PR per RECIST v1.1 among a set of 
subjects analyzed.  Subjects with a CR or PR will be defined as responders.  Subjects 
who do not have any follow-up tumor assessments will be regarded as non-responders 
per RECIST v1.1. 
Overall Survival (OS) 
OS is defined as the interval from first dose (phase 1b) to the event of death from any 
cause; otherwise, OS is censored at the date the subject was last known to be alive. 
Subjects with a vital status (alive or dead) obtained after the data cut off will be censored 
at the date cutoff date. 
Pembrolizumab Adverse Events of Special Interest (AEOSI) 
AEOSI for pembrolizumab are immune-mediated events and infusion-related 
reactions, which represent the known risks for and are considered causally 
associated with, pembrolizumab. A pre-specified list of preferred terms (PTs) 
based on MedDRA was developed by Merck to consistently characterize the 
nature and frequency of each AEOSI across the clinical program, regardless of 
causality as reported by investigators. These PTs are considered to be medically 
equivalent to the identified risks for pembrolizumab. 
Pembrolizumab Event of Clinical Interest (ECI)  
Pembrolizumab Events of Clinical Interest include:  an overdose of pembrolizumab as 
defined in protocol Section 9.6, and potential drug-induced liver injury (DILI) from 
pembrolizumab as defined in protocol Section 9.7. 
Potential Follow-Up Time 
Potential follow-up time for a subject is calculated from the enrollment  
(phase 1b) date to the analysis data cutoff date.   
Progression-free survival (iPFS) per irRECIST 
Progression-free survival (iPFS) per irRECIST is defined as the interval from first dose 
(phase 1b) to the earlier of a subject overall response of iPD (see protocol Table 14) or 
death from any cause; otherwise, iPFS is censored at the last evaluable tumor 
assessment. The initial date of an iPD that is consecutively confirmed will be the iPFS 
date.   


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Progression-free survival (PFS) per RECIST v1.1 
Progression-free survival (PFS) per RECIST v1.1 is defined as the interval from first 
dose (phase 1b) to the earlier of a subject overall response of PD (see protocol 
Table 16) or death from any cause; otherwise, PFS is censored at the last evaluable 
tumor assessment.  
Safety Follow-up Visit 
Safety follow-up visit will be performed approximately 30 (+7) days after the last dose of 
IP.  In addition, serious adverse events will be reported that occur through 90 (+7) days 
after the cessation of all study treatment or 30 (+7) days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier.  
Serious Adverse Events (SAE) 
Serious adverse events (SAE) are defined as any adverse event categorized as serious 
as determined by investigator per protocol Section 9.1.3. 
Study day 
Study day is calculated from the first day IP is administered (ie, non-zero dosing) to the 
subject.  Study day = visit date – first dose date +1 if visit date is on or after the first dose 
date. Study day = visit date – first dose date, if visit date is before the first dose date. 
Study Day 1 
Study day 1 is defined as the first day of IP administration (ie, non-zero dosing) of the IP 
after enrollment.  The day prior to Study Day 1 is considered Day -1.   
Study Week 0 
The start of IP administration (ie, non-zero dosing) to the subject is study week 0. Study 
day 1 is corresponding to study week 0. 
Treatment period 
Treatment period is defined as the period between the first IP dose date and 30 days 
after the last IP dose date. 
Treatment-emergent Adverse Events (TEAE) 
Treatment-emergent adverse events (TEAE) are defined as any adverse event with an 
onset date during the treatment period, through 30 days after the last dose of 
talimogene laherparepvec or pembrolizumab, whichever is later.  Adverse events 


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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 question “Did 
event start before first dose of IP” is answered “Yes” 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 Disease-Related Events (DREs) 
Treatment-emergent Disease-Related Events (DREs) are defined as events determined 
by the investigator to be disease-related, with an onset during the treatment period, 
through 30 days after the last dose of talimogene laherparepvec or 
pembrolizumab, whichever is later.  DREs that occur on the same day as the first 
dose 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 the 
eCRF, then the event will not be counted as a treatment-emergent DRE). 
Treatment-emergent Serious Adverse Events (TESAE) 
Treatment-emergent serious adverse events (TESAE) are defined as any SAE with 
an onset date during the treatment period through 90 days after the last dose of 
talimogene laherparepvec or pembrolizumab, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier. 
SAEs that occur on the same day as the first dose date of IP will be treated as 
treatment-emergent SAE unless indicated otherwise (for example, if an event 
occurs on the same date as the first administration of talimogene laherparepvec 
and the question “Did event start before first dose of IP” is answered “Yes” on 
eCRF, then the event will not be counted as a treatment-emergent SAE. 
Additionally, if an event is identified as disease-related on the eCRF, it will not be 
counted as a treatment-emergent SAE). 
7. 
Analysis Subsets 
7.1 
DLT Analysis Set 
The DLT analysis set will include DLT-evaluable subjects who have had the opportunity 
to be on treatment for at least 6 weeks from the initial dosing of study treatment and 
have received at least 2 doses of talimogene laherparepvec and 2 doses of 


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pembrolizumab in combination, or have a DLT during the DLT evaluation period after at 
least 1 dose of talimogene laherparepvec and pembrolizumab in combination. 
7.2 
Efficacy Analysis Set 
The Efficacy Analysis Set (EAS) will be used for the primary efficacy analysis of the 
phase 1b.  It is a subset of the Safety Analysis Set where subjects with locoregionally 
advanced disease with a recurrence < 3 months after prior platinum-containing curatively 
intended multimodal therapy are excluded. 
7.3 
Full Analysis Set 
Secondary efficacy analyses for the phase 1b part of the study will be conducted on the 
Full Analysis Set (FAS) defined as all subjects who have received at least 1 dose of 
talimogene laherparepvec and 1 dose of pembrolizumab in combination. Efficacy will be 
analyzed with the FAS overall and excluding subjects in the EAS.   
7.4 
Safety Analysis Set 
The Safety Analysis Set (SAS) will include all enrolled subjects (phase 1b) who received 
at least 1 dose of talimogene laherparepvec or pembrolizumab.   
7.5 
Biomarker Analysis Set 
A Biomarker Analysis Set will be defined separately for each individual candidate 
biomarker.  For exploratory and predictive analyses, the analysis set will include all 
treated (phase 1b) subjects with a baseline biomarker result and, for analyses of 
biomarker changes, the analysis set will include all treated (phase 1b) subjects that have 
a baseline and at least one subsequent biomarker result. 
7.6 
qPCR Suspicious Lesion Swab Analysis Set 
The qPCR Suspicious Lesion Swab Analysis Set will include subjects who are enrolled 
(phase 1b), receive at least one dose of talimogene laherparepvec / placebo, and have 
at least one swab sample evaluable result from lesions suspicious to be herpetic in 
origin during the study. Evaluable samples are sample with either positive, BQL, or not 
detected results. 
7.7 
qPCR Blood Analysis Set 
The qPCR Blood Analysis Set applies only to the phase 1b and will include treated 
subjects that have at least one post-dose blood sample evaluable result for qPCR 
testing of talimogene laherparepvec DNA. 


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7.8 
qPCR Urine Analysis Set 
The qPCR Urine Analysis Set applies only to the phase 1b and will include treated 
subjects that have at least one post-dose urine sample evaluable result for qPCR testing 
of talimogene laherparepvec DNA. 
7.9 
qPCR Exterior Occlusive Dressing Analysis Set 
The qPCR Exterior Occlusive Dressing Analysis Set applies only to the phase 1b and 
will include treated subjects that have at least one post-dose exterior occlusive dressing 
surface swab evaluable result for qPCR testing of talimogene laherparepvec DNA. 
7.10 
qPCR Injected Lesion Analysis Set 
The qPCR Injected Lesion Analysis Set applies only to the phase 1b and will include 
treated subjects that have at least one post-dose swab of an injected lesion with an 
evaluable result for qPCR testing of talimogene laherparepvec DNA. 
7.11 
qPCR Oral Mucosa Analysis Set 
The qPCR Oral Mucosa Analysis Set applies only to the phase 1b and will include 
treated subjects that have at least one post-dose swab of oral mucosa with an evaluable 
result for qPCR testing of talimogene laherparepvec DNA. 
7.12 
qPCR Blood Clearance Analysis Set 
The qPCR Blood Clearance Analysis Set applies only to the phase 1b and will include 
treated subjects that have at least one qPCR positive talimogene laherparepvec DNA 
blood sample, and at least one evaluable subsequent sample at any time during the 
same cycle. 
7.13 
qPCR Urine Clearance Analysis Set 
The qPCR Urine Clearance Analysis Set applies only to the phase 1b and will include 
treated subjects that have at least one qPCR positive talimogene laherparepvec DNA 
urine sample, and at least one evaluable subsequent sample at any time during the 
same cycle. 
7.14 
Lesion Analysis Sets 
The Injected Lesion Analysis Set includes any target lesion that was ever injected and 
the Uninjected Lesion Analysis Set includes any target lesion that was never injected. 
The Injected Lesion Evaluable and Uninjected Lesion Evaluable analysis sets will 
include the corresponding subset of target lesions with at least one post-baseline 
measurement prior to a censoring event, ie, non-study anticancer therapy, merged with 
another lesion, or resection (except if it is completely resected and pathology indicates 


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absence of malignant cells).  If a lesion splits, the sum of the length of the split lesions 
will be added together prior to analysis.    
8. 
Interim Analysis and Early Stopping Guidelines 
8.1 
Interim Analyses 
DLT interim safety analyses are planned and conducted by the study team for the 
phase 1b with data being reviewed by a DLRT. 
8.1.1 
DLT Safety Analysis (Phase 1b) 
Up to 3 planned safety interim analyses will occur during the phase 1b to evaluate the 
incidence of DLT according to timing/rules described in protocol Table 1 (Section 3.1.1).  
At each interim analysis, a DLT listing will be generated.  The number and percentage of 
subjects with DLTs will be tabulated in a summary table among DLT-evaluable subjects.  
DLT evaluations will be based on the DLT Analysis Set. Data will be reviewed by a 
DLRT. 
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  
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data, with the exception of biomarker data, to be used in the planned 
analyses.  This study will use the RAVE database.  PD-L1 and HPV data will be 
transferred electronically to Amgen via secure server. 
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 will be imputed. Adverse events 
and disease-related events (DRE) with missing IP relatedness (AEs only), seriousness, 
or CTCAE severity grades will be included in analyses as long as the events qualify for 
the reporting period.  Events with missing relatedness (AEs only), seriousness, or 
severity grades will be excluded from corresponding treatment-related, serious, and 
worst grade analyses, respectively. If an AE or DRE end date is completely missing and 
the death date is available, the end date will be imputed with the death date.  Details of 
the imputation algorithm for partial or missing dates, including death dates, are provided 
in 
 Section 13. 


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9.4 
Detection of Bias 
Lack of protocol compliance may introduce potential bias in the estimation of protocol 
endpoints. All important protocol deviations (IPDs) will be reported, documented and 
stored in eClinical (a clinical trial management system). IPD reports will be produced 
using Cognos by the study manager and will be regularly reviewed in the study team’s 
IPD review meetings as well as before analysis.  
9.5 
Outliers 
Descriptive statistics will be used to identify potential outliers for 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 KM estimates 
for the probability of time-to-event endpoints are based on non-parametric methods.  
Time to event endpoints will be evaluated with the non-parametric log-rank test.  
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 9.4 or 
later. 
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
For the phase 1b part of the study, the DLT Analysis Set will be used to summarize the 
subject incidence of DLT and, unless specified otherwise, the SAS will be used for all 
analyses of safety.  Safety may also be analyzed using the EAS. The primary analysis of 
efficacy for the phase 1b will be based on the EAS with secondary analyses based on 
the FAS overall and excluding subjects in the EAS.  
In principle, summary statistics including mean, standard deviation, median, first and 
third quartiles, will be provided for continuous variables.  Frequency and percentage will 
be summarized by treatment arm for binary and categorical variables.  Proportions and 
the corresponding 95% confidence intervals will be based on normal approximations and 


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the treatment comparison will be based on a Cochran-Mantel-Haenszel test.  Exact tests 
will be considered for subgroup analyses when the cell size is considered small.   
Time to-event endpoints will be estimated using the KM method.   
Descriptive statistics will be provided for efficacy, safety, talimogene laherparepvec 
DNA, and biomarker endpoints as appropriate 
10.2 
Subject Accountability 
The number of subjects enrolled will be tabulated by countries and investigator sites 
overall and by treatment group (when applicable). Subject disposition (including the 
number screened, enrolled, treated, ended treatment, ended radiographic follow-up, and 
that completed the safety follow-up visit) will be summarized separately for all enrolled 
subjects in phase 1b. Subject accountability will be tabulated by respective treatment 
group when applicable. Reasons for not receiving treatment, for ending treatment, 
endpoint radiographic follow-up, and not completing the 30-day safety follow-up visit 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 SAS for phase 1b of the study. 
 
Region (South America vs North America vs EU vs Asia vs Other for phase 1b;  
South America vs North America vs EU vs Japan vs Other Asia vs Other for 
phase 3) 
 
Age at baseline: < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 
 
Sex (female vs. male) 
 
Prior smoking (never vs former vs current) 
 
HSV-1 serostatus (positive vs negative) 
 
The sum of diameters of target lesions 
 
Weight loss > 5% in the previous 6 months 


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 
Primary tumor site (oral cavity vs oropharynx vs hypopharynx vs. larynx) 
 
Brain metastasis status (baseline brain metastasis vs no baseline brain 
metastasis) 
 
Prior radiotherapy for treatment of SCCHN 
 
Extent of disease (metastatic vs locoregionally recurrent) 
 
Prior lines of therapy in recurrent/metastatic setting (0, 1 or 2) 
 
PD-L1 status at baseline (positive versus not positive)   
 
CD8+ T cell density 
 
HPV (HPV- negative vs HPV-positive vs unknown)  
 
ECOG performance status (0 vs 1) 
 
Maximum blinded investigational product total volume per treatment 
administration > 4 mL at highest concentration (yes, no)  
10.5 
Efficacy Analyses  
10.5.1 
Analyses of Primary Efficacy Endpoint(s) 
10.5.1.1 
Phase 1b 
The subject incidence of DLT will be summarized using the DLT Analysis Set. 
10.5.2 
Analyses of Secondary Efficacy Endpoints 
10.5.2.1 
Phase 1b 
The primary analysis of efficacy for the phase 1b will be based on the EAS, with 
secondary analysis based on the FAS overall and excluding subjects in the EAS.  All 
endpoints of the phase 1b will be descriptively analyzed.   
The main efficacy endpoint in the phase 1b for the phase 3 decision will be the iORR 
with or without confirmation of response.  Given the observed iORR in the Efficacy 
Analysis Set, the Bayesian posterior probability will be calculated that the true 
combination iORR exceeds the expected ORR for pembrolizumab by an absolute 
amount (delta).  The expected iORR for pembrolizumab in the study population with 
9 weeks minimum potential follow-up is approximately 11% and will be represented by a 
beta(2.2,17.8) distribution with mean 0.11 and precision 20.0.  The iORR for the 
combination will be represented by a beta(0.2,1.8) distribution with mean 0.11 and 
precision 2.0.  Given the observed iORR, the posterior probability will be calculated for a 
delta increase from 0% to 30% in 5% increments as well as a 90% credible region for 
delta (see 
).   


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10.5.3 
Analyses of Exploratory Endpoints 
10.5.3.1 
Phase 1b 
The exploratory analysis for Phase 1b for ORR, CRR, BOR, DCR, and DOR (response 
by investigator using modified RECIST v1.1) will be analyzed using the analysis 
methods described in the first paragraph of Section 10.5.2.1 above, where applicable. 
 
Response rates in injected and uninjected lesions: 
L-ORR and the incidence of L-PR and L-CR separately at the lesion level will be 
summarized by enrolled/randomized treatment for subjects in the EAS (phase 
1b) and FAS(G)(phase 3) for the Injected Lesion Analysis Set and the Uninjected 
Lesion Analysis Set separately, and also for the corresponding evaluable 
analysis sets.  Waterfall plots for the maximum percent decrease in the lesion 
diameter will also be provided.  The number of subjects will be provided with at 
least one lesion in each analysis as well as the distribution of the number of 
lesions per subject. The subject incidence of an L-CR or L-PR and each 
individually will also be summarized separately for subjects with a lesion included 
in the Injected Lesion and Uninjected Lesion analysis sets and corresponding 
evaluable analysis sets. 
10.5.4 
Biomarker Endpoints 
The analysis of biomarkers for other exploratory objectives will be described and 
reported separately.   
Phase 1b 
 
Potential biomarkers which predict and/or are correlated with clinical outcomes to 
talimogene laherparepvec and pembrolizumab  
10.5.5 
Sensitivity Analyses 
The Bayesian analyses of phase 1b efficacy in Section 10.5.2.1 may be repeated to 
assess sensitivity due to the choice of prior for pembrolizumab and/or to account for new 
external results, such as from KEYNOTE-040. 
10.6 
Safety Analyses 
Safety analyses will be conducted separately for phase 1b based on the SAS analysis 
sets, as follows. 
10.6.1 
Adverse Events and Disease-Related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or later will be 
used to code all adverse events (AE) and disease-related events (DRE) to a system 


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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 (AEs only), 
seriousness, or CTCAE severity grades will be included in the analysis as long as the 
event is considered treatment-emergent. However, analyses of treatment-related (AEs 
only), SAE, or grade 3 or higher, or combinations thereof will exclude events with 
missing relatedness, seriousness, and severity grades, respectively. 
The analyses for AEs will include TEAEs unless otherwise specified.  The subject 
incidence of TEAEs will be summarized for all AEs, SAEs, AEs leading to withdrawal of 
investigational product, grade 3 or higher AEs, fatal AEs, talimogene laherparepvec 
events of interest (EOI), pembrolizumab events of clinical interest (ECI), and 
pembrolizumab adverse event of specific interest (AEOSI).  
Preferred term and worst grade within each category of EOI (including 
treatment-emergent EOIs and treatment-related EOIs), EOI SAEs (including 
treatment-emergent EOIs SAE and treatment-related EOI SAEs), AEOSI (including 
treatment-emergent AEOSIs and treatment-related AEOSIs) and AEOSI SAE 
(including treatment-emergent AEOSI SAEs and treatment-related AEOSI SAEs) 
will be summarized.   
The subject incidence of all TEAEs, SAEs, AEs leading to withdrawal of investigational 
product, grade 3 or higher AEs, and fatal AEs will be tabulated by system organ class, 
preferred term in descending order of frequency and worst grade.  
Summaries of all TEAEs, SAEs, AEs leading to withdrawal of investigational 
product, grade 3 or higher AEs, fatal AEs, treatment-related AEs, TEAEs and SAEs 
occurring in at least 1% of the subjects by preferred term in any treatment arm will be 
provided in descending order of frequency.  
Sensitivity analyses of TEAEs, SAEs, AE leading to withdrawal of investigational 
product and fatal AEs will be conducted, considering any DRE as an AE.   
Subject incidence of DREs, serious DREs, DREs leading to withdrawal of 
investigational product and fatal DREs will be tabulated by system organ class, 
preferred term, and worst grade. Summaries of DREs, serious DREs, and DREs 
leading to withdrawal of investigational product and fatal DREs will be tabulated 
by preferred term. 
Including all the preferred terms, a comparison of all TEAEs side by side to the 
TEAE/TEDRE and a comparison of all TESAEs side by side to the 


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TESAE/TESDREs will be produced, sorting by system organ class, preferred term, 
and worst grade.  
A listing of fatal AEs and fatal DREs will be provided. A listing of SAEs and SAE for 
EOIs will be provided.  Listing of SAEs from consent and before first dose of study 
therapy will also be provided separately. 
A listing of treatment-related AEs reported in long term follow-up will be provided for the 
final CSR and may be analyzed earlier as part of a program-wide analysis.  
Potential or known unintended exposure to Talimogene Laherparepvec, related 
suspected signs or symptoms, and detection of Talimogene Laherparepvec DNA in 
swabs of suspected herpetic-like lesions in a subject’s household member, caregiver, or 
healthcare provider will be reported in the final CSR. Individual reported cases with 
available qPCR testing results will be reviewed.  Additionally, unintended exposures will 
be analyzed periodically as part of a program-wide analysis. 
10.6.2 
Laboratory Test Results 
Shifts in grades of safety laboratory values between the baseline and the worst on-study 
value will be tabulated. Subject incidence of potential hepatotoxicity 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. 
10.6.3 
Vital Signs 
Analysis of vital signs will not be performed as routine monitoring and collection of vital 
sign data is not sufficient to require an analysis. 
10.6.4 
Electrocardiogram (ECG) 
The ECG measurements from this clinical study will performed as per standard of care 
for routine safety monitoring.  Summaries and statistical analyses of ECG 
measurements are not planned. 
10.6.5 
Antibody Formation 
The incidence and percentage of subjects who develop anti-pembrolizumab antibodies 
(binding and if positive, neutralizing) at any time and at last post baseline assessment 
will be analyzed by Merck. 
10.6.6 
Exposure to Investigational Product 
Summary statistics for exposure to talimogene laherparepvec, including total doses 
administered, total volume administered, distribution of the number of administrations 


Product:  Talimogene Laherparepvec 
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with a total volume > 4 mL, 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). Subject incidence and reasons for IP dose 
change/withheld will be tabulated. 
Exposure to pembrolizumab including total doses (in mg) administered, relative dose 
intensity, duration from the first to the last administration, and the average dose received 
by subject per visit will be provided. Subject incidence rate and reasons for IP delay, 
dose change/withheld dose delay, and dose interruption of pembrolizumab will be 
examined. 
A listing of the unique manufacturing lot numbers, and a listing of the subjects 
administered each manufacturing lot number will be provided. 
10.6.7 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category for each treatment group as coded by the 
World Health Organization Drug (WHO DRUG) dictionary.   
10.6.8 
Talimogene Laherparepvec DNA 
10.6.8.1 
Incidence of Detection of Talimogene Laherparepvec DNA in 
Lesions Suspected to be Herpetic in Origin 
Phase 1b 
The number and proportion of subjects with positive qPCR for talimogene laherparepvec 
DNA detection in any swab of a lesion suspected to be herpetic in origin will be 
calculated based on the qPCR Suspicious Lesion Swab Analysis Set.  An exact 95% CI 
for the binomial proportion will be calculated (Clopper & Pearson, 1934). 
Individual subjects having a positive qPCR results for talimogene laherparepvec DNA 
detection will be reviewed.   
10.6.8.2 
Incidence of Clearance of Talimogene Laherparepvec DNA From 
Blood and Urine  
Phase 1b 
The number and proportion of subjects with undetectable talimogene laherparepvec 
DNA per qPCR among subjects with sample collected in each cycle will be presented.  
Incidence of clearance of talimogene laherparepvec DNA from Cycle 1, 2, 3, and 4 will 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
Page 31 
 
be calculated by cycle.  An exact 95% CI for the binomial proportion will be calculated 
(Clopper & Pearson, 1934). 
Analysis of incidence of clearance of talimogene laherparepvec DNA from blood and 
urine will be analyzed using the qPCR Blood Clearance Analysis Set and qPCR Urine 
Clearance Analysis Set, respectively. 
10.6.8.3 
Rate of Detection and Subject Incidence of Talimogene 
laherparepvec DNA and Virus From Blood, Urine, Exterior of 
Occlusive Dressing, Surface of Injected Lesions, and Oral Mucosa  
Phase 1b 
Rate of detection and subject incidence of talimogene laherparepvec DNA and virus will 
be analyzed separately for blood, urine, exterior of occlusive dressing, surface of 
injected lesions, and oral mucosa using qPCR Blood Analysis Set, qPCR Urine Analysis 
Set, qPCR Exterior Occlusive Dressing Analysis Set, qPCR Injected Lesion Analysis 
Set, and qPCR Oral Mucosa Analysis Set, respectively. 
The number and proportion of subjects who have at least 1 positive qPCR result will be 
presented.  The number and proportion of subjects exhibiting detectable virus from 
TCID50 assay will also be presented.  Numeric results of positive qPCR, and separately 
for detectable virus from TCID50, will be summarized as a continuous variable.  An 
exact 95% CI for the binomial proportion will be calculated (Clopper & Pearson, 1934). 
Subject incidence and rate of subsequent positive TCID50 testing for positive qPCR 
testing results will be presented using qPCR Exterior Occlusive Dressing Analysis Set, 
qPCR Injected Lesion Analysis Set, and qPCR Oral Mucosa Analysis Set. 
qPCR and TCID50 results for subjects having a positive qPCR testing will be reviewed. 
10.7 
Pharmacokinetic or Pharmacokinetic/Pharmacodynamic Analysis 
Pembrolizumab PK sample and data analysis will be provided by Merck. 
Pembrolizumab concentrations and pharmacokinetic (PK) parameters including the Cmin, 
Cmax, and AUC will be listed and summarized using descriptive statistics. Preliminary 
analysis will include examining the PK parameters for extreme values falling out of the 
standardized ranges of deviations as predicted by the existing population PK model. The 
impact of any outliers on the results of the analyses will be evaluated. Population PK 
analysis, based on pharmacokinetic PK data obtained in this study together with that 
obtained from other studies, will be conducted.  


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
Page 32 
 
The analysis plan and report from that population PK analysis will be described in 
separate documents.   
11. 
Changes From Protocol-specified Analyses 
Following the review of the phase 1b primary analysis of efficacy and safety, a decision 
was made by the sponsor to not proceed with the phase 3 portion of this study.  
Therefore, all study design and statistical methods related to the phase 3 that are 
described in the protocol are not included in this SAP.  None of the phase 3 analyses 
specified in the protocol will be performed. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
Page 33 
 
12. 
Literature Citations / References 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and 
Research, Food and Drug Administration. Guidance for industry. Drug-induced liver 
injury: premarketing clinical evaluation. Drug Safety. July 2009. 
Clopper, C. and Pearson, E. (1934) The Use of Confidence or Fiducial Limits Illustrated 
in the Case of the Binomial. Biometrika, 26, 404–413  
Council for International Organizations of Medical Sciences (CIOMS) Working Group VI. 
CIOMS; Geneva, Switzerland: 2005. Management of safety information from clinical 
trials. 
Eisenhauer, A., et al. (2009) New Response Evaluation in Solid Tumors: Revised 
RECIST Guideline (version 1.1). EJC, 45, 228-247. 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
Date:  15 July 2020 
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13. 
Appendices 


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Product:  Talimogene Laherparepvec 
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Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
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Product:  Talimogene Laherparepvec 
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Product:  Talimogene Laherparepvec 
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Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20130232 
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Prot_000.pdf: 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 2 of 158 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1b/3 Multicenter, Randomized Trial of 
Talimogene Laherparepvec in combination with Pembrolizumab for the Treatment of 
Subjects With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck, 
dated 11 May 2018, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent 
children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] 
and dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 3 of 158 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1b/3 Multicenter, Randomized Trial of Talimogene Laherparepvec in combination 
with Pembrolizumab for theTreatment of Subjects With Recurrent or Metastatic Squamous Cell 
Carcinoma of the Head and Neck 
Study Phase:  Phase 1b/3 
Indication:  Squamous Cell Carcinoma of the Head and Neck (SCCHN) 
Primary Objective:   
Phase 1b:  To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of 
talimogene laherparepvec in combination with pembrolizumab in subjects with recurrent or 
metastatic SCCHN 
Phase 3:  To evaluate the efficacy, as assessed by overall survival (OS), of treatment with 
talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab in subjects 
with recurrent or metastatic SCCHN 
Secondary Objective(s):   
Phase 1b 
• To evaluate the efficacy of talimogene laherparepvec in combination with pembrolizumab as 
assessed by: 
o Objective response rate (iORR), complete response rate (iCRR), and best overall 
response (iBOR); duration of response (iDOR), disease control rate (iDCR), and 
progression-free survival (iPFS) (response evaluation by investigator using 
immune-related Response Evaluation Criteria in Solid Tumors [irRECIST]) 
o OS  
• To evaluate the safety of talimogene laherparepvec in combination with pembrolizumab as 
assessed by incidence of adverse events and laboratory abnormalities. 
Phase 3 
o To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with 
pembrolizumab, as assessed by: 
o Objective response rate (ORR) and progression-free survival (PFS) (response 
evaluation by investigator using RECIST v1.1) 
o iORR and iPFS (response evaluation by investigator using irRECIST)  
o iCRR, iBOR; iDOR, and iDCR (response evaluation by investigator using irRECIST) 
o CRR, BOR, DOR, and DCR (response evaluation by investigator using RECIST v1.1) 
o 1-year, 2-year, and 3-year survival 
o Subject incidence of treatment-emergent and treatment-related adverse events (all 
adverse events, grade ≥ 3 adverse events, serious adverse events, fatal adverse 
events, adverse events and serious adverse events leading to discontinuation of 
treatment, and adverse events defined as events of interest) 
o To evaluate patient reported outcomes (PRO) as assessed by the European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 
(QLQ-C30) Global Health Status/Quality of life (GHS/QoL) subscale. 
Hypotheses: 
Phase 1b  
Talimogene laherparepvec in combination with pembrolizumab will be safe and well tolerated in 
subjects with recurrent or metastatic SCCHN. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 4 of 158 
CONFIDENTIAL 
 
 
Phase 3 
The clinical hypothesis is that talimogene laherparepvec with pembrolizumab compared to 
placebo with pembrolizumab will improve OS.  In addition to the hypothesis test for the primary 
endpoint, ORR, PFS, iORR, and iPFS in subjects given talimogene laherparepvec plus 
pembrolizumab versus placebo plus pembrolizumab will be compared. 
Primary Endpoint: 
Phase 1b  
• Subject incidence of DLT 
Phase 3 
• OS 
Secondary Endpoint(s):  
Phase 1b 
• iORR (complete response [iCR]+ partial response [iPR]), iCRR, iBOR, iDOR, iDCR, and 
iPFS (response evaluation by investigator using irRECIST) 
• OS 
• Subject incidence of treatment-emergent and treatment-related adverse events (all 
adverse events, grade ≥ 3 adverse events, serious adverse events, fatal adverse events, 
adverse events and serious adverse events leading to discontinuation of treatment, and 
adverse events defined as events of interest) and laboratory abnormalities. 
Phase 3 
• ORR and PFS (response evaluation by investigator using RECIST v1.1) 
• iORR and iPFS (response evaluation by investigator using irRECIST) 
• iCRR, iBOR; iDOR, and iDCR (response evaluation by investigator using irRECIST) 
• CRR, BOR, DOR, and DCR (response evaluation by investigator using RECIST v1.1) 
• 1-year, 2-year, and 3-year survival 
• Subject incidence of  treatment-emergent and treatment-related adverse events (all 
adverse events, grade ≥ 3 adverse events, serious adverse events, fatal adverse events, 
adverse events and serious adverse events leading to discontinuation of treatment, and 
adverse events defined as events of interest). 
• Summary scores at each assessment and changes from baseline of PROs as assessed by 
QLQ-C30 GHS/QoL subscale. 
Study Design: This is a phase 1b/3, multicenter clinical trial. The study will be conducted in 
2 parts (phase 1b and phase 3).  In phase 1b talimogene laherparepvec will be administered in 
combination with pembrolizumab to approximately 40 subjects with recurrent or metastatic 
SCCHN.  DLT will be evaluated based on the first 18 DLT-evaluable subjects.  An expansion 
cohort of an additional 22 treated subjects will be enrolled to further evaluate the safety and to 
estimate the efficacy of the combination of talimogene laherparepvec with pembrolizumab to 
support a decision to initiate the phase 3 study. The phase 3 is a multicenter, placebo-controlled, 
double-blind, randomized study to evaluate the efficacy, as assessed by OS, of treatment with 
talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab in subjects 
with recurrent or metastatic SCCHN.  Subjects will be randomized 1:1 to receive the following:  
- Arm 1:  talimogene laherparepvec plus pembrolizumab (n = 225) 
- Arm 2:  placebo plus pembrolizumab (n = 225) 
Randomization will be stratified by human papillomavirus (HPV) status at baseline (HPV-negative 
versus HPV-positive) and Eastern Cooperative Oncology Group (ECOG) performance status 
(0 versus 1).   


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
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All subjects who receive investigational product will complete a safety follow-up visit 
approximately 30 (+ 7) days after the last dose of study treatment.  After the safety follow-up visit, 
all subjects will enter the long-term follow-up. Subjects will be followed for survival, subsequent 
anticancer therapies and talimogene laherparepvec/placebo related adverse events every 
12 weeks from safety follow-up visit (± 28 days) for approximately 36 months after the last subject 
is enrolled.   
Sample Size:  Approximately 490 subjects will be enrolled in the study; 40 in the phase 1b study 
and 450 in phase 3 Global Full Analysis Set (FAS[G]).  
Summary of Subject Eligibility Criteria:  Subjects must be 18 years of age or older at the time 
of informed consent. Subjects must have histologically confirmed diagnosis of metastatic or 
recurrent SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx, and disease must be 
unsuitable for curative surgical resection and must not be amenable to curative radiotherapy. The 
disease must have progressed after treatment with a platinum-containing regimen defined as 
either disease progression or recurrence between 3 to 6 months of prior curatively intended 
multimodal therapy including platinum therapy for locoregionally advanced SCCHN or disease 
progression or recurrence after prior platinum therapy in the recurrent or metastatic setting.  
Subjects with history of progression of disease within 3 months of completion of curatively 
intended treated for locoregionally advanced settings are excluded (note:  this exclusion criteria is 
only applicable for subjects who have not had treatment in the metastatic/recurrent setting).  The 
subject must be a candidate for intralesional therapy. Subject must have radiographically 
measurable disease per RECIST v1.1 and have ECOG performance status of 0 or 1 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 4.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Talimogene laherparepvec (or 
placebo in phase 3) will be administered into injectable cutaneous, subcutaneous, and nodal 
lesions with or without image ultrasound guidance.  Talimogene laherparepvec/placebo must not 
be administered into the mucosal surface of tumor lesions or visceral metastases.  See 
Section 6.2.1.1 for additional information regarding dosage and administration information.  
Phase 1b: 
The first dose of talimogene laherparepvec will be up to 8.0 mL of 106 PFU/mL.  The second 
injection, up to 8.0 mL of 108 PFU/mL, will be administered 3 weeks (+3 days) after the initial 
injection (ie, no sooner than day 22 but should not be delayed more than 3 days after the 3 week 
time point).  All subsequent injections, up to 8.0 mL of 108 PFU/mL, will be administered every 
3 weeks (±3 days). The maximum volume of talimogene laherparepvec administered at any dose 
is 4.0 mL for any individual tumor lesion.  The maximum volume in any treatment visit is 8.0 mL.  
When talimogene laherparepvec and pembrolizumab are administered on the same day, it is 
recommended that talimogene laherparepvec be administered first.  Refer to Section 6.2.1. 
Phase 3: 
The initial dose of double-blind treatment is up to 8.0 mL of 106 PFU/mL talimogene 
laherparepvec/placebo (talimogene laherparepvec formulation excipients as described in the 
Talimogene Laherparepvec Investigator’s Brochure).  The second dose up to 8.0 mL of 
108 PFU/mL talimogene laherparepvec/placebo should be administered 21  (+ 3)  days after the 
initial dose.  Subsequent doses up to 8.0 mL of 108 PFU/mL talimogene laherparepvec/placebo 
should be given every 3 weeks (± 3 days).  The maximum volume of talimogene 
laherparepvec/placebo administered at any dose is 4.0 mL for any individual tumor lesion.  The 
maximum volume at any treatment visit is 8.0 mL.  When talimogene laherparepvec/placebo and 
pembrolizumab are administered on the same day, it is recommended that talimogene 
laherparepvec/placebo be administered first. 
Non-Amgen Investigational Product Dosage and Administration:  Pembrolizumab will be 
manufactured by Merck. Pembrolizumab is supplied in 100 mg/4mL vials (25 mg/mL) solution for 
intravenous infusion.   


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 6 of 158 
CONFIDENTIAL 
 
 
Phase 1b/3: 
Pembrolizumab at a dose of 200 mg will be administered intravenously every 3 weeks (± 3 days).  
See Section 6.2.2.2 for additional information regarding dosage and administration of 
pembrolizumab. 
Procedures:  Written informed consent must be obtained from all subjects before any study 
specific screening procedures are performed.  The following procedures will occur per the 
Schedule of Assessments (Table 5, Table 6, and Table 7): medical, surgical and medication 
history, physical examination and vital signs, body weight, height, ECOG performance status, 
12-lead electrocardiogram (ECG), recording of concomitant medications, survival assessment, 
review of adverse events, disease related events and serious adverse events as well as reporting 
of potential or known unintended exposure to talimogene laherparepvec/placebo by a household 
member, caregiver, or healthcare provider. Blood will be collected for local laboratory testing 
including: chemistry, hematology, prothrombin time (PT) (seconds) or international normalization 
ratio (INR) (ratio) and partial thromboplastin time (PTT) (seconds) or activated PTT (aPTT) 
(seconds), thyroid function, hepatitis  B surface antigen, hepatitis B core antibody and hepatitis C 
virus antibody.  Urine will be collected for urinalysis. In females of childbearing potential urine or 
serum pregnancy test will be performed locally. Additional blood or urine for pregnancy testing 
(for women of child bearing potential) may be performed at the investigator’s discretion or as 
defined in a country-specific protocol supplement at the end of the Appendix Section of the 
protocol as required by local laws and regulations. Central laboratory tests include:  blood for 
biomarker analysis, herpes simplex virus type-1 (HSV-1) serostatus, anti-pembrolizumab 
antibodies and pembrolizumab pharmacokinetics (PK).  Tumor tissue from either the primary 
tumor or a metastatic lesion (block or unstained tumor slides) and the associated pathology 
reports must be submitted within 28 days after enrollment for phase 1b and within 28 days before 
randomization for phase 3.  See Section 7.5.2 for more details.  A swab of all suspected herpetic 
lesions will be collected for qPCR testing.  Radiographic (computed tomography [CT], positron 
emission tomography [PET]/contrast enhanced CT or magnetic resonance imaging [MRI]) scans 
and tumor assessment will also be performed. Biodistribution and shedding of talimogene 
laherparepvec will be performed in the phase 1b portion of the study only.  Study treatment will be 
administered per Section 6.2. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 5, Table 6, and Table 7).   
Statistical Considerations:   
Sample size consideration: 
For phase 1b, a maximum of 18 DLT-evaluable subjects will be enrolled to assess the DLT profile 
of the combination therapy based on a sequential stopping rule.  If > 18 subjects receive the 
combination they will contribute to the overall safety analysis, but only the first 18 DLT-evaluable 
will be considered in the decision to declare the combination safe.  Subjects may be replaced if 
they are not evaluable for DLT to obtain 18 DLT-evaluable subjects. An expansion cohort of up to 
an additional 22 treated subjects will be enrolled so there will be approximately 
40 treated subjects in total to estimate the efficacy of the combination of talimogene 
laherparepvec with pembrolizumab. 
For phase 3, the primary endpoint is OS.  A hazard ratio ([HR] talimogene laherparepvec with 
pembrolizumab vs placebo with pembrolizumab) of 0.7 for OS is hypothesized in the FAS(G).  
The overall 2-sided Type 1 error rate is 0.05.  The event goal for OS to achieve 90% power for a 
2-sided 0.05 significance level test is 336.  Assuming approximately 75% of subjects have an OS 
event at the time of OS primary analysis, the sample size is estimated to be 450 (225 per arm).  
The OS event goal is adjusted for the interim efficacy analysis but not for the interim futility 
assessment; however, the power loss due to futility is < 1% if considered binding.   
Planned method of analyses: 
For the Phase 1b part of the study, the DLT analysis set will be used to summarize the subject 
incidence of DLT for the study and, unless specified otherwise, the safety analysis set (SAS) will 
be used for all other analyses of safety endpoints including incidence of treatment-emergent and 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 7 of 158 
CONFIDENTIAL 
 
 
treatment-related adverse events.  Summaries of the incidence of DLTs will be provided.  
Descriptive statistics will be provided for efficacy, safety, talimogene laherparepvec DNA, and 
biomarker endpoints as appropriate. 
Efficacy endpoints will be summarized using the Efficacy Analysis Set (EAS) and FAS.  The 
subject incidence for binary response endpoints will be summarized with an associated 
95% confidence interval (CI).  Duration of response (DOR) among responders, and other  
time-to-event endpoints will be estimated using the Kaplan-Meier method. 
For the phase 3 part of the study, efficacy analyses will be conducted on the FAS(G).  Treatment 
effects on efficacy endpoints will be evaluated and compared between the 2 treatment arms 
according to the treatment as randomized. 
For analysis of the primary endpoint of OS, a stratified log-rank test will be used as the primary 
method for testing the null hypothesis of no treatment difference.  The randomization factors, 
along with programmed death-ligand 1 (PD-L1) status at baseline (PD-L1 positive vs PD-L1 not 
positive) will be used as stratification factors.  A hazard ratio will be estimated using the Cox 
proportional hazards (PH) model stratified by the randomization factors per interactive voice 
response (IVR) system and PD-L1 status at baseline with Efron’s method (Efron, 1977) used to 
handle ties.  Kaplan-Meier time to event curves will be presented based on randomized treatment 
arm. 
Statistical testing of OS, iORR, PFS, and iPFS will follow the multiple hypothesis testing 
procedure described in Section 10.5.1. 
Two planned interim safety data reviews will occur after approximately 40 and 100 subjects have 
been enrolled in phase 3 and have had an opportunity to be followed up for at least 6 weeks after 
receiving study treatment.  An additional, planned interim safety data review will occur when at 
least 10 subjects have received at least one treatment with a total volume > 4 mL of 108 PFU/mL 
of talimogene laherparepvec plus pembrolizumab and have had the opportunity to be followed up 
to 6 weeks after receiving the > 4 mL of 108 PFU/mL dose of talimogene laherparepvec and 
approximately every 6 months after the Data Monitoring Committee (DMC) meeting for the OS 
interim analysis.  An interim safety data review will also occur that includes the first 8 subjects 
enrolled with 3 or more randomized into treatment arm from Japan in the phase 3 part of the 
study and have had the opportunity to be followed for at least 6 weeks after receiving study 
treatment.  Additional analyses may be conducted for Japan enrolled subjects as needed for 
regulatory or safety. 
An interim efficacy analysis for futility on OS will be conducted by the DMC when approximately 
280 events have occurred..  The DMC will provide oversight of the analysis and indicate if the 
futility criterion at the OS interim analysis has been met.  It is not planned for 
enrollment/randomization to be suspended during these ongoing phase 3 safety analyses. 
For the phase 1b part of the study, the primary analysis will be repeated 1 year after the 
last subject enrolled. 
ORR and iORR will be summarized by treatment arm as randomized with associated 95% CIs, 
and with treatment comparisons based on the Cochran-Mantel-Haenszel test stratified by the 
randomization stratification factors and PD-L1 status at baseline.  Analysis of PFS and iPFS will 
follow the analysis described for the the primary endpoint of OS. 
In addition, CRR, iCRR, DCR and iDCR will be summarized by treatment arm as randomized with 
associated 95% CIs.  DOR and iDOR among responders will be summarized as a continuous 
variable. 
Safety data, including laboratory test results, vital signs, treatment-emergent adverse events, 
serious adverse event and disease related events, will be summarized by treatment received. 
Subject incidence of anti-pembrolizumab antibodies and serum concentration of pembrolizumab 
will be summarized. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc.  
Data Element Standards 
Version(s)/Date(s):  
 
5: 20 March 2015 


Product:  Talimogene Laherparepvec 
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Phase 1b Study Design and Treatment Schema 
 
Figure legend defined on next page.of the figure 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
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iCR = complete response (per irRECIST); iPD= progressive disease (per irRECIST); Rx = treatment 
a Talimogene laherparepvec will be administered in combination with pembrolizumab starting on week 0, day 1. Talimogene laherparepvec: 106 PFU/mL followed 
3 weeks (+ 3 days) later by 108 PFU/mL every 3 weeks (± 3 days). 
b Pembrolizumab: 200 mg will be administered intravenously every 3 weeks (± 3 days). The second dose of pembrolizumab will be administered 3 weeks (+ 3 days) 
after the initial dose. 
c Subjects will be followed up for serious adverse events until 90 (+ 7) days after the cessation of all study treatment or 30 (+7) days following cessation of treatment if 
the subject initiates new anticancer therapy (whichever is earlier)  
d Long-term follow-up every 12 weeks (± 28 days) from safety follow-up visit until approximately 36 months after last subject enrolled.  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. 
e Pembrolizumab may continue to be administered. 


Product:  Talimogene Laherparepvec 
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Phase 3 Study Design and Treatment Schema 
 
Figure legend defined on next page.of the figure 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 11 of 158 
CONFIDENTIAL 
 
 
iCR= complete response (per irRECIST); iPD= progressive disease (per irRECIST); Rx = treatment 
a Talimogene laherparepvec/placebo will be administered in combination with pembrolizumab starting on week 0, day 1. Talimogene laherparepvec: 106 PFU/mL 
followed 3 weeks (+ 3 days) later by 108 PFU/mL every 3 weeks (± 3 days). 
b Pembrolizumab: 200 mg will be administered intravenously every 3 weeks (± 3 days).  The second dose of pembrolizumab will be administered 3 weeks (+ 3 days) 
after the initial dose.  
c Subjects will be followed up for serious adverse events until 90 (+ 7) days after the cessation of all study treatment or 30 (+7) days following cessation of treatment if 
the subject initiates new anticancer therapy (whichever is earlier). 
d Long-term follow-up every 12 weeks (± 28 days) from safety follow-up visit until approximately 36 months after last subject enrolled. Talimogene 
laherparepvec/placebo related adverse events that occur after the safety follow-up visit through the end of the long-term follow-up will be reported. 
e pembrolizumab may continue to be administered. 
 


Product:  Talimogene Laherparepvec 
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Study Glossary 
Abbreviation or Term Definition/Explanation 
ADA 
anti-drug antibodies 
AE 
adverse event 
AJCC 
American Joint Commission on Cancer 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
AST  
aspartate aminotransferase   
BICR 
Blinded Independent Central Review 
BOR 
best overall response (per RECIST v1.1) 
cHL 
classical Hodgkin lymphoma 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response (per RECIST v1.1) 
CRF  
case report form 
CRR 
complete response rate (per RECIST v1.1) 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate (per RECIST v1.1) 
DILI 
drug-induced liver injury 
DLRT 
Dose Level Review Team 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response (per RECIST v1.1) 
DRE 
disease-related event 
EAS 
Efficacy Analysis Set 
ECG 
electrocardiogram 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
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 
from the study, completes the safety follow-up visit or long-term 
follow-up [whichever is later] or death). 


Product:  Talimogene Laherparepvec 
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Abbreviation or Term Definition/Explanation 
End of Study (primary 
completion) 
Primary Completion:  defined as when the last subject is assessed or 
receives an intervention for the purposes of final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early.  
Primary Completion Phase 1b only:  The time when the last 
phase 1b subject is assessed or receives an intervention for the 
purposes of final collection of data for the primary efficacy 
endpoint of phase 1b.  The primary completion is anticipated to 
occur when the last phase 1b subject completes the week 9 tumor 
response assessment. 
End of Study (end of 
trial) 
defined as 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.  This is anticipated to occur 36 months after 
the last subject is enrolled. 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-5L 
EuroQoL-5D-5 Level 
EU 
European Union 
FAS 
Full Analysis Set 
FAS(G) 
Global Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
Heart rate 
number of cardiac cycles per unit of time 
HIV 
human immunodeficiency virus 
HNC 
Head and neck carcinomas 
HPV 
Human papillomavirus 
HR 
hazard ratio 
HSV-1 
herpes simplex virus, herpes simplex virus type-1 
IA 
interim analysis 
iBOR 
best overall response (per irRECIST) 
ICH 
International Conference on Harmonisation 
iCR 
complete response (per irRECIST) 


Product:  Talimogene Laherparepvec 
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Abbreviation or Term Definition/Explanation 
ICP 
infected cell protein 
iCRR 
complete response rate (per irRECIST) 
iDCR 
disease control rate (per irRECIST) 
iDOR 
duration of response (per irRECIST) 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
INR 
international normalization ratio 
iORR 
objective response rate (per irRECIST) 
iPD 
progressive disease (per irRECIST) 
iPFS 
progression-free survival (per irRECIST) 
IPIM 
Investigational Product Instruction Manual 
iPR 
partial response (per irRECIST) 
IRB/IEC 
institutional review board/independent ethics committee 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors (RECIST)  
iSD 
stable disease (per irRECIST) 
iUE 
unable to evaluate (per irRECIST) 
IV 
intravenous 
Interactive Voice 
Response (IVR) 
telecommunication technology that is linked to a central computer in real 
time as an interface to collect and process information.   
LDH 
lactate dehydrogenase 
LSE(G) 
global last subject enrolled 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability-high 
NCI 
National Cancer Institute 
NSAIDS 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non-small cell lung cancer 
OR 
odds ratio 
ORR 
objective response rate (per RECIST v1.1) 
OS 
overall survival 
PA 
primary analysis 
PD 
progressive disease (per RECIST v1.1) 
PD-1 
programmed cell death-1 
PD-L1 
programmed death ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival (per RECIST v1.1) 
PFU 
plaque-forming unit 


Product:  Talimogene Laherparepvec 
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Abbreviation or Term Definition/Explanation 
PK 
pharmacokinetics 
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 
PRO 
patient reported outcome 
PT 
prothrombin time 
PTT/aPTT 
partial thromboplastin time/activated partial thromboplastin time 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QLQ-H&N35 
Quality of Life Questionnaire Head & Neck 35 
QOL 
Quality of Life 
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 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SAS(G) 
Global Safety Analysis Set 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease (per RECIST v1.1) 
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. 
SSAP 
Supplemental Statistical Analysis Plan 
Study day 1 
defined as the first day that protocol-specified investigational products 
are administered to the subject 
T3 
triiodothyronine 
TCIP-H 
T-cell enriched high phenotypes 
TNM 
Tumor, node, metastases 
TSH 
thyroid stimulating hormone 


Product:  Talimogene Laherparepvec 
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Abbreviation or Term Definition/Explanation 
UE 
unable to evaluate (per RECIST v1.1) 
ULN 
upper limit of normal 
US 
ultrasound 
VAS 
visual analog scale 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Phase 1b Study Design and Treatment Schema ............................................................. 8 
Phase 3 Study Design and Treatment Schema ............................................................. 10 
Study Glossary .............................................................................................................. 12 
1. 
OBJECTIVES ....................................................................................................... 24 
1.1 
Primary ..................................................................................................... 24 
1.2 
Secondary ................................................................................................. 24 
1.3 
Exploratory ................................................................................................ 25 
2. 
BACKGROUND AND RATIONALE ...................................................................... 26 
2.1 
Disease ..................................................................................................... 26 
2.1.1 
The Role of HPV ....................................................................... 27 
2.1.2 
Etiologies of SCCHN ................................................................. 28 
2.1.3 
Programmed Cell Death-1 (PD-1) in SCCHN ............................ 29 
2.2 
Amgen Investigational Product Background: Talimogene 
Laherparepvec .......................................................................................... 29 
2.3 
Non-Amgen Investigational Product Background: 
Pembrolizumab ......................................................................................... 32 
2.4 
Rationale ................................................................................................... 35 
2.5 
Clinical Hypotheses ................................................................................... 37 
3. 
EXPERIMENTAL PLAN ........................................................................................ 37 
3.1 
Study Design ............................................................................................. 37 
3.1.1 
Phase 1b Study Design ............................................................. 37 
3.1.1.1 
Rules for DLT Evaluation in Phase 1b ..................... 37 
3.1.1.2 
Definition of DLT in Phase 1b .................................. 38 
3.1.2 
Phase 3 Study Design ............................................................... 39 
3.1.3 
Tumor Assessment.................................................................... 40 
3.1.3.1 
Eligibility Assessment .............................................. 40 
3.1.3.2 
Response Assessment ............................................ 40 
3.1.4 
Follow-up ................................................................................... 40 
3.1.4.1 
Safety Follow-up ..................................................... 40 
3.1.4.2 
Long-term Follow-up ............................................... 41 
3.2 
Number of Sites ........................................................................................ 41 
3.3 
Number of Subjects ................................................................................... 41 
3.4 
Replacement of Subjects .......................................................................... 41 
3.5 
Estimated Study Duration .......................................................................... 42 
3.5.1 
Study Duration for Subjects ....................................................... 42 
3.5.2 
End of Study .............................................................................. 42 


Product:  Talimogene Laherparepvec 
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4. 
SUBJECT ELIGIBILITY ........................................................................................ 43 
4.1 
Inclusion Criteria ....................................................................................... 43 
4.2 
Exclusion Criteria ...................................................................................... 45 
5. 
SUBJECT ENROLLMENT .................................................................................... 48 
5.1 
Treatment Assignment Phase 1b .............................................................. 49 
5.2 
Randomization/Treatment Assignment Phase 3 ........................................ 49 
6. 
TREATMENT PROCEDURES .............................................................................. 50 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 50 
6.2 
Investigational Product .............................................................................. 50 
6.2.1 
Amgen Investigational Product: Talimogene 
Laherparepvec/Placebo ............................................................ 50 
6.2.1.1 
Dosage, Administration, and Schedule .................... 51 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 53 
6.2.2 
Non-Amgen Investigational Product: Pembrolizumab ................ 55 
6.2.2.1 
Pembrolizumab Dosage, Administration, 
and Schedule .......................................................... 55 
6.2.2.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 56 
6.2.3 
Rescue Medications and Supportive Care Guidelines 
for Pembrolizumab .................................................................... 62 
6.2.3.1 
Infusion Reactions ................................................... 62 
6.2.3.2 
Pembrolizumab Events of Clinical Interest .............. 64 
6.2.3.3 
Diet and Other Considerations While 
Taking Pembrolizumab ............................................ 64 
6.3 
Other Protocol-required Therapies ............................................................ 65 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 66 
6.4.1 
Criteria for Permanent Discontinuation of 
Investigational Products and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 66 
6.4.2 
Criteria for Conditional Withholding of Investigational 
Products and Other Protocol-required Therapies Due 
to Potential Hepatotoxicity ......................................................... 67 
6.4.3 
Criteria for Rechallenge of Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity............................................................................ 67 
6.5 
Concomitant Therapy ................................................................................ 68 
6.6 
Other Treatment Procedures ..................................................................... 68 
6.7 
Medical Devices ........................................................................................ 68 
6.8 
Product Complaints ................................................................................... 69 
6.9 
Excluded Treatments and/or Procedures During Study Period .................. 69 
7. 
STUDY PROCEDURES ....................................................................................... 70 


Product:  Talimogene Laherparepvec 
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7.1 
Schedule of Assessments ......................................................................... 70 
7.2 
General Study Procedures ........................................................................ 82 
7.2.1 
Screening and Enrollment ......................................................... 82 
7.2.2 
Rescreening .............................................................................. 82 
7.2.3 
Treatment .................................................................................. 83 
7.2.4 
Follow-up ................................................................................... 84 
7.2.5 
Safety Follow–up ....................................................................... 84 
7.2.6 
Long term Follow-up .................................................................. 84 
7.3 
Description of Study Procedures ............................................................... 84 
7.3.1 
Informed Consent ...................................................................... 85 
7.3.2 
Demographic Data..................................................................... 85 
7.3.3 
Medical History .......................................................................... 85 
7.3.4 
Prior Therapies .......................................................................... 85 
7.3.5 
Concomitant Therapy ................................................................ 85 
7.3.6 
Adverse Events, Disease Related Events, and Serious 
Adverse Events ......................................................................... 85 
7.3.7 
Physical Examination ................................................................ 86 
7.3.8 
Vital Signs ................................................................................. 86 
7.3.9 
Physical Measurements ............................................................ 86 
7.3.10 
ECG .......................................................................................... 86 
7.3.11 
ECOG Performance Status ....................................................... 86 
7.3.12 
Exposure to Talimogene Laherparepvec ................................... 86 
7.3.13 
Radiographic Tumor Assessment .............................................. 87 
7.4 
Laboratory Assessments ........................................................................... 87 
7.4.1 
qPCR for Biodistribution and Shedding Samples ....................... 88 
7.4.2 
qPCR for Suspicious Herpetic Lesions ...................................... 88 
7.4.3 
Optional Photography Substudy (Selected Phase 1b 
Sites And Phase 3 Sites) ........................................................... 89 
7.5 
Biomarker Sample Collection .................................................................... 89 
7.5.1 
Blood Samples .......................................................................... 90 
7.5.2 
Tumor Tissue Samples .............................................................. 90 
7.5.3 
HPV Testing .............................................................................. 91 
7.6 
Optional Pharmacogenetic Studies ........................................................... 92 
7.7 
Patient Reported Outcomes (Phase 3 only) .............................................. 92 
7.7.1 
EORTC QLQ-C30 ..................................................................... 93 
7.7.2 
EORTC QLQ-H&N35 ................................................................. 93 
7.7.3 
Health State Utility Estimates .................................................... 93 
7.8 
Sample Storage and Destruction ............................................................... 94 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 95 
8.1 
Subjects’ Decision to Withdraw ................................................................. 95 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 96 


Product:  Talimogene Laherparepvec 
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8.3 
Reasons for Removal From Treatment or Study ....................................... 96 
8.3.1 
Reasons for Removal From Treatment ...................................... 96 
8.3.2 
Reasons for Removal From Study ............................................. 97 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 97 
9.1 
Definition of Safety Events ........................................................................ 97 
9.1.1 
Disease Related Events ............................................................ 97 
9.1.2 
Adverse Events ......................................................................... 97 
9.1.3 
Serious Adverse Events ............................................................ 98 
9.2 
Safety Event Reporting Procedures .......................................................... 99 
9.2.1 
Reporting Procedures for Disease Related Events .................... 99 
9.2.2 
Adverse Events ......................................................................... 99 
9.2.2.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 99 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ................................................................... 100 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................. 102 
9.3 
Pregnancy and Lactation Reporting ........................................................ 102 
9.4 
Reporting of Exposure to Talimogene Laherparepvec/Placebo ............... 103 
9.5 
Pembrolizumab Events of Clinical Interest .............................................. 103 
9.6 
Definition of an Overdose of Pembrolizumab for this Protocol 
and Reporting of Pembrolizumab Overdose ............................................ 104 
9.7 
Definition and Reporting of Pembrolizumab Drug-induced Liver 
Injury ....................................................................................................... 104 
10. 
STATISTICAL CONSIDERATIONS .................................................................... 105 
10.1 
Study Endpoints, Analysis Sets, and Covariates ..................................... 105 
10.1.1 
Study Endpoints ...................................................................... 105 
10.1.1.1 
Primary Endpoints ................................................. 105 
10.1.1.2 
Secondary Endpoints ............................................ 105 
10.1.1.3 
Exploratory Endpoints ........................................... 106 
10.1.2 
Analysis Sets ........................................................................... 107 
10.1.2.1 
DLT Analysis Set ................................................... 107 
10.1.2.2 
Efficacy Analysis Set ............................................. 107 
10.1.2.3 
Full Analysis Set .................................................... 107 
10.1.2.4 
Safety Analysis Set ............................................... 108 
10.1.2.5 
PD-L1 Analysis Set ............................................... 108 
10.1.2.6 
HPV Analysis Set .................................................. 108 
10.1.2.7 
Biomarker Analysis Sets ....................................... 108 
10.1.2.8 
PRO Analysis Set .................................................. 109 
10.1.3 
Covariates and Subgroups ...................................................... 109 
10.2 
Sample Size Considerations ................................................................... 110 
10.2.1 
Sample Size Considerations for Phase 1b ............................... 110 


Product:  Talimogene Laherparepvec 
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10.2.2 
Sample Size Considerations for Phase 3 ................................. 112 
10.3 
Access to Individual Subject Treatment Assignments by 
Sponsor or Designees ............................................................................. 115 
10.4 
Planned Analyses ................................................................................... 115 
10.4.1 
Interim Analyses ...................................................................... 115 
10.4.1.1 
DLT Safety Analysis (Phase 1b) ............................ 115 
10.4.1.2 
Interim Safety Analysis (Phase 3) .......................... 115 
10.4.1.3 
Interim OS Efficacy and Futility Analysis 
(Phase 3) .............................................................. 116 
10.4.2 
Blinded Independent Central Review for Secondary 
Endpoints ................................................................................ 118 
10.4.3 
Dose Level Review Team ........................................................ 119 
10.4.4 
Data Monitoring Committee ..................................................... 119 
10.4.5 
Primary Analysis ...................................................................... 119 
10.4.5.1 
Primary Analysis Phase 1b .................................... 119 
10.4.5.2 
Primary Analysis Phase 3...................................... 119 
10.4.6 
Follow-Up Analysis for Phase 1b ............................................. 119 
10.4.7 
Final Analysis .......................................................................... 120 
10.5 
Planned Methods of Analysis .................................................................. 120 
10.5.1 
General Considerations ........................................................... 120 
10.5.2 
Primary Efficacy Endpoint ........................................................ 121 
10.5.3 
Secondary Efficacy Endpoints ................................................. 122 
10.5.4 
Safety Endpoints ..................................................................... 123 
10.5.5 
PRO Endpoints ........................................................................ 123 
10.5.6 
Health State Utility Estimates .................................................. 124 
11. 
REGULATORY OBLIGATIONS .......................................................................... 124 
11.1 
Informed Consent .................................................................................... 124 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 125 
11.3 
Subject Confidentiality ............................................................................. 125 
11.4 
Investigator Signatory Obligations ........................................................... 126 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 126 
12.1 
Protocol Amendments and Study Termination ........................................ 126 
12.2 
Study Documentation and Archive .......................................................... 127 
12.3 
Study Monitoring and Data Collection ..................................................... 128 
12.4 
Investigator Responsibilities for Data Collection ...................................... 129 
12.5 
Language ................................................................................................ 129 
12.6 
Publication Policy .................................................................................... 129 
12.7 
Compensation ......................................................................................... 130 
13. 
REFERENCES ................................................................................................... 131 
14. 
APPENDICES .................................................................................................... 134 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 22 of 158 
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List of Tables 
Table 1.  Cumulative Increments of DLT-evaluable Subjects and 
Corresponding Acceptable Maximum Number and Percentage 
of DLTs at Each Planned Interim Safety Analysis ................................... 38 
Table 2.  Talimogene Laherparepvec Injection Volume Guideline Based on 
Tumor Size ............................................................................................. 52 
Table 3.  Pembrolizumab-related Adverse Event Management ..................................... 57 
Table 4.  Infusion Reaction Treatment Guidelines ......................................................... 63 
Table 5.  Schedule of Assessments for Phase 1b .......................................................... 71 
Table 6.  Schedule of Assessments for Biodistribution and Shedding of 
Talimogene Laherparepvec for Phase 1b Only ....................................... 75 
Table 7.  Schedule of Assessments for Phase 3 ............................................................ 77 
Table 8.  Laboratory Analytes ........................................................................................ 88 
Table 9.  Timing of Primary Analysis for OS (at 336 events) in the Phase 3 
Study .................................................................................................... 114 
Table 10.  Hypothesized Effect Sizes and Hypothesis Test Powers ............................ 114 
Table 11.  Possible Hypothesis Tests at the Two-planned Analyses ........................... 118 
Table 12.  Definition of Measurable Tumor Response (Baseline Target, 
Non-target, and New Lesions) per irRECIST ........................................ 146 
Table 13.  Imaging and Treatment After First Radiologic Evidence of PD per 
irRECIST .............................................................................................. 147 
Table 14.  Matrix for Determining the Overall Response at Each Assessment 
Point for irRECIST ................................................................................ 151 
Table 15.  Definition of Tumor Response for RECIST v1.1 .......................................... 155 
Table 16.  Matrix for Determining the Overall Response at Each Assessment 
Point for RECIST v1.1 .......................................................................... 157 
List of Figures 
Figure 1.  Probability of a Combination Delta Absolute Objective Response 
Rate Increase Over Pembrolizumab ..................................................... 111 
Figure 2.  Delta Mean and 90% Credible Region of Absolute Objective 
Response Rate Increase of Combination Over Pembrolizumab ........... 112 
Figure 3.  Overall Survival Assumptions ...................................................................... 113 
Figure 4.  Initial Graph of Maurer-Bretz Multiple Testing Procedure ............................. 121 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 23 of 158 
CONFIDENTIAL 
 
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 135 
Appendix B.  Sample Serious Adverse Event Report Form ......................................... 137 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 140 
Appendix D.  Radiological Guidance for Assessment of Disease Response ................ 142 
Appendix E.  RECIST v1.1 Guidelines for Assessment of Disease Response ............. 152 
Appendix F.  Eastern Cooperative Oncology Group (ECOG) Performance 
Status ................................................................................................... 158 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 24 of 158 
CONFIDENTIAL 
 
 
1. 
OBJECTIVES 
1.1 
Primary 
Phase 1b 
• 
To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), 
of talimogene laherparepvec in combination with pembrolizumab in subjects with 
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) 
Phase 3 
• 
To evaluate the efficacy, as assessed by overall survival (OS), of treatment with 
talimogene laherparepvec with pembrolizumab versus placebo with 
pembrolizumab in subjects with recurrent or metastatic SCCHN 
1.2 
Secondary 
Phase 1b 
• 
To evaluate the efficacy of talimogene laherparepvec in combination with 
pembrolizumab as assessed by: 
o Objective response rate (iORR), complete response rate (iCRR), and best 
overall response (iBOR); duration of response (iDOR), disease control 
rate (iDCR), and progression-free survival (iPFS) (response evaluation by 
investigator using immune-related Response Evaluation Criteria in Solid 
Tumors [irRECIST]) 
o OS  
• 
To evaluate the safety of talimogene laherparepvec in combination with 
pembrolizumab as assessed by incidence of adverse events and laboratory 
abnormalities. 
Phase 3 
• 
To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus 
placebo with pembrolizumab, as assessed by: 
- Objective response rate (ORR) and progression-free survival (PFS) (response 
evaluation by investigator using RECIST v1.1) 
- iORR and iPFS (response evaluation by investigator using irRECIST) 
- iCRR, iBOR; iDOR, and iDCR (response evaluation by investigator using 
irRECIST) 
- CRR, BOR, DOR, and DCR (response evaluation by investigator using 
RECIST v1.1) 
- 1-year, 2-year, and 3-year survival 
- Subject incidence of treatment-emergent and treatment-related adverse events 
(all adverse events, grade ≥ 3 adverse events, serious adverse events, fatal 
adverse events, adverse events and serious adverse events leading to 
discontinuation of treatment, and adverse events defined as events of 
interest) 
• 
To evaluate patient reported outcomes (PRO) as assessed by the European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life 


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Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 27 of 158 
CONFIDENTIAL 
 
 
advanced SCCHN develop locoregional or distant relapses which are usually detected 
within the first 2 years of treatment  
(Argiris et al, 2008).  For this population, the prognosis is extremely poor with DCR 
estimating 45%, and median OS estimates of 6 to 9 months (Vermorken et al, 2007).  
For distant metastases, the usual pattern of spread is to lung, liver, and bone, although 
this pattern may be different in HPV-positive disease which can spread to a range of 
other sites including intra-abdominal lymph nodes, pleural cavity, bowel and brain. 
Chemotherapy is an integral part of the treatment of locally recurrent and metastatic 
SCCHN. Palliation is the main goal of treatment for patients with metastatic disease and 
locally recurrent disease not curable by radiation and/or surgery.  The current standard 
of care for locally recurrent and/or metastatic SCCHN is concurrent platinum-based 
chemotherapy in patients with good performance status without severe comorbidities.  
The median OS is 7 to 10 months (Cohen et al, 2004; Peron et al, 2014). In a phase 3 
randomized trial of patients with recurrent or metastatic SCCHN , cetuximab plus 
5-fluorouracil/cisplatin or 5-fluorouracil/carboplatin improved median OS compared to the 
standard of care chemotherapy doublet (10.1 months compared to 7.4 months 
[Vermorken et al, 2008]).  A similar trial design was employed for the SPECTRUM study, 
which evaluated panitumumab. Patients in both groups received up to six 3-weekly 
cycles of intravenous cisplatin (100 mg/m2) and 5-fluorouracil (1 g/m2 per day for 
4 days), while those in the experimental group also received intravenous panitumumab. 
A total of 657 patients were randomized and the median overall survivals were 
11.1 versus 9.0 months (hazard ratio [HR] 0.873; P=0.1403) in the panitumumab and 
control group, respectively (Vermorken et al, 2013).  
After failure of first-line platinum based chemotherapy, cetuximab monotherapy in a 
phase 2 study demonstrated ORR 10% with a median OS of 5.8 months representing an 
increase of 2.5 months compared with platinum-refractory historical controls 
(Vermorken et al, 2007).  Objective response to second-line cytotoxic chemotherapy are 
uncommon with little impact on prolonging OS (Leon et al, 2005).  Locally advanced, 
metastatic and recurrent SCCHN remains an area of high unmet medical need. 
Therefore, clinical evaluation of novel therapeutic approaches such as modulation of the 
immune system is needed. 
2.1.1 
The Role of HPV 
Genetic material from high risk-oncogenic strains (HPV types 16 and 18) is found in 
approximately 60% of oropharyngeal cancers arising from the palatine and lingual tonsils 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 28 of 158 
CONFIDENTIAL 
 
 
(Ang et al, 2010).  Patients with locoregionally advanced HPV-positive oropharyngeal 
SCCHN treated with chemo radiation have better survival than do HPV-negative patients 
(Ang et al, 2010; Chaturvedi et al, 2011; Licitra et al, 2006).  The transforming potential 
of HPV infection is driven by viral proteins E6 and E7, which inactivate the tumor 
suppressor proteins p53 and pRb, which results in loss of cell cycle regulation, cellular 
proliferation, and chromosomal instability (Fakhry and Gillison, 2006).  Squamous cell 
carcinoma of the head and neck patients with tumors that are HPV-positive have an 
improved survival compared with SCCHN patients who are HPV-negative.  A 
retrospective multivariate analysis of a randomized, phase 3 trial, Radiation Therapy 
Oncology Group 0129 originally designed to compare accelerated-fractionation to 
standard fractionation radiotherapy when delivered with concurrent cisplatin has been 
reported (Ang et al, 2010).  This analysis revealed significantly improved 3-year survival 
among SCCHN patients who were HPV-positive compared with SCCHN patients who 
were HPV negative (84% vs. 57% respectively).  Patients with HPV-positive tumors had 
a 58% reduction in risk of death compared with patients with HPV-negative tumors 
(HR 0.42, 95% confidence interval [CI 0.27, 0.66]).  In a multicenter Eastern Cooperative 
Oncology Group (ECOG) study in which patients with newly diagnosed stage III or IV 
SCCHN were treated with induction chemotherapy followed by chemoradiation, 60% of 
oropharynx primary tumors were found to be HPV-positive (Fakhry et al, 2008).  The 
two-year PFS rate (86% vs.53%; p=0.02) and OS rate (95% vs. 62%; p=0.005) were 
also significantly better for patients with HPV-associated cancer compared to 
HPV-negative cancer.  Another retrospective analysis of the SEER (Surveillance, 
Epidemiology, and End Results) data for patients with oropharyngeal cancer revealed a 
4-fold higher median OS in patients who were HPV-positive compared with patients who 
were HPV-negative (131 months vs 20 months) (Chaturvedi et al, 2011).  In contrast, the 
outcome for HPV-negative SCCHN patients has not improved despite intensification of 
standard chemotherapeutic agents and combinations.  Novel therapeutic approaches 
are needed in this population. 
2.1.2 
Etiologies of SCCHN 
SCCHN is caused by the accumulation of multiple gene alterations modulated by genetic 
predisposition and chronic inflammation, enhanced by environmental influences such as 
tobacco and alcohol abuse (non-HPV related) or by infection with HPV  
(The Cancer Genome Atlas Network, 2015).  These etiologies involve a multistep 
process and result in alterations in both oncogenes and tumor suppressor genes. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 29 of 158 
CONFIDENTIAL 
 
 
2.1.3 
Programmed Cell Death-1 (PD-1) in SCCHN 
Recently a new class of monoclonal antibodies has been engineered to block or activate 
co-signaling pathways resulting in enhanced anti-tumor immunity.  One of the most 
promising pathways for manipulation involves program death ligand 1 (PD-L1).  PD-L1 
expression is up regulated in solid tumors where it allows the tumor to evade attack by 
the immune system (Dong et al, 2002; Hirano et al, 2005).  Inhibition of the interaction 
between PD-1 receptors (expressed on activated T cells) and PD-L1 has been shown to 
enhance T-cell responses (Fife et al, 2009). 
Down-regulation of T-cells in SCCHN has been implicated in pathogenesis and 
progression of tumors (Albers et al, 2010; Tong et al, 2012;).  High levels of PD-1 
expression have been demonstrated in human SCCHN tissue samples across multiple 
primary sites (Strome et al, 2003) on 46% to 87% of tumors  
(Cho et al, 2011; Lyford-Pike et al, 2013; Strome et al, 2003; Ukpo et al, 2013).  While 
most studies have analyzed surgical samples from initial diagnosis, one evaluation of 
oropharyngeal squamous cell samples included 28 recurrent tumors and 10 distant 
metastases of which 43% and 70% expressed PD-L1 respectively (Ukpo et al, 2013). 
PD-L1 expression was considered binarily positive in tumor cells if >5% staining (versus 
negative if 0 to 5% staining). These data suggest PD-L1 is expressed on SCCHN in the 
primary, recurrent, and metastatic settings and manipulation of the PD-L1: PD-1 
pathway may be an important therapeutic target. 
Given the importance of HPV in the etiology of oropharyngeal SCCHN, several studies 
have examined the correlation between HPV status and PD-L1 status.  
Three independent studies have revealed higher expression of PD-L1 in HPV-positive 
compared to negative patients: 70 vs 29% (Lyford-Pike et al, 2013), 49.2% vs 34.1% 
(Ukpo et al, 2013), and 62.5% vs 40% (Badoual et al, 2013).  Additionally, a 12-gene 
chemokine signature identifying a subset of CD-8 enriched (T-cell enriched 
phenotype-high) tumors was developed in SCCHN tumors.  T-cell enriched high 
phenotypes (TCIP-H) were found in 51% of HPV-positive-tumors and in 21% of 
HPV-negative tumors indicating that the TCIP-H population may be a particularly 
important target in SCCHN (Saloura et al, 2014). 
2.2 
Amgen Investigational Product Background: Talimogene 
Laherparepvec 
Talimogene laherparepvec is a virally-based oncolytic immunotherapy consisting of an 
immune-enhanced herpes simplex virus type-1 (HSV-1) that selectively replicates in 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 30 of 158 
CONFIDENTIAL 
 
 
tumors.  In this genetically modified strain, the HSV-1 viral genes encoding infected-cell 
protein (ICP) 34.5 (a neurovirulence factor) and ICP47 (which blocks viral antigen 
presentation to major histocompatibility complex class I and II molecules) have been 
functionally deleted.  The coding sequence for human granulocyte macrophage 
colony-stimulating factor (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 and lytic tumor cell death.  Thus, talimogene laherparepvec has two 
mechanisms of action: (a) direct oncolysis of infected tumor cells and (b) immune 
activation through tumor-associated antigen release and local virus-mediated GM-CSF 
expression.  Talimogene laherparepvec is administered by direct injection into tumors. 
Intralesional injection of talimogene laherparepvec, also known as IMLYGIC, has been 
approved by the United States Food and Drug Administration (FDA) for the local 
treatment of unresectable cutaneous, subcutaneous, and nodal lesions in adult patients 
with melanoma recurrent after initial surgery.  However, it has not been shown to 
increase OS or have an effect on metastases to internal organs including the liver and 
lungs.  Additionally, in the European Union, talimogene laherparepvec (ImlygicTM) has 
been approved for the treatment of adults with unresectable melanoma that is regionally 
or distantly metastatic (stage IIIB, IIC, and IVM1a) with no bone, brain, lung, or other 
visceral disease. 
As of 30 June 2015, 15 clinical studies (including 2 extension studies) have been or are 
being conducted in several advanced tumor types with over 400 subjects treated with 
talimogene laherparepvec.  For additional information, refer to the talimogene 
laherparepvec Investigator’s Brochure. 
Refer to the specific section of the Investigator’s Brochure for additional information 
related to the physical, chemical, and pharmaceutical properties and formulation(s). 
Talimogene Laherparepvec in SCCHN 
A phase 1/2 study has been completed with talimogene laherparepvec in combination 
with radiotherapy and cisplatin in subjects with untreated stage III/IV SCCHN.  
Seventeen subjects with stage III/IVA/IVB SCCHN were enrolled and received 
chemoradiotherapy (70 Gray [Gy]/35 fractions with concomitant cisplatin 100 mg/m2 on 
days 1, 22 and 43) and dose-escalating (106, 106, 106, 106 plaque-forming units 
(PFU)/mL for cohort 1; 106, 107, 107, 107 PFU/mL for cohort 2, 106, 108, 108, 
108 PFU/mL, for cohort 3) talimogene laherparepvec injected into malignant cervical 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 31 of 158 
CONFIDENTIAL 
 
 
lymph nodes on days 1, 22, 43, and 64. No injections were administered to mucosal 
surfaces of tumor lesions.  Injections were administered using topical local anesthetics 
with lidocaine/prilocaine.  Subjects underwent neck dissection 6 to 10 weeks later 
(Harrington et al, 2010).  The recommended phase 2 dose of 106, 108, 108, 108 PFU/mL 
was established.  Analysis of viral clearance of talimogene laherparepvec through 
biodistribution in blood and urine and shedding of live virus at various time points post 
injection was performed. 
All 17 subjects were treated without delays to chemoradiotherapy or DLT.  All subjects 
experienced at least 1 adverse event during the course of the study.  The most common 
treatment-emergent adverse events observed across 4 cohorts were decreased weight 
(16 subjects; 94%), constipation (15 subjects; 88%), mucosal inflammation and radiation 
skin injury (each 14 subjects; 82%), anemia and nausea (each 13 subjects; 76% each), 
and dysphagia (12 subjects; 71%).  The incidence of events was generally balanced 
across cohorts.  Most adverse events (86%) were Common Terminology Criteria for 
Adverse Events (CTCAE) grade 1 or 2, and most (91.0%) were not considered related to 
talimogene laherparepvec by the investigator.  Thirteen (2.7%) adverse events 
considered related to talimogene laherparepvec were grade 1 and 12 (2.3%) events 
were grade 2.  There were no grade 3, grade 4, or grade 5 treatment-emergent adverse 
events considered related to talimogene laherparepvec.  The most common grade 
3 adverse events were mucosal inflammation (6 subjects; 35%); radiation skin injury 
(5 subjects; 29%); weight decreased and dysphagia (each 4 subjects; 24%); dehydration 
and leukopenia (each 3 subjects; 18%); febrile neutropenia, neutropenia, 
thrombocytopenia and nausea (each 2 subjects; 12%). Only three grade 4 adverse 
events were reported (lymphopenia, dysphagia, and respiratory failure).  None of these 
events were considered related to treatment.  
Sixteen of 17 subjects (94%) experienced treatment-emergent serious adverse events 
during the study.  The most commonly reported serious adverse events were mucosal 
inflammation (5 subjects; 29%), febrile neutropenia (3 subjects, 18%), and pyrexia, renal 
failure, nausea, dysphagia and dehydration (each 2 subjects; 12%).  All serious adverse 
events were considered unrelated to talimogene laherparepvec by the investigator and 
all but 6 events (grade 3 skin graft infection, grade 3 ulcerative colitis, grade 2 mucositis 
and dysphagia, grade 3 urinary tract infection, and grade 3 dysphagia) resolved by end 
of study.  The ongoing events did not result in treatment discontinuation. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 32 of 158 
CONFIDENTIAL 
 
 
Two subjects experienced events of febrile neutropenia and neutropenia, respectively 
that were considered DLTs; however neither event was considered related to talimogene 
laherparepvec.  The events of neutropenia were considered related to cisplatin 
administration, and in both cases, the cisplatin dose was reduced and the events 
resolved.  No deaths or withdrawals due to adverse events occurred during the study. 
Three of 17 subjects (18%) had talimogene laherparepvec DNA detected by swab 
analysis of the injection site following talimogene laherparepvec administration.  This 
was detected in one subject at visit 0 (24 and 96 hours post injection, in another subject 
at visit 6 (48 hours post injection) and at the end of study (24 hours post injection), and 
for a third subject in cohort 4 at visit 3 (24 hours post injection).  Swabs obtained from 
the dressings covering the injection site(s) were negative for the presence of virus for all 
subjects at all timepoints.  
Biopsy samples (3 from needle biopsy, 12 from neck dissection specimens, and 1 from 
both needle biopsy and neck dissection specimens) were obtained for analysis of 
talimogene laherparepvec copy number from injected and uninjected nodes in 16 of the 
17 subjects (94%).  Viral DNA was detected in 42% of injected nodes and in 
1 neighboring uninjected node (14%) suggesting virus replication and demonstrating 
spread of talimogene laherparepvec to an adjacent node.  In 31% of subjects, 
talimogene laherparepvec viral levels were >50,000 copies per microgram of DNA, a 
level suggestive of productive viral replication in tumors. 
The detection of virus in injected tumors at delayed time points after dosing appeared to 
be more likely at the highest dose administered.  Overall, 3 of 17 subjects (18%) had 
positive plaque assays of the tumor swab at any time point and no subjects had a 
positive plaque assay of the exterior dressing swab.  Urine and blood were not tested for 
viral shedding and biodistribution in this study. 
Fourteen subjects (82.3%) showed tumor response by RECIST v1.1, and pathologic 
complete remission was confirmed in 93% of subjects at neck dissection.  No subject 
developed locoregional recurrence, and disease-specific survival was 82.4% at a 
median follow-up of 29 months (Harrington et al, 2010). 
2.3 
Non-Amgen Investigational Product Background: Pembrolizumab 
Pembrolizumab (KeytrudaTM [US]), a humanized monoclonal antibody against the PD-1 
protein, has been developed by Merck & Co for the treatment of cancer.  Pembrolizumab 
is approved for treatment of melanoma in several countries; in the US and EU it is 


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approved for the treatment of advanced (unresectable or metastatic) melanoma in 
adults.  Pembrolizumab has also been approved for treatment of non-small cell lung 
cancer (NSCLC) in several countries; in the US it is indicated for the treatment of 
patients with metastatic NSCLC whose tumors express PD-L1 as determined by an 
FDA-approved test and who have disease progression on or after platinum-containing 
chemotherapy.  Patients with NSCLC and EGFR or ALK genomic tumor aberrations 
should also have disease progression on FDA-approved therapy for those aberrations 
prior to receiving pembrolizumab.   
Most recently, pembrolizumab has gained approval for the treatment of patients with 
locally advanced or metastatic urothelial carcinoma who have disease progression 
during or following platinum-containing chemotherapy or within 12 months of 
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 
Pembrolizumab has also gained accelerated conditional approval in the United States 
and several countries in the EU in the second line setting for recurrent/metastatic 
SCCHN with disease progression on or after platinum containing chemotherapy without 
any biomarker testing requirement based on the updated data of the phase 1b 
KEYNOTE-012 study (NCT01848834).  
Mostly recently, pembrolizumab has further gained accelerated approval based on tumor 
response rate and durability of response in following tumor types:  (1) adult and pediatric 
patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 
or more prior lines of therapy; (2) urothelial carcinoma in locally advanced or metastatic 
setting for pts who are not eligible for cisplatin containing chemotherapy; (3) adult or 
pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) 
or mismatch repair deficient solid tumors that have progressed following prior treatment 
and who have no satisfactory alternative treatment options, or colorectal cancer that has 
progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.  
Continued approval for above indications may be contingent upon verification description 
of clinical benefit in the confirmatory trials. 
Note:  The safety and effectiveness of pembrolizumab in pediatric patients with MSI-H 
central nervous system cancers have not been established. 
Pembrolizumab also has demonstrated initial clinical efficacy in single arm monotherapy 
trials including subjects with gastric cancer, triple negative breast cancer, and Hodgkin’s 
Lymphoma as determined by response rate.  Ongoing clinical trials are being conducted 


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in other tumor types including hematologic malignancies.  For study details, please refer 
to the pembrolizumab Investigator’s Brochure.  
The first dose-escalation phase 1 study involving subjects with solid tumors showed that 
pembrolizumab was safe at the dose levels tested (1 mg/kg of body weight, 3 mg/kg, 
and 10 mg/kg, administered every 2 weeks) without reaching a maximum tolerated dose 
(Hamid et al, 2013).  In addition, clinical responses were observed at all the dose levels 
(Patnaik et al, 2012).   
For additional information, refer to the pembrolizumab Investigator’s Brochure. 
Pembrolizumab in SCCHN 
On 08 August 2016, pembrolizumab gained accelerated conditional approval in the 
United States and several countries in the EU in the second line setting for 
recurrent/metastatic SCCHN based on the results of a pooled analysis of 
2 recurrent/metastatic squamous cell carcinoma head and neck cohorts from 
KEYNOTE 012 (NCT01848834).  In one cohort, subjects with positive PD-L1 expression 
(defined as a proportion score of > 1% PD-L1 immunohistochemistry expression in 
tumor cells or stroma) received pembrolizumab 10 mg/kg every 2 weeks.  In a second 
cohort, subjects with both positive and negative PD-L1 expression received 
pembrolizumab 200 mg every 3 weeks.  The evaluable population (n = 173) was 
heterogeneous in terms of numbers of prior lines of therapy; however, most patients had 
received prior platinum therapy.  The ORR in the entire population was 23.7% (24.1% in 
the HPV-negative subset and 23.6% in the HPV-positive subset).  The median PFS was 
2.2 months (95% CI:  2.0 to 3.6) and the median overall survival was reported to be 
9.6 months (95% CI:  6.6 to not reached).  Treatment was well tolerated with grade 3/4 
drug-related adverse events occurring in 12.5% of patients (Chow et al, 2015). 
A phase 2 clinical trial of single agent pembrolizumab in platinum and cetuximab failure 
subjects is currently being conducted (NCT02255097).  The primary endpoint will be 
ORR by RECIST v1.1. A phase 3 clinical trial of pembrolizumab versus standard of care 
(methotrexate, docetaxel, or cetuximab) in recurrent or metastatic SCCHN subjects after 
treatment with platinum-based cetuximab therapy is being conducted (NCT02252042) 
with primary endpoint of OS.  A third study of pembrolizumab alone versus 
pembrolizumab plus platinum plus 5-Fluorouracil versus cetuximab plus platinum plus 
5-Fluorouracil for first line treatment of recurrent or metastatic SCCHN is currently being 
conducted (NCT02358031).  The primary endpoint of this study will be PFS by 


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RECIST v1.1.  For all three studies, subjects will receive pembrolizumab 200 mg 
intravenously on Day 1 of each 3 week cycle.  
As existing data suggest 200 mg every 3 weeks as the appropriate dose for 
pembrolizumab and pembrolizumab is currently being tested at this fixed dose in 
ongoing head and neck cancer studies, this is the dose of pembrolizumab planned to be 
studied in this trial. 
2.4 
Rationale 
Talimogene laherparepvec and pembrolizumab blockade likely play complementary 
roles in regulating adaptive immunity.  Talimogene laherparepvec likely augments 
dendritic cell-mediated tumor antigen presentation through local expression of GM-CSF 
(Kaufman et al, 2010) and local antigen release by direct tumor lysis. PD-1 plays an 
important role in SCCHN. Pembrolizumab is a PD-1 regulator and prevents T-cell 
exhaustion in peripheral tissues.  After evidence of activity in SCCHN, pembrolizumab is 
being evaluated in 2 phase 3 trials.  
The combination of an agent that increases tumor-specific immune activation 
(talimogene laherparepvec) with one that blocks inhibitory T-cell checkpoints 
(pembrolizumab) could produce greater antitumor activity than either agent alone.   
There are currently 2 ongoing combination immunotherapy studies with talimogene 
laherparepvec and a checkpoint inhibitor in advanced stage melanoma.  The first is a 
phase 1b/2 study of ipilimumab with or without talimogene laherparepvec in unresected 
melanoma (NCT01740297).  In the phase 1b portion, 18 of 19 subjects (more than half 
with stage IV M1b disease) received both talimogene laherparepvec and ipilimumab in 
combination.  Full dose of talimogene laherparepvec and ipilimumab 3 mg/kg every 
3 weeks starting at week 6 were tolerable.  Per immune-related response criteria (data 
cutoff of 22 December 2014), the ORR in 18 evaluable subjects was 56% 
(33% complete responses [CRs]), and the durable response rate (DRR) was 44%.  
Median PFS was 10.6 months (2.6 to 19.3+ months).  Median OS was not reached; 
12-month and 18-month survival rates were 72.2% and 67%, respectively.  On a lesion 
level, 8 and 5 of 16 uninjected index lesions regressed ≥ 50% and 100%, respectively.  
Grade 3/4 treatment-emergent A occurred in 32% of subjects, and grade 3/4 
immune-related adverse events occurred in 2 subjects (grade 3 hypophysitis and 
adrenal insufficiency; and grade 4 amylase + lipase elevations).  There were no 
treatment-related deaths (Puzanov et al, 2014).  More recently, an interim analysis of the 
phase 2 portion of the study which was performed when 82 patients had ≥ 48 weeks of 


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follow up was reported (Chesney et al, 2016).  One-hundred and seventy three subjects 
were randomized:  88 in the talimogene laherparepvec + ipilimumab arm and 85 in the 
ipilimumab arm.  Characteristics for all subjects were similar:  54% stage IIIB-IVM1a, 
45% IVM1b/c.  Median follow up time for 82 subjects was 61.2 weeks 
(range: 0.14-113.9).  Confirmed ORR was 35.7% in the combination arm and 17.5% in 
the ipilimumab arm with odds ratio for response of 2.6 (95% CI; 0.9-7.3).  Unconfirmed 
ORR was 50% in the combination arm and 27.5% in the ipilimumab arm.  Safety data in 
the analysis were as expected based on the phase 1b data; of 165 subjects in the safety 
set (85 in the combination arm and 80 in the ipilimumab arm), the incidences of grade 3 
and 4 treatment related adverse events were similar in both arms (total of 20% in the 
combination arm and 19% in the ipilimumab arm) with the exception of diarrhea (4% in 
combination arm vs 0% in ipilimumab arm) and colitis (4% in combination arm vs 8% in 
ipilimumab arm).  A grade 5 autoimmune hepatitis occurred in the combination arm 
which was attributed to ipilimumab per investigator. 
The second study is a phase 1b/3 multicenter open-label trial of talimogene 
laherparepvec in combination with pembrolizumab for treatment of unresected, stage IIb 
to IVM1c melanoma (NCT02263508).  In the phase 1b portion of the study, subjects with 
stage IIB-IV melanoma with injectable lesions and no prior systemic therapy received up 
to 4.0 mL of talimogene laherparepvec monotherapy for 2 doses followed by talimogene 
laherparepvec and pembrolizumab every 2 weeks thereafter.  All 21 evaluable subjects 
had an adverse event:  29% grade 3, no grade 4 and 1 grade 5 (not treatment related).  
The most common adverse events by preferred term were fatigue (52%), pyrexia (48%), 
chills (43%), and rash (38%).  Of 16 subjects evaluable for response, the unconfirmed 
response rate per investigator was 56%; DCR was 69% (12.5% CR, 44% partial 
response [PR], 12.5% stable disease [SD]) (Long et al, 2015). 
This registrational study is intended to provide evidence that a regimen of an oncolytic 
immunotherapy (talimogene laherparepvec) and a checkpoint inhibitor (pembrolizumab) 
is safe and tolerable, and that the combination might enhance the clinical efficacy of 
single agent pembrolizumab in recurrent or metastatic SCCHN.  The choice of PD-1 
inhibitors for the control arm is based on the assumption that this class of agent may 
become the new standard of care in this indication.  The study is an accelerated design 
leading from a phase 1b to a phase 3 study without a conventional phase 2 evaluation. 
However, activity of the combination will be evaluated at the end of the phase 1b study 
to support a decision to initiate the phase 3 study. 


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2.5 
Clinical Hypotheses 
Phase 1b:  
Talimogene laherparepvec in combination with pembrolizumab will be safe and well 
tolerated in subjects with recurrent or metastatic SCCHN. 
Phase 3: 
The clinical hypothesis is that talimogene laherparepvec with pembrolizumab compared 
to placebo with pembrolizumab will improve OS.  In addition to the hypothesis test for 
the primary endpoint, ORR, PFS, iORR, and iPFS in subjects given talimogene 
laherparepvec plus pembrolizumab versus placebo plus pembrolizumab will be 
compared. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 1b/3, multicenter clinical trial.  The study will be conducted in 2 parts 
(phase 1b and phase 3) as described below.  The overall study design is described by a 
Study Design and Treatment Schema at the end of the protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.1.1 
Phase 1b Study Design 
Phase 1b is a multicenter, single-arm study.  Talimogene laherparepvec will be 
administered in combination with pembrolizumab to approximately 40 subjects with 
recurrent or metastatic SCCHN.  DLT will be evaluated based on first 18 DLT-evaluable 
subjects.  An expansion cohort of up to an additional 22 treated subjects will be enrolled 
to obtain a total of approximately 40 treated subjects to further evaluate the safety and to 
estimate the efficacy of the combination of talimogene laherparepvec with 
pembrolizumab to support a decision to initiate the phase 3 study. 
3.1.1.1 
Rules for DLT Evaluation in Phase 1b 
A Dose Level Review Team (DLRT) will review the safety data to evaluate DLT.  This 
team will recommend either to enroll more subjects for DLT evaluation in phase 1b, to 
prematurely stop enrollment into phase 1b, or to declare that the combination is tolerable 
based on the criteria described in Table 1 below. 
The DLT evaluation period is 6 weeks from the initial administration of study treatment.  
To be evaluable for a DLT, subjects must have had the opportunity to be on treatment 
for at least 6 weeks from the initial dosing of study treatment and have received at least 
2 doses of talimogene laherparepvec and 2 doses of pembrolizumab in combination, or 


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have a DLT during the DLT evaluation period after at least 1 dose of talimogene 
laherparepvec and pembrolizumab in combination.  Subjects may be replaced if they are 
not evaluable for DLT to obtain 18 DLT-evaluable subjects (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). 
Safety will be evaluated considering the incidence of DLTs among all DLT-evaluable 
subjects enrolled in the phase 1b.  A sequential stopping rule is derived based on a 
hypothesis testing approach considering only the first 18 DLT-evaluable subjects 
(Goldman, 1987).  There will be up to 3 planned safety interim analyses.  The cumulative 
increments of DLT-evaluable subjects and corresponding acceptable maximum number 
and percentage of DLTs at each analysis are indicated in Table 1.  The combination will 
not be declared safe if the number of DLTs exceeds the acceptable maximum number 
and phase 1b will stop. 
Table 1.  Cumulative Increments of DLT-evaluable Subjects and Corresponding 
Acceptable Maximum Number and Percentage of DLTs at Each Planned Interim 
Safety Analysis  
Analysis 
Number DLT Evaluable 
Subjects 
Number DLT 
Evaluable 
Acceptable Maximum 
Number (%) of DLTs 
#1 
First 4 to 6 
4 
5 
6 
71 
2 (50) 
2 (40) 
2 (33) 
2 (29) 
#2 
4 to 6 new after 
Analysis #1 
8 
9 
10 
11 
12 
131 
2 (25) 
3 (33) 
3 (30) 
3 (27) 
3 (25) 
3 (23) 
#3 
Exactly 18 total 
182 
4 (22) 
DLT = dose limiting toxicity 
The design achieves a 7.7% 1-sided significance level and 81.6% power to test the null hypothesis of a DLT 
rate ≤ 10% versus the alternative hypothesis of a rate ≥ 33%.  
1 Although the target is 4 to 6 DLT-evaluable subjects at Analysis #1, and 4 to 6 new subjects at Analysis 
#2, all DLT-evaluable subjects will be included in each analysis. 
2 If > 18 subjects receive the combination they will contribute to the overall safety analysis, but only the first 
18 DLT-evaluable will be considered in the decision to declare the combination safe. 
3.1.1.2 
Definition of DLT in Phase 1b 
All toxicities will be graded using the CTCAE version 4.0 (Appendix A). 
The occurrence of any of the following toxicities during DLT evaluation period 
(ie, 6-week period from the initial administration of talimogene laherparepvec and 


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pembrolizumab in combination) will be considered a DLT, if judged by the investigator to 
be related to the administration of talimogene laherparepvec and/or pembrolizumab: 
• 
Grade 4 non-hematologic (non-laboratory) toxicity 
• 
Grade 3 or higher pneumonitis  
• 
Grade 3 non-hematologic (non-laboratory) 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 
− 
the abnormality persists at grade 3 or higher for >1 week unless deemed not 
clinically important per both investigator and sponsor 
• Grade 3 or grade 4 febrile neutropenia 
• Thrombocytopenia < 25 x 109/L associated with bleeding event requiring intervention 
• Serious herpetic event: 
− 
Herpetic encephalitis, encephalomyelitis, or disseminated herpetic infection 
• 
Grade 5 toxicity (ie, death) 
• 
Any other intolerable toxicity leading to permanent discontinuation of talimogene 
laherparepvec or pembrolizumab  
If a subject experiences a DLT during the DLT evaluation period, study treatments will 
be discontinued for that subject. 
An expansion cohort of up to 22 treated subjects will be enrolled so there will be 
approximately 40 treated subjects in total to estimate the efficacy of the combination of 
talimogene laherparepvec with pembrolizumab.  
3.1.2 
Phase 3 Study Design 
Phase 3 is a multicenter, placebo-controlled, double-blind, randomized trial to evaluate 
the efficacy, as assessed by OS, of treatment with talimogene laherparepvec with 
pembrolizumab versus placebo with pembrolizumab in subjects with recurrent or 
metastatic SCCHN.  Approximately 450 subjects will be randomized 1:1 to receive the 
following: 
• Arm 1:  talimogene laherparepvec plus pembrolizumab 
• Arm 2:  placebo plus pembrolizumab 
Randomization will be stratified by HPV status at baseline (HPV- negative versus 
HPV-positive) and ECOG performance status (0 versus 1).   


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3.1.3 
Tumor Assessment 
3.1.3.1 
Eligibility Assessment 
Phase 1b 
Conventional RECIST v1.1 (Eisenhauer et al, 2009) , with the following modification, will 
be used by the investigator to determine eligibility: 
• 
Increased total target lesions to a maximum of 10 (up to a maximum of 5 per 
organ) 
Phase 3 
Conventional RECIST v1.1 (Eisenhauer et al, 2009) with no modifications will be used 
by the investigator to determine eligibility. 
3.1.3.2 
Response Assessment 
For both phase 1b and phase 3, a variation of RECIST v1.1, irRECIST, will be used by 
the investigator to assess tumor response and make treatment decisions, and to assess 
the secondary tumor response related endpoints in the phase 1b and phase 3 portions 
of the study.  In addition, for phase 3 only, investigators will also be asked to determine 
and document tumor responses per standard RECIST v1.1, although treatment 
decisions should NOT be made based on RECIST v1.1.  Details for irRECIST can be 
found in Appendix D, and details for RECIST v1.1 can be found in Appendix E. 
Radiographic tumor assessments will be performed independent of treatment cycle at 
week 9 (±1 week), week 18 (±1 week), and then every 9 weeks (±1 week) or more 
frequently if clinically indicated until confirmed progressive disease per irRECIST (iPD) 
or start of a new anticancer treatment.  Radiographic tumor assessments should not be 
adjusted for cycle initiation delays and performed according to the calendar.  
Radiographic tumor imaging assessment at screening (baseline) (computed tomography 
[CT] scan, positron emission tomography [PET]/contrast enhanced CT scan, or magnetic 
resonance imaging [MRI]) must include the neck, chest, abdomen and all other sites of 
disease.  A CT scan or MRI of the brain should only be performed if signs or symptoms 
suggestive of central nervous system [CNS] metastases are present. The imaging 
modality selected (eg, CT or MRI) should remain constant for any individual subject. 
3.1.4 
Follow-up 
3.1.4.1 
Safety Follow-up 
All subjects who receive investigational product will complete a safety follow-up visit 
approximately 30 (+7) days after the last dose of study treatment.  Adverse events and 


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disease related events will be collected as described in Section 9.2.  Serious adverse 
events and any concomitant medications associated with serious adverse events 
observed by the investigators or reported by the subjects that occur through 
90 (+7) days after the cessation of all study treatment or 30 (+7) days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier, will be reported to Amgen and recorded in the CRF. 
3.1.4.2 
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 subsequent anticancer therapies every 12 weeks 
(± 28 days) from safety follow-up for approximately 36 months after the last subject is 
enrolled.  In addition, talimogene laherparepvec/placebo related adverse events that 
occur through the end of the long-term follow-up will be reported. 
For subjects who discontinue study treatment without documented iPD and have not 
initiated a new anticancer therapy, every effort should be made to continue monitoring 
tumor response status by clinical and radiographic tumor assessments, and to complete 
PRO questionnaires as described in Section 7.7.   
3.2 
Number of Sites 
The study will be conducted at approximately 140 sites in Australia, Europe, 
North America, Latin America, Asia, and other regions. Additional sites and countries 
may be added.  Sites that do not enroll subjects within approximately 4 months of site 
initiation may be closed.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Approximately 490 subjects will be enrolled in this study: approximately 40 subjects will 
be enrolled in phase 1b and approximately 450 subjects will be enrolled in phase 3 
Global Full Analysis Set (FAS[G]).  Refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects enrolled in phase 1b may be replaced if they are not evaluable for DLT 
(eg, a subject did not receive study treatment, or ended the study treatment before 
completion of DLT evaluation period for a reason other than experiencing a DLT).  
Subjects enrolled in phase 3 who are withdrawn or removed from treatment or from the 
study will not be replaced. 


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3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The duration of screening for each subject will be approximately 28 days.  The duration 
of treatment will vary for each subject.  Subjects enrolled (phase 1b)/randomized 
(phase 3) have an estimated median treatment period of 7 months, but can be treated 
for up to 24 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 approximately 36 months after the last subject is enrolled.  The study 
duration for an individual subject is expected to be 45 months.  The actual duration of 
the study for an individual subject may vary depending upon the time required to reach 
the study specified number of OS events. 
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the 
last subject is assessed or receives an intervention for the final collection of data 
for the primary endpoint(s), for the purposes of conducting the primary analysis, 
whether the study concluded as planned in the protocol or was terminated early.  
If a 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). 
Primary Completion Phase 1b only:  The time when the last phase 1b subject is 
assessed or receives an intervention for the purposes of final collection of data 
for the primary efficacy endpoint of phase 1b.  The primary completion is 
anticipated to occur when the last phase 1b subject completes the week 9 tumor 
response assessment. 
End of Study (end of trial):  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.  This is anticipated to occur 36 months after 
the last subject is enrolled. 


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4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures 
102 
Male or female age ≥ 18 years at the time of informed consent 
103 
Histologically confirmed diagnosis of metastatic or recurrent SCCHN of the oral 
cavity, oropharynx, hypopharynx, or larynx.  Disease must be unsuitable for 
curative surgical resection and must not be amenable to curative radiotherapy. 
104 
Disease must have progressed after treatment with a platinum-containing 
regimen and should be defined as one of the following: 
• 
disease progression or recurrence between 3 to 6 months of prior curatively 
intended multimodal therapy (which includes platinum therapy) for 
locoregionally advanced SCCHN. 
Note:  This criterion is only applicable for subjects who have not had treatment in 
the recurrent/metastatic setting. 
• 
disease progression or recurrence after prior platinum therapy in the 
recurrent or metastatic setting 
105 
Subject must be candidate for intralesional therapy administration defined as one 
or more of the following: 
• 
at least 1 injectable cutaneous, subcutaneous, or nodal SCCHN tumor 
≥ 10 mm in longest diameter 
• 
multiple injectable cutaneous, subcutaneous, or nodal SCCHN tumors that in 
aggregate have a longest diameter of ≥ 10 mm   
Note:  Mucosal surfaces of tumor lesions and visceral metastases should not be 
injected. 
106 
Subject must have radiographically measurable disease per RECIST v1.1 
(Eisenhauer et al, 2009). Target lesions must not be chosen from a previously 
irradiated field unless there has been radiographically and/or pathologically 
documented tumor progression in that lesion prior to enrollment 
107 
ECOG performance status of 0 or 1 


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108 
Adequate organ function determinedprior to enrollment, defined as follows: 
• 
Hematological 
− 
ANC ≥ 1.5 x 109/L 
− 
platelet count ≥ 100 x 109/L 
− 
hemoglobin ≥ 9 g/dL  
Note:  Subjects who have received transfusion of blood products (including 
platelets or red blood cells, or administration of colony stimulating factors 
[including G-CSF, GM-CSF, or recombinant erythropoietin) within 4 weeks prior 
to the first study treatment will be excluded. 
• 
Renal 
− 
serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR creatinine 
clearance ≥ 60 mL/min for a subject with creatinine levels > 1.5 x ULN. 
(Note: Creatinine clearance need not be determined if the baseline serum 
creatinine is within normal limits. Creatinine clearance should be 
determined per institutional standard). 
• 
Hepatic 
− 
total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total 
bilirubin level > 1.5 x ULN 
− 
aspartate aminotransferase (AST) ≤ 2.5 x ULN OR ≤ 5 x ULN for a 
subject with liver metastases 
− 
alanine aminotransferase (ALT) ≤ 2.5 x ULN OR ≤ 5 x ULN for a subject 
with liver metastases 
• 
Coagulation 
− 
international normalization ratio (INR) or prothrombin time (PT) 
≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy, in 
which case PT and partial thromboplastin time (PTT)/activated PTT 
(aPTT) must be within therapeutic range of intended use of 
anticoagulants 
− 
PTT or aPTT ≤ 1.5 x ULN unless the subject is receiving anticoagulant 
therapy as long as PT and PTT/aPTT is within therapeutic range of 
intended use of anticoagulants 
109 
Female subject of childbearing potential must have a negative  pregnancy test 
within 72 hours prior to enrollment. If urine pregnancy test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required. 
110 
Phase 1b:  Subject has a formalin fixed paraffin-embedded tumor sample from 
the primary or metastatic lesion that must be submitted within 4 weeks of 
enrollment for PD-L1, HPV-testing of oropharyngeal cancer (if not performed 
locally) and biomarker analyses.   
Phase 3: Subject has a formalin fixed paraffin embedded tumor sample that is 
adequate for PD-L1 assessment prior to randomization (sites will be blinded to 
PD-L1 analysis).  Tumor tissue from the subject must be submitted to a central 
laboratory during screening.  Refer to the laboratory manual for more detailed 
tissue collection procedures. 


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111 
Phase 3: Have results from local testing of HPV of tumor specimen for 
oropharyngeal cancer defined as p16 IHC testing using the CINtec assay and a 
70% cutoff point. If the assay is unavailable locally, sites must submit archived or 
recently biopsied formalin-fixed paraffin-embedded tumor tissue (block or 
unstained tumor slides) from either the primary or metastatic lesion for central 
laboratory testing.  Note: HPV stratification in this trial will be performed using 
local or central testing of HPV status in subjects with oropharynx cancer. Oral 
cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing 
by p16 IHC as by convention, they are assumed to be HPV negative.  Please 
note that results from local testing of HPV of tumor specimen for oropharyngeal 
cancer patients are required for both phases of the study.  Performing p16-IHC 
testing using the CINtec assay is only required for phase 3. 
4.2 
Exclusion Criteria 
201 
Has known active CNS metastases and/or carcinomatous meningitis. Subjects 
with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least four weeks prior to the 
first dose of trial treatment and any neurologic symptoms have returned to 
baseline), and are not using steroids for at least 7 days prior to trial treatment.  
This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability. 
202 
Primary nasopharyngeal carcinoma. 
203 
Subject at risk of airway compromise in the event of postinjection tumor 
swelling/inflammation based on investigator judgment. 
204 
Phase 3:  Previous treatment with 3 or more systemic regimens given for 
recurrent and/or metastatic disease. 
205 
History of other malignancy within the past 3 years with the following exceptions: 
• 
malignancy treated with curative intent and with no known active disease 
present and has not received chemotherapy for ≤ 3 years before enrollment 
and felt to be at low risk for recurrence by the treating physician 
• 
adequately treated non-melanoma skin cancer without evidence of disease at 
the time of enrollment 
• 
adequately treated cervical carcinoma in situ without evidence of disease at 
the time of enrollment 
• 
adequately treated breast ductal carcinoma in situ without evidence of 
disease at the time of enrollment 
• 
prostatic intraepithelial neoplasia without evidence of prostate cancer at the 
time of enrollment 
• 
adequately treated superficial or in situ carcinoma of the bladder without 
evidence of disease at the time of enrollment 
207 
History of interstitial lung disease (ILD). 


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208 
Prior therapy with talimogene laherparepvec, pembrolizumab, other anti-PD-1, 
any other antibody or drug specifically targeting T-cell co-stimulation or immune 
check point pathway. 
210 
History or evidence of active autoimmune disease that has required systemic 
treatment in the past 2 years (ie, with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs).   
Note:  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a 
form of systemic treatment. 
211 
Evidence of clinically significant immunosuppression such as the following: 
• 
organ transplant/bone marrow transplant or other signs or symptoms of 
clinical immune system suppression 
• 
any severe congenital or acquired cellular and/or humoral immune deficiency 
• 
diagnosis of immunodeficiency 
• 
concurrent opportunistic infection 
• 
receiving systemic immunosuppressive therapy > 2 weeks or within 7 days 
prior to the first dose of study treatment, including oral steroid doses 
> 10 mg/day of prednisone or equivalent  
Note:  Subjects that require intermittent use of bronchodilators or local steroid 
injection are not excluded from the study. 
212 
Active herpetic skin lesions or prior complications of herpetic infection 
(eg, herpetic keratitis or encephalitis). 
213 
Requires intermittent or chronic treatment with an antiherpetic drug 
(eg, acyclovir), other than intermittent topical use. 
214 
Prior chemotherapy, radiotherapy, biological cancer therapy, targeted therapy, or 
major surgery within 28 days prior to enrollment or has not recovered to CTCAE 
grade 1 or better from adverse event due to cancer therapy administered more 
than 28 days prior to enrollment.  
Note: Subjects with ≤ grade 2 neuropathy and/or alopecia are an exception to 
this criterion and may qualify for the study. 
215 
Currently participating or have participated in a study (treatment period only) of 
an investigational agent or used an investigational device within 28 days of 
enrollment/randomization. 
216 
Expected to require other cancer therapy while on study with the exception of 
local palliative radiation treatment to the site of bone and other metastasis. 
217 
Subject who is unwilling to forgo other investigational procedures during study 
treatment. 
218 
Known human immunodeficiency virus (HIV) disease. 


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219 
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, entecavir), 
ribavirin, or interferon alpha within 12 weeks of initiation of study treatment. 
220 
Received live vaccine within 28 days prior to enrollment/randomization. 
221 
Subject is pregnant or breast-feeding, or expecting to conceive or father children 
within the duration of the trial, starting with the screening visit and through 
3 months after the last dose of talimogene laherparepvec/placebo or 4 months 
after the last dose of pembrolizumab, whichever is later. 
222 
Female subject of childbearing potential or male subject of reproductive 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/placebo or 4 months after the last dose of pembrolizumab, 
whichever is later.  Note: Women not of childbearing potential are defined as: 
• 
Postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone [FSH] level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient) 
OR 
• 
Have had a hysterectomy and/or bilateral oophorectomy, or bilateral 
salpingectomy at least 6 weeks prior to screening 
OR 
• 
Has a congenital or acquired condition that prevents childbearing 
For this trial, male subjects will be considered to be of non-reproductive potential 
if they have azoospermia (whether due to having had a vasectomy or due to an 
underlying medical condition).Note: Acceptable methods of effective 
contraception are defined in the informed consent form.  Additional 
country-specific contraception requirements may be defined in a country-specific 
protocol supplement at the end of the Appendix Section of the protocol as 
required by local laws and regulations. 
If there is any question that a subject of reproductive potential will not reliably 
comply with the requirements for contraception, that subject should not be 
enrolled into the study. 
223 
Sexually active subjects or their partners unwilling to use male or female latex 
condom to avoid potential viral transmission during sexual contact while on 
treatment and within 30 days after treatment with talimogene 
laherparepvec/placebo.  For those with latex allergies, polyurethane 
condoms may be used. 
224 
Subject has known sensitivity to any of the products or components to be 
administered during study treatment. 


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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 psychiatric, 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 sponsor medical monitor, if 
consulted, would pose a risk to subject safety or interfere with the study 
evaluation, procedures or completion. 
227 
Subject or subject’s immediate family member (eg, spouse, parent/legal 
guardian, sibling, or child) is investigational site or sponsor staff directly involved 
in this trial.  
Note:  If prospective institutional review board (IRB)/independent ethics 
committee (IEC) approval (by chair or designee) is given, an exception to this 
criterion for a specific subject is permitted. 
228 
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 
(eg, immunosuppressed individuals, HIV-positive individuals, pregnant women, 
or children under the age of 1 year) during talimogene laherparepvec treatment 
and through 30 days after the last dose of talimogene laherparepvec/placebo. 
229 
Has a known history of active bacillus tuberculosis. 
230 
Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
231 
Subjects with tumor that directly contacts or encases a major blood vessel AND 
there is ulceration and/or fungation onto the skin surface. 
232 
History of re-irradiation to a field which includes the carotid arteries. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written IRB/IEC approval of the protocol, informed consent 
form, and all other subject information and/or recruitment material, if applicable 
(see Section 11.2).  All subjects must personally sign and date the IRB/IEC and Amgen 
approved informed consent form before commencement of study-specific 
activities/procedures.   
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined when the 
subject signs the informed consent) receives a unique subject identification number 
before any study-related activities/procedures are performed.  The subject identification 


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number will be assigned by the Interactive voice response (IVR) system (referred to as 
IxRS throughout the protocol).  This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that 
subject.   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
5.1 
Treatment Assignment Phase 1b 
All subjects enrolled in the phase 1b of the study will receive open-label talimogene 
laherparepvec in combination with pembrolizumab.  The treatment assignment date is to 
be documented in the subject’s medical record and on the enrollment CRF. 
5.2 
Randomization/Treatment Assignment Phase 3  
Upon confirmation of eligibility, the site staff will use the IVR system to randomize a 
subject.  The IVR system will assign a randomization number. Approximately 
450 subjects will be randomized 1:1 ratio to receive the following: 
• Arm 1:  talimogene laherparepvec plus pembrolizumab 
• Arm 2:  placebo plus pembrolizumab 
Randomization will be stratified by HPV status at baseline (HPV- negative versus 
HPV-positive) and ECOG performance status (0 versus 1).   
Following randomization via the IVR system, study treatment must commence within  
5 days after enrollment. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.  
The subject, site personnel, and sponsor study personnel and designees are blinded to 
the randomization treatment group assigned unless otherwise specified in the protocol.   
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study.  If a 
subject discontinues study treatment due to documented disease progression and the 
knowledge of treatment assignment alters the subject’s eligible treatment options outside 
of the trial, then the investigator may request to unblind the treatment assignment for 
that subject after discussion with the sponsor.  All precaution and efforts will be taken to 


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ensure the sponsor and blinded site personal will remain blinded to the study treatment.  
Unblinding at the study site for any other reason will be considered a protocol deviation. 
The investigator is strongly encouraged to contact the sponsor clinical study manager 
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the event and must document the unblinding in the subject’s electronic CRF. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product (except if required by local regulation) used in this 
study includes: talimogene laherparepvec/placebo.   
The Non-Amgen Investigational product(s) used in this study includes:  pembrolizumab. 
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/placebo and pembrolizumab.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product: Talimogene Laherparepvec/Placebo  
Talimogene laherparepvec/placebo 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. 
Placebo (talimogene laherparepvec formulation excipients as described in the 
Talimogene Laherparepvec Investigator’s Brochure) will be supplied as sterile frozen 
liquid in the same presentation, packaging, and with blinded labeling as for talimogene 
laherparepvec. 


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Talimogene laherparepvec or placebo may be supplied as open-label or blinded.  Where 
talimogene laherparepvec or placebo is supplied as open-label, the site pharmacist or 
designee will need to be unblinded to prepare blinded talimogene 
laherparepvec/placebo. 
 
For talimogene laherparepvec or placebo supplied as open-label investigational 
medicinal product, IxRS will confirm to the unblinded site pharmacist or designee, 
from which lot number(s) the vial(s) should be selected from each dosing visit.  In 
no circumstances should an unblinded pharmacist reveal the treatment 
assignment to the other site staff. 
 
For talimogene laherparepvec or placebo supplied as a blinded investigational 
medicinal product, IxRS will confirm to the site pharmacist or designee from which 
box number(s) vial(s) should be selected from each dosing visit.  All site 
personnel will be blinded to study treatment. 
6.2.1.1 
Dosage, Administration, and Schedule 
Talimogene laherparepvec/placebo 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 5 and Table 7) and the results should be checked before each 
treatment.  For subjects on anticoagulant therapy, close monitoring of coagulation 
parameters is recommended during the study treatment phase.  Dosing will occur only if 
these test values are acceptable per Section 6.2.1.2. 
Talimogene laherparepvec/placebo will be administered by intralesional injection only 
into injectable cutaneous, subcutaneous, and nodal tumors, with or without image 
ultrasound (US) guidance.  Talimogene laherparepvec/placebo must not be 
administered into the mucosal surface of tumor lesions or visceral metastases.  For 
subjects with tumor(s) which directly contacts or encases a major vessel but does not 
have ulceration and/or fungation onto the skin surface, talimogene laherparepvec 
injections should be given no closer than 2 cm from the wall of the major vessel.  This 
should be done under image guidance and by skilled personnel (eg, a surgeon). 
For the first cycle, the dose of talimogene laherparepvec/placebo will be up to 8.0 mL of 
106 PFU/mL administered on week 0, day 1.  For the second cycle, subjects may receive 
up to 8.0 mL of talimogene laherparepvec 108 PFU/mL or placebo 3 weeks (+ 3 days) 
after the initial injection (ie, no sooner than day 22 but should not be delayed more than 
3 days after the 3 week time point).  All subsequent doses up to 8.0 mL of talimogene 


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laherparepvec108 PFU/mL or placebo will be administered every 3 weeks (± 3) days.  If 
a delay of > 3 days is anticipated due to reasons other than toxicity, permission should 
be sought from the medical monitor.  The treatment cycle interval may be increased due 
to toxicity as described in Section 6.2.1.2.  It is recommended that talimogene 
laherparepvec/placebo be administered before pembrolizumab on treatment days. 
The maximum volume of talimogene laherparepvec/placebo administered at any dose is 
4.0 mL for any individual tumor lesion.  The maximum volume at any treatment visit is 
8.0 mL.  Investigators are encouraged to use the maximum volume whenever lesions 
allow. The recommended volume of talimogene laherparepvec/placebo 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. 
Table 2.  Talimogene Laherparepvec Injection Volume Guideline 
Based on Tumor Size 
Tumor Size (longest dimension) 
Maximum Injection Volume 
> 5.0 cm (50 mm) 
4.0 mL 
> 2.5 cm (25 mm) to 5.0 cm (50 mm) 
2.0 mL 
> 1.5 cm (15 mm) to 2.5 cm (25 mm) 
1.0 mL 
> 0.5 cm (5 mm) to 1.5 cm (15 mm) 
0.5 mL 
≤ 0.5 cm (5 mm) 
0.1 mL 
On each treatment day, prioritization of injections is recommended as follows: 
• 
any new injectable tumor that has appeared since the last injection 
• 
by tumor size, beginning with the largest tumor  
• 
any previously uninjectable tumor(s) that is now injectable  
It is recommended that each lesion should receive the maximum amount possible to 
inject due to tumor properties at each visit before moving on the next lesion, using the 
prioritization model above and the injection volume guideline based on tumor size per 
Table 2.  Tumor measurements for injection volume determination may be done by 
caliper measurements and/or by ultrasound guided measurements.  Most recent prior 
radiographic tumor assessment measurements may be used to determine injection 
volume if caliper measurements and/or ultrasound guided measurements are not 
feasible and/or unavailable.  The lesions injected will be recorded on the CRF. 
Note:  Continued injection into nodal lesions that have decreased to < 10 mm is up to 
the discretion of the investigator. 


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Subjects will be treated with talimogene laherparepvec/placebo until subjects have 
achieved a iCR, no injectable lesions, confirmed iPD (response per irRECIST), 
intolerance of study treatment, 24 months from the date of the first dose of talimogene 
laherparepvec/placebo, or end of study, 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 study therapy.  The dose, start date, and lot 
number of talimogene laherparepvec/placebo are to be recorded on each subject’s CRF. 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Dose reductions of talimogene laherparepvec/placebo are not permitted, other than with 
respect to a reduction in the volume injected due to a disease response. 
If a subject experiences any of the following treatment-related toxicities, 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  
Talimogene laherparepvec should be withheld if subject experiences any adverse event 
which, in the opinion of the investigator, warrants withholding investigational product.   
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) 
for related toxicities, talimogene laherparepvec/placebo dosing must be withheld until the 
corticosteroid dose has decreased to ≤ 10 mg prednisone daily (or equivalent). 
All necessary supportive therapies except for those listed in Section 6.9 shall be 
available to subjects.  Talimogene laherparepvec/placebo treatment should be continued 
based on the potential benefit/risk assessment of the subject.  
If talimogene laherparepvec/placebo dosing is delayed by more than 4 weeks from the 
date of the planned dose (ie, approximately 7 weeks since the previous dose) due to the 
occurrence of an adverse event that is considered related to talimogene 
laherparepvec/placebo, the subject must be permanently withdrawn from talimogene 
laherparepvec/placebo treatment. If talimogene laherparepvec/placebo dosing is 
delayed by more than 4 weeks from the date of the planned dose (ie, 7 weeks from the 
previous dose) for reasons other than treatment-related toxicity, the case must be 
reviewed by the sponsor medical monitor in conjunction with the investigator to 
determine if the subject can resume talimogene laherparepvec/placebo treatment.  


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Talimogene laherparepvec/placebo doses may be given no less than 15 days apart, if 
needed, for the purpose of re-aligning dosing schedules after a dose delay. 
Talimogene laherparepvec in phase 1b or talimogene laherparepvec/placebo in phase 3 
is to be permanently discontinued for subjects meeting any of the following criteria: 
• 
Phase 1b subject developed DLT during the DLT evaluation period. 
• 
The subject, for any reason, requires treatment with another anticancer therapeutic 
agent for treatment of the study disease (other than the exceptions noted in 
Excluded Treatments and/or Procedures During Study Period [Section 6.9].  In this 
case, discontinuation from the treatment occurs immediately upon introduction of the 
new agent.  
• 
Confirmed iPD occurs as defined per the irRECIST (Appendix D).  
• 
A grade 2 or greater immune-mediated adverse event (with the exception of vitiligo) 
or allergic reactions attributed to talimogene laherparepvec/placebo that would 
require a dose delay of greater than 4 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/placebo-related non-hematologic or 
hematologic toxicities grade 3 or greater occur that, in the opinion of the investigator, 
would require a dose delay of greater than 4 weeks from the date of the planned 
dose. 
• 
The subject develops clinical evidence of any systemic herpes infection (such as 
encephalitis or disseminated infection). 
• 
A female subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception (for those subjects who are able to conceive).  
• 
A female subject breast feeds while on study treatment. 
• 
Concurrent medical illness that, in the judgment of the investigator, would make 
continued treatment with talimogene laherparepvec/placebo dangerous for the 
subject. 
For additional information, related special warnings, and precautions for the use of 
talimogene laherparepvec/placebo please refer to the latest version of the talimogene 
laherparepvec Investigator’s Brochure. 
In the event talimogene laherparepvec/placebo is delayed or permanently discontinued 
for talimogene laherparepvec/placebo-related toxicity, pembrolizumab may continue to 
be administered, as long as the toxicity is clearly not related to pembrolizumab. Likewise 
in the event pembrolizumab is delayed or permanently discontinued for 
pembrolizumab-related toxicity, talimogene laherparepvec/placebo may continue to be 


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administered, as long as the toxicity is clearly not related to talimogene 
laherparepvec/placebo. 
6.2.2 
Non-Amgen Investigational Product: Pembrolizumab  
Non-Amgen investigational product, pembrolizumab, will also be used in this study. 
Pembrolizumab will be manufactured by Merck.  Pembrolizumab will be labeled, 
packaged, and distributed by Amgen (or designee) using Amgen (or designee) clinical 
study drug distribution procedures.  Pembrolizumab is supplied as pembrolizumab 
100 mg/4mL vials (25 mg/mL) solution for intravenous infusion.  
Additional details regarding pembrolizumab are provided in the IPIM. 
6.2.2.1 
Pembrolizumab Dosage, Administration, and Schedule 
Pembrolizumab 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) and thyroid function tests (triiodothyronine [T3] or free T3 [FT3] per local 
standard, free thyroxine [FT4], and thyroid stimulating hormone [TSH]) should be 
obtained according to the Schedule of Assessments (Table 5 and Table 7) and the 
results should be checked before each treatment.  Dosing will occur only if these test 
values are acceptable per Section 6.2.2.2.   
Note:  Thyroid Function Tests must be collected, but if there are no symptoms of 
hypothyroidism or hyperthyroidism, study treatment can be initiated prior to the reporting 
of the laboratory results. 
Pembrolizumab at a dose of 200 mg will be administered intravenously every 3 weeks 
(± 3 days) after the initial dose.  When talimogene laherparepvec/placebo and 
pembrolizumab are administered on the same day, it is recommended that talimogene 
laherparepvec/placebo be administered first. Pembrolizumab dosing will continue until a 
iCR is achieved, confirmed iPD (response per irRECIST), intolerance to treatment, 
24 months from the date of the first dose of study treatment, or end of study, whichever 
occurs first.   
Pembrolizumab infusion will be administered as a 30-minute intravenous infusion.  
Investigators should make every effort to target infusion timing to be as close to 
30 minutes as possible. However, given the variability of infusion pumps from site to site, 
a window of -5 and +10 minutes is permitted (ie, infusion time is 


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30 minutes:-5 minutes/+ 10 minutes).  A central catheter is not required for infusion; 
however if a subject has a central venous catheter in place, it is recommended that it be 
used for the infusion.  A 0.2 or 0.22 µm in-line filter made of polyethersulfone must be 
used during administration to remove any adventitious particles.  If the infusion set does 
not contain a 0.2 or 0.22 µm in-line filter, it is recommended to use an extension line 
containing the filter.  Details on the dose calculation, preparation, and administration are 
provided the IPIM. 
The dose, start date, and lot number of pembrolizumab are to be recorded on each 
subject’s CRF. 
6.2.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment.  
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening 
adverse events as per Table 3 below.  See Section 6.2.3 for supportive care guidelines, 
including use of corticosteroids. 


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Table 3.  Pembrolizumab-related Adverse Event Management 
General instructions: 
Corticosteroid taper should be initiated upon AE improving to grade 1 or less and continue to taper over 
at least 4 weeks. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered.  Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE 
management 
with 
corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
Monitor participants 
for signs and 
symptoms of 
pneumonitis 
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid 
treatment 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
Grade 3 or 4, or 
recurrent 
Grade 2 
Permanently 
discontinue 
Page 1 of 5 


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Table 3.  Pembrolizumab-related Adverse Event Management 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE 
management 
with 
corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
Monitor participants 
for signs and 
symptoms of 
enterocolitis (ie, 
diarrhea, abdominal 
pain, blood or mucus 
in stool with or without 
fever) and of bowel 
perforation 
(ie, peritoneal signs 
and ileus). 
Participants with 
≥ Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
to rule out colitis.  
Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids.  If 
sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted 
via IV infusion. 
Grade 4 
Permanently discontinue 
Page 2 of 5 


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Table 3.  Pembrolizumab-related Adverse Event Management 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE 
management 
with 
corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
AST/ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Permanently 
discontinue, if: 
AST or ALT > 3x ULN; 
and total bilirubin 
> 2 x ULN; and no 
other cause for the 
combination of 
laboratory 
abnormalities is 
immediately apparent 
(see Section 6.4.1) 
Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Monitor with liver 
function tests 
(consider weekly or 
more frequently until 
liver enzyme value 
returned to baseline 
or is stable 
Grade 3 or 4  
Permanently discontinue 
Administer 
corticosteroids 
(initial dose of  
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemi
a associated 
with evidence 
of β-cell 
failure 
Withhold 
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM  
Administer 
antihyperglycemi
c in participants 
with 
hyperglycemia  
 
Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated.   
 
Monitor for signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or permanently 
discontinue1  
Page 3 of 5 


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Table 3.  Pembrolizumab-related Adverse Event Management 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE 
management 
with 
corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Hyperthyroidism  Grade 2 
Continue  
Treat with 
non-selective 
beta-blockers 
(eg, propranolol) 
or thionamides 
as appropriate  
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
Administer 
corticosteroids 
(prednisone  
1-2 mg/kg or 
equivalent) 
followed by 
taper. 
Monitor changes of 
renal function 
 
Grade 3 or 4  
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on 
severity of AE 
administer 
corticosteroids 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes 
 
Grade 3 or 4 
Permanently discontinue 
Page 4 of 5 


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Table 3.  Pembrolizumab-related Adverse Event Management 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE 
management 
with 
corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
All other 
immune-related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
Based on type 
and severity of 
AE administer 
corticosteroids  
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes 
 
Grade 3 
Withhold or discontinue 
based on the type of 
event.  Events that 
require discontinuation 
include and not limited 
to:  Gullain-Barre 
Syndrome, encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently discontinue 
Page 5 of 5 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.  
NOTES:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when adverse event resolves to ≤ Grade 2 and is controlled 
with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
For myocarditis, in certain circumstances, pembrolizumab may be resumed at grade 1 only if the 
investigator believes that the myocarditis has clinically resolved and the investigator has obtained written 
permission from the medical monitor to resume therapy. 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase  
In case of toxicity that does not resolve to grade 0 or 1 or baseline within 12 weeks after 
the last infusion of pembrolizumab, pembrolizumab treatment should be discontinued 
after consultation with the sponsor medical monitor.  With the investigator and sponsor 
medical monitor agreement, subjects with laboratory adverse events still at grade 2 after 
12 weeks may continue pembrolizumab treatment in the trial only if asymptomatic and 
controlled. 
Subjects enrolled in phase 1b who develop a DLT during the DLT evaluation period will 
permanently discontinue pembrolizumab. 


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6.2.3 
Rescue Medications and Supportive Care Guidelines for 
Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. 
Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below.  Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional 
anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other cases such as metastatic disease or bacterial 
or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
Note:  If after the evaluation the event is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance.  Refer to Section 6.2.1.2 
for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
6.2.3.1 
Infusion Reactions 
Pembrolizumab may cause severe or life threatening infusion reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  Dose modification and toxicity management guidelines on pembrolizumab 
associated infusion reaction are provided in Table 4. 


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Table 4.  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(eg, antihistamines, 
NSAIDS, narcotics, 
IV fluids); prophylactic 
medications indicated 
for ≤ 24 hours 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be 
premedicated 
1.5 hours 
(± 30 minutes) 
prior to infusion of 
pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 
50 mg orally 
 (or equivalent 
dose of 
antihistamine). 
 
Acetaminophen 
500 - 1000 mg 
orally (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Stop Infusion. 
No subsequent 
dosing 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer 
Institute; NSAID = nonsteroidal anti-inflammatory drug 


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6.2.3.2 
Pembrolizumab Events of Clinical Interest  
Events of Clinical Interest 
Events of Clinical Interest that occur after the first dose of pembrolizumab through 
30 (+7) days after the last dose of pembrolizumab must be reported to Amgen within 
24 hours of the investigator’s knowledge of the event regardless of attribution to 
pembrolizumab.  Information on how to identify and report Events of Clinical Interest can 
be referenced in Section 9.5. 
6.2.3.3 
Diet and Other Considerations While Taking Pembrolizumab 
6.2.3.3.1 
Diet During Treatment With Pembrolizumab 
Subjects should maintain a normal diet unless modifications are required to manage 
adverse events such as diarrhea, nausea or vomiting. 
6.2.3.3.2 
Contraception Requirements for Pembrolizumab 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm. 
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 
acceptable method(s) of effective contraception or are considered of non-childbearing 
potential.  Female subjects of childbearing potential and male subjects of reproductive 
potential must agree to avoid becoming pregnant or impregnating a partner, 
respectively, while receiving study drug and for 4 months after the last dose of study 
drug by complying with one of the following: 
1 Practice abstinence† from sexual activity; 
OR 
2 Use (or have their partner use) acceptable effective contraception, as defined in 
the informed consent form, during sexual activity 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and IRBs/IECs.  Periodic 
abstinence (eg, calendar, ovulation, sympto-thermal, post-ovulation methods, etc) and 
withdrawal are not acceptable methods of contraception. 
Refer to Section 4.2, exclusion criteria 221 and 222, for contraception requirements for 
men and women and definition of women of non-childbearing potential and men of 
reproductive potential for this study.  Refer to the informed consent form for acceptable 


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method(s) of effective contraception for subjects to use in this study.  Additional 
country-specific contraception requirements may be defined in a country-specific 
protocol supplement at the end of the Appendix Section of protocol as required by local 
laws and regulations. 
Subjects should be informed that taking pembrolizumab may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study, men and women of reproductive potential must adhere to the 
contraception requirements (described above) from the day of study medication initiation 
(or 14 days prior to the inititation of study medication for oral contraception) throughout 
the study period and for 4 months after the last dose of trial therapy.  If there is any 
question that a subject of reproductive potential will not reliably comply with the 
requirements for contraception, that subject should not be enrolled into the study. 
6.2.3.3.3 
Use of Pembrolizumab in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The pregnancy and the outcome 
of the pregnancy will be reported to Amgen and followed as described in 
Section 9.3 (Pregnancy and Lactation Reporting). 
6.2.3.3.4 
Use of Pembrolizumab in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, female subjects who are breast-feeding are not eligible for enrollment in 
this study.  If a female subject breastfeeds while taking pembrolizumab, report the 
lactation case to Amgen as described in Section 9.3 (Pregnancy and Lactation 
Reporting). 
6.3 
Other Protocol-required Therapies 
All other protocol-required therapies, including topical anesthetic or an injectable local 
anesthetic medications used for pretreatment of the talimogene laherparepvec/placebo 
injection site and oral or systemic steroids for management of pembrolizumab immune 
related adverse events, that are commercially available are not provided or reimbursed 
by the sponsor (except if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these protocol-required therapies. 
Additional details regarding these protocol-required therapies are provided in the IPIM. 


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6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin and/or international normalized ratio [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 investigational product as specified in the United States 
Food and Drug Administration Guidance for Industry Drug-Induced Liver Injury (DILI):  
Premarketing Clinical Evaluation, July 2009). 
6.4.1 
Criteria for Permanent Discontinuation of Investigational Products 
and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
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 following baseline total bilirubin < ULN or INR > 1.5 
• 
AND current AST or ALT > 3x ULN 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, 
Herpes Simplex Virus, 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 (NASH)  
− 
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 patient population and/or 


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severity of the hepatotoxicity or event) if 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 Investigational Products and 
Other Protocol-required Therapies Due to Potential Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of  
investigational product outlined above and have no underlying liver disease, and 
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 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  
≤ 3 x ULN 
> 5 x ULN for ≥ 2 weeks 
≤ 3 x ULN 
> 5 x ULN and unable to adhere to enhanced monitoring 
schedule 
≤ 5 x ULN 
> 8 x ULN at any time 
• 
OR: total bilirubin > 3x ULN at any time 
• 
OR: ALP > 8x ULN at any time 
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 Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and sponsor medical monitor. 
If signs or symptoms recur with rechallenge, then investigational product and other 
protocol-required therapies, 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 sponsor medical 
monitor. 


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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. 
Concomitant therapies are to be collected in the CRF from informed consent through 
30 (+7) days after the last dose of talimogene laherparepvec/placebo or pembrolizumab, 
whichever is later.  In addition, any concomitant medications associated with serious 
adverse events that occur through 90 (+7) days after the cessation of all study treatment 
or 30 (+7) days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, will be reported to the sponsor and recorded in the CRF. 
For concomitant therapies, therapy name, indication, dose, unit, frequency, route, start 
date, and stop date must be documented. 
6.6 
Other Treatment Procedures 
Local radiation treatment to the site of bone and other metastasis will be permitted for 
palliative 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 and all study treatments should be withheld.  Re-exposure to 
talimogene laherparepvec/placebo and pembrolizumab may occur post palliative 
radiation treatment only if the investigator and sponsor medical monitor agree that the 
subject’s safety will not be compromised. 
If a subject demonstrates evidence of new or worsening CNS metastases, all study 
treatments should be withheld.  Subjects may be allowed to remain on study after 
discussion with the sponsor medical monitor provided the CNS metastases are 
adequately treated and the investigator determines the appropriateness of treatment 
resumption.  In addition, in order to resume study treatment, the corticosteroid dose 
must not exceed 10 mg of prednisone or equivalent.  Re-exposure to talimogene 
laherparepvec/placebo and pembrolizumab may occur only if the investigator and 
sponsor medical monitor agree that the subject’s safety will not be compromised. 
6.7 
Medical Devices 
Medical devices (eg, 0.2 or 0.22 μm in-line filter made of polyethersulfone, intravenous 
administration set, infusion pump syringes, sterile needles, alcohol prep pads) that are 
commercially available are not usually provided or reimbursed by the Sponsor (except, 


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for example, 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 and/or Procedures During Study Period 
Subjects must not use any of the following therapies during screening or the treatment 
period, unless indicated otherwise: 
• 
other investigational agents or procedures concurrent experimental or approved 
antitumor therapies immunosuppressive agents with the exception of treatment for 
adverse events (see Sections 6.2.2.2 and 6.2.3) 
• 
any live vaccine therapies used for the prevention of infectious disease within 
28 days prior to enrollment/randomization and during treatment period.  Examples of 
live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines; non-live vaccines 
are allowed. Intranasal influenza vaccines (eg, Flu - Mist) are live attenuated 
vaccines and are not allowed. 
• 
systemic antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir) 
• 
Note:  Subjects may receive a topically administered antiherpetic drug more than 
20 cm from the injection site.  
• 
Any elective surgery or non-palliative definitive radiotherapy for SCCHN (refer to 
Section 6.6 
• 
The exclusion criteria describe other medications and procedures which are 
prohibited in this study (refer to Section 4.2) 
Subjects must not schedule any elective surgeries during the treatment period and for at 
least 30 days after the last administration of study drugs.  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 


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possible.  A subject may be allowed to resume study drugs if both the investigator and 
sponsor’s medical monitor agree. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
For Schedule of Assessments of phase 1b and phase 3 please refer to Table 5, Table 6, 
and Table 7 respectively. 


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Table 5.  Schedule of Assessments for Phase 1b 
 
Screening 
Treatment 
(week number) 
Follow-up 
Study Procedures 
≤ 28 
days 
≤ 14 
days 
≤ 72 
hour 
0 
3 
6 
9 
12 
15 
18 
21 
24a 
Safety 
Within 30 days 
after last 
treatment 
Long-term 
Every 
3 months 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical, Surgical 
and Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recording of Concomitant 
Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
Physical Exam and Vital Signs 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Review of adverse events, 
disease related events and 
serious adverse events 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Laboratory Tests 
Chemistry 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisd 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
PT or INR and PTT or aPTTe 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T3 (or FT3), FT4, TSH 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Urine or Serum Pregnancy Testf 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Page1 of 3 
Footnotes defined on the last page of the table. 


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Table 5.  Schedule of Assessments for Phase 1b 
Screening 
Treatment  
(week number) 
Follow-up 
Study Procedures 
≤ 28 
days  
≤ 14 
days  
≤ 72 hour  
0 
3 
6 
9 
12 
15 
18 
21 
24a 
Safety 
Within 
30 days 
after last 
treatment  
Long-term  
Every 
3 months 
Central Laboratory Tests 
Optional Blood for 
Pharmacogenetic Analysisg 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Biomarker Analysesh 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
Blood for HSV-1 Serostatus 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor tissue for biomarker 
analysisi 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Optional Tumor tissue for 
biomarker analysesj 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Archival Tumor Tissue (if 
applicable)k 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Swab of Herpetic Lesion for qPCR 
 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
Radiographic Tumor/Response Assessments 
Radiographic (CT, PET/contrast 
enhanced CT or MRI,) Scans & 
Tumor Assessmentl,m 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Optional Photographs of Visible 
Tumor Lesions  
Any Time  
Page 2 of 3 
Footnotes defined on the last page of the table. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 73 of 158 
CONFIDENTIAL 
 
 
Table 5.  Schedule of Assessments for Phase 1b 
Screening 
Treatment  
(week number) 
Follow-up 
Study Procedures 
≤ 28 
days  
≤ 14 
days  
≤ 72 
hour  
0 
3 
6 
9 
12 
15 
18 
21 
24a 
Safety 
Within 
30 days 
after last 
treatment  
Long-term 
Every 
3 months  
Treatment Administrationl  
Talimogene laherparepvecn 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pembrolizumabo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Reporting Exposure to Talimogene Laherparepvec 
Exposure of Subject’s Household 
member of Caregiver 
Anytime 
Exposure of Subject’s Healthcare 
Provider 
Anytime 
Page 3 of 3 
CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; FT4 = free thyroxine; HSV-1 = herpes simplex virus type 1; 
INR = international normalized ratio; MRI = magnetic resonance imaging; PET = positron emission tomography; PT = prothrombin time; PTT/aPTT = partial 
thromboplastin time/activated partial thromboplastin time; qPCR = real-time polymerase chain reaction; T3/FT3=free triiodothyronine; TSH = thyroid stimulating 
hormone  
a Repeat week 24 procedures and assessments every 3 weeks until end of study treatment, with the exceptions of thyroid function testing, which is required every 
6 weeks unless otherwise indicated.  Furthermore, blood for biomarker analysis is only required as indicated in the visit schedule, up to week 24.  Thyroid Function 
Tests must be collected, but if there are no symptoms of hypothyroidism or hyperthyroidism, study treatment can be initiated prior to the reporting of the laboratory 
results. 
b Only subsequent anticancer treatment for SCCHN will be recorded. 
c See Section 9.2 for long-term follow-up assessments and reporting. 
d Urine samples for urinalysis will be collected at screening within 14 days prior to enrollment.  During treatment urine samples for urinalysis will be collected if clinically 
indicated.  Urine sample for urinalysis will also be collected at the safety follow-up visit. 
e Blood sample for coagulation will be collected (PT/aPTT measured in seconds and INR as a ratio) at screening within 14 days prior to enrollment.  During the 
treatment phase, close monitoring of coagulation parameters is recommended for subjects on anticoagulant therapy.   
f Urine or serum pregnancy test to be performed on female of childbearing potential.  A urine pregnancy test should be performed within 72 hour prior to enrollment and 
at the safety follow-up. Note: Additional blood or urine for pregnancy testing (for women of child-bearing potential) may be performed during treatment at the 
investigator’s discretion or as defined in a country-specific protocol supplement at the end of the Appendix Section of the protocol as required per local country’s laws 
and regulatory requirements.  If urine pregnancy test result is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  
g Optional pharmacogenetic blood sampling will be performed prior to study treatment administration. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 74 of 158 
CONFIDENTIAL 
 
 
h Blood samples for biomarker analyses will be collected prior to study treatment administration at the following time points: at day 1 of week 0, week 3,  week 6, 
week 9 and either at time of initial unconfirmed iPR, confirmed iPD, or at 24 weeks for subjects with SD, whichever comes first.  A blood sample should be collected 
at the safety follow-up visit. 
i Subject has a formalin fixed paraffin embedded tumor sample  from the primary or metastatic lesion that must be submitted within 4 weeks of enrollment for PD-L1, 
HPV testing for oropharyngeal cancer (if not performed locally), and biomarker analyses. See Section 7.5.2 for more details.  Refer to the Laboratory Manual for 
detailed tissue collection procedures.   
j Optional tumor tissue biopsy via core needle within 3 days prior to day 1 of week 6, if subject has consented.  Refer to laboratory manual for detailed tissue collection 
procedures.   
k Archival tumor tissue, of any age since diagnosis, that is available in addition to the baseline sample, if applicable, should be submitted within 4 weeks after 
enrollment. 
l At screening (baseline) and throughout the study, radiographic tumor imaging assessments (CT scan, PET/contrast enhanced CT scan or MRI) must include the neck, 
chest, abdomen, and all other sites of disease.  A CT scan or MRI of the brain should only be performed if signs or symptoms suggestive of CNS metastases are 
present.  The screening (baseline) scans must be done within 28 days prior to enrollment.  During treatment, radiographic imaging  will be performed independent of 
treatment cycle at week 9 (±1 week), week 18 (±1 week), and then every 9 weeks (±1 week) or more frequently if clinically indicated until confirmed iPD or start of 
new anticancer treatment.  Imaging should not be adjusted for cycle initiation delays and performed according to the calendar.  The imaging modality selected (eg, 
CT or MRI) should remain constant for any individual subject.  Response or progression should be confirmed by repeated radiographic imaging ≥ 4 weeks after the 
first indication of response or progression.  Radiographic imaging is required at the safety follow-up visit if the subject ended treatment prior to confirmed iPD and has 
not had radiographic tumor imaging performed within 9 weeks (+1 week) of the visit.  During the long-term follow-up period, for subjects who discontinued treatment 
for any reason other than confirmed iPD, every effort should be made to complete radiographic assessments every 12 weeks (±1 week) or more frequently if clinically 
indicated until documentation of confirmed iPD, start of new anticancer therapy, or end of study whichever occurs first.   
m Response (iCR, or iPR) or iPD to be confirmed by second consecutive radiographic assessments no less than 4 weeks from the date of the first documented 
response or iPD. 
n Talimogene laherparepvec will be administered on day 1 of week 0, day 1 of week 3 (+ 3 days), and every 3 weeks (± 3 days) thereafter.  The initial dose of 
talimogene laherparepvec is up to 8.0 mL of 106 PFU/mL.  Subsequent doses of talimogene laherparepvec are up to 8.0 mL of 108 PFU/mL.   
o Pembrolizumab will be administered at a dose of 200 mg starting at day 1 of week 0, day 1 of week 3 (+ 3 days), and every 3 weeks (± 3 days) thereafter.  When 
alimogene laherparepvec and pembrolizumab are administered on the same day, it is recommended that talimogene laherparepvec be administered first. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 75 of 158 
CONFIDENTIAL 
 
 
Table 6.  Schedule of Assessments for Biodistribution and Shedding of Talimogene Laherparepvec for Phase 1b Only 
Study Treatment a 
Follow-up Period 
Week 
0 
0 
0 
1 
2 
3 
3 
3 
4 
5 
6 
7 
9 
Safety Follow-up 
Talimogene Laherparepvec Cycle 
1 
1 
1 
1 
1 
2 
2 
2 
2 
2 
3 
3 
4 
Day 30 Safety Follow-up 
Visit 
Day 
1 
2 
3 
8 
15 
1 
2 
3 
8 
15 
1 
8 
1 
30 (+ 7) days after end of 
treatment 
Blood a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Swab of Surface of Exterior of Occlusive Dressingb 
 
X 
X 
X 
(X) 
(X) 
X 
X 
X 
(X) 
(X) 
X 
(X) 
(X) 
Swab of Surface of Injected Lesion b 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Swab of Oral Mucosa c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Blood and urine sample for real-time polymerase chain reaction (qPCR) testing of talimogene laherparepvec DNA will be performed at the following time points: 
Cycle 1: day 1 (prior to and approximately 1 hour [± 15 minutes], 4 hours [± 30 minutes], after talimogene laherparepvec administration), day 2 (24 [± 4] hours after 
talimogene laherparepvec administration), day 3 (48 [± 4] hours after talimogene laherparepvec administration), day 8 (± 2 days), and day 15 (± 2 days). Cycle 2: 
day 1 (prior to and approximately 1 hour [± 15 minutes], 4 hours [± 30 minutes], after talimogene laherparepvec administration), day 2 (24 [± 4] hours after talimogene 
laherparepvec administration), day 3 (48 [± 4] hours after talimogene laherparepvec administration), and day 8 (± 2 days), and day 15 (± 2 days).  Cycle 3: day 1 
(prior to talimogene laherparepvec administration) and day 8 (± 2 days). Cycle 4: day 1 (prior to talimogene laherparepvec administration). Blood and urine samples 
for qPCR testing will also be collected at the 30-day safety follow-up visit (+7 days). Please refer to the Central Laboratory Manual for instructions regarding sample 
collection, storage, and shipment procedures. 
b Swabs of the exterior of the occlusive dressing and the surface of injected lesions for qPCR testing of talimogene laherparepvec DNA and if positive, a TCID50 assay 
will be performed.  The occlusive dressing can be removed 7 days after the talimogene laherparepvec injection (see Injection Site Care Instructions for details).  
However, an occlusive dressing should be kept on longer if the lesions at the injection sites are weeping or oozing.  During treatment: Select the largest injected 
lesion at baseline (ie, on day 1 of cycle 1)..  The exterior of the selected occlusive dressing and the surface of the selected injected lesion will be swabbed starting on 
day 2 of cycle 1, at the following time points and only re-swabbed if the lesion is injected subsequently up to and including day 1 of cycle 4.  The outside of the 
occlusive dressing will be swabbed first.  The occlusive dressing will thereafter be removed and the surface of the injected lesion will be swabbed.  Swabs of the 
exterior of the occlusive dressing will also be collected at day 1 of cycles 2, 3, and 4 and day 15 (± 2 days) at cycles 1 and 2, as well as at the 30-day safety follow up 
visit (+ 7 days) if the lesion is ulcerated or weeping that requires the occlusive dressing to be kept on for more than 7 days after the injection (as marked with 
parentheses in Table 6).   


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 76 of 158 
CONFIDENTIAL 
 
 
Cycle 1:  day 2 (24 [± 4] hours after talimogene laherparepvec administration), day 3 (48 [± 4] hours after talimogene laherparepvec administration), day 8 (± 2 days) 
and day 15 (± 2 days).  Cycle 2: day 1 (prior to talimogene laherparepvec administration), day 2 (24 [± 4] hours after talimogene laherparepvec administration), day 3 
(48 [± 4] hours after talimogene laherparepvec administration), day 8 (± 2 days) and day 15 (± 2 days).  Cycle 3: day 1 (prior to talimogene laherparepvec 
administration) and day 8 (± 2 days).  Cycle 4: day 1 (prior to talimogene laherparepvec administration).  During safety follow-up: Swabs of the surface of the injected 
lesion(s) (if a lesion is in complete response [CR], the place of the prior injection will be swabbed) will also be collected at the 30-day safety follow-up visit (+7 days). At 
each time point only if qPCR of talimogene laherparepvec DNA testing is positive, then a TCID50 assay will be performed to evaluate whether the presence of infective 
talimogene laherparevec virus is detectable in the sample.  Please refer to the Central Laboratory Manual for instructions regarding sample collection, storage, and 
shipment procedures.  
c Swabs of oral mucosa for qPCR of talimogene laherparepvec DNA testing and TCID50 assay will be collected at the following timepoints: Cycle 1: day 1 (prior to 
talimogene laherparepvec administration), day 2 (24 [± 4] hours after talimogene laherparepvec administration), day 3 (48 [± 4] hours after talimogene laherparepvec 
administration), day 8 (± 2 days), and day 15 (± 2 days).  Cycle 2: day 1 (prior to talimogene laherparepvec administration), day 2 (24 [± 4] hours after talimogene 
laherparepvec administration, day 3 (48 [± 4] hours after talimogene laherparepvec administration), day 8 (± 2 days) and day 15 (± 2 days).  Cycle 3: day 1 (prior to 
talimogene laherparepvec administration) and day 8 (± 2 days).  Cycle 4: day 1 (prior to talimogene laherparepvec administration).  If qPCR testing of talimogene 
laherparepvec DNA is positive, then a TCID50 assay will be performed to evaluate whether the talimogene laherparepvec virus is detectable in the sample.  During 
safety follow-up: swab of oral mucosa for qPCR testing will be collected at the 30 day safety follow-up visit (+ 7 days).  Please refer to the Central Laboratory Manual 
for instructions regarding sample collection, storage, and shipment procedures.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 77 of 158 
CONFIDENTIAL 
 
 
Table 7.  Schedule of Assessments for Phase 3 
Screening 
Treatment 
(Week Number) 
Follow-up 
Study Procedures 
≤ 28 
days 
≤ 14 
days 
≤ 72 
hour 
0 
3 
6 
9 
12 
15 
18 
21 
24a 
Safety 
Within 30 days 
after last 
treatment 
Long-term  
(Every 
3 months) 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical, Surgical 
and Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recording of Concomitant 
Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
Physical Exam and Vital Signs 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Review of Adverse Events, 
Disease Related Events and 
Serious Adverse Events 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
EORTC QLQ H&N35, EORTC 
QLQ C30d 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
EQ-5D-5Le 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Laboratory Tests 
Chemistry 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Hematology 
  
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 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisf 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 3 
Footnotes defined on the last page of the table 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 78 of 158 
CONFIDENTIAL 
 
 
Table 7.  Schedule of Assessments for Phase 3 
Screening 
Treatment 
(Week Number) 
Follow-up 
Study Procedures 
≤ 28 
days 
≤ 14 
days 
≤ 72 
hour 
0 
3 
6 
9 
12 
15 
18 
21 
24a 
Safety 
Within 
30 days 
after last 
treatment 
Long-term  
(Every 
3 months) 
PT or INR and PTT or aPTTg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T3 (or FT3), FT4, TSH 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Urine or Serum Pregnancy 
Testh 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Central Laboratory Tests 
Optional Blood for 
Pharmacogenetic Analysisi 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Biomarker Analysesj 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
Blood for HSV-1 Serostatus 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor Tissue for PD-L1, HPV 
Testing and Biomarker 
Analysesk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Tumor Tissue for 
Biomarker Analysesl 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Archival Tumor Tissue (if 
applicable)m 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Anti-Pembrolizumab 
Antibodyn 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood for Pembrolizumab PKo 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Swab of Herpetic Lesion for 
qPCR 
 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
Page 2 of 3 
Footnotes defined on the last page of the table  


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 79 of 158 
CONFIDENTIAL 
 
 
Table 7.  Schedule of Assessments for Phase 3 
Screening 
Treatment 
(Week Number) 
Follow-up 
Study Procedures 
≤ 28 
days 
≤ 14 
days 
≤ 72 
hour 
0 
3 
6 
9 
12 
15 
18 
21 
24a 
Safety 
Within 
28 days 
after last 
treatment 
Long-term  
(Every 
3 months) 
Radiographic Tumor/Response Assessments 
Radiographic (CT, 
PET/contrast enhanced CT or 
MRI) Scans and Tumor 
Assessment by RECIST v1.1r 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Radiographic (CT, 
PET/contrast enhanced CT or 
MRI) Scans and Tumor 
Assessment by irRECISTp,q 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Optional Photographs of Visible 
Tumor Lesions  
Any Time 
Talimogene 
Laherparepvec/Placebos 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pembrolizumabt 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Reporting Exposure to Talimogene Laherparepvec 
Exposure of Subject’s 
Household Member or 
Caregiver 
Anytime 
Exposure of Subject’s 
Healthcare Provider 
Anytime 
Page 3 of 3 
iCR = complete response (per irRECIST); CNS = central nervous system; EQ-5D-5L = EuroQoL-5D; HPV = human papilloma virus irRECIST = immune-related 
Response Evaluation Criteria in Solid Tumors; iPD = progressive disease (per irRECIST); PD-L1 = programmed death ligand 1;  
ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; PT = prothrombin time; INR = international normalized ratio; PTT/aPTT = partial 
thromboplastin time/activated partial thromboplastin time; T3/FT3 = free tri-iodothyronine; FT4 = free thyroxine; TSH = thyroid stimulation hormone; HSV-1 = herpes 
simplex virus type 1; PK = pharmacokinetics; qPCR = real-time polymerase chain reaction; CT = computed tomography; PET = positron emission tomography; 
MRI = magnetic resonance imaging; iPR = partial response (per irRECIST); PRO = patient reported outcomes; SCCHN = squamous cell carcinoma of the head and 
neck; iSD = stable disease (per irRECIST) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 80 of 158 
CONFIDENTIAL 
 
 
a Repeat week 24 procedures and assessments every 3 weeks until end of study treatment, with the exceptions of the thyroid function testing which is required every 
6 weeks unless otherwise indicated.  Furthermore, blood for biomarker analysis is only required up to week 24 as indicated in the schedule of assessments.  Note:  
Thyroid Function Tests must be collected, but if there are no symptoms of hypothyroidism or hyperthyroidism, study treatment can be initiated prior to the reporting of 
the laboratory results. 
b Only subsequent anticancer treatment for SCCHN will be recorded. 
c See Section 9.2 for long-term follow-up assessments and reporting 
d Completion of the EORTC QLQ-H&N35 and EORTC QLQ-C30 questionnaires prior to study treatment administration at day 1 of weeks 0, 3, 6, 9, 12, 15, 18, and 
then every 9 weeks until end of study treatment, and at the safety follow-up visit.  During long-term follow-up, for subjects who discontinued treatment for any reason 
other than confirmed iPD, every effort should be made to complete the questionnaires every 3 months until documentation of confirmed iPD, start of new anticancer 
therapy, or end of study, whichever occurs first. 
e The EQ-5D-5L questionnaire will be completed at weeks 0, 3, 6, 9, 12, 15, 18, and then every 9 weeks. until end of study treatment and at safety follow-up visit.  For 
subjects who discontinued treatment for any reason other than confirmed iPD, every effort should be made to complete the questionnaires every 3 months until 
documentation of confirmed iPD, start of new anticancer therapy, or end of study, whichever occurs first.  For subjects with confirmed disease progression, EQ-5D-5L 
will be collected within 1 to 3 weeks of confirmed disease progression, at safety follow-up, and every 3 months thereafter in long-term follow-up.  During long-term 
follow-up after confirmed iPD or start of new anticancer therapy, if subjects are too ill to self-complete the EQ-5D-5L, collection of EQ-5D-5L can be via telephone 
interview conducted by trained study staff using a standardized script. 
f Urine samples for urinalysis will be collected at screening within 14 days prior to enrollment.  During treatment urine samples for urinalysis will be collected if clinically 
indicated.  Urine sample for urinalysis will also be collected at the safety follow-up visit. 
g Blood sample for coagulation will be collected (PT/aPTT measured in seconds and INR as a ratio) at screening within 14 days prior to enrollment.  During the 
treatment phase, close monitoring of coagulation parameters is recommended for subjects on anticoagulant therapy.   
h Urine or serum pregnancy test to be performed on female of childbearing potential.  A urine pregnancy test should be performed within 72 hour prior to enrollment and 
at the safety follow-up. Note: Additional blood or urine for pregnancy testing (for women of child-bearing potential) may be performed during treatment at the 
investigator’s discretion or as defined in a country-specific protocol supplement at the end of the Appendix Section of the protocol as  required per local country’s 
laws and regulatory requirements.  If urine pregnancy test result is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  
i Optional pharmacogenetic blood sampling will be performed prior to study treatment administration if subject has consented to the pharmacogenetics substudy.. 
j Blood samples for biomarker analyses will be collected prior to study treatment administration at the following time points: at day 1 of week 0, week 3,  week 6, week 9 
and either at time of initial unconfirmed PR, confirmed iPD, or at 24 weeks for subjects with iSD, whichever comes first.  A blood sample should be collected at the 
safety follow-up visit.  Refer to Laboratory Manual for blood sample procedures.  
k Tumor tissue  from the primary or metastatic lesion and the associated pathology report must be submitted within 28 days before randomization to the central 
laboratory for PD-L1, HPV testing, and biomarker analyses,  See Section 7.5.2 for further details.  Refer to the Laboratory Manual for detailed tissue collection 
procedures. 
l Optional tumor tissue biopsy via core needle within 3 days prior to day 1 of week 6 if subject has consented.  Refer to Laboratory Manual for detailed tissue collection 
procedures.  
m Archival tumor tissue, of any age since diagnosis, that is available in addition to the required baseline tumor sample (Section 7.5.2) should be submitted within 
4 weeks after randomization. 
n Blood for anti-pembrolizumab antibody (also termed immunogenicity) will be collected at week 0 (ie, cycle 1 of pembrolizumab), week 3 (ie, cycle 2 of 
pembrolizumab), week 9 (ie, cycle 4 of pembrolizumab), week 15 (ie, cycle 6 of pembrolizumab), week 21 (ie, cycle 8 of pembrolizumab) and every 12 weeks 
(4 cycles of pembrolizumab) thereafter starting at week 33 (ie, cycle 12 of pembrolizumab), at safety follow-up visit (30 [+7] days after discontinuation of study 
treatment), and again 3 and 6 months after discontinuation of study treatment or until the subject starts new anticancer treatment, whichever is first.  All samples 
should be drawn within 24 hours before infusion of pembrolizumab and at the same time as pre dose trough blood collection for the PK sample. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 81 of 158 
CONFIDENTIAL 
 
 
o Blood for PK of pembrolizumab: Predose trough and post-dose peak PK samples will be collected at week 0 (ie, cycle 1 of pembrolizumab).  Pre-dose trough samples 
only will be collected at week 3 (ie, cycle 2 of pembrolizumab), week 9 (ie, cycle 4 of pembrolizumab), week 15 (ie, cycle 6 of pembrolizumab), week 21 (ie, cycle 8 of 
pembrolizumab) and every 12 weeks (4 cycles) thereafter, starting at week 33 (ie, cycle 12 of pembrolizumab), at safety follow-up visit (30 [+7] days after 
discontinuation of study treatment), and again 3 and 6 months after discontinuation of study treatment or until the subject starts new anticancer treatment, whichever 
is first.  All trough samples should be drawn within 24 hours before infusion of pembrolizumab.  The peak sample should be drawn within 30 minutes after the end of 
the infusion. A one-time PK sample should also be drawn between 48 to 168 hours after week 0 (ie, cycle 1) dosing.   
p Throughout the study, radiographic imaging assessments (CT scan, PET/contrast enhanced CT scan, or MRI) must include the neck, chest, abdomen, and all other 
sites of disease.  A CT scan or MRI of the brain should only be performed if signs and symptoms suggestive of CNS metastases are present.  During treatment, 
radiographic imaging  will be performed independent of treatment cycle at week 9 (±1 week), week 18 (± 1 week), and then every 9 weeks (±1 week) or more 
frequently if clinically indicated until confirmed iPD or start of new anticancer treatment.  Imaging should not be adjusted for cycle initiation delays and performed 
according to the calendar.  The imaging modality selected (eg, CT or MRI) should remain constant for any individual subject.  Radiographic imaging is required at the 
safety follow-up visit if the subject ended treatment prior to confirmed iPD and has not had radiographic tumor imaging performed within 28 days (+1 week) of the 
visit.  During long-term follow-up, for subjects who discontinued treatment for any reason other than confirmed iPD, every effort should be made to complete 
radiographic assessments every 12 weeks (±1 week) or more frequently if clinically indicated until documentation of confirmed iPD, start of new anticancer therapy, 
or end of study whichever occurs first.  The radiologic imaging assessments are performed locally. 
q Response (iCR, or iPR) or iPD to be confirmed by second consecutive radiographic assessments no less than 28 days from the date of the first documented response 
or iPD. 
r RECIST v1.1 assessments done at screening for eligibility and throughout the study.   
s Talimogene laherparepvec/placebo will be administered on day 1 of week 0, day 1 of week 3 (+ 3 days), and every 3 weeks (± 3 days) thereafter.  The initial dose of 
talimogene laherparepvec/placebo is up to 8.0 mL of 106 PFU/mL.  Subsequent doses of talimogene laherparepvec/placebo are up to 8.0 mL of 108 PFU/mL.  The 
maximum volume of talimogene laherparepvec administered at any dose is 4.0 mL for any individual lesion.  The maximum volume at any treatment visit is 8.0 mL. 
t Pembrolizumab will be administered at a dose of 200 mg starting at day 1 of week 0, day 1 of week 3 (+ 3 days), and every 3 weeks (± 3 days) thereafter.  When 
talimogene laherparepvec/placebo and pembrolizumab are administered on the same day, it is recommended that talimogene laherparepvec/placebo be 
administered first. 
.


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 82 of 158 
CONFIDENTIAL 
 
 
Refer to the applicable supplemental (eg, laboratory, imaging,) manuals for detailed 
collection and handling procedures. 
7.2 
General Study Procedures  
The procedures performed and timing of each study visit are outlined in the Schedule of 
Assessments (Table 5, Table 6, and Table 7).  Details regarding each type of procedure 
are provided in subsequent subsections.  Procedures that are part of routine care are 
not considered study specific procedures and may be used at screening to determine 
eligibility. 
Refer to the applicable supplemental central laboratory, IVR system IPIM, and study 
manuals for detailed collection and handling procedures. 
7.2.1 
Screening and Enrollment 
Informed consent must be obtained before completing any screening procedures ensue.  
After signing the written informed consent form, the site will register the subject in the 
IVR system and screen the subject in order to assess eligibility for participation.  
Screening procedures are to be completed during the screening period within 4 weeks 
prior to enrollment or randomization.  If a subject has not met all eligibility criteria at the 
end of the 4 week window, the subject will be registered as a screen failure.  Screen fail 
subjects may be eligible for re-screening once as described in Section 7.2.2.  Prior to 
enrollment, subject eligibility must be confirmed with screening procedures.  Subjects 
satisfying eligibility requirements will be enrolled. 
7.2.2 
Rescreening 
Subjects who are unable to complete or meet eligibility requirements on initial screening 
will be permitted to rescreen once.  Rescreened subjects must first be registered as 
screen failed in the IVR system and subsequently registered as rescreened.  Subjects 
will retain the same subject identification number assigned at the original screening.  
Once the subject is registered as rescreened, a new 4 week screening window will 
begin.  If the rescreening period begins more than 4 weeks after the original signing of 
the informed consent form, all screening procedures, including informed consent, must 
be repeated.  If the rescreening occurs less than 4 weeks after the original signing of the 
informed consent, then only those criteria that were originally failed are required to be 
repeated. 


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7.2.3 
Treatment 
The date of the first dose of talimogene laherparepvec/placebo is defined as day 1 
(week 0).  All subsequent doses and study visits will be scheduled based on the day 1 
date.  During treatment, assessments and procedures can be performed within 3 days of 
the planned visit.  It is recommended that dosing occur on the same day of the week  
(eg, if first dose is administered on Monday, all subsequent doses should be 
administered on a Monday), however, a ± 3 day dosing and study procedure window is 
allowed unless otherwise specified (eg, second dose window is + 3 days).  Study 
treatment administration should begin as soon as possible after enrollment via the IVR 
system but no later than 5 days after enrollment.  Study treatment is to be administered 
after all required study procedures are completed for each visit.   
Phase 1b: 
The first dose of talimogene laherparepvec will be up to 8.0 mL of 106 PFU/mL.  The 
second injection, up to 8.0 mL of 108 PFU/mL, will be administered 3 weeks (+3 days) 
after the initial injection (ie, no sooner than day 22 but should not be delayed more than 
3 days after the 3 week time point).  All subsequent injections, up to 8.0 mL of 
108 PFU/mL, will be administered every 3 weeks (±3 days). The maximum volume of 
talimogene laherparepvec administered at any dose is 4.0 mL for any individual lesion.  
The maximum volume at any treatment visit is 8.0 mL. 
When talimogene laherparepvec and pembrolizumab are administered on the same day, 
it is recommended that talimogene laherparepvec be administered first.  Refer to 
Section 6.2.1. 
Phase 3: 
The initial dose of double-blind treatment is up to 8.0 mL of 106 PFU/mL talimogene 
laherparepvec/placebo (talimogene laherparepvec formulation excipients as described in 
the Talimogene Laherparepvec Investigator’s Brochure).  The second dose up to 8.0 mL 
of 108 PFU/mL talimogene laherparepvec/placebo should be administered 21  (+ 3)  
days after the initial dose.  Subsequent doses up to 8.0 mL of 108 PFU/mL talimogene 
laherparepvec/placebo should be given every 3 weeks (± 3 days).  The maximum 
volume of talimogene laherparepvec/placebo administered at any dose is 4.0 mL for any 
individual tumor lesion.  The maximum volume at any treatment visit is 8.0 mL.  When 
talimogene laherparepvec/placebo and pembrolizumab are administered on the same 
day, it is recommended that talimogene laherparepvec/placebo be administered first. 


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Phase 1b/3: 
Pembrolizumab at a dose of 200 mg will be administered intravenously every 3 weeks 
(± 3 days).  See Section 6.2.2.2 for additional information regarding dosage and 
administration of pembrolizumab. 
7.2.4 
Follow-up 
7.2.5 
Safety Follow–up 
All subjects who receive investigational product will complete a safety follow-up visit 
approximately 30 (+ 7) days after the last dose of study treatment. 
7.2.6 
Long term Follow-up 
After the safety follow-up visits, subjects will enter the long-term follow-up.  Subjects will 
be contacted to assess survival, initiation of additional anticancer treatment and 
EQ-5D-5L (for phase 3). 
Contact for all subjects will be attempted every 12 weeks (± 28 days) following the safety 
follow-up visit until death, subject withdraws full consent, or up to 36 months after the 
last subject is enrolled/randomized that is included in the primary OS analysis, 
whichever comes first.  Anticancer therapies for SCCHN and talimogene 
laherparepvec/placebo related adverse events that occur through the end the long term 
follow-up will be reported.  The phase 1b subjects will be followed for approximately 
36 months after the last subject is enrolled.   
For subjects who discontinued treatment for any reason other than confirmed PD, every 
effort should be made to collect PROs for phase 3 subjects (QLQ-C30, QLQ-HN35, and 
EQ-5D-5L), perform radiographic scans for tumor imaging every 12 weeks (± 1 week) 
until documentation of confirmed iPD (response per irRECIST), start of new anticancer 
therapy, or end of study, whichever occurs first. 
For those subjects who are randomized but do not receive any doses of investigational 
product, every effort should be made to continue monitoring tumor response status by 
clinical and radiographic assessments as described in Table 5 and Table 7.  They 
should continue into the long-term follow-up and be followed for survival and subsequent 
anticancer therapies every 12 weeks (± 28 days) for approximately 36 months after the 
last subject is enrolled.   
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 


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7.3.1 
Informed Consent 
All subjects or legally acceptable representative must sign and personally date the 
IRB/IEC approved informed consent and if required, the subject must provide assent 
before any study specific procedures are performed. 
7.3.2 
Demographic Data 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarker variability 
of the study treatment. 
7.3.3 
Medical History 
The investigator or designee will collect complete medical and surgical history.  Medical 
history will include information on the subject’s concurrent medical conditions, clinically 
significant diseases, surgeries, cancer history (including HPV status if known), 
reproductive status, smoking history, use of alcohol, and drugs of abuse.  The current 
toxicity grade will be collected for each condition that has not resolved.  Squamous cell 
carcinoma of the head and neck history must date back to original diagnosis.  All 
findings are to be recorded on the medical history Case Report Form (CRF). 
7.3.4 
Prior Therapies 
Prior therapies (eg, prescription drugs, over the counter drugs, herbal or homeopathic 
remedies, nutritional supplements) that were being taken from 4 weeks prior to 
screening through informed consent should be collected. 
Therapy name, indication, dose, unit, frequency, and start and stop dates will be 
collected for prior therapies taken for current or prior malignancies. 
7.3.5 
Concomitant Therapy 
All concomitant medications that are administered after the subject has signed informed 
consent through 30 (+ 7) days after the last administration of study treatment will be 
recorded in the CRF.  Concomitant medications should be assessed on an ongoing 
basis and recorded at each subject visit.  Only subsequent anticancer therapy for 
SCCHN will be recorded during the long-term follow-up period.  Please see Section 6.5 
for additional details. 
7.3.6 
Adverse Events, Disease Related Events, and Serious Adverse 
Events 
Safety event reporting procedures are described in Section 9.2. 


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7.3.7 
Physical Examination 
A physical examination will be performed at screening per standard of care.  At 
subsequent visits (or as clinically indicated), limited symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded as adverse events on the adverse event CRF.  Physical examination findings 
should be recorded on the appropriate CRF (eg, medical history, event). 
7.3.8 
Vital Signs 
Vital signs include systolic/diastolic blood pressure, heart rate, respiratory rate, and 
temperature.  It is recommended that subjects 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 the most 
recumbent position possible.  The position selected and temperature location for a 
subject should be the same that is used throughout the study and document on the vital 
sign CRF.  All measurements are to be recorded on the vital signs CRF.   
Vital signs should be obtained prior to study treatment administration, and if necessary, 
during and after administration of study treatment. 
7.3.9 
Physical Measurements 
Body weight will be recorded in kilograms.  Height will be collected in centimeters. 
7.3.10 
ECG 
A 12-lead ECG will be performed per standard of care.  Subject must be in a 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 
the most recumbent position possible.  The ECG must include the following 
measurements:  heart rate, PR interval, QRS, QT, and QTc intervals.  The investigator 
or designated site physician will review all ECGs.  Once signed, the original ECG tracing 
will be retained with the subject’s source documents.  At the request of the sponsor, a 
copy of the original ECG will be made available to the sponsor. 
7.3.11 
ECOG Performance Status 
ECOG performance status will be collected as outlined in Appendix F. 
7.3.12 
Exposure to Talimogene Laherparepvec 
If a household member, caregiver, or healthcare provider who has had close contact 
with a subject treated with talimogene laherparepvec/placebo on this study is suspected 
to have been exposed to talimogene laherparepvec (eg, have or who have had signs or 


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symptoms suspected to be herpetic in origin or who have been accidentally exposed to 
talimogene laherparepvec) while the subject is taking talimogene 
laherparepvec/placebo, the exposure must be reported to the sponsor.  Refer to 
Section 9.4. 
7.3.13 
Radiographic Tumor Assessment 
At screening (baseline) and throughout the study, radiographic tumor imaging 
assessments must include CT scan, PET/contrast enhanced CT scan, or MRI of the 
neck, chest, abdomen, and other relevant sites of disease.  A CT scan or MRI of the 
brain will only be performed if signs or symptoms suggestive of CNS metastasis are 
present.  A spiral CT scan of the chest may be obtained but is not a requirement.  An 
MRI or non-contrast CT scan may be used in subjects for whom CT scans with contrast 
are contraindicated (ie, subjects with contrast allergy or impaired renal clearance. 
Imaging will be performed per the Schedule of Assessments (Table 5 and Table 7) or 
more frequently if clinically indicated until confirmed iPD (response per irRECIST), or 
start of new anticancer treatment.  Response (iCR, or iPR) or iPD is to be confirmed by 
second consecutive assessments no less than 4 weeks from the date of the first 
documented response or iPD.  Imaging should not be adjusted for cycle initiation delays 
and performed according to the calendar.  The imaging modality selected (eg, CT scan 
or MRI) should remain constant for any individual subject 
Furthermore, the same radiographic procedure used to assess disease sites at 
screening (baseline) should be used throughout the study (eg, the same contrast 
protocol for CT scans).  All known sites of disease must be documented at screening 
and re-assessed at each subsequent tumor evaluation.  The radiographic tumor imaging 
assessments and measurements are performed locally and the response will be 
assessed by the investigator using irRECIST criteria (Appendix D).  For phase 3 only, 
investigators will also be asked to assess and document tumor responses using the 
standard RECIST v1.1 criteria (Appendix E).  However, treatment decisions should NOT 
be made based on RECIST v1.1. 
7.4 
Laboratory Assessments 
On-treatment tests can be performed within 3 days of the planned visit.  Results should 
be reviewed prior to the administration of study treatment.  All tests (except for real-time 
polymerase chain reaction [qPCR], HSV-1 antibody, tumor biopsy, pembrolizumab PK 
and ADAs, and blood for biomarkers) are to be performed at the local laboratory.  See 
Table 8 for laboratory analytes to be assessed. 


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Table 8.  Laboratory Analytes 
Chemistry 
Coagulation 
Thyroid 
Function 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Calcium 
Magnesium 
Phosphorus 
Uric acid 
Total protein 
Albumin 
Blood urea nitrogen 
Creatininea 
Total bilirubin 
Direct bilirubin 
Alkaline-phosphatase 
AST 
ALT 
Glucose 
PT 
(seconds) or 
INR (ratio) 
PTT or 
aPTT 
(seconds) 
TSH 
T3 (or FT3 per 
local standard) 
FT4 
Red blood cell 
Hemoglobin 
Hematocrit 
Platelets 
White blood cell 
Differential 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
Urine or serum 
pregnancy test 
Urinalysis 
Blood 
Glucose 
Protein 
Specific gravity 
Microscopic exam 
(only reflexively for 
abnormal urinalysis 
results) 
Hepatitis B surface 
antigen and Hepatitis 
B core antibody 
Hepatitis C virus 
antibody 
qPCR for talimogene 
laherparepvec DNA 
HSV-1 antibody 
HPV-testing 
PD-L1 testing 
Anti-pembrolizumab 
antibody 
Pembrolizumab PK 
Biomarker blood 
Archived tumor tissue 
Fresh tumor biopsy 
tissue 
AST = aspartate aminotransferase; ALT = alanine aminotransferase ; PT = prothrombin time; 
INR = international normalization ratio; PTT/aPTT = partial thromboplastin time/activated partial 
thromboplastin time; TSH = thyroid stimulating hormone; T3/FT3=free triiodothyronine ; FT4 = free thyroxine; 
qPRC = real-time polymerase chain reaction; HSV-1 = herpes simplex virus type-1; HPV = Human 
papillomavirus;  PD-L1 = programmed cell death-1 ligand 1.  
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. 
7.4.1 
qPCR for Biodistribution and Shedding Samples 
At each time point, only if qPCR testing is positive, a TCID50 assay will be performed to 
evaluate whether the talimogene laherparepvec virus is detectable in the sample.  
Please refer to the Laboratory Manual for more details. 
7.4.2 
qPCR for Suspicious Herpetic Lesions 
Swab of cold sore, vesicles, and other lesions suspected to be herpetic in origin (if any) 
must be collected for qPCR testing of talimogene laherparepvec DNA.  Subjects should 


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return to the clinic within 3 days of the occurrence of a reportable lesion suspected to be 
herpetic in origin.  The lesion should be evaluated by the investigator and swabbed if 
HSV-1 infection is suspected.  A qPCR analysis will be performed on the swab sample 
by the central laboratory to evaluate whether talimogene laherparepvec DNA is 
detectable in the sample.  Refer to the Laboratory Manual for more details. 
7.4.3 
Optional Photography Substudy (Selected Phase 1b Sites And 
Phase 3 Sites) 
For sites selected to participate in the photography substudy, photographs of visible 
lesions may be taken at any time during the study period, or copies of pre-existing 
photographs may be collected if available. . The sponsor may use, copy, and/or 
distribute the photographs for educational purposes, in scientific lectures, journal 
articles, and textbooks.  The sponsor may also use the photographs for general 
commercial purposes and may have the photographs published, circulated, or presented 
in any way either alone or with other written, printed, graphic, or audio matter to 
members of the medical, nursing, pharmaceutical and related progressions, as well as to 
the public at large.  The subjects’ identity will not be disclosed in any photographs.  The 
sponsor would only show the photographs of subjects without identifying the subject 
facial characteristics. Any tattoos or other body marks that may identify the subjects will 
be covered. The sponsor may edit, reduce, enlarge, or otherwise change the 
photographs.  The photographs may have commercial value to the sponsor.  Neither the 
sponsor nor the investigator will compensate the subject for the photographs or the use 
of the photographs.  Refer to the Photography Manual for further instructions.  
7.5 
Biomarker Sample Collection 
Biomarkers are objectively measured and evaluate indicators of normal biologic 
processes, pathogenic processes, or pharmacological responses to a therapeutic 
intervention.  In oncology, there is particular interest in the molecular changes underlying 
the oncogenic processes that may identify cancer subtypes, stage of disease, assess 
the amount of tumor growth, or predict disease progression, metastasis, and responses 
to study treatment. 
The sponsor may attempt to develop test(s) designed to identify subjects most like to 
respond positively or negatively to investigational product(s) (eg, Amgen or non-Amgen 
investigational product or protocol required therapies). 


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7.5.1 
Blood Samples 
Blood samples are to be collected for biomarker analysis prior to study treatment at the 
following time points:  at day 1 of weeks 0, 3, 6, 9, and either at the time of initial 
unconfirmed iPR, confirmed iPD, or at week 24 for subjects with iSD, whichever comes 
first.  A blood sample should be collected at the safety follow-up visit.  Refer to the 
Laboratory Manual for blood sample procedures. 
7.5.2 
Tumor Tissue Samples 
Tumor tissue biopsies are to be collected and CD8 and PD-L1 will be evaluated to 
explore molecular mechanisms associated with response or resistance to treatment. 
Baseline Tumor Tissue Samples 
Phase 1b 
Formalin fixed paraffin embedded tumor tissue and associated pathology report sample 
from the primary or metastatic lesion should be submitted within 4 weeks of enrollment 
to the central laboratory 
Phase 3 
Formalin fixed paraffin embedded tumor tissue and associated pathology report  from 
the primary or metastatic lesion will be collected and must be submitted within 28 days 
before randomization to the central laboratory. 
Both Phases 
Tissue prioritization is as follows: 
(1) Whenever possible fresh tissue from newly obtained biopsy is preferred.  If 
not available, archival tissue may be submitted. 
(2) When submitting a previously archived tissue sample, the most recent tissue 
available is preferred.  
(3) Tissue samples from metastatic sites are preferred over those from the 
primary tumor. 
(4) Tissue sample should be from outside of the field of maximum radiation dose 
delivered, whenever possible. 
Note:  If no tumor sample is available, the subject should be willing to undergo and 
submit tissue from a new biopsy.  Biopsies should be obtained outside of the field of 
maximum radiation dose delivered, whenever possible.  Subjects with an unevaluable 
tumor sample for PD-L1 expression testing may obtain a new biopsy and subjects with 
an unevaluable newly obtained biopsy may undergo re-biopsy at the discretion of the 


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investigator.  If repeat sample is also unevaluable and the subject is otherwise eligible, 
the investigator may enroll the subject with or without a second re-biopsy. 
Week 6 Optional Tumor Tissue Samples 
There will be an optional tumor biopsy at week 6 for phase 1b and phase 3 subjects who 
have consented for the procedure. 
Archival tumor tissue 
Whenever possible for phase 1b and phase 3 subjects, it is asked that an additional 
archival sample of any age, preferably predating the baseline tumor tissue by greater 
than 6 months be submitted to assess for potential changes in biomarkers that may 
result from cancer progression over time.  If archival tumor samples are submitted in 
addition to required samples for enrollment/randomization, a block of formalin-fixed 
paraffin-embedded tumor tissue is to be sent to the central laboratory along with the 
corresponding pathology report within 4 weeks after randomization/enrollment.  The 
tumor block is to be carefully selected by a pathologist or a skilled experience histology 
associate to include generous tumor tissue using the pathology report as a guide.  In lieu 
of a block, approximately 20 to 25 unstained sections on charged slides from the same 
block can be submitted.  When the samples of tumor tissues are available, analyses of 
tumor specific mutations or epigenetic changes may be performed (eg, somatic 
mutations). 
7.5.3 
HPV Testing 
Both phases 
HPV status in subjects with oropharyngeal cancer is required.  
Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by 
p16 IHC as by convention, they are assumed to be HPV-negative.   
HPV p16 testing, defined as p16 IHC testing using the CINtec assay and a 70% cutoff 
point, can be done at a local laboratory (if the test can be performed locally per standard 
of care). 
Phase 1b 
Results of HPV testing performed at a local laboratory and the assay that was used 
should be recorded on the CRF form. 


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If previously performed HPV result is not available, sites should be willing to submit for 
central laboratory HPV testing using the baseline tumor tissue sample submitted. 
Phase 3 
Results of HPV testing for all subjects with oropharyngeal cancer will be required for 
stratification.  HPV stratification in this trial will be performed using local or central testing 
of HPV status on tumor tissue samples that were obtained during the screening period.  
The testing of HPV of tumor specimen for oropharyngeal cancer in this study is defined 
as p16 IHC testing using the CINtec assay and a 70% cutoff point.  If this assay is 
unavailable locally, central laboratory HPV testing should be done using the tumor tissue 
sample submitted within 28 days of randomization.  Pembrolizumab PK and Anti-Drug 
Antibodies (ADA) Testing  
Pembrolizumab PK and ADA testing should be collected per the timepoints listed in the 
Schedule of Assessments (Table 5 and Table 7). 
7.6 
Optional Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of these optional 
pharmacogenetic studies include the use of genetic markers to help in the investigation 
of cancer and/or to identify subjects who may have positive or negative response to 
talimogene laherparepvec and/or pembrolizumab.  For this optional pharmacogenetics 
analysis, 1 additional blood sample will be collected prior to study treatment  
7.7 
Patient Reported Outcomes (Phase 3 only) 
PROs will be assessed using the following 3 questionnaires: EORTC QLQ-C30, 
QLQ-H&N35, and EQ-5D-5L.  The three questionnaires are commonly used, uniformly 
accepted and validated instruments to evaluate health outcomes in subjects with cancer.  
PRO questionnaires will be administered to subjects where translations are available. 
Subjects should be given sufficient space and time to complete the questionnaire.  
Family members or friends should not assist the subject in completing the questionnaire.  
The time required to complete the questionnaire will be less than 10 minutes. 
The study coordinator should check the responses for completeness and encourage the 
subject to complete any missing responses.  Detailed instructions relating to the 
administrative procedures of the questionnaires will be provided to the sites.  Subject’s 


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refusal (including reason for refusal) to complete all or any part of the questionnaire 
should be documented in the study data capture system. 
The study coordinator should not interpret any items or the response options.  If a 
subject asks what an item means then repeat the item to them verbatim.  Ask the subject 
to answer the item according to what they think the question means.  If they have trouble 
deciding on an answer, ask them to choose the response that comes closest to how they 
feel.  Subjects have the option of not answering a question if they truly do not 
understand the question. 
PRO questionnaires will be collected via paper.  During long-term follow-up, EQ-5D may 
be collected via telephone (upon identification of the subject). 
7.7.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 Version 3.0 is a 2-page, self-reporting 30-item generic instrument 
for use in cancer subjects across tumor types (Bjordal et al., 2000).  It assesses 
15 domains consisting of 5 functional domains (physical, role, emotional, cognitive, 
social), 9 symptom domains (fatigue, nausea and vomiting, pain, dyspnea, insomnia, 
appetite loss, constipation, diarrhea, financial difficulties), and a global health status or 
QOL scale (Aaronson et al, 1993). 
7.7.2 
EORTC QLQ-H&N35 
EORTC QLQ-H&N35 is a head and neck–specific questionnaire designed to assess the 
quality of life of patients with head and neck cancer.  The questionnaire contains 
35 items, which can be condensed into 7 multi-item and 11 single-item scales.  The 
questionnaire results in scales that score from 0 to 100.  For the function scales, a score 
of 100 means perfect quality of life, whereas for the symptom scales it would indicate 
heavy burden. 
7.7.3 
Health State Utility Estimates 
HSU estimates for the purpose of inclusion in a health economic model will be derived 
using the EQ-5D-5L. 
The EQ-5D-5L questionnaire is a 2-page, generic preference-based QOL measure 
comprised of a 5-item health status measure and a visual analogue scale (VAS)  
(Kind, 1996; Rabin and de Charro, 2001) and is used to generate 2 scores.  The  
EQ-5D-5L utility score is based on answers to 5 questions that evaluate mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  The EQ-5D-5L VAS 
generates a single health status index an analogue scale ranges from 0 to 100 in which 


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subjects are asked to rate their current health state by drawing a line from a box marked, 
“Your health today.” 
7.8 
Sample Storage and Destruction 
Any blood, swabs, or tumor sample collected according to the Schedule of Assessments 
(Table 5, Table 6, and Table 7) 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 that analytical methods produce reliable and valid data throughout the 
course of the study.  This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, the sponsor can do additional testing on 
remaining samples (ie, residual and back up) to investigate and better understand the 
cancer, the dose response, and/or prediction of response to talimogene laherparepvec 
and/or pembrolizumab, characterize antibody response, and characterize aspects of the 
molecule (eg, mechanism of action/target, metabolites).  Results from this analysis are 
to be document 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 alter the 
treatment course, the results of pharmacogenetics, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the study 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 the sponsor. 


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The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such a project and has no commercial rights to the data, 
information, discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 5, 
Table 6, and Table 7) including different options for follow-up (eg, in person, by 
phone/email, through family/friends, in correspondence/communication with other 
treating physicians, the review of medical records) and collection of data, including 
endpoints and adverse events.  Subjects that have discontinued investigational product 
and/or protocol required therapies or procedures should not be automatically removed 
from the study.  Whenever safe and feasible, it is imperative that subjects remain on 
study to undergo safety surveillance and/or collection of outcome data.  The investigator 
must document the change to the Schedule of Assessments (Table 5, Table 6, and 
Table 7) 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). 
For subjects who discontinue investigational product without documented iPD and have 
not initiated a new anticancer therapy, every effort should be made to continue 
monitoring tumor response status by clinical and radiographic assessments, and to 
complete PRO questionnaires as described in Table 5 and Table 7. 


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Those subjects who discontinue investigational product should continue into the 
long-term follow-up.  Subjects will be followed for survival and subsequent anticancer 
therapies every 12 weeks (± 28 days) for approximately 36 months after the last subject 
is enrolled.  In addition, talimogene laherparepvec- or placebo-related adverse events 
that occur through the end of the long-term follow-up will be reported.Withdrawal of full 
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 request 
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
• 
other protocol specified criteria see Sections 6.2.1.1, 6.2.1.2, 6.2.2.1 and 6.2.2.2). 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
• 
disease progression 
• 
subject’s treatment assignment is unblinded during the double-blind phase of the 
study via the IVR system for the future management of the subject, and subject is not 
allowed to continue treatment (see Section 5.2) 


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8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
full withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease Related Events 
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  These could include events such as 
pain or discomfort caused by growing tumors due to overall worsening of disease.  Such 
events do not meet the definition of an Adverse Event unless assessed to be more 
severe than expected for the subject’s condition and/or if the investigator believes that 
the event is related to the investigational product(s)/study treatment/protocol required 
therapies. 
Further, any disease related event which meets any of the seriousness criteria in 
Section 9.1.3 should be reported as a Serious Disease Related Event. 
Note:  For situations where disease related events are due to 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 
(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 


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an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event. 
Note:  For situations where adverse events are due to SCCHN, the primary tumor type 
(eg, metastatic SCCHN) should be used, rather than the term “disease progression”. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease related event (eg, PD or pain or discomfort caused by growing tumors) is to 
be reported as a serious adverse event if  
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
• 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event,  
• 
and the event meets at least 1 of the serious criteria above. 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  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 


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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 
non-serious) observed by the investigator or reported by the subject that occur after the 
first dose of talimogene laherparepvec/placebo or pembrolizumab through the safety 
follow-up visit (ie, 30 [+7] days after the last dose of talimogene laherparepvec/placebo 
or pembrolizumab, whichever is later), are recorded on the Event CRF as a Disease 
Related Event. 
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/placebo and/or 
pembrolizumab and, 
• 
action taken 
CTCAE version 4.0 will be used to grade a disease related event.  The grading scale 
used in this study is described in Appendix A. 
Note:  If the event is more severe than expected for the subject’s condition or if the 
investigator believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol required therapies and disease worsening, the event 
should be reported as an adverse event, not a disease related event. 
The investigator is expected to follow reported disease related events (serious or 
non-serious) until stabilization or reversibility. 
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of talimogene 
laherparepvec/placebo or pembrolizumab through the safety follow-up visit (ie, 
30 [+7] days after the last dose of talimogene laherparepvec/placebo or pembrolizumab, 
whichever is later) are reported using the Event CRF.  


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The investigator must assign the following attributes to each adverse event: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity (and/or toxicity per protocol), 
• 
Assessment of relatedness to talimogene laherparepvec/placebo and/or 
pembrolizumab 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/placebo 
and/or pembrolizumab.  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. 
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events, 
follow-up to a serious adverse event, including death due to any cause other than 
progression of the cancer under study, observed by the investigator or reported 
by the subject that occur after signing of the informed consent through 
90 (+7) days after the last dose of talimogene laherparepvec or pembrolizumab, or 
30 (+7) days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, are recorded in the subject’s medical 
record and are submitted to Amgen.  Additionally, all study drug-related serious 
adverse events that occur during the long-term safety follow-up period until the 


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Protocol Number:  20130232 
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end of study should also be captured in the Event CRF although these events will 
not be considered treatment-emergent adverse events. 
All serious adverse events must be submitted to the sponsor within 24 hours 
following the investigator’s knowledge of the event via the Event CRF. 
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 the sponsor 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.  The data must 
be entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
All new information relating to a previously reported serious adverse event must be 
submitted to the sponsor 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 the sponsor. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by the sponsor before submission to regulatory authorities. 
The sponsor 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 regulatory 
requirements and procedures. 


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The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from the sponsor, 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 the sponsor.  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 the sponsor within 24 hours following the investigator’s 
knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking talimogene laherparepvec/placebo or pembrolizumab, report the 
pregnancy to Amgen Global Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur 3 months after the last dose of talimogene laherparepvec 
or 4 months after the last dose of pembrolizumab. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow up with the investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event. 


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If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
9.4 
Reporting of Exposure to Talimogene Laherparepvec/Placebo 
If a household member, caregiver, or healthcare provider who has had close contact 
with a subject treated with talimogene laherparepvec/placebo on this study is suspected 
to have been exposed to talimogene laherparepvec/placebo (eg, have or who have had 
signs or symptoms suspected to be herpetic in origin or who have been accidentally 
exposed to talimogene laherparepvec/placebo), while the subject is taking talimogene 
laherparepvec/placebo, report the exposure to the sponsor as specified below. In 
addition to reporting an unintended exposure case during the study treatment, 
investigators should monitor for potential exposure cases that occur  through 
30 (+7) days after the last dose of talimogene laherparepvec/placebo. 
Any potential or known unintended exposure should be reported to the sponsor within 
24 hours of the investigator’s knowledge of the event of exposure.  The sponsor 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/placebo exposure, the exposed individual may be asked to have a swab 
taken to evaluate for the presence of talimogene laherparepvec DNA in the suspected 
herpetic lesion by qPCR testing. 
9.5 
Pembrolizumab Events of Clinical Interest 
Selected adverse events known as Pembrolizumab Events of Clinical Interest (ECI) 
must be reported to the sponsor within 24 hours of the investigator’s knowledge of the 
event regardless of attribution to pembrolizumab. 


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For the time period beginning when the consent form is signed until treatment 
enrollment/randomization, any pembrolizumab ECI, or follow up to an ECI, that occurs to 
any subject must be reported within 24 hours to the sponsor if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment, or a 
procedure. 
For the time period beginning at treatment enrollment/randomization through 
30 (+7) days following cessation of pembrolizumab treatment, any Pembrolizumab ECI, 
or follow-up to a Pembrolizumab ECI, whether or not related to pembrolizumab, must be 
reported within 24 hours to the sponsor. 
Pembrolizumab Events of Clinical Interest for this trial include: 
• 
an overdose of pembrolizumab, as defined in Section 9.6 
• 
potential drug-induced liver injury (DILI) from pembrolizumab as defined in 
Section 9.7 
Subjects should be assessed for possible Pembrolizumab ECI prior to each dose.  
9.6 
Definition of an Overdose of Pembrolizumab for this Protocol and 
Reporting of Pembrolizumab Overdose 
For the purpose of this trial, an overdose of pembrolizumab will be defined as any dose 
of pembrolizumab equal to or greater than 1000 mg.  No specific information is available 
on the treatment of overdose of pembrolizumab.  In the event of overdose, 
pembrolizumab should be discontinued and the subject should be observed closely for 
signs of toxicity.  Appropriate treatment should be provided if clinically indicated. 
If an adverse event(s) or serious adverse event(s) is associated with (“result from”) the 
overdose of pembrolizumab, the adverse event(s) or serious adverse event is to be 
reported to the sponsor as described in Section 9.2.2.  In addition, the adverse event(s) 
or serious adverse event(s) associated with (“result from”) the overdose of 
pembrolizumab should be reported as an ECI as described in Section 9.5. 
9.7 
Definition and Reporting of Pembrolizumab Drug-induced Liver 
Injury 
For the purpose of this trial, potential DILI associated with (“resulting from”) 
pembrolizumab will be defined as: 
• 
elevated AST or ALT ≥ 3 x ULN 
• 
AND elevated total bilirubin ≥ 2 x ULN 


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• 
AND ALP < than 2 x ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
• 
Note:  These criteria are based upon available regulatory guidance documents.  The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow-up of these criteria can be found in the separate guidance 
document entitled, the pembrolizumab Event of Clinical Interest Guidance for 
Potential DILI in Clinical Trials.   
To facilitate appropriate monitoring for signals of DILI associated with pembrolizumab, 
cases of concurrent DILI according to the criteria specified above require the following: 
• 
The event is to be reported to the sponsor as an adverse event of potential DILI 
within 24 hours of discovery or notification of the event (ie, before additional etiologic 
investigations have been concluded) 
• 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed. 
• 
Workup to confirm DILI should be immediately initiated as described in the 
pembrolizumab Event of Clinical Interest Guidance for Potential DILI in Clinical Trials 
document.  Any confirmed event of DILI is to be reported as a serious adverse event 
within 24 hours after confirmation of the event. 
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. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoints 
Phase 1b 
• 
Subject incidence of DLT 
Phase 3 
• 
Overall survival (OS):  Time from randomization date to the date of death from any 
cause 
10.1.1.2 
Secondary Endpoints 
Phase 1b 
• 
iORR (iCR+iPR), iCRR, iBOR, iDOR, iDCR, and iPFS (response evaluation by 
investigator using irRECIST) 
• 
OS 
• 
Subject incidence of treatment-emergent and treatment-related adverse events (all 
adverse events, grade ≥ 3 adverse events, serious adverse events, fatal adverse 
events, adverse events and serious adverse events leading to discontinuation of 


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Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 109 of 158 
CONFIDENTIAL 
 
 
10.1.2.8 
PRO Analysis Set 
The analysis used for EORTC QLQ-C30, EORTC QLQ-HN35, and EQ-5D-5L will be 
performed using the PRO FAS(G) population, which constitutes randomized subjects 
defined by the FAS(G) population who have at least 1 PRO assessment available and 
have received at least 1 dose of the study medication.  Subjects in the PRO FAS(G) 
population will be included in the treatment group to which they are randomized. 
10.1.3 
Covariates and Subgroups 
To explore the robustness of efficacy signal in phase 1b, iORR may also be estimated 
separately by PD-L1 status (positive/not positive) or other covariates listed below. 
Besides the stratification factors for randomization in phase 3 of HPV status at baseline 
(HPV- negative vs HPV-positive) and ECOG performance status (0 vs 1), the following 
covariates will be used to examine efficacy and safety in subgroups or in multivariate 
analyses as appropriate: 
• 
Region (South America vs North America vs. EU vs. Asia vs Other or phase 1b; 
South America vs North America vs EU vs Japan vs Other Asia vs Other for 
phase 3) 
• 
Age at baseline: < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 
• 
Sex (female vs male) 
• 
Prior smoking (never vs former vs current) 
• 
HSV-1 serostatus (positive vs negative) 
• 
HPV status (positive vs negative vs unknown) (phase 1b) 
• 
The sum of diameters of target lesions 
• 
Weight loss >5% in the previous 6 months 
• 
Primary tumor site(oral cavity vs oropharynx vs hypopharynx vs. larynx) 
• 
Brain metastasis status (baseline brain metastasis vs no baseline brain metastasis) 
• 
Prior radiotherapy for the treatment of SCCHN 
• 
Extent of disease (metastatic vs locoregionally recurrent only) 
• 
Prior lines of therapy in recurrent/metastatic setting (0, 1 or 2) 
• 
PD-L1 status at baseline (PD-L1 positive vs PD-L1 not positive) 
• 
Baseline CD8 + T cell density 
• 
Maximum blinded investigational product total volume per treatment administration 
≥ 4 mL at highest concentration (yes, no) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 110 of 158 
CONFIDENTIAL 
 
 
10.2 
Sample Size Considerations 
10.2.1 
Sample Size Considerations for Phase 1b 
In testing for the null hypothesis H0 that the combination of talimogene laherparepvec 
and pembrolizumab has a DLT rate ≤ 10% versus the alternative hypothesis (Ha) that 
the true DLT rate is ≥ 33%, the sample size goal is to have ≥ 80% power for 
a 1-sided ≤ 10% significance level test to reject H0 when Ha is true (Goldman AI, 1987). 
With up to 3 safety interim analyses, the sequential stopping rules shown in Table 1 
(Section 3.1.1) gives 81.6% power for a 7.7% 1-sided significance level test.  A 
maximum of 18 DLT-evaluable subjects will be enrolled.  If > 18 subjects receive the 
combination they will contribute to the overall safety analysis, but only the first 
18 DLT-evaluable will be considered in the decision to declare the combination safe.  
Subjects may be replaced if they are not evaluable for DLT to obtain 18 DLT-evaluable 
subjects (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 null hypothesis may be accepted and the combination declared safe prior to 
18 DLT-evaluable subjects if it can be definitively determined that the stopping rule will 
not be exceeded with additional subjects. 
An expansion cohort of up to an additional 22 treated subjects will be enrolled so there 
will be 40 treated subjects in total.  The decision to proceed to phase 3 will consider 
safety data in all treated subjects and efficacy among all treated subjects excluding 
those with locoregionally advanced disease with disease progression or recurrence 
< 3 months after prior platinum-containing curatively intended multimodal therapy.  The 
efficacy analysis is expected to include approximately 27 subjects. The decision to 
proceed to phase 3 will consider, for example, long-term tolerability and minimum 
efficacy consistent with pembrolizumab monotherapy historical data.   
The main efficacy endpoint in the phase 1b for the phase 3 decision will be the iORR 
(response per irRECIST by investigator assessment) with or without confirmation of 
response.  Given the observed iORR, the Bayesian posterior probability will be 
calculated that the true combination iORR exceeds the expected iORR for 
pembrolizumab by an absolute amount (delta).  The expected iORR for pembrolizumab 
in the study population with 9 weeks minimum potential follow-up is approximately 11% 
and will be represented by a beta(2.2,17.8) distribution with mean 0.11 and 
precision 20.0.  The iORR for the combination will be represented by a beta(0.2,1.8) 
distribution with mean 0.11 and precision 2.0.  Figure 1 provides the posterior probability 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 111 of 158 
CONFIDENTIAL 
 
 
of a delta increase from 0% to 30% in 5% increments for an observed iORR ranging 
from 11.1% (3/27) to 51.9% (14/27).  Figure 2 provides the delta mean and 90% credible 
region of the absolute iORR increase of combination over pembrolizumab. 
Figure 1.  Probability of a Combination Delta Absolute Objective Response Rate 
Increase Over Pembrolizumab 
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
Probability Combo ORR > Pembro ORR + Delta
Observed Combination ORR
0%
5%
10%
15%
20%
25%
30%
Delta
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 112 of 158 
CONFIDENTIAL 
 
 
Figure 2.  Delta Mean and 90% Credible Region of Absolute Objective Response 
Rate Increase of Combination Over Pembrolizumab 
Delta
-.20
-.10
0.00
0.10
0.20
0.30
0.40
0.50
0.60
Observed Experimental Response Rate
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
Upper Limit
Mean
Lower Limit
 
10.2.2 
Sample Size Considerations for Phase 3 
The primary endpoint for phase 3 is OS.  A hazard ratio (HR) (talimogene laherparepvec 
with pembrolizumab/placebo with pembrolizumab) of 0.7 for OS is hypothesized in the 
FAS(G).  Assuming OS follows a piece-wise exponential distribution (Figure 3), the 
hypothesized HR translates into a relative increase of 43% (absolute increase of 
3.7 months) in median OS from 8.4 to 12.1 months.  The minimum statistically significant 
OS effect corresponds to an HR of 0.769 (increase of median OS of 2.6 months,  
8.4 to 11.0) at the OS interim analysis and 0.801 (increase of 2.1 months, 8.4 to 10.5) at 
the OS primary analysis. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 113 of 158 
CONFIDENTIAL 
 
 
Figure 3.  Overall Survival Assumptions 
 
HR = hazard ratio; pembro = pembrolizumab; T-VEC = talimogene laherparepvec 
Median OS (pembrolizumab) = 8.4 months; p(t) = survival rate at month t; 
p(12) = 0.373, p(24)= 0.15, p(36)=0.10, p(60)=0.05, and p(80)=0.04 constant hazard in 
each interval between 5 consecutive pieces; a constant hazard ratio across all pieces. 
The overall Type 1 error rate is 2-sided 0.05.  The event goal for OS to achieve 90% 
power for a 2-sided 0.05 significance level test is 336 (Lan and DeMets, 1983).  
Assuming approximately 75% of subjects have an OS event at the time of OS primary 
analysis, the sample size is estimated to be 450 (225 per arm).  The OS event goal is 
adjusted for the interim efficacy analysis but not for the interim futility assessment; 
however, the power loss due to futility is < 1% if considered binding.  Assuming 50% of 
cumulative enrollment is accrued after 2/3 of total enrollment period (that is, a concave 
shape of the cumulated enrollment curve) and exponential distributions for loss to 
follow-up with an annual rate of 5% per year for OS, Table 9 displays the timing of 
analyses based on an average enrollment rates at 21 subjects per month. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 114 of 158 
CONFIDENTIAL 
 
 
Table 9.  Timing of Primary Analysis for OS (at 336 events) in the Phase 3 Study 
Average Enrollment 
Rate 
Enrollment Duration 
(month) 
OS Interim Analysis 
DCO (month) 
OS Primary Analysis 
DCO (month) 
21 /month 
21 
30 
38 
OS = overall survival; DCO = data cut-off, interim and primary after 280 and 336 events, respectively 
In addition to the hypothesis test for the primary endpoint, statistical tests for the 
secondary endpoints of ORR, PFS, iORR, and iPFS will be performed conditional on 
rejecting the OS null hypothesis. Table 10 shows event goals (or analysis time) based 
on hypothesized effect sizes and simulated powers for testing 5 endpoints.  The 
simulated powers are based on the Maurer-Bretz graphical multiple testing procedure 
(Maurer and Bretz, 2013) assuming a concurrent primary analysis of all hypotheses.  
Details of the multiple testing procedure are described in Section 10.5.1. 
Table 10.  Hypothesized Effect Sizes and Hypothesis Test Powers 
Hypothesis 
Effect Size 
Primary Analysis 
Timing  
Simulated Powera 
H1 (OS) 
HR = 0.70 
336 events in FAS(G) 
90% 
H2 (ORR):  20% vs 
40% 
OR = 2.67 
FAS(G) with 19 
weeks minimum 
potential follow-up 
90% 
H3 (PFS) 
HR = 0.70 
360 events in FAS(G) 
84% 
H4 (iORR): 20% vs 
45% 
OR = 3.27 
FAS(G) 19 weeks 
minimum potential 
follow-up 
90% 
H5 (iPFS) 
HR = 0.65 
336 events in FAS(G) 
88% 
FAS(G) = Global Full Analysis Set; H = hypothesis; HR = hazard ratio; iPFS = progression-free survival (per 
irRECIST); iORR = objective response rate (per irRECIST); OR = odds ratio; OS = overall survival; 
ORR = objective response rate; PFS = progression-free survival 
a Simulated power (10,000 repetitions) using version 0.8.10 qMCP R package with a correlation of 0.67 
between H1/H2, H1/H3, H2/H4, and a correlation of 0.25  between H1/H3, H1/H5, H2/H5, H2/H3, H3/H4, 
and H4,H5 test statistics. 
Assuming exponential PFS, the hypothesized PFS HR of 0.70 translates into a relative 
increase of 43% (absolute increase of 1.6 months) in median PFS time from 3.8 to 
5.4 months.  Odds ratios of 2.67 and 3.27 are hypothesized for ORR and iORR, 
respectively, in the phase 3 part of the study assuming a 20% rate in the placebo with 
pembrolizumab arm and 40% and 45%in the talimogene laherparepvec with 
pembrolizumab arm.  Assuming exponential iPFS, the hypothesized iPFS HR of 0.65 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 115 of 158 
CONFIDENTIAL 
 
 
translates into a relative increase of 54% (absolute increase of 2 months) in median 
iPFS time from 3.8 to 5.8. 
10.3 
Access to Individual Subject Treatment Assignments by Sponsor or 
Designees 
Unblinding and potentially unblinding information for subjects and investigators should 
not occur prior to the study being formally unblinded (eg, the formal unblinding may 
occur at the final analysis rather than at the interim or primary analysis) except as 
specified (eg, Section 5.2 and Section 9.2.2).  The study team, with exceptions noted 
above, will remain blinded until either results of the OS interim analysis are 
communicated or otherwise the OS primary analysis.  To support the review of 
unblinded safety and efficacy data by the Data Monitoring Committee (DMC), an 
external biostatistics group will be responsible for analyzing the data per the DMC 
charter.  The sponsor study personnel will remain blinded with exceptions where 
necessary for study conduct (eg, processing and analyzing biomarkers, regulatory safety 
reporting requirements). 
10.4 
Planned Analyses 
10.4.1 
Interim Analyses 
DLT interim safety analyses are planned and conducted by the study team for the 
phase 1b, with data being review by a DLRT. 
Interim analysis of safety monitoring and futility analysis based on OS prior to the 
primary analysis of OS in phase 3 will be conducted by an external independent 
biostatistics group and reviewed by the DMC per the DMC charter.  The study team is 
responsible for conducting the primary analysis of OS and all subsequent analyses. 
10.4.1.1 
DLT Safety Analysis (Phase 1b)  
The planned interim safety data reviews in phase 1b to evaluate DLT will be conducted 
according to timing/rules described in Table 1 (Section 3.1.1).  Data will be reviewed by 
a DLRT. 
10.4.1.2 
Interim Safety Analysis (Phase 3) 
Two planned interim safety data reviews will occur after approximately 40 and 
100 subjects have been enrolled in phase 3 and have had an opportunity to be followed 
up for at least 6 weeks after receiving study treatment and approximately every 
6 months after the DMC meeting for the OS interim analysis.  Survival data may be 
reviewed by the DMC from a safety perspective, therefore no multiplicity adjustment is 
needed.  Monitoring guidelines will be provided in the DMC charter.  An interim safety 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 116 of 158 
CONFIDENTIAL 
 
 
data review will also occur that includes the first 8 subjects enrolled with 3 or more 
randomized into treatment arm from Japan in the phase 3 part of the study and have had 
the opportunity to be followed for at least 6 weeks after receiving study treatment.  
Additional analyses may be conducted for Japan enrolled subjects as needed for 
regulatory or safety. 
An additional, interim safety data review will occur when at least 10 subjects have 
received at least one treatment with a total volume >4 ml of 108 PFU/mL talimogene 
laherparepvec plus pembrolizumab and have had the opportunity to be followed up to 
6 weeks after receiving the > 4 mL dose of 108 PFU/mL.  Data will be reviewed by the 
DLRT if it includes phase 1b subjects only, otherwise it will be reviewed by the DMC. 
It is not planned for the enrollment/randomization to be suspended during these ongoing 
phase 3 safety analyses. 
10.4.1.3 
Interim OS Efficacy and Futility Analysis (Phase 3) 
OS Efficacy 
An OS interim efficacy analysis is planned when approximately 280 events have been 
observed.  The OS null hypothesis H1 will be tested at a nominal alpha level determined 
by the Lans DeMets type spending function approximating the O’Brien-Fleming stopping 
boundary (O’Brien and Fleming, 1979).  Assuming exactly 280 and 336 events at the 
interim and primary analysis, the interim and primary analysis nominal alpha levels will 
be 2.81% and 4.19%, respectively.  The timing of the interim analysis was selected to 
ensure approximately 70% power in a potential scenario in which there is a non-constant 
OS effect with HR = 0.95 prior to 3 months and HR = 0.618 thereafter.  The expected 
observed HR for this lag effect scenario is 0.718 and 0.700 at 280 and 336 events.  
Overall power for the lag effect scenario is about 89% whether or not futility is 
considered binding.  If the OS treatment effect is constant with HR = 0.700, then the 
interim power will be about 78%. 
OS Futility 
If the null OS hypothesis H1 is not rejected at the interim analysis, then OS futility will be 
evaluated by the DMC.  The futility criterion will be an observed HR > 0.92.  If there is no 
treatment effect on OS (HR of 1.0), there is a 76% probability of declaring OS futile; 
however, the probability of falsely declaring futility is only about 1% given a constant OS 
HR of 0.70 and it is about 2% for the above lag effect scenario.  The futility analysis in 
the phase 3 study will be non-binding. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 117 of 158 
CONFIDENTIAL 
 
 
The null hypothesis tests for ORR, PFS, iORR, and iPFS will be tested if the OS null 
hypothesis H1 is rejected at either the OS interim or primary analysis.  The analysis of 
ORR and iORR will include the subset of the FAS(G) with at least 19 weeks minimum 
potential follow-up (ie, week 18 response assessment +1 week window).  If the null OS 
Hypothesis, H1, is rejected at the interim analysis, the study will continue to the OS 
primary analysis (ie, follow-up continued), if required, to perform the primary analysis for 
any secondary hypothesis that had an interim analysis at the OS interim analysis with its 
null not rejected. 
At the time of the interim analysis, Amgen senior management will make the decision to 
unblind the study team based on the DMC’s recommendation. 
Interim versus Primary Efficacy Analysis of Secondary Hypothesis 
The earliest planned OS analysis will be considered primary for ORR and iORR that 
includes at least 390 subjects in the ORR and iORR analyses; otherwise, interim 
analyses of ORR and iORR will be performed with an O’Brien-Fleming nominal alpha 
level and the primary analysis of ORR and iORR will be performed at the first 
subsequent planned OS analysis that includes all FAS(G) subjects in the ORR and 
iORR analyses (ie, the OS primary or final analysis). 
The earliest planned OS analysis will be considered primary for PFS that includes at 
least 330 PFS events; otherwise, an interim analysis of PFS will be performed with an 
O’Brien-Fleming nominal alpha level and the primary analysis of PFS will be performed 
at the first subsequent planned OS analysis with at least 360 PFS events. 
The earliest planned OS analysis will be considered primary for iPFS that includes at 
least 300 iPFS events; otherwise an interim analysis of iPFS will be performed with an 
O’Brien-Fleming nominal alpha level and the primary analysis of iPFS will be performed 
at the first subsequent planned OS analysis with at least 336 iPFS events. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 118 of 158 
CONFIDENTIAL 
 
 
Table 11.  Possible Hypothesis Tests at the Two-planned Analyses 
Planned Efficacy Analyses for 
OS Primary Endpoint 
Testing of Secondary Hypothesis 
 
Trigger 
 
ORR/iORR 
PFS 
iPFS 
Analysis 
# of  
eventsa 
Analysis 
Type 
Na 
Analysis 
Type 
# of  
eventsa 
Analysis  
Type 
# of  
eventsa 
Analysis  
Type 
#1 
280 
IA 
< 
390 
IA 
< 330 
IA 
< 300 
IA 
#2 
336 
PA 
≥ 
390 
PA 
≥ 330 
PA 
≥ 300 
PA 
ORR = objective response rate (per RECIST v1.1);  iORR = objective response rate (per irRECIST); 
OS = overall survival; PFS = progression-free survival (per RECIST v1.1); iPFS = progression-free survival 
(per irRECIST); IA = interim analysis; PA = primary analysis 
a In the Global Full Analysis Set (FAS[G]). 
10.4.2 
Blinded Independent Central Review for Secondary Endpoints 
A blinded Independent Central Review (BICR) by a third party imaging laboratory of the 
tumor imaging data will be considered in the event of a statistically and clinically 
significant investigator assessed RECIST v1.1 ORR and/or PFS effect.  An initial audit 
will be performed with approximately 116 (26%) randomly selected subjects from the 
FAS(G). 
The investigator assessed estimate of the ORR effect in the FAS(G) will be considered 
consistent with a BICR assessed estimate if a high degree of concordance is observed 
at the subject level in the initial audit sample for achievement of an objective response 
pooling all subjects.  Specifically, consistency will be declared if the null hypothesis of a 
kappa concordance statistic of 0.65 or less for an objective response is rejected at a 
1-sided 2.5% significance level.  Assuming an overall ORR of 30% and a true kappa of 
0.90, the initial audit size will provide approximately 90% power and rejection of the null 
hypothesis will require and observed kappa statistic of at least 0.77, 89% agreement, 
and a maximum investigator versus BICR ORR absolute difference about 11% in the 
audit sample. 
The consistency of the investigator-assessed estimate of the PFS effect in the FAS(G) 
with a BICR-assessed estimate will be evaluated with a 2-stage procedure  
(Dodd et al 2011).  The PFS consistency criterion will be achievement of a 1-sided 
95% CI for the BICR-assessed PFS log HR below zero.  The initial audit sample would 
provide a greater than 80% probability of achieving the PFS consistency criterion for 
Stage 1 of the procedure if the investigator-assessed PFS HR is 0.70 in the FAS(G) with 
360 events and the correlation is 0.85 between the  


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investigator- and BICR-assessed PFS log-HR.  The audit size for Stage 1, however, will 
be re-calculated based on a bootstrap estimate of the correlation obtained from the initial 
audit and the observed investigator-assessed PFS HR in the FAS(G). Stage 1 will be 
considered with a complete-case BICR if the final audit size exceeds 300 subjects, 
67% of the FAS(G).  Stage 1 may alternatively be assessed with the initial audit if it is 
not feasible to achieve an 80% probability of consistency. 
10.4.3 
Dose Level Review Team 
A DLRT consisting of the Sponsor study team, including at least one medical monitor, 
safety representative, and biostatistician, at least one representative of the Merck study 
team, and at least one investigator participating in the study who has recruited subjects 
into the phase 1b part of the study, will review the safety data to evaluate possible drug 
effects and DLT.  The DLRT will recommend either to enroll more subjects for DLT 
evaluation in phase 1b, to prematurely stop enrollment into phase 1b, or to declare that 
the combination is tolerable based on the criteria described in Table 1. 
10.4.4 
Data Monitoring Committee 
An independent, external to the sponsor, multidisciplinary DMC consisting of a 
biostatistician and 2 clinicians that collectively have experience in the management of 
subjects with SCCHN and in the conduct and monitoring of randomized clinical trials will 
be established before the start of the phase 3 part of the trial.  The DMC will monitor the 
overall conduct of the phase 3 trial including OS futility based on the criterion in 
Section 10.4.1.3. 
10.4.5 
Primary Analysis 
10.4.5.1 
Primary Analysis Phase 1b 
For the phase 1b part of the study, the primary analysis will occur when the last subject 
enrolled has had the opportunity to complete the 9-week response assessment. 
10.4.5.2 
Primary Analysis Phase 3 
For the phase 3 part of the study, the timing for the primary analysis of OS will be 
event-driven based on the FAS(G).  The event goal for OS is 336.  Detailed approximate 
timings of the analyses are shown in Table 9. 
10.4.6 
Follow-Up Analysis for Phase 1b 
For the phase 1b part of the study, the primary analysis will be repeated 1 year 
after the last subject enrolled. 


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10.4.7 
Final Analysis  
The final analysis of the study will be conducted after the last subject enrolled has had 
the opportunity to complete the long-term follow-up (ie, 36 months after the last subject 
is enrolled in the FAS.  
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
For the phase 1b part of the study, the DLT analysis set will be used to summarize the 
subject incidence of DLT and, unless specified otherwise, the SAS will be used for all 
analyses of safety.  The EAS, FAS, and the FAS excluding subject in the EAS will be 
used for all efficacy analyses.  
For the phase 3 part of the study, the efficacy analyses will be conducted on the FAS(G).  
Treatment effects on efficacy endpoints will be evaluated and compared between the 
2 treatment arms according to the treatment as randomized.  Formal treatment 
comparisons will be performed on the primary endpoints and the 4 key secondary 
endpoints.  The SAS(G), unless specified otherwise, will be used for all analyses of 
safety in the phase 3.  Descriptive efficacy and safety analyses of subjects randomized 
after the global last subject enrolled (LSE[G]) will be provided separately at the time of 
the OS interim and primary analyses. 
In principle, summary statistics including mean, standard deviation, median, first and 
third quartiles, will be provided for continuous variables.  Frequency and percentage will 
be summarized by treatment arm for binary and categorical variables.  Proportions and 
the corresponding 95% confidence intervals will be based on normal approximations and 
the treatment comparison will be based on a Cochran-Mantel-Haenszel test.  Exact tests 
will be considered for subgroup analyses when the cell size is considered small.  
Time-to-event endpoints will be estimated using the K-M method.  Stratified Log-rank 
test statistics and associated p-values will also be calculated.  Hazard ratios will be 
estimated using stratified Cox PH models. 
Descriptive statistics will be provided for efficacy, safety, talimogene laherparepvec 
DNA, and biomarker endpoints as appropriate.  
Multiple statistical hypothesis tests will be conducted which include testing for the 
primary endpoint of OS and the 4 secondary endpoints (ORR, PFS, iORR, and iPFS 
response evaluation by investigator using RECIST v1.1 and irRECIST) at multiple 
analysis time points.  To control the study-level overall Type I error, a graphical multiple 


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Phase 3 
The efficacy analyses will be conducted on the FAS(G).  Treatment effects on efficacy 
endpoints will be evaluated and compared between the 2 treatment arms according to 
the treatment as randomized. 
For analysis of the primary endpoint OS, a stratified log-rank test will be used as the 
primary method for testing the null hypothesis of no treatment difference.  The 
randomization factors, along with PD-L1 status at baseline (PD-L1 positive vs PD-L1 not 
positive), will be used as stratification factors.  A hazard ratio will be estimated using the 
Cox proportional hazards (PH) model stratified by the randomization factors per IVR and 
PD-L1 status at baseline with Efron’s method (Efron 1977) used to handle ties.  
Kaplan-Meier time to event curves will be presented based on randomized treatment 
arm. 
Statistical testing of OS will follow the multiple hypothesis testing procedure described in 
Section 10.5.1. 
Covariates to define subgroups for analysis of efficacy endpoints will include, but not be 
limited to, the randomization stratification factors. 
10.5.3 
Secondary Efficacy Endpoints 
All endpoints of the phase 1b will be descriptively analyzed. 
ORR and iORR will be treated as binary endpoints and summarized by treatment arm as 
randomized with associated 95% CIs, and with treatment comparisons based on the 
Cochran-Mantel-Haenszel test stratified by the randomization stratification factors and 
PD-L1 at baseline.  Following the intent-to-treat principle, subjects who do not have any 
follow up tumor assessments will be determined to be non-complete responders.  
Analysis of PFS and iPFS will follow the analysis described for the primary endpoint of 
OS.   
Hypothesis testings for ORR, PFS, iORR, and iPFS are described in the multiple testing 
procedure in Section 10.5.1.  Analyses of the remaining secondary endpoints in phase 3 
will be descriptive. 
CRR, iCRR, DCR, and iDCR will be summarized by treatment arm as randomized 
(phase 3).  Subjects who do not have any follow-up tumor assessments will be 
determined to be non-responders for CRR and iCRR or to not have had a response of 


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stable or better for DCR and iDCR.  DOR and iDOR among responders will be analyzed 
and estimated using the Kaplan-Meier method. 
10.5.4 
Safety Endpoints 
Subject incidence of all treatment emergent adverse events will be tabulated by system 
organ class and preferred term.  Treatment-emergent adverse events are defined as 
adverse events with an onset from the first dose of study therapy up to 30 days after the 
last dose of study therapy.  Tables of fatal adverse events, serious adverse events, 
adverse events, disease related events leading to withdrawal from investigational 
product or other protocol required therapies, and significant treatment emergent adverse 
events will also be provided. 
Subject incidence of disease related events (DREs) and fatal disease related events will 
be tabulated by system organ class and preferred term.   
Medical Dictionary for Regulatory Activities will be used to code adverse events to a 
system organ class and a preferred term within the system organ class.  The CTCAE 
version 4.0 will be used to grade severity of adverse events. 
Summary statistics over time by treatment group will be provided for selected key safety 
laboratory endpoints.  Shifts in grades of these safety laboratory endpoints between the 
baseline and the worst on-study value will be tabulated by treatment group. 
The ECG measurements from this clinical study will performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Summaries and statistical analyses of ECG measurements are not planned. 
The qPCR analysis result of talimogene laherparepvec DNA in swab samples taken from 
exterior of occlusive dressing, surface of injected lesions, and oral mucosa suspected to 
be herpetic in origin (if any) in phase 1b samples will be summarized.  The incidence 
and percentage of subjects who develop anti-pembrolizumab antibodies (binding and if 
positive, neutralizing) at any time will be tabulated. 
Potential or known unintended exposure to talimogene laherparepvec/placebo, related 
suspected signs or symptoms, and detection of talimogene laherparepvec DNA in a 
subject’s household member, caregiver, or healthcare provider will be reported. 
10.5.5 
PRO Endpoints 
The PRO analyses will be conducted on FAS(G) population.  Summary scores at each 
assessment and changes from baseline of PROs as assessed by EORTC QLQ-H&N35, 


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EORTC QLQ-C30 questionnaire subscales will be reported.  The calculation of scores 
will be based on the questionnaire’s standard scoring guidelines.  Methods for assessing 
and handling missing data together with the full details the PRO analyses will be 
provided in a supplemental statistical analysis plan (SSAP).  Comparisons between 
groups for the QLQ-C30 GHS/QoL subscale (secondary endpoint) and select subscales 
from the QLQ-C30 and QLQ-HN35 will be analyzed as per the PRO SSAP. 
10.5.6 
Health State Utility Estimates 
For the EQ-5D-5L questionnaire, two scores will be estimated; the utility score calculated 
from the 5 domains using a scoring algorithm and the VAS score based on the 0-100 
feeling thermometer.  Changes from baseline will be summarized and at specified time 
points of interest, differences between treatment groups for each defined score will be 
analyzed.  The calculation of scores and methods for handling missing data will be 
based on the questionnaire’s standard scoring guidelines.  Details for deriving the HSU 
estimates and the full analysis plan will be provided in the PRO SSAP. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the sponsor Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject  after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.   


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The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by the sponsor before recruitment of subjects into the study and 
shipment of investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from the sponsor, 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 the sponsor. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to the sponsor. 
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/randomization. 
For Serious Adverse Events reported to the sponsor, 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 the sponsor(eg, signed informed consent forms) 
are to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit such individuals to have access to his/her 
study-related records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by the sponsor, 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 the sponsor 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 the sponsor. 
The sponsor reserves the right to terminate the study at any time.  Both the sponsor 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 


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study’s completion or early termination and send a copy of the notification to the 
sponsor.  
Subjects may be eligible for continued treatment with investigational product(s) by an 
extension protocol or as provided for by the local country’s regulatory mechanism.  
However, the sponsor reserves the unilateral right, at its sole discretion, to determine 
whether to supply 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 IVR system captures the following data points and these are 
considered source data:  subject identification number and randomization 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).  In this study, 
EQ-5D-5L, QLQ-C30, and QLQ-H&N35 can be used as source documents.  
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 the sponsor and/or applicable regulatory 
authorities.   
Elements to include: 
• 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and the sponsor 


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• 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
• 
Non-investigational product(s) and or medical device(s) documentation, as 
applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The sponsor 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 sponsor’s 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 Audit (or designees).  
Inspection of site facilities (eg, pharmacy, protocol-required therapy storage areas, 
laboratories) and review of study-related records will occur to evaluate the study conduct 
and compliance with the protocol, ICH GCP, and applicable regulatory requirements.  
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 


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• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received by the sponsor.  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 a sponsor 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. 
The sponsor (or designee) will perform self-evident corrections to obvious data errors in 
the clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by the sponsor (or 
designee) include deletion of obvious duplicate data (eg, same results sent twice with 
the same date with different visit-week 4 and early termination) and clarifying “other, 
specify” if data are provided (eg, race, physical examination).  Each investigative site will 
be provided a list of the types of corrections applied to study data at the initiation of the 
trial and at study closeout. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 5, Table 6, and Table 7) 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, 


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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. 
• 
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. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international 
clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376. 
Albers AE, Strauss L, Liao T, et al.  T-cell tumor interaction directs the development of 
immunotherapies in head and neck cancer.  Clin Dev Immunol.  2010; Article ID 236378. 
Ang KK, Harris J, Wheeler R, et al.  Human papillomavirus and survival of patients with 
oropharyngeal Cancer.  N Engl J Med.  2010;363(1):24-35. 
Argiris A, Karamouzis M, Raben D, et al.  Head and neck cancer.  Lancet.  
2008:371:1695-1709. 
Badoual C, Hans S, Merillon N, et al.  PD-1-expressing tumor-infiltrating T cells are a 
favorable prognostic biomarker in HPV-associated head and neck cancer.  Cancer 
Research.  2013;73(1):128-138. 
Bjordal K, de Graeff A, Fayers PM, Hammerlid E, van Pottelsberghe C, Curran D, et al. 
A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck 
cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC 
Quality of Life Group. Eur J Cancer. 2000;36(14):1796-807. 
Chaturvedi A, Engels E, Pfeiffer R, et al.  Human papillomavirus (HPV) and rising 
oropharyngeal cancer incidence and survival in the United States.  J Clin Oncol. 
2011;29:(suppl; abstract 5529). 
Chesney et al. Interim safety and efficacy of a randomized (1:1), open-label phase 2 
study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected, stage 
IIIB-IV melanoma. Ann Oncol 2016;27 (suppl 6):abstract 1108PD  (doi: 
10.1093/annonc/mdw379.04) 
Cho Y, Yoon H, Lee J, et al.  Relationship between the expressions of PD-L1 and 
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Pembrolizumab in Subgroups of Patients with Recurrent/Metastatic Head and Neck 
Squamous Cell Carcinoma (R/M HNSCC):  Exploratory Analysis from KEYNOTE-12 
(abstract) 2015; European Cancer Congress.  
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search?abstractid=21182 
Cohen EW, Lingen MW, Vokes, EE.  The expanding role of systemic therapy in head 
and neck cancer.  J Clin Oncol. 2004;22(9)1743-1752. 
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Dong H, Strome SE, Salomao DR, et al.  Tumor-associated B7-H1 promotes T-cell 
apoptosis: a potential mechanism of immune evasion.  Nat Med.  2002;8(8):793-800. 
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557-565 
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tumours: revised RECIST guideline (version 1.1).  Eur J Cancer.  2009;45:228-247. 
Fakhry C, Gillison ML.  Clinical implications of human papillomavirus in head and neck in 
head and neck Cancers.  J Clin Oncol.  2006;24:2606-2611. 


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Fakhry C, Westra WH, Li S, et al.  Improved survival of patients with human 
papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical 
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tolerance by blocking the TCR-induced stop signal.  Nature immunol.  
2009;10(11)1185-1193. 
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neck.  Cancer.  2009;115(5):922-935. 
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in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell 
cancer of the head and neck.  Clin Cancer Res.  2010;16(15):4005-4015. 
Hirano F, Katsumi K, Tamura H, et al.  Blockade of B7-H1 and PD-1 by monoclonal 
antibodies potentiates cancer therapeutic immunity.  Cancer Res.  2005;65:1089-1096. 
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for International Cancer Control TNM Stage and Prognostic Groups for Human 
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Kaufman HL, Kim DW, De Raffele, et al.  Local and distant immunity induced by 
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2006;24:5630-5636 
Long GV, Reinhard D, Ribas A, et al.  Primary analysis of MASTERKEY-265 phase 1b 
study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for 
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cts.pdf 
Lyford-Pike S, Peng S, Young G, et al.  Evidence for a role of the PD-1:PD-L1 pathway 
in immune resistance in HPV-associated head and neck squamous cell carcinoma.  
Cancer Res.  2013;73:1733-1741. 


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Puzanov I, Milhem MM, Andtbacka RHI, et al.  Primary analysis of a phase 1b 
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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 AST or ALT and total bilirubin and/or INR elevation according to the criteria 
specified in Section 6.4 require the following: 
• 
The event is to be reported to the sponsor 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 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 sponsor.  
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 ULN 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, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of total bilirubin > 2x ULN 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 
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. 


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• 
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 CPK, haptoglobin, LDH, 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 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.  Sample Serious Adverse Event Report Form 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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Appendix D.  Radiological Guidance for Assessment of Disease Response 
Initially developed in 2000 and modified in 2009, RECIST guidelines provide a standard 
approach to solid tumor measurement and definitions for objective assessment of 
change in tumor size in adult and pediatric cancer clinical trials.  More recently, however, 
to account for the unique tumor response characteristics seen with treatment with 
immunotherapeutic agents, standard RECIST v1.1 will be adapted (irRECIST) to assess 
tumor responses in this study for treatment decisions only. Immunotherapeutic agents 
such as pembrolizumab and talimogene laherparepvec may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses.  The response patterns 
seen with such an approach may extend beyond the typical time course of responses 
seen with cytotoxic agents, and can manifest a clinical response after an initial increase 
in tumor burden or even the appearance of new lesions.  Standard RECIST v1.1 
therefore may not be the optimal method for response assessment of 
immunotherapeutic agents. Immune-related RECIST (irRECIST) is RECIST v1.1 
adapted to account for the unique tumor response seen with immuno-therapeutics.  
irRECIST will be used by local site investigators to assess tumor response and 
progression, and make treatment decisions.  Adaptations for irRECIST include the 
following: 
• 
For initial progressive disease (PD), tumor assessment should be repeated  
≥4 weeks later in order to confirm PD with the option of continuing treatment per 
below while awaiting radiologic confirmation of progression. 
• 
If repeat imaging shows < 20% tumor burden compared to nadir, stable or improved 
previous new lesion (if identified as cause for initial PD), and stable/improved 
non-target disease (if identified as cause for initial PD), treatment may be 
continued/resumed. 
• 
In determining whether or not the tumor burden has increased or decreased, all 
target lesions as well as non-target lesions should be considered. 
Note:  For phase 3 only, investigators will also be asked to assess and document tumor 
response per standard RECIST v1.1.  However, RECIST v1.1 response assessment 
should NOT be used in treatment decisions. 
Method of Measurement of Tumor Lesions: 
CT scans (or MRI):  
Computed tomography (CT) scans by contrast-enhanced or spiral scan (or magnetic 
resonance imaging [MRI] scan) will be performed to evaluate tumor response for visceral 


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or nodal/soft tissue disease (including lymph nodes).  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.  
Ultrasound:  
Ultrasound (US) should not be used as a primary method to assess lesion 
measurements in response to treatment. 
Baseline Lesions 
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  
• 
A lymph node must be ≥ 15 mm in short axis when assessed by CT scan or MRI. 
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.  Examples of non-measurable lesions include 
some bone lesions, ascites, pleural/pericardial effusion, lymphangitic involvement of the 


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skin or (lymphangitis cutis/pulmonis), cystic lesions, and groups of lesions that are small 
and numerous. 
Documentation of “Target”, “Non-Target” and “New” Lesions: 
Baseline evaluations will be used to prospectively identify all sites of disease present as 
close as possible to the enrollment and never greater than or equal to 28 days before 
the enrollment date.  Sites of disease will be characterized as either target, non-target 
lesions or new lesions. 
Baseline Documentation of Target Lesions: 
Up to 10 target lesions with a maximum of 5 per organ (phase 1b) and up to 5 target 
lesions with a maximum of 2 per organ (phase 3) 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.  
Target lesions should be selected on the basis of their size (lesions with longest 
diameter) and suitability for accurate repeated measurements by radiographic imaging.  
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. 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).   
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 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:  
Any measurable lesions that were not chosen as target lesions and pathological lymph 
nodes with short axis ≥ 10 mm but < 15 mm, as well as non-measurable lesions should 
be identified as non-target lesions.  Non-target lesions are evaluated at each timepoint 
but measurements are not required. 


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Documentation of New Lesions: 
Any new lesion that appears during the course of study will be categorized as a new 
lesion.  New lesions are evaluated at each timepoint but measurements are not required.  
Follow-up Assessment of Tumor Lesions: 
At each subsequent tumor assessment, the sum of diameters of target lesions will 
contribute to the total tumor burden. 
Tumor Burden = sum of diameter of target lesions  
New lesions and non-target lesion measurements are not required and these lesions 
should be followed qualitatively. 
For radiographically assessed non-nodal disease the convention will be used that if a 
lesion being measured decreases in size to ≤ 5 mm in diameter or if it is believed to be 
present and faintly seen but 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 it is in the opinion of the radiologist that 
the non-nodal lesion has likely disappeared, the measurement should be recorded as 
“0 mm”.  If a lymph node is nonpathological (< 10 mm), dimensions should be recorded 
as 5 mm. 
Response Evaluation: 
Evaluation of Objective Response: 
The subject response will be assessed based on tumor burden (the sum of diameters of 
target lesions) and qualitative assessment of non-target lesions per the definitions in 
Table 12.  The overall response is derived from time-point response assessments as 
described in Table 14.  Treatment decisions based on initial progressive disease are 
described in Table 13. 


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Table 12.  Definition of Measurable Tumor Response 
(Baseline Target, Non-target, and New Lesions) per irRECIST 
Complete Response (iCR): 
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 is required.  Any pathological lymph 
nodes (whether target or nontarget) must have reduction in 
short axis to <10 mm. 
Partial Response (iPR): 
Decrease in tumor burden* ≥ 30% relative to baseline.  
Confirmation by a consecutive assessment at least 4 weeks 
(28 days) after first documentation required. 
Progressive Disease (iPD): 
Increase in tumor burden* ≥ 20 % and at least 5 mm absolute 
increase compared to nadir (minimum recorded tumor burden)  
or qualitative worsening of non-target lesions or a new lesion.  
For irRECIST, confirmation by a repeat, consecutive 
assessment no less than 4 weeks (28 days) from the date first 
documented progressive disease is required.  
Stable Disease (iSD): 
Neither sufficient shrinkage to qualify for iCR or iPR nor 
sufficient increase to qualify for iPD. 
Unable to Evaluate (iUE): 
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 
irRECIST = immune-related Response Evaluation Criteria in Solid Tumors 
* Tumor Burden = sum of diameter of target lesions  
Diameters used: 
For nodal disease, shortest axis 
For non-nodal disease, longest diameters 


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Table 13.  Imaging and Treatment After First Radiologic Evidence of PD per 
irRECIST 
 
Clinically Stable 
Clinically Unstable/Rapid Clinical 
Deterioration 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of 
iPD 
(progressive 
disease by 
irRECIST) 
Repeat 
imaging at 
> 4 weeks at 
site to 
confirm iPD 
May continue 
study treatment at 
the local site 
Investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
irRECIST. 
Repeat imaging at 
> 4 weeks to 
confirm iPD per 
investigator 
discretion* 
Discontinue 
treatment 
Repeat 
tumor 
imaging 
confirms iPD 
(progressive 
disease by 
irRECIST) at 
the local site 
No additional 
imaging 
required 
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
sponsor) 
No additional 
imaging required 
N/A 
Repeat 
tumor 
imaging 
shows iSD, 
iPR or iCR 
by the local 
site 
Continue 
regularly 
scheduled 
imaging 
assessments  
Continue study 
treatment at the 
local site 
Investigator’s 
discretion 
Continue regularly 
scheduled 
imaging 
assessments  
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
Investigator’s 
discretion.  
iCR = complete response per irRECIST; iPD = progressive disease per irRECIST; iPR = partial response 
per irRECIST; irRECIST = immune-related Response evaluation Criteria in Solid Tumors; 
PD = progressive disease 
*Note: Clinically unstable patients are not required to undergo confirmation of PD. This decision is left to the 
discretion of the investigator. 
Confirmation of Disease Progression: 
In subjects who have initial evidence of radiological iPD, it is at the discretion of the PI 
whether to continue a subject on study treatment until repeat imaging is obtained based 
on their assessment of clinical stability.  Subjects may receive study treatment and tumor 
assessment should be repeated ≥ 4 weeks later in order to confirm iPD by per site 
assessment.   
Clinical stability is defined as the following:  
1) absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values 
2) no decline in ECOG performance status  


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3) absence of rapid progression of disease  
4) absence of progressive tumor at critical anatomical sites (eg, compression) requiring 
urgent alternative medical intervention   
In determining whether or not the tumor burden has increased or decreased per 
irRECIST, the local site investigator should consider all target and non-target lesions as 
well as any incremental new lesion(s). 
iPD is confirmed at repeat imaging if ANY of the following occur by irRECIST: 
• 
Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to 
nadir 
• 
Non-target disease resulting in initial PD is worse (qualitative assessment) 
• 
New lesion resulting in initial PD is worse (qualitative assessment) 
• 
Additional new lesion(s) since last evaluation 
• 
Additional new non-target progression since last evaluation (i.e non-target 
progression following initial iPD in which iPD was due to either increased target 
lesion tumor burden or a new lesion but was not confirmed on repeat imaging).  
Note:  Rapid clinical deterioration does not require confirmation of iPD 
If repeat imaging confirms iPD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.  
NOTE:  If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered 
following consultation with the sponsor. 
iPD is not confirmed at repeat imaging if ALL of the following occur by irRECIST:  
• 
Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir 
• 
Non-target disease resulting in initial iPD is stable or improved (qualitative 
assessment) 
• 
New lesion resulting in initial iPD is stable or improved (qualitative assessment) 
• 
No incremental new lesion(s) since last evaluation 
• 
No incremental new non-target progression since last evaluation 
If repeat imaging does not confirm iPD by irRECIST and the subject continues to be 
clinically stable, treatment may continue and follow the regular imaging schedule.  If iPD 
is confirmed by a consecutive assessment, the first date of iPD documented should be 
the date of iPD.  However, if iPD is not confirmed by a consecutive assessment but is 


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again noted at a subsequent assessment, the date of iPD documented should be the 
second date of iPD to capture incremental benefit. 
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiographic assessment.  This allowance to continue treatment 
despite initial radiologic PD takes into account the observation that some subjects can 
have a transient tumor flare in the first few months after the start of immunotherapy, and 
then experience subsequent disease response.  New lesions will be documented on the 
CRF form.  
Confirmation of Response (iCR or iPR): 
To be assigned a status of iCR or iPR 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. 
The confirmatory assessments for complete response (CR)/partial response (PR) should 
be completed as close to the 28 day period without waiting for the next scheduled 
assessment (ie, 9 weeks later in case of subjects on treatment and 12 weeks later for 
subjects in long term follow-up (LTFU) who have ended treatment for reasons other than 
PD. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of iCR depends on this determination, it is recommended 
that the residual lesion be investigated (ie, biopsy) to confirm the iCR status. 
Subjects who have had Complete or Partial Removal/Reduction of the Lesion will be 
Evaluated as Follows: 
The procedure itself and all post-procedure lesion assessments should always be 
recorded in the CRF.  A completely resected lesion should be assigned a default code of 
0 mm (for target lesions) or “absent” (for non-target lesions).  A partially resected lesion 
should be assigned its measurement post-procedure (for target lesions) or “present” (for 
non-target lesions).  If the resected lesion contains 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 contains 
cancer or pathology results are unknown, the recorded tumor assessments 
post-procedure may be used for tumor burden calculations, but determination of visit 
overall response will be considered unable to evaluate (iUE or UE) for response except 
in the case of iPD or PD.  Similarly, the visit overall response will be considered iUE and 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 150 of 158 
CONFIDENTIAL 
 
 
UE, respectively, due to an incomplete tumor response assessment unless the criteria 
for iPD and PD, respectively, is met based on the subset of lesions assessed. 
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 
iPD and PD will be determined from the nadir. 
Merging Lesions 
When two or more target lesions merge, the smaller lesion should have 0 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 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 lesion merges with a non-target lesion, the non-target lesion 
should be absent for the current visit and all future assessments, and the target lesion 
should include both merged lesions for recording measurements.  New lesions and 
enlarging non-target lesions are measured qualitatively. 
Separating Lesions 
When a target lesion splits into 2 or more lesions, the largest measurable part of the split 
lesion should be considered to be the previously recorded target lesion with 
measurements provided for the current assessment and followed for future 
assessments.  The dimensions of the split parts would still be target lesions. When a 
non-target lesion splits into 2 or more lesions, the split parts remain non-target lesions 
for the duration of the study.  Any new lesions that result from separating should be 
documented as lesions that were generated by separating and not truly new lesions. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 151 of 158 
CONFIDENTIAL 
 
 
Table 14.  Matrix for Determining the Overall Response at Each Assessment Point 
for irRECIST 
Target Lesions 
(tumor burden)a 
Non-target Lesions 
New 
Lesions 
Visit 
Overall 
Response 
Subject Overall 
Response 
↓ 100% 
Absent / NA 
Absent 
iCR 
iCRb 
 
Stable 
Absent 
iPR 
iPRb 
 
Qualitatively worse 
Absent 
iPD 
iPR if no further 
worsening of non-target 
lesionsb,c 
 
Absent / Stable / 
NA 
Present 
iPD 
iPR if stable new lesions 
and no additional new 
lesionsb,c 
↓ ≥ 30% 
Absent / Stable / 
NA 
Absent 
iPR 
iPRb 
 
Qualitatively worse 
Absent 
iPD 
iPR if no further 
worsening of non-target 
lesionsbc 
 
Absent / Stable / 
NA 
Present 
iPD 
iPR if news lesions stable 
and no additional new 
lesionsb,c 
↓ < 30% to ↑ < 
20% 
Absent / Stable / 
NA 
Absent 
iSD 
iSD if ≥ 8 weeks from 
start of study therapy; 
otherwise, UE 
 
Qualitatively worse 
Absent 
iPD 
iSD if no further 
worsening of non-target 
lesionsc 
 
Absent / Stable / 
NA 
Present 
iPD 
iSD if stable new lesions 
and no additional new 
lesionsc 
↑ ≥ 20% and ↑ ≥ 5 
mm absolute  
Any 
Any 
iPD 
iPDc 
UE 
Absent / Stable / 
NA 
Absent 
iUE 
iUE 
 
Qualitatively worse 
Absent 
iPD 
iPDc 
 
Absent / Stable / 
NA 
Present 
iPD 
iPDc 
iCR/iPR/iSD 
ND/iUE 
Absent 
iUE 
iUE 
 
ND/iUE 
Present 
iPD 
iPD 
iCR  = complete response (per irRECIST); NA =  not applicable; ND = not done; iPD = progressive disease 
(per irRECIST); iPR = partial response (per irRECIST); iSD = stable disease (per irRECIST); iUE = unable to 
evaluate (per irRECIST) 
a Decrease relative to baseline; increase relative to nadir. 
b Confirmation or iCR/iPR required by a repeat consecutive assessment no less than 4 weeks (28 days) 
from the date first documented.  For iCR, any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to < 10 mm.  The subject overall response will be iSD if iCR/iPR is not 
confirmed. 
c In the absence of clinical instability, an initial visit overall response of iPD must be consecutively confirmed 
no less than 4 weeks (28 days) from the date first documented for a subject overall response of iPD. The 
onset of iPD will be at the initial visit overall response of iPD when it is confirmed.  If the initial visit overall 
response of iPD is not confirmed, then a subsequent iPD does not need to be confirmed for a subject 
overall response of iPD. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 152 of 158 
CONFIDENTIAL 
 
 
Appendix E.  RECIST v1.1 Guidelines for Assessment of Disease Response 
(Phase III Only) 
For phase III only, investigators will be asked to obtain and document tumor responses 
per standard RECIST v1.1 along with those per irRECIST at every scheduled and 
unscheduled tumor assessment following the same target and non-target lesions 
determined for irRECIST tumor response assessment.  Clinical decisions for treatment, 
however, should only be made based on tumor assessment using irRECIST. 
Method of Measurement of Tumor Lesions: 
Note: Imaging scans obtained for irRECIST tumor response assessment should also be 
used for RECIST v1.1 assessment 
CT scans (or MRI):  
Computed tomography (CT) scans by contrast-enhanced or spiral scan (or magnetic 
resonance imaging [MRI] scan) will be performed to evaluate tumor response for visceral 
or nodal/soft tissue disease (including lymph nodes).  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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Protocol Number:  20130232 
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Ultrasound:  
Ultrasound (US) should not be used as a primary method to assess lesion 
measurements in response to treatment.  
Note: Tumor Lesions designated for irRECIST response assessment should also be 
used for RECIST v1.1. 
Baseline Lesions 
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  
A lymph node must be ≥ 15 mm in short axis when assessed by CT scan or MRI. 
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.  Examples of non-measurable lesions include 
some bone lesions, ascites, pleural/pericardial effusion, lymphangitic involvement of the 
skin or (lymphangitis cutis/pulmonis), cystic lesions, and groups of lesions that are small 
and numerous. 
Documentation of “Target”, “Non-Target” and “New” Lesions: 
Baseline evaluations will be used to prospectively identify all sites of disease present as 
close as possible to the enrollment and never greater than or equal to 28 days before 
the enrollment date.  Sites of disease will be characterized as either target, non-target 
lesions or new lesions. 
Baseline Documentation of Target Lesions: 
Up to 5 target lesions (a maximum of 2 per organ) will be chosen to measure over the 
course of therapy (Phase III).  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. 
Target lesions should be selected on the basis of their size (lesions with longest 
diameter) and suitability for accurate repeated measurements by radiographic imaging.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
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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.  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). 
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 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:  
Any measurable lesions that were not chosen as target lesions and pathological lymph 
nodes with short axis ≥ 10 mm but < 15 mm, as well as non-measurable lesions should 
be identified as non-target lesions.  Non-target lesions are evaluated at each timepoint 
but measurements are not required. 
Documentation of New Lesions: 
Any new lesion that appears during the course of study will be categorized as a new 
lesion. New lesions are evaluated at each timepoint but measurements are not required.  
Tumor Assessment per RECIST v1.1: 
At each subsequent tumor assessment after baseline, the sum of diameters of target 
lesions (longest for non-nodal lesions and short axis for nodal) will contribute to the total 
tumor burden.   
Tumor Burden = sum of diameter of target lesions 
New lesions and non-target lesion measurements are not required and these lesions 
should be followed qualitatively. 
Response Evaluation: 
Evaluation of Objective Response: 
The subject response will be assessed based on tumor burden (the sum of diameters of 
target lesions) and qualitative assessment of non-target lesions per the definitions in 
Table 15.   


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
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Table 15.  Definition of Tumor Response for RECIST v1.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all non-nodal target lesions. 
Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 
<10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is 
the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note:  the 
appearance of one or more new lesions is also 
considered progression) 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
Unable to Evaluate (UE) 
Any non-target lesion present at baseline which 
was not assessed or was unable to be evaluated 
leading to an inability to determine the status of that 
particular tumor for that time point  
Not Done (ND) 
Scans were not performed at this time point to 
evaluate target lesions 
Evaluation of Non-target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalisation of tumour marker level.  All lymph 
nodes must be non-pathological in size (<10mm 
short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Unequivocal progression of existing non-target 
lesions. (Note:  the appearance of one or more new 
lesions is also considered progression). 
Unable to Evaluate (UE) 
Any non-target lesion present at baseline which 
was not assessed or was unable to be evaluated 
leading to an inability to determine the status of that 
particular tumor for that time point  
Not Done (ND) 
Scans were not performed at this time point to 
evaluate target lesions 
RECIST = Response Evaluation Criteria in Solid Tumors 
Target Lesions:  
• 
All target lesions (nodal or non-nodal) should have the actual measurements 
recorded at each subsequent evaluation even when very small (eg, 2 mm) if 
possible.  
• 
Any non-nodal target lesion that become ‘too small to measure’ a default value of 
5 mm should be assigned.  If the lesion has disappeared, 0 mm should be recorded. 
• 
Any nodal target lesion that become ‘too small to measure’ a default value of 5 mm 
should be assigned for its short axis.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
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• 
Coalescing lesions:  If a plane is maintained in aiding the demarcation of the 
2 lesions, then the maximal diameter of each individual lesion should be recorded.  If 
the lesions have truly coalesced, then the longest diameter should be used for the 
coalesced lesion and assigned to the largest of the coalesced lesions.  The smaller 
of the lesions then should be recorded as 0 mm.  If target lesion(s) coalesces with 
non-target lesion(s), the longest diameter should be used for the coalesced lesions 
and assigned to the largest of the coalesced target lesion(s).  If a target lesion 
merges with a non-target lesion, the non-target lesion should be absent from the 
current visit and all future assessments, and the target lesion should include both 
merged lesions for recording measurements.  New lesions and enlarging non-target 
lesions are measured qualitatively. 
• 
Splitting lesions:  When a target lesion splits into 2 or more lesions, the largest 
measurable part of the split lesion should be considered to be the previously 
recorded target lesion with measurements provided for the current assessment and 
followed for future assessments.  The dimensions of the split parts would still be 
target lesions.  Any new lesions that result from separating should be documented as 
lesions that were generated by separating and not truly “new” lesions.  
Non-Target Lesions 
• 
Coalescing lesions:  When 2 or more non-target lesions merge, the smaller lesion 
should be recorde 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.   
• 
Splitting lesions:  When a non-target lesion splits into 2 or more lesions, the split 
parts remain non-target lesions for the duration of the study.  Any new lesions that 
result from separating should be documented as lesions that were generated by 
separating and not truly new lesions. 
• 
In contrast to irRECIST, to achieve progression of disease of non-target lesions, 
‘unequivocal progression’ of these lesions must be documented on the basis that  
there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  A modest increase in the 
size or “qualitative worsening” as described for irRECIST assessment would not 
suffice to achieve ‘unequivocal progression’ status per RECIST v1.1. 
New Lesions 
• 
A new lesion should be unequivocal.  If a new lesion is equivocal, continued therapy 
and follow-up evaluation should ensue until it is clear that it represents a new lesion, 
then progression should be declared using the date of the initial scan. 
• 
Appearance of new malignant lesions on a follow up study in an anatomical location 
that was not scanned at baseline is considered a new lesion and will indicate disease 
progression.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 157 of 158 
CONFIDENTIAL 
 
 
Subjects who have had Complete or Partial Removal/Reduction of the Lesion will be 
Evaluated as Follows: 
• 
The procedure itself and all post-procedure lesion assessments should always be 
recorded in the CRF.  A completely resected lesion should be assigned a default 
code of 0 mm (for target lesions) or “absent” (for non-target lesions).  A partially 
resected lesion should be assigned its measurement post-procedure (for target 
lesions) or “present” (for non-target lesions).  If the resected lesion contains 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 contains cancer or pathology results are unknown, the recorded 
tumor assessments post-procedure may be used for tumor burden calculations, but 
determination of response will be considered unable to evaluate (UE) for response 
except in the case of PD.  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. 
Evaluation of visit overall response 
A summary of the overall response determination at each evaluation time point is 
provided in Table 16. 
Table 16.  Matrix for Determining the Overall Response at Each Assessment Point 
for RECIST v1.1 
Target Lesions 
Non-target Lesions 
New Lesions 
Visit overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
UE/ND 
No 
PR 
CR 
NA 
No 
CR 
PR 
Non-PD/NA/UE/ND 
No 
PR 
SD 
Non-PD/NA/UE/ND 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
UE 
Non-PD/NA 
No 
UE 
ND 
Non-PD/NA 
No 
UE 
CR = complete response; NA = no non-target lesions at baseline; PD = progressive disease; PR = partial 
response; SD = stable disease 
Non-/CR/Non-PD : Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits; UE = unevaluable 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  11 May 2018 
Page 158 of 158 
CONFIDENTIAL 
 
 
Appendix F.  Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to a bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair 
5 
Dead 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 1 of 11 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Phase 1b/3 Multicenter, Randomized Trial of Talimogene 
Laherparepvec in Combination With Pembrolizumab for the Treatment of Subjects 
With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
 
Amgen Protocol Number TVEC 20130232 
EudraCT number 2015-003011-38 
 
Amendment Date: 
11 May 2018 
Rationale: 
This protocol is being amended to: 
• 
Add language to clarify long term follow-up for subjects in phase 1b due to decision 
to not proceed to the phase 3 part of the study 
• 
Remove PK and ADA samples from phase 1b portion of protocol per discussion with 
FDA, EMA, and PDMA (Merck request). 
• 
Update End of Study language to align with most recent Amgen template text and to 
include the definition of Primary Completion and End of Trial for subjects who 
completed phase 1b 
• 
Include a follow-up analysis for phase 1b 
• 
Add text providing guidance about latex allergies to exclusion criteria no. 223 
• 
Update serious adverse event reporting procedures to align with current safety 
language 
• 
Update pembrolizumab safety language regarding pregnancy reporting and 
breastfeeding 
• 
Update Key Sponsor Contacts 
• 
Make administrative and editorial changes 


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Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 3 of 11 
CONFIDENTIAL 
 
 
Section:  Synopsis, Study Design, paragraph 3 
Replace: 
Subjects will be followed for survival, subsequent anticancer therapies and talimogene 
laherparepvec/placebo related adverse events every 12 weeks from safety follow-up visit  
(± 28 days) for approximately 36 months after the last subject is randomized in phase 3. 
With: 
Subjects will be followed for survival, subsequent anticancer therapies and talimogene 
laherparepvec/placebo related adverse events every 12 weeks from safety follow-up visit 
(± 28 days) for approximately 36 months after the last subject is enrolled.   
Section:  Synopsis, Statistical Considerations, paragraph 3 
Delete: 
Summaries of the incidence of DLTs will be provided.  Descriptive statistics will be 
provided for efficacy, safety, PK, antibodies, talimogene laherparepvec DNA, and 
biomarker endpoints as appropriate. 
Section:  Synopsis, Statistical Considerations, paragraph 10 
Add: 
For the phase 1b part of the study, the primary analysis will be repeated 1 year 
after the last subject enrolled. 
Section:  Phase 3 Study Design and Treatment Schema, footnote d 
Delete: 
d Long-term follow-up every 12 weeks (± 28 days) from safety follow-up visit until 
approximately 36 months after last subject enrolled in phase 3.  Talimogene 
laherparepvec/placebo related adverse events that occur after the safety follow-up visit 
through the end of the long-term follow-up will be reported. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 4 of 11 
CONFIDENTIAL 
 
 
Section:  Study Glossary  
Replace: 
End of Study (primary 
completion) 
defined as when the last subject is assessed or receives an intervention 
for the purposes of final collection of data for the primary endpoint of 
phase 3.  The primary completion is anticipated to occur when 
approximately 336 deaths occur in phase 3.   
With: 
End of Study (primary 
completion) 
Primary Completion:  defined as when the last subject is assessed or 
receives an intervention for the purposes of final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early.  
Primary Completion Phase 1b only:  The time when the last 
phase 1b subject is assessed or receives an intervention for the 
purposes of final collection of data for the primary efficacy 
endpoint of phase 1b.  The primary completion is anticipated to 
occur when the last phase 1b subject completes the week 9 tumor 
response assessment. 
Section:  Study Glossary  
Replace: 
End of Study (end of 
trial) 
defined as when the last subject is assessed or receives an intervention 
for evaluation in the study.  This is anticipated to occur 36 months after 
the last subject is randomized in phase 3. 
With: 
End of Study (end of 
trial) 
defined as 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.  This is anticipated to occur 36 months after 
the last subject is enrolled. 
Section:  1.3 Exploratory  
Delete: 
• 
To evaluate the incidence of anti-pembrolizumab antibodies when 
pembrolizumab is administered in combination with talimogene laherparepvec 
• 
To evaluate the pharmacokinetics (PK) of pembrolizumab when administered in 
combination with talimogene laherparepvec 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 5 of 11 
CONFIDENTIAL 
 
 
Section:  3.1.4.2 Long-Term Follow-up, paragraph 1 
Delete: 
Subjects will be followed for survival and subsequent anticancer therapies every 
12 weeks (± 28 days) from safety follow-up for approximately 36 months after the last 
subject is enrolled in phase 3. 
Section:  3.5.1 Study Duration for Subjects 
Replace: 
During this period, subjects will be followed for survival for approximately 36 months 
after the last subject is randomized in phase 3.   
With: 
During this period, subjects will be followed for survival for approximately 36 months 
after the last subject is enrolled.   
Section:  3.5.2 End of Study 
Replace: 
Primary Completion:  The time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis; the 
primary completion is anticipated to occur when approximately 336 deaths occur in 
phase 3 among subjects included in the primary OS analysis. 
End of Trial:  The time when the last subject is assessed or receives an intervention for 
evaluation in the study.  This is anticipated to occur 36 months after the last subject 
included in the primary OS analysis is randomized in phase 3. 
With: 
Primary Completion:  The primary completion date is defined as the date when the 
last subject is assessed or receives an intervention for the final collection of data 
for the primary endpoint(s), for the purposes of conducting the primary analysis, 
whether the study concluded as planned in the protocol or was terminated early.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 6 of 11 
CONFIDENTIAL 
 
 
If a 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). 
Primary Completion Phase 1b only:  The time when the last phase 1b subject is 
assessed or receives an intervention for the purposes of final collection of data 
for the primary efficacy endpoint of phase 1b.  The primary completion is 
anticipated to occur when the last phase 1b subject completes the week 9 tumor 
response assessment. 
End of Study (end of trial):  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.  This is anticipated to occur 36 months after 
the last subject is enrolled. 
Section:  4.2 Exclusion Criteria, Criterion no. 223 
Add: 
223. 
Sexually active subjects or their partners unwilling to use male or female latex 
condom to avoid potential viral transmission during sexual contact while on treatment 
and within 30 days after treatment with talimogene laherparepvec/placebo.  For those 
with latex allergies, polyurethane condoms may be used. 
Section:  6.2.2.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation, Table 3 
Add: 
AST/ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Permanently discontinue, 
if: 
AST or ALT > 3x ULN; and 
total bilirubin > 2 x ULN; 
and no other cause for the 
combination of laboratory 
abnormalities is 
immediately apparent (see 
Section 6.4.1) 
Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Monitor with liver 
function tests 
(consider weekly or 
more frequently 
until liver enzyme 
value returned to 
baseline or is 
stable 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 7 of 11 
CONFIDENTIAL 
 
 
Section:  6.2.3.3.3 Use of Pembrolizumab in Pregnancy  
Replace: 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to 
the mother or newborn).  The study investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the fetus 
or newborn to the sponsor. 
With: 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The pregnancy and the outcome 
of the pregnancy will be reported to Amgen and followed as described in 
Section 9.3 (Pregnancy and Lactation Reporting). 
Section:  6.2.3.3.4 Use of Pembrolizumab in Nursing Women 
Add: 
If a female subject breastfeeds while taking pembrolizumab, report the lactation 
case to Amgen as described in Section 9.3 (Pregnancy and Lactation Reporting). 
Section:  Table 5.  Schedule of Assessments for Phase 1b 
Delete 
Blood for Anti-
Pembrolizuma
b antibodyl 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood for 
Pembrolizuma
b PKm 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Section:  Table 5.  Schedule of Assessments for Phase 1b, abbreviations 
Delete: 
PK = pharmacokinetics 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 8 of 11 
CONFIDENTIAL 
 
 
Section:  Table 5.  Schedule of Assessments for Phase 1b, footnotes l and m 
Delete: 
l Blood for anti-pembrolizumab antibody (also termed immunogenicity) will be collected at 
week 0 (ie, cycle 1 of pembrolizumab), week 3 (ie, cycle 2 of pembrolizumab), week 9 
(ie, cycle 4 of pembrolizumab), week 15 (ie, cycle 6 of pembrolizumab), week 21 (ie, 
cycle 8 of pembrolizumab) and every 12 weeks (4 cycles of pembrolizumab) thereafter 
starting at week 33 (ie, cycle 12 of pembrolizumab), at safety follow-up visit (30 [+7] 
days after discontinuation of study treatment), and again 3 and 6 months after 
discontinuation of study treatment or until the subject starts new anticancer treatment, 
whichever is first.  All samples should be drawn within 24 hours before infusion of 
pembrolizumab and at the same time as pre dose trough blood collection for the PK 
sample. 
m Blood for PK of pembrolizumab: Predose trough and post-dose peak PK samples will 
be collected at week 0 (ie, cycle 1 of pembrolizumab).  Pre-dose trough samples only 
will be collected at week 3 (ie, cycle 2 of pembrolizumab), week 9 (ie, cycle 4 of 
pembrolizumab), week 15 (ie, cycle 6 of pembrolizumab), week 21 (ie, cycle 8 of 
pembrolizumab) and every 12 weeks (4 cycles) thereafter, starting at week 33 (ie, 
cycle 12 of pembrolizumab), at safety follow-up visit (30 [+7] days after discontinuation 
of study treatment), and again 3 and 6 months after discontinuation of study treatment 
or until the subject starts new anticancer treatment, whichever is first.  All trough 
samples should be drawn within 24 hours before infusion of pembrolizumab.  The peak 
sample should be drawn within 30 minutes after the end of the infusion. A one-time PK 
sample should also be drawn between 48 to 168 hours after week 0 (ie, cycle 1) 
dosing.   
Section:  7.2.6 Long term Follow-up, paragraph 2 
Add: 
Contact for all subjects will be attempted every 12 weeks (± 28 days) following the safety 
follow-up visit until death, subject withdraws full consent, or up to 36 months after the 
last subject is enrolled/randomized that is included in the primary OS analysis, 
whichever comes first.  Anticancer therapies for SCCHN and talimogene 
laherparepvec/placebo related adverse events that occur through the end the long term 
follow-up will be reported.  The phase 1b subjects will be followed for approximately 
36 months after the last subject is enrolled.   
Section:  7.2.6 Long term Follow-up, paragraph 4 
Delete: 
They should continue into the long-term follow-up and be followed for survival and 
subsequent anticancer therapies every 12 weeks (± 28 days) for approximately 
36 months after the last subject is enrolled in phase 3.   


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 9 of 11 
CONFIDENTIAL 
 
 
Section:  8.1 Subjects’ Decision to Withdraw, paragraph 4 
Delete: 
Those subjects who discontinue investigational product should continue into the 
long-term follow-up.  Subjects will be followed for survival and subsequent anticancer 
therapies every 12 weeks (± 28 days) for approximately 36 months after the last subject 
is enrolled in phase 3.   
Section:  9.2.2.2 Reporting Procedures for Serious Adverse Events, paragraph 1 
Replace: 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 90 (+7) days after the cessation of all study treatment or 30 (+7) days 
following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier are recorded in the subject’s medical record and are submitted to the sponsor. 
Additionally, all study drug related serious adverse events that occur after the safety 
follow-up visit through the end of the long-term follow-up will be reported.  Any serious 
adverse event, or follow-up to a serious adverse event, including death due to any cause 
other than progression of the cancer under study (refer to Section 9.1.3 for additional 
details) that occurs to any subject must be reported within 24 hours to the sponsor if it 
causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure. 
With: 
The investigator is responsible for ensuring that all serious adverse events, 
follow-up to a serious adverse event, including death due to any cause other than 
progression of the cancer under study, observed by the investigator or reported 
by the subject that occur after signing of the informed consent through 
90 (+7) days after the last dose of talimogene laherparepvec or pembrolizumab, or 
30 (+7) days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, are recorded in the subject’s medical 
record and are submitted to Amgen.  Additionally, all study drug-related serious 
adverse events that occur during the long-term safety follow-up period until the 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 10 of 11 
CONFIDENTIAL 
 
 
end of study should also be captured in the Event CRF although these events will 
not be considered treatment-emergent adverse events. 
All serious adverse events must be submitted to the sponsor within 24 hours 
following the investigator’s knowledge of the event via the Event CRF. 
Section:  10.1.1.3 Exploratory Endpoints, Phase 1b 
Delete: 
• 
Subject incidence of anti-pembrolizumab antibodies 
• 
Serum concentration of pembrolizumab 
Section:  10.1.3 Covariates and Subgroups 
Add: 
• 
HPV status (positive vs negative vs unknown) (phase 1b) 
Section:  10.2.2 Sample Size Considerations for Phase 3, paragraph 2 
Replace: 
Median OS (pembrolizumab) = 8.4 months; p(t) = event rate at month t; p(12) = 0.373, 
p(24)= 0.15, p(36)=0.10, p(60)=0.05, and p(80)=0.04 constant hazard in each interval 
between 5 consecutive pieces; a constant hazard ratio across all pieces. 
With: 
Median OS (pembrolizumab) = 8.4 months; p(t) = survival rate at month t; 
p(12) = 0.373, p(24)= 0.15, p(36)=0.10, p(60)=0.05, and p(80)=0.04 constant hazard in 
each interval between 5 consecutive pieces; a constant hazard ratio across all pieces. 
Section:  10.4.6 Follow-Up Analysis for Phase 1b 
Add: 
10.4.6 Follow-Up Analysis for Phase 1b 
For the phase 1b part of the study, the primary analysis will be repeated 1 year 
after the last subject enrolled. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232  
Date:  11 May 2018 
Page 11 of 11 
CONFIDENTIAL 
 
 
Section:  10.4.7 Final Analysis 
Replace: 
10.4.6 Final Analysis 
The final analysis of the study will be conducted after the last subject enrolled in phase 3 
has had the opportunity to complete the long-term follow-up (i.e, 36 months after the last 
subject is randomized in the FAS(G).  
With: 
10.4.7 Final Analysis 
The final analysis of the study will be conducted after the last subject enrolled has had 
the opportunity to complete the long-term follow-up (ie, 36 months after the last subject 
is enrolled in the FAS.  
Section:  10.5.1 General Considerations, paragraph 4 
Delete: 
Descriptive statistics will be provided for efficacy, safety, PK, antibodies, talimogene 
laherparepvec DNA, and biomarker endpoints as appropriate for phase 1b and phase 3 
part of the study. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  25 October 2017 
Page 1 of 100 
CONFIDENTIAL
Amendment 3 
Protocol Title:  A Phase 1b/3 Multicenter, Randomized Trial of Talimogene 
Laherparepvec in Combination With Pembrolizumab for the Treatment of Subjects 
With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
Amgen Protocol Number (Talimogene Laherparepvec) 20130232 
EudraCT number 2015-003011-38 
Rationale: 
This protocol is being amended to: 
•
Add the investigator-assessed RECIST v1.1 secondary tumor response
endpoints of objective response rate (ORR) and progress-free survival (PFS) as
secondary endpoints and remove Complete Response Rate (CRR) per irRECIST
as a secondary endpoint.  Complete Response Rate (CRR) per irRECIST was
removed as a secondary endpoint.
•
Replace EQ-5D-3L with EQ-5D-5L to utilize the most recent PRO version
•
Revised exclusion criteria regarding re-irradiation
•
Replaced modified RECIST v1.1 of 10 maximum lesions with 5 per organ with
standard RECIST v1.1 for screening (5 maximum lesions with 2 per organ) to
align with the use of standard RECIST v1.1 introduced for key secondary
endpoints.
•
Added RECIST v1.1 assessment in addition to irRECIST assessment for
response assessment.
•
The set of secondary hypotheses to be tested with the Maurer-Bretz procedure
was revised to potentially generate more robust efficacy conclusions.  Testing of
CRR was replaced with ORR.  Testing was added for RECIST v1.1 ORR and
PFS.  The total number of potential hypotheses tested as a result increased from
3 to 5.
•
The number of events at the OS interim analysis was increased from
approximately 255 to 280 to preserve 70% power in the event of a potential
treatment lag effect.
•
Sample size considerations were revised due to the OS interim analysis change
and to discuss the power for the revised secondary hypothesis tests.
•
The OS futility criterion at the interim analysis was changed from a conditional
power < 10% given a true HR of 0.70 to an observed HR > 0.92 considering a
potential treatment lag effect.
•
An audit-based Blind Independent Central Review (BICR) was added to assess
the consistency of investigator- and BICR-assessed treatment effects for
RECIST v1.1 ORR and PFS.


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  25 October 2017 
Page 2 of 100 
CONFIDENTIAL 
 
• 
The definition of the phase 3 primary efficacy and safety analysis sets, primary 
completion, and end of trial were revised to maintain the study’s statistical 
considerations.   
• 
Updated language on disease related events and reporting procedures – per 
internal Amgen recommendations. 
• 
Updated language on disease related events and reporting procedures to align 
across program. 
• 
Made minor administrative changes, text clarifications, and edits throughout the 
protocol. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  05 January 2017 
Page 1 of 103 
Amendment 2 
Protocol Title:  A Phase 1b/3 Multicenter, Randomized Trial of Talimogene 
Laherparepvec in Combination With Pembrolizumab for the Treatment of Subjects 
With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
Amgen Protocol Number (Talimogene Laherparepvec) 20130232 
Rationale: 
This protocol is being amended to: 
• 
Update eligibility criteria triggered by recent safety signal – carotid blowout 
syndrome, and efficacy signal – lack of benefit in primary refractory patients with 
progressive disease within 3 months of curative intent multimodality therapy. 
• 
Remove progression free survival as a primary endpoint for phase 3 and make it 
a secondary endpoint, along with CRR 
o The decision to forego of PFS as a dual primary endpoint hinged upon a 
few factors which included: the recent outcome of CHECKMATE 141 
which led to approval of nivolumab based upon OS and also the final 
approval or pembrolizumab which is dependent upon OS from KEYNOTE 
040.  Considering the fact that OS is a superior outcome measure of a 
treatment over PFS especially in a poor prognosis disease and that PFS 
is not always a surrogate for OS, combined with the precedent set by 
nivolumab approval on OS, we felt that PFS did not have a truly 
meaningful role in the assessment of the efficacy of 
TVEC+pembrolizumab in second line head and neck cancer as well as for 
regulatory purposes.   
• 
Add the use of irRECIST investigator assessment for response assessments and 
remove RECIST 1.1 central review. 
• 
Update QOL/PRO wording and elevation of QLQ C30-3L to secondary endpoint 
from exploratory. 
• 
Update statistical methods to justify the endpoint changes and also to introduce 
OS IA and futility analyses. 
• 
To add more detail around go no go decision from Phase 1b to 3. 
• 
Add additional pembrolizumab background information. 
• 
Add additional talimogene laherparepvec background information. 
• 
Update IP discontinuation/withholding rules. 
• 
Update radiographic tumor assessments (sites of disease, spiral CT). 
• 
Add additional information for archival tumor tissue. 
• 
Add additional information for HPV testing. 
• 
Update safety reporting information. 
• 
Administrative changes and editorial changes for clarification. 
CONFIDENTIAL 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  28 June 2016 
Page 1 of 145 
CONFIDENTIAL 
Amendment 1 
Protocol Title:  A Phase 1b/3 Multicenter, Randomized Trial of Talimogene 
Laherparepvec in combination with Pembrolizumab for the Treatment of Subjects 
With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
Amgen Protocol Number Talimogene Laherparepvec [AMG678] 20130232 
EudraCT Number 2015-003011-38 
Amendment Date: 
07 June 2016 
Superseding Amendment 
28 June 2016 
Rationale: 
The protocol is amended primarily so that an injectable placebo may be added to 
pembrolizumab in the control arm and to convert the study from open-label to 
double-blind in phase 3.  This is necessary in order to reduce the bias of having 
intralesional injections in only 1 arm of the study. 
The following key changes have been incorporated into protocol amendment 1: 
•
Updated key contacts
•
Changed phase 3 portion of study to be double-blind and added placebo to the
pembrolizumab arm.
•
Reordered sections to separate phase 1b and phase 3 in the synopsis,  and general
study procedures sections in order to more clearly delineate which sections are 
specific to each phase of the study.  Additionally, to reduce the number of footnotes, 
reorganized Section 7 to provide more description to study procedures.
•
Updated background information for talimogene laherparepvec and pembrolizumab
to reflect recent publications or presentations and approvals.
•
Updated biopsy requirements in inclusion criteria
•
Removed biodistribution and shedding at select sites in phase 3 as we will have
sufficient data from phase 1
•
Removed PD-L1 status as a stratification factor
•
Removed registry study option
•
Updated contraception language for exclusion criterion and also sections related to
pembrolizumab. This is to align with other pembrolizumab protocols.
•
Added exclusion criteria for active tuberculosis in order to align with other
pembrolizumab protocols.
•
Updated text related to pembrolizumab, rescue medications, dose adjustment,
overdose, and supportive care guidelines to align with other pembrolizumab
protocols.
•
Updated pregnancy and lactation reporting language to align with other talimogene
laherparepvec and pembrolizumab protocols.


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  28 June 2016 
Page 2 of 145 
CONFIDENTIAL 
•
Updated language to clarify the modified response criteria in the appendices
(eg, how to evaluate separated lesions, criteria for confirmation of PD).
•
Added optional photography substudy
Additional errors were identified and rectified in the superseding amendment, and 
administrative errors were corrected. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20130232 
Date:  07 June 2016 
Page 1 of 145 
CONFIDENTIAL 
Amendment 1 
Protocol Title:  A Phase 1b/3 Multicenter, Randomized Trial of Talimogene 
Laherparepvec in combination with Pembrolizumab for the Treatment of Subjects 
With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
Amgen Protocol Number Talimogene Laherparepvec [AMG678] 20130232 
EudraCT Number 2015-003011-38 
Amendment Date: 
07 June 2016 
Rationale: 
The protocol is amended primarily so that an injectable placebo may be added to 
pembrolizumab in the control arm and to convert the study from open-label to 
double-blind in phase 3.  This is necessary in order to reduce the bias of having 
intralesional injections in only 1 arm of the study. 
The following key changes have been incorporated into protocol amendment 1: 
•
Updated key contacts
•
Changed phase 3 portion of study to be double-blind and added placebo to the
pembrolizumab arm.
•
Reordered sections to separate phase 1b and phase 3 in the synopsis,  and general 
study procedures sections in order to more clearly delineate which sections are 
specific to each phase of the study.  Additionally, to reduce the number of footnotes, 
reorganized Section 7 to provide more description to study procedures.
•
Updated background information for talimogene laherparepvec and pembrolizumab
to reflect recent publications or presentations and approvals.
•
Updated biopsy requirements in inclusion criteria
•
Removed biodistribution and shedding at select sites in phase 3 as we will have
sufficient data from phase 1
•
Removed PD-L1 status as a stratification factor
•
Removed registry study option
•
Updated contraception language for exclusion criterion and also sections related to
pembrolizumab. This is to align with other pembrolizumab protocols.
•
Added exclusion criteria for active tuberculosis in order to align with other
pembrolizumab protocols.
•
Updated text related to pembrolizumab, rescue medications, dose adjustment,
overdose, and supportive care guidelines to align with other pembrolizumab
protocols.
•
Updated pregnancy and lactation reporting language to align with other talimogene
laherparepvec and pembrolizumab protocols.
•
Updated language to clarify the modified response criteria in the appendices (eg,
how to evaluate separated lesions, criteria for confirmation of PD).
•
Added optional photography substudy