Clinical trial NCT02509507
Conditions: Hepatocellular Carcinoma Liver Metastases Cutaneous or Subcutaneous Lymph Node Liver Tumors
Keywords: Liver tumours
Sponsor: Amgen
Start date: 2016-02-05; Completion date: 2023-07-11
Enrollment: 127 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a phase 1b/2, multicenter, open-label, basket trial to evaluate the safety of talimogene laherparepvec injected intrahepatically into liver tumors alone and in combination with systemic intravenous (IV) administration of pembrolizumab, in subjects with non-hepatocellular carcinoma (HCC) liver metastases from breast adenocarcinoma (BC), colorectal adenocarcinoma (CRC), gastroesophageal cancer (GEC), melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (RCC) in Part 1 Group A, and subjects with HCC with and without viral hepatitis in Part 1 Group B (viral hepatitis is only applicable in combination setting), and to evaluate the efficacy and safety of intratumoral talimogene laherparepvec in combination with systemic pembrolizumab in subjects with advanced triple negative breast cancer (TNBC), hormone receptor positive breast cancer, CRC, cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC) in Part 2 Group A and subjects with HCC with and without viral hepatitis in Part 2 Group B. The objective of Part 1 is to evaluate the safety of intrahepatic injection of talimogene laherparepvec into liver tumors alone and in combination with systemically administered pembrolizumab for the non-HCC (Group A) and HCC (Group B) cohorts separately. Part 2 consists of 2-stage design to evaluate the efficacy and safety of talimogene laherparepvec in combination with systemic pembrolizumab. Efficacy and safety will be evaluated in each of the five non-HCC tumor types from Group A separately. Similarly, the efficacy and safety of the combination treatment will be determined for Group B HCC subjects. As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study. Enrollment for this study has stopped.

Detailed description:

Arms: arm 1: Talimogene Laherparepvec arm 2: Combination treatment of Talimogene Laherparepvec and Pembrolizumab
Interventions: intervention 1: Talimogene Laherparepvec intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Talimogene laherparepvec (T-VEC) administered by intralesional injection into liver tumors, with ultrasound/computed tomography (US/CT) guidance. Part 1: initial dose of T-VEC is 10\^6 plaque forming unit (PFU)/mL up to 4mL in Cohorts 1 \& 2, up to 8mL in Cohorts 3 \& 4 of the Group A \& Group B. The 1st cycle of T-VEC will be 21 (+3) days (from the 1st dose at 10\^6 PFU/mL to the 2nd dose at 10\^7 or 10\^8 PFU/mL). Subsequent cycles of T-VEC will be 21 (±3) days. Max. volume of T-VEC administered at any dose is 4mL (Cohorts 1, 2, 5, and 6) or 8mL (Cohorts 3 \& 4) for any individual lesion or for all lesions combined. Part 2: Initial dose of T-VEC is 10\^6 PFU/mL followed by subsequent T-VEC doses at a concentration of 10\^8 PFU/mL. T-VEC volume is up to 8mL based on the size of the inejected lesions. NOTE: as of Protocol Amendment 6 \[dated 26 October 2021\], intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study. intervention 2: Pembrolizumab is a non-Amgen Investigational product that is 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/4 mL vials (25 mg/mL) solution for IV infusion. The trial treatment will consist of a total dose of 200mg administered intravenously every 3 weeks (day 1 of each cycle) for up to 35 cycles.

Protocol documents:
Prot_000.pdf: 
Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 1 of 196 
CONFIDENTIAL 
 
 
Title:  A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the Safety of 
Talimogene Laherparepvec Injected into Liver Tumors Alone and in Combination 
With Systemic Pembrolizumab in Phase 1b and to Evaluate the Efficacy and 
Safety of Intratumoral Talimogene Laherparepvec in Combination With Systemic 
Pembrolizumab to Treat Subjects With Advanced Solid Tumors in Phase 2 
(MASTERKEY-318) 
 
Amgen Protocol Number (Talimogene Laherparepvec 20140318) 
EudraCT number:  2014-005386-67 
NCT number:  NCT02509507 
Clinical Study Sponsor: 
Amgen, Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 1-805-447-1000 
Key Sponsor Contacts: 
, PhD 
Clinical Research Medical Director 
Telephone:
Email:  
 
Date: 
27 March 2015 
Amendment 1 Date:    
26 April 2016 
Amendment 2 Date: 
18 October 2017 
Amendment 3 Date: 
21 October 2019 
Amendment 4 Date: 
30 June 2020 
Amendment 5 Date:  
02 July 2021 
Amendment 6 Date: 
26 October 2021 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6). 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 2 of 196 
CONFIDENTIAL 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:   USA sites, 1- 800-77-AMGEN, for all other 
countries, 1-805-447-1000.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 3 of 196 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1b/2, Multicenter, Open-label, Basket 
Trial to Evaluate the Safety of Talimogene Laherparepvec Injected into Liver Tumors 
Alone and in Combination With Systemic Pembrolizumab in Phase 1b and to Evaluate 
the Efficacy and Safety of Intratumoral Talimogene Laherparepvec in Combination with 
Systemic Pembrolizumab to Treat Subjects with Advanced Solid Tumors in Phase 2 
(MASTERKEY-318), dated 26 October 2021, and agree to abide by all provisions set 
forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 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:  20140318 
Date:  26 October 2021 
Page 4 of 196 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the Safety of Talimogene 
Laherparepvec Injected into Liver Tumors Alone and in Combination with Systemic 
Pembrolizumab in Phase 1b and to Evaluate the Efficacy and Safety of Intratumoral Talimogene 
Laherparepvec in Combination with Systemic Pembrolizumab to Treat Subjects with Advanced 
Solid Tumors in Phase 2 (MASTERKEY-318) 
Study Phase:  1b/2  
Indication:   
Part 1 (NOTE:  as of Protocol Amendment 6 [dated 26 October 2021], intrahepatic 
injections of talimogene laherparepvec and liver biopsies are no longer performed in this 
study):   
Intrahepatic injection of talimogene laherparepvec into metastatic liver tumors (non-HCC) and 
hepatocellular carcinoma (HCC)  
Part 2: 
Intratumoral injection of talimogene laherparepvec into cutaneous, subcutaneous, lymph node, or 
liver tumors  
Primary Objectives:   
Part 1 (NOTE:  as of Protocol Amendment 6 [dated 26 October 2021], intrahepatic 
injections of talimogene laherparepvec and liver biopsies are no longer performed in this 
study):   
To evaluate the following, as assessed by the incidence of dose-limiting toxicities (DLTs), in 
subjects with liver metastases (non-hepatocellular carcinoma [HCC]) and subjects with primary 
HCC in: 
 
Monotherapy Cohorts:  the maximum tolerated volume and concentration (MTV and MTC) of 
intrahepatic injection of talimogene laherparepvec into liver tumors in subjects with non-HCC 
and subjects with primary HCC without active viral hepatitis 
 
Combination Cohorts:  the MTC of intrahepatic injection of talimogene laherparepvec into 
liver tumors in combination with systemic intravenous (IV) administration of pembrolizumab in 
subjects with non-HCC, and subjects with primary HCC with or without viral hepatitis 
Part 2:   
 
To evaluate the efficacy, as assessed by objective response rate (ORR) of intratumoral 
injection of talimogene laherparepvec in combination with systemic IV administration of 
pembrolizumab, separately, for each non-HCC tumor type (hormone receptor positive breast 
adenocarcinoma [BC], triple negative breast cancer [TNBC], colorectal adenocarcinoma 
[CRC], cutaneous squamous cell carcinoma (CSCC)], basal cell carcinoma [BCC], as well as 
primary HCC with and without viral hepatitis. 
 
To evaluate safety separately for each tumor type as assessed by subject incidence of 
treatment-emergent and treatment-related adverse events, including DLTs 
Secondary Objectives:  The secondary objectives of the study are as follows: 
EFFICACY: 
Part 1:   
To evaluate the efficacy separately by monotherapy versus combination for non-HCC tumors and 
HCC with and without viral hepatitis when applicable as assessed by: 
 
ORR, best overall response (BOR), durable response rate (DRR), duration of response 
(DOR), response in injected and uninjected lesions, disease control rate (DCR), 
progression-free survival (PFS), and overall survival (OS) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 5 of 196 
CONFIDENTIAL 
 
 
Part 2:   
 
To evaluate the efficacy in individual tumor types in the non-HCC group and HCC group with 
and without viral hepatitis as assessed by: 
- 
BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and OS by 
primary tumor type (TNBC, Hormone receptor positive BC, CRC, CSCC, BCC, and HCC 
with and without viral hepatitis) 
SAFETY (Parts 1 and 2) 
 
To evaluate the safety in each monotherapy and combination cohorts in Part 1 and each arm 
separately in Part 2, as assessed by subject incidence of treatment-emergent and 
treatment-related adverse events  
 
To estimate the incidence of detectable talimogene laherparepvec deoxyribonucleic acid 
(DNA) in blood and urine 
 
To estimate the incidence of clearance of talimogene laherparepvec DNA from blood and 
urine 
 
To estimate the rate of detection (per sample) and incidence (per subject) of talimogene 
laherparepvec DNA and virus at the surface of talimogene laherparepvec injection site, the 
exterior of occlusive dressing, and the oral mucosa 
 
To estimate the incidence of talimogene laherparepvec DNA detection in lesions suspected 
to be herpetic in origin 
Clinical Hypotheses: 
Part 1:   
Monotherapy cohorts 1-4:  Talimogene laherparepvec injected intrahepatically into liver tumors 
will be safe in subjects with non-HCC with liver metastases and subjects with HCC without active 
viral hepatitis as assessed by subject incidence of DLTs. 
Combination cohorts 5 and 6:  Talimogene laherparepvec injected intrahepatically into liver 
tumors in combination with systemically administered pembrolizumab will be safe in subjects with 
non-HCC with liver metastases and subjects with HCC with and without viral hepatitis. 
Part 2: 
Talimogene laherparepvec injected intratumorally in combination with systemic IV administration 
of pembrolizumab will demonstrate at least a 40 ORR in each tumor type and be safe in the 
non-HCC tumor types as well as primary HCC with and without viral hepatitis. 
Primary Endpoint:   
Part 1:   
Monotherapy cohorts 1-4:  Subject incidence of DLTs with intrahepatic injection of talimogene 
laherparepvec into liver tumors in subjects with non-HCC with liver metastases and subjects with 
HCC without active viral hepatitis. 
Combination cohorts 5 and 6:  Subject incidence of DLTs with intrahepatic injection into liver 
tumors of talimogene laherparepvec in combination with systemic IV administration of 
pembrolizumab in subjects with non-HCC with liver metastases and subjects with HCC with and 
without viral hepatitis as assessed by subject incidence of DLTs. 
Part 2:   
 
ORR per the modified immune-related response criteria simulating Response Evaluation 
Criteria in Solid Tumors version 1.1 (irRC-RECIST) with intralesional injection of talimogene 
laherparepvec into cutaneous, subcutaneous, lymph node, and liver tumors in combination 
with systemic IV administration of pembrolizumab separately by tumor type arm (TNBC, 
Hormone receptor positive BC, CRC, CSCC, BCC, and HCC with and without viral hepatitis) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 6 of 196 
CONFIDENTIAL 
 
 
 
Subject incidence for each tumor type of treatment-emergent and treatment-related adverse 
events, including DLTs 
Secondary Endpoints:   
Efficacy: 
Part 1: 
 
ORR, BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and OS 
separately for non-HCC and HCC tumors in monotherapy and combination cohorts 
Part 2:   
 
BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and OS by 
primary tumor type arm (TNBC, Hormone receptor positive BC, CRC, CSCC, BCC, and HCC 
with and without viral hepatitis) 
Safety: 
Parts 1 and 2: 
 
Subject incidence of treatment-related and treatment-emergent adverse events (monotherapy 
and combination cohorts in Part 1, and each tumor type separately in Part 2, and HCC with 
and without viral hepatitis) 
 
Subject incidence of detectable talimogene laherparepvec DNA in blood and urine 
 
Incidence of clearance of talimogene laherparepvec DNA from blood and urine 
 
Subject incidence (per subject) and rate of detection (per sample) of talimogene 
laherparepvec DNA and virus at the surface of injection site, the exterior of occlusive 
dressing, and the oral mucosa 
 
Subject incidence of talimogene laherparepvec DNA detection in lesions suspected to be 
herpetic in origin 
Study Design:  This is a phase 1b/2, multicenter, open-label, basket trial to evaluate the safety of 
talimogene laherparepvec injected intrahepatically into liver tumors alone and in combination with 
systemic IV administration of pembrolizumab, in subjects with non-HCC liver metastases from 
BC, CRC, gastroesophageal cancer (GEC), melanoma, NSCLC, RCC in Part 1 Group A, and 
subjects with HCC with and without viral hepatitis in Part 1 Group B (viral hepatitis is only 
applicable in combination setting), and to evaluate the efficacy and safety of intratumoral 
talimogene laherparepvec in combination with systemic pembrolizumab in subjects with 
advanced TNBC, hormone receptor positive breast cancer, CRC, CSCC, and BCC in Part 2 
Group A and subjects with HCC with and without viral hepatitis in Part 2 Group B.  The study 
consists of 2 parts and 2 groups, and Part 2 includes 2 stages.  
The objective of Part 1 is to evaluate the safety of intrahepatic injection of talimogene 
laherparepvec into liver tumors alone and in combination with systemically administered 
pembrolizumab for the non-HCC (Group A) and HCC (Group B [with and without viral hepatitis; 
viral hepatitis is only applicable in combination setting]) cohorts separately.  NOTE:  as of 
Protocol Amendment 6 [dated 26 October 2021], intrahepatic injections of talimogene 
laherparepvec and liver biopsies are no longer performed in this study.  In the monotherapy 
cohorts (Cohorts 1-4), the safety of administering increasing concentration  
(107 plaque forming unit [PFU]/mL or 108 PFU/mL) and volumes (maximum up to 4 or 8 mL) of 
talimogene laherparepvec will be determined using a standard 3  3 design.  The concentration of 
the first dose of talimogene laherparepvec in all cohorts is always 106 PFU/mL.  Cohort 1 of 
Group B will be initiated only after safety has been established in Cohort 1 of Group A.  
Combination cohorts (Cohorts 5 and 6) in Part 1 will determine the safety of administering 
intrahepatic injection of talimogene laherparepvec at 107 PFU/mL or 108 PFU/mL in sequential 
cohorts (volume up to 4 mL for both doses) in combination with systemic IV administration of 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 7 of 196 
CONFIDENTIAL 
 
 
pembrolizumab (200 mg).  A modified toxicity probability interval (mTPI) up-and-down design will 
be used to determine safety in the combination cohorts.   
Once the MTC is determined from Cohorts 5 and 6, Part 2 will open to evaluate efficacy and 
safety of the combination treatment in the respective tumor types (5 non-HCC tumor types in 
Group A and HCC tumor type in two cohorts [with and without viral hepatitis] in Group B).  Timing 
of opening Part 2 for the non-HCC (Group A) and HCC (Group B) groups will be based on when 
the MTC for talimogene laherparepvec (from the combination cohorts) is determined for the 
respective Groups.  Talimogene laherparepvec will be used at a maximum volume of 8 mL 
(established from monotherapy Cohort 3 in Part 1).  If the safety of administering up to 8 mL from 
the monotherapy cohorts is not established at the time of opening Part 2, newly enrolled subjects 
in Part 2 will be allowed to receive up to a maximum of 8 mL, only if and when, safety of 
administering 8 mL in monotherapy from Part 1 is established.  No intrasubject concentration or 
volume escalation is allowed. 
Cohorts 
in Part 1 
Talimogene 
laherparepvec 
Volume (mL) 
Initial Talimogene 
Laherparepvec 
Concentration (PFU/mL) 
Second and Subsequent 
Talimogene Laherparepvec 
Concentration (PFU/mL) 
Pembrolizumab 
dose (mg) 
1 
4 
106 
107 
n/a 
2a 
4 
106 
108 
n/a 
3b 
8 
106 
108 
n/a 
4c 
8 
106 
107 
n/a 
5 
4 
106 
107 
200 
6d 
4 
106 
108 
200 
DLT  dose-limiting toxicity; n/a  not applicable; PFU  plaque forming unit 
a If Cohort 6 is deemed safe, then cohort 2 will stop enrolling in the respective Group 
b If Cohort is deemed safe in either Group A or B, further enrollment into cohort 3 into either group will be 
suspended, then up to 8 ml will be used in Part 2 for Group A and B. 
c Cohort will be opened only if one of these conditions are met:  1) DLT rate  1/3 in Cohort 2; 
2) DLT rate  1/3 in Cohort 3 and Part 2 dose for talimogene laherparepvec not determined yet; or 
3) DLT rate  1/3 in Cohort 3 and Part 2 concentration for talimogene laherparepvec is determined to be 
107 PFU/mL 
d Includes Group B Cohort 6a and Cohort 6b 
Part 2 consists of 2-stage design to evaluate the efficacy and safety of talimogene laherparepvec 
in combination with systemic pembrolizumab.  Efficacy and safety will be evaluated in each of the 
5 non-HCC tumor types from Group A separately.  Similarly, the efficacy and safety of the 
combination treatment will be determined for Group B HCC subjects with and without viral 
hepatitis.  The primary analysis of efficacy will include subjects that receive any volume of 
talimogene laherparepvec and pembrolizumab.  In Stage 1 of Part 2, enrollment into a tumor type 
(arm) will stop for efficacy analysis when 10 subjects with that tumor type are enrolled.    If 
efficacy for that tumor type is not futile, Stage 2 can open where an additional 11 subjects can be 
enrolled for that tumor type arm.  The Dose Level Review Team (DLRT) will consider prospective 
guidelines to monitor safety in Part 2 separately by tumor type and, if introduced, talimogene 
laherparepvec total volumes  4 mL within Group A and Group B.   
For details on study design, please refer to the Study Design and Treatment Schema and 
Section 3.1. 
Sample Size:  Total number of subjects enrolled in Part 1 and Part 2 of the study is 127 subjects 
(74 subjects in Part 1; 53 subjects in Part 2).  The Part 2 efficacy will include all treated subjects 
who received at least one dose of talimogene laherparepvec and pembrolizumab; therefore, 
dose-limiting toxicity non-evaluable subjects will not be replaced in Part 2. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
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Summary of Subject Eligibility Criteria: 
Key Inclusion Criteria: 
Subjects must be age  18 years at the time of informed consent.  Subjects must have 
histologically or cytologically confirmed disease.   
 
Part 1 is restricted to BC, CRC, GEC, melanoma, NSCLC, or RCC with liver metastases or 
HCC.   
 
Part 2 Group A is restricted to advanced hormone receptor positive BC, CRC, TNBC, CSCC, 
and BCC with or without liver metastases.   
o 
Part 2 Hormone receptor positive Breast Cancer Arm only:  Histologically and/or 
cytologically confirmed diagnosis of estrogen receptor (ER) positive and/or progesterone 
receptor (PrR) positive (ER  1, PrR  1) breast cancer.  
o 
Triple negative breast cancer:  Histologically and/or cytologically confirmed diagnosis of 
ER negative, PR negative, human epidermal growth factor receptor 2 (HER2)-Neu 
negative (ER 1; PR 1; HER2-Neu  3 by immunohistochemistry or fluorescence in 
situ hybridization ratio  2.2 or  6 copies HER2 gene copies/nucleus).   
 
Part 2 Group B is restricted to HCC (fibrolamellar and mixed 
hepatocellular/cholangiocarcinoma subtypes are not eligible).   
For HCC subjects with a diagnosis of hepatitis B, they must be on hepatitis antiviral therapy for at 
least 4 weeks prior to enrollment and HBV viral load by real-time polymerase chain reaction 
(qPCR) must be  100 IU/mL.  HCC subjects with past or ongoing hepatitis C infection must have 
completed treatment for hepatitis C at least 1 month prior to study enrollment and hepatitis C viral 
load must be undetectable; subjects with hepatitis B and C must fulfill the eligibility criteria for 
hepatitis B and hepatitis C.  Subjects with locally recurrent TNBC are eligible.   
Non-HCC subjects must have received at least 1 prior standard of care systemic anti-cancer 
therapy for their locally advanced or metastatic disease.  For the combination cohorts (Cohorts 5 
and 6 in Part 1) and Part 2, subjects with melanoma CSCC or NSCLC do not need to have 
received prior therapy.  In Part 1, subjects must have measurable liver tumors and liver tumors 
that are suitable for injection.  In Part 2, subjects must have measurable disease and cutaneous, 
subcutaneous, lymph node, or liver tumors suitable for injection.  Eastern Cooperative Oncology 
Group (ECOG) performance status must be 0 or 1, and life expectancy should be approximately 
5 months or more.  Adequate hematological, renal, hepatic, and coagulation function is required.  
Liver function tests may be mildly abnormal but within the parameters defined in Section 4.1.1.  
Child-Pugh score must be A. 
Key Exclusion Criteria: 
Subjects must not be candidates for surgery or locoregional therapy with curative intent or 
planned systemic anti-cancer therapy, with the exception of immunotherapy in the combination 
cohorts (Cohorts 5 and 6 in Part 1 and all subjects in Part 2).  Liver tumors must not be 
estimated to invade approximately more than one-third of the liver.  Liver tumor-directed therapy, 
hepatic surgery or major surgery, antibody-based therapy, or immunotherapy must not have 
been performed  28 days, chemotherapy  21 days, and targeted small molecule therapy or 
hormonal therapy  14 days prior to enrollment.  Subjects must either (1) have no central 
nervous system (CNS) metastasis, or carcinomatous meningitis, or (2) if CNS metastasis is 
present, must have stable treated cerebral metastases from BC, NSCLC, RCC, CRC, GEC, or 
melanoma.  Subjects must not have symptomatic auto-immune disease or be symptomatically 
immunosuppressed.  They must not have a history of solid organ transplantation.  For non-HCC, 
there must not be acute or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.  
For HCC with prior hepatitis B and/or C infection, HBV and/or HCV viral load by qPCR must be 
undetectable, and they must not have had recent treatment within 12 weeks for HBV or HCV 
with certain antiviral medications in Part 1 Group B cohorts 1-5 and 6a, and Part 2 Group B HCC 
without viral hepatitis.  For all patients in Part 1 and for patients in Part 2 where intrahepatic liver 
injection is planned (NOTE:  as of Protocol Amendment 6 [dated 26 October 2021], 
intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 9 of 196 
CONFIDENTIAL 
 
 
performed in this study), there should be no macroscopic intravascular invasion of tumors into 
the main portal vein, hepatic vein, or vena cava.  Subjects must not:  have active herpetic skin 
lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis); require 
treatment with an antiherpetic drug; have received live-virus vaccination within 30 days of 
planned treatment start; have previous therapy with talimogene laherparepvec, oncolytic viruses, 
or tumor vaccine.  They must not require concomitant treatment with warfarin.  Subjects in the 
combination treatment cohort must not have:  a history or evidence of psychiatric, substance 
abuse, or any other clinically significant disorder; toxic effects of the most recent prior 
chemotherapy not resolved to grade 1 or less (except alopecia); or expected other cancer 
therapy while on study with the exception of local radiation to the site of bone or other 
metastasis for palliative treatment.  Male subjects of reproductive potential in the combination 
treatment must be willing to use acceptable methods of effective contraception during treatment 
and through 4 months after the last dose of pembrolizumab.   
For a full list of eligibility criteria, please refer to Section 4.1.  
Investigational Product 
In Part 1, talimogene laherparepvec will be administered by image guided injection (either by 
ultrasound [US] or computed tomography [CT] scan) into injectable liver lesions only.  In Part 2, 
talimogene laherparepvec can be administered into liver lesions, lymph nodes, cutaneous or 
subcutaneous lesions (non-hepatic lesions).  As of Protocol Amendment 6 (dated 
26 October 2021), intrahepatic injections of talimogene laherparepvec and liver biopsies 
are no longer performed in this study.  It is mandatory that administration into liver lesions or is 
by image guided injection (either by US or CT scan).  Image guidance may also be used for other 
non-hepatic intratumoral injections.  Dosing concentrations and volumes will be determined 
during dose escalation in Part 1.  The initial concentration for all subjects will be at 106 PFU/mL.  
Twenty-one ( 3) days later, either 107 or 108 PFU/mL will be given.  Subsequent doses will be 
given every 21 days (Q21D;  3 days) thereafter.  The volume will be either up to 4 mL or 8 mL.  
For Part 1, up to 6 doses of talimogene laherparepvec may be administered (including 106 
PFU/mL dose), and there is an investigator option to continue for up to 6 additional doses Q21D 
( 3 days).  Additional cycles of talimogene laherparepvec may be given in combination with 
pembrolizumab in Part 2 if the investigator determines the subject is having clinical benefit and 
approval from the sponsor medical monitor is obtained.  In Part 2, a maximum of 35 cycles of 
talimogene laherparepvec will be administered Q21D ( 3 days).  Talimogene laherparepvec will 
be provided at either 106 PFU/mL or 108 PFU/mL concentrations.  The 107 PFU/mL concentration 
will be prepared from the 108 PFU/mL concentration diluted 1:10.   
See Section 6.2.1 for additional information regarding dosage and administration of talimogene 
laherparepvec. 
Pembrolizumab at a dose of 200 mg will be administered every 3 weeks (Q3W;  3 days) using 
30-minute IV infusion.  When talimogene laherparepvec and pembrolizumab are administered on 
the same day, talimogene laherparepvec should be administered first, if possible. 
Subjects can receive up to 35 cycles (approximately 24 months) with pembrolizumab.  During that 
time, subjects may continue until progressive disease (PD) per the modified irRC-RECIST 
(Appendix D), unacceptable toxicity, withdrawal of consent, physician's decision to stop therapy 
for the subject, or sponsor’s decision to terminate the study.  Discontinuation of treatment may be 
considered for subjects who have attained a confirmed complete response (CR) that have been 
treated for at least 8 cycles (24 weeks) with pembrolizumab, and had at least 2 cycles of 
pembrolizumab beyond the date when the initial CR was declared.  
See Section 6.2.2 for additional information regarding dosage and administration of 
pembrolizumab. 
Procedures: 
Screening Procedures: 
The following procedures are to be completed during the screening period at the time points 
indicated in the Schedule of Assessments (Table 8 and Table 10) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 10 of 196 
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 
Confirmation that the informed consent form (ICF) has been signed and registration of 
screening in Interactive Voice Response (IVR) system followed by review of eligibility, 
medical and surgical history, demographic data, vital signs, physical examination per 
standard of care including body weight, ECOG performance status, electrocardiogram (ECG), 
and Child-Pugh score 
 
Laboratory assessments:  hematology panel; chemistry panel; coagulation tests; lactate 
dehydrogenase (LDH); hepatitis serology including HBV, and HCV panel; qualitative serum or 
urine pregnancy testing for women of childbearing potential;carcinoembryonic antigen (CEA) 
in CRC and GEC adenocarcinoma only; alpha fetoprotein (AFP) in HCC only; cancer 
antigen 19-9 (CA 19-9) (Part 1 only) in CRC, GEC, and HCC only; and thyroid function tests 
(combination treatment only) 
 
Disease specific assessments (see Section 7.2.1) 
 
For subjects in Part 1, liver tumor biopsy unless already performed as standard of care.  For 
subjects in Part 2, tumor biopsy unless already performed as standard of care. 
 
Radiographic and clinical (if applicable) tumor assessment 
 
Documentation of concomitant medications 
 
Review of serious adverse events 
Treatment Procedures: 
The following procedures will be completed during the treatment at the times designated in the 
Schedule of Assessments (Table 8 through Table 13) 
 
Vital signs, physical examination including weight, and ECOG performance status 
 
Local laboratory assessments:  hematology panel, chemistry panel, LDH, coagulation tests, 
CEA in CRC and GEC adenocarcinoma only, AFP in HCC only, CA 19-9 (Part 1 only) in 
CRC, GEC, and HCC only, HBV DNA by qPCR or HCV RNA by PCR for subjects with history 
of or chronic HBV or HCV infection, respectively 
 
Combination treatment only (Part 1 Cohorts 5 & 6 and Part 2):  Thyroid Function Tests 
(triiodothyronine [T3] or free triiodothyronine [FT3], free thyroxine [FT4] and 
thyroid-stimulating hormone [TSH]) 
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 
 
Central laboratory assessments: 
, herpes 
simplex virus type 1 (HSV-1) immunoglobulin G (IgG) antibody serostatus, and blood and 
urine for qPCR testing for talimogene laherparepvec DNA; swabs of the injection site, exterior 
of occlusive dressing, and oral mucosa for qPCR testing of talimogene laherparepvec DNA 
with or without 50 Tissue Culture Infective Dose (TCID50) assay for talimogene 
laherparepvec virus; swabs of cold sores, vesicles and other lesions suspected to be herpetic 
in origin (if any) for qPCR testing of talimogene laherparepvec DNA. 
 
In Part 1, biopsies of injected and, when available, uninjected liver tumors for 
 
  In Part 2, biopsies of injected and, when available, uninjected tumors for 
 
.  As of Protocol Amendment 6 (dated 26 October 2021), liver biopsies are no 
longer performed in this study.   
 
Radiographic tumor assessments, clinical tumor assessment and tumor response 
assessments by modified irRC-RECIST (Appendix D) 
 
Reporting disease related events, adverse events, serious adverse events, and 
documentation of concomitant medications 
 
Administration of study treatment (refer to Section 6) with observation period, where 
applicable.  As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic 
injections of talimogene laherparepvec are no longer performed in this study.   


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 11 of 196 
CONFIDENTIAL 
 
 
 
Reporting potential or known unintended exposure to talimogene laherparepvec as specified 
in Section 9.4 
Safety Follow-up Procedures: 
Upon permanent discontinuation from the study treatment for any reason, the following 
procedures will be performed 30 (7) days after the last dose of talimogene laherparepvec for the 
monotherapy cohorts (Cohorts 1, 2, 3 and 4, in Part 1); and will be performed 30 ( 7) days after 
the last dose of talimogene laherparepvec or pembrolizumab, whichever is later, for the 
combination treatment (Cohorts 5 and 6 in Part 1 and all arms in Part 2): 
 
Vital signs, physical examination including weight, ECOG, and ECG 
 
Local laboratory assessments: hematology panel, chemistry panel, LDH, coagulation tests, 
serum or urine pregnancy test for females of childbearing potential, CEA in CRC and GEC 
adenocarcinoma only, AFP in HCC only, CA 19-9 (Part 1 only) in CRC, GEC, HCC only, HBV 
DNA by PCR or HCV RNA by PCR for subjects with history of or chronic HBV or HCV 
infection, respectively 
 
Child-Pugh score 
 
Central laboratory assessments: 
, HSV-1 IgG antibody 
serostatus, and qPCR testing for talimogene laherparepvec DNA; urine for qPCR testing of 
talimogene laherparepvec DNA; swabs of the oral mucosa for qPCR testing of 
talimogene laherparepvec DNA; swabs of cold sores, vesicles and other lesions suspected to 
be herpetic in origin (if any) for qPCR testing of talimogene laherparepvec DNA. 
 
Radiographic and clinical tumor assessment 
 
Reporting disease related events, adverse events, serious adverse events and 
documentation of concomitant medications 
 
Reporting potential or known unintended exposure to talimogene laherparepvec as specified 
in Section 9.4 
Long-term Follow-up Procedures: 
All subjects who permanently discontinue study drug for any reason other than withdrawal of full 
consent will be contacted by clinic visit or telephone to assess survival, talimogene 
laherparepvec-related adverse events, and initiation of additional anti-tumor treatment.  For 
subjects in the combination treatment cohort, the long-term follow-up starts after the 
discontinuation of whichever study drug is discontinued last. 
For Part 1, contact for all subjects will be attempted approximately every 12 weeks ( 28 days) 
following the safety follow-up visit until death, subject withdrawal, or up to approximately 
24 months after the date of the last subject enrolled in Part 1.  Subjects in Cohort 5 and 6 will be 
followed approximately 24 months after the last subject enrolled in their cohort in Part 1, or 
approximately 24 months after the last subject enrolled with their tumor type in Part 2, whichever 
is later. 
For Part 2, contact for all subjects will be attempted approximately every 12 weeks ( 28 days) 
following the safety follow-up visit until death, subject withdrawal, or up to approximately 
24 months after the date of the last subject enrolled in that tumor cohort. 
Radiographic Tumor Assessment:  Every effort should be made to complete radiographic 
assessments approximately every 12 (1) weeks during the long-term follow-up until 
documentation of PD per modified irRC-RECIST (Appendix D), start of new anticancer treatment, 
death, or end of study, whichever occurs first, for subjects discontinuing treatment for any reason 
other than PD.  Response (CR, or partial response [PR]) or disease progression to be confirmed 
by second consecutive radiographic assessments no less than 4 weeks from the date of the first 
documented response or disease progression. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 8 through Table 13). 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 12 of 196 
CONFIDENTIAL 
 
 
Statistical Considerations: 
The data will be analyzed by cohort/group (non-HCC and HCC), in the overall population and by 
tumor type, if applicable.  Descriptive statistics will be provided for demographic, safety, efficacy, 
and biomarkers as appropriate.  Formal analysis will be performed on the primary endpoints in 
Part 2. 
For Part 1, the DLT analysis set will be used to summarize the subject incidence of DLT as 
defined in Section 3.1.4.3.  For talimogene laherparepvec monotherapy, safety will be assessed 
for non-HCC and HCC groups based on the 3  3 design.  For the combination of talimogene 
laherparepvec with pembrolizumab, safety will be assessed for non-HCC and HCC groups based 
on the mTPI up-and-down design.  The DLRT will consider prospective guidelines in the DLRT 
Charter to monitor safety in Part 2 separately by tumor type and, if introduced, talimogene 
laherparepvec total volumes  4 mL within Group A and Group B as discussed in Section 10.  If 
the concentration is reduced in Part 2 for a tumor type, then the sample size considerations for 
the 2-stage futility and efficacy analyses of that tumor type will include only subjects treated in 
Part 1 and 2 at the reduced concentration. 
Objective response rate, BOR, DRR, DOR, response in injected and uninjected lesions, DCR, 
PFS, and OS will be summarized separately for non-HCC and HCC tumors in monotherapy and 
combination cohorts.  Objective response rate, DRR, and DCR will be summarized with an 
associated 95 CI.   
For Part 2, the efficacy analysis will be conducted using the full analysis set from Part 2, unless 
otherwise specified.  The primary analysis of efficacy will include subjects that receive any 
volume of talimogene laherparepvec (in monotherapy cohorts) or any volume of talimogene 
laherparepvec and pembrolizumab (in combination cohorts).  The 2-stage design will be used to 
evaluate the ORR per the modified irRC-RECIST.  The null hypothesis of a 10 ORR for a given 
tumor type that continued to Stage 2 will be rejected if an exact binomial 95 CI for the ORR is 
above 10 (Atkinson and Brown, 1985). 
Best overall response, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and 
OS will be summarized by primary tumor type arm (hormone receptor positive BC, TNBC, CSCC, 
CRC, BCC, and HCC with and without viral hepatitis).  Objective response rate, DRR, and DCR 
will be summarized with an associated 95 CI.  Duration of response among responders, PFS 
and OS will be estimated using the Kaplan-Meier method. 
For both Part 1 and Part 2, the safety analysis set will be used for all safety analyses.  The safety 
analyses will include the incidence of treatment-emergent and treatment-related adverse events 
(all adverse events,  grade 3 adverse events, serious adverse events, fatal adverse events and 
adverse events defined as events of interest).  The qPCR analysis result of talimogene 
laherparepvec DNA in swab samples taken from cold sore, vesicles, and other lesions suspected 
to be herpetic in origin (if any) will be summarized.  Interim safety analyses will be performed for 
evaluation of DLT for Parts 1 and 2 for DLRT meetings.  All available Part 1 and 2 safety data 
from both Group A and B will be considered at each interim safety analysis.  At the discretion of 
the DLRT, additional safety analyses may be conducted.  For a full description of statistical 
analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc. 
Data Element Standards 
Version/Date:  
Version 4.0, 31 October 2013  
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date: 26 October 2021 
Page 13 of 196 
CONFIDENTIAL  
 
 
Study Design and Treatment Schema:  Part 1 - Group A 
 
DLT  dose-limiting toxicity; HCC  hepatocellular carcinoma; MTC  maximum tolerated concentration; mTPI  modified Toxicity Probability Interval; MTV  maximum 
tolerated volume; PFU  plaque forming unit; T-VEC  talimogene laherparepvec 
a First dose concentration of talimogene laherparepvec is always 106 PFU/mL  
b Cohort 4 will be opened only if one of these conditions are met: 1) DLT rate  1/3 in Cohort 2, or 2) DLT rate  1/3 in Cohort 3 and Part 2 dose for talimogene 
laherparepvec not determined yet, or 3) DLT rate  1/3 in cohort 3 and Part 2 concentration for talimogene laherparepvec is determined to be 107 PFU/mL 
c MTV determined from monotherapy cohorts, when available, may be used in Part 2  
d If both Cohorts 3 or 4 and the combination Cohorts (5 or 6) are open in the same institution, subjects with a tumor burden who can receive 8 mL (see Section 6.2.1) 
enrollment into Cohorts 3 or 4 must be strongly preferred until the MTV in monotherapy is determined. 
e Refer to Section 3.1.4.2 and Table 17 for mTPI dose decision outcomes 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date: 26 October 2021 
Page 14 of 196 
CONFIDENTIAL  
 
 
Study Design and Treatment Schema:  Part 1 - Group B 
Part 1 Screening/Enrollment
Group B 
(HCC)
Up to 4mL 
of T-VEC
107
PFU/mL
Cohort 1e
(n = 3-6)
Safety Follow-up
Up to 4mL of 
T-VEC
107 PFU/mL
+ 
Pembrolizumab
DLT 
<33%
YES
NO
Up to 4mL of 
T-VEC
108 PFU/mL
+ 
Pembrolizumab
Cohort 2
(n = 3-6)
Use 108  dose 
in Part 2 Arm 
VI if S or E 
per mTPI
table and 
DLRT charterf
Part 2 Screening / Enrollment
Cohort 5
(n > 4)
Cohort 6a
(n > 4)
Up to 4mL 
of T-VEC
108 PFU/mL
YES
NO
Stop Study 
for group
DLT 
<33%
COMBINATION COHORTS
(max n for Cohort 5 and 6a = 28 total)
*First dose of T-VEC is always 106PFU/mL
Determine MTC for 
Part 2 Arm VIc
Up to 8 mL 
of TVEC 
108 PFU/mL
Cohort 3
(n = 3-6)
Cohort 4a
(n = 3-6)
Determine MTC and MTV 
in monotherapyb
Up to 8 mL 
of TVEC 
107 PFU/mL
mTPI
up-and-down 
design
Up to 4mL of 
T-VEC
108 PFU/mL
+ 
Pembrolizumab
Cohort 6b
(well controlled viral hepatitis)d
(n > 4)
If S or E obtained per 
mTPI table after > 4 
DLT evaluable subjects 
in cohort 6a
YES
NO
Stop enrollment of 
cohort
D or DU 
per mTPI
table or 
charter
Footnotes defined on next page 
D  de-escalate to the next lower dose; DLT  dose-limiting toxicity; DU  de-escalate to the next lower dose/the current dose is unacceptably toxic; E  escalate; 
HCC  hepatocellular carcinoma; MTC  maximum tolerated concentration; mTPI  modified Toxicity Probability Interval; MTV  maximum tolerated volume; 
PFU  plaque forming unit; S  stay at current dose; T-VEC  talimogene laherparepvec 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date: 26 October 2021 
Page 15 of 196 
CONFIDENTIAL  
 
 
a Cohort 4 will be opened only if cohort 3 talimogene laherparepvec dose was 108 and 1) DLT33 in Cohort 3 and Part 2 dose for talimogene laherparepvec not 
determined yet or 2) DLT  33 in cohort 3 and Part 2 dose for TVEC is determined to be 107 PFU/mL 
b MTV determined from monotherapy cohorts, when available, may be used in Part 2 depending on TVEC combination dose determined for Part 2 from Cohort 5 and 6. 
c If cohort 6b completes prior to cohorts 5 and 6a mTPI dose finding is completed, and 6b is deemed safe, then cohorts 5 and 6a will close to enrollment and the cohort 
6b dose will be used for Arm VI in Part 2. 
d Cohorts 1-5 and 6a will consist of subjects without viral hepatitis whereas Cohort 6b will consist of subjects with well-controlled viral hepatitis. 
e Cohort 1 of Group B will be initiated only after safety has been established in Cohort 1 of Group A. 
f If either Cohort 6a or Cohort 6b in Group B of Part 1 is deemed unsafe to move to Part 2, then only the cohort that is deemed safe will be enrolled in Arm VI in Part 2. 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date: 26 October 2021 
Page 16 of 196 
CONFIDENTIAL  
 
 
Study Design and Treatment Schema – Part 2 
Part 2 Screening/Enrollment
Part 2: Assess efficacy of combination therapy in separate tumor types 
(n = 60-126) 
≥ 2 
responder
Stop arm due 
to efficacy 
futility
Safety Follow-up
Survival Follow-up
Part 2:  Stage 2 (up to 11 additional 
subjects per arm arm)
Group A
Arm I:  Hormone receptor 
positive breast cancer
Arm II:  Triple negative breast 
cancer
Arm III:  Cutaneous squamous 
cell carcinoma
Arm IV:  Basal cell carcinoma
Arm V:  Colorectal 
adenocarcinoma
Group B
Arm VI:  Hepatocellular 
carcinoma with or without viral 
hepatitisb
Completion of combination cohort in Part1
Efficacy 
Analysis
(Each Arm 
assessed 
separately at 
n=10)
Part 2:  Stage 1 of efficacy assessment (n=10 per arm)
NO
YES
Efficacy 
Analysis 
n = 21
subjects
(each Arm 
assessed 
separately)
Talimogene
laherparepvec
(MTV & MTC 
from Part 1)a
+ 
Pembrolizumab
 
MTC  maximum tolerated concentration; MTV  maximum tolerated volume. 
a May increase up to 8 ml after safety shown in Cohort 3 or 4 in Part 1.  
b If either Cohort 6a or Cohort 6b in Group B of Part 1 is deemed unsafe to move to Part 2, then only the cohort that is deemed safe will be enrolled in Arm VI in Part 2. 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 17 of 196 
CONFIDENTIAL  
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AFP 
alpha fetoprotein 
ANC 
absolute neutrophil count 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase 
AST  
aspartate aminotransferase   
BC 
breast adenocarcinoma 
BCC 
basal cell carcinoma 
BOR 
best overall response 
BRAF 
B-Raf sarcoma viral oncogene homolog 
BUN 
blood urea nitrogen 
CA 19-9 
cancer antigen 19-9 
CD 
cluster of differentiation 
CEA 
carcinoembryonic antigen 
CI 
confidence interval 
CNS 
central nervous system 
Cohort 
both Group A and B consists of cohorts that enroll DLT-evaluable 
subjects administering a maximum of 4 mL or 8 mL talimogene 
laherparepvec with or without pembrolizumab 
CR 
complete response 
CRC 
colorectal adenocarcinoma 
CRF 
case report form 
CRO 
contact research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
CSCC 
cutaneous squamous cell carcinoma 
CZ 
Crystal Zenith 
D 
de-escalate to the next lower dose 
DCR 
disease control rate 
DILI 
drug-induced liver injury  
DLRT 
Dose Level Review Team 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DRR 
durable response rate 
DU 
de-escalate to the next lower dose/the current dose is unacceptably 
toxic 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 18 of 196 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
EDC 
electronic data capture 
ECG 
electrocardiogram 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary endpoints, 
whether the study concluded as planned in the protocol or was 
terminated early.  The primary completion date is the date when all 
subjects (Parts 1 and 2) have a minimum potential follow-up of  29 
weeks. 
If the study concludes prior to the primary completion date originally 
planned in the protocol (ie, early termination of the study), then the 
primary completion will be the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, 
last subject last visit). 
End of Study (end of trial) defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, last subject last visit), 
following any additional parts in the study (eg, long-term follow-up), 
as applicable.  The end of study will occur when the last subject 
discontinues talimogene laherparepvec and/or pembrolizumab 
(whichever is later) and has had the opportunity to complete both the 
safety follow-up visit and the long-term survival follow-up. 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
ER 
estrogen receptor 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GEC 
gastroesophageal cancer (adenocarcinoma or squamous cell 
carcinoma) 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
Group A Part 1 
subjects with non-hepatocellular carcinoma (BC, CRC, GEC, 
melanoma, NSCLC, or RCC) with liver metastases 
Group A Part 2 
subjects with non-hepatocellular carcinoma (BC, CRC, CSCC, BCC) 
with or without liver metastases 
Group B 
subjects with hepatocellular carcinoma with and without 
well-controlled viral hepatitis 
H0 
null hypothesis 
H1 
alternative hypothesis 
HBV 
hepatitis B virus 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 19 of 196 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HepBcAb 
total Hepatitis B Core Antibody 
HepBsAg 
Hepatitis B Surface Antigen 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormonal replacement therapy 
HSV-1 
herpes simplex virus type 1 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IFNg 
interferon gamma 
Ig 
immunoglobulin 
IgC 
immunoglobulin constant-type 
IgG 
immunoglobulin G 
IgG4 
immunoglobulin G4 
IgV 
immunoglobulin variable-type 
IHC 
immunohistochemistry 
INR 
international normalization ratio 
Interactive Voice 
Response (IVR) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information 
IPIM 
Investigational Product Instruction Manual 
IRB 
institutional review board 
irRC-RECIST 
immune-related response criteria (irRC) simulating RECIST 
version 1.1 
IT 
intratumorally 
ITSM 
immunoreceptor tyrosine-based switch motif 
IV 
intravenous 
JX-594 
pexastimogene devacirepvec (Pexa-Vec) 
KRAS 
Kristen rat sarcoma viral oncogene homolog 
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
major histocompatibility complex class 
MRI 
magnetic resonance imaging 
MTC 
maximum tolerated concentration 
MTD 
maximum tolerated dose 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 20 of 196 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
mTPI 
modified toxicity probability interval 
mTPI Outcomes:   
E  Escalate to the next higher dose 
S  Stay at the current dose 
D  De-escalate to the next lower dose 
U  The current dose is unacceptably toxic 
MTV 
maximum tolerated volume 
NK 
natural killer cells 
non-HCC 
metastatic liver tumors (if tumors are present in liver) 
NRAS 
neuroblastoma RAS viral oncogene homolog 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
Part 1 
Part 1 is a dose escalation study to evaluate the safety of 
intrahepatic injection of talimogene laherparepvec into liver tumors 
alone and in combination with systemic IV administration of 
pembrolizumab 
Part 2 
Part 2 is a 2-stage design to evaluate the efficacy of talimogene 
laherparepvec in combination with systemic pembrolizumab 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 or 2 
programmed cell death ligand 1 or 2 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFU 
plaque forming unit 
PK 
pharmacokinetics 
POR 
proof of receipts 
PR 
partial response 
PrR 
progesterone receptor 
PT 
prothrombin time 
PTT/aPTT 
partial thromboplastin time/activated PTT 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q21D 
every 21 days 
qPCR 
real-time polymerase chain reaction 
RBC 
red blood cell 
RCC 
clear cell renal cell carcinoma 
RP2D 
recommended phase 2 dose 
RT-PCR 
reverse transcriptase by polymerase chain reaction 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SCC 
squamous cell carcinoma 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 21 of 196 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical 
research.  The information may include, but is not limited to, clinical 
findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents (original records or certified copies). 
(ICH Guideline (E6)).  Examples of source data include subject 
identification. 
SD 
stable disease 
SOC 
system organ class 
Study Day 1 
defined as the first day that protocol-specified investigational product 
is administered to the subject 
T3 
triiodothyronine 
TBL 
total bilirubin 
TCID50 
50 Tissue Culture Infective Dose 
tk 
thymidine kinase 
TEAE 
treatment-emergent adverse event is an event that emerges during 
treatment, having been absent pretreatment, or worsens relative to 
the pretreatment state 
TNBC 
triple negative breast cancer 
TRAE 
treatment-related adverse events is a TEAE that is suspected to be 
related to the study treatment 
TSH 
thyroid-stimulating hormone 
T-VEC 
talimogene laherparepvec 
ULN 
upper limit of normal 
US 
ultrasound 
USA 
United States of America 
WBC 
white blood cell 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 22 of 196 
CONFIDENTIAL  
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 4 
Study Design and Treatment Schema:  Part 1 - Group A............................................... 13 
Study Design and Treatment Schema:  Part 1 - Group B............................................... 14 
Study Design and Treatment Schema – Part 2 .............................................................. 16 
Study Glossary .............................................................................................................. 17 
TABLE OF CONTENTS ................................................................................................ 22 
1. 
OBJECTIVES ....................................................................................................... 28 
1.1 
Primary ..................................................................................................... 28 
1.2 
Secondary ................................................................................................. 28 
1.3 
Exploratory ................................................................................................ 29 
2. 
BACKGROUND AND RATIONALE ...................................................................... 29 
2.1 
Hepatocellular Carcinoma and Metastatic Liver Tumors ............................ 29 
2.2 
Oncolytic Virus Studies with Intrahepatic Administration ........................... 30 
2.3 
Talimogene Laherparepvec Investigational Product Background .............. 32 
2.4 
Non-Amgen Investigational Product:  Pembrolizumab 
Background ............................................................................................... 35 
2.4.1 
Pharmaceutical and Therapeutic Background ........................... 35 
2.4.2 
Pre-clinical Studies .................................................................... 37 
2.4.3 
Pembrolizumab Background and Clinical Trials ......................... 37 
2.4.4 
Rationale for Pembrolizumab Dose Selection ............................ 37 
2.5 
Rationale ................................................................................................... 39 
2.5.1 
Rationale for Combination Therapy of Talimogene 
Laherparepvec and Pembrolizumab .......................................... 41 
2.6 
Clinical Hypotheses ................................................................................... 44 
3. 
EXPERIMENTAL PLAN ........................................................................................ 45 
3.1 
Study Design ............................................................................................. 45 
3.1.1 
Study Design for Part 1 ............................................................. 45 
3.1.1.1 
Part 1 Monotherapy Cohorts:  Non-HCC 
Subjects (Group A) and HCC Without Viral 
Hepatitis Subjects (Group B) ................................... 48 
3.1.1.2 
Part 1 Combination Cohorts:  Non-HCC 
Subjects (Group A) and HCC Subjects 
With and Without Viral Hepatitis (Group B) .............. 49 
3.1.2 
Study Design for Part 2 (Non-HCC and HCC Groups) ............... 50 
3.1.3 
Optional Additional Dosing for Talimogene 
Laherparepvec .......................................................................... 52 
3.1.4 
Safety Evaluation for Parts 1 and 2 ........................................... 52 
3.1.4.1 
Rules for DLT Evaluation and Dose 
Escalation for Part 1 ................................................ 53 


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3.1.4.2 
Safety Evaluation for Combination 
Therapy in Parts 1 and 2 ......................................... 54 
3.1.4.3 
Definition of DLT ..................................................... 55 
3.2 
Number of Sites ........................................................................................ 56 
3.3 
Number of Subjects ................................................................................... 56 
3.4 
Replacement of Subjects .......................................................................... 56 
3.5 
Estimated Study Duration .......................................................................... 56 
3.5.1 
Study Duration for Subjects ....................................................... 56 
3.5.2 
End of Study .............................................................................. 58 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 58 
4.1 
Inclusion and Exclusion Criteria ................................................................ 58 
4.1.1 
Inclusion Criteria ........................................................................ 58 
4.1.2 
Exclusion Criteria ...................................................................... 61 
5. 
SUBJECT ENROLLMENT .................................................................................... 65 
5.1 
Treatment Assignment .............................................................................. 66 
6. 
TREATMENT PROCEDURES .............................................................................. 66 
6.1 
Classification of Product ............................................................................ 66 
6.2 
Investigational Product .............................................................................. 66 
6.2.1 
Talimogene Laherparepvec ....................................................... 66 
6.2.1.1 
Dosage, Administration, and Schedule .................... 66 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 72 
6.2.2 
Non-Amgen Investigational Product:  Pembrolizumab ............... 75 
6.2.2.1 
Pembrolizumab Dosage, Administration, 
and Schedule .......................................................... 75 
6.2.2.2 
Dosage Modification and Toxicity 
Management Guidelines for 
Pembrolizumab ....................................................... 76 
6.2.2.3 
Supportive Care Guidelines for 
Pembrolizumab ....................................................... 84 
6.2.2.4 
Diet and Other Considerations While 
Taking Pembrolizumab ............................................ 84 
6.3 
Other Protocol-required Therapies ............................................................ 84 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 84 
6.4.1 
Criteria for Permanent Discontinuation of 
Talimogene Laherparepvec Due to Potential 
Hepatotoxicity............................................................................ 85 
6.4.2 
Criteria for Conditional Withholding of Talimogene 
Laherparepvec Due to Potential Hepatotoxicity ......................... 86 
6.4.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ............................................................. 86 


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6.5 
Concomitant Therapy ................................................................................ 87 
6.6 
Other Treatment Procedures ..................................................................... 87 
6.7 
Medical Devices ........................................................................................ 89 
6.8 
Product Complaints ................................................................................... 89 
6.9 
Excluded Treatments and/or Procedures During Study Period .................. 89 
7. 
STUDY PROCEDURES ....................................................................................... 90 
7.1 
Schedule of Assessments ......................................................................... 90 
7.2 
General Study Procedures ...................................................................... 112 
7.2.1 
Screening and Enrollment ....................................................... 114 
7.2.2 
Treatment ................................................................................ 117 
7.2.3 
Long-term Follow-up ................................................................ 124 
7.2.3.1 
Safety Follow-up ................................................... 124 
7.2.3.2 
Survival Follow-up ................................................. 126 
7.2.4 
Reporting Exposure to Talimogene Laherparepvec ................. 127 
 127 
 127 
 128 
 128 
 128 
7.4 
Pharmacogenetic Studies ....................................................................... 128 
7.5 
Sample Storage and Destruction ............................................................. 129 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ................ 130 
8.1 
Subjects’ Decision to Withdraw ............................................................... 130 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion .................................... 131 
8.3 
Reasons for Removal From Treatment or Study ..................................... 131 
8.3.1 
Reasons for Removal From Treatment .................................... 131 
8.3.1.1 
Discontinuation of Pembrolizumab 
treatment ............................................................... 132 
8.3.2 
Reasons for Removal From Study ........................................... 132 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ..................... 132 
9.1 
Definition of Safety Events ...................................................................... 132 
9.1.1 
Definition of Disease Related Events ....................................... 132 
9.1.2 
Definition of Adverse Events .................................................... 133 
9.1.3 
Definition of Serious Adverse Events ....................................... 134 
9.2 
Safety Event Reporting Procedures ........................................................ 135 
9.2.1 
Reporting Procedures for Disease Related Events .................. 135 
9.2.2 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria ............................................................... 136 
9.2.3 
Reporting Procedures for Serious Adverse Events .................. 137 
9.2.3.1 
Follow-up of Adverse Events and Serious 
Adverse Events ..................................................... 139 


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9.2.3.2 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................. 139 
9.2.3.3 
Safety Monitoring Plan .......................................... 139 
9.2.4 
Pembrolizumab Events of Clinical Interest (ECI) ..................... 139 
9.2.5 
Information Related to Events of Clinical Interest 
Specifically for Group B HCC Subjects .................................... 140 
9.2.5.1 
Guidance for Management of Hepatic 
Events of Clinical Interest ...................................... 140 
9.2.6 
Events of Clinical Interest for Group B HCC Subjects .............. 144 
9.2.6.1 
Definition of an Overdose of 
Pembrolizumab for This Protocol and 
Reporting of Pembrolizumab Overdose ................. 144 
9.3 
Pregnancy and Lactation Reporting ........................................................ 145 
9.4 
Reporting Exposure to Talimogene Laherparepvec ................................. 146 
10. 
STATISTICAL CONSIDERATIONS .................................................................... 147 
10.1 
Study Endpoints, Analysis Sets, and Covariates ..................................... 147 
10.1.1 
Study Endpoints ...................................................................... 147 
10.1.2 
Analysis Sets ........................................................................... 148 
10.2 
Sample Size Considerations ................................................................... 149 
10.3 
Planned Analyses ................................................................................... 153 
10.3.1 
Interim Analyses ...................................................................... 153 
10.3.1.1 
DLT Safety Analysis (Part 1) ................................. 153 
10.3.1.2 
Interim Safety Analysis (Part 2) ............................. 154 
10.3.1.3 
Interim Futility Analysis (Part 2) ............................. 154 
10.3.2 
Dose Level Review Team (DLRT) ........................................... 155 
10.3.3 
Primary Analysis ...................................................................... 155 
10.3.4 
Final Analysis .......................................................................... 155 
10.4 
Planned Methods of Analysis .................................................................. 155 
10.4.1 
Primary Endpoint ..................................................................... 156 
10.4.2 
Secondary Endpoints .............................................................. 156 
10.4.3 
Exploratory Endpoints ............................................................. 157 
10.5 
Handling of Missing and Incomplete Data ............................................... 158 
11. 
REGULATORY OBLIGATIONS .......................................................................... 158 
11.1 
Informed Consent .................................................................................... 158 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 159 
11.3 
Subject Confidentiality ............................................................................. 159 
11.4 
Investigator Signatory Obligations ........................................................... 160 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 160 
12.1 
Protocol Amendments and Study Termination ........................................ 160 
12.2 
Study Documentation and Archive .......................................................... 161 
12.3 
Study Monitoring and Data Collection ..................................................... 161 
12.4 
Investigator Responsibilities for Data Collection ...................................... 162 


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12.5 
Language ................................................................................................ 163 
12.6 
Publication Policy .................................................................................... 163 
12.7 
Compensation ......................................................................................... 164 
13. 
REFERENCES ................................................................................................... 165 
14. 
APPENDICES .................................................................................................... 171 
Appendix A.  Additional Safety Assessment Information .............................................. 171 
Appendix B.  Sample Electronic Serious Adverse Event Contingency Report 
Form (paper-based form) .................................................................................... 172 
Appendix C.  Pregnancy and Lactation Notification Forms .......................................... 177 
Appendix D.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response ........................................................................................................... 179 
Appendix E.  Drug-induced Liver Injury Reporting and Additional Assessment ............ 190 
Appendix F.  Child-Pugh Score.................................................................................... 191 
 
List of Tables 
Table 1.  Part 1 Cohort Dependencies ........................................................................... 47 
Table 2.  Part 1 Dose Details for Each Cohort ............................................................... 67 
Table 3.  Talimogene Laherparepvec Liver Injection Volume Guideline ......................... 69 
Table 4.  PART 2 Only:  Talimogene Laherparepvec Injection Volume 
Guideline Based on Tumor Size for Cutaneous, Subcutaneous 
and Nodal Lesions .................................................................................. 70 
Table 5.  Pembrolizumab Trial Treatment ...................................................................... 75 
Table 6.  Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events Associated With 
Pembrolizumab ....................................................................................... 77 
Table 7.  Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines .............................................................................................. 82 
Table 8.  Schedule of Assessments for Talimogene Laherparepvec 
Monotherapy .......................................................................................... 91 
Table 9.  Schedule of Assessments for Talimogene Laherparepvec 
Monotherapy:  Post Cycle 6 .................................................................... 93 
Table 10.  Part 1 Schedule of Assessments for Talimogene Laherparepvec 
and Pembrolizumab Combination Treatment .......................................... 98 
Table 11.  Part 1 Schedule of Assessments for Talimogene Laherparepvec 
and Pembrolizumab Combination Treatment:  Post Cycle 6 ................. 100 
Table 12.  Part 2 Schedule of Assessments for Talimogene Laherparepvec 
and Pembrolizumab Combination Treatment ........................................ 105 


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Table 13.  Part 2 Schedule of Assessments for Talimogene Laherparepvec 
and Pembrolizumab Combination Treatment:  Post Cycle 6 ................. 107 
Table 14.  Laboratory Analytes .................................................................................... 113 
Table 15.  Management of Hepatic Events of Clinical Interest for 
Pembrolizumab: .................................................................................... 142 
Table 16.  Probability of Declaring a Monotherapy Cohort Safe or Unsafe .................. 150 
Table 17.  mTPI Dose Decision Outcomes With a 40 Target DLT Ratea,b,c ............... 151 
Table 18.  MTC Selection Probabilities For True DLT Rate Scenarios ......................... 152 
Table 19.  Definition of Measurable Tumor Response (Baseline Target and 
New, Measurable Lesions) ................................................................... 184 
Table 20.  Matrix for Determining the Overall Response at Each Assessment 
Point ..................................................................................................... 185 
Table 21.  Quantitative/Qualitative Reporting of Fully Resected Lymph Nodes ............ 188 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 171 
Appendix B.  Sample Electronic Serious Adverse Event Contingency Report 
Form (paper-based form) ...................................................................... 172 
Appendix C.  Pregnancy and Lactation Notification Forms .......................................... 177 
Appendix D.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response ............................................................................................. 179 
Appendix E.  Drug-induced Liver Injury Reporting and Additional Assessment ............ 190 
Appendix F.  Child-Pugh Score.................................................................................... 191 
Appendix G.  Eastern Cooperative Oncology Group Performance Status 
Scale .................................................................................................... 193 
Appendix H.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information For Talimogene Laherparepvec .......................... 194 
Appendix I.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information For Pembrolizumab ............................................ 196 
 


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1. 
OBJECTIVES 
1.1 
Primary 
Part 1 (NOTE:  as of Protocol Amendment 6 [dated 26 October 2021], intrahepatic 
injections of talimogene laherparepvec and liver biopsies are no longer performed 
in this study):   
To evaluate the following, as assessed by the incidence of dose-limiting toxicities (DLTs) 
in subjects with liver metastases (non-HCC) and subjects with primary hepatocellular 
carcinoma (HCC) in: 
 
Monotherapy Cohorts:  the maximum tolerated volume and concentration (MTV and 
MTC) of intrahepatic injection of talimogene laherparepvec into liver tumors in 
subjects with non-HCC and subjects with primary HCC without active viral hepatitis 
 
Combination Cohorts:  the MTC of intrahepatic injection of talimogene laherparepvec 
into liver tumors in combination with systemic intravenous (IV) administration of 
pembrolizumab in subjects with non-HCC, and subjects with primary HCC with or 
without viral hepatitis 
Part 2:   
 
To evaluate the efficacy, as assessed by objective response rate (ORR) of 
intratumoral injection of talimogene laherparepvec in combination with systemic  
IV administration of pembrolizumab, separately, for each non-HCC tumor type 
(hormone receptor positive breast adenocarcinoma [BC], triple negative breast 
cancer [TNBC], colorectal adenocarcinoma [CRC], cutaneous squamous cell 
carcinoma (CSCC)], basal cell carcinoma [BCC], as well as primary HCC with and 
without viral hepatitis 
 
To evaluate safety separately for each tumor type as assessed by subject incidence 
of treatment-emergent and treatment-related adverse events, including DLTs 
1.2 
Secondary 
The secondary objectives of the study are as follows: 
Efficacy 
Part 1: 
 
To evaluate the efficacy separately by monotherapy versus combination for 
non-HCC and HCC with and without viral hepatitis when applicable as assessed by: 
- 
ORR, best overall response (BOR), durable response rate (DRR), duration of 
response (DOR), response in injected and uninjected lesions, disease control 
rate (DCR), progression-free survival (PFS), and overall survival (OS) 
Part 2:   
 
To evaluate the efficacy in individual tumor types in the non-HCC group and 
HCC group with and without viral hepatitis as assessed by: 


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- 
BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and 
OS by primary tumor type arm (TNBC, Hormone receptor positive BC, CRC 
CSCC, BCC, and HCC with and without viral hepatitis) 
Safety (Parts 1 and 2) 
 
To evaluate the safety in each monotherapy and combination cohorts in Part 1 and 
each arm separately in Part 2, as assessed by subject incidence of treatment-
emergent and treatment-related adverse events 
 
To estimate the incidence of detectable talimogene laherparepvec deoxyribonucleic 
acid (DNA) in blood and urine 
 
To estimate the incidence of clearance of talimogene laherparepvec DNA from blood 
and urine 
 
To estimate the rate of detection (per sample) and incidence (per subject) of 
talimogene laherparepvec DNA and virus at the surface of talimogene laherparepvec 
injection site, the exterior of the occlusive dressing, and the oral mucosa 
 
To estimate the incidence of talimogene laherparepvec DNA detection in lesions 
suspected to be herpetic in origin 
1.3 
Exploratory 
The exploratory objectives of the study are as follows: 
2. 
BACKGROUND AND RATIONALE 
2.1 
Hepatocellular Carcinoma and Metastatic Liver Tumors 
In addition to being the organ of origin for HCC, the liver is one of the major sites of 
metastasis for many tumor types.  In autopsy studies, the incidence of liver metastases 
was 48.6 to 61.1 for breast cancer, 33.4 to 40 for lung cancer, 34.3 to 44.5 for 
gastric cancer, 65.3 for colon cancer, 33.3 to 47.1 for rectal cancer, 16 to 27 for 
kidney cancer (Abrams et al, 1950), and 58.3 for melanoma (Patel et al, 1978).  
Metastasectomy is an option for limited CRC liver metastases, but generally systemic 
therapies such as chemotherapy are the primary modality of treatment for most cancers 
which have metastasized to the liver.  Traditionally, melanoma and RCC are thought to 
be the most sensitive tumor types to immunotherapy, but recent advances in immune 
checkpoint blockade therapies have suggested benefit of immunotherapy in other tumor 
types as well (eg, NSCLC) (Nguyen et al, 2014). 
Localized HCC is primarily treated by surgery, transplant or locally ablative therapies.  
Resection of HCC is generally reserved for those patients with limited disease.  Other 
localized therapies against liver tumors may include bland embolization, transarterial 


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chemoembolization, transarterial radioembolization, radiofrequency ablation, laser and 
microwave ablation, cryoablation, or percutaneous ethanol injection and are more 
commonly used in the setting of unresectable HCC but may also be used in the setting 
of liver metastases.  The currently FDA-approved systemic therapies for unresectable or 
metastatic HCC are the small molecule multi-kinase inhibitors sorafenib (for treatment 
unresectable HCC) (Llovet et al, 2008), lenvatinib (for first line treatment of unresectable 
HCC) (Kudo et al, 2018) and regorafenib (for those previously treated with sorafenib) 
(Bruix et al, 2017), and cabozantinib (for those previously treated with sorafenib) (Abou-
Alfa et al, 2018) and accelerated approval for the PD-1 inhibitors nivolumab (for those 
previously treated with sorafenib)  
(El-Khoueiry, et al, 2017) and pembrolizumab (for those previously treated with 
sorafenib) (Zhu et al, 2018) and the monoclonal antibody ramicirumab (for patients with 
alpha fetal protein 400 ng/ml who were previously treated with sorafenib) (Zhu, et al, 
2019).  Of note, the phase 3 KEYNOTE-240 trial evaluating pembrolizumab plus best 
supportive care compared to placebo plus best supportive care for the treatment of 
patients with advanced HCC previously treated with systemic therapy did not meet its 
co-primary endpoints of improved overall survival and progression free survival.  While 
the numbers numerically favored the pembrolizumab plus best supportive care arm, they 
did not reach statistical significance (Finn, et al, 2019). 
Even with the currently available treatment options, unresectable HCC and metastases 
of other solid tumors to the liver generally portend a poor prognosis, and thus, new 
therapies are urgently needed for these patients. 
2.2 
Oncolytic Virus Studies with Intrahepatic Administration 
The safety and activity of oncolytic viruses has been studied against various tumor types 
in the liver.  JX-594 (pexastimogene devacirepvec [Pexa-Vec]) is a modified vaccinia 
virus with a disrupted thymidine kinase (tk) gene to improve selectivity for cancer and 
insertions of human granulocyte-macrophage colony-stimulating factor (GM-CSF) for 
immune stimulation and -galactosidase for assessment of replication.  It was 
administered intratumorally (IT) in a phase 1 trial to 14 subjects with primary HCC or 
non-HCC in a dose escalation study (Park et al, 2008).  DLT occurred at the highest 
dose of 3 x 109 plaque forming unit (PFU) with grade 3 hyperbilirubinemia due to 
obstruction of the intrahepatic bile duct by the injected tumor and grade 3 anorexia and 
abdominal pain, which was a serious adverse event.  Thus, 109 PFU was determined as 
the maximum tolerated dose (MTD).  No treatment-related deaths occurred.  All subjects 


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had grade 1 to 2 flu-like symptoms.  Of 10 evaluable subjects, 3 had partial responses 
(PRs) (lung SCC, HCC, and melanoma), and 6 had stable disease (SD) by Response 
Evaluation Criteria in Solid Tumors (RECIST).  By Choi response criteria, an additional  
5 subjects with SD by RECIST were found to also have a PR (CRC, 2 subjects and 
RCC, thymic SCC, and extragonadal germ cell tumor, 1 subject each).  In a subsequent  
dose-finding phase 2 study, 30 subjects with advanced HCC were randomized to either 
108 or 109 PFU JX-594 injected IT into up to five HCC tumors on days 1, 15, and 29  
(Heo et al, 2013).  Treatment was generally well tolerated at both doses, and there were 
no treatment-related deaths.  There was one treatment-related serious adverse event of 
nausea and vomiting at the 109 PFU dose.  Grade 1 to 2 flu-like symptoms occurred in 
all subjects in the first 12 to 24 hours after treatment.  The only grade 3 event was 
pyrexia which occurred in 19 of subjects treated at the 109 PFU dose and one grade 4 
event of lymphopenia occurred at the 109 PFU dose.  The trial was stopped early due to 
significant survival benefit favoring the higher-dose group (14.1 months vs 6.7 months) 
with median OS at 9.0 months for the entire study population.  There was no significant 
difference, however, in either modified RECIST or modified Choi responses between the 
higher and lower dose (7 vs 23 and 57 vs 67, respectively).  A subsequent phase 
2b study evaluating JX-594 for 6 treatments on days 1 (IV), 8 (IT), 22 (IT), and weeks 6 
(IT), 12 (IT), 18 (IT) vs best supportive care in 120 second-line advanced subjects with 
HCC refractory or intolerant to sorafenib did not meet its primary endpoint of OS 
(Transgene, 2013).  However, a pivotal phase 3 study evaluating sorafenib with or 
without JX-594 in the first line setting for approximately 600 subjects with HCC is 
ongoing (United States National Institutes of Health, 2016; Transgene, 2014). 
NV1020, an attenuated derivative of herpes simplex virus type 1 (HSV-1) that has 
deletions of the genes encoding ICP34.5, UL56, UL24, and tk and reinsertion of a 
functional HSV-1 tk gene, was administered into the liver intra-arterially for unresectable 
CRC liver metastases in a phase 1/2 study (Geevarghese et al, 2010).  Doses from 
3 x 106 to 1 x 108 PFU were administered for up to four infusions to 13 subjects in the 
dose-escalation phase 1 portion, and no DLTs were seen.  For phase 2, the 
1 x 108 PFU dose was administered to 19 subjects.  The most common adverse events 
were transient chills, headache, nausea, vomiting, myalgia, body pains, and fatigue.  No 
treatment-related disturbances in liver function were seen.  An asymptomatic grade 3 
lymphopenia occurred after infusions in 1 subject.  At the 1 x 108 PFU dose, 1 PR and 


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13 SD were seen in 22 evaluable subjects.  Mean time to progression was 6.4 months, 
and mean OS was 11.8 months at the highest treatment dose. 
2.3 
Talimogene Laherparepvec Investigational Product Background 
Talimogene laherparepvec is an intralesionally delivered oncolytic immunotherapy 
comprised of a genetically engineered HSV-1 that selectively replicates in tumors 
(Talimogene Laherparepvec Investigator’s Brochure [IB]).  The neurovirulence factor 
ICP34.5 and the ICP47-encoding gene from HSV-1 are functionally deleted in 
talimogene laherparepvec, while the gene for GM-CSF is inserted.  The 
ICP34.5 functional deletion allows the virus to replicate selectively in tumors over normal 
tissue.  Normal cells have intact antiviral response pathways to which the HSV-1 
protein ICP34.5 confers resistance.  Because talimogene laherparepvec lacks ICP34.5, 
it cannot replicate as effectively in normal cells as wild type HSV-1.  However, in many 
cancer cells, the antiviral response pathway is dysregulated and permits talimogene 
laherparepvec replication eventually leading to oncolysis.  The oncolytic activity of 
talimogene laherparepvec has been demonstrated either in vitro or in vivo against a 
number of different solid tumor types including BC, CRC, prostate cancer, glioblastoma, 
hypopharyngeal SCC, and melanoma cell lines (Liu et al, 2003).  The role of ICP47 is to 
block antigen presentation to major histocompatibility complex class (MHC) I molecules 
by blocking the transporter associated with antigen processing 1 and 2.  Deletion of 
ICP47 allows for improved antigen presentation by MHC molecules and also allows the 
increased expression of the US11 gene, which promotes virus growth in cancer cells 
without decreasing tumor selectivity. 
Additionally, the virus contains the coding sequence for human GM-CSF, a pleiotropic 
cytokine involved in the stimulation of cellular immune responses by promoting the 
generation of dendritic cells from blood monocytes (Demir et al, 2003; Lonial, 2004; 
Conti and Gessani, 2008).  Dendritic cells have the capacity to capture antigens, migrate 
in response to chemotactic stimuli, and induce proliferative responses and Th1 cytokine 
production in cluster of differentiation 4 (CD4) and CD8 T-lymphocytes (Hart, 1997; 
Ikeda et al, 2004; Paul, 2007).  These Th1-type cytokines have the capacity to produce 
proinflammatory responses, eradicate tumors, and perpetuate autoimmune responses 
(Nishimura et al, 2000; Ikeda et al, 2004; Knutson and Disis, 2005).  This immune 
component of talimogene laherparepvec is thought to help mediate systemic responses 
beyond the injected tumors. 


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Talimogene laherparepvec has clinical efficacy in patients with regionally and distantly 
metastatic melanoma (Talimogene Laherparepvec IB).  In the melanoma setting, 
talimogene laherparepvec has been administered into cutaneous or subcutaneous 
lesions or lymph nodes accessible by ultrasound (US) but not yet into visceral lesions.  
The largest study to evaluate the activity of talimogene laherparepvec in melanoma was 
the pivotal OPTiM study (Study 20110263).  In this open-label, phase 3 study, 436 
subjects with stages lllB to IV unresectable melanoma were randomized 2:1 to 
intralesional talimogene laherparepvec or subcutaneous GM-CSF.  Treatment was 
administered until complete response (CR), clinically significant disease progression, 
intolerable side effects, 12 months of therapy without an objective response, or 
withdrawal of consent).  The primary endpoint of the OPTiM study was DRR, defined as 
the rate of subjects with an objective response by central review (CR or PR) lasting 
continuously for 6 months and starting any time within 12 months of initiating therapy.  
Secondary endpoints included OS, BOR, modified PFS, changes in tumor burden and 
safety. 
Primary analysis of the OPTiM study showed a statistically significant difference 
between the DRR among subjects treated with talimogene laherparepvec (16; 95 
confidence interval [CI]: 12, 21) versus those treated with GM-CSF (2; 95 CI: 0, 
5, p-value  0.0001).  Overall response rate was 26.4 (CR 10.8) for talimogene 
laherparepvec vs 5.7 (CR 0.7) for GM-CSF (p-value  0.0001 descriptive).  Median 
OS among subjects treated with talimogene laherparepvec was 23.3 months vs 18.9 
months among subjects treated with GM-CSF with an OS hazard ratio (HR) of 0.79 and 
p-value of 0.051 (Andtbacka et al, 2013; Kaufman et al, 2014). 
In a lesion level analysis, 64 and 47 of injected lesions, 34 and 22 of uninjected 
non-visceral lesions, and 15 and 9 of uninjected visceral lesions regressed  50 
and 100, respectively, demonstrating the systemic effect of talimogene laherparepvec 
beyond injected lesions (Andtbacka et al, 2014). 
The most common side effects in the OPTiM study were chills (talimogene 
laherparepvec, 49; GM-CSF, 9), pyrexia (43; 9), injection-site pain (28; 6), 
nausea (36; 20), influenza-like illness (30; 15), and fatigue (50; 36).  
Grade  3 adverse events occurred in 36 of subjects receiving talimogene 
laherparepvec and 21 of subjects receiving GM-CSF.  The only grade 3/4 adverse 
events occurring in  5 subjects was cellulitis (talimogene laherparepvec, n6 [2.1]; 


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GM-CSF, n1 [1]).  Of 10 fatal adverse events in the talimogene laherparepvec arm, 
eight were attributable to disease progression.  The remaining two fatal adverse events 
(sepsis in the setting of salmonella infection; myocardial infarction) were not considered 
treatment-related per investigator (Andtbacka et al, 2013). 
The injection of talimogene laherparepvec into visceral tumors has been studied in the 
005/04 phase 1 study for pancreatic cancer in subjects who either failed standard 
therapy or could not receive/refused alternative therapy (Chang et al, 2012).  There were 
17 subjects who received endoscopic US guided injections into their pancreatic tumors 
at either 1 dose of 104 PFU/mL followed by 2 doses of 105 PFU/mL every 3 weeks 
(Q3W; Cohort 1, n3), 1 dose of 105 PFU/mL followed by 2 doses of 106 PFU/mL Q3W  
(Cohort 2, n4), or 1 dose of 106 PFU/mL followed by 2 doses of 107 PFU/mL Q3W 
(Cohort 3, n10).  A fourth dose schedule of 106 PFU/mL followed by 2 doses of 
108 PFU/mL Q3W was planned but not opened because the study was terminated early 
due to a business decision.  The maximal volume that could be administered was 4 mL. 
The primary analysis of efficacy was an assessment of the change from baseline in the 
diameter of injected tumors.  Two of the 4 subjects in Cohort 3 with postdose 
computed tomography (CT) scans achieved substantial size reductions (-36 and -33) 
in injected tumors.  No subjects in the lower dose cohorts (n  2 evaluable subjects in 
each cohort) showed clinically relevant size reductions of the injected tumors, 
suggesting a dose trend for response of injected tumors.  Three subjects also showed 
decreases in the diameters of 1 or more uninjected tumors (in the liver, pancreas, 
kidney, and chest) at any point in the study, and 1 subject had complete disappearance 
of a non-measurable tumor in the liver.  A dose trend was not observed for size 
reductions of uninjected tumors.  In the evaluation of overall tumor burden per RECIST 
version 1.0, no subjects achieved an overall CR or PR; 3 subjects (Cohorts 1, 1, and 3) 
had an assessment of overall SD at 1 or more time points.  
Eight subjects (47) had at least 1 treatment-emergent adverse event considered 
related to talimogene laherparepvec.  Treatment-related adverse events included 
pyrexia in 3 subjects; abdominal pain, ascites, influenza-like illness, and dehydration in 
2 subjects; and constipation, vomiting, chills, pain, headache, weight decrease, and 
diarrhea in 1 subject each.  Grade 3 treatment-related adverse events included 
abdominal pain (12), ascites (12), and dehydration (6); all occurred in Cohort 3.  
Eleven deaths were reported, mostly due to pancreatic cancer-related complications.  


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One subject with a fatal outcome had an adverse event of ascites considered possibly 
related to study treatment by the investigator.  This subject was hospitalized for severe 
ascites 1 week after the first dose of talimogene laherparepvec, and later experienced 
disease progression and received home hospice care; the event of ascites was ongoing 
at the time of the subject’s death approximately 1 month later. 
Prior to initiating enrollment of this study, no injections of hepatic tumors in humans 
have been attempted with talimogene laherparepvec.  However, the hepatotoxicity of 
talimogene laherparepvec administration in the liver has been evaluated in 
immunocompetent rats.  Up to 107 PFU of talimogene laherparepvec per animal or 
vehicle was administered via intrahepatic artery injection.  No differences in morbidity or 
mortality were noted between talimogene laherparepvec and vehicle treated groups 
(Data on file). 
Refer to the Talimogene Laherparepvec IB, for additional information.  
2.4 
Non-Amgen Investigational Product:  Pembrolizumab Background 
2.4.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis, 2010).  Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
prognosis in various malignancies (Mei et al, 2014; Salgado et al, 2014;  
Schatton et al, 2014; Bremnes et al, 2011; Gooden et al, 2011; Schreiber et al, 2011; 
Talmadge, 2011; Nosho et al, 2010; Shirabe et al, 2010; Bellati et al, 2009;  
Oble et al, 2009; Uppaluri et al, 2008; Dunn et al, 2007).  In particular, the presence of 
CD8 T cells and the ratio of CD8 effector T cells/FoxP3 regulatory T cells seem to 
correlate with improved prognosis and long-term survival in many solid tumors  
(Chang et al, 2014; Kim et al, 2013; Preston et al, 2013; Mathai et al, 2012;  
Yoon et al, 2012; Liu et al, 2011; Kirk, 2010; Nosho et al, 2010). 
The programmed cell death-1 (PD-1) receptor-ligand interaction is a major pathway 
hijacked by tumors to suppress immune control (Pedoeem et al, 2014).  The normal 
function of PD-1, expressed on the cell surface of activated T cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4), which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2).  The structures of murine PD-1 alone 


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(Zhang et al, 2004) and in complex with its ligands were first resolved  
(Lázár-Molnár et al, 2008; Lin et al, 2008), and more recently the nuclear magnetic 
resonance-based structure of the human PD-1 extracellular region and analyses of its 
interactions with its ligands were also reported (Cheng et al, 2013).  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (IgV) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif and an 
immunoreceptor tyrosine-based switch motif (ITSM).  Following T cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules, such as cluster 
of differentiation 3-zeta (CD3), protein kinase C-theta (PKCθ), and zeta-chain-
associated protein kinase 70 (ZAP70), which are involved in the CD3 T cell signaling 
cascade (Sheppard et al, 2004).  The mechanism by which PD-1 down-modulates T cell 
responses is similar to, but distinct from that of CTLA-4 (Ott et al, 2013).  PD-1 was 
shown to be expressed on activated lymphocytes, including peripheral CD4 and CD8 
T cells, B cells, T regs and Natural Killer cells (Yao and Chen, 2014).  Expression has 
also been shown during thymic development on CD4-CD8- (double negative) T cells 
(Nishimura et al, 1996), as well as subsets of macrophages (Huang et al, 2009) and 
dendritic cells (Pena-Cruz et al, 2010).  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types (Keir et al, 2008).  
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on  
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments  
(Keir et al, 2008).  Both ligands are type I transmembrane receptors containing both  
IgV- and immunoglobulin constant-type (IgC)-like domains in the extracellular region and 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand 
to PD-1 inhibits T cell activation triggered through the T cell receptor.  PD-L2 is thought 
to control immune T cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T cell function in peripheral tissues.  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T cell inhibitor (Taube et al, 2012; Karim et al, 2009), which, via 
its interaction with the PD-1 receptor on tumor-specific T cells, plays a critical role in 
immune evasion by tumors (Sanmamed and Chen, 2014).  As a consequence, the  


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PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in cancer  
(Topalian et al, 2012). 
2.4.2 
Pre-clinical Studies 
Therapeutic studies in mouse models have shown that administration of antibodies 
blocking PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8 T cells and 
ultimately leads to tumor rejection, either as a monotherapy or in combination with other 
treatment modalities (Spranger et al, 2014; Curran et al, 2010; Pilon-Thomas et al, 2010; 
Weber, 2010; Hirano et al, 2005; Blank et al, 2004; Strome et al, 2003).  Anti-mouse  
PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor responses in 
models of squamous cell carcinoma, pancreatic carcinoma, melanoma, acute myeloid 
leukemia and colorectal carcinoma (Curran et al, 2010; Pilon-Thomas et al, 2010; 
Zhang et al, 2009; Nomi et al, 2007; Strome et al, 2003).  In such studies, tumor 
infiltration by CD8 T cells and increased IFNg, granzyme B and perforin expression 
were observed, indicating that the mechanism underlying the antitumor activity of PD-1 
checkpoint inhibition involved local infiltration and activation of effector T cell function in 
vivo (Curran et al, 2010).  Experiments have confirmed the in vivo efficacy of anti-mouse 
PD-1 antibody as a monotherapy, as well as in combination with chemotherapy, in 
syngeneic mouse tumor models (see the IB). 
2.4.3 
Pembrolizumab Background and Clinical Trials 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction 
with PD-L1 and PD-L2.  Based on preclinical in vitro data, pembrolizumab has high 
affinity and potent receptor blocking activity for PD-1.  Pembrolizumab has an 
acceptable preclinical safety profile and is in clinical development as an IV 
immunotherapy for advanced malignancies.  Keytruda (pembrolizumab) is indicated for 
the treatment of patients across a number of indications.  For more details on specific 
indications refer to the IB (Pembrolizumab IB). 
2.4.4 
Rationale for Pembrolizumab Dose Selection 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.  The dose 
recently approved in the United States and several other countries for treatment of 
melanoma subjects is 2 mg/kg Q3W.  Information on the rationale for selecting 200 mg 
Q3W is summarized below. 
In KEYNOTE-001, an open-label Phase I study conducted to evaluate the safety, 
tolerability, PK and pharmacodynamics, and anti-tumor activity of pembrolizumab when 


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administered as monotherapy, the dose escalation portion of this trial evaluated 3 dose 
levels, 1, 3, and 10 mg/kg, administered every 2 weeks (Q2W) and dose expansion 
cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced solid 
tumors.  All dose levels were well tolerated and no DLTs were observed.  This  
first-in-human study of pembrolizumab showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels.  No MTD has been 
identified.  In addition, 2 randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, and 
1 randomized cohort evaluating 10 mg/kg Q3W versus 10 mg/kg Q2W has also been 
completed.  The clinical efficacy and safety data demonstrate a lack of important 
differences in efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide 
similar response to 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W.  Previously, a 
flat pembrolizumab exposure-response relationship for efficacy and safety has been 
found in subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  
Exposures for 200 mg Q3W are expected to lie within this range and will be close to 
those obtained with 2 mg/kg Q3W dose. 
A population PK model, which characterized the influence of body weight and other 
patient covariates on exposure, has been developed.  The PK profile of pembrolizumab 
is consistent with that of other humanized mAbs, which typically have a low clearance 
and a limited volume of distribution.  The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose and 
importantly will maintain individual patient exposures within the exposure range 
established in melanoma as associated with maximal clinical response.  
Pharmacokinetic properties of pembrolizumab, and specifically the weight-dependency 
in clearance and volume of distribution are consistent with no meaningful advantage to 
weight-based dosing relative to fixed dosing. 
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the  
anti-tumor effect of pembrolizumab is driven through immune system activation rather 
than through a direct interaction with tumor cells, rendering it independent of the specific 
tumor type.  In addition, available PK results in subjects with melanoma, NSCLC, and 
other tumor types support a lack of meaningful difference in PK exposures obtained at 


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tested doses among tumor types.  Thus, the 200 mg Q3W fixed-dose regimen is 
considered an appropriate fixed dose for other tumor indications as well.   
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage.  The 
existing data suggest 200 mg Q3W as the appropriate dose for pembrolizumab. 
2.5 
Rationale 
Based on the safety profile of other oncolytic viruses administered into the tumors of the 
liver and the safety profile of talimogene laherparepvec to date, it is hypothesized that 
talimogene laherparepvec injected intrahepatically into liver tumors will be tolerable and 
safe.  It is also hypothesized that intrahepatic injection of talimogene laherparepvec into 
liver tumors will provide control of injected and uninjected hepatic lesions, and uninjected 
non-hepatic lesions, in subjects with unresectable HCC or liver metastases.  The local 
oncolytic effect of talimogene laherparepvec, as well as its systemic effects through 
stimulation of an anti-tumor immune response, may provide an alternative approach over 
purely localized therapies such as liver resection and traditional interventional radiology 
techniques.  A favorable toxicity profile could support further clinical investigation of 
combination therapy of intrahepatic tumor injections of talimogene laherparepvec with 
other immunotherapies such as immune checkpoint inhibitors, which overcome signals 
that might be inhibiting anti-tumor T cells and could potentially enhance the activity of 
tumor antigen-specific T cells cross-primed by talimogene laherparepvec.  On-treatment 
biomarker studies evaluating biologic or immunologic changes in blood or liver tumor 
biopsies may provide additional insights on how intrahepatic talimogene laherparepvec 
treatment might be further optimized in the future. 
Thus far in this study, as of a data cutoff of 7 August 2019, subject incidence of 
treatment-emergent adverse events of any grade that occurred in 20 or more of 26 
subjects in the monotherapy cohorts included pyrexia (84.6), fatigue (46.2), nausea 
(30.8), abdominal pain (38.5), vomiting (23.1), headache (30.8), anemia (26.9), 
back pain (23.1), decreased appetite (23.1), and dyspnea (23.1).  Treatment 
emergent treatment related adverse events in the monotherapy cohort that occurred in 
10 or more of subjects included pyrexia (80.8), chills (19.2), nausea (15.4), 
fatigue (19.2), blood alkaline phosphatase increased (23.1), headache (26.9), 
abdominal pain (19.2), decreased appetite (11.5), myalgia (11.5), procedural pain 
(11.5), and anemia (11.5).  Subject incidence of treatment emergent grade  3 


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adverse events that occurred in 5 or more in the monotherapy cohort included alanine 
aminotransferase (ALT) increased (15.4), anemia (11.5), aspartate aminotransferase 
(AST) increased (7.7), blood alkaline phosphatase increased (7.7), abdominal pain 
(7.7) and hypokalemia (7.7).  Treatment emergent treatment-related serious adverse 
events included pyrexia (7.7), abdominal pain (3.8), ALT increased (3.8), AST 
increased (3.8), blood alkaline phosphatase increased (3.8), and nausea (3.8). 
As of a data cutoff of 7 August 2019, subject incidence of treatment-emergent adverse 
events of any grade that occurred in 20 or more of 23 subjects enrolled in the 
combination cohorts of talimogene laherparepvec and pembrolizumab included pyrexia 
(87), fatigue (30.2), nausea (43.5, chills (43.5), vomiting (26.1), upper 
abdominal pain (21.7), diarrhea (26.1), and AST increased (26.1).  Treatment-
emergent treatment-related adverse events related to talimogene laherparepvec 
included pyrexia (78.3), chills (30.4), nausea (30.4), fatigue (21.7), AST 
increased (13.0), vomiting (13.0), and hypotension (13.0).  Treatment-emergent 
treatment related adverse events related to pembrolizumab included pyrexia (39.1), 
chills (13.0), nausea (17.4), fatigue (26.1), and AST increased (13.0).  Subject 
incidence of treatment emergent grade  3 adverse events that occurred in 5 or more 
in the combination cohort included ALT increased (8.7), AST increased (8.7), blood 
bilirubin increased (8.7), and hyponatremia (8.7).  Treatment emergent treatment-
related serious adverse events related to talimogene laherparepvec included pyrexia 
(13.0), acute kidney injury (4.3), fatigue (4.3), and pericarditis (4.3).  Treatment 
emergent treatment-related serious adverse events related to pembrolizumab included 
pyrexia (13.0), acute kidney injury (4.3), hepatitis cholestatic (4.3), fatigue (4.3), 
and pericarditis (4.3). 
Once safety of intrahepatic injections of talimogene laherparepvec in combination with 
systemic pembrolizumab is demonstrated in Part I, in Part 2, liver injections as well as 
injections of other sites previously shown to be safe will be allowed in combination with 
systemic pembrolizumab to explore efficacy in select solid tumor types.   
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of 
talimogene laherparepvec and liver biopsies are no longer performed in this 
study.  The risk/benefit evaluation of performing intrahepatic injections of 
talimogene laherparepvec did not support continued intrahepatic injections (see 
IB).  


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2.5.1 
Rationale for Combination Therapy of Talimogene Laherparepvec 
and Pembrolizumab 
Talimogene laherparepvec and PD-1 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.  Pembrolizumab 
prevents T cell exhaustion in peripheral tissues.  The combination of an agent that 
increases tumor-specific immune activation with one that blocks inhibitory T cell 
checkpoints could produce greater antitumor activity than either agent alone. 
The combination of talimogene laherparepvec with ipilimumab, an immune checkpoint 
inhibitor, for the treatment of subjects with unresected stage IIIB-IV melanoma is 
currently being evaluated in the ongoing 20110264 phase 1b/2 study.  Talimogene 
laherparepvec was administered initially with maximum volume of 4 mL at 106 PFU/mL.  
The subsequent doses were administered with maximum volume of 4 mL at 108 
PFU/mL.  The phase 1b portion of this study enrolled 19 treatment naïve patients of 
whom 18 were treated with the combination of both talimogene laherparepvec and 
ipilimumab (Puzanov et al, 2014).  One subject withdrew consent after 1 dose of 
talimogene laherparepvec.  There were no reported DLT during the DLT evaluation 
period (the 6 weeks following the first administration of ipilimumab).  The most common 
adverse events were chills, fatigue, and pyrexia occurring in 11 subjects (58) each.  
Grade 3 or 4 adverse events of any kind occurred in 6 subjects (32).  The only grade 3 
or 4 adverse event occurring in more than one subject was grade 3 nausea in two 
subjects.  There were no unexpected adverse events attributable to the combination 
therapy that have not been seen previously with either ipilimumab or talimogene 
laherparepvec individually.  Two subjects (11) experienced possible immune-related 
grade 3 or 4 adverse events attributed to either ipilimumab or the combination of 
ipilimumab and talimogene laherparepvec.  Of the subjects who experienced possible 
immune-related grade 3 or 4 adverse event, 1 subject experienced grade 3 hypophysitis 
attributed to ipilimumab and grade 3 adrenal insufficiency and grade 3 diarrhea, both of 
which were attributed to the combination of products.  The other subject experienced 
grade 4 amylase and lipase elevations which were attributed to ipilimumab.  These 
grade 3/4 adverse event rates and possible immune-related adverse event are 
consistent with what has been reported with ipilimumab alone (Hodi et al, 2010).  One 
grade 5 adverse event of metastases to the central nervous system occurred during the 
treatment and safety follow-up period.  Analysis performed at a median tumor follow-up 


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time of 15.6 months revealed 9 objective responses (50) with 4 confirmed CRs (33) 
and DRR 44 by immune-related response criteria (irRC) (Puzanov et al, 2015).  
Median PFS was not yet reached with 50 of patients still without progression at  
18 months.  Median OS was not yet reached with 67 of patients still alive at 
18 months.  Median time to response was 4.1 months, and median duration of treatment 
was 13.3 weeks.  Phase 2 of the study is currently ongoing.  An interim analysis of the 
phase 2 portion of the study which was performed when 82 patients had  48 weeks of 
follow up was reported (Chesney et al, 2016).  One-hundred and seventy-three patients 
were randomized:  88 in the talimogene laherparepvec  ipilimumab arm and 85 in the 
ipilimumab arm.  Characteristics for all patients were similar:  54 stage IIIB-IVM1a, 
45 IVM1b/c.  Median follow-up time for 82 patients was 61.2 weeks (range:  0.14 to 
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 to 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 patients in the safety set 
(85 in the combination arm and 80 in the ipilimumab arm), the incidences of grade 3/4 
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. 
In Study 20110265, a phase 1b/3, multicenter trial of talimogene laherparepvec in 
combination with pembrolizumab for the treatment of unresectable stage IIIB to IVM1c 
melanoma, an interim analysis for efficacy of the phase 1b portion of the study was done 
following minimum of 24 weeks follow-up (data cutoff 09 October 2015).  Talimogene 
laherparepvec was administered initially with maximum volume of 4 mL at 106 PFU/mL.  
The subsequent doses were administered with maximum volume of 4 mL at 108 
PFU/mL.  The confirmed overall response rate was 47 (CR rate, 14) with a DCR of 
71 (Amgen Data on File).  The primary analysis of the phase 1b portion of this study 
has been completed following a minimum of 36 weeks follow up (data cutoff 06 January 
2016) and the updated clinical data is now available (Long et al, 2016).  Twenty-one 
subjects received talimogene laherparepvec plus pembrolizumab.  Median follow-up was 
44 weeks.  No DLTs occurred.  The most frequent adverse events were fatigue (67), 


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fever (52), chills (48), and diarrhea (43).  There were no unexpected adverse 
events attributable to the combination therapy that have not been seen previously with 
either pembrolizumab or talimogene laherparepvec individually.  All patients had  1 
treatment-related adverse event; 6 (29) were grade 3, and 1 (5) was grade 4 
(pneumonitis).  Talimogene laherparepvec-related serious adverse events occurred in 2 
(10) subjects which included grade 1 cytokine release syndrome and grade 3 aseptic 
meningitis.  Pembrolizumab-related serious adverse events occurred in 4 (19) subjects 
which included grade 3 autoimmune hepatitis, grade 1 cytokine release syndrome, grade 
3 aseptic meningitis, and grade 4 pneumonitis.  The confirmed ORR was 57 (CR rate 
24) with a median time to response of 17 weeks.  Unconfirmed response rate was 
66.7 with a CR rate of 28.  The DCR was 71.  Median PFS was not reached with 
71 of patients being progression free at 6 months.  Talimogene laherparepvec and 
pembrolizumab could be administered at full doses with no unexpected toxicity, and was 
associated with clinical benefits as assessed by ORR and CR rate.  Phase 3 portion of 
the study was completed 11 March 2021 (IB; Gogas et  al, 2021).   
This phase 1b/2, multicenter study is intended to provide confirmation that a regimen of 
an oncolytic immunotherapy (intrahepatic injection of talimogene laherparepvec) and an 
immune checkpoint inhibitor (pembrolizumab) is safe and tolerable, and that the 
combination treatment might enhance the clinical efficacy shown with anti-PD-1/PD-L1 
mAbs in subjects with primary HCC and non- HCC.  Given that subjects with HCC may 
have underlying liver dysfunction compared to subjects with non-HCC primary tumors 
with liver metastases, this study will determine the feasibility and safety of the initial dose 
cohort (A1) in the non-HCC group prior to initiating enrollment in cohort B1 in the HCC 
group.  Following implementation of Protocol Amendment 5 (dated 02 July 2021), 
non-HCC and HCC cohorts will enroll independently after safety is established in the 107 
PFU/mL monotherapy cohorts. 
The safety and efficacy of nivolumab, a PD-1 immune checkpoint inhibitor, was 
evaluated in CheckMate 040.  This phase 1b/2, open-label, non-comparative, dose 
escalation and expansion trial of nivolumab enrolled adults ( 18 years) with 
histologically confirmed advanced HCC with or without hepatitis C or B virus (H 
CV or HBV) infection.  Previous sorafenib treatment was allowed.  In this study, 262 
eligible patients were treated (48 patients in the dose-escalation phase and 214 in the 
dose-expansion phase).  Nivolumab had a manageable safety profile and no new 
signals were observed in patients with advanced HCC.  Nivolumab 3 mg/kg was chosen 


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for dose expansion.  The ORR was 20 (95 CI 15–26) in patients treated with 
nivolumab 3 mg/kg in the dose-expansion phase and 15 (95 CI 6–28) in the  
dose-escalation phase (El-Khoueiry et al, 2017).   
The safety and efficacy of pembrolizumab was evaluated in KEYNOTE-224.  This phase 
2, randomized, multicentre, open-label trial of pembrolizumab enrolled adults 
( 18 years) with histologically confirmed advanced HCC with or without hepatitis C or B 
virus (HCV or HBV) infection.  Previous sorafenib treatment was allowed.  In this study, 
104 eligible patients were treated.  Pembrolizumab had a manageable safety profile that 
was generally similar to that of pembrolizumab in other tumour types.  The ORR was 
17 (95 CI 11–26).  Among the 18 responders, the best overall responses were 1 
complete response, 16 partial responses, 44 of participants had stable disease, 33 
had progressive disease, and 6 could not be assessed because they did not have 
assessment data after baseline (Zhu et al, 2018). 
As this is the first use of intrahepatic injection of talimogene laherparepvec with systemic 
IV administration of pembrolizumab, it is necessary to evaluate the safety of intrahepatic 
injection of talimogene laherparepvec in combination with systemic IV administration of 
pembrolizumab.  As such, this study will evaluate potential blood and tumor biomarkers 
which predict and/or are correlated with clinical outcomes to intrahepatic injection of 
talimogene laherparepvec into liver tumors alone and in combination with intrahepatic 
injection of talimogene laherparepvec and systemic IV administration of pembrolizumab. 
2.6 
Clinical Hypotheses 
PART 1:   
Monotherapy cohorts 1-4:  Talimogene laherparepvec injected intrahepatically into liver 
tumors will be safe in subjects with non-HCC with liver metastases and subjects with 
HCC without active viral hepatitis as assessed by subject incidence of DLTs. 
Combination cohorts 5 and 6:  Talimogene laherparepvec injected intrahepatically into 
liver tumors in combination with systemically administered pembrolizumab will be safe in 
subjects with non-HCC with liver metastases and subjects with HCC with and without 
viral hepatitis as assessed by subject incidence of DLTs. 
PART 2:   
Talimogene laherparepvec injected intratumorally in combination with systemic IV 
administration of pembrolizumab will demonstrate at least a 40 ORR in each tumor 


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type and be safe in the individual non-HCC tumor types as well as primary HCC with and 
without viral hepatitis. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 1b/2, multicenter, open-label, basket trial to evaluate the safety of 
talimogene laherparepvec injected intrahepatically into liver tumors alone and in 
combination with systemic IV administration of pembrolizumab, in subjects with 
non-HCC liver metastases from BC, CRC, GEC, melanoma, NSCLC, RCC in Part 1 
Group A, and subjects with HCC with and without viral hepatitis in Part 1 Group B (viral 
hepatitis is only applicable in combination setting), and to evaluate the efficacy and 
safety of intratumoral talimogene laherparepvec in combination with systemic 
pembrolizumab to treat subjects with advanced TNBC, hormone receptor positive breast 
cancer, CRC, CSCC, and BCC in Part 2 Group A and subjects with HCC with and 
without viral hepatitis in Part 2 Group B.  NOTE:  as of Protocol Amendment 6 [dated 
26 October 2021], intrahepatic injections of talimogene laherparepvec and liver 
biopsies are no longer performed in this study.  The study consists of 2 parts and 
2  groups and Part 2 includes 2 stages. 
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 
Study Design for Part 1 
Part 1 is a dose escalation study to evaluate the safety of intrahepatic injection of 
talimogene laherparepvec into liver tumors alone and in combination with systemic IV 
administration of pembrolizumab, and will consist of 2 groups:  Group A (non-HCC) and 
Group B (HCC) (with and without viral hepatitis; viral hepatitis is only applicable in 
combination setting).  The starting dose concentration used for this study will be at 
106 PFU/mL for the first cycle (to convert HSV-seronegative subjects to seropositive and 
reduce the possibility of intolerance in these subjects) followed by 107 PFU/mL with 
volumes initially up to 4 mL with 21 days separating doses, which is consistent with the 
highest dose administered in the 005/04 pancreatic tumor injection study 
(Chang et al, 2012).  Progression of the study through dosing cohorts in Part 1 and 
selections of MTC (see Table 1 and Study Design and Treatment Schema) and MTV will 
depend on the DLT evaluations that occur for each cohort.  For talimogene 
laherparepvec monotherapy, safety will be assessed for the non-HCC and HCC groups 


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based on the “3  3” design.  The concentration of the first dose of talimogene 
laherparepvec in all cohorts will always be 106 PFU/mL.  Maximum total volumes (up to 
4 mL or 8 mL) and subsequent concentrations (107 or 108 PFU/mL) to be administered 
will depend on the specific cohort (refer to Table 1).  Combination cohorts (Cohorts 5 
and 6) in Part 1 will determine the safety of administering intrahepatic injection of 
talimogene laherparepvec in combination with systemic IV administration of 
pembrolizumab using a modified toxicity probability interval (mTPI) up-and-down design.   


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Table 1.  Part 1 Cohort Dependencies 
MONOTHERAPY COHORTS 
 
DLT  1/3 in 6 subjects 
DLT  1/3 in 3 to 6 subjects 
Group A Cohort 1 
Hold study in treatment group 
Open Group A Cohort 2 
Open Group B Cohort 1 
Non-HCC (Group A) or HCC (Group B)a 
Cohort 1  
(4 mL of 107 PFU/mL 
T-VEC) 
Hold study in treatment group 
Open Group B Cohort 2b 
Open Cohort 5 in corresponding 
group 
Cohort 2c 
(4 mL of 108 PFU/mL 
T-VEC) 
Open Cohort 4 
 
Set MTC to  
107 PFU/mL in 
monotherapy 
Open Cohort 3  
 
Set MTC to 108 PFU/mL 
in monotherapy 
 
Cohort 3d 
(8 mL of 108 PFU/mL 
T-VEC) 
Open Cohort 4, if: 
Part 2 dose for talimogene 
laherparepvec not determined 
yet 
OR 
Part 2 concentration for 
talimogene laherparepvec is 
determined to be 107 PFU/mL 
 Use maximum tolerated 
volume of 8 mL talimogene 
laherparepvec in Part 2 
Cohort 4e (if needed) 
(8 mL of 107 PFU/mL 
T-VEC) 
Retain maximum volume of 4 mL 
talimogene laherparepvec in Part 
2 
Introduce volumes up to 8 mL 
talimogene laherparepvec in 
Part 2 
COMBINATION COHORTS 
Non-HCC (Group A) 
or HCC with and 
without viral hepatitis 
(Group B) 
Initial or Subsequent mTPI Outcomef 
Cohort 5 
(4 mL of 107 PFU/mL 
T-VEC  
pembrolizumab 
D or DU:  Stop;  
Hold study in treatment group 
S:  Stay; expand cohort 
E:  Escalate to Cohort 6 if 
sample size is allowed and no 
DU from the previous decision. 
Cohort 6 (Group A 
only) 
DU:  De-escalate to Cohort 5 
and do not re-escalate 
D:  De-escalate to Cohort 5 
S or E:  DLRT can declare MTC 
as 108 PFU/mL, or expand 
Cohort 6 
Cohort 6ag 
(4 mL of 108 PFU/mL 
T-VEC  
pembrolizumab 
DU:  De-escalate to Cohort 5 
and do not re-escalate 
D:  De-escalate to Cohort 5 
S or E:  DLRT can declare MTC 
as 108 PFU/mL, or expand 
Cohort 6a 
If S or E after at least 4 DLT 
evaluable subjects: open Cohort 
6b 
Page 1 of 2 
Footnotes on the next page 


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Table 1.  Part 1 Cohort Dependencies 
COMBINATION COHORTS 
Cohort 6bg 
(well-controlled viral 
hepatatis) 
(4 mL of 108 PFU/mL 
T-VEC  
pembrolizumab 
D or DU:  Stop; 
No further exploration of this 
cohort. 
S or E:  DLRT can declare MTC 
as 108 PFU/mL for both Cohort 
6a and 6b 
Page 2 of 2 
D  de-escalate to the next lower dose; DLRT  Dose Level Review Team; DLT  dose limiting toxicity; 
DU  de-escalate to the next lower dose/the current dose is unacceptably toxic; E  escalate; 
HCC  hepatocellular carcinoma;  MTC  maximum tolerated concentration; mTPI  modified toxicity 
probability interval; PFU  plaque forming unit; S  stay at current dose; T-VEC  talimogene laherparepvec. 
a Prior to Institutional Review Board (IRB) approval of Amendment 2, the opening of Group A Cohort 2 and 
Group B Cohort 1 was dependent on Group A Cohort 1 results.  After IRB approval of Amendment 2, 
Group A and Group B are independent of each other. 
b Group A Cohort 2 opened prior to IRB approval of Amendment 2. 
c If Cohort 6 is deemed safe, then cohort 2 will stop enrolling in the respective Group. 
d If Cohort 3 is deemed safe in either Group A or B, further enrollment into cohort 3 into either group will be 
suspended, then up to 8 mL will be used in Part 2 for Group A and B. 
e Cohort 4 will be opened only if one of these conditions are met:  1) DLT rate  1/3 in Cohort 2; 2) DLT rate 
 1/3 in Cohort 3 and Part 2 dose for talimogene laherparepvec not determined yet; or 3) DLT rate  1/3 in 
Cohort 3 and Part 2 concentration for talimogene laherparepvec is determined to be 107 PFU/mL. 
f Refer to Section 3.1.4.2 and Table 17 for mTPI dose decision outcomes 
g Group B only. 
3.1.1.1 
Part 1 Monotherapy Cohorts:  Non-HCC Subjects (Group A) and 
HCC Without Viral Hepatitis Subjects (Group B)   
Part 1 of the study will enroll subjects with non-HCC (BC, CRC, GEC, melanoma, 
NSCLC, or RCC) with liver metastases (Group A) and HCC subjects without viral 
hepatitis (Group B).  Both Group A and B will each consist of at most 4 sequential 
monotherapy dose cohorts. 
Cohort 1 will enroll from 3 to 6 DLT-evaluable subjects administering a maximum of 
4 mL talimogene laherparepvec.  Subjects in Cohort 1 will be administered 106 PFU/mL 
of talimogene laherparepvec in the first cycle.  Twenty-one (3) days later they will be 
administered 107 PFU/mL of talimogene laherparepvec to start the second cycle.  
Subsequent cycles (1 dose per cycle) will be given every 21 days (Q21D) ( 3 days), for 
a total of 6 cycles with an optional 6 additional cycles (see Section 3.1.3). 
Cohort 2 will enroll from 3 to 6 DLT-evaluable subjects administering a maximum of 
4 mL talimogene laherparepvec.  Subjects in Cohort 2 will be administered 106 PFU/mL 
of talimogene laherparepvec for the first cycle.  Twenty-one (21) ( 3) days later they will 
be administered 108 PFU/mL of talimogene laherparepvec to start the second cycle.  
Subsequent cycles (1 dose per cycle) will be given every 21 days (Q21D) ( 3 days), for 
a total of 6 cycles with an optional 6 additional cycles (see Section 3.1.3). 


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Protocol Number:  20140318 
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Cohort 3 will enroll from 3 to 6 DLT-evaluable subjects administering a maximum of 
8 mL talimogene laherparepvec.  Subjects in Cohort 3 will be administered 106 PFU/mL 
of talimogene laherparepvec for the first cycle, and 108 PFU/mL of talimogene 
laherparepvec, up to 8 mL, 21 days later ( 3 days) and Q21D ( 3 days) for a total of  
6 cycles, with an optional 6 additional cycles (see Section 3.1.3).   
Cohort 4 will be opened only if any of the following scenarios occur:  1) DLT rate  1/3 in 
Cohort 2; 2) DLT rate  1/3 in Cohort 3 and Part 2 dose for talimogene laherparepvec 
not determined yet; or 3) DLT rate  1/3 in Cohort 3 and Part 2 concentration for 
talimogene laherparepvec is determined to be 107 PFU/mL.  Subjects in this cohort will 
be administered a maximum of 8 mL talimogene laherparepvec.  Subjects will be 
administered 106 PFU/mL of talimogene laherparepvec for the first cycle, and 107 
PFU/mL of talimogene laherparepvec, up to 8 mL, 21 days later ( 3 days) and Q21D 
( 3 days) for a total of 6 cycles, with an optional 6 additional cycles (see Section 3.1.3). 
If both Cohorts 3 or 4 and the combination cohorts (5 or 6) are open in the same 
institution, subjects with a tumor burden who can receive 8 mL (see Section 6.2.1.1) 
enrollment into Cohorts 3 or 4 must be strongly preferred until the MTV in monotherapy 
is determined. 
Refer to Table 1 and the Study Design and Treatment Schema at the end of the 
synopsis section for additional information regarding progression of the study through 
the monotherapy dosing cohorts in Part 1. 
3.1.1.2 
Part 1 Combination Cohorts:  Non-HCC Subjects (Group A) and 
HCC Subjects With and Without Viral Hepatitis (Group B) 
Safety of the combination will be evaluated with the mTPI up-and-down design in Part 1 
to determine the talimogene laherparepvec MTC with a target DLT rate of 40.  A 
maximum of 28 DLT-evaluable subjects will be enrolled across Cohort 5 and Cohort 6 in 
Group A and a maximum of 28 DLT evaluable subjects will be enrolled across Cohort 5 
and Cohort 6a (without viral hepatitis) in Group B.  A maximum of 12 DLT evaluable 
subjects will be enrolled in Cohort 6b (with viral hepatitis) in Group B.  The MTC used as 
part of the recommended phase 2 dose (RP2D) will be selected as the highest cohort 
concentration with an mTPI outcome of either S (stay at the current dose) or E (escalate 
to the next higher dose) at the last Dose Level Review Team (DLRT) analysis.  Full 
details of the mTPI design implementation will be specified in the DLRT Charter. 


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Cohort 5 will begin enrollment if and when safety is established from Cohort 1 in the 
respective non-HCC and HCC groups.  Subjects in Cohort 5 will be administered a 
maximum total volume of 4 mL talimogene laherparepvec in combination with 
pembrolizumab.  The minimum and maximum number of DLT-evaluable subjects for a 
dose decision will be specified in the DLRT Charter.  Subjects in Cohort 5 will be 
administered a concentration of 106 PFU/mL for the first cycle and 107 PFU/mL for 
talimogene laherparepvec, up to 4 mL, 21 ( 3) days later, and Q21D ( 3 days) for a 
total of 6 cycles, with an optional 6 additional cycles (see Section 3.1.3).  
Pembrolizumab at 200 mg Q3W can be administered for up to 35 cycles (approximately 
24 months) (see Section 3.5.1 for additional study duration details). 
If the mTPI outcome for Cohort 5 is E, then Cohort 6 (Group A) or Cohort 6a (Group B) 
will open.  If cohort 6b completes sooner than 6a, and 6b is deemed safe, then cohorts 5 
and 6a will stop enrollment, and both 6a and 6b are deemed safe.  Subjects in Cohort 6 
(Group A) or 6a (Group B) will be administered a concentration of 106 PFU/mL for the 
first cycle and 108 PFU/mL of talimogene laherparepvec, up to 4 mL, 21 ( 3) days later, 
and Q21D ( 3 days) for a total of 6 cycles with an optional 6 additional cycles (see 
Section 3.1.3).  Pembrolizumab at 200 mg Q3W can be administered for up to 35 cycles 
(approximately 24 months) (see Section 3.5.1 for additional study duration details). 
If the mTPI outcome for Cohort 6a (without viral hepatitis) for Group B is S or E after a 
minimum of 4 DLT evaluable subjects, then Cohort 6b (with viral hepatitis) in Group B 
will open. Subjects in Cohort 6b will be administered a concentration of 106 PFU/mL for 
the first cycle and 108 PFU/mL of talimogene laherparepvec, up to 4 mL, 21 ( 3) days 
later, and Q21D ( 3 days) for a total of 6 cycles with an optional 6 additional cycles (see 
Section 3.1.3).  Pembrolizumab at 200 mg Q3W can be administered for up to 35 cycles 
(approximately 24 months) (see Section 3.5.1 for additional study duration details). 
Due to the mTPI up-and-down design, there is the possibility of de-escalating and  
re-escalating between Cohort 5 and 6.  There will be no de-escalation for Cohort 6b 
(Group B) if the mTPI outcome is D or DU, and Cohort 6b will close if D or DU is 
obtained.  Please see Table 1 above for more details. 
3.1.2 
Study Design for Part 2 (Non-HCC and HCC Groups) 
Part 2 is a 2-stage design to evaluate the efficacy of talimogene laherparepvec in 
combination with systemic pembrolizumab separately by tumor type.  The DLRT will 
consider prospective guidelines in the DLRT Charter to monitor safety in Part 2 


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separately by tumor type and, if introduced, talimogene laherparepvec total volumes  
 4 mL within Group A and Group B as discussed in Section 10.  Subjects will be 
enrolled into one of the following treatment groups and arms based on the underlying 
tumor type: 
 
Group A (non-HCC): 
- 
Arm I:  Hormone receptor positive breast cancer 
- 
Arm II:  TNBC 
- 
Arm III:  CSCC 
- 
Arm IV:  BCC 
- 
Arm V:  CRC 
 
Group B (HCC): 
- 
Arm VI:  HCC with or without viral hepatitis  
Part 2 (Group A) of the study will enroll subjects of non-HCC tumors (hormone receptor 
positive BC, TNBC, CSCC, CRC, BCC).  Subjects will be enrolled separately into each 
tumor type.  Stage 1 of Part 2 (Group A) will begin enrolling after MTC has been 
determined from Cohort 5 and 6 in Part 1. 
Part 2 (Group B) of the study will enroll subjects with HCC with and without viral 
hepatitis.  Stage 1 of Part 2 (Group B) will begin enrolling after MTC has been 
determined from Cohorts 5 and 6 in Part 1. 
Subject enrollment and study conduct during Part 2 of the study will progress 
independently in the non-HCC and HCC groups. 
During Stage 1 of Part 2, non-HCC and HCC groups will enroll approximately 
10 subjects for each tumor type arm (5 tumor type arms in Group A and 1 tumor type 
arms in Group B with and without viral hepatitis).  Subjects with specific tumor types 
from the combination cohorts in Part 1 (Cohorts 5 and 6) that are treated at the MTC 
used in Part 2, will not be included as part of the enrollment numbers for that tumor type 
arm in Part 2.  Subjects enrolled in Part 2 will initially be administered up to 8 mL of 
talimogene laherparepvec MTC determined from Cohorts 5 or 6 in Part 1.  
Administration of up to 8 mL of talimogene laherparepvec was established from Part 1, 
Cohort 3 of either Group, any newly enrolled subjects in Part 2 can be administered up 
to 8 mL of talimogene laherparepvec.  No intrasubject concentration or volume 


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Protocol Number:  20140318 
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escalation is allowed.  The primary analysis of efficacy will include subjects that receive 
any volume of talimogene laherparepvec (monotherapy cohorts) and subjects that 
receive any volume of talimogene laherparepvec and pembrolizumab (combination 
cohorts).  Stage 1 of a 2-stage efficacy assessment will occur once 10 subjects have 
been enrolled in a tumor type arm.  Stage 1 efficacy assessments will occur separately 
per tumor type arm.  If efficacy is not futile, Stage 2 will open for that particular tumor 
type arm where approximately an additional 11 subjects can be enrolled. 
3.1.3 
Optional Additional Dosing for Talimogene Laherparepvec 
After the subjects in either Part 1 or Part 2 have received the first 6 cycles of talimogene 
laherparepvec, there is an option to continue dosing with up to 6 additional cycles (Part 1 
only) or a maximum of 35 cycles (Part 2) of talimogene laherparepvec at the same dose 
level as in cycles 2 to 6 provided that the subject has lesions to inject, has not reached a 
confirmed progressive disease (PD) by modified immune-related response criteria (irRC) 
simulating RECIST version 1.1 (irRC-RECIST; Nishino et al, 2014), has not had rapid 
clinical deterioration or worsening symptomatic disease, has not had intolerance of 
treatment, has no significantly better alternative treatment options in the opinion of the 
investigator, and agrees to the additional doses of talimogene laherparepvec after 
investigator discussion with the medical monitor (medical monitor approval required in 
Part 1 only).  In Part 2, additional dosing of talimogene laherparepvec beyond a total of 
12 cycles of talimogene laherparepvec may be allowed if in the opinion of the 
investigator and after discussion with the medical monitor, the subject is deriving clinical 
benefit from the study regimen, the subject is still receiving pembrolizumab. 
3.1.4 
Safety Evaluation for Parts 1 and 2 
A DLRT, consisting of an Amgen medical clinician, safety representative, biostatistician, 
Global Clinical Study Manager (GCTM), representative(s) from Merck, and at least one 
participating investigator who enrolled subjects into Part 1 and/or Part 2, will review the 
safety data to evaluate the subject incidence of DLTs and adverse events.  
Representative(s) from Merck will participate in DLRT meetings for all cohorts (voting 
member only for cohort 5 and 6 of Part 1 and all cohorts in Part 2).  The DLRT will make 
recommendations in Part 1 according to the DLT 3  3 rules for monotherapy cohorts, 
mTPI up-and-down design rules for combination cohorts, and in Part 2 the DLRT will 
make recommendations considering prospective guidelines to monitor safety, in the 
DLRT Charter.  For each dosing cohort in Part 1, the DLRT will recommend either to 
enroll more subjects for DLT evaluation, to prematurely stop enrollment, or to declare the 


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Protocol Number:  20140318 
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dose tolerable.  In Part 2, the DLRT may consider reducing the RP2D talimogene 
laherparepvec concentration and/or discontinuation of total volumes  4 mL, if 
introduced.  If the concentration is reduced in Part 2 for a tumor type arm, then the 
sample size considerations for the 2-stage futility and efficacy analyses of that tumor 
type arm will include only subjects treated at the reduced concentration.  The DLRT can 
consider the totality of available clinical data when reviewing a given cohort. 
3.1.4.1 
Rules for DLT Evaluation and Dose Escalation for Part 1 
Monotherapy Cohorts:   
The DLT evaluation period for a given subject will consist of the period between the 
initial 106 PFU/mL dose of talimogene laherparepvec and 3 weeks following the initial 
107 or 108 PFU/mL dose of talimogene laherparepvec.  A subject will be considered to 
have had a DLT if they experience a DLT event (as outlined in Section 3.1.4.3) during 
the DLT evaluation period.  Any subject who discontinues treatment or is lost to 
follow-up before the end of the DLT evaluation period for any reason other than DLT will 
not be considered evaluable for DLT and may need to be replaced by another subject in 
the same cohort. 
Combination Cohorts:   
The DLT evaluation period for a given subject will consist of the period between the 
initial 106 PFU/mL concentration of talimogene laherparepvec and 3 weeks following the 
initial 107 or 108 PFU/mL dose of talimogene laherparepvec.  Any subject who has not 
received at least 2 doses of talimogene laherparepvec (106, and 107 or 108 PFU/mL) and 
2 doses of pembrolizumab, will not be considered DLT-evaluable unless they experience 
a DLT after the first dose.  A subject will be considered to have had a DLT if they 
experience a DLT event (as outlined in Section 3.1.4.3) during the DLT evaluation 
period.  Any subject who discontinues treatment, or is lost to follow-up before the end of 
the DLT evaluation period for any reason other than DLT, will not be considered 
evaluable for DLT and may need to be replaced by another subject in the same cohort. 
The DLRT will meet whenever 3 to 6 subjects in each monotherapy dose cohort 
(Cohorts 1, 2, 3, and 4) of Part 1 or when a sufficient number of additional subjects (per 
the DLRT Charter), in the combination treatment cohorts (Cohorts 5 and 6 [including 6a 
and 6b]) in Part 1 are evaluable for subject incidence of DLT, and a decision regarding 
cohort escalation/modification is being considered.  The DLRT will declare a dose safe 
for Cohorts 1, 2, 3, and 4 if the subject incidence of DLT is  1/3 during the DLT 
evaluation period subject to the following rules: 


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Monotherapy Cohorts (Cohorts 1, 2, 3, and 4) of Part 1.  See Section 3.1.4.2 below for 
combination therapy (Cohorts 5 and 6): 
 
If no subjects among the initial 3 evaluable subjects in Part 1 experience DLT, then 
the dose will be deemed safe. 
 
If 1 subject among the initial 3 evaluable subjects in Part 1 experiences DLT, an 
additional 3 evaluable subjects will be enrolled. 
 
If  2 subjects among the expanded cohort of 6 evaluable subjects in Part 1 
experience DLT, then the dose will be deemed safe. 
 
If  2 subjects among the initial 3 evaluable subjects or among the expanded cohort 
of 6 evaluable subjects experiences a DLT, then the dose will be declared not safe.  
Additional DLRT meetings will occur after additional DLT-evaluable subjects in each 
dose cohort of Part 1 of Group A and Group B, respectively, are enrolled per above 
DLT rules.  The MTC will be determined as the highest concentration (either 
107 or 108 PFU/mL) evaluated with a subject incidence of DLT  1/3 between 
Cohorts 1 and 2, and the MTV will be determined as the highest volume (4 or 8 mL) 
evaluated with a subject incidence of DLT  1/3 between Cohorts 1, 2, 3, and 4.  The 
MTC for Part 2 is established from Cohorts 5 and 6.  If the initial MTV in Part 2 is 4 mL, 
the MTV for Part 2 will change to 8 mL, if and when, safety of administering the higher 
volume is established from Cohorts 3 and 4 in Part 1. 
3.1.4.2 
Safety Evaluation for Combination Therapy in Parts 1 and 2 
For subjects enrolled in combination therapy (Cohort 5 and 6) in Part 1, safety will be 
evaluated separately for each Group (A and B) with a common mTPI up-and-down 
design to determine the talimogene laherparepvec MTC for each Group with a target 
DLT rate of 40.  For Cohorts 5 and 6 in Part 1, the mTPI model will be used for each 
Group (A and B).  A review of safety data in Part 1 will occur when a sufficient number of 
additional DLT-evaluable subjects (per the DLRT Charter), have been enrolled in a 
Group.   
For Part 2, the DLRT will consider prospective guidelines in the DLRT Charter to monitor 
safety within Group A and Group B and, if introduced, talimogene laherparepvec total 
volumes  4 mL within Group A and Group B.  During Part 2 of the study, a planned 
review of efficacy data will occur after a total of 10 treated subjects have been enrolled in 
a particular tumor type arm with at least 20 weeks minimum potential follow-up (see 
Section 10.2 and Section 10.3.1.2 for more details).  An interim safety data review will 
occur for each tumor type separately after approximately 10 subjects have been treated 
in Part 2 with the specific tumor type with at least 6 weeks of follow-up. 


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Protocol Number:  20140318 
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  The enrollment will be suspended after 10 treated subjects for a particular tumor type 
for the Stage 1 efficacy futility analysis if a non-futile efficacy outcome cannot be verified 
after the 10th treated subject.  The subject incidence of DLT and adverse events will be 
monitored in Part 2 and additional safety analyses may be conducted as warranted 
during the conduct of the study at the discretion of the DLRT. 
3.1.4.3 
Definition of DLT 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 (Appendix A). 
The occurrence of any of the following toxicities during DLT evaluation period (ie, 
occurred during the first 2 dosing cycles) will be considered a DLT, if judged by the 
investigator to be related to talimogene laherparepvec and/or pembrolizumab: 
 
Grade 4 non-hematologic toxicity 
 
Grade 3 non-hematologic toxicity lasting  3 days despite optimal supportive care, 
except grade 3 fatigue 
 
Any grade 3 or higher non-hematologic laboratory value if medical intervention is 
required, leads to hospitalization, or persists for  1 week.  Laboratory values that 
persist for  1 week but are deemed not clinically important per both investigator and 
sponsor will not be considered DLTs 
 
Either AST or ALT 3x above baseline/upper limit of normal (ULN) (whichever is 
higher) AND either international normalization ratio (INR) or total bilirubin (TBL) 
2x above baseline/ULN (whichever is higher) 
 
Grade 3 or 4 febrile neutropenia 
- 
Grade 3 is defined as absolute neutrophil count (ANC)  1.0 x 109/L with a single 
temperature of  38.3ºC (101ºF) or sustained temperature of  38ºC (100.4ºF) for 
more than 1 hour 
- 
Grade 4 is defined as ANC  1.0 x 109/L with a single temperature of  38.3ºC 
(101ºF) or sustained temperature of  38ºC (100.4ºF) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated  
 
Grade 4 thrombocytopenia associated with a bleeding event requiring intervention 
- 
a bleeding event which does not result in hemodynamic instability but requires an 
elective platelet infusion, or 
- 
a life-threatening bleeding event which results in urgent intervention and admission 
to intensive care unit 
 
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 and/or pembrolizumab 


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 
Grade 3 or higher adverse events related to talimogene laherparepvec and/or 
pembrolizumab, that results in a study treatment delay by  2 weeks 
If a subject experiences a DLT during the DLT evaluation period, study treatments will 
be discontinued for that subject.  However, if a subject demonstrates clinical benefit as 
assessed by the treating physician, the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.  Subjects may be allowed to remain on 
study treatment after discussion between the sponsor’s medical monitor and the 
investigator to determine the appropriateness of treatment resumption.  Prior to 
continuing study treatment, investigator will be required to document that, in the 
investigator’s opinion, the subject continues to receive clinical benefit and that the 
subject agreed to continue following a discussion of all available treatment options. 
3.2 
Number of Sites 
Approximately 50 sites located in the United States of America (USA), Europe, Australia, 
and Asia will participate in the study.  Additional sites, countries, and regions may be 
added to the study as necessary.  Sites that do not enroll subjects within 6 months of 
site initiation may be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  A total of 
127  subjects are enrolled in this study (74 subjects in Part 1; 53 subjects in Part 2).   
Refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects enrolled and treated may be replaced in Part 1 if they are not evaluable for DLT 
(eg, did not receive talimogene laherparepvec or ended study treatment before 
completion of DLT-evaluation period for a reason other than experiencing a DLT).  
Dose-limiting toxicity non-evaluable subjects will not be replaced in Part 2.  The 
minimum and maximum number of DLT-evaluable subjects for a dose decision will be 
specified in the DLRT Charter. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The subject accrual period is planned to be approximately 58 months.  
The estimated average per-subject study duration is approximately 32 months.  The 
duration of the screening period for each subject will be up to 28 days.  The duration of 
treatment will vary for each subject.  Subjects can receive a maximum of 12 cycles of 


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talimogene laherparepvec in Part 1 and 35 cycles in Part 2.  Subjects will be treated with 
talimogene laherparepvec until a CR is achieved, all injectable tumors have 
disappeared, PD per the modified irRC-RECIST (Appendix D), confirmed by 2 
consecutive scans  4 weeks apart (Nishino et al, 2014), intolerance of study treatment, 
a total of 6 cycles (including the initial 106 PFU/mL cycle) have been administered and in 
the investigator’s opinion further talimogene laherparepvec is not advisable, the subject 
has received the maximum allowable cycles of talimogene laherparepvec, or the 
investigator determines it is in the best interest of the subject to discontinue treatment 
(eg, rapid clinical deterioration or worsening symptomatic disease requiring alternative 
systemic anti-cancer therapy), whichever occurs first.  Confirmation of disease 
progression is required only in the absence of rapid clinical deterioration (ie, rapid 
decline in performance status or requiring other therapy) or worsening symptomatic 
disease requiring a rapid switch to alternative systemic anti-cancer therapy.   
Subjects can receive up to 35 cycles (approximately 24 months) with pembrolizumab.  
During that time, subjects may continue until PD per the modified irRC-RECIST 
(Appendix D), unacceptable toxicity, withdrawal of consent, physician's decision to stop 
therapy for the subject, or sponsor’s decision to terminate the study.  Discontinuation of 
treatment may be considered for subjects who have attained a confirmed CR that have 
been treated for at least 8 cycles (24 weeks) with pembrolizumab, and had at least  
2 cycles of pembrolizumab beyond the date when the initial CR was declared.   
Subjects will be followed for safety for approximately 30 ( 7) days after the last dose of 
talimogene laherparepvec for the monotherapy cohorts, and after the last dose of 
talimogene laherparepvec or pembrolizumab, whichever is later, for the combination 
treatment (Cohort 5 and 6 in Part 1, and all arms in Part 2).   
For Part 1, contact for all subjects will be attempted approximately every 12 weeks 
( 28 days) following the safety follow-up visit until death, subject withdrawal, or up to 
approximately 24 months after the date of the last subject enrolled in Part 1.  Subjects in 
Cohort 5 and 6 will be followed approximately 24 months after the last subject enrolled in 
their cohort in Part 1, or approximately 24 months after the last subject enrolled with their 
tumor type in Part 2, whichever is later. 
For Part 2, contact for all subjects will be attempted approximately every 12 weeks  
( 28 days) following the safety follow-up visit until death, subject withdrawal, or up to 
approximately 24 months after the date of the last subject enrolled in that tumor cohort. 


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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 endpoints, whether the study concluded as planned in the protocol or was 
terminated early.  The primary completion date is the date when all subjects (Parts 1 and 
2) have a minimum potential follow-up of  29 weeks. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Trial:  The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up), as applicable.  
The end of study will occur when the last subject discontinues talimogene laherparepvec 
and/or pembrolizumab (whichever is later) and has had the opportunity to complete both 
the safety follow-up visit and the long-term survival follow-up (which is up to 
approximately 24 months after the date of the last subject enrolled in Part 2).  
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, tumor type).  Screening logs may be required to be shared with Amgen.  
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.1).   
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of 
talimogene laherparepvec and liver biopsies are no longer performed in this 
study.  Enrollment for this study has stopped. 
4.1 
Inclusion and Exclusion Criteria  
4.1.1 
Inclusion Criteria  
101 
Subject has provided informed consent prior to initiation of any protocol-specific 
activities/procedures 
102 
Male or female age  18 years at the time of informed consent 
114 
Subjects must have histologically or cytologically confirmed disease.   
 
Part 1 is restricted to BC, CRC, GEC, melanoma, NSCLC, or RCC with liver 
metastasis or HCC.   


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 
Part 2 Group A is restricted to advanced hormone receptor positive BC, 
TNBC, CSCC, CRC and BCC with or without liver metastases.   
o Part 2 Hormone receptor positive Breast Cancer Arm only:  
Histologically and/or cytologically confirmed diagnosis of ER positive 
and/or PrR positive (ER  1, PrR  1) breast cancer. 
o Triple negative breast cancer:  Histologically and/or cytologically 
confirmed diagnosis of ER negative, PrR negative, human epidermal 
growth factor receptor 2 (HER2)-Neu negative (ER  1; PrR  1; 
HER2-Neu  3 by immunohistochemistry or fluorescence in situ 
hybridization ratio  2.2 or  6 copies HER2 gene copies/nucleus) 
(Wolff et al, 2007; Hammond et al, 2010).  Subjects with unresectable 
locally recurrent TNBC are eligible.   
 
Part 2 Group B is restricted to HCC (fibrolamellar and mixed 
hepatocellular/cholangiocarcinoma subtypes are not eligible). 
112 
HCC subjects with well-controlled viral hepatitis Cohort 6b:  Subjects must have 
a diagnosis of hepatitis B and/or C (HBV and HCV).   
116 
HCC subjects with well-controlled viral hepatitis Cohort 6b and Arm VI: Subjects 
with HCV infection must have completed treatment for their hepatitis C at least 4 
weeks prior to study enrollment, and HCV viral load must be undetectable. 
Subjects with controlled HBV will be eligible as long as they meet the following criteria: 
 
Antiviral therapy for HBV must be given for at least 4 weeks and HBV 
viral load must be  100 IU/mL prior to enrollment.  Participants on active 
HBV therapy with viral loads  100 IU/mL should stay on the same 
therapy throughout study treatment. 
 
Subjects who are positive for anti-hepatitis B core antibody HBc, negative 
for hepatitis B surface antigen (HBsAg), and negative or positive for anti-
hepatitis B surface antibody (HBs), and who have an HBV viral load  100 
IU/mL, do not require HBV anti-viral prophylaxis. 
104 
Non-HCC subjects with progression on or following at least 1 prior standard of 
care systemic anti-cancer therapy (eg, chemotherapy, hormone therapy, targeted 
therapy) for locally advanced or metastatic disease.  For the combination cohorts 
(Cohorts 5 and 6 in Part 1) and Part 2, subjects with melanoma NSCLC or CSCC 
do not need to have received prior therapy.  Subjects with HCC do not 
necessarily need to be treated previously with prior systemic anti-cancer therapy.  
If no standard of care therapies exist for the subject, or the subject cannot 
tolerate or refuses standard of care anti-cancer therapy, the subject may be 
allowed to participate on the study after discussion between the investigator and 
Amgen medical monitor. 
113 
Subjects with measurable disease. 
 
In Part 1, measurable disease as defined by: 
at least 1 liver lesion that can be accurately and serially measured in at least 
1 dimension and for which the longest diameter is  10 mm (non-HCC) or 


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 20 mm (HCC) as measured by multiphase CT scan or magnetic resonance 
imaging (MRI) 
lesion(s) must not be from an area of the liver that received prior localized 
therapies (eg, radiation, ablation, embolization), unless there is documented 
evidence of disease progression in the area that is measurable and 
distinguishable from the effects of prior therapy prior to enrollment 
 
In Part 2, at least 1 measurable lesion by CT scan or MRI as defined by 
RECIST 1.1 (Eisenhauer et al, 2009). 
115 
All Part 1 subjects and any Part 2 subjects where liver injection is planned: 
at least one injectable liver lesion without necrosis  10 mm in longest 
diameter or at least one liver lesion with necrosis where the longest diameter 
of the necrotic region subtracted from longest diameter of the lesion is 
 10 mm 
tumors selected for injection must not be located where any potential tumor 
swelling after injection may lead to significant biliary tract obstruction (eg,  1 cm 
adjacent to the left main, right main, or common biliary ducts) or where there may 
be significant risk of bleeding (eg,  1 cm from the hepatic capsule)  
Part 2 only:   
Subjects where deep lymph node injections are planned: 
Lesions selected for injection must not, in the investigator’s opinion, be 
located where any potential tumor swelling after injection may lead to 
significant morbidity or obstruction or where there may be significant risk of 
bleeding 
107 
Cohort 3 and 4: sum of tumor diameters from injectable lesions is at least 8 cm 
(or possibly greater if there are lesions with necrotic cores) and must be eligible 
to receive 4 mL of talimogene laherparepvec as defined in Section 6.2.1.1 
108 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(see Appendix G) 
109 
Life expectancy approximately 5 months or more 
110 
Adequate organ function determined within 10 days prior to enrollment, defined 
as follows: 
 
Hematological (without need for transfusion and or growth factor support 
within 10 days): 
- 
ANC  1500/mm3 (1.5 x 109/L) 
- 
platelet count  100 000/mm3 (100 x 109/L) 
- 
hemoglobin  9 g/dL (90 g/L)  
 
Renal: 
- 
serum creatinine  1.5 x ULN, or 24-hour creatinine clearance 
 60 mL/min for 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 
calculated per institutional standard).  


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 
Hepatic: 
- 
serum TBL  1.5 x ULN 
- 
AST  5 x ULN  
- 
ALT  5 x ULN  
- 
Alkaline phosphatase (ALP)  5 x ULN 
 
Coagulation: 
- 
Prothrombin time (PT) or INR  1.5 x ULN partial thromboplastin time 
(PTT) or activated PTT (aPTT)  1.5 x ULN 
111 
Child-Pugh score of A (Appendix F) 
4.1.2 
Exclusion Criteria  
Exclusion for all subjects (monotherapy and combination subjects): 
201 
Candidate for any surgery or locoregional therapy for their cancer with curative 
intent. 
202 
More than one-third of the liver estimated to be involved with tumor 
203 
Candidate for whom systemic anti-cancer therapy is planned in the immediate 
future, with the exception of immunotherapy in the combination cohorts 
(Cohorts 5 and 6 in Part 1 and all subjects in Part 2). 
235 
All Part 1 subjects and any subject planned to have intrahepatic injections during 
the first cycle: 
 
Currently receiving, or less than 28 days prior to enrollment since receiving 
liver tumor-directed therapy (eg, radiation, ablation, embolization),  
All Subjects: 
 
Currently receiving, or less than 28 days prior to enrollment since receiving 
antibody-based therapy, or immunotherapy or hepatic surgery or major 
surgery; or less than 28 days prior to enrollment since receiving radiation 
therapy to a site of planned injection for the first cycle, or less than 21 days 
prior to enrollment since receiving chemotherapy; or less than 14 days prior 
to enrollment from receiving targeted small molecule therapy or hormonal 
therapy. 
236 
Part 1:  
 
Any tumor type with history of central nervous system (CNS) metastases or 
carcinomatous meningitis.  
Part 2:  
 
History or evidence of active CNS metastases, except subjects with 
previously treated cerebral metastases may be enrolled, provided that all 
lesions have been adequately treated with stereotactic radiation therapy, 
craniotomy, or gamma knife therapy, with no evidence of progression, and 


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have not required steroids, for at least 1 month prior to enrollment.  
Carcinomatous meningitis is excluded regardless of clinical stability.   
206 
History of organ transplant. 
207 
History or evidence of symptomatic autoimmune glomerulonephritis, vasculitis, or 
other symptomatic autoimmune disease, or active autoimmune disease or 
syndrome that has required systemic treatment in the past 2 years (ie, with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs) 
except vitiligo or resolved childhood asthma/atopy.  Replacement therapy (eg, 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
238 
Has a history of (non-infectious) pneumonitis / interstitial lung disease that 
required steroids or has current pneumonitis / interstitial lung disease. 
208 
Evidence of clinically significant immunosuppression such as: 
 
primary immunodeficiency state such as Severe Combined 
Immunodeficiency Disease. 
 
concurrent opportunistic infection. 
 
requires concomitant treatment with immunosuppressive agents, including 
chronic oral or systemic steroid medication use at a dose of  10 mg/day of 
prednisone or equivalent or has received  10 mg/day of prednisone or 
equivalent within 7 days of enrollment.  Subjects that require intermittent use 
of steroid inhalers, topical steroids, or local steroid injection will not be 
excluded from the study.  
209 
Non-HCC: has acute or chronic active hepatitis B virus (HBV) or hepatitis C virus 
(HCV) infection.  
210 
Part 1 Group B cohort 1-5, 6a, and Part 2 Arms I-V:   
 
History of HBV and/or HCV infection with viral load detectable by real-time 
polymerase chain reaction (qPCR) testing (with sensitivity to detect at least a 
minimum of 20 IU/mL); or received treatment with nucleotide analogs such as 
those used in the treatment of HBV (eg, lamivudine, adefovir, tenofovir, 
telbivudine, entecavir), ribavirin, or interferon alpha within 12 weeks of 
initiation of study treatment for control of hepatitis B or C.   
Part 1 Group B cohort 6b and Part 2 Arm VI :   
 
Subjects with concurrent well-controlled viral hepatitis B and hepatitis C, 
unless subject fulfills all the eligibility criteria for Hepatitis B and hepatitis C 
stated in eligibility criteria 116.   
211 
All Part 1 subjects and any subject planned to have intrahepatic injections: 
Has macroscopic intravascular invasion into the main portal vein, hepatic vein, or 
vena cava. 
212 
Known to have human immunodeficiency virus (HIV) infection. 
213 
Active herpetic skin lesions or prior complications of HSV-1 infection (eg, herpetic 
keratitis or encephalitis). 


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214 
Requires intermittent or chronic systemic (IV or oral) treatment with an 
anti-herpetic drug (eg, acyclovir), other than intermittent topical use. 
215 
All Part 1 subjects who require concomitant treatment with warfarin.  Other 
anticoagulants (ie, low molecular weight heparins, non-steroidal 
anti- inflammatory drugs) that do not prolong the PT/INR may be allowed after 
investigator discussion with the sponsor and as long as the institutional 
guidelines requiring their withholding for interventional radiology procedures can 
be followed.   
All Part 2 subjects who receive an intrahepatic liver injection or liver biopsy and 
require concomitant treatment with warfarin.  As of Protocol Amendment 6 
(dated 26 October 2021), intrahepatic injections of talimogene 
laherparepvec and liver biopsies are no longer performed in this study.  
Other anticoagulants (ie, low molecular weight heparins, non-steroidal anti-
inflammatory drugs) that do not prolong the PT/INR may be allowed as long as 
the institutional guidelines requiring their withholding for interventional radiology 
procedures can be followed. 
216 
Currently receiving treatment with another investigational device or drug study, or 
less than 28 days prior to enrollment since ending treatment with another 
investigational device or drug study(s). 
217 
Other investigational procedures while participating in this protocol are excluded. 
218 
History of other malignancy within the past 3 years with the following exceptions: 
 
malignancy treated with curative intent and with no known active disease 
present for  3 years before enrollment and felt to be at low risk for 
recurrence by the treating physician. 
 
adequately treated non-melanoma skin cancer without evidence of disease. 
 
adequately treated cervical carcinoma in situ without evidence of disease. 
 
adequately treated breast ductal carcinoma in situ without evidence of 
disease. 
 
prostatic intraepithelial neoplasia without evidence of prostate cancer. 
 
adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ. 
219 
Subject has known sensitivity to talimogene laherparepvec or its components to 
be administered during dosing. 
220 
Subject who is unwilling to minimize exposure with his/her blood or other body 
fluids to individuals who are at higher risks for HSV-1 induced complications 
(immunosuppressed individuals, HIV-positive individuals, pregnant women, or 
children under the age of 1 year) during talimogene laherparepvec treatment and 
through 28 days after the last dose of talimogene laherparepvec. 
221 
Subject likely to not be available to complete all protocol-required visits or 
procedures, and/or to comply with all required protocol procedures to the best of 
the subject’s and investigator’s knowledge. 


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222 
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 Amgen medical monitor, if 
consulted, would pose a risk to subject safety or interfere with the protocol 
evaluation, procedures or completion. 
223 
Subject has entered this protocol previously. 
224 
Female subject is pregnant or breast-feeding, or planning to become pregnant 
during protocol treatment and through 4 months after the last dose of talimogene 
laherparepvec or pembrolizumab, whichever is later.  (Females of childbearing 
potential should only be included in the study after a negative highly sensitive 
urine or serum pregnancy test). 
225 
Female subjects of childbearing potential who are unwilling to use 1 acceptable 
method(s) of effective contraception during protocol treatment and through 
4 months after the last dose of talimogene laherparepvec or pembrolizumab, 
whichever is later.  Refer to Appendix H and Appendix I for additional 
contraceptive information. 
226 
Sexually active subjects and their partners who are unwilling to use a barrier 
method (eg, condom) to avoid potential viral transmission during sexual contact 
during and within 30 days after treatment with talimogene laherparepvec. 
227 
Has received a live-virus vaccination within 30 days of planned treatment start.  
Seasonal flu vaccines that do not contain live virus are permitted.  
228 
Prior therapy with talimogene laherparepvec or any other oncolytic viruses. 
229 
Prior therapy with tumor vaccine. 
230 
Has an active infection requiring systemic therapy. 
231 
Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator. 
Additional Criteria for Combination treatment cohorts: 
232 
Toxic effect(s) of the most recent prior chemotherapy not resolved to Grade 1 or 
less (except alopecia).  Unresolved toxicity and/or complications from received 
major surgery or radiation therapy of  30 Gy. 
233 
Male subject who is unwilling to use acceptable method of effective contraception 
during pembrolizumab treatment and through 4 months after the last dose of 
pembrolizumab.  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 (ICF).  Where required by local laws and regulations, additional 
country-specific contraception requirements may be defined in a country-specific 
protocol supplement at the end of the Appendix section of the protocol. 


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234 
Has severe hypersensitivity ( Grade 3) to pembrolizumab and/or any of its 
excipients. 
237 
Part 2 Hormone receptor positive BC subjects who had prior treatment with a 
checkpoint inhibitor. 
5. 
SUBJECT ENROLLMENT 
Before subjects may be entered into the study, Amgen requires a copy of the site’s 
written IRB/IEC approval of the protocol, ICF, and all other subject information and/or 
recruitment material, if applicable (see Section 11.2).  All subjects must personally sign 
and date the ICF before commencement of study-specific activities /procedures (ie, 
non-standard of care procedures).  
All subjects who enter into the screening period for the protocol (defined as the point 
when the subject signs the informed consent) must be registered as screened subjects 
in the interactive voice response (IVR) system and will receive a unique subject 
identification number before any protocol-specific procedures are performed.  This 
number will be used to identify the subject throughout the study and must be used on all 
study documentation related to that subject.  The subject identification number must 
remain constant throughout the entire study; it must not be changed at the time of 
rescreening or enrollment. 
Subjects who are determined not eligible after screening must be screen-failed in the 
IVR system and the reason for the screen-failure provided.  Subjects who do not meet all 
eligibility criteria may be rescreened once at the discretion of the investigator.  If a 
subject is being rescreened, he or she may need to re-consent to the study to ensure 
that the IRB/IEC-approved main ICF is signed within 28 days of enrollment.  Subjects 
who are determined not eligible after rescreen must be screen-failed in the IVR system 
and the reason for the screen-failure provided.  Subjects may be enrolled only once into 
this protocol. 
Upon confirmation of eligibility, the site staff will use the IVR system to enroll a subject.  
A subject will be considered enrolled when the investigator confirms that the subject has 
met all eligibility criteria and the subject is registered as enrolled in the IVR system.  The 
investigator is to document confirmation of eligibility in the subject’s medical record and 
in the case report form (CRF).  


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5.1 
Treatment Assignment 
Treatment assignment will be managed through IVR system.  Additional details on the 
process and method of assignments are available in the IVR system manual.  The IVR 
system manual will be provided to each investigative site. 
This is an open-label trial; therefore, Amgen, the investigator, and the subject will know 
the treatment administered.  Subjects participating in this trial will be allocated by 
non-random assignment.  Subjects will be enrolled according to their primary tumor type 
into Group A or Group B. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment CRF.  
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product 
The Amgen Investigational Product used in this study is talimogene laherparepvec.   
The non-Amgen Investigational Product used in this study is pembrolizumab.   
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, and 
administration of talimogene laherparepvec and pembrolizumab.  
6.2 
Investigational Product 
6.2.1 
Talimogene Laherparepvec 
Talimogene laherparepvec will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures.  Talimogene 
laherparepvec is supplied as a sterile frozen liquid in a single-use 2-cc Crystal Zenith 
(CZ resin) vial with a gray Fluorotec-coated chlorobutyl elastomer stopper, aluminum 
seal, and polypropylene cap.  Each vial contains a minimum of 1.0 mL talimogene 
laherparepvec at either 106 PFU/mL or 108 PFU/mL concentrations.  The supply for 
106 PFU/mL concentration will be packaged separately from the supply for 108 PFU/mL 
concentration.  As necessary, talimogene laherparepvec 108 PFU/mL will be diluted  
1:10 for a concentration of 107 PFU/mL immediately prior to injection. 
6.2.1.1 
Dosage, Administration, and Schedule 
Talimogene laherparepvec must be prepared and administered by a qualified healthcare 
professional.  Subjects should be assessed clinically for adverse events/toxicity prior to 
each dose using the CTCAE version 4.03 (Appendix A).  Hematology, chemistry and 
coagulation panels should be obtained according to the Schedule of Assessments 


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(Table 8 through Table 13) and the results should be checked before each treatment 
administration.  Dosing will occur only if these test values are acceptable, per 
Section 6.2.1.2. 
In Part 1, talimogene laherparepvec will be administered by intralesional injection only 
into liver tumors, with US or CT guidance.  In Part 2, talimogene laherparepvec will be 
administered by intralesional injection into liver tumors with US or CT guidance.  In 
Part 2, intratumoral injection into lymph nodes, cutaneous or subcutaneous tumor 
lesions may be done with or without image guidance, based on investigator preference. 
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of 
talimogene laherparepvec and liver biopsies are no longer performed in this 
study.   
PART 1: 
The initial dose of talimogene laherparepvec is 106 PFU/mL up to 4 mL in 
Cohorts 1 and 2, and up to 8 mL in Cohorts 3 and 4 (if needed) of the non-HCC 
(Group A) and HCC (Group B) of Part 1.  The subsequent concentrations and volumes 
used in the various cohorts are shown below in the table: 
Table 2.  Part 1 Dose Details for Each Cohort 
Cohorts 
in Part 1 
Talimogene 
laherparepvec  
Volume (mL) 
Initial Talimogene 
Laherparepvec 
Concentration (PFU/mL) 
Second and Subsequent 
Talimogene Laherparepvec 
Concentration (PFU/mL) 
Pembrolizumab 
dose (mg) 
1 
4 
106 
107 
n/a 
2a 
4 
106 
108 
n/a 
3b 
8 
106 
108 
n/a 
4c 
8 
106 
107 
n/a 
5 
4 
106 
107 
200 
6d 
4 
106 
108 
200 
DLT  dose limiting toxicity; PFU  plaque forming unit 
a If Cohort 6 is deemed safe, then cohort 2 will stop enrolling in the respective Group 
b If Cohort is deemed safe in either Group A or B, further enrollment into cohort 3 into either group will be 
suspended, then up to 8 ml will be used in Part 2 for Groups A and B. 
c Cohort will be opened only if one of these conditions are met: 1) DLT rate  1/3 in Cohort 2; 
2) DLT rate  1/3 in Cohort 3 and Part 2 dose for talimogene laherparepvec not determined yet; or 
3) DLT rate  1/3 in Cohort 3 and Part 2 concentration for talimogene laherparepvec is determined to be 
107 PFU/mL  
d Includes Group B Cohort 6a and Cohort 6b 


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The first cycle of talimogene laherparepvec will be 21 (3) days (from the first dose at 
106 PFU/mL to the second dose at 107 or 108 PFU/mL).  Subsequent cycles of 
talimogene laherparepvec will be 21 (3) days. 
The maximum volume of talimogene laherparepvec administered at any dose is 4 mL 
(Cohorts 1, 2, 5, and 6) or 8 mL (Cohorts 3 and 4) for any individual lesion or for all 
lesions combined.   
Part 2:   
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of 
talimogene laherparepvec and liver biopsies are no longer performed in this 
study.   
In Part 2, talimogene laherparepvec can be administered into liver lesions, lymph nodes, 
cutaneous or subcutaneous tumors (non-hepatic lesions).  It is mandatory that 
administration into liver lesions is by image guided injection (either by US or CT scan).  
Image guidance may also be used for other non-hepatic intratumoral injections but is not 
required if the lesion is easily visible or palpable.  The concentration of talimogene 
laherparepvec (107 or 108 PFU/mL) to be administered in Part 2 will be determined on 
completion of the combination treatment, Cohorts 5 and 6, in Part 1.  Talimogene 
laherparepvec will be used at a maximum volume of 8 mL (established from 
monotherapy Cohort 3 in Part 1).  No intrasubject concentration or volume escalation is 
allowed.  Investigators are encouraged to use the maximum amount whenever lesions 
allow.  Dose reduction for adverse events is not allowed.  However, if in the course of 
administration of talimogene laherparepvec the subject cannot tolerate the full volume 
due to an injection-related adverse event such as pain, the total volume given should be 
recorded, and the reason for intolerance should be documented as an adverse event. 
The recommended volume of talimogene laherparepvec to be injected into the tumor(s) 
depends on the longest diameters of the tumor(s) and necrotic core of the tumor(s) (if 
applicable) and should be dosed according to the injection volume guideline in Table 3.  
Liver Lesions with Necrotic Cores 
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of 
talimogene laherparepvec and liver biopsies are no longer performed in this 
study.  Liver lesions with a necrotic core contain less viable cancer cells for talimogene 
laherparepvec to infect. Thus, there are two separate dosing guidelines depending on 
whether there is a significantly sized necrotic core (the longest diameter of the necrotic 


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Protocol Number:  20140318 
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core is  75 of the longest diameter of the tumor) or not (Table 3).  When determining 
the percent of the tumor diameter that is necrotic, measurements from the most recent 
multiphase CT or MRI should be used.  However, the longest diameters of tumors 
assessed by US or CT in preparation for injection guidance of each treatment should be 
used to determine the maximum injection volumes from Table 3.  Talimogene 
laherparepvec should not be injected directly into necrotic tissue and should be 
administered into viable tissue.  Tumors which do not have a large enough non-necrotic 
portion to reliably inject should not be injected with talimogene laherparepvec regardless 
of the overall tumor size. 
Table 3.  Talimogene Laherparepvec Liver Injection Volume Guideline 
Part 1:  Cohorts 1, 2, 5 and 6a 
Individual Tumor Diameterb 
 
 75 necrotic tumor 
diameterc  
 75 necrotic tumor 
diameterc  
Maximum Injection Volume 
 4 cm 
 5 cm 
4 mL 
 2 to  4 cm 
 2.5 to  5 cm 
2 mL 
 2 cm 
 2.5 cm 
1 mL 
Part 1:  Cohort 3 and 4a 
Individual Tumor Diameterb 
 
 75 necrotic tumor 
diameterc  
 75 necrotic tumor 
diameterc  
Maximum Injection Volume 
 8 cm  
 10 cm  
8 mL 
 6 to  8 cm 
 7.5 to  10 cm 
6 mL 
 4 to  6 cm 
 5 to  7.5 cm 
4 mL 
 2 to  4 cm 
 2.5 to  5 cm 
2 mL 
 2 cm 
 2.5 cm 
1 mL 
a One of the two injection volume guidelines above will be used for each Group in Part 2 
b Longest tumor diameter assessed by ultrasound or CT in preparation for injection guidance 
c Based on longest necrotic core diameter divided by longest tumor diameter from most recent multiphase 
Computed Tomography or Magnetic Resonance Imaging 
Excluded liver lesions for injection:  any lesions  1 cm from the hepatic capsule 
(bleeding risk) or the right main, left main, or common hepatic bile ducts (biliary 
obstruction risk).   


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Any lesion selected for injection must not be located, in the Investigator’s opinion, where 
any potential tumor swelling after injection may lead to significant morbidity or 
obstruction or where there may be significant risk of bleeding. 
When biopsies of lesions are scheduled on treatment days (Table 8), they should occur 
prior to injection of talimogene laherparepvec.  When injecting liver lesions, only lesions 
that have been visualized on CT or MRI multiphase scans used for tumor assessments 
may be injected.  New lesions that have appeared on injection guidance CT scans or US 
between tumor assessments CT or MRI scans, may not be injected until they have been 
visualized on tumor assessment CT or MRI scans.  All reasonably injectable lesions 
should be injected with the maximum dosing volume available on an individual dosing 
occasion (Table 3 and Table 4).  
For cutaneous, subcutaneous or superficial nodes, calipers or ruler can be used to 
measure lesions for injection.  
Table 4.  PART 2 Only:  Talimogene Laherparepvec Injection Volume Guideline 
Based on Tumor Size for Cutaneous, Subcutaneous and Nodal Lesions  
Tumor Size (longer dimension) 
Maximum Injection Volume 
 10 cma 
8.0 mL 
 7.5 to  10 cma 
6.0 mL 
 5.0 cm to  7.5 cmb 
4.0 mL 
 2.5 cm to  5.0 cm 
2.0 mL 
 1.5 cm to  2.5 cm 
1.0 mL 
 0.5 cm to  1.5 cm 
0.5 mL 
 0.5 cm 
0.1 mL 
a Volumes  4.0 mL are only to be used if 8.0 mL is the MTV determined from Part 1 and is allowed in 
Part 2. 
b If the MTV from Part 1 is determined to be 4 mL, then maximum volume for lesions  5 cm, including those 
 7.5 cm, is 4.0 mL. 
On each treatment day, prioritization of injections is recommended as follows: 
Part 1: 
 
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections 
of talimogene laherparepvec and liver biopsies are no longer performed in this 
study.  Any new injectable liver tumor that has appeared on tumor assessment CT 
or MRI scans since the start of treatment (from newest to oldest).  New liver lesions 
that appear between tumor assessments scans on the CT scans or US used for 
needle guidance should not be injected until they have been imaged and measured 
on tumor assessment CT or MRI scans.  Lesion selected for injection must not be 
located, in the Investigator’s opinion, where any potential tumor swelling after 


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Protocol Number:  20140318 
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injection may lead to significant morbidity or obstruction or where there may be 
significant risk of bleeding. 
 
By tumor size, beginning with the largest liver tumor. 
 
Any previously uninjectable liver tumor(s) that are now large enough to inject. 
Part 2: 
 
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections 
of talimogene laherparepvec and liver biopsies are no longer performed in this 
study.  Any new injectable cutaneous or sub-cutaneous lesion or superficial lymph 
node that has appeared since the last injection or any new injectable liver lesion that 
has appeared on tumor assessment CT or MRI scan since the start of treatment 
(newest to oldest).  New liver or deep lymph node lesions that appear between tumor 
assessments scans on the CT scans or US used for needle guidance should not be 
injected until they have been imaged and measured on tumor assessment CT or MRI 
scans.  Lesion selected for injection must not be located, in the Investigator’s 
opinion, where any potential tumor swelling after injection may lead to significant 
morbidity or obstruction or where there may be significant risk of bleeding. 
 
By tumor size, beginning with the largest tumor. 
 
Any previously uninjectable tumor(s) that are now large enough to inject. 
It is recommended that each lesion should receive the maximum amount possible to 
inject due to tumor properties at each visit before moving on to the next lesion, using the 
prioritization model above and injection volume guideline based on tumor size per 
Table 3 and Table 4 as applicable.  Volumes of less than 0.05 mL should not be planned 
for administration into a lesion.  Lesions should be injected until the maximum volume 
per day (either 4 or 8 mL) has been reached, or there are no further injectable lesions, 
whichever comes first.  In Part 1, subjects must be monitored in the hospital for 23 hours 
after each injection for the first 3 cycles of talimogene laherparepvec before discharge to 
home.  The observation period may be reduced, at the investigator’s discretion, to a 
minimum of 6 hours after each injection for cycles 4 onwards In Part 2, subjects 
receiving intrahepatic injections must be monitored for a minimum of 6 hours after each 
talimogene laherparepvec injection.  Subjects who do not receive an intrahepatic 
injection of talimogene laherparepvec but receive only, cutaneous, subcutaneous, or 
nodal injections must be monitored for a minimum of 1 hour after each talimogene 
laherparepvec injection, including vital signs.  Monitoring should continue if there are any 
signs of clinical deterioration. 
Subjects will be treated with talimogene laherparepvec until a CR is achieved, all 
injectable tumors have disappeared, confirmed PD per modified irRC-RECIST, 
intolerance of study treatment, until they have received 6 cycles and in the investigator’s 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
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opinion no further talimogene laherparepvec injection would be of clinical benefit, or the 
investigator determines it is in the best interest of the subject to discontinue treatment 
(eg, rapid clinical deterioration or worsening symptomatic disease requiring alternative 
systemic anti-cancer therapy), whichever occurs first.  After 6 cycles have been 
received, the subject may be a candidate for up to 6 additional cycles of talimogene 
laherparepvec (Section 3.1.3).  In Part 2, if the subject has completed  
12 cycles of talimogene laherparepvec, the subject may be a candidate for additional 
cycles of talimogene laherparepvec, up to a total of 35 cycles, if there are still 
cutaneous, subcutaneous, or nodal lesions suitable for injection provided that in the 
opinion of the investigator, the subject has clinical benefit and provided sponsor medical 
monitor approval has been obtained by the investigator.  Due to the mechanism of action 
of talimogene laherparepvec, subjects may experience growth in existing tumors or the 
appearance of new tumors prior to maximal clinical benefit of talimogene laherparepvec.  
Therefore, talimogene laherparepvec dosing should continue provided that the subject 
has no evidence of confirmed PD per modified irRC-RECIST (Appendix D) and is able to 
tolerate treatment.  In Part 2, in the event that talimogene laherparepvec was 
discontinued for reasons other than toxicity (e.g., no further injectable lesion), and 
subject subsequently developed progressive disease or injectable disease while still on 
pembrolizumab, talimogene laherparepvec may be resumed if investigator and medical 
monitor are in agreement.  If the liver is to be injected, subjects must be monitored for a 
minimum of 6 hours after each talimogene laherparepvec injection.   
The concentration, start date, volume, and lot number of talimogene laherparepvec are 
to be recorded on the CRF. 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Dose concentration reductions of talimogene laherparepvec are not permitted.  
However, a reduction in the volume injected due to a disease response is permitted. 
For subjects that have an INR of  1.5 or platelet  50,000/mm3 (50 x 109/L) prior to 
injection, talimogene laherparepvec administration should be delayed until INR is  1.5 
or platelet  50,000/mm3 (50 x 109/L) without transfusion.  Any planned correction of INR 
or platelet count with transfusion prior to injection should be first discussed and 
approved with the sponsor medical monitor. 


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Protocol Number:  20140318 
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If a subject experiences any of the following treatment-related toxicities, talimogene 
laherparepvec administration should be delayed until the toxicity has resolved to at least 
CTCAE version 4.03 grade 1: 
 
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 toxicity  
 
any grade 3 or higher non-hematologic laboratory value unless deemed not clinically 
important per both investigator and sponsor. 
For hepatotoxicity stopping rules refer to Section 6.4. 
If a subject requires corticosteroid dosing of  10 mg prednisone daily (or equivalent, eg, 
1.5 mg dexamethasone) for any reason, talimogene laherparepvec and pembrolizumab 
dosing must be held until the corticosteroid dose has decreased to  10 mg prednisone 
daily (or equivalent). 
All necessary supportive care shall be available to subjects except for those listed in 
Section 6.9.  Talimogene laherparepvec treatment should be continued based on the 
potential risk/benefit assessment of the subject. 
If talimogene laherparepvec treatment was delayed by  2 weeks, that dose will be 
deemed to have been missed and the subject will proceed to the next scheduled 
treatment visit.  
If talimogene laherparepvec dosing is delayed by more than 6 weeks from the date of 
the planned dose (ie, approximately 9 weeks from the previous dose) due to the 
occurrence of an adverse event that is considered related to talimogene laherparepvec, 
the subject must be permanently taken off talimogene laherparepvec treatment.  
If talimogene laherparepvec dosing is delayed by more than 6 weeks from the date of 
the planned dose (ie, approximately 9 weeks from the previous dose) for reasons other 
than treatment-related toxicity, the case must be reviewed by the Amgen medical 
monitor in conjunction with the investigator to determine if the subject can resume 
talimogene laherparepvec therapy. 
Talimogene laherparepvec is to be permanently discontinued for subjects meeting any of 
the following criteria: 
 
Subject developed a DLT during the DLT evaluation period (please refer to 
Section 3.1.4.3).  


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Protocol Number:  20140318 
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 
The subject, for any reason, requires treatment with another anti-cancer therapeutic 
agent for treatment of the study disease (other than the exceptions noted in 
Section 6.6).  In this case, discontinuation from the treatment occurs immediately 
upon introduction of the new agent. 
 
Confirmed PD occurs as defined per modified irRC-RECIST (Appendix D).  
 
A grade 2 or greater immune-mediated adverse event (with the exception of vitiligo) 
or allergic reactions attributed to talimogene laherparepvec that would require a dose 
delay of greater than 6 weeks from the date of the planned dose (ie, approximately 
9 weeks from the previous dose). 
NOTE: immune-mediated glomerulonephritis, vasculitis, and pneumonitis and 
exacerbation of psoriasis have been observed in subjects receiving talimogene 
laherparepvec in clinical trials.  Most of these subjects had a history of other 
autoimmune disease and/or prior treatment with agents that offered plausible 
alternative etiologies, however, immune-mediated adverse events can potentially 
involve any organ system. 
 
Any other talimogene laherparepvec-related non-hematologic or hematologic 
toxicities Grade 3 or greater occur that, in the opinion of the investigator, would 
require a dose delay of greater than 6 weeks from the date of the planned dose 
(ie, approximately 9 weeks from the previous dose). 
 
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 dangerous for the subject. 
Dosing should be permanently discontinued if, in the opinion of the investigator, the 
subject develops clinical evidence of any serious herpes infection (such as HSV 
hepatitis, encephalitis, or disseminated infection).  Systemic anti-herpetic drugs 
(eg, acyclovir, valacyclovir, or famciclovir) should only be reserved for suspected cases 
of severe herpetic infection as outlined in the Guidelines for Suspected Serious Herpetic 
Infections document, but topically administered anti-herpetic drugs may be administered 
for limited suspected herpetic skin lesions after they are swabbed and tested for 
talimogene laherparepvec using qPCR. 
For Part 1 Group A Cohorts 1-6, Part 1 Group B Cohorts 5 and 6a, and Part 2 Arms I-VI, 
in subjects with history of HBV and HCV, viral load should be rechecked when ALT or 
AST are elevated more than twice their baseline value. If reactivation of HBV or HCV is 
confirmed, discontinuation of talimogene laherparepvec and starting hepatitis antiviral 
medication should be considered after consultation with the sponsor medical monitor. 
For Part 1 Group B Cohort 6b and Part 2 Group B Arm VI subjects with well-controlled 
viral hepatitis, please see Table 15.  Subjects who discontinue talimogene 
laherparepvec are to continue to return for all other study procedures and 


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Protocol Number:  20140318 
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measurements including the 30-day safety follow-up visit (ie, until approximately 30 [ 7] 
days after the last dose of study drug) and long term survival follow-up. 
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/4 mL vials (25 mg/mL) solution for IV infusion.  
Additional details regarding pembrolizumab are provided in the IPIM. 
6.2.2.1 
Pembrolizumab Dosage, Administration, and Schedule 
The Pembrolizumab treatment to be used in this trial is outlined in Table 5 below.   
Table 5.  Pembrolizumab Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen 
Use 
Pembrolizumab 
200 mg 
Every three 
weeks 
Intravenous 
Day 1 of each 
cycle (3 week 
cycles) 
Experimental 
Pembrolizumab should begin on the day of enrollment or as close as possible to the 
date on which the subject is allocated/assigned. 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of trial treatments in accordance with the protocol and any applicable laws and 
regulations. 
Trial treatment of pembrolizumab will be administered on Day 1 of each 3-week 
treatment cycle after all procedures and assessments have been completed as detailed 
in the Schedule of Assessments (Table 10 and Table 13).   
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  
Sites 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 
between -5 minutes and 10 minutes is permitted (ie, infusion time is 30 minutes - 
5 min/10 min). 


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The dose, start date/time, stop date/time, and lot number of pembrolizumab are to be 
recorded on the CRF. 
 
 
6.2.2.2 
Dosage Modification and Toxicity Management Guidelines for 
Pembrolizumab 
6.2.2.2.1 
Dose Modification and Toxicity Management for Immune-related 
Adverse Events Associated With Pembrolizumab 
Adverse events associated with pembrolizumab exposure may represent an 
immunologic etiology.  These immune-related adverse events may occur shortly after 
the first dose or several months after the last dose of pembrolizumab treatment and may 
affect more than one body system simultaneously.  Therefore, early recognition and 
initiation of treatment is critical to reduce complications.  Based on existing clinical trial 
data, most immune-related adverse events were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care.  For suspected immune-related adverse events, ensure adequate evaluation to 
confirm etiology or exclude other causes.  Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation.  
Based on the severity of immune-related adverse events, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.  Dose modification and 
toxicity management guidelines for immune-related adverse events associated with 
pembrolizumab are provided in Table 6.  See Section 6.2.2.3 for supportive care 
guidelines, including use of corticosteroids. 
 


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Protocol Number:  20140318 
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Table 6.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With 
Pembrolizumab  
General instructions: 
1.  Corticosteroid taper should be initiated upon irAE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2.  For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after irAE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered.  Pembrolizumab must be permanently discontinued if irAE 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.  
3.  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 
(CTCAEv4.03) 
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 to 2 mg/kg prednisone or equivalent) 
followed by taper 
Add prophylactic antibiotics for 
opportunistic infections 
Monitor subjects for signs and symptoms of 
pneumonitis 
Evaluate subjects with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment 
 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
 
Monitor subjects 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). 
Subjects with  Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis.  
Subjects 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. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
Page 1 of 3 
Footnotes on the last page of the table 


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Protocol Number:  20140318 
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Table 6.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With 
Pembrolizumab 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2a 
Withhold 
Administer corticosteroids (initial dose of 
0.5 to 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 3b or 4c 
Permanently 
discontinue 
Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
New onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withholdd 
Initiate insulin replacement therapy for 
subjects with T1DM  
Administer antihyperglycemic in 
participants with hyperglycemia  
Monitor subjects 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 
discontinued  
Hyperthyroidism  
Grade 2 
Continue  
Treat with nonselective beta-blockers 
(e.g., propranolol) or thionamides as 
appropriate  
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinued 
Page 2 of 3 
Footnotes on the last page of the table 


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Date: 26 October 2021   
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Table 6.  Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With 
Pembrolizumab 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.03) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Hypothyroidism 
Grade 2, 3 or 4 
Continue  
Initiate thyroid replacement hormones (eg, 
levothyroxine or liothyroinine) per standard 
of care. 
Monitor for signs and symptoms of thyroid 
disorders.  
Nephritis: grading 
according to 
increased 
creatinine or acute 
kidney injury  
Grade 2 
Withhold  
Administer corticosteroids (prednisone 1 to 
2 mg/kg or equivalent) followed by taper. 
Monitor changes of renal function 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 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 
Myocarditis 
Grade 1 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All other irAEs 
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 evente.   
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
Page 3 of 3 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
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Page 80 of 196 
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AE  adverse event; ALT  alanine aminotransferase; AST  aspartate aminotransferase; CTCAE  Common Terminology Criteria for Adverse Events; DRESS  Drug 
Rash with Eosinophilia and Systemic Symptom; GI  gastrointestinal; irAE  immune-related adverse event; IV  intravenous; SJS  Stevens-Johnson Syndrome; 
v  version; T1DM  type 1 diabetes mellitus; TEN  Toxic Epidermal Necrolysis; ULN  upper limit of normal. 
 
Note:  Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT:   3.0 to 5.0 x ULN if baseline normal;  3.0 to 5.0 x baseline, if baseline abnormal; bilirubin:  1.5 to 3.0 x ULN if baseline normal;  1.5 to 3.0 x baseline if 
baseline abnormal 
b AST/ALT:   5.0 to 20.0 x ULN, if baseline normal;  5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:  3.0 to 10.0 x ULN if baseline normal;  3.0 to 10.0 x 
baseline if baseline abnormal 
c AST/ALT:   20.0 x ULN, if baseline normal;  20.0 x baseline, if baseline abnormal; bilirubin:  10.0 x ULN if baseline normal;  10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  If control achieved or  Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 


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6.2.2.2.2 
Dose Modification and Toxicity Management of Infusion-reactions 
Related to Pembrolizumab 
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 7. 
 


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Table 7.  Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
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 therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for  24 hrs 
Stop Infusion. 
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 
1 hour of stopping drug infusion, 
the infusion may be restarted at 
50 of the original infusion rate 
(e.g. 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 study drug treatment 
Subject may be premedicated 
1.5 hr ( 30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 
Page 1 of 2 
Footnotes on the last page of the table 


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Table 7.  Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
 
Epinephrine** 
 
IV fluids 
 
Antihistamines 
 
NSAIDs 
 
Acetaminophen 
 
Narcotics 
 
Oxygen 
 
Pressors 
 
Corticosteroids 
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. 
**In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Subject is permanently 
discontinued from further study 
drug treatment. 
No subsequent dosing 
Page 2 of 2 
CTCAE  Common Terminology Criteria for Adverse Events; IV  intravenous; NSAIDs  Nonsteroidal anti-
inflammatory drugs; PO  oral 
a Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.  For further information, please refer to the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE) at http://ctep.cancer.gov 
6.2.2.2.3 
Other Allowed Dose Interruption for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related adverse 
events such as medical / surgical events or logistical reasons not related to study 
therapy.  Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the sponsor.  The reason for 
interruption should be documented in the subject’s study record. 


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6.2.2.3 
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 along with the dose 
modification guidelines in Section 6.2.2.2, (Table 6).  Where appropriate, these 
guidelines include the use of oral or IV 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 causes 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 of the event, it is determined not to be related to 
pembrolizumab, the Investigator does not need to follow the treatment guidance.  Refer 
to in Section 6.2.2.2, for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. 
6.2.2.4 
Diet and Other Considerations While Taking Pembrolizumab 
Subjects should maintain a normal diet unless modifications are required to manage 
adverse events such as diarrhea, nausea, or vomiting. 
6.3 
Other Protocol-required Therapies 
All other protocol-required therapies including, topical anesthetic or injectable local 
anesthetic medications used for pretreatment of the talimogene laherparepvec injection 
site and oral or systemic steroids for management of pembrolizumab immune related 
adverse events, that are commercially available are not provided by Amgen (except if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these protocol-required therapies.  
Additional details regarding these protocol-required therapies are provided in the IPIM. 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, ALP, AST, ALT, TBL) and/or INR 
and/or signs/symptoms of hepatitis (as described in Sections 6.4.1 and 6.4.2) may meet 
the criteria for withholding or permanent discontinuation of Amgen investigational 


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Protocol Number:  20140318 
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product as specified in the Guidance for Industry Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation, July 2009.  Refer to Section 9.2.5.1 for 
management of hepatic events of clinical interest associated with pembrolizumab. 
6.4.1 
Criteria for Permanent Discontinuation of 
Talimogene Laherparepvec Due to Potential Hepatotoxicity 
Talimogene laherparepvec should be discontinued permanently and the subject should 
be followed according to the recommendations in Appendix E (Drug-induced Liver Injury 
Reporting and Additional Assessment) for possible drug-induced liver injury (DILI), if ALL 
of the criteria below are met: 
 
Current TBL  2x ULN following baseline TBL  
 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 (ie, dosing should not continue while awaiting the results of 
pending investigations); important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
Hepatobiliary tract disease 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, HSV 
excluding talimogene laherparepvec, 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, rhabdomyolysis, hemolysis) 
Please refer to the Guidelines for Suspected Serious Herpetic Infections for conditions 
where talimogene laherparepvec may be suspected as a cause of hepatitis and for 
further management. 


Product:  Talimogene Laherparepvec 
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6.4.2 
Criteria for Conditional Withholding of Talimogene Laherparepvec 
Due to Potential Hepatotoxicity  
For subjects who do not meet the criteria for permanent discontinuation of talimogene 
laherparepvec outlined above, talimogene laherparepvec should be withheld if ANY of 
the following criteria are met, and the subject should be evaluated for DILI: 
 
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: TBL  3 x ULN at any time 
 
or: ALP  8 x ULN at any time 
Talimogene laherparepvec should be withheld pending investigation into alternative 
causes of DILI.  If talimogene laherparepvec is withheld, the subject is to be followed 
according to recommendations in Appendix E (Drug-induced Liver Injury Reporting and 
Additional Assessment) for possible DILI.  Re-challenge may be considered if an 
alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is 
discovered and the laboratory abnormalities resolve to normal or baseline. 
Please refer to the Guidelines for Suspected Serious Herpetic Infections for conditions 
where talimogene laherparepvec may be suspected as a cause of hepatitis and for 
further management. 
6.4.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to re-challenge the subject should be discussed and agreed upon 
unanimously between the subject and investigator, and between the investigator and 
Amgen Medical Monitor. 
If signs or symptoms recur with re-challenge, then talimogene laherparepvec should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.4.1) should not be re-challenged without 
consulting the Amgen Medical Monitor. 
Pembrolizumab should be permanently discontinued for pembrolizumab-related Grade 3 
or 4 increase in AST or ALT with no further rechallenge.  If there is another etiology for 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
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the AST or ALT elevation, rechallenge with pembrolizumab may only occur with approval 
of the medical monitor. 
6.5 
Concomitant Therapy  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.9. 
All prescription and nonprescription concomitant medication administered from the 
signing of the main informed consent, on an ongoing basis at enrollment, as well as 
changes in such concomitant medication, and, any new concomitant medication taken 
while the subject is on study, should be recorded on the appropriate CRF until 
approximately 30 (7) days after the last dose of talimogene laherparepvec or 
pembrolizumab, whichever is later.  The therapy name, indication, dose, unit, frequency, 
start date, and stop date will be collected. 
Investigators should use supportive care agents in compliance with their respective 
regional label.  Investigators may not use supportive care agents as part of a separate 
clinical trial. 
6.6 
Other Treatment Procedures  
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of 
talimogene laherparepvec and liver biopsies are no longer performed in this 
study.   
Treatment with talimogene laherparepvec and pembrolizumab in the combination setting 
may result in the reduction of tumor burden such that surgical resection of previously 
unresected lesion becomes possible. Investigators may choose to resect lesions which 
become suitable for resection to render the subject free of macroscopic disease.  
Additionally, biopsies may be taken of liver lesions for tumor analysis during study.  In 
the event of a CR, any residual target lesions must be documented by representative 
biopsy to not contain viable tumor.  If a subject undergoes resection of the lesion in the 
event other than CR, the investigator or designee should notify the sponsor medical 
monitor and the procedure should be recorded in the source document and CRF.  In 
these instances, if the response of other lesions is at least PR (if other lesions remain), 
the response should be designated PR with the date of surgery as the date of response.  
If no residual disease remains following surgery, this should also be noted in the CRF, 
the response definition again being PR if viable cancer was noted in the surgical 


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Protocol Number:  20140318 
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specimen, and CR if no viable cancer was identified in the surgical specimen.  Best 
response of CR or PR due to surgeries will not be considered for assessment of ORR or 
BOR. 
Palliative surgery for relief of symptoms is allowed.  Treatment with talimogene 
laherparepvec and/or pembrolizumab should be held, and the investigator or designee 
should notify the sponsor as soon as possible.  Subjects may be allowed to remain on 
study after discussion between the sponsor medical monitor and the investigator.  
Investigator must get approval from the sponsor medical monitor before resuming 
talimogene laherparepvec and/or pembrolizumab.  
Local palliative radiation treatment for relief of various symptoms, including but not 
limited to bleeding or pain associated with the underlying disease will be permitted at 
any time during the study.  Subjects with local symptoms suggestive of disease 
progression should be evaluated for tumor response per modified irRC-RECIST (see 
Appendix D) prior to the administration of palliative radiotherapy.  If a subject undergoes 
local radiation, the investigator or designee should notify the sponsor medical monitor as 
soon as possible and the treatment should be recorded in the source document and 
CRF. 
If a subject demonstrates evidence of new or worsening CNS metastases, talimogene 
laherparepvec and/or pembrolizumab treatment should be withheld and the investigator 
or designee should notify the sponsor’s medical monitor as soon as possible.  Subjects 
may be allowed to remain on study after discussion between the sponsor medical 
monitor and the investigator to determine the appropriateness of treatment resumption 
provided CNS lesions can be treated with stereotactic radiotherapy (including Gamma 
Knife), whole brain radiation, or craniotomy and if there is no change in the baseline 
ECOG performance status.  Subjects may be allowed to resume talimogene 
laherparepvec treatment per Section 6.2.1 following treatment of CNS metastases while 
receiving dexamethasone or a similar corticosteroid at no more than 1.5 mg 
dexamethasone (or 10 mg prednisone) per day.  If higher doses of corticosteroid are 
used, talimogene laherparepvec must be held until that dose level is reached during the 
period of steroid tapering. 
If a subject with confirmed PD (ie, two consecutive tumor assessments at least 4 weeks 
[28 days] apart demonstrating PD) is clinically stable or clinically improved, and there is 
no further increase in tumor burden at the confirmatory assessments (assessed by the 


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Protocol Number:  20140318 
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investigator and site radiologist, if applicable), an exception may be considered to 
continue treatment upon consultation with the sponsor medical monitor. 
6.7 
Medical Devices 
Non-investigational medical devices may be used in the conduct of this study as part of 
standard care. 
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles, alcohol 
prep pads), that are commercially available are not usually provided or reimbursed by 
Amgen (except, for example, if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these devices. 
6.8 
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 any investigational or non-investigational product(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. 
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.9 
Excluded Treatments and/or Procedures During Study Period  
Subjects must not use any of the following therapies during screening or treatment 
period (including retreatment for post-CR relapse) of this trial: 
 
investigational agents (other than pembrolizumab and talimogene laherparepvec) or 
procedures   
 
warfarin.  Other anticoagulants (ie. low molecular weight heparins, non-steroidal 
anti-inflammatory drugs) that do not prolong the PT/INR may be administered after 
investigator discussion with the sponsor and as long as there is adherence to 
institutional guidelines requiring their withholding for interventional radiology 
procedures. 
 
concurrent experimental or approved anti-tumor therapies or biological therapy other 
than study drug and radiation therapy required for palliation (as noted in Section 6.5) 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case by case basis after consultation with Sponsor.  The 
subject must have clear measurable disease outside the radiated field.  Administration of 
palliative radiation therapy will be considered clinical progression for the purposes of 
determining PFS. 
 
immunotherapy not specified in this protocol 
 
chemotherapy not specified in this protocol 


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 
chronic oral or systemic steroid medication use at a dose of 10 mg/day of 
prednisone (1.5 mg/day dexamethasone) or equivalent (with the exception of 
treatment for adverse events [see Section 6.2.1.2] and CNS metastases 
[see Section 6.5]).  Steroids with low systemic absorption [eg, triamcinolone 
hexacetonide] injected into a joint space, and intermittent use of steroid inhalers or 
topical steroid is allowed). 
 
antiherpetic drugs, except those topically administered 
 
live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 
Calmette-Guerin (BCG), and typhoid (oral) vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed. However, intranasal 
influenza vaccines (eg, Flu - Mist) are live attenuated vaccines, and are not allowed. 
 
any surgery for cancer (other than the exceptions noted in Section 6.6) 
 
Subjects must not schedule any elective non-cancer-related surgeries during the 
treatment period and for at least 30 days after the last administration of study drug.  
If a subject undergoes any unexpected surgery during the course of the study, study 
treatment must be withheld and the investigator or designee should notify the 
sponsor medical monitor as soon as possible.  A subject may be allowed to resume 
study drug if both the investigator and sponsor medical monitor agree to restart study 
therapy. 
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the 
trial.  Subjects may receive other medications that the investigator deems to be 
medically necessary. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
The schedule of the assessments for the study is summarized in Table 8 through 
Table 13. 
Refer to the applicable supplemental laboratory manuals for detailed collection and 
handling of laboratory samples. 
 


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Table 8.  Schedule of Assessments for Talimogene Laherparepvec Monotherapy 
Part 1 
 
Screening 
Study Treatmentd 
(week/cycle number) 
Follow-
up 
Study Procedures 
 28 
daysa 
 10 
days
b 
 72 
hour
c 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
1
1 
12 13 
14 
15 
1
6 
17  18   
Safetye 
Survivalf 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
General Assessments 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg,w 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Physical Exam 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Child-Pugh Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Recording of Concomitant Medicationh 
    X 
X 
Xi 
Review of DREs, AEs and SAEsh 
    X 
X 
X 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Laboratory Tests 
Chemistryj 
 
X 
 
X 
X 
X 
X 
X 
X 
X X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Hematologyj 
 
X 
 
X 
X 
X 
X 
X 
X 
X X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Coagulation (PT/INR and PTT or aPTT)j 
 
X 
 
X 
X 
X 
X 
X 
X 
X X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urine or Serum Pregnancy Testk 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Disease Specific Assessmentsl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum LDHm 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B and C Testingn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA (CRC and GEC Adenocarcinoma 
Subjects Only)m 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
AFP (HCC Subjects Only)m 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
CA 19-9 (GEC, CRC, and HCC Only)m 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 2 
Footnotes and abbreviations are defined after Table 9 below  


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Table 8.  Schedule of Assessments for Talimogene Laherparepvec Monotherapy 
Part 1 
 
Screening 
Study Treatmentd 
(week/cycle number) 
Follow-
up 
Study Procedures 
 28 
daysa 
 10 
days
b 
 72 
hour
c 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 
12 
13 
1
4 
15 
1
6 
17 
18  
Safetye 
Survivalf 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Central Laboratory Tests 
HSV-1 IgG Antibody Serostatus 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood and Urine for qPCRq 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Swab of Injection Site Surfaces and 
Occlusive Dressingsr 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
 
X 
 
 
 
 
 
 
 
 
 
 
Swab of Oral Mucosas 
 
 
 
X 
X 
X 
X 
X 
X 
X X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Swab of Herpetic Lesion for qPCRt 
 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
Radiographic Tumor/Response Assessments 
Radiographic (CT, PET/CT, or MRI) 
Scans & Tumor Assessment u 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Optional liver ultrasoundv 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Administration 
Talimogene Laherparepvecw 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X
w 
 
 
 
 
Post-treatment Observationx 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X  
 
 
 
 
Reporting Exposure to Talimogene Laherparepvec 
Exposure of Subject’s Household 
member or Caregivery 
 
 
 
 
 
Exposure of Subject’s Healthcare 
Providery 
 
 
 
 
 
Page 2 of 2 
Footnotes and abbreviations are defined after Table 9 below 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 93 of 196 
CONFIDENTIAL 
 
 
Table 9.  Schedule of Assessments for Talimogene Laherparepvec Monotherapy:  Post Cycle 6 
 
Study Treatmentd 
(week/cycle number) 
Follow-up 
Study Procedures 
19 
2
0 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35  
36   
Safetye 
Survivalf 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
GENERAL ASSESSMENTS 
Informed Consent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg,x 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Child-Pugh Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Recording of Concomitant Medicationh 
 
X 
Xi 
Review of DREs, AEs and SAEsh 
 
X 
X 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LOCAL LABORATORY TESTS 
Chemistryj 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Hematologyj 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Coagulation (PT/INR and PTT or aPTT)j 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urine or Serum Pregnancy Testk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum LDHl 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B and C Testingn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA (CRC and GEC Adenocarcinoma 
Subjects Only)l 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
AFP (HCC Subjects Only)l 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
CA 19-9 (GEC , CRC, and HCC Only)l 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 2 
Footnotes and abbreviations are defined after Table 9 below 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 94 of 196 
CONFIDENTIAL 
 
 
Table 9.  Schedule of Assessments for Talimogene Laherparepvec Monotherapy:  Post Cycle 6 
 
Study Treatmentd 
(week/cycle number) 
Follow-up 
Study Procedures 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35  
36   
Safetye 
Survivalf 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
CENTRAL LABORATORY TESTS 
HSV-1 IgG Antibody Serostatus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood and Urine for qPCRq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Swab of Oral Mucosas 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Swab of Herpetic Lesion for qPCRq,t 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
RADIOGRAPHIC TUMOR/RESPONSE ASSESSMENTS 
Radiographic (CT, PET/CT, or MRI) Scans 
& Tumor Assessmentu 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
TREATMENT ADMINISTRATION 
Talimogene Laherparepvecw 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Post-treatment Observationx 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X  
 
 
 
 
REPORTING EXPOSURE TO TALIMOGENE LAHERPAREPVEC 
Exposure of Subject’s Household member 
or Caregivery 
 
 
 
 
 
Exposure of Subject’s Healthcare Providery 
 
 
 
 
Page 2 of 2 
AE  adverse event; AFP  alpha fetoprotein; aPTT  activated partial thromboplastin time; CA 19-9  cancer antigen 19-9; CEA  carcinoembryonic antigen; 
CRC  colorectal adenocarcinoma; CRF  case report form; CT  computed tomography; DRE  disease related event; ECG  electrocardiogram; ECOG  Eastern 
Cooperative Oncology Group; GEC  gastroesophageal cancer (adenocarcinoma or squamous cell carcinoma); HCC  hepatocellular carcinoma; HSV-1  herpes 
simplex virus type 1;  IgG  imunoglobulin G; INR  international normalization ratio; LDH   lactate dehydrogenase; MRI  magnetic resonance imaging; PET  
positron emission tomography; PT   prothrombin time; PTT  partial thromboplastin time; qPCR  real-time polymerase chain reaction; SAE  serious adverse event 
a Procedures to be performed  28 days prior to enrollment. 
b Procedures to be performed  10 days prior to enrollment. 
c Procedures to be performed  72 hours prior to enrollment. 
d During treatment, assessments and procedures will be performed within  3 days of the planned visit, unless otherwise specified. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 95 of 196 
CONFIDENTIAL 
 
 
e Safety follow-up will be performed approximately 30 ( 7) days after the last dose of talimogene laherparepvec.  
f Subjects will be followed for survival by clinic visit or telephone contact approximately every 12 weeks  28 days from the date of the safety follow-up visit until up to 
approximately 24 months after the date of last subjects enrolled in Part 1.  Subsequent anti-cancer treatments will be collected as part of the long-term follow-up 
survival assessment. 
g Vital signs (blood pressure, resting heart rate, respiration rate, and temperature) must be performed prior to each talimogene laherparepvec administration. 
h All serious adverse events, follow up to a serious adverse event, including death due to any cause that occur after the subject has signed the main informed consent 
through 90 (7) days after the last administration of talimogene laherparepvec, 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 case report form.  In addition, all serious adverse events that occur during the long-term 
safety follow-up period until the end of study are to be reported to Amgen and recorded in the CRF.  As described in Section 9.2.3.2, there is no requirement to 
monitor study subjects for serious adverse events following the protocol required reporting period (as defined in Section 9.2.3) or after the end of study.  However, 
these serious adverse events should be reported to Amgen (regardless of causality) if the investigator becomes aware of them (per regional regulatory 
requirements).  All serious adverse events must be submitted to Amgen within 24 hours following the investigator’s awareness of the event via the applicable CRF.  
All disease related events and nonserious adverse events that occur and concomitant medications that are administered after the subject has signed the main 
informed consent through 30 (7) days after the last administration of talimogene laherparepvec will be recorded in the events CRF. 
i Only subsequent anti-tumor treatment will be recorded. 
j During treatment blood samples for chemistry, hematology and coagulation panels will be collected weekly for the first 8 weeks of treatment and then prior to each 
talimogene laherparepvec administration until end of study treatment. 
k Urine or serum pregnancy test to be performed on female of childbearing potential.  Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion or as defined in a county-specific protocol supplement at the end of the Appendix Section of the protocol as required per local laws and 
regulations. 
l Disease specific assessments will only be performed on archived tissue (preferred) or screening biopsy tissue if results from previous testing are not available.  
Results should be submitted during screening and any time after enrollment.  For details and a list of disease specific assessments refer to Section 7.2.1. 
m During treatment blood samples for lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP),and cancer antigen 19-9 (CA 19-9) will 
be collected at screening and at week 10 ( 1 week) and then every 9 weeks ( 1 week) prior to talimogene laherparepvec administration until end of study 
treatment. 
n Hepatitis C and B panel should be performed at screening if serology has not been performed previously.  Subjects who are positive for hepatitis B virus (HBV) and 
hepatitis C virus (HCV) infection should receive additional testing of viral load by polymerase chain reaction (PCR) at screening,, and at the safety follow-up.  For 
additional information refer to Section 7.2.1 through 7.2.3.1. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 96 of 196 
CONFIDENTIAL 
 
 
q During treatment blood and urine sample for real-time polymerase chain reaction (qPCR) testing of talimogene laherparepvec DNA will be performed at the following 
time points: on Weeks 1 and 4 prior to talimogene laherparepvec administration and approximately 1 hour ( 15 minutes), 4 hours ( 30 minutes), 8 hours ( 1 hour), 
24 ( 4) hours, 48 ( 4) hours, 7 days ( 2 days), and 14 days ( 2 days) following talimogene laherparepvec administration; on Week 7 prior to talimogene 
laherparepvec administration and 7 days ( 2 days) following talimogene laherparepvec administration; on week 10 prior to talimogene laherparepvec 
administration; and at safety follow-up visit.   
r Swabs of the surface of the injection sites and exterior of occlusive dressings for qPCR testing of talimogene laherparepvec DNA with or without 50 Tissue Culture 
Infective Dose (TCID50) assay of talimogene laherparepvec virus.  During treatment the surface of the injection site will be swabbed at the following timepoints: on 
Weeks 1 and 4 prior to talimogene laherparepvec administration and 24 ( 4) hours, 48 ( 4) hours, 7 ( 2) days, and 14 ( 2) days following talimogene 
laherparepvec administration; on Week 7 prior to talimogene laherparepvec administration and 7 ( 2 days) following talimogene laherparepvec administration; and 
on Week 10 prior to talimogene laherparepvec administration.  During treatment the exterior surface of the injection site dressings will be swabbed at the following 
timepoints: 24 ( 4) hours and 48 ( 4) hours after Week 1 and 4 talimogene laherparepvec administration and 7 ( 2) days after Week 1, 4, and 7 talimogene 
laherparepvec administrations. 
s Swabs of oral mucosa:  During treatment swabs of oral mucosa for qPCR testing of talimogene laherparepvec DNA with or without TCID50 assay for talimogene 
laherparepvec virus will be collected at the following visits:  Week 1 and 4 prior to talimogene laherparepvec administration and 7 ( 2) days and 14 ( 2) days 
following talimogene laherparepvec administration; Week 7 prior to talimogene laherparepvec administration and 7 ( 2) days following talimogene laherparepvec 
administration; Week 10 and subsequent cycles prior to each talimogene laherparepvec administration.  During safety follow-up, swabs of oral mucosa will be 
collected at the 30 (7) day safety follow-up visit for qPCR testing of talimogene laherparepvec DNA.   
t Swabs of any lesion suspected to be herpetic in origin (if any) will be collected during treatment and safety follow-up as follows:  subject should return to clinic within  
3 days of the occurrence of reportable lesion suspected to be herpetic in origin such as cold sores or vesicles.  The lesion should be evaluated by the investigator 
and swabbed if HSV infection is suspected.  The sample will be sent to the central laboratory for detection of talimogene laherparepvec DNA using qPCR testing. 
u Radiographic tumor imaging:  During treatment, radiographic tumor imaging will be performed independent of treatment cycle at week 10 ( 1 week) and then every 
9 weeks ( 1 week) until confirmed progressive disease (PD) per modified immune-related response criteria (irRC) simulating RECIST version 1.1 (irRC-RECIST) 
(Appendix D).  Radiographic imaging is required at the safety follow up visit if the subject ended treatment prior to documentation of confirmed PD per modified 
irRC-RECIST and has not had radiographic tumor imaging performed within 9 weeks ( 1 week) of the visit.  Every effort should be made to complete radiographic 
assessments during the long-term follow-up approximately every 12 weeks ( 1 week) until documented confirmed PD per modified irRC-RECIST, start of new 
anticancer treatment, death, or end of study, whichever occurs first, for subjects discontinuing study treatment for any reason other than confirmed PD.  Response 
(complete response [CR], or partial response [PR]) or disease progression to be confirmed by second consecutive radiographic assessments no less than 4 weeks 
from the date of the first documented response or disease progression.  Note:  Confirmation of disease progression is required only in the absence of rapid clinical 
deterioration (ie, rapid decline in performance status) or symptomatic disease requiring rapid initiation of alternative systemic anti-cancer therapy. 
v To be performed if required by site for assessment of the intrahepatic lesion injection location.  As of Protocol Amendment 6 (dated 26 October 2021), 
intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study.   
w If no progression is seen after a total of 6 cycles, up to 6 additional cycles of talimogene laherparepvec, at maximum tolerated dose if known or otherwise previously 
received dose, every 21 ( 3 days) may be administered, or the subject may proceed to alternative therapies depending on investigator discretion. 
x All subjects will undergo a 23 hour observation period following the first 3 cycles of talimogene laherparepvec treatment with vital signs (temperature, resting heart 
rate, systolic and diastolic blood pressure and respiratory rate) recorded every 30 minutes for the first 2 hours, hourly for the next 4 hours, then once every 4 to 
6 hours with vital signs also obtained at the end of the observation period.  For cycles 4 onwards, the observation period after each dose of talimogene laherparepvec 
may be reduced to a minimum of 6 hours at the investigator’s discretion with vital signs recorded every 30 minutes for the first 2 hours and hourly for the next 4 hours 
and once at the end of the observational period.  The subjects should be hospitalized if there is clinical deterioration during any observation period. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 97 of 196 
CONFIDENTIAL 
 
 
y Reporting potential or known unintended exposure to talimogene laherparepvec:  If a household member, caregiver, or healthcare provider who has had close contact 
with the subject is suspected to have been exposed to talimogene laherparepvec (eg, has signs or symptoms suspected to be herpetic origin or is accidentally 
exposed to talimogene laherparepvec), report the potential or known unintended exposure to talimogene laherparepvec, suspected related signs or symptoms, and 
detection of talimogene laherparepvec DNA by qPCR testing in a swab taken from a lesion, if any, in a subject’s household member, caregiver, or healthcare 
provider.   


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 98 of 196 
CONFIDENTIAL 
 
 
Table 10.  Part 1 Schedule of Assessments for Talimogene Laherparepvec and Pembrolizumab Combination Treatment 
 
Screening 
Study Treatmentd  
(week/cycle number) 
Follow-
up 
Study Procedures 
 28 daysa 
 10 daysb 
 72 hourc 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17  
18   
Safetye 
Survivalf 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
GENERAL ASSESSMENTS 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg,h 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Physical Exam 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Child-Pugh Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Recording of Concomitant Medicationi 
X 
 
X 
Xj 
Review of DREs, AEs and SAEsi 
X 
 
X 
X 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LOCAL LABORATORY TESTS 
Chemistryk 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Hematologyk 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Coagulation (PT/INR and PTT or aPTT)k 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Thyroid Function Tests (T3, FT3, FT4, 
TSH)l 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urine or Serum Pregnancy Testm 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Disease Specific Assessmentsn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum LDHo 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B and C Testingp 
 
X 
 
 
 
 
 
 
 
Xq 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA (CRC and GEC Adenocarcinoma 
Subjects Only)o 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
AFP (HCC Subjects Only)o 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
CA 19-9 (GEC , CRC, and HCC Only)o 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 2 
Footnotes and abbreviations after Table 11 below. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 99 of 196 
CONFIDENTIAL 
 
 
Table 10.  Part 1 Schedule of Assessments for Talimogene Laherparepvec and Pembrolizumab Combination Treatment 
 
Screening 
Study Treatmentd 
(week/cycle number) 
Follow-
up 
Study Procedures 
 28 daysa 
 10 daysb 
 72 hourc 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Safetye 
Survivalf 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
CENTRAL LABORATORY TESTS 
HSV-1 IgG Antibody Serostatus 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood and Urine for qPCRt 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Swab of Injection Site Surfaces and 
Occlusive Dressingsu 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Swab of Oral Mucosav 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Swab of Herpetic Lesion for qPCRw 
 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
Blood for Anti-Pembrolizumab antibodyx 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Blood for Pembrolizumab PKy 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Radiographic (CT, PET/CT, or MRI) 
Scans & Tumor Assessment z 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Optional liver ultrasoundaa 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT ADMINISTRATION 
Talimogene Laherparepvecab 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xw 
 
 
 
 
Pembrolizumabac 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Post-treatment Observationh  
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
REPORTING EXPOSURE TO TALIMOGENE LAHERPAREPVEC 
Exposure of Subject’s Household 
member or Caregiverad 
 
 
 
 
 
 
 
Exposure of Subject’s Healthcare 
Providerad 
 
 
 
 
 
 
 
Page 2 of 2 
Footnotes and abbreviations after Table 11 below. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 100 of 196 
CONFIDENTIAL 
 
 
Table 11.  Part 1 Schedule of Assessments for Talimogene Laherparepvec and Pembrolizumab Combination Treatment:  Post 
Cycle 6 
 
Study Treatmentd  (week/cycle number) 
Follow-up 
Study Procedures 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35  
36   
Pembrolizumab 
Cycles 7-35 
Safetye 
Survivalf 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
GENERAL ASSESSMENTS 
Informed Consent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg, h 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
ECOG Performance Status 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Child-Pugh Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Recording of Concomitant Medicationi 
X 
Xj 
Review of DREs, AEs and SAEsi 
X 
X 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LOCAL LABORATORY TESTS 
Chemistryk 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Hematologyk 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Coagulation (PT/INR and PTT or aPTT)k 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Thyroid Function Tests (T3, FT3, FT4, 
TSH)l 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine or Serum Pregnancy Testm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum LDHo 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B and C Testingp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA (CRC and GEC Adenocarcinoma 
Subjects Only)o 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
AFP (HCC Subjects Only)o 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
CA 19-9 (GEC , CRC, and HCC Only)o 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Footnotes and abbreviations after Table 11 below.  
 
Page 1 of 2 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 101 of 196 
CONFIDENTIAL 
 
 
Table 11.  Part 1 Schedule of Assessments for Talimogene Laherparepvec and Pembrolizumab Combination Treatment:  Post 
Cycle 6 
 
Study Treatmentd  
(week/cycle number) 
Follow-
up 
Study Procedures 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35  
36   
Pembrolizumab 
Cycles 7-35 
Safetye 
Survivalf 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
CENTRAL LABORATORY TESTS 
HSV-1 IgG Antibody Serostatus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood and Urine for qPCRt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Swab of Oral Mucosav 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Swab of Herpetic Lesion for qPCRw 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
Blood for Anti-Pembrolizumab antibodyx 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Pembrolizumab PKy 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RADIOGRAPHIC TUMOR/RESPONSE ASSESSMENTS 
Radiographic (CT, PET/CT, or MRI) 
Scans & Tumor Assessment z 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
TREATMENT ADMINISTRATION 
Talimogene Laherparepvecab 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xab 
 
 
 
 
 
Pembrolizumabac 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Post-treatment Observationg,h 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
REPORTING EXPOSURE TO TALIMOGENE LAHERPAREPVEC 
Exposure of Subject’s Household 
member or Caregiverad 
 
 
 
 
Exposure of Subject’s Healthcare 
Providerad 
 
 
 
 
Page 2 of 2 
Footnotes on the next page of the table 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 102 of 196 
CONFIDENTIAL 
 
 
AE  adverse event; AFP  alpha fetoprotein; aPTT  activated partial thromboplastin time; CA 19-9  cancer antigen 19-9; CEA  carcinoembryonic antigen; 
CRC  colorectal adenocarcinoma; CRF  case report form; CT  computed tomography; DRE  disease related event; ECG  electrocardiogram; ECOG  Eastern 
Cooperative Oncology Group; FT3  free triiodothyronine; FT4  free thyroxine; GEC  gastroesophageal cancer (adenocarcinoma or squamous cell carcinoma); 
HCC  hepatocellular carcinoma; HSV-1  herpes simplex virus type 1; IgG  imunoglobulin G; INR  international normalization ratio; LDH  lactate 
dehydrogenase; MRI  magnetic resonance imaging; PET  positron emission tomography; PK  pharmacokinetics; PT  prothrombin time; PTT  partial 
thromboplastin time; qPCR  real-time polymerase chain reaction; SAE  serious adverse event; T3  triiodothyronine; TSH  thyroid-stimulating hormone 
a Procedures to be performed  28 days prior to enrollment. 
b Procedures to be performed  10 days prior to enrollment. 
c Procedures to be performed  72 hours prior to enrollment. 
d During treatment, assessments and procedures will be performed within  3 days of the planned visit, unless otherwise specified. 
e Safety follow-up will be performed approximately 30 ( 7) days after the last dose of talimogene laherparepvec. 
f Subjects will be followed for survival by clinic visit or telephone contact approximately every 12 weeks  28 days from the date of the safety follow-up visit until up to 
approximately 24 months after the date of last subjects enrolled in Part 2 per tumor type.  Subsequent anti-cancer treatments will be collected as part of the long-
term follow-up survival assessment. 
g Vital signs (blood pressure, resting heart rate, respiration rate, and temperature) must be performed prior to each talimogene laherparepvec administration. 
h All subjects will undergo a 23 hour observation period following the first 3 cycles of talimogene laherparepvec treatment with vital signs (temperature, resting heart 
rate, systolic and diastolic blood pressure and respiratory rate) recorded every 30 minutes for the first 2 hours, hourly for the next 4 hours, then once every 4 to 
6 hours with vital signs also obtained at the end of the observation period.  For cycles 4 onwards, the observation period after each dose of talimogene 
laherparepvec may be reduced to a minimum of 6 hours at the investigator’s discretion with vital signs recorded every 30 minutes for the first 2 hours and hourly for 
the next 4 hours and once at the end of the observational period.  The subjects should be hospitalized if there is clinical deterioration during any observation period. 
i All serious adverse events follow up to a serious adverse event, including death due to any cause that occur after the subject has signed the main informed consent 
through 90 (7) days after the last administration of talimogene laherparepvec or pembrolizumab, 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 case report form. In addition, all serious adverse events that 
occur during the long-term safety follow-up period until the end of study are to be reported to Amgen and recorded in the CRF. As described in Section 9.2.3.2, there 
is no requirement to monitor study subjects for serious adverse events following the protocol required reporting period (as defined in Section 9.2.3) or after the end 
of study.  However, these serious adverse events should be reported to Amgen (regardless of causality) if the investigator becomes aware of them (per regional 
regulatory requirements).  All serious adverse events must be submitted to Amgen within 24 hours following the investigator’s awareness of the event via the 
applicable CRF.  All disease-related events and non-serious adverse events that occur, and concomitant medications that are administered after the first dose of 
talimogene laherparepvec or pembrolizumab through 30 (7) days after the last administration of talimogene laherparepvec or pembrolizumab will be recorded in 
the events CRF. 
j Only subsequent anti-tumor treatment will be recorded. 
k During treatment blood samples for chemistry, hematology and coagulation panels will be collected weekly for the first 8 weeks of treatment and then prior to each 
talimogene laherparepvec administration until end of study treatment. 
l Blood samples for thyroid function tests (triiodothyronine [T3] or free T3 [FT3] per local standard, free thyroxine [FT4], and thyroid-stimulating hormone [TSH]) will be 
collected at screening.  Samples will be collected prior to study treatment administration on day 1 of weeks 1, 7, 13, 19, 25 and every 12 weeks thereafter until end 
of pembrolizumab treatment.  Blood sample will also be collected at the safety follow-up visit.  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. 
m Urine or serum pregnancy test to be performed on female of childbearing potential.  Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion or as defined in a county-specific protocol supplement at the end of the Appendix Section of the protocol as required per local laws and 
regulations. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
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CONFIDENTIAL 
 
 
n Disease specific assessments will only be performed on archived tissue (preferred) or screening biopsy tissue if results from previous testing are not available.  
Results should be submitted during screening and any time after enrollment.  For details and a list of disease specific assessments refer to Section 7.2.1. 
oDuring treatment blood samples for lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP),and cancer antigen 19-9 (CA 19-9) will 
be collected at screening and at week 10 ( 1 week) and then every 9 weeks ( 1 week) prior to talimogene laherparepvec administration until end of study 
treatment. 
p Hepatitis C and B panel should be performed at screening if serology has not been performed previously.  Subjects who are positive for hepatitis B virus (HBV) and 
hepatitis C virus (HCV) infection should receive additional testing of viral load by polymerase chain reaction (PCR) and HCV genotype (if applicable) at screening 
and at the safety follow-up. For additional information refer to Section 7.2.1 through 7.2.3.1.  In addition, HBSAg testing should be performed if ALT is elevated  5x 
ULN and/or  3 x baseline in subjects with hepatitis B.  Refer to Table 15 for more details. 
q Repeated Hepatitis B and/or C testing is only needed for Group B Cohort 6b 
t During treatment blood and urine sample for real-time polymerase chain reaction (qPCR) testing of talimogene laherparepvec deoxyribonucleic acid (DNA) will be 
performed at the following time points:  on Weeks 1 and 4 prior to talimogene laherparepvec administration and approximately 1 hour [ 15 minutes], 4 hours 
[ 30 minutes], 8 hours [ 1 hour], 24 [ 4] hours, 48 [ 4] hours, 7 days ( 2 days), and 14 days ( 2 days) following talimogene laherparepvec administration; on 
Week 7 prior to talimogene laherparepvec administration and 7 days ( 2 days) following talimogene laherparepvec administration; on Week 10 prior to talimogene 
laherparepvec administration; and at safety follow-up visit.   
u Swabs of the surface of the injection sites and exterior of occlusive dressings for qPCR testing of talimogene laherparepvec DNA with or without 50 Tissue Culture 
Infective Dose (TCID50) assay of talimogene laherparepvec virus.  During treatment the surface of the injection site will be swabbed at the following timepoints:  on 
Weeks 1 and 4 prior to talimogene laherparepvec administration and 24 ( 4) hours, 48 ( 4) hours, 7 ( 2) days, and 14 ( 2) days following talimogene 
laherparepvec administration; on Week 7 prior to talimogene laherparepvec administration and 7 ( 2 days) following talimogene laherparepvec administration; and 
on Week 10 prior to talimogene laherparepvec administration.  During treatment the exterior surface of the injection site dressings will be swabbed at the following 
timepoints:  24 ( 4) hours and 48 ( 4) hours after Week 1 and 4 talimogene laherparepvec administration and 7 ( 2) days after Week 1, 4, and 7 talimogene 
laherparepvec administrations. 
v Swabs of oral mucosa:  During treatment swabs of oral mucosa for qPCR testing of talimogene laherparepvec DNA with or without TCID50 assay for talimogene 
laherparepvec virus will be collected at the following visits:   Week 1 and 4 prior to talimogene laherparepvec administration and 7 ( 2) days and 14 ( 2) days 
following talimogene laherparepvec administration; Week 7 prior to talimogene laherparepvec administration and 7 ( 2) days following talimogene laherparepvec 
administration; Week 10 and subsequent cycles prior to each talimogene laherparepvec administration.  During safety follow-up, swabs of oral mucosa will be 
collected at the 30 (7) day safety follow-up visit for qPCR testing of talimogene laherparepvec DNA. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 104 of 196 
CONFIDENTIAL 
 
 
w Swabs of any lesion suspected to be herpetic in origin (if any) will be collected during treatment and safety follow-up as follows:  subject should return to clinic within  
3 days of the occurrence of reportable lesion suspected to be herpetic in origin such as cold sores or vesicles.  The lesion should be evaluated by the investigator 
and swabbed if HSV infection is suspected.  The sample will be sent to the central laboratory for detection of talimogene laherparepvec DNA using qPCR testing. 
x Blood for anti-pembrolizumab antibody (also termed immunogenicity) will be collected at day 1 of:  cycle 1, cycle 2 , cycle 4, cycle 6, and cycle 8 of the additional 
treatment.  All samples should be drawn within 24 hours before infusion of pembrolizumab and at the same time as predose trough blood collection for the PK 
sample.   
y Blood for PK of pembrolizumab:  Predose trough will be collected at day 1 of:  cycle 1, cycle 2 , cycle 4, cycle 6, and cycle 8 of the additional treatment.  All trough 
samples should be drawn within 24 hours before infusion of pembrolizumab. 
z Radiographic tumor imaging:  During treatment, radiographic tumor imaging will be performed independent of treatment cycle at week 10 ( 1 week) and then every 
9 weeks ( 1 week) until confirmed progressive disease (PD) per modified immune-related response criteria (irRC) simulating RECIST version 1.1 (irRC-RECIST) 
(Appendix D).  Radiographic imaging is required at the safety follow up visit if the subject ended treatment prior to documentation of confirmed PD per modified 
irRC-RECIST and has not had radiographic tumor imaging performed within 9 weeks ( 1 week) of the visit.  Every effort should be made to complete radiographic 
assessments during the long-term follow-up approximately every 12 weeks ( 1 week) until documented confirmed PD per modified irRC-RECIST, start of new 
anticancer treatment, death, or end of study, whichever occurs first, for subjects discontinuing study treatment for any reason other than confirmed PD.  Response 
(complete response [CR], or partial response [PR]) or disease progression to be confirmed by second consecutive radiographic assessments no less than 4 weeks 
from the date of the first documented response or disease progression.  Note:  Confirmation of disease progression is required only in the absence of rapid clinical 
deterioration (ie, rapid decline in performance status) or symptomatic disease requiring rapid initiation of alternative systemic anti-cancer therapy. 
aa To be performed if required by site for assessment of the intrahepatic lesion injection location.  As of Protocol Amendment 6 (dated 26 October 2021), 
intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study.   
ab If no progression is seen after a total of 6 cycles, up to 6 additional cycles of talimogene laherparepvec, at maximum tolerated dose if known or otherwise previously 
received dose, every 21 ( 3 days) may be administered, or the subject may proceed to alternative therapies depending on investigator discretion. 
ac Pembrolizumab will be administered intravenously to subjects randomized at a dose of 200 mg every 3 weeks ( 3 days) starting at day 1 of week 1 until confirmed 
PD per modified irRC-RECIST (The same pattern of assessments continue if treatment exceeds week 18).  Subjects can receive up to 35 cycles (approximately  
24 months) with pembrolizumab.   
ad Reporting potential or known unintended exposure to talimogene laherparepvec:  If a household member, caregiver, or healthcare provider who has had close 
contact with the subject is suspected to have been exposed to talimogene laherparepvec (eg, has signs or symptoms suspected to be herpetic origin or is 
accidentally exposed to talimogene laherparepvec), report the potential or known unintended exposure to talimogene laherparepvec, suspected related signs or 
symptoms, and detection of talimogene laherparepvec DNA by qPCR testing in a swab taken from a lesion, if any, in a subject’s household member, caregiver, or 
healthcare provider.   


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 105 of 196 
CONFIDENTIAL 
 
 
Table 12.  Part 2 Schedule of Assessments for Talimogene Laherparepvec and Pembrolizumab Combination Treatment 
 
Screening 
Study Treatmentd  
(week/cycle number) 
Follow-
up 
Study Procedures 
 28 daysa 
 10 daysb 
 72 hourc 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17  
18   
Safetye 
Survivalf 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
GENERAL ASSESSMENTS 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg,h 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Physical Exam 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Child-Pugh Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Recording of Concomitant Medicationi 
X 
 
X 
Xj 
Review of DREs, AEs and SAEsi 
X 
 
X 
X 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LOCAL LABORATORY TESTS 
Chemistryk 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Hematologyk 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Coagulation (PT/INR and PTT or aPTT)k 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Thyroid Function Tests (T3, FT3, FT4, 
TSH)l 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urine or Serum Pregnancy Testm 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Disease Specific Assessmentsn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum LDHo 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B and C Testingp 
 
X 
 
 
 
 
 
 
 
Xq 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA (CRC Subjects Only)o 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
AFP (HCC Subjects Only)o 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 2 
Footnotes and abbreviations after Table 13 below. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 106 of 196 
CONFIDENTIAL 
 
 
Table 12.  Part 2 Schedule of Assessments for Talimogene Laherparepvec and Pembrolizumab Combination Treatment 
 
Screening 
Study Treatmentd 
(week/cycle number) 
Follow-
up 
Study Procedures 
 28 daysa 
 10 daysb 
 72 hourc 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18  
Safetye 
Survivalf 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
CENTRAL LABORATORY TESTS 
HSV-1 IgG Antibody Serostatus 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood and Urine for qPCRt 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Swab of Injection Site Surfaces and 
Occlusive Dressingsu 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Swab of Oral Mucosav 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Swab of Herpetic Lesion for qPCRw 
 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
Radiographic (CT, PET/CT, or MRI) 
Scans & Tumor Assessment x 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Optional liver ultrasoundy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT ADMINISTRATION 
Talimogene Laherparepvecz 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Pembrolizumabaa 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Post-treatment Observationh  
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
REPORTING EXPOSURE TO TALIMOGENE LAHERPAREPVEC 
Exposure of Subject’s Household 
member or Caregiverab 
 
 
 
 
 
 
 
Exposure of Subject’s Healthcare 
Providerab 
 
 
 
 
 
 
 
Page 2 of 2 
Footnotes and abbreviations after Table 13 below. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 107 of 196 
CONFIDENTIAL 
 
 
Table 13.  Part 2 Schedule of Assessments for Talimogene Laherparepvec and Pembrolizumab Combination Treatment:  Post 
Cycle 6 
 
Study Treatmentd  (week/cycle number) 
Follow-
up 
Study Procedures 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35  
36   
Pembrolizumab 
and Talimogene 
Lapherparepvec  
Cycles 7-35 
Safetye 
Survivalf 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
GENERAL ASSESSMENTS 
Informed Consent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg, h 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
ECOG Performance Status 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Child-Pugh Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Recording of Concomitant Medicationi 
X 
Xj 
Review of DREs, AEs and SAEsi 
X 
X 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LOCAL LABORATORY TESTS 
Chemistryk 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Hematologyk 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Coagulation (PT/INR and PTT or aPTT)k 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Thyroid Function Tests (T3, FT3, FT4, 
TSH)l 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine or Serum Pregnancy Testm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum LDHo 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B and C Testingp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA (CRC Subjects Only)o 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
AFP (HCC Subjects Only)o 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 2 
Footnotes and abbreviations after Table 13 below. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 108 of 196 
CONFIDENTIAL 
 
 
Table 13.  Part 2 Schedule of Assessments for Talimogene Laherparepvec and Pembrolizumab Combination Treatment:  Post 
Cycle 6 
 
Study Treatmentd  
(week/cycle number) 
Follow-
up 
Study Procedures 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35  
36   
Pembrolizumab 
and Talimogene 
Lapherparepvec  
Cycles 7-35
Safetye 
Survivalf 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
CENTRAL LABORATORY TESTS 
HSV-1 IgG Antibody Serostatus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood and Urine for qPCRt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Swab of Oral Mucosav 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Swab of Herpetic Lesion for qPCRw 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
RADIOGRAPHIC TUMOR/RESPONSE ASSESSMENTS 
Radiographic (CT, PET/CT, or MRI) 
Scans & Tumor Assessmentx 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
TREATMENT ADMINISTRATION 
Talimogene Laherparepvecz 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pembrolizumabaa 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Post-treatment Observationg,h 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xac 
 
 
REPORTING EXPOSURE TO TALIMOGENE LAHERPAREPVEC 
Exposure of Subject’s Household 
member or Caregiverab 
 
 
 
 
Exposure of Subject’s Healthcare 
Providerab 
 
 
 
 
 
Page 2 of 2 
Footnotes on the next page of the table 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 109 of 196 
CONFIDENTIAL 
 
 
AE  adverse event; AFP  alpha fetoprotein; aPTT  activated partial thromboplastin time; CEA  carcinoembryonic antigen; CRC  colorectal adenocarcinoma; CRF 
 case report form; CT  computed tomography; DRE  disease related event; ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; FT3  free 
triiodothyronine; FT4  free thyroxine; HCC  hepatocellular carcinoma; HSV-1  herpes simplex virus type 1; IgG  imunoglobulin G; INR  international 
normalization ratio; LDH  lactate dehydrogenase; MRI  magnetic resonance imaging; PET  positron emission tomography; PK  pharmacokinetics; PT  
prothrombin time; PTT  partial thromboplastin time; qPCR  real-time polymerase chain reaction; SAE  serious adverse event; T3  triiodothyronine; 
TSH  thyroid-stimulating hormone 
a Procedures to be performed  28 days prior to enrollment. 
b Procedures to be performed  10 days prior to enrollment. 
c Procedures to be performed  72 hours prior to enrollment. 
d During treatment, assessments and procedures will be performed within  3 days of the planned visit, unless otherwise specified. 
e Safety follow-up will be performed 30 ( 7) days after the last dose of talimogene laherparepvec. 
f Subjects will be followed for survival by clinic visit or telephone contact every 12 weeks  28 days from the date of the safety follow-up visit until up to approximately 
24 months after the date of last subjects enrolled in Part 2 per tumor type.  Subsequent anti-cancer treatments will be collected as part of the long-term follow-up 
survival assessment. 
g Vital signs (blood pressure, resting heart rate, respiration rate, and temperature) must be performed prior to each talimogene laherparepvec administration. 
h Subjects having intrahepatic injections will undergo a 6 hour observation period after each dose of talimogene laherparepvec with vital signs (temperature, resting 
heart rate, systolic and diastolic blood pressure and respiratory rate) recorded every 30 minutes for the first 2 hours and hourly for the next 4 hours and once at the 
end of the observation period.  The subjects should be hospitalized if there is clinical deterioration during any observation period.  Subjects who have cutaneous, 
subcutaneous, or nodal injections (no intrahepatic injections) must undergo a 1 hour observation period including vital signs at 30 minutes and 1 hour.  As of 
Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this 
study.   
i All serious adverse events follow up to a serious adverse event, including death due to any cause that occur after the subject has signed the main informed consent 
through 90 (7) days after the last administration of talimogene laherparepvec or pembrolizumab, 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 case report form. In addition, all serious adverse events that 
occur during the long-term safety follow-up period until the end of study are to be reported to Amgen and recorded in the CRF. As described in Section 9.2.3.2, there 
is no requirement to monitor study subjects for serious adverse events following the protocol required reporting period (as defined in Section 9.2.3) or after the end 
of study.  However, these serious adverse events should be reported to Amgen (regardless of causality) if the investigator becomes aware of them (per regional 
regulatory requirements).  All serious adverse events must be submitted to Amgen within 24 hours following the investigator’s awareness of the event via the 
applicable CRF.  All disease-related events and non-serious adverse events that occur, and concomitant medications that are administered after the first dose of 
talimogene laherparepvec or pembrolizumab through 30 (7) days after the last administration of talimogene laherparepvec or pembrolizumab will be recorded in 
the events CRF. 
j Only subsequent anti-tumor treatment will be recorded. 
k During treatment blood samples for chemistry, hematology and coagulation panels will be collected weekly for the first 7 weeks of treatment and then prior to each 
talimogene laherparepvec administration until end of study treatment. 
l Blood samples for thyroid function tests (triiodothyronine [T3] or free T3 [FT3] per local standard, free thyroxine [FT4], and thyroid-stimulating hormone [TSH]) will be 
collected at screening.  Samples will be collected prior to study treatment administration on day 1 of weeks 1, 7, 13, 19, 25 and every 12 weeks thereafter until end 
of pembrolizumab treatment.  Blood sample will also be collected at the safety follow-up visit.  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. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 110 of 196 
CONFIDENTIAL 
 
 
m Urine or serum pregnancy test to be performed on female of childbearing potential.  Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion or as defined in a county-specific protocol supplement at the end of the Appendix Section of the protocol as required per local laws and 
regulations. 
n Disease specific assessments will only be performed on archived tissue (preferred) or screening biopsy tissue if results from previous testing are not available.  
Results should be submitted during screening and any time after enrollment.  For details and a list of disease specific assessments refer to Section 7.2.1.  For CRC 
subjects, if historical results are not available, the tests have to be completed locally.  However, they do not need to be available at the time of enrollment. 
o During treatment blood samples for lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP) will be collected at screening and at 
week 10 ( 1 week) and then every 9 weeks ( 1 week) prior to talimogene laherparepvec administration until end of study treatment. 
p If serology was negative and  1 month ago the hepatitis panel should be repeated during screening.  Subjects who are positive for hepatitis B virus (HBV) and 
hepatitis C virus (HCV) infection should receive additional testing of viral load by polymerase chain reaction (PCR) and HCV genotyping (if applicable) at screening, 
, and at the safety follow-up.  For additional information refer to Section 7.2.1 through 7.2.3.1.  In addition, HBSAg testing should be performed if ALT is elevated  5 
x ULN and/or  3 x baseline in subjects with hepatitis B.  Refer to Table 15 for more details. 
q Repeated Hepatitis B and/or C testing is only needed for Arm VI (HCC with well-controlled hepatitis.  
t During treatment blood and urine sample for real-time polymerase chain reaction (qPCR) testing of talimogene laherparepvec deoxyribonucleic acid (DNA) will be 
performed at the following time points:  all subjects at weeks 1 and 4 will have samples taken prior to talimogene laherparepvec administration and 7 days ( 2 days) 
and 14 days ( 2 days) after talimogene laherparepvec administration and for subjects receiving intrahepatic injections additional samples will be taken at 1 hour 
[ 15 minutes]; following talimogene laherparepvec administration; on Week 7 prior to talimogene laherparepvec administration; on Week 10 prior to talimogene 
laherparepvec administration; and at safety follow-up visit.  As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of talimogene 
laherparepvec and liver biopsies are no longer performed in this study.   
u Swabs of the surface of the injection sites and exterior of occlusive dressings for qPCR testing of talimogene laherparepvec DNA with or without 50 Tissue Culture 
Infective Dose (TCID50) assay of talimogene laherparepvec virus.  During treatment the surface of the injection site will be swabbed at the following timepoints:  on 
Weeks 1 and 4 prior to talimogene laherparepvec administration 7 ( 2) days, and 14 ( 2) days following talimogene laherparepvec administration; on Week 7 prior 
to talimogene laherparepvec administration.  During treatment the exterior surface of the injection site dressings will be swabbed at the following timepoints:  7 ( 
2)days after Week 1 and 4 talimogene laherparepvec administrations. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date 26 October 2021 
Page 111 of 196 
CONFIDENTIAL 
 
 
v Swabs of oral mucosa:  During treatment swabs of oral mucosa for qPCR testing of talimogene laherparepvec DNA with or without TCID50 assay for talimogene 
laherparepvec virus will be collected at the following visits:   Week 1 and 4 prior to talimogene laherparepvec administration and 7 ( 2) days and 14 ( 2) days 
following talimogene laherparepvec administration; Week 7 prior to talimogene laherparepvec administration.  During safety follow-up, swabs of oral mucosa will be 
collected at the 30 ( 7) day safety follow-up visit for qPCR testing of talimogene laherparepvec DNA. 
w Swabs of any lesion suspected to be herpetic in origin (if any) will be collected during treatment and safety follow-up as follows:  subject should return to clinic within 
3 days of the occurrence of reportable lesion suspected to be herpetic in origin such as cold sores or vesicles.  The lesion should be evaluated by the investigator 
and swabbed if HSV infection is suspected.  The sample will be sent to the central laboratory for detection of talimogene laherparepvec DNA using qPCR testing. 
x Radiographic tumor imaging:  During treatment, radiographic tumor imaging will be performed independent of treatment cycle at week 10 ( 1 week) and then every 
9 weeks ( 1 week) until confirmed progressive disease (PD) per modified immune-related response criteria (irRC) simulating RECIST version 1.1 (irRC-RECIST) 
(Appendix D).  Radiographic imaging is required at the safety follow up visit if the subject ended treatment prior to documentation of confirmed PD per modified 
irRC-RECIST and has not had radiographic tumor imaging performed within 9 weeks ( 1 week) of the visit.  Every effort should be made to complete radiographic 
assessments during the long-term follow-up every 12 weeks ( 1 week) until documented confirmed PD per modified irRC-RECIST, start of new anticancer 
treatment, death, or end of study, whichever occurs first, for subjects discontinuing study treatment for any reason other than confirmed PD.  Response (complete 
response [CR], or partial response [PR]) or disease progression to be confirmed by second consecutive radiographic assessments no less than 4 weeks from the 
date of the first documented response or disease progression.  Note:  Confirmation of disease progression is required only in the absence of rapid clinical 
deterioration (ie, rapid decline in performance status) or symptomatic disease requiring rapid initiation of alternative systemic anti-cancer therapy. 
y To be performed if required by site for assessment of the intrahepatic lesion injection location.  As of Protocol Amendment 6 (dated 26 October 2021), 
intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study.   
z If no progression is seen after a total of 12 cycles, a total of 35 cycles of talimogene laherparepvec, at maximum tolerated dose if known or otherwise previously 
received dose, every 21 ( 3 days) may be administered, or the subject may proceed to alternative therapies depending on investigator discretion.  Dosing with 
talimogene laherparepvec beyond 12 cycles may be done if in the opinion of the investigator, the subject is deriving clinical benefit.   
aa Pembrolizumab will be administered intravenously to subjects randomized at a dose of 200 mg every 3 weeks ( 3 days) starting at day 1 of week 1 until confirmed 
PD per modified irRC-RECIST (The same pattern of assessments continue if treatment exceeds week 18).  Subjects can receive up to 35 cycles (approximately 24 
months) with pembrolizumab.   
ab Reporting potential or known unintended exposure to talimogene laherparepvec:  If a household member, caregiver, or healthcare provider who has had close 
contact with the subject is suspected to have been exposed to talimogene laherparepvec (eg, has signs or symptoms suspected to be herpetic origin or is 
accidentally exposed to talimogene laherparepvec), report the potential or known unintended exposure to talimogene laherparepvec, suspected related signs or 
symptoms, and detection of talimogene laherparepvec DNA by qPCR testing in a swab taken from a lesion, if any, in a subject’s household member, caregiver, or 
healthcare provider. 
ac Post treatment observation will only be needed after cycle 12 where talimogene laherparepvec is being injected into liver. 
 


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7.2 
General Study Procedures  
A signed and dated IRB-approved informed consent must be obtained before any study 
specific procedures are performed.  Procedures that are part of routine care are not 
considered study specific procedures and may be used at screening to determine 
eligibility.  All subjects will be screened for eligibility before enrollment.  Only eligible 
subjects will be enrolled into the study.  
During treatment, assessments and procedures can be performed within  3 days of the 
planned visit, unless otherwise indicated.  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 noted.  
Copies of imaging studies may be collected and held at an independent centralized 
radiology vendor for potential retrospective evaluation. 
The following laboratory analytes in Table 14 will be assessed at various times 
throughout the study: 


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Table 14.  Laboratory Analytes 
Chemistry 
Hematology 
Biodistribution 
and Shedding 
Biomarker 
Other Labs 
Sodium 
Potassium 
Chloride 
Total protein 
Albumin 
Calcium 
Creatinine 
BUN 
Glucose 
TBL 
Alkaline- 
phosphatase 
AST 
ALT 
 
Pembrolizumab 
related labs: 
Thyroid function 
tests (T3, FT3, 
FT4, TSH) 
Part 1 only: 
Blood for anti-
pembrolizumab 
antibody 
Blood for 
pembrolizumab 
PK 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differentiala 
 
 Neutrophils 
 Eosinophils 
 Basophils 
 Lymphocyt
es 
 Monocytes 
qPCR for 
talimogene 
laherparepvec 
DNA 
 
TCID50 assay 
for talimogene 
laherparepvec 
virus  
 
HSV-1 IgG 
antibody  
Pregnancy 
HBV and HCV 
testing 
LDH 
CEA (CRC, GEC 
adenocarcinoma 
only) 
AFP (HCC only) 
Part 1 only:  CA  
19-9 (GEC, CRC, 
HCC only) 
Coagulation (PT, 
INR, PTT, aPTT) 
Biopsy Labs 
KRAS exon 2, RAS 
(KRAS non exon 2, 
NRAS), BRAF (CRC 
only) 
ALK, ROS1 (NSCL 
only)  
HER2-neu IHC  
 FISH (GEC only) 
Estrogen receptor, 
progesterone 
receptor, HER2-neu 
(BC) 
BRAF for melanoma 
AFP  alpha-fetoprotein; ALK  anaplastic lymphoma kinase; ALT  alanine aminotransferase; 
aPTT  activated partial thromboplastin time; AST  aspartate aminotransferase; BC  breast 
adenocarcinoma; BCC  basal cell carcinoma, BRAF  v-raf murine sarcoma viral oncogene homolog B; 
BUN  blood urea nitrogen; CA 19-9  cancer antigen 19-9;
CEA  carcinoembryonic antigen; CRC  colorectal adenocarcinoma; FISH  fluorescence in situ 
hybridization; FT3  free triiodothyronine; FT4  free thyroxine; GEC gastroesophageal adenocarcinoma; 
HBV  hepatitis B virus; HCC  hepatocellular carcinoma; HCV  hepatitis C virus; HER2  human 
epidermal growth factor receptor 2; HSV-1  herpes simplex virus;
IgG  immunoglobulin G; IHC  immunohistochemistry; INR  international normalized ratio; KRAS  Kristen 
rat sarcoma viral oncogene homolog; LDH  lactate dehydrogenase; NRAS  neuroblastoma 
retrovirus-associated DNA sequences (RAS); NSCL  non-small cell lung; PD-L1  programmed cell death 
ligand 1; PK  pharmacokinetic; PT  prothrombin time; PTT  partial thromboplastin time; qPCR  real-time 
polymerase chain reaction; RBC  red blood cell count; ROS1  proto-oncogene receptor tyrosine kinase; 
T3  triiodothyronine; TBL  total bilirubin; TCID50  50 tissue culture infectious dose; 
TSH  thyroid-stimulating hormone; WBC  white blood cell count 
a 3-part differential if 5-part unable to be performed. 


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Protocol Number:  20140318 
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All tests (
) are to be 
performed at a local laboratory and to be fully and routinely recorded on eCRFs.  
Chemistry, hematology and coagulation panels performed during treatment will be 
collected prior to each talimogene laherparepvec and/or pembrolizumab administration 
until the end of study treatment.  Missed tests that are not done must be reported as 
such on the CRFs.  
 
 
 
Procedures deemed necessary as part of standard of care or as required by local laws 
and regulations may be performed at the Investigator’s discretion. 
Where required by local laws or regulations, additional assessments are defined in a 
country-specific protocol supplement at the end of the protocol. 
7.2.1 
Screening and Enrollment 
The following procedures are to be completed during the screening period within 
28 days of enrollment (unless otherwise noted) at time points designated in the 
Schedule of Assessments (Table 8 and Table 10, Section 7.1):  
Within  28 days prior to enrollment: 
 
Confirmation that the ICF has been signed 
 
Registration of screening in IVR system (refer to Section 5). 
 
Review eligibility criteria 
 
Demographic Data:  Gender, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness. 
 
Medical and Surgical History:  The Investigator or designee will collect complete 
medical and surgical history.  Medical history will include information on the subject’s 
concurrent medical conditions.  Record all findings on the medical history CRF. 
 
Vital Signs:  Systolic/diastolic blood pressure, resting heart rate, respiratory rate and 
temperature must be performed prior to enrollment.  Subject is preferred to be in a 
supine position in a rested and calm state for at least 5 minutes before blood 
pressure assessments are conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The position 
selected for a subject should be the same that is used throughout the study and 
documented on the vital sign CRF.  Record all measurements on the vital signs CRF.  
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs CRF. 
 
Physical Examination:  Performed as per standard of care. 
 
Weight in kilogram should be measured without shoes 
 
ECOG performance status assessment 


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Protocol Number:  20140318 
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 
12-lead Electrocardiogram (ECG): The ECG must include the following 
measurements: heart rate, PR, QRS, QT and QTc intervals.  Subject must be in 
supine position in a rested and calm state for at least 5 minutes before ECG 
assessment is conducted.  If the subject is unable to be in the supine position, the 
subject should be in most recumbent position as possible.  The investigator or 
designated site physician will review all ECGs.  Once signed, the original ECG 
tracing will be retained with the subject’s source documents.  At the request of the 
sponsor, a copy of the original ECG will be made available to Amgen.  
 
Child-Pugh Score (Appendix F) 
 
Recording of Concomitant Medications:  Concomitant medications that are 
administered after the subject has signed the main ICF through 30 (7) days after 
the last administration of talimogene laherparepvec will be recorded in the 
concomitant medications CRF. 
 
Review of Serious Adverse Events:  All serious adverse events, follow-up to a 
serious adverse event, including death due to any cause that occur after the subject 
has signed the main ICF through 90 (7) days after last administration of talimogene 
laherparepvec and/or pembrolizumab, or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier will be reported to 
Amgen, within 24 hours of the investigator’s awareness of the event, and recorded in 
the events CRF.  
 
Liver Tumor Biopsy (Part 1) or Tumor Biopsy (Part 2): Screening biopsy should only 
be performed for those subjects who have no prior biopsy to confirm that their 
disease is one of the eligible tumor types.  Those that have had prior pathology 
reports supporting their diagnosis do not need screening biopsy. 
 
Radiographic Tumor Assessment: radiographic tumor imaging (CT, positron 
emission tomography [PET]/CT with contrast, and/or MRI with contrast) 
encompassing the chest, abdomen, pelvis and all other sites of disease will be 
performed at screening and will be used as baseline.  If intrahepatic injections are 
planned, a liver MRI with contrast or multiphase CT of the liver must also be 
performed at screening.  A brain MRI or CT with contrast must be performed for 
subjects with NSCLC or melanoma and all subjects that have had a history of 
cerebral metastases. Any of the above radiographic tumor assessments that are part 
of routine care but were completed prior to informed consent may be used if still 
within the required window. 
 
Disease Specific Assessments:  If no historical results are available from standard of 
care assessments, the disease specific assessments can be performed on archived 
tissue by central laboratory.  Results should be submitted during screening and any 
time after enrollment.  Assessments will include the following:  
BCC subjects:  PTCH mutation status if known will also be collected but is not 
mandatory. 
CRC subjects:  
Kristen rat sarcoma viral oncogene homolog (KRAS) exon 2 gene status,  
Extended RAS testing (KRAS non-exon 2 and neuroblastoma RAS viral 
oncogene homolog (NRAS) gene status) only if KRAS exon 2 gene is wild 
type  
B-Raf sarcoma viral oncogene homolog (BRAF) gene status 
microsatellite instability or mismatch repair. 


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Protocol Number:  20140318 
Date: 26 October 2021 
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CRC subjects (Part 2 only): 
If historical results are not available, the above tests have to be completed 
locally.  However, they do not need to be available at the time of enrollment. 
GEC subjects: HER2-neu immunohistochemistry (IHC)  fluorescent in situ hybridization 
(FISH).  
Melanoma subjects: BRAF gene status.  
NSCLC non-squamous cell subjects: anaplastic lymphoma kinase (ALK) and EGFR 
mutation testing.  ROS1 mutation status if known will also be collected but is not 
mandatory.   
BC subjects: estrogen receptor, progesterone receptor, and HER2-neu testing.  Breast 
cancer susceptibility gene 1 and 2 (BRCA 1 and 2) mutation status if known will also be 
collected but is not mandatory 
Within  10 days prior to enrollment by local laboratory: 
 
Chemistry Panel:  sodium, potassium, chloride, total protein, albumin, calcium, 
creatinine, BUN, glucose, TBL, ALP, AST, ALT 
 
Hematology Panel: RBC count, hemoglobin, hematocrit, platelets, white blood cell 
(WBC) count with 5-part differential (3-part differential if 5-part unable to be 
performed): neutrophils, eosinophils, basophils, lymphocytes, monocytes 
 
Coagulation (PT or INR and PTT or aPTT) 
 
Combination treatment only (Part 1 Cohorts 5 & 6 and Part 2):  Thyroid Function 
Tests (triiodothyronine [T3] or free triiodothyronine [FT3], free thyroxine [FT4] and 
thyroid-stimulating hormone [TSH])  
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 
 
Serum lactate dehydrogenase (LDH) 
 
Carcinoembryonic antigen (CEA) (CRC and GEC adenocarcinoma subjects only) 
 
Alpha fetoprotein (AFP) (HCC subjects only) 
 
Cancer antigen 19-9 (CA 19-9; Part 1 only) (GEC, CRC and HCC subjects only) 
 
Determination of Hepatitis B and C Status:  
If Hepatitis B status is known to be positive by serology and subject is candidate for 
Group B, additional testing for HBV DNA by polymerase chain reaction (PCR) is 
necessary. 
If Hepatitis C status is known to be positive by serology, additional testing for HCV DNA 
by PCR and genotyping (if not previously done) is necessary  
If Hepatitis B and/or Hepatitis C status is not known to be positive by serology, the 
following laboratory testing is required: 
Hepatitis B Surface Antigen (HepBsAg) and total Hepatitis B Core Antibody 
(HepBcAb): 
 
If results are HepBcAb positive and HepBsAg negative, additional testing 
for HBV DNA by PCR is necessary 
HCV antibody:  


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date: 26 October 2021 
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 
If results are HCV antibody positive, additional testing for HCV RNA by 
PCR and HCV genotyping is necessary.  
Within  10 days prior to enrollment by local imaging (Optional test): 
 
Liver ultrasound is not required during screening but may be done by site 
for intrahepatic injection evaluation and planning 
Within  72 hours prior to enrollment: 
 
Serum or urine pregnancy test for female subjects of childbearing potential.  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as defined in a country-specific supplement at the end of the Appendix 
Section of the protocol as required per local laws and regulations. 
Subjects who are determined not eligible after screening must be screen-failed in the 
IVR system and the reason for the screen failure provided.  Subjects who do not meet all 
eligibility criteria may be rescreened once at the discretion of the investigator.  If a 
subject is being rescreened, he or she may need to reconsent to the study to ensure that 
the IRB/IEC-approved main consent form is signed within 28 days of enrollment.  
Subjects who are determined not eligible after rescreen must be screen-failed in the IVR 
system and the reason for the screen-failure provided.  Subjects may only be enrolled 
once into this study. 
7.2.2 
Treatment  
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of 
talimogene laherparepvec and liver biopsies are no longer performed in this 
study.   
Treatment begins when the first dose of talimogene laherparepvec alone or in 
combination with pembrolizumab is administered to a subject.  If possible, talimogene 
laherparepvec should be administered before pembrolizumab.  Study treatment should 
begin as soon as possible after registering enrollment of the subject via IVRS but no 
later than 5 days after enrollment.  Study treatment is to be administered after all other 
procedures are completed during each visit unless otherwise stated.   
Observation Period for Subjects Enrolled into Part 1: 
Subjects must be monitored in the hospital for 23 hours after each injection for the first 
3 cycles of talimogene laherparepvec before discharge to home.  The observation period 
may be reduced, at the investigator’s discretion, to a minimum of 6 hours after each 
injection for cycles 4 onwards.  Monitoring should continue if there are any signs of 
clinical deterioration.  


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date: 26 October 2021 
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Observation Period for Subjects Enrolled into Part 2: 
As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of 
talimogene laherparepvec and liver biopsies are no longer performed in this 
study.   
Subjects receiving intrahepatic injections must be monitored in the hospital for a 
minimum of 6 hours after injection of talimogene laherparepvec before discharge home.  
The monitoring should continue if there are any signs of clinical deterioration and at the 
investigator’s discretion.  
Subjects who do not receive an intrahepatic injection (ie., only nodal, cutaneous, or 
subcutaneous) must be monitored for 1 hour following the talimogene laherparepvec 
injections. 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 8 through Table 13, Section 7.1).  
During treatment, assessments and procedures will be performed within  3 days of the 
planned visit, unless otherwise specified. 
 
Vital Signs: Systolic/diastolic blood pressure, resting heart rate, respiratory rate, and 
temperature must be performed prior to each talimogene laherparepvec 
administration and during the observation period (if applicable) following each dose.  
During the observation period vital signs must be recorded: 
 
every 30 minutes for the first 2 hours (every 30 minutes for 1 hour for subjects 
who do not have an intrahepatic injection) 
 
hourly for the next 4 hours 
 
once every 4 to 6 hours until the end of the observation period, where applicable 
 
once at the end of the observation period 
 
Subject is preferred to be in a supine position in a rested and calm state for at least 
5 minutes before blood pressure assessments are conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
as possible.  The position selected for a subject should be the same that is used 
throughout the study and documented on the vital signs CRF.  Record all 
measurements on the vital signs CRF.  The temperature location selected for a 
subject should be the same that is used throughout the study and documented on 
the vital signs CRF. 
 
Physical Examination:  Performed as per standard of care (week 1 only) 
 
Weight in kilogram should be measured without shoes prior to each talimogene 
laherparepvec administration 
 
ECOG Performance Status prior to each talimogene laherparepvec administration 
 
Local laboratory tests: Screening laboratory values may be used for day 1 week 1 
assessment if completed within 3 days of study treatment initiation.  On treatment 


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Protocol Number:  20140318 
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tests can be performed within  3 days of the planned visit.  Results should be 
reviewed prior to the administration of scheduled dose of study drug. 
Chemistry Panel:  sodium, potassium, chloride, total protein, albumin, calcium, 
creatinine, BUN, glucose, TBL, ALP, AST, ALT.  In Part 1, chemistry panel will be 
performed weekly for the first 8 weeks of treatment and then prior to each study drug 
administration until end of study treatment.  In Part 2, chemistry panel will be performed 
weekly for the first 7 weeks of treatment and then prior to each study drug administration 
until end of study treatment. 
Hematology Panel: RBC count, hemoglobin, hematocrit, platelets, WBC count with 5-
part differential (3-part differential if 5-part unable to be performed): neutrophils, 
eosinophils, basophils, lymphocytes, monocytes.  In Part 2, hematology panel will be 
performed weekly for the first 7 weeks of treatment and then prior to each study drug 
administration until end of study treatment. 
In Part 1, coagulation (PT or INR and PTT or aPTT) will be performed weekly for the first 
8 weeks of treatment and then prior to each study drug administration until end of study 
treatment.  In Part 2, coagulation will be performed weekly for the first 7 weeks of 
treatment and then prior to each study drug administration until end of study treatment. 
Serum LDH at week 10 and then every 9 ( 1) weeks until end of treatment prior to study 
drug administration 
CEA (CRC and GEC adenocarcinoma subjects only) at week 10 and then every 9 ( 1) 
weeks until end of treatment prior to study drug administration 
AFP (HCC subjects only) at week 10 and then every 9 ( 1) weeks until end of treatment 
prior to study drug administration 
CA 19-9 (GEC, CRC and HCC subjects only) at week 10 and then every 9 ( 1) weeks 
until end of treatment prior to study drug administration 
For HCC subjects with well-controlled hepatitis (Part 1 Group B, Cohort 6b and Part 2 
Arm VI with well-controlled hepatitis):  HBV DNA by PCR and HCV RNA by RT-PCR at 
week 7 and as clinically indicated 
 
Specialized / Central Laboratory Tests at the following timepoints during study 
treatment: 
Blood for HSV-1 IgG Antibody Serostatus: prior to talimogene laherparepvec 
administration at weeks 1 and 7 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
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In Part 1, blood for anti-pembrolizumab antibody (immunogenicity): 
▪ 
Day 1 of:  cycle 1, cycle 2 , cycle 4, cycle 6, and cycle 8 of the additional 
treatment.   
▪ 
Note:  All samples should be drawn within 24 hours before infusion of 
pembrolizumab and at the same time as the predose trough blood collection 
for the PK sample. 
In Part 1, blood for PK of pembrolizumab: 
▪ 
Predose trough will be collected at day 1 of:  cycle 1, cycle 2 , cycle 4, 
cycle 6, and cycle 8 of the additional treatment.   
▪ 
Note:  All trough samples should be drawn within 24 hours before infusion of 
pembrolizumab. 
Liver Tumor Biopsy/Tumor biopsies (As of Protocol Amendment 6 [dated 
26 October 2021], liver biopsies are no longer performed in this study):  Liver tumor 
biopsies (Part 1) or tumor biopsies (Part 2) will be performed immediately prior to the 
talimogene laherparepvec administration at weeks 1, 7 and 16.  Screening biopsy may 
be used for baseline (week 1) biopsy if subject is eligible, provided enough tissue has 
been obtained.  Biopsies will be taken at the following timepoints: 
▪ 
Week 1 – biopsy a lesion planned for injection 
▪ 
Week 7 – biopsy a lesion planned for injection and/or a lesion you have 
already injected and plan to inject again 
▪ 
Week 16 – biopsy a lesion planned for injection and/or a lesion you plan to 
inject again  
Refer to Laboratory Manual for further detail on tumor biopsy procedures. 
Blood and Urine for qPCR Testing of Talimogene Laherparepvec DNA:  
Part 1 
▪ 
Week 1 prior to talimogene laherparepvec administration and approximately 
1 hour ( 15 minutes), 4 hours ( 30 minutes), 8 hours ( 1 hour), 24 hours 
( 4 hours), 48 hours ( 4 hours), 7 ( 2) days and 14 ( 2) days) after 
talimogene laherparepvec administration  
▪ 
Week 4 prior to talimogene laherparepvec administration and approximately 
1 hour ( 15 minutes), 4 hours ( 30 minutes), 8 hours ( 1 hour), 24 hours 
( 4 hours), 48 hours ( 4 hours), 7 ( 2) days, and 14 ( 2) days after 
talimogene laherparepvec administration 
▪ 
Week 7 prior to talimogene laherparepvec administration and 7 ( 2) days 
after talimogene laherparepvec administration 
▪ 
Week 10 prior to talimogene laherparepvec administration  


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Part 2 
▪ 
Week 1 prior to talimogene laherparepvec administration and: 
o For subjects receiving intrahepatic injections; 1 hour  
( 15 minutes) 
o For all subjects 7 ( 2) days and 14 ( 2) days) after talimogene 
laherparepvec administration  
▪ 
Week 4 prior to talimogene laherparepvec administration and  
o For subjects receiving intrahepatic injections 1 hour  
( 15 minutes) 
o For all subjects 7 ( 2) days, and 14 ( 2) days after talimogene 
laherparepvec administration 
▪ 
Week 7 prior to talimogene laherparepvec administration and  
▪ 
Week 10 prior to talimogene laherparepvec administration. 
Swabs of Surface of Injection Site for qPCR Testing with or without 50 Tissue Culture 
Infective Dose (TCID50) Assay: during treatment swabs of the surface of the injection 
site for qPCR testing of talimogene laherparepvec DNA Swabs of the surface of the 
injection site for qPCR testing of talimogene laherparepvec DNA and if qPCR testing is 
positive, then a TCID50 assay will be performed to evaluate whether the talimogene 
laherparepvec virus is detectable in the sample:  
Part 1 
▪ 
Week 1 prior to talimogene laherparepvec administration and 24 hours 
( 4 hours), 48 hours ( 4 hours), 7 ( 2) days and 14 ( 2) days after 
talimogene laherparepvec administration 
▪ 
Week 4 prior to talimogene laherparepvec administration and 24 hours 
( 4 hours), 48 hours ( 4 hours), 7 ( 2) days, 14 ( 2) days after talimogene 
laherparepvec administration 
▪ 
Week 7 prior to talimogene laherparepvec administration and 7 ( 2) days 
after talimogene laherparepvec administration, 
▪ 
Week 10 prior to talimogene laherparepvec administration. 
Part 2 
▪ 
Week 1 prior to talimogene laherparepvec administration and 7 ( 2) days 
and 14 ( 2) days after talimogene laherparepvec administration 
▪ 
Week 4 prior to talimogene laherparepvec administration and 7 ( 2) days, 14 
( 2) days after talimogene laherparepvec administration 
▪ 
Week 7 prior to talimogene laherparepvec administration. 
Swabs of Exterior Surface of Injection Site Dressing for qPCR Testing with or without 
TCID50 Assay: during treatment swabs of the exterior surface of injection site dressing 
for qPCR testing of talimogene laherparepvec DNA and if qPCR testing is positive, then 
a TCID50 assay will be performed to evaluate whether the talimogene laherparepvec 
virus is detectable in the sample:  
Part 1 
▪ 
Week 1: 24 hours ( 4 hours), 48 hours ( 4 hours), 7 ( 2) days after 
talimogene laherparepvec administration 


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Protocol Number:  20140318 
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▪ 
Week 4: 24 hours ( 4 hours), 48 hours( 4 hours), 7 ( 2) days after 
talimogene laherparepvec administration 
▪ 
Week 7: 7 ( 2) days after talimogene laherparepvec administration. 
Part 2 
▪ 
Week 1:  7 ( 2) days after talimogene laherparepvec administration 
▪ 
Week 4:  7 ( 2) days after talimogene laherparepvec administration 
Swabs of Oral Mucosa for qPCR Testing with or without TCID50 Assay: during treatment 
swabs of oral mucosa for qPCR testing of talimogene laherparepvec DNA and if qPCR 
testing is positive, then a TCID50 assay will be performed to evaluate whether the 
talimogene laherparepvec virus is detectable in the sample: 
Part 1 
 
Week 1 prior to talimogene laherparepvec administration and 7 ( 2) days 
and 14 ( 2) days after talimogene laherparepvec administration 
 
Week 4 prior to talimogene laherparepvec administration and 7 ( 2) days 
and 14 ( 2) days after talimogene laherparepvec administration 
 
Week 7 prior to talimogene laherparepvec administration and 7 ( 2 days) 
after talimogene laherparepvec administration 
 
Week 10 and subsequent cycles prior to talimogene laherparepvec 
administration. 
Part 2 
 
Week 1 prior to talimogene laherparepvec administration and 7 ( 2) days 
and 14 ( 2) days after talimogene laherparepvec administration 
 
Week 4 prior to talimogene laherparepvec administration and 7 ( 2) days 
and 14 ( 2) days after talimogene laherparepvec administration 
 
Week 7 prior to talimogene laherparepvec administration. 
Swabs of Herpetic Lesions for qPCR Testing of Talimogene Laherparepvec DNA: Swab 
of any lesions suspected to be herpetic in origin (if any) will be collected as follows: 
subject should return to clinic within 3 days of the occurrence of reportable lesion 
suspected to be herpetic in origin such as cold sore or vesicles.  Lesions should be 
evaluated and swabbed if HSV infection is suspected.  Sample should be sent to the 
central laboratory for detection of talimogene laherparepvec DNA using qPCR testing.  
 
Radiographic Tumor Assessment (Week 10 and every 9 weeks thereafter):  During 
treatment, radiographic tumor imaging of the chest, abdomen, and pelvis and any 
other sites of known disease will be performed independent of treatment cycle at 
week 10 ( 1 week) and then every 9 weeks ( 1 week) until confirmed PD per 
modified irRC-RECIST.  Radiographic imaging is required at the safety follow up visit 
if the subject ended treatment prior to clinically relevant disease progression and has 
not had radiographic tumor imaging performed within 9 weeks ( 1 week) of the visit.  
In Part 2, clinical tumor assessment should be documented as well, if applicable.  
Every effort should be made to complete radiographic assessments during the long-
term follow-up until documentation of confirmed PD per modified irRC-RECIST for 
subjects discontinuing treatment for any reason other than PD.  Response (CR, or 
PR) or disease progression to be confirmed by second consecutive radiographic 
assessments no less than 4 weeks from the date of the first documented response or 
disease progression.  Note:  Confirmation of disease progression is required only in 


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the absence of rapid clinical deterioration (ie, rapid decline in performance status) or 
symptomatic disease requiring rapid initiation of alternative systemic anti-cancer 
therapy). 
 
Talimogene laherparepvec administration (Q21D [ 3 days] for cycle 1, and Q21D 
[ 3 days] for all subsequent cycles) with observation period as applicable.   
 
Part 1 – Maximum of 12 cycles of talimogene laherparepvec will be 
administered 
 
Part 2 – Maximum of 35 cycles of talimogene laherparepvec will be 
administered   
 
Clinical tumor assessments for talimogene laherparepvec administration must 
include clinical measurement of cutaneous, subcutaneous, or palpable nodal tumor 
lesions by caliper.  Note:  When a tumor lesion can be accurately evaluated by both, 
radiographic imaging and clinical examination, radiographic imaging evaluations 
should be undertaken. 
 
Pembrolizumab administration 
- 
Day 1 of weeks 1, 4, 7, 10, 13, 16, and Q3W ( 3 days) thereafter until end of 
study treatment  
- 
Subjects can receive up to 35 cycles (approximately 24 months) with 
pembrolizumab 
 
Recording of Concomitant Medications: Concomitant medications should be 
assessed on an ongoing basis and recorded in the concomitant CRF at each subject 
visit. 
 
Review of Disease Related Events:  Disease related adverse events should be 
assessed on an ongoing basis.  All disease adverse events that occur after the first 
dose of talimogene laherparepvec or pembrolizumab through 30 (7) days after the 
last administration of talimogene laherparepvec or pembrolizumab, whichever is 
later, will be recorded in the events CRF.  All serious disease-related events will be 
recorded and reported to the sponsor or designee within 24 hours of the 
investigator’s awareness of the event. 
 
Review of Adverse Events and Serious Adverse Events: Adverse events should be 
assessed on an ongoing basis.  All non-serious treatment-emergent adverse events 
that occur after the first dose of talimogene laherparepvec or pembrolizumab through 
30 (7) days after the last administration of talimogene laherparepvec or 
pembrolizumab, whichever is later, will be recorded in the events CRF.   
All serious adverse events that occur after the subject has signed the main informed 
consent through 90 (7) days after the last administration of talimogene 
laherparepvec or pembrolizumab, or 30 days following cessation of study drugs if the 
subjects initiates new anticancer therapy, whichever is earlier), will be reported to 
Amgen, within 24 hours of the investigator’s awareness of the event, and recorded in 
the events CRF.   
 
Report potential or known unintended exposure to talimogene laherparepvec, 
suspected related signs or symptoms, and detection of talimogene laherparepvec in 
a subject’s household member, caregiver, or healthcare provider as specified 
Section 9.4. 


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7.2.3 
Long-term Follow-up 
7.2.3.1 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, the following 
procedures will be performed 30 (7) days after the last dose of talimogene 
laherparepvec for the monotherapy cohorts (Cohorts 1, 2, 3 and 4 in Part 1), or 30  
( 7) days after the last dose of talimogene laherparepvec or pembrolizumab, whichever 
is later, for the combination treatment (Cohorts 5 and 6 in Part 1, and all arms in Part 2).  
 
Vital signs (systolic/diastolic blood pressure, resting heart rate, respiratory rate, 
temperature):  Subject must be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
possible.  The position selected for a subject should be the same that is used 
throughout the study and documented on the vital sign CRF.  Record all 
measurements on the vital signs CRF.  The temperature location selected for a 
subject should be the same that is used throughout the study and documented on 
the vital signs CRF. 
 
Physical examination as per standard of care 
 
Weight in kilogram should be measured without shoes 
 
ECOG performance status assessment 
 
12-lead ECG: The ECG must include the following measurements: heart rate, PR, 
QRS, QT and QTc intervals.  Subject must be in supine position in a rested and calm 
state for at least 5 minutes before ECG assessment is conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
as possible.  The investigator or designated site physician will review all ECGs.  
Once signed, the original ECG tracing will be retained with the subject’s source 
documents.  At the request of the sponsor, a copy of the original ECG will be made 
available to Amgen. 
 
Recording of Concomitant Medications:  All concomitant medications that are 
administered after the subject has signed the main informed consent through 
30 (7) days after the last administration of talimogene laherparepvec will be 
recorded in the concomitant medications CRF. 
 
Review of Disease Related Events:  Disease related adverse events should be 
assessed on an ongoing basis.  All disease adverse events that occur after the first 
dose of talimogene laherparepvec or pembrolizumab through 30 (7) days after the 
last administration of talimogene laherparepvec or pembrolizumab, whichever is 
later, will be recorded in the events CRF.  All serious disease-related events will be 
recorded and reported to the sponsor or designee within 24 hours of the 
investigator’s awareness of the event. 


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 
Review of Adverse events and Serious Adverse Events:  Adverse events should be 
assessed on an ongoing basis.  All nonserious adverse events that occur after the 
first dose of talimogene laherparepvec or pembrolizumab through 30 (7) days after 
the last administration of talimogene laherparepvec or pembrolizumab, whichever is 
later, will be recorded in the events CRF.   
All serious adverse events that occur after the subject has signed the main informed 
consent through 90 (7) days after the last administration of talimogene 
laherparepvec, or pembrolizumab, or 30 days following cessation of study drugs if 
the subject initiates new anticancer therapy, whichever is earlier), will be reported to 
Amgen and recorded in the events CRF. In addition, all serious adverse events that 
occur during the long-term safety follow-up period until the end of study are to be 
reported to Amgen and recorded in the CRF. As described in Section 9.2.3.2, there 
is no requirement to monitor study subjects for serious adverse events following the 
protocol required reporting period (as defined in Section 9.2.3) or after the end of 
study.  However, these serious adverse events should be reported to Amgen 
(regardless of causality) if the investigator becomes aware of them (per regional 
regulatory requirements).  All serious adverse events must be submitted to Amgen 
within 24 hours following the investigator’s awareness of the event via the applicable 
CRF.   
 
Child-Pugh score 
 
Local laboratory tests: 
- 
Chemistry panel:  sodium, potassium, chloride, total protein, albumin, calcium, 
creatinine, BUN, glucose, TBL, ALP, AST, ALT 
- 
Hematology panel: RBC count, hemoglobin, hematocrit, platelets, WBC count 
with 5-part differential (3-part differential if 5-part unable to be performed): 
neutrophils, eosinophils, basophils, lymphocytes, monocytes 
- 
Coagulation (PT or INR and PTT or aPTT) 
- 
Serum LDH 
- 
For subjects with chronic HBV and HCV infection repeat testing for HBV DNA by 
PCR or HCV RNA by PCR, respectively 
 
Local laboratory, if available, or central laboratory:  
- 
CEA (CRC and GEC adenocarcinoma subjects only)  
- 
AFP (HCC subjects only)  
- 
CA 19-9 (Part 1 only GEC, CRC and HCC subjects only) 
- 
Serum or urine pregnancy test for female subjects of childbearing potential 
 
Specialized / Central Laboratory Tests 
- 
HSV-1 IgG Antibody Serostatus 
- 
Blood and Urine for qPCR Testing of Talimogene Laherparepvec DNA 
- 
Swab of Oral Mucosa 
- 
Swab of Herpetic Lesion for qPCR Testing of Talimogene Laherparepvec DNA 
 
Radiographic Tumor Assessment:  During treatment, radiographic tumor imaging will 
be performed independent of treatment cycle at week 10 ( 1 week) and then every 
9 weeks ( 1 week) until confirmed PD per modified irRC simulating RECIST 
version 1.1 (irRC-RECIST) (Appendix D). Radiographic imaging is required at the 
safety follow-up visit if the subject ended treatment prior to documentation of 
confirmed PD and has not had radiographic tumor imaging performed within 9 weeks 
( 1 week) of the visit.  Every effort should be made to complete radiographic 


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assessments during the long-term follow-up approximately every 12 weeks  
( 1 week) until documented confirmed PD per modified irRC-RECIST, start of new 
anticancer treatment, death, or end of study, whichever occurs first, for subjects 
discontinuing treatment for any reason other than confirmed PD.  In Part 2, clinical 
tumor assessment, if applicable, should be performed and documented at these 
timepoints as well.  Response (CR, or PR) or PD to be confirmed by second 
consecutive radiographic assessments no less than 4 weeks from the date of the first 
documented response or PD. 
 
Report potential or known unintended exposure to talimogene laherparepvec, 
suspected related signs or symptoms, and detection of talimogene laherparepvec in 
a subject’s household member, caregiver, or healthcare provider as specified 
Section 9.4. 
7.2.3.2 
Survival Follow-up 
All subjects who permanently discontinue study drug for any reason other than 
withdrawal of full consent will be contacted by clinic visit or telephone to assess survival, 
talimogene laherparepvec-related adverse events, and initiation of additional anti-tumor 
treatment.  For subjects in the combination treatment cohort, the long-term follow-up 
starts after the discontinuation of whichever study drug is discontinued last.   
For Part 1, contact for all subjects will be attempted approximately every 12 weeks 
( 28 days) following the safety follow-up visit until death, subject withdrawal, or up to 
approximately 24 months after the date of the last subject enrolled in Part 1.  Subjects in 
Cohort 5 and 6 will be followed approximately 24 months after the last subject enrolled in 
their cohort in Part 1, or approximately 24 months after the last subject enrolled with their 
tumor type in Part 2, whichever is later. 
For Part 2, contact for all subjects will be attempted approximately every 12 weeks  
( 28 days) following the safety follow-up visit until death, subject withdrawal, or up to 
approximately 24 months after the date of the last subject enrolled in that tumor cohort. 
Radiographic Tumor Assessment:  Every effort should be made to complete 
radiographic assessments approximately every 12 (1) weeks during the long-term 
follow-up until documentation of PD per modified irRC-RECIST (Appendix D), start of 
new anticancer treatment, death, or end of study, whichever occurs first, for subjects 
discontinuing treatment for any reason other than PD.  In Part 2, clinical tumor 
assessment, if applicable, should be performed and documented at these timepoints as 
well.  Response (CR, or PR) or disease progression to be confirmed by second 
consecutive radiographic assessments no less than 4 weeks from the date of the first 
documented response or disease progression.  Note: Confirmation of disease 
progression is required only in the absence of rapid clinical deterioration (ie, rapid 


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decline in performance status) symptomatic disease requiring rapid initiation of 
alternative systemic anti-cancer therapy. 
Subjects who have received talimogene laherparepvec and completed the long term 
follow-up for any reason other than death or withdrawal of full consent and who provide 
consent and are eligible for a separate ongoing registry protocol may have the 
opportunity to follow-up for survival under this registry protocol which is in place for the 
long-term follow-up of subjects treated with talimogene laherparepvec in clinical trials.  
The registry protocol will also monitor for late and long-term adverse events thought to 
be potentially related to talimogene laherparepvec. 
7.2.4 
Reporting Exposure to Talimogene Laherparepvec  
If a household member, caregiver, or healthcare provider who has had close contact 
with the subject is suspected to have been exposed to talimogene laherparepvec (eg, 
has signs or symptoms suspected to be herpetic in origin or is accidentally exposed to 
talimogene laherparepvec), report the potential or known unintended exposure to 
talimogene laherparepvec, suspected related signs or symptoms, and detection of 
talimogene laherparepvec in a subject’s household member, caregiver, or healthcare 
provider as specified Section 9.4. 


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7.4 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses on blood samples may be performed.  These optional pharmacogenetic 
analyses focus on inherited genetic variations to evaluate their possible correlation to the 
disease and/or responsiveness to the therapies used in this study.  The goals of the 


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optional studies include the use of genetic markers to help in the investigation of cancer 
and/or to identify subjects who may have positive or negative responses to talimogene 
laherparepvec.  No additional samples are collected for this part of the study.  DNA may 
be extracted from blood of subjects who consent to pharmacogenetic analyses. 
7.5 
Sample Storage and Destruction  
Any blood or tumor samples collected according to the Schedule of Assessments 
(Table 8 through Table 13) can be analyzed for any of the tests outlined in the protocol 
and for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
cancer, the dose response and/or prediction of response to talimogene laherparepvec, 
characterization of antibody response, and characterization of aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years. 
Since the evaluations are not expected to be available in time to benefit the subject 
directly or to alter the treatment course, the results of qPCR testing from swabs of cold 
sores, vesicles, and other lesions suspected to be herpetic in origin will not be provided 
unless requested by the investigator or the subject.  Results may not be available until 
the end of the study.  
 
 
 
 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 


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 and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects 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 8 
through Table 13) 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 8 through Table 13) 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).   


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For subjects who discontinue investigational product without documented PD 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 as 
described in Table 8 through Table 13. 
Those subjects who discontinue investigational product should continue into long-term 
follow-up.  Subjects in Part 1 will be followed for survival, talimogene laherparepvec 
related adverse events, and subsequent anticancer therapies every 12 weeks  
( 28 days) for approximately 24 months after the last subject is enrolled in Part 1.  
Subjects in Part 2 will be followed for survival, talimogene laherparepvec related adverse 
events, pembrolizumab related adverse events (if applicable), and subsequent 
anticancer therapies every 12 weeks ( 28 days) for approximately 24 months after the 
last subject is enrolled per tumor type cohort. 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.    
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Subjects can remain on either treatment if one is stopped prematurely assuming the 
subject meets criteria for continuing. 
Reasons for removal from protocol-required investigational product or procedural 
assessments include any of the following: 


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 
subject request   
 
safety concern (eg, due to an adverse event)  
 
ineligibility determined  
 
protocol deviation 
 
non-compliance  
 
requirement for alternative therapy  
 
protocol-specified criteria (see Section 6.2.1.2) 
 
pregnancy 
 
death 
 
lost to follow-up 
 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
 
disease progression  
8.3.1.1 
Discontinuation of Pembrolizumab treatment 
 
Subjects can receive up to 35 cycles (approximately 24 months) with 
pembrolizumab.  During that time, subjects may continue until disease progression, 
or sponsor’s decision to terminate the study. 
 
Discontinuation of treatment may be considered for subjects who have attained a 
confirmed CR that have been treated for at least 24 weeks with systemic 
pembrolizumab and had at least 2 cycles of systemic pembrolizumab beyond the 
date when the initial CR was declared.   
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Definition of 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. 
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s awareness of the event.   


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Disease-related events that would qualify as an adverse event or serious adverse event: 
 
An event based on the underlying disease that is worse than expected as assessed 
by the investigator 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, this must be reported as an adverse 
event or serious adverse event. 
Disease-related events that do not qualify as adverse events or serious adverse events: 
 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a disease-related event.    
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 the subject’s primary 
cancer, the primary tumor type (eg, metastatic hepatocellular carcinoma) should be 
used, rather than the term “disease progression”. 
9.1.2 
Definition of Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease (eg, 
diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
Note:  For situations where an adverse event due to the subject’s primary cancer, the 
primary tumor type (eg, metastatic hepatocellular carcinoma) 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 


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the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.3 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
A disease related event (eg, disease progression) is to be reported as a serious adverse 
event if:   
 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a subject with the same underlying condition, or 
 
if the investigator believes a causal relationship exists between talimogene 
laherparepvec and/or pembrolizumab and the event,  
 
and the event meets at least 1 of the serious criteria above. 
 
additionally, the investigator is required to report a fatal disease related event as 
serious adverse event 
*Note:  In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per the International Council for Harmonisation (ICH) 
definition, are reportable to Amgen in the same timeframe as serious adverse 
events to meet certain local requirements. 
Therefore, these events are considered serious by Amgen for collection purposes. 
 
Is a new cancer (that is not a condition of the study); 
 
Is associated with an overdose. 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 


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include allergic bronchospasm, convulsions, blood dyscrasias, DILI, 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 
Disease-related events are defined in Section 9.1.1. 
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 or pembrolizumab through 30 (7) days after the 
last dose of talimogene laherparepvec or pembrolizumab, whichever is later, are 
reported using the events CRF.  Additionally, the investigator is required to report a fatal 
disease related event on the events CRF as a serious adverse event. 
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours. The investigator will submit any updated serious disease-
related event data to the sponsor within 24 hours of it being available. 
Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the talimogene laherparepvec or pembrolizumab, and determined to be 
serious must be reported on the events CRF as serious adverse events and recorded 
and reported per Section 9.2.3.  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), 
 
Did the event start prior to first dose of investigational product and other protocol-
required therapies, 
 
Assessment of seriousness, 
 
Severity (and/or toxicity per protocol), 
 
Assessment of relatedness to talimogene laherparepvec/placebo and/or 
pembrolizumab, and/or study-mandated activity and/or procedures, 
 
Action taken, and  
 
Outcome of event 
CTCAE version 4.03 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 


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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 
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 or pembrolizumab through 30 (7) days after the last dose of talimogene 
laherparepvec or pembrolizumab, whichever is later, are reported using the applicable 
CRF (eg, events CRF). 
All adverse events that occur after the consent form is signed but before enrollment must 
be reported by the investigator if they cause the subject to be excluded from the trial, or 
are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure.  Refer to Section 9.2.5.1 for 
management of hepatic events of clinical interest. 
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), 
 
did the event start prior to first dose of investigational product and other protocol-
required therapies, 
 
assessment of seriousness, 
 
severity (and/or toxicity per protocol), 
 
assessment of relatedness to talimogene laherparepvec and/or pembrolizumab, 
 
action taken, and  
 
outcome of event 
The adverse event grading scale used will be the CTCAE version 4.03.  The grading 
scale used in this protocol is described in Appendix A.  The investigator must assess 
whether the adverse event is possibly related to the talimogene laherparepvec 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 
talimogene laherparepvec and/or pembrolizumab”? 


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The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of talimogene laherparepvec and/or 
procedure [including any screening 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 (eg, administration of talimogene laherparepvec, 
and/or procedure”?  
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
If the severity of an adverse event worsens from the date of onset to the date of 
resolution, record a single event for each increased level of severity on the events CRF.  
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to (sponsor/responsible contact research organization [CRO]) in lieu of 
completion of the Events CRF page. 
9.2.3 
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, 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.  All serious adverse events must be submitted to Amgen within 
24 hours following the investigator’s awareness of the event via the applicable 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 Amgen via a paper Serious 
Adverse Event Contingency Report Form within 24 hours of the investigator’s awareness 


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of the event.  See Appendix B for a sample of the Serious Adverse Event Worksheet 
/electronic Serious Adverse Event Contingency Report Form.  For EDC studies where 
the first notification of a Serious Adverse Event is reported to Amgen via the eSerious 
Adverse Event Contingency Report Form, the data must be entered into the EDC 
system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
talimogene laherparepvec or, if applicable, 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 talimogene laherparepvec”? 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”? 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable CRF (eg, Events 
CRF). 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and Good 
Clinical Practice (GCP).  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 


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9.2.3.1 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Adverse Events CRF. 
9.2.3.2 
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 (as defined in Section 9.1.3) or after the end of 
study.  However, these serious adverse events must be reported to Amgen (regardless 
of causality) if the investigator becomes aware of them.  Per local requirements in some 
countries (eg, European Union [EU] member states), investigators are required to report 
serious adverse events that they become aware of after the end of study.  If serious 
adverse events are reported, the investigator is to report them to Amgen within 24 hours 
following the investigator’s awareness of the event. 
Serious adverse events reported outside the protocol-required reporting period that 
occur during the long-term follow-up period until the end of study are to be captured in 
the Adverse Events CRF, although these events will not be considered treatment-
emergent adverse events. Serious adverse events reported outside of the 
protocol-required reporting period that occur after the end of the study will be captured 
within the safety database as clinical trial cases for the purposes of expedited reporting. 
9.2.3.3 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
9.2.4 
Pembrolizumab Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events known as pembrolizumab ECI must 
be reported to Amgen within 24 hours. 


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For the time period beginning when the consent form is signed until enrollment, any ECI, 
or follow-up to an ECI, that occurs to any subject must be reported within 24 hours to 
Amgen 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, or a procedure. 
For the time period beginning at enrollment through 30 days following cessation of 
treatment, any ECI, or follow-up to an ECI, whether or not related to pembrolizumab, 
must be reported within 24 hours to Amgen. 
Pembrolizumab ECI for this trial for Group A include: 
 
an overdose of pembrolizumab, as defined in Section 9.2.6.1 
 
an elevated AST or ALT lab value that is greater than or equal to 3x the ULN and an 
elevated TBL lab value that is greater than or equal to 2x the ULN and, at the same 
time, an ALP lab value that is less than 2x the 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 
Investigator Trial File Binder (or equivalent). 
9.2.5 
Information Related to Events of Clinical Interest Specifically for 
Group B HCC Subjects 
9.2.5.1 
Guidance for Management of Hepatic Events of Clinical Interest 
Hepatic ECIs (HECIs) have been described in Section 9.2.6.  All of these HECIs will 
require holding study intervention and notification of the Sponsor within 24 hours.  All 
cases of retreatment after interruption of study intervention for HECI must be reported to 
the Sponsor and recorded in the database. 
Immediate assessment in case of HECI: 
All Participants 
 
All participants should be considered for evaluation according to the directions below 
within 72 hours of the alert for a non-overdose ECI.  For lab assessments of HECIs, 
central laboratory is preferred; local laboratory is acceptable if central laboratory is 
not available. 
 
Procedures: 
○ Consider obtaining a consultation with a hepatologist 


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○ Obtain a work-up for hepatitis if there is no underlying hepatitis, including 
hepatitis A, B, C, D, E, Epstein-Barr virus, and cytomegalovirus 
○ Assess for ingestion of drugs/supplements with hepatotoxic potential 
○ Assess for alcohol ingestion 
○ Assess for potential bacterial infection, biliary obstruction, or occult 
gastrointestinal bleeding 
○ Repeat ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, -glutamyl 
transpeptidase, INR, and complete blood count with differential 
○ Measure HCV RNA viral load (applies only for participants who have current 
active HCV infection or had infection in the past) 
○ HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe, and anti-HBs 
regardless of prior HBV status (Note:  participants should be questioned about 
compliance with the use of antiviral agents) 
○ Other laboratories or imaging studies as clinically indicated 
○ Consider liver biopsy if indicated 
HCC patients are at risk for a range of complications that can cause hepatic laboratory 
abnormalities with or without clinical decompensation.  Those with a history of chronic 
HCV or HBV infection also have the potential to experience virologic flares.  Immune-
related hepatitis has been observed in approximately 1-2 of participants who received 
pembrolizumab.  The following section provides further guidance on the diagnosis and 
management of potential hepatic complications among HCC participants in this study.  
The recommendation is to hold pembrolizumab interventions and initiate per table.  


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Table 15.  Management of Hepatic Events of Clinical Interest for Pembrolizumab: 
 
Diagnosis 
Management 
Hepatitis B 
consider flare or 
change in HBV 
immunologic 
status 
Rapid elevation of 
ALT to  5 x ULN 
and/or  3x baseline 
Interrupt pembrolizumab and talimogene 
laherparepvec intervention for up to 12 weeks. 
Start antiviral therapy or check for compliance if 
HBV is detectable. 
Measure safety labs for AST, ALT, ALP, T Bili, D 
Bili, and INR on weekly basis. 
Measure HBsAg and HBV DNA on weekly basis (if 
detected at the time of onset of ECI). 
Evaluate the following every 2-3 weeks: 
anti-HBe, HBe antigen, anti-HBs, and HBV DNA 
levels (if not detected at the onset of ECI) 
Restart pembrolizumab and talimogene 
laherparepvec intervention only if ALT returns to 
normal or Grade 1 (if normal at baseline), or to 
baseline grade (if Grade 2 at baseline) within 12 
weeks, and the participant is clinically stable; 
otherwise, the participant should be permanently 
discontinued. 
Hepatitis C 
exacerbation in 
participants with 
HCV RNA 
positive 
Rapid elevation of 
ALT to  5 x ULN 
and/or  3x baseline 
Interrupt pembrolizumab and talimogene 
laherparepvec intervention for up to 12 weeks. 
Assess use of injection or inhalation drugs. 
Recheck HCV genotype at the time of relapse of 
HCV RNA to rule out new infection. 
Measure safety labs for AST, ALT, ALP, T Bili, D 
Bili, and INR on weekly basis 
Measure HCV RNA levels every 2 weeks. 
Please discuss risk benefit with Sponsor prior to 
starting HCV antiviral therapy. 
Restart pembrolizumab and talimogene 
laherparepvec intervention only if ALT returns to 
normal or Grade 1 (if normal at baseline), or to 
baseline grade (if Grade 2 at baseline) within 
12 weeks, and the participant is clinically stable; 
otherwise, the participant should be permanently 
discontinued. 
Relapse of HCV 
infection for 
participants with 
successfully 
treated or new 
HCV infection  
If HCV RNA was 
TND at baseline, and 
now has confirmed 
detectable HCV RNA 
(2 specimens, 1 
week apart) 
Immune-related 
Hepatitis 
If any of the HECI 
criteria is met as 
defined in the 
protocol Section 
Section 9.2.6 
Interrupt pembrolizumab and talimogene 
laherparepvec study treatment for up to  
12 weeks. 
Start IV corticosteroid 60 mg/day of prednisone or 
equivalent followed by oral corticosteroid. 
Monitor with biweekly laboratory tests, including 
AST, ALT, T Bili, D Bili, ALP, and INR. 
Page 1 of 2 
 


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Table 15.  Management of Hepatic Events of Clinical Interest for Pembrolizumab: 
 
Diagnosis 
Management 
Immune-related 
Hepatitis 
(continue) 
Note:  
Immune-related 
hepatitis is a 
diagnosis made after 
excluding other 
possible etiologies 
such as viral flare, 
biliary or vascular 
obstruction, infection, 
medications, and 
alcohol use usually 
immune-related 
hepatitis response to 
dechallenge and/or 
steroids and re-
occurs with 
rechallenge 
Restart pembrolizumab and talimogene 
laherparepvec intervention only if:  
a) Abnormal laboratory values resolve to Grade 
 1 or baseline (if abnormal at baseline) 
b) Taper steroid over 28 days 
c) Steroid treatment is tapered to prednisone 
 10 mg/day or equivalent 
Permanently Discontinue pembrolizumab and 
talimogene laherparepvec intervention if: 
a) Laboratory abnormalities do not resolve within 
3 weeks 
b) Steroids cannot be lowered to  10 mg/day (or 
prednisone equivalent) within 12 weeks 
c) Decompensation to CP-C status 
Other Causes 
Rule out infection 
with blood, urine, and 
ascites culture – 
antibiotics should be 
started if infection is 
found 
If total bilirubin is 
elevated, imaging 
should be obtained to 
rule out vascular 
compromise, biliary 
obstruction, and/or 
tumor progression by 
imaging 
Ruled out alcohol use 
and hepatotoxic 
drugs including 
herbal and alternative 
medications 
Restart pembrolizumab and talimogene 
laherparepvec only if laboratory values have 
returned to Grade 1 or baseline (if normal or 
Grade 1 at start) or to baseline grade within  
3 weeks. 
If biliary obstruction is present, consultation with a 
gastroenterologist and/or an interventional 
radiologist should be obtained to see if the 
obstruction may be relieved. 
 
Page 2 of 2 


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9.2.6 
Events of Clinical Interest for Group B HCC Subjects 
Selected nonserious and serious adverse events are also known as ECIs and must be 
reported to the Sponsor.  
Events of clinical interest for HCC subjects in this study include:  
1. An overdose of Sponsor's product, as defined in Section 9.2.6.1, that is not 
associated with clinical symptoms or abnormal laboratory results.  
2. Hepatic ECIs include any of the following events if the events are considered not 
due to disease progression as judged by the investigator.  All of these events (if 
not associated with disease progression under study) will require holding study 
treatment, notification of the event(s) to the Sponsor within 24 hours after 
awareness via electronic media or paper. 
For dose interval modification, refer to Section 6.2.2.2.1 and 6.2.2.2.2.  For guidance 
related to the diagnosis and management of HECIs, refer to Section 9.2.5.1. 
 
ALT: 
a. Among subjects with Baseline ALT  2 x ULN:  ALT  5 x ULN 
b. Among subjects with Baseline ALT  2 x ULN:  ALT  3 x the Baseline level 
c. ALT  500 U/L regardless of baseline level 
 
Total Bilirubin: 
a. Total bilirubin  3.0 mg/dL 
 
Regardless of laboratory values, hepatic decompensation diagnosed clinically, 
including: 
o New onset clinically detectable ascites requiring intervention for  3 days 
o Hepatic Encephalopathy 
o Gastrointestinal bleeding suggestive of portal hypertension (e.g., esophageal 
or gastric varices 
Progression of the cancer under study is not considered an ECI for pembrolizumab 
unless it is considered to be drug-related by the investigator. 
9.2.6.1 
Definition of an Overdose of Pembrolizumab for This Protocol and 
Reporting of Pembrolizumab Overdose 
For this trial, an overdose of pembrolizumab will be defined as  1000 mg (5 times the 
dose) of pembrolizumab.  No specific information is available on the treatment of 
overdose of pembrolizumab.  In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 


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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 Amgen as described in Sections 9.2.2 and 9.2.3, respectively.  In addition, 
the adverse event(s) or serious adverse event(s) associated with (“result from”) the 
overdose of pembrolizumab should be reported as Event of Clinical Interest as 
described in Section 9.2.4. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking protocol-required therapies, 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 through 4 months after the last dose of talimogene 
laherparepvec or pembrolizumab, whichever is later (or 30 days following cessation of 
pembrolizumab if the subject initiates a new anticancer therapy, whichever is earlier).   
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s awareness of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Forms (Appendix C).  The Amgen’s 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, neonatal death, or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event.  
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen Global Patient Safety as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies through 
4 months after the last dose of talimogene laherparepvec or pembrolizumab, whichever 
is later (or 30 days following cessation of pembrolizumab if the subject initiates a new 
anticancer therapy, whichever is earlier).  


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Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the investigator’s awareness 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. 
Pregnancies and lactations that occur after the consent form is signed but before 
enrollment must be reported by the investigator if they cause the subject to be excluded 
from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure. 
9.4 
Reporting Exposure to Talimogene Laherparepvec 
If a household member, caregiver, or healthcare provider who has had close contact 
with the subject is suspected to have been exposed to talimogene laherparepvec 
(eg, has signs or symptoms suspected to be herpetic in origin or is accidentally exposed 
to talimogene laherparepvec), while the subject is taking talimogene laherparepvec, 
report the exposure to Amgen as specified below.  In addition to reporting an unintended 
exposure case during the study treatment, investigators should monitor for potential 
exposure cases that occur after the last dose of talimogene laherparepvec through  
30 ( 7) days after the last dose of talimogene laherparepvec. 
Any potential or known unintended exposure should be reported to Amgen within 
24 hours of the investigator’s awareness of the event of exposure.  Amgen will seek to 
follow-up with the exposed individual, if necessary, to collect more information about the 
exposed individual contact with clinical trial subject, signs and/or symptoms related to 
the exposure, medical history, and/or outcome of the exposure.  If the exposed individual 
is reporting signs or symptoms suspected to be related to talimogene laherparepvec 
exposure, the exposed individual may be asked to have a swab taken from suspected 
lesions that are present to evaluate for the presence of talimogene laherparepvec DNA 
in the lesions by qPCR testing. 


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10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
Primary Endpoint:  
Part 1:   
Monotherapy cohorts 1-4:  Subject incidence of DLTs with intrahepatic injection of 
talimogene laherparepvec into liver tumors in subjects with non-HCC with liver 
metastases and subjects with HCC without active viral hepatitis. 
Combination cohorts 5 and 6:  Subject incidence of DLTs with intrahepatic injection into 
liver tumors of talimogene laherparepvec in combination with systemic IV administration 
of pembrolizumab in subjects with non-HCC with liver metastases and subjects with 
HCC with and without viral hepatitis. 
Part 2: 
 
ORR per modified irRC-RECIST with intralesional injection of talimogene 
laherparepvec into cutaneous, subcutaneous, lymph node, and liver tumors in 
combination with systemic IV administration of pembrolizumab separately by tumor 
type arm (hormone receptor positive BC, TNBC, CRC, CSCC, BCC, and HCC with 
and without viral hepatitis) 
 
Subject incidence, for each tumor type arm, of treatment-emergent and 
treatment-related adverse events, including DLTs 
Secondary Endpoint(s):   
Efficacy: 
Part 1:   
 
ORR, BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and 
OS separately for non-HCC and HCC tumors in monotherapy and combination 
cohorts 
Part 2:   
 
BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and OS 
by primary tumor type arm (hormone receptor positive BC, TNBC, CSCC, CRC, 
BCC, and HCC with and without viral hepatitis) 
Safety: 
Parts 1 and 2:   
 
Subject incidence of treatment-related and treatment-emergent adverse events in 
each monotherapy and combination cohorts in Part 1 and each tumor type 
separately in Part 2, and HCC with and without viral hepatitis in Part 2 
 
Subject incidence of detectable talimogene laherparepvec DNA in blood and urine 


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 
Incidence of clearance of talimogene laherparepvec DNA from blood and urine 
 
Subject incidence (per subject) and rate of detection (per sample) of talimogene 
laherparepvec DNA and virus at the surface of injection site, the exterior of the 
occlusive dressing, and the oral mucosa 
 
Subject incidence of talimogene laherparepvec DNA detection in lesions suspected 
to be herpetic in origin 
Exploratory Endpoint: 
10.1.2 
Analysis Sets 
DLT Analysis Set:  The DLT analysis set will include DLT-evaluable subjects enrolled in 
Part 1 defined as follows: 
 
Monotherapy Cohorts:  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 
1 additional dose of talimogene laherparepvec 
 
Combination Cohorts:  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 pembrolizumab in combination  
 
Subjects experiencing a DLT:  Have a DLT during the DLT-evaluation period after at 
least 1 dose of talimogene laherparepvec (for monotherapy cohorts) and talimogene 
laherparepvec and pembrolizumab (for combination cohorts) 
Full Analysis Set:  For efficacy analyses of talimogene laherparepvec monotherapy, the 
full analysis set will be defined as all subjects who received at least 1 dose of talimogene 
laherparepvec and no treatment with systemic pembrolizumab, and for efficacy analyses 
of talimogene laherparepvec in combination with systemic pembrolizumab, it will be 
defined as all subjects who received at least 1 dose of talimogene laherparepvec and at 
least 1 dose of pembrolizumab in combination. 
Safety Analysis Set:  The safety analysis set will be defined as all subjects who received 
study therapy.  For monotherapy cohort, subjects will be included for analysis of safety if 
they received at least 1 dose of talimogene laherparepvec.  For the combination therapy 
cohorts or part 2, subjects will be included for analysis of safety if they received at least 
1 dose of talimogene laherparepvec or at least 1 dose of pembrolizumab. 


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Covariates and Subgroups 
The following covariates may be used whenever applicable to examine efficacy and 
safety in subgroups or in multivariate analyses: 
 
Region, if applicable (USA vs non-USA) 
 
Age at baseline ( 50,  50;  65,  65;  75,  75 years) 
 
Baseline LDH ( ULN vs  ULN) 
 
Gender (Female vs Male) 
 
Baseline ECOG (0 vs 1) 
 
Baseline sum of lengths of measurable lesions 
 
Baseline sums of lengths of measurable liver lesions 
 
Prior exposure to chemo therapy (Yes vs No) 
 
HSV-1 serostatus (Yes vs No) 
 
Maximum talimogene laherparepvec volume at highest concentration per visit 
( 4 mL vs  4 mL) 
 
Baseline HBV or HCV status 
 
Baseline Microsatellite Instability status for CRC subjects 
10.2 
Sample Size Considerations 
Sample Size Considerations for Part 1 
The sample size of approximately 3 to 6 subjects per monotherapy cohort is determined 
empirically and is consistent with those used in traditional “33” phase 1 designs to 
evaluate safety assuming a true DLT rate of less than 1/3.  There are up to 
4 monotherapy cohorts in Groups A / B in Part 1.  Subjects enrolled in a monotherapy 
cohort may be replaced if they are not evaluable for DLT (eg, did not receive talimogene 
laherparepvec or ended the study treatment before completion of the DLT evaluation 
period for a reason other than experiencing a DLT).  Table 16 summarizes the 
probability of declaring a monotherapy cohort safe or unsafe for a range of true cohort 
DLT probabilities. 


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Table 16.  Probability of Declaring a Monotherapy Cohort Safe or Unsafe  
True Cohort DLT Probability 
Probability Declare Cohort Safe 
Probability Declare Cohort 
Unsafe 
0.1 
0.91 
0.09 
0.2 
0.71 
0.29 
0.3 
0.49 
0.51 
0.4 
0.31 
0.69 
0.5 
0.17 
0.83 
DLT  dose-limiting toxicity 
Safety of the combination will be evaluated with the mTPI up-and-down design in Part 1 
to determine the talimogene laherparepvec MTC with a target DLT rate of 40.  The 
maximum sample size in the combination cohorts 5 and 6 or 6a will be 28 (maximum of 
12 DLT evaluable subjects, evaluated at 6b).  Unless the cohort 5 is deemed too toxic, 
patients may be enrolled and assigned to appropriate doses until the maximum sample 
size is reached or minimum of 12 subjects are enrolled in Cohort 6 provided the mTPI 
outcome is not at a D or DU in cohort 6.  If in HCC group, cohort 6b completes prior to 
cohorts 5 and 6a enrollment, and 6b is deemed safe, then cohorts 5 and 6a will close to 
enrollment.  Full details of the mTPI will be specified in the DLRT Charter. 


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Table 17.  mTPI Dose Decision Outcomes With a 40 Target DLT Ratea,b,c 
 
 
DLRT  Dose Level Review Team; DLT  dose limiting toxicity; MTD  Maximum tolerated dose; modified 
toxicity probability interval 
a Vertical axis is the maximum allowed subject incidence of DLT among the number of DLT-evaluable 
subjects on the horizontal axis 
b First DLRT evaluation is planned after the first 4-6 subjects have been enrolled with a minimum of 4 DLT 
evaluable subjects.  DLRT evaluation may occur earlier at the DLRT’s discretion.  Please see details in the 
DLRT charter.   
c Sample Size  28 across cohorts 5 and 6 
Part 2 for non-HCC tumor types (Group A) or HCC (Group B) will open if the 
corresponding group MTC is selected at the end of Part 1. 
The probability of selecting 108 PFU/mL as the MTC in Part 2 for Group A/B is 97 (3 
for selection of 107 PFU/mL) if the true DLT rate is 10 for 107 PFU/mL and 30 for 
108 PFU/mL, respectively (Table 17).   


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Table 18.  MTC Selection Probabilities For True DLT Rate Scenarios 
True Cohort DLT Probability 
Probability of Selection 
107 
108 
107 
108 
No RP2D 
0.01 
0.05 
0.00 
1.00 
0.00 
0.05 
0.25 
0.01 
0.99 
0.00 
0.15 
0.25 
0.04 
0.96 
0.00 
0.1 
0.3 
0.03 
0.97 
0.00 
0.3 
0.4 
0.40 
0.58 
0.02 
0.3 
0.6 
0.73 
0.25 
0.02 
0.4 
0.5 
0.66 
0.21 
0.13 
0.6 
0.6 
0.23 
0.02 
0.76 
DLT  dose-limiting toxicity;  HCC  hepatocellular carcinoma; MTC  maximum tolerated concentration; 
mTPI  modified toxicity probability interval; RP2D  recommended phase 2 dose 
a Assumptions:  Maximum 28 DLT-evaluable subjects in each group (non-HCC vs HCC); 40 target DLT 
rate; 4 additional subjects prior to each analysis. 
Sample Size Considerations for Part 2 
The recommended phase 2 dose from Part 1 (RP2D) for non-HCC (Group A) and HCC 
(Group B) will be evaluated in Part 2 independently for each tumor type arm for the 
combination of talimogene laherparepvec with systemic pembrolizumab.  Subjects that 
initiate treatment at the corresponding RP2D in Part 1 will not be included in the Part 2 
efficacy analysis according to their respective tumor type arm. 
The primary objective in Part 2 for each tumor type arm will be to evaluate the ORR per 
modified irRC-RECIST with a minimum potential follow-up of at least 29 weeks.  The null 
hypothesis (H0) for each tumor type is an ORR  10 which, if true, would not warrant 
further evaluation in contrast to the alternative hypothesis (H1) of an ORR  40.   
The following 2-stage design will be used to reject H0 at a  2.5 1-sided significance 
level.  The efficacy analysis will be based on the Full Analysis Set in Part 2 only.A 
cumulative total of 10 subjects will be treated in Stage 1 and enrollment is planned to 
stop.  If there are 2 or more responders (PR or CR no confirmation is needed), then a 
total of 11 additional subjects will be treated in Stage 2; otherwise, H0 will be accepted 
and enrollment will be permanently discontinued.  If the required number of responders 
to continue to Stage 2 is observed before the end of Stage 1 enrollment, then enrollment 
will not be suspended. 
H0 will be rejected after Stage 2 if there are  6 responders (with confirmation) in 21 
treated subjects, ie, the observed ORR is  28.6.  In the event precisely 21 subjects 
are not included in the analysis in total, H0 will be rejected if the lower limit of the 


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95 exact binomial CI is  10 (Atkinson and Brown, 1985).  If exactly 10 and 11 
subjects are included at Stage 1 and 2, respectively, the design achieves a 1-sided 1.3 
significance level, 88.4 power, and the probability of stopping at Stage 1 if H0 (H1) is 
true is 73.6 (4.6). 
For each tumor type that advances to Stage 2, a Bayesian framework will be utilized to 
assess evidence that the combination ORR exceeds that expected for pembrolizumab 
alone to aid in decision-making as to whether further evaluation is warranted.  Further 
detail will be described in the Statistical Analysis Plan. 
From 10 to 21 subjects per tumor type are expected to be treated at the RP2D for a total 
of 60 to 126 subjects. 
For Part 2, the DLRT will consider prospective guidelines in the DLRT Charter to monitor 
safety separately by tumor type arm and, if introduced, talimogene laherparepvec total 
volumes  4 mL within Group A and Group B.   
The subject incidence of DLT in Part 2 will be based on the DLT Analysis Set with at 
least 6 weeks minimum potential follow-up.   
The maximum total sample size for Parts 1 and 2 is 127 subjects (74 subjects in 
Part 1; 53 subjects in Part 2).  Dose-limiting toxicity non-evaluable subjects will not be 
replaced in Part 2. 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
Dose-limiting toxicities interim safety analyses will be performed to support the 
evaluation of safety and determination of the MTC and MTV of talimogene 
laherparepvec administered as monotherapy and in combination with systemic 
pembrolizumab.  Interim efficacy analysis for part 1 will be performed as needed Interim 
safety and efficacy futility analyses are planned for this study in Part 2 separately for 
each tumor type arm.   
10.3.1.1 
DLT Safety Analysis (Part 1) 
The planned interim safety data reviews for monotherapy cohorts in Part 1 to evaluate 
the subject incidence of DLTs will be conducted according to timing/rules described in 
Table 1 (Section 3.1.1).  Data will be reviewed by a DLRT.  The DLRT will recommend 
either to declare the cohort dose intolerable, to reassess safety after 3 additional 


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DLT-evaluable subjects, or to declare the cohort dose tolerable and to apply the same 
evaluation rules to subsequent cohorts.   
For combination cohorts in Part 1, the DLRT will recommend according to the DLRT 
Charter whether it is safe to continue enrollment based on the mTPI up-and-down 
design. 
10.3.1.2 
Interim Safety Analysis (Part 2) 
An interim safety data review will occur for each tumor type separately after 
approximately 10 subjects have been treated in Part 2 with the specific tumor type with 
at least 6 weeks of follow-up. 
Additional safety analyses may be conducted as warranted during Part 2 if a DLT event 
occurs in the first 4 DLT-evaluable subjects or after a target of approximately 6 and 16 
DLT-evaluable subjects.  As appropriate the DLRT will be convened to monitor safety. 
A total volume  4 mL of talimogene laherparepvec may be allowed in Part 2 with 
systemic pembrolizumab if it is declared safe without pembrolizumab in Part 1.  In this 
event, the DLRT will also monitor safety in Part 2 separately among subjects in 
non-HCC (Group A) and HCC (Group B) arms that receive at least 1 dose of talimogene 
laherparepvec with a total volume  4 mL at the combination MTC with systemic 
pembrolizumab.  Subjects will be included in the safety assessment of  4 mL with at 
least 3 weeks follow-up from an initial total volume  4 mL at the combination MTC.   
Safety analyses, including analyses of the subjects receiving a total volume  4 mL 
talimogene laherparepvec, will be performed at the time of the planned analyses for 
each tumor type arm or more frequently at the DLRTs discretion.   
10.3.1.3 
Interim Futility Analysis (Part 2) 
One interim efficacy futility analysis will occur after 10 subjects have been treated with 
the combination in Part 2 by tumor type and have had an opportunity to be followed up 
for at least 20 weeks.  Enrollment will be suspended for the specific tumor type pending 
the outcome of the interim analysis.  If there are 2 or more responders (CR or PR 
confirmation not required), then a total of 11 additional subjects will be treated; 
otherwise, further enrollment of the tumor type arm will be permanently discontinued.  If 
at least 2 responders are observed by the enrollment of the 10th treated subject, then 
enrollment will not be suspended.   


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10.3.2 
Dose Level Review Team (DLRT) 
A DLRT consisting of the Amgen study team, including at least one medical clinician, 
safety representative and biostatistician, at least one representative of the Merck study 
team, and at least one participating investigator who has recruited subjects into Part 1, 
will review the safety data to evaluate possible DLTs.  Representative(s) from Merck will 
participate in DLRT meetings for all cohorts (voting member only for Cohorts 5 and 6 of 
Part 1 and all cohorts of Part 2).  The DLRT will make recommendations in Part 1 and 2 
according to a DLRT Charter.  The DLRT Charter will include guidelines to monitor 
safety in Part 2 separately by tumor type arm and, if introduced, talimogene 
laherparepvec total volumes  4 mL within Group A and Group B.  In Part 2, the DLRT 
may consider reducing the RP2D talimogene laherparepvec concentration and/or 
discontinuation of total volumes  4 mL, if introduced.   
10.3.3 
Primary Analysis 
One clinical study report (CSR) will be written based on the results of the primary 
analyses across Part 1 and Part 2.  
Primary Analysis:  The primary analysis for each combination cohort from Part 2 will 
occur independently when all subjects in each tumor type arm have a minimum potential 
follow-up of  29 weeks.  The primary analysis for part 1 will occur after all subjects have 
a minimum potential follow-up of  29 weeks. 
10.3.4 
Final Analysis  
Final Analysis:  The final analysis will occur when all subjects have discontinued the 
study treatment and have had the opportunity to complete the long-term survival 
follow-up.  One CSR will be written with the updated results from the final analyses at 
the completion of the study. 
10.4 
Planned Methods of Analysis  
The data will be analyzed by cohort/group (non-HCC and HCC), in the overall population 
and by tumor type, if applicable. 
Descriptive statistics will be provided for demographic, safety, efficacy and 
 
endpoints.  Formal analysis will be performed on the primary endpoints in Part 2. 
A separate comprehensive Statistical Analysis Plan will be developed. 


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10.4.1 
Primary Endpoint 
Part 1:   
The DLT analysis set will be used to summarize the subject incidence of DLT for the 
study and the safety analysis set will be used for all other analyses of safety endpoints 
(including but not limited to all adverse events, grade  3 adverse events, serious 
adverse events, fatal adverse events, adverse events requiring discontinuation of study 
drug, and adverse events defined as events of interest).  For talimogene laherparepvec 
monotherapy, safety will be assessed for non-HCC (Group A) and HCC (Group B) 
groups based on the “3  3” design.  For the combination of talimogene laherparepvec 
with pembrolizumab, safety will be assessed for non-HCC (Group A) and HCC 
(Group B) groups based on the mTPI up-and-down design. 
Part 2 
The 2 stage efficacy analysis will be conducted using the full analysis set from Part 2, 
unless otherwise specified.  The 2-stage design will be used to evaluate the ORR per 
the modified irRC-RECIST.  The null hypothesis of a 10 ORR for a given tumor type 
that continued to Stage 2 will be rejected if an exact binomial 95 CI for the ORR is 
above 10 (Atkinson and Brown, 1985). The primary analysis of efficacy will include 
subjects that receive at least 1 dose of talimogene laherparepvec and at least 1 dose of 
pembrolizumab in combination from Part 2.   
For each tumor type that advances to Stage 2, a Bayesian framework will be utilized to 
assess evidence that the combination ORR exceeds that expected for pembrolizumab 
alone to aid in decision-making as to whether further evaluation is warranted.  Further 
detail will be described in the Statistical Analysis Plan. 
10.4.2 
Secondary Endpoints 
Efficacy Endpoints: 
Part 1: 
Objective response rate, BOR, DRR, DOR, response in injected and uninjected lesions, 
DCR, PFS, and OS will be summarized separately for non-HCC and HCC tumors in 
monotherapy cohorts and combination cohorts.  Objective response rate, DRR, and 
DCR will be summarized with an associated 95 CI.  Duration of response among 
responders, PFS and OS will be estimated using the Kaplan-Meier method.  A listing of 
efficacy endpoints will be provided for whichever combination cohort is not the RP2D, if 
applicable. 


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Part 2: 
BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and OS will 
be summarized by primary tumor type arm (hormone receptor positive BC, TNBC, CRC, 
CSCC, BCC, and HCC with and without viral hepatitis).  Objective response rate, DRR, 
and DCR will be summarized with an associated 95 CI.  Duration of response among 
responders, PFS and OS will be estimated using the Kaplan-Meier method.  Tumor 
response endpoints may also be evaluated based on modified RECIST v 1.1 for 
historical comparison for each tumor type that continues to Stage 2 of Part 2. 
Safety Endpoints (Parts 1 and 2): 
Subject incidence of treatment-emergent and treatment-related adverse events 
(monotherapy and combination cohorts in Part 1 and each tumor type arm separately in 
Part 2; including all treatment-emergent adverse events, grade  3 adverse events, 
serious adverse events, adverse events of interest and events requiring the 
discontinuation of study drug, and local effects on the tumor [ie, pain, inflammation and 
ulceration]) will be summarized.  Medical Dictionary for Regulatory Activities (MedDRA) 
will be used to code adverse events to a system organ class (SOC) and a preferred term 
within the SOC.  The CTCAE version 4.03 will be used to grade severity of adverse 
events.   
Subject incidence of all disease related events, fatal disease related events, serious 
disease related events, disease related events leading to withdrawal from study drug, 
and significant disease related events will also be provided. 
A summary of deaths after initiation of the study through 90 days since the last dose of 
talimogene laherparepvec or pembrolizumab, whichever is discontinued last will be 
provided. 
The qPCR analysis result of talimogene laherparepvec DNA in swab samples taken from 
cold sore, vesicles, and other lesions suspected to be herpetic in origin (if any) will be 
summarized.  
Summary statistics will be provided for vital signs, physical measurements and 
laboratory data, details of the analysis will be provided in statistical analysis plan. 
10.4.3 
Exploratory Endpoints 


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10.5 
Handling of Missing and Incomplete Data 
Partial or missing dates of adverse events and concomitant medications will be imputed.  
Adverse events with missing severity and/or possible relationship to talimogene 
laherparepvec will be included in the all adverse events analyses, except by severity 
grade and treatment-related.  Every effort will be made to obtain complete dates for 
deaths.  Details of the imputation algorithms will be specified in the study-specific 
statistical analysis plan. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be communicated 
formally in writing from the Amgen Clinical Study Manager to the investigator.  The 
written informed consent document is to be prepared in the language(s) of the potential 
subject 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 is 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 ICF is to be signed and personally dated by the subject and by the 
person who conducted the informed consent discussion.  The original signed ICF 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 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, 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 ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval /renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 


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local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with Federal regulations/International Council for Harmonization 
(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 Amgen, will be any or all of the following: 
 
a recognized expert in the therapeutic area 
 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an Investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study, a treatment group, cohort or arm at any 
time.  Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the study contract.  The investigator is to notify the 
IRB/IEC in writing of the study’s completion or early termination and send a copy of the 
notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 


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whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the IVR system captures the following data points and these are 
considered source data: subject identification. 
CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data).   
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include the following: 
 
subject files containing completed CRFs, ICFs, and subject identification list 
 
study files containing the protocol with all amendments, IB, copies of prestudy 
documentation, and all correspondence to and from the IRB/IEC and Amgen 
 
investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 


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upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen clinical monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The clinical monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. 
Data capture for this study is planned to be electronic: 
 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries and/or site notifications are created in the EDC system 
database for site resolution and subsequently closed by the EDC system or by an 
Amgen reviewer. 
 
All subject data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data, 
centrally or adjudicated data).  The investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the CRF. 
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 


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to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 8 through Table 13), 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.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical 
Journals, 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; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, 3, and 4. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should 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. 


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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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14. 
APPENDICES 
Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


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Appendix B.  Sample Electronic Serious Adverse Event Contingency Report Form 
(paper-based form) 
 


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Appendix C.  Pregnancy and Lactation Notification Forms 
 
 


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Appendix D.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response 
Note: Immune-related Response Criteria (irRC) simulating Response Evaluation Criteria 
in Solid Tumors version (RECIST) version 1.1 [irRC-RECIST] defined by 
Nishino et al, 2014, with modification will employed to account for unique tumor 
response characteristics observed with immunotherapies to enable treatment beyond 
progression, if the subject is clinically stable. 
Method of Measurement 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 
or nodal/soft tissue disease (including lymph nodes).  Measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm or less.  Scan 
slices should ideally be 3 to 5 mm.  MRI is acceptable to assess disease extent if used 
throughout the study. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  A 
switch from contrast enhanced CT to noncontrast CT or to MRI (or vice versa) should 
not preclude response assessment if, in the judgment of the site radiologist, there is no 
significant difference in the assessment by changing modalities.  This may occur if a 
subject has developed a medical contraindication to intravenous (IV) 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 IV and oral 
contrast) then the CT portion of the PET/CT can be used for tumor measurements.  


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Ultrasound:  
Ultrasound (US) should not be used as a primary method to assess liver lesion 
measurements in response to treatment.  If new lesions are identified by US in the 
course of the study, confirmation by CT or MRI is advised. 
At baseline, lesions are categorized as measurable or non-measurable according to the 
following definitions: 
Measurable Lesions: 
Measurable lesions are defined at baseline as lesions that can be accurately measured 
in at least one dimension (ie, longest diameter for non-nodal lesions and short axis for 
lymph nodes will be measured and followed) with a minimum size of: 
 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI  
 
A lymph node must be  15 mm in short axis when assessed by CT scan or MRI. 
Target lesions must not be chosen from a previously irradiated field unless there has 
been documented tumor progression in that field prior to enrollment.  The distribution of 
the target lesions should be representative of the subject’s overall disease (eg, largest 
lesions per organ). 
Non-Measurable Lesions: 
All other lesions, including small lesions (longest diameter  10 mm or pathological 
lymph nodes with  10 mm but  15 mm short axis) and other truly non-measurable 
lesions are considered non-measurable and characterized as non-target lesions.  This 
will include any measurable lesions beyond the maximum number of 10 that were not 
chosen as target lesions.  Only cancerous lesions should be selected as 
non-measurable lesions and not indeterminate lesions and lesions that could be cancer.  
Other examples of  
non-measurable lesions include some bone lesions*, leptomeningeal disease, 
inflammatory breast disease, lymphangitic involvement of the skin or (lymphangitis 
cutis/pulmonis), and groups of lesions that are small and numerous. 
Fluid Collections 
Ascites, pleural effusion, or pericardial effusion should not be selected as 
non-measurable disease at baseline or, if new or increased, as evidence of progressive 
disease (PD).  These collections may occur with both benign and malignant conditions, 
and their etiology is often not clear.  These collections may often be removed via 


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interventional procedures, which can lead to a false interpretation of disease response.  
Thus, these fluid collections should not be used as a baseline non-target or as evidence 
of disease response. 
* Bone Lesions: 
 
Bone scans, PET scans or plain films are not considered adequate imaging 
techniques to measures bone lesions.  However, these techniques can be used to 
confirm the presence or absence of bone lesions. 
 
Osteolytic (lytic) bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross-sectional imaging technique such 
as CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.  Only the soft tissue 
component of the bone lesion should be measured. 
 
Many osteoblastic (blastic) bone abnormalities can be benign and should not be 
selected as baseline lesions.  An isolated new small blastic lesion should not be 
selected as a new lesion unless there is demonstrated growth on subsequent scans.  
Multiple new blastic lesions that are clearly cancerous may be considered for new 
lesions. 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable or non-measurable) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same subject, these are preferred 
for selection as target lesions.  If a cystic lesion is clearly cancerous and has both 
cystic and solid components, then the complete lesion should be measured including 
both components without excluding the cystic portion of a cystic tumor lesion when 
measuring. 
Lesions with Prior Local Treatment: 
Tumor lesions situated in a previously irradiated area, or an area subject to other 
loco-regional therapy, should not be considered measurable unless there has been 
demonstrated progression in the lesion. 
Baseline Documentation of “Target” and “Non-Target” Lesions: 
Baseline evaluations will be used to prospectively identify all sites of disease present as 
close as possible to the enrollment and never more than 4 weeks before the enrollment 
date.  Sites of disease will be characterized as either target or non-target lesions. 
Baseline Documentation of Target Lesions: 
Up to 10 target lesions (a maximum of 5 per organ) will be chosen to measure over the 
course of therapy.  Pathological lymph nodes that are defined as measurable must meet 


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the criterion of a short axis of  15 mm by CT scan in order to be identified as target 
lesions.  
The distribution of these target lesions should be representative of the subject’s overall 
disease status.  Target lesions should be selected on the basis of their size (lesions with 
longest diameter) and suitability for accurate repeated measurements by imaging 
techniques.  In situations where larger lesions cannot be accurately measured 
repeatedly (eg, near the diaphragm where respiratory changes may affect 
measurements), smaller lesions that meet criteria for measurability may be selected 
instead. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  The 
baseline sum of diameters will be used as reference by which to characterize the 
objective tumor response.   
Baseline Documentation of Non-Target Lesions:  
All other lesions (or sites of disease), including any measurable lesions that were not 
chosen as target lesions and pathological lymph node with short axis  10 mm but 
 15 mm, should be identified as non-target lesions.  Measurable non-target lesions 
(ie, lesions in an organ beyond the allowed maximum number of targets that would 
otherwise qualify as target lesions) should also be recorded and assessed qualitatively 
over the course of therapy.  Non-measurable non-target disease measurements are not 
required, but these lesions are evaluated at each timepoint and will be evaluated as 
‘present’, ‘absent’, or in rare cases ‘unequivocal progression’.  If a significant partial 
response (PR) is observed in a non-target lesion, it should be described as a comment. 
Follow-up Assessment of Tumor Lesions: 
At each subsequent tumor assessment, the sum of diameters of target lesions identified 
at baseline plus the sum of diameters of up to 10 (maximum 5 per organ) new 
measurable lesions (ie, accurately and serially measured in at least 2 dimensions and 
for which the longest diameter is  10 mm for non-nodal lesions or the short axis is 
 15 mm for non-nodal lesions) are added together to provide the total tumor burden.  
If more than 10 new measurable lesions total (or 5 per organ) are present at a single 
timepoint, the new measurable lesions should be selected on the basis of their size and 
suitability for accurate repeated measurements by imaging techniques (CT or MRI).  If 


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there are lesions beyond of the new measurable lesion limit, the additional lesions would 
be considered new non-measurable lesions. 
Tumor Burden  sum of diameters of target lesions  sum of diameter of up to 
10 (maximum 5 per organ) new, measurable lesions. 
Non-target disease measurements are not required and these lesions should be 
followed as “present”, “absent”, or “unequivocal progression”. 
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”.  Nodal disease should always have the actual short axis measurement recorded 
even if the nodes regress to below 10 mm on study.  For complete response (CR), each 
node must achieve a short axis 10 mm. 
Response Evaluation: 
Evaluation of Objective Response: 
The subject response will be assessed based on tumor burden (the sum of diameters of 
target lesions plus the sum of up to 10 [maximum 5 per organ] new measurable lesions), 
and, in the case of CR, the presence of any non-target and/or new non-measurable 
lesions.  The overall response is derived from time-point response assessments as 
described in Table 19 and Table 20.   


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Table 19.  Definition of Measurable Tumor Response 
(Baseline Target and New, Measurable Lesions)  
Complete Response (CR): 
Disappearance of all lesions (whether measurable or not 
and whether baseline or new) and confirmation by a repeat, 
consecutive assessment no less than 4 weeks (28 days) 
from the date first documented.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to 10 mm. 
Partial Response (PR): 
Decrease in tumor burden*  30 relative to baseline 
confirmed by a consecutive assessment at least 4 weeks 
(28 days) after first documentation  
Progressive Disease (PD): 
Increase in tumor burden*  20  and at least 5 mm 
absolute increase relative to nadir (minimum recorded tumor 
burden) confirmation by a repeat, consecutive assessment 
no less than 4 weeks (28 days) from the date first 
documented PD.  
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD. 
Unable to Evaluate (UE): 
Any lesion present at baseline which was not assessed or 
was unable to be evaluated leading to an inability to 
determine the status of that particular tumor for that time 
point. 
Note:  If a subset of target / new measurable lesions were 
assessed and the tumor burden increase of the subset is 
sufficient to declare PD without the contribution of the 
unevaluated lesions, then PD should be reported. 
Not Applicable (NA) 
No target lesions were identified at baseline 
Not Done (ND) 
Radiographic imaging or clinical assessment was not 
performed at this time point to evaluate the response of 
measurable lesions 
* Tumor Burden  sum of diameters of target lesions  sum of diameter of new, measurable lesions.  
Diameters used: 
 
For nodal disease, shortest axis 
 
For non-nodal disease, longest diameters 


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Table 20.  Matrix for Determining the Overall Response at Each Assessment Point 
Measurable Response 
Non-measurable Response 
Overall 
Response 
Target and new, 
measurable lesions 
(tumor burden)a,  
Non-target 
New, nonmeasurable 
lesions 
Using 
irRC-RECIST 
↓100e 
Absent/NAd 
Absent 
CRb 
↓100 
Stable/ND 
Any 
PRb 
↓100 
Unequivocal progression 
Any 
PRb 
↓ 30 
Absent/Stable/ND/NAd 
Any 
PRb 
↓ 30 
Unequivocal progression 
Any 
PRb 
↓ 30 to ↑ 20 
Absent/Stable/ND/NAd 
Any 
SD 
↓ 30 to ↑ 20 
Unequivocal progression 
Any 
SD 
↑ 20f 
Any 
Any 
PDb 
UE 
Any 
Any 
UE 
ND 
Any 
Any 
UE 
NAc 
Any 
Any 
UE 
a Decrease disease relative to baseline, including new measurable lesions only ( 10 mm). 
b Assuming response (CR or PR) or progression are confirmed by a second, consecutive assessment at 
least 4 weeks (28 days) apart. 
c No target lesions identified at baseline. When a patient has only nonmeasurable disease (ie, no target 
lesions identified at baseline) the response will be unevaluable. 
d No non-target lesions identified at baseline. 
e Disappearance of all non-lymph node lesions and all lymph nodes  10 mm in short axis would also be CR 
even if lymph node measurements prevent 100 tumor burden reduction. 
f In addition to relative increase of  20, the tumor burden must also demonstrate an absolute increase of 
 5 mm from nadir for PD. 
CR   complete response; PR  partial response; SD  stable disease; PD  progressive 
disease; UE  unable to evaluate; ND  not done; NA  not applicable.Determination of 
best overall response is based on changes in total tumor burden from the baseline 
(nadir, for PD) tumor assessment, regardless of any initial increase in baseline lesions or 
the appearance of new lesions. 
Subjects are considered to have PR or stable disease (SD) even if new lesions were 
present, as long as they met the respective thresholds of response as described in 
Table 20. 
Subjects with SD, particularly those with slow-declining tumor burden  20 from 
baseline at the last tumor assessment, are considered clinically meaningful because 
they show an objectively measurable reduction in tumor burden without reaching the 
30 threshold that defines PR. 


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A best overall response of SD requires a visit response of SD or better no earlier than 
77 days after the first dose date; otherwise the overall response will be UE. 
Confirmation of Response (CR or PR): 
To be assigned a status of CR or PR changes in tumor measurements must be 
confirmed by consecutive repeat assessments performed no less than 4 weeks 
(28 days) after the criteria for response are first met. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of CR depends on this determination, it is recommended 
that the residual lesion be investigated (ie, biopsy) to confirm the CR status. 
Confirmation of Disease Progression: 
If a subject is classified as having PD at a postbaseline tumor assessment, then 
confirmation of PD by a second assessment  4 weeks (28 days) later in the absence of 
rapid clinical deterioration (ie, rapid decline in performance status) or symptomatic 
disease requiring rapid initiation of alternative systemic anti-cancer therapy is required.  
The definition of confirmation of progression represents a  20 and at least 5 mm 
absolute increase in the total tumor burden (ie, the sum of diameters of target lesions 
plus up to 10 [maximum 5 per organ] new measurable lesions) compared to the nadir at 
two consecutive time-points at least 4 weeks (28 days) apart (with the date of 
progression considered to be the time of the initial evaluation showing PD).  It is 
recommended that this be done at the discretion of the investigator because follow-up 
with observation alone may not be appropriate for subjects with a rapid decline in 
performance status.  Confirmation of PD allows for the capture of all observed 
responses using the irRC-RECIST as most of these late responding subjects have a 
trend toward response within 4 weeks (28 days) after initial PD. 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of PD at the time should have the reason for 
treatment discontinuation specified.  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
Determining a New Nadir After Intervention-therapy: 
After the intervention-therapy for liver lesions is completed, subjects will undergo 
radiological imaging by either CT or MRI or US according to the schedule defined in 
Section 7 of the protocol.  The first post intervention tumor assessment will provide the 
“new nadir” from which progression will be assessed.  Any remaining sites of disease 


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must continue to be followed as target and non-target lesions as designated at study 
screening.  Post intervention tumor assessment will be performed until confirmed PD, 
according to the schedule of the study protocol. 
Subjects who have had Complete Removal of the Lesion will be Evaluated as 
Follows: 
The completely resected lesion should continue to be documented on the case report 
forms (CRFs) and assigned a default code of absent (for nontarget lesions) or a value of 
0 mm for the longest diameter for the purpose of calculating the sum of the diameters 
(for target lesion), and determining the post intervention-therapy response.  This will 
allow continued response determination from screening. 
If the resected lesion contained no tumor under pathology evaluation, subsequent tumor 
assessments post-procedure may be used for tumor burden calculations and/or 
determination of response.  If the resected lesion contained tumor or pathology results 
were unknown, the recorded tumor assessments post-procedure may be used for tumor 
burden calculations, but determination of response will be considered unevaluable (UE) 
for response except in the case of PD.  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. 
Guidance on quantitative/qualitative reporting of fully resected lymph nodes is below 
(see Table 21). 
If new radiographic imaging findings develop at the surgical/treatment site that were not 
present on the immediate post intervention-therapy imaging assessments and are 
indicative of tumor recurrence, the tumor will be considered a new lesion, and measured 
accordingly, with the response assessed as PD if increase in tumor burden  20 and at 
least 5 mm absolute increase relative to nadir compared with the first post intervention-
therapy nadir at two time points at least 4 weeks (28 days) apart. 


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Table 21.  Quantitative/Qualitative Reporting of Fully Resected Lymph Nodes 
Lymph Node 
Type/Presence 
Contained Cancer 
Under Pathology 
Evaluation? 
Quantitative/qualitative Reporting 
Target lymph node 
previously present 
Yes/Unknown 
If measurement available:  Actual short axis 
If measurement not available: 10 mm short axis 
No 
If measurement available:  Actual short axis 
If measurement not available:  9 mm short axis 
Non-target lymph 
node previously 
present 
Yes/Unknown 
Present 
No 
Absent 
Lymph node not 
previously present 
Yes/Unknown 
If measurement available and short axis 
 15 mm:  New non-measurable lymph nodea 
If measurement available and short axis 
 15 mm:  please enter actual measurements 
(do not default to 10 mm)a 
If measurement not available: New 
non-measurable lymph nodea 
No 
Not to be recorded as target or non-target 
lesion.  Instead to be reported on Procedures 
electronic CRF. 
a The initial dimension of a new measurable lymph node or presence of a new non-measurable lymph node 
should be reported at all subsequent assessments. 
Subjects who have had Partial Removal/ Reduction of the Lesion will be Evaluated 
as Follows: 
In subjects where the tumor can still be confidently identified, it should be measured 
(target lesion) or qualitatively evaluated (nontarget lesion) and response (CR, PR or SD) 
or progression should be determined.  Response is judged compared to the screening 
time point and PD should be judged compared with the nadir as detailed in Table 19 and 
Table 20. 
In subjects where the interventional-therapy was not thought to be completely effective 
and residual tumor cannot be distinguished from the effects of therapy, the size of the 
residual tumor should be considered too small to measure and assigned a default code 
of present (for nontarget lesion) or a default value of 5 mm as the sum of the diameters 
(for target lesion).  If this is the nadir, PD will be judged from this sum of the diameters. 
A partially resected lesion should be assigned its measurement post-procedure (for 
target lesions) or “present” (for non-target lesions).  If the resected lesion contained no 


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tumor under pathology evaluation, subsequent tumor assessments post-procedure may 
be used for tumor burden calculations and/or determination of response.  If the resected 
lesion contained tumor or pathology results were unknown, the recorded tumor 
assessments post-procedure may be used for tumor burden calculations, but 
determination of response will be considered unevaluable (UE) for response except in 
the case of PD.  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. 
Merging Lesions 
When two or more target/new measurable 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/new non-measurable 
lesions merge, the smaller lesion should be recorded as absent for the current and all 
future assessments, and the larger lesion should be recorded as present for the current 
assessment and followed for future assessments.  If a target/new measurable lesion and 
a non-target/new non-measurable lesion merge, the non-target/new non-measurable 
lesion should be absent for the current and all future assessments while the target 
lesion/new measurable lesion should include both merged lesions for recording 
measurements. 
Separating Lesions 
When a target/new measurable lesion splits into 2 or more lesions, the largest 
measurable part of the split lesion should be considered to be the previously recorded 
target/new measurable lesion with measurements provided for the current assessment 
and followed for future assessments.  The dimensions of the split parts would still be 
target lesions.  When a nontarget/new nonmeasurable lesion splits into 2 or more 
lesions, the split parts remain nontarget lesions for the duration of the study.   


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Appendix E.  Drug-induced Liver Injury Reporting and Additional Assessment 
Reporting 
To facilitate appropriate monitoring for signals of drug induced liver injury (DILI), cases of 
concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and 
total bilirubin (TBL) and/or international normalization ratio (INR) elevation according to 
the criteria specified in Section 6.4, require the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate CRF (eg, events CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to Amgen 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for serious adverse events defined in Section 9.1.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product is withheld (either permanently or 
conditionally) due to potential DILI as specified in Section 6.4 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 TBL  2x upper limit of normal (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 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
Obtain complete blood count with differential to assess for eosinophilia 
Obtain serum total immunoglobulin G (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: 
Prior and/or concurrent diseases or illness 
Exposure to environmental and/or industrial chemical agents 


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Symptoms (if applicable) including right upper quadrant pain, hypersensitivity 
type reactions, fatigue, nausea, vomiting and fever 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
Obtain viral serologies 
Obtain creatinine phosphokinase, haptoglobin, lactate dehydrogenase (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, TBL, 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 investigational product. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
Appendix F.  Child-Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/l (mg/dl) 
 34 ( 2) 
34-50 (2-3) 
 50 ( 3) 
Serum albumin, g/dl 
 3.5 
2.8-3.5 
 2.8 
INR/PT 
 1.7/4.0 
1.7-2.3/4.0-6.0 
 2.3/6.0 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade 1 to 2 (or 
suppressed with 
medication) 
Grade 3 to 4 (or 
refractory) 
 
Points 
Class 
5 to 6 
A 
7 to 9 
B 
10 to15 
C 
References: 
Child CG, Turcotte JG.  Surgery and portal hypertension.  Major Prob Clin Surg.  
1964;1:1-85. 


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Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, William R.  Transection of the 
oesophagus for bleeding oesophageal varices.  The Br J Surg.  1973;60(8):646-649.  


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


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Appendix H.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information For Talimogene Laherparepvec 
Study-specific contraception requirements for female of childbearing potential are 
outlined in Section 4.1.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and 
after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and for an increased length of time.  In addition, male subjects 
may also be required to use contraception.  The investigator must discuss these 
contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
Premenopausal female with 1 of the following: 
- 
Documented hysterectomy; 
- 
Documented bilateral salpingectomy; or 
- 
Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:   
1) review of subject’s medical records; 2) subject’s medical examination; or  
3) subject’s medical history interview. 
Premenarchal female 
Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy (HRT).  
However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 195 of 196 
CONFIDENTIAL 
 
 
Acceptable Methods of Effective Contraception 
- 
Combined (estrogen and progestogen containing) or progestogen-only hormonal 
methods given via oral, intravaginal, transdermal, injectable, or implantable route) 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormonal-releasing system (IUS) 
- 
Bilateral tubal ligation/occlusion 
- 
Vasectomized partner (provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success) 
- 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject) 
- 
Double barrier method:  the male uses a condom and the female may choose 
either a cap, diaphragm, or sponge with spermicide (a female condom is not an 
option due to the risk of tearing when both partners use a condom) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
- 
Periodic abstinence (calendar, symptothermal, postovulation methods) 
- 
Withdrawal (coitus interruptus) 
- 
Spermicides only 
- 
Lactational amenorrhoea method 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 196 of 196 
CONFIDENTIAL 
 
 
Appendix I.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 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.   
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 (See Section 4.1.2, exclusion criteria 224, 225, and 226) 
from the day of pembrolizumab initiation (or 14 days prior to the initiation of 
pembrolizumab for oral contraception) throughout the study period up to 4 months  
(120 days) after the last dose of pembrolizumab.  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. 
Use of Pembrolizumab in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with systemic 
pembrolizumab, the subject will immediately be removed from the study.  The outcome 
of the pregnancy will be reported to the sponsor and followed as described in 
Section 9.3 (Pregnancy and Lactation Reporting).  If a male subject impregnates his 
female partner, the investigator must be informed immediately and the pregnancy 
reported to the sponsor and followed as described in Section 9.3 (Pregnancy and 
Lactation Reporting). 
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. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 October 2021 
Page 1 of 12 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 6 
Protocol Title:  A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the Safety 
of Talimogene Laherparepvec Injected into Liver Tumors Alone and in Combination With 
Systemic Pembrolizumab in Phase 1b and to Evaluate the Efficacy and Safety of 
Intratumoral Talimogene Laherparepvec in Combination With Systemic Pembrolizumab 
to Treat Subjects With Advanced Solid Tumors in Phase 2 (MASTERKEY-318) 
 
Amgen Protocol Number (Talimogene Laherparepvec 20140318) 
EudraCT number:  2014-005386-67 
NCT number:  NCT02509507 
 
Amendment Date: 
26 October 2021 
 
Rationale: 
This protocol is being amended to stop study-related hepatic biopsies and hepatic injections of 
talimogene laherparepvec based on the overall safety assessment of the hepatic hemorrhage 
signal following two serious adverse events of hepatic haemorrhage that resulted in death in the 
study.  While the full safety assessment results did not suggest an increased risk of hepatic 
haemorrhage with talimogene laherparepvec as a medication, there is a potential risk of hepatic 
haemorrhage with the transcutaneous intrahepatic route of administration of talimogene 
laherparepvec and hepatic biopsies.  As a result, the protocol is amended to remove these 
procedures from study conduct.  Additionally, the final enrollment numbers have been updated 
in the protocol as enrollment has stopped for this study.


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  02 July 2021 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529, Effective Date:  02 Mar 2020, Version:  6.0 
Amendment 5 
Protocol Title:  A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the 
Safety of Talimogene Laherparepvec Injected into Liver Tumors Alone and in 
Combination With Systemic Pembrolizumab in Phase 1b and to Evaluate the 
Efficacy and Safety of Intratumoral Talimogene Laherparepvec in Combination 
With Systemic Pembrolizumab to Treat Subjects With Advanced Solid Tumors in 
Phase 2 (MASTERKEY 318) 
 
Amgen Protocol Number 20140318 
EudraCT number:  2014-005386-67 
NCT number:  NCT02509507 
 
Amendment Date: 
02 July 2021 
 
Rationale: 
This protocol amendment dated 02 July 2021 is being amended to: 
 
fix the minor discrepancies and inconsistencies within the protocol 
o removed ‘Swab of Injection Site Surfaces and Occlusive Dressings’ at 
Week 10 from the table 12 to maintain consistency with footnotes 
o corrected number of days (missing in brackets) in footnote ‘t’ of table 13 for 
the samples collected post 14 days after talimogene laherparepvec 
administration for all subjects at week 1 and 4 
o updated time points for specialized/central laboratory tests and tumor biopsy 
procedures in the section 7.2.2 to maintain consistency with footnotes of 
table 13 
 
clarified medical monitor approval requirements for continuing talimogene in 
Part 1 and Part 2 (section 3.1.3) 
 
updated exclusion criteria 207 to separate pneumonitis into standalone 
criteria 238 
 
removed the exclusion of prior checkpoint inhibitors for basal cell carcinoma 
(BCC) patients to reflect the approval of cemiplimab in this population 
 
updated Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events Associated With Pembrolizumab 
 
updated an exception considered to continue treatment beyond progression 
(Section 6.6) 
 
updated the requirement to report fatal disease related events (DREs) as serious 
adverse events (SAEs) 
 
clarified the interim safety analysis language in Part 2 (Section 10.3.1.2) 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  02 July 2021 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529, Effective Date:  02 Mar 2020, Version:  6.0 
 
updates SAE reporting forms 
 
updated pregnancy and lactation notification forms 
 
clarified primary and final analyses clinical study report (CSR) plans 
 
aligned the protocol with current Amgen protocol template and safety reporting 
language 
 
typographical, formatting, and editorial changes were done throughout the 
protocol 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  30 June 2020 
Page 1 of 1 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the 
Safety of Talimogene Laherparepvec Injected into Liver Tumors Alone and in 
Combination With Systemic Pembrolizumab in Phase 1b and to Evaluate the 
Efficacy and Safety of Intratumoral Talimogene Laherparepvec in Combination 
With Systemic Pembrolizumab to Treat Subjects With Advanced Solid Tumors in 
Phase 2 (MASTERKEY-318) 
Amgen Protocol Number 20140318 
EudraCT number:  2014-005386-67 
NCT number:  NCT02509507 
Amendment Date: 
30 June 2020 
 
Rationale: 
 
This protocol is being amended to: 
 
 
Remove the 6 hour observation period and associated assessments for Part 2 
subjects not receiving intrahepatic injections 
 
Only include Part 2 enrolled subjects as part of the efficacy futility analyses 
 
Combine study Arms VI and VII  
 
Make updates to collection time points of cytokines and quantitative polymerase 
chain reaction (qPCR) 
 
Decrease sample size from 244 to 206 
 
Clarify inclusion criterion for triple negative breast cancer subjects (inclusion 
criterion 114) 
 
Update administrative edits 
 


Product:  Talimogene Laherparepvec
Protocol Number:  20140318
Date:  21 October 2019
Page 1 of 130
CONFIDENTIAL
Amendment 3
Protocol Title:  A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the 
Safety of Talimogene Laherparepvec Injected into Liver Tumors Alone and in 
Combination With Systemic Pembrolizumab in Phase 1b and to Evaluate the 
Efficacy and Safety of Intratumoral Talimogene Laherparepvec in Combination 
With Systemic Pembrolizumab to Treat Subjects With Advanced Solid Tumors in 
Phase 2 (MASTERKEY-318)
Amgen Protocol Number 20140318
EudraCT number:  2014-005386-67
NCT number:  NCT02509507
Amendment Date:
21 October 2019
Rationale:

This protocol is being amended to:

Update study title to reflect phase and type of study, combination therapy, and to 
indicate primary purpose of Phases 1b and 2

Allow intratumoral injection of talimogene laherparepvec into cutaneous, 
subcutaneous, and liver lesions and involved lymph nodes in Part 2 of the study, 
as safety of intrahepatic injection of talimogene laherparepvec in combination 
with systemic pembrolizumab will be established in Part 1.  Intrahepatic injection 
is not required in Part 2, but it is allowed if there are injectable liver lesions

Clarify that liver injection is not a requirement or priority in Part 2

Expand allowable injectable disease to include subcutaneous and cutaneous 
tumor lesions and involved lymph nodes 

Change the tumor types in Part 2 to the following non-HCC tumor types to reflect 
the expanded allowable injection sites:  hormone receptor positive breast 
adenocarcinoma [BC], triple negative breast cancer [TNBC], colorectal 
adenocarcinoma [CRC], cutaneous squamous cell carcinoma (CSCC), basal cell 
carcinoma (BCC)

Create additional BC cohort to include separate cohorts for triple negative breast 
cancer (TNBC) and hormone receptor positive subjects

Create additional hepatocellular carcinoma (HCC) cohort to include separate 
cohorts for HCC subjects with and without viral hepatitis

Allow for well controlled viral hepatitis and allow antiviral therapy for hepatitis in 
new cohort 6B for HCC in Part 1 and Arm VI in Part 2 of the study

Change the sample size in Part 1 and Part 2 to reflect the number of 
cohorts/arms now under study

Update the study schema to reflect new cohort in Part 1 and new tumor types in 
Part 2

Update the eligibility criteria based on new cohorts and revised tumor types
Approved 
 
 


Product:  Talimogene Laherparepvec
Protocol Number:  20140318
Date:  21 October 2019
Page 2 of 130
CONFIDENTIAL

Shorten 23 hour observation window to 6 hours in Part 2, after review of safety 
data from monotherapy and combination cohorts enrolled to date in Part 1

Add collection of Patch 1 (PTCH) mutation status in BCC cohort if available

Add collection of BRCA1 and 2 mutation status in BC cohort if available

Add optional liver ultrasound to schedule of assessments for monotherapy and 
combination cohorts enrolled to date in Part 1 and combination cohorts Part 2.

Remove 24 hour and 48 hour timepoints in Week 1 and Week 4 from Part 2 
schedule of assessments, after review of available data from Part 1

Remove assessments for anti-pembrolizumab antibodies, and pembrolizumab 
pharmacokinetics (PK) in Part 2

Remove blood, urine, and swab collection at 24, and 48 hours in Part 2, after 
review of available data from Part 1

Allow continuation of talimogene laherparepvec after cycle 12 in Part 2 if in the 
opinion of the investigator, the subject is deriving clinical benefit from the study 
regimen, the subject is still receiving pembrolizumab, and the investigator obtains 
approval from the sponsor medical monitor

Clarify that subjects can receive a maximum of 12 cycles of talimogene 
laherparepvec in Part 1 and 35 cycles in Part 2

Allow resumption of talimogene laherparepvec at progression if previously 
discontinued

Allow up to 8 mL of talimogene laherparepvec to be used in Part 2 if 8 mL is 
shown safe in either Group A or B in Part 1

Add clinical tumor assessments in Part 2

Create a separate schedule of assessment table for Part 2 to reflect the changes 
to cohort, tumor types, and time points 

Revise the list of laboratory analytes to align with new tumor types

Add language regarding events of clinical interest specifically for Group B HCC 
subjects

Add disease related events (DRE) language that instructs sites to transmit 
serious DREs in the same manner that they transmit serious adverse events and 
with the same timeline expectations

Remove language on self-evident corrections from the protocol to be consistent 
with current regulations

Update HCC data in the Background and Rationale section to reflect new 
available clinical data since the last amendment

Update CTCAE version to 4.03

Update references to reflect added information in the Background and Rationale 
section

Make editorial and administrative changes for grammatical reasons as well as for 
internal consistency within the protocol
Approved 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  18 October 2017 
Page 1 of 161 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 1b/2, Multicenter, Open-label Trial to Evaluate the Safety 
of Talimogene Laherparepvec Injected Into Liver Tumors Alone and in 
Combination With Systemic Pembrolizumab (MASTERKEY-318) 
 
Amgen Protocol Number Talimogene Laherparepvec 20140318 
EudraCT number 2014-005386-67 
NCT number NCT02509507 
Amendment 2 Date: 
18 October 2017 
Rationale: 
This amendment was revised to: 
• 
Add a collaborator drug, pembrolizumab, from Merck. This resulted in: 
• 
Adding combination cohorts (talimogene laherparepvec and 
pembrolizumab) in Part 1 of the study 
• 
The opening on Group B will now be independent of Group A safety 
results 
• 
Phase of study changed to 1b/2 
• 
Changing Part 2 of the study to include combination cohorts only 
• 
Pembrolizumab-specific requirements added to the protocol 
• 
Align with more recent protocol template text: 
• 
Section 9 (Safety Data Collection, Recording, and Reporting) 
• 
Updated the pregnancy and lactation reporting forms 
• 
Added contraception, pregnancy, and lactation information to Appendix H 
and Appendix I 
• 
Section 12.6 (Publication Policy) 
• 
Editorial changes (ie, typographic, grammatical, and formatting errors) and 
abbreviation corrections were made throughout the protocol in accordance with 
Amgen Inc. Style Guide. 
Approved 
 
 


Product:  Talimogene Laherparepvec
Protocol Number:  20140318
Date:  26 April 2016
Page 1 of 17
CONFIDENTIAL
Amendment 1
Protocol Title:  A Phase 1, Multicenter, Open-label Trial to Evaluate the Safety of 
Talimogene Laherparepvec Injected into Liver Tumors
Amgen Protocol Number TVEC 20140318
EudraCT number 2014-005386-67
Amendment Date:
26 April 2016
Rationale:
The previous version of the protocol considered a grade 3 or higher non-hematologic 
laboratory value that persisted for > 1 week as meeting the criteria for a DLT, even if the 
abnormal laboratory value did not result in a medical intervention or hospitalization.  This 
criterion could result in dose limiting toxicities (DLTs) being determined for abnormal 
laboratory values that were not clinically important.  To date, 1 subject has had a grade 3 
or higher gamma-glutamyl transferase (GGT) elevation that persisted for over 1 week, 
which was considered related to talimogene laherparepvec, and was subsequently 
defined as a DLT under the original protocol.  The subject was asymptomatic, and the 
GGT elevation was considered to not be of any clinical significance. In order to prevent 
abnormal laboratory values that are not clinically significant from being classified as 
DLTs, the Dose Level Review Team (DLRT) decided that the protocol should be 
amended.  This modification will also be consistent with the protocol language in 
Section 9.2.2, where abnormal laboratory findings without clinical significance (based on 
investigator’s judgement) are not to be recorded as adverse events.
The following key changes have been incorporated into protocol amendment 1:

The criteria for grade 3 or higher non-hematologic laboratory values that define 
DLT have been changed so that those that persist for > 1 week which are 
deemed not clinically important by both the investigator and sponsor do not 
trigger a DLT.  Any grade 3 or higher non-hematologic laboratory value will still 
be considered a DLT if medical intervention is required or if it leads to 
hospitalization.

Treatment can continue for grade 3 or higher non-hematologic laboratory values 
that persist for > 1 week and are deemed not clinically important by both the 
investigator and sponsor so that subjects can continue study treatment in spite of 
persistently elevated non-hematologic laboratory values with no clinical 
significance and long half-lives such as GGT.

Added hepatitis D viral RNA as another acceptable method of testing as some 
institutions do not use hepatitis D serology testing.


Product:  Talimogene Laherparepvec
Protocol Number:  20140318
Date:  26 April 2016
Page 2 of 17
CONFIDENTIAL

The irRC-RECIST criteria definition has been edited to make it more consistent 
with the conventional RECIST criteria and irRC simulating RECIST as described 
by Nishino et al.

Clarified certain laboratory tests and timing of study procedures.

Other minor changes include:

Administration and editorial corrections

Updating adverse event and disease related event language to clarify definitions 
and reporting periods

Specifying time points for liver tumor biopsies

SAP_001.pdf: 
Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 January 2022   
     
 
 
 
 
            Page 1 of 50 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 1b/2 Multicenter, Open-label, Basket Trial 
to Evaluate the Safety of Talimogene 
Laherparepvec Injected into Liver Tumors Alone and 
in Combination With Systemic Pembrolizumab in 
Phase 1b and to Evaluate the Efficacy and Safety of 
Intratumoral Talimogene Laherparepvec in 
Combination With Systemic Pembrolizumab to Treat 
Subjects with Advanced Solid Tumors in Phase 2 
(MASTERKEY-318) 
Short Protocol Title: 
MASTERKEY 318 
Protocol Number: 
20140318 
NCT Number: 
NCT02509507 
Authors: 
 
Sponsor: 
Amgen, Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
20 August 2015 
Amendment 1.0 (v2.0) 
16 February 2021  
Amendment 2.0 (v3.0) 
26 January 2022 
 
Version Number 
Date 
(DDMMMYYYY
) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
 20AUG2015 
  
Amendment 1 (v2.0) 
 16FEB2021 
Aligned the SAP with the changes of 
protocol amendment 4; clarified the study 
endpoints for both part 1 and part 2; added 
details in study design and analyses 
method; updated the definition of safety 
analysis set; general typographical, 
formatting, and editorial changes. 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 January 2022   
     
 
 
 
 
            Page 2 of 50 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Amendment 2 (v3.0) 
 26JAN2022 
Aligned the SAP with the changes of 
protocol amendment 5 and 6; clarified the 
study safety and efficacy endpoints; 
updated the definition of BOR, L-ORR and 
max tumor burden decrease; general 
typographical, formatting, and editorial 
changes 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 January 2022   
     
 
 
 
 
            Page 3 of 50 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Table of Contents 
Table of Contents ................................................................................................... 3 
1. 
Introduction ............................................................................................................. 8 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 8 
2.1 
Objectives and Endpoints ............................................................................ 8 
2.2 
Hypotheses and/or Estimations ................................................................. 10 
3. 
Study Overview .................................................................................................... 11 
3.1 
Study Design ............................................................................................. 11 
3.1.1 
Study Design for Part 1 ............................................................. 11 
3.1.2 
Study Design for Part 2 (Non-HCC and HCC Groups) ............... 12 
3.2 
Sample Size .............................................................................................. 12 
4. 
Covariates and Subgroups ................................................................................... 15 
4.1 
Planned Covariates and Subgroups .......................................................... 15 
4.2 
Subgroups ................................................................................................. 16 
5. 
Definitions ............................................................................................................. 16 
6. 
Analysis Sets ........................................................................................................ 25 
6.1 
Full Analysis Set........................................................................................ 25 
6.2 
Safety Analysis Set ................................................................................... 26 
6.3 
DLT Analyses Set(s) ................................................................................. 26 
...................................................................... 26 
6.5 
Reactive Swab Analysis Set ...................................................................... 26 
6.6 
Blood and Urine Evaluable Analysis Sets .................................................. 27 
6.7 
Blood and Urine Clearance Analysis Sets ................................................. 27 
6.8 
Exterior of Occlusive Dressing Evaluable Analysis Sets ............................ 27 
6.9 
Skin Surface of Injections Evaluable Analysis Sets ................................... 27 
6.10 
Oral Mucosa Evaluable Analysis Sets ....................................................... 27 
6.11 
Lesion Analysis Sets ................................................................................. 28 
7. 
Planned Analyses ................................................................................................. 28 
7.1 
Interim Analysis ......................................................................................... 28 
7.1.1 DLT Safety Analysis (Part 1) ............................................................ 28 
7.1.2 Interim Safety Analysis (Part 2) ........................................................ 28 
7.1.3 Interim Futility Analysis (Part 2) ........................................................ 29 
7.1.4 Dose Level Review Team (DLRT) .................................................... 29 
7.2 
Primary Analysis ....................................................................................... 30 
7.3 
Final Analysis ............................................................................................ 30 
8. 
Data Screening and Acceptance ........................................................................... 30 
8.1 
General Principles ..................................................................................... 30 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 30 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 January 2022   
     
 
 
 
 
            Page 4 of 50 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
8.3 
Handling of Missing and Incomplete Data ................................................. 30 
8.4 
Detection of Bias ....................................................................................... 31 
8.5 
Outliers ..................................................................................................... 31 
8.6 
Distributional Characteristics ..................................................................... 31 
8.7 
Validation of Statistical Analyses ............................................................... 31 
9. 
Statistical Methods of Analysis.............................................................................. 31 
9.1 
General Considerations ............................................................................. 31 
9.2 
Subject Accountability ............................................................................... 32 
9.3 
Important Protocol Deviations ................................................................... 32 
9.4 
Demographic and Baseline Characteristics ............................................... 32 
9.5 
Efficacy Analyses ...................................................................................... 32 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 34 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 35 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 35 
9.6 
Safety Analyses ........................................................................................ 35 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 35 
9.6.2 
Adverse Events and Disease-related Events ............................. 36 
9.6.3 
Laboratory Test Results ............................................................ 40 
9.6.4 
Vital Signs ................................................................................. 40 
9.6.5 
Physical Measurements ............................................................ 40 
9.6.6 
Exposure to Investigational Product .......................................... 41 
9.6.7 
Exposure to Other Protocol-required Therapy ........................... 41 
9.6.8 
Exposure to Concomitant Medication ........................................ 41 
9.7 
Other Analyses ......................................................................................... 41 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 41 
........................ 41 
10. 
Changes From Protocol-specified Analyses.......................................................... 42 
11. 
Literature Citations / References ........................................................................... 42 
12. 
Prioritization of Analyses....................................................................................... 42 
13. 
Data Not Covered by This Plan............................................................................. 42 
14. 
Appendices ........................................................................................................... 43 
Appendix A.  Reference Values/Toxicity Grades ................................................... 43 
Appendix B.  Conventions for Clinical Data That Require Imputation for 
Partial or Missing Date .............................................................................. 43 
Appendix C.  Wilson’s Score Method with Continuity Correction in 
Calculating the 95% Confidence Intervals for Difference in 2 
Independent Proportions ........................................................................... 45 
Appendix D.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ........................................................ 46 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 January 2022   
     
 
 
 
 
            Page 5 of 50 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
List of Table 
Table 9-1.  Example Primary Efficacy Endpoint Summary Table ................................... 10 
Table 9-2.  Example Secondary Efficacy Endpoint Summary Table .............................. 10 
Table 9-3.  Example Exploratory Efficacy Endpoint Summary Table ............................. 11 
Table 9-4.  Example Safety Endpoint Summary Table ................................................... 11 
 
List of Figures 
No table of figures entries found. 
 
 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 January 2022   
     
 
 
 
 
            Page 6 of 50 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase 
AST  
aspartate aminotransferase   
BC 
breast adenocarcinoma 
BCC 
basal cell carcinoma 
BOR 
best overall response 
BRAF  
B-Raf sarcoma viral oncogene homolog 
CD 
cluster of differentiation 
CI 
confidence interval 
CR 
complete response 
CRC 
colorectal adenocarcinoma 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSCC 
cutaneous squamous cell carcinoma 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DLRT 
dose level review team 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DRR 
durable response rate 
ECG 
electrocardiogram 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 January 2022   
     
 
 
 
 
            Page 7 of 50 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
HCV 
hepatitis C virus 
 
 
irRC-RECIST 
immune-related response criteria (irRC) simulating RECIST 
version 1.1 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTC 
maximum tolerated concentration 
mTPI 
modified toxicity probability interval 
MTV 
maximum tolerated volume 
non-HCC 
metastatic liver tumors (if tumors are present in liver) 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
 
 
PR 
partial response 
PFS 
progression-free survival 
qPCR 
real-time polymerase chain reaction 
RP2D 
recommended phase 2 dose 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TNBC 
triple negative breast cancer 
T-VEC 
talimogene laherparepvec 
 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20140318, Talimogene 
Laherparepvec dated 26 Oct 2021. The scope of this plan includes the interim, primary 
and the final analyses that are planned and will be executed by the Amgen Global 
Biostatistical Science department unless otherwise specified. A separate supplementary 
SAP may be prepared for the exploratory objectives and these analyses may be 
reported separately.  
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
Part 1:  
To evaluate the following, as 
assessed by the incidence of 
dose-limiting toxicities (DLTs), in 
subjects with liver metastases 
(non-HCC) and subjects with primary 
hepatocellular carcinoma (HCC) in:  
Monotherapy Cohorts:  the 
maximum tolerated volume and 
concentration (MTV and MTC) of 
intrahepatic injection of talimogene 
laherparepvec into liver tumors in 
subjects with non-HCC and subjects 
with primary HCC without active viral 
hepatitis 
Combination Cohorts:  the MTC of 
intrahepatic injection of talimogene 
laherparepvec into liver tumors in 
combination with systemic 
intravenous (IV) administration of 
pembrolizumab in subjects with non-
HCC, and subjects with primary HCC 
with or without viral hepatitis 
 
Part 1:  
Monotherapy cohorts 1-4:  
Subject incidence of DLTs with 
intrahepatic injection of 
talimogene laherparepvec into 
liver tumors in subjects with 
non-HCC with liver metastases 
and subjects with HCC without 
active viral hepatitis. 
Combination cohorts 5 and 6:  
Subject incidence of DLTs with 
intrahepatic injection into liver 
tumors of talimogene 
laherparepvec in combination with 
systemic IV administration of 
pembrolizumab in subjects with 
non-HCC with liver metastases 
and subjects with HCC with and 
without viral hepatitis as assessed 
by subject incidence of DLTs. 
 
 
Part 2:  
To evaluate the efficacy, as assessed 
by objective response rate (ORR) of 
intratumoral injection of talimogene 
laherparepvec in combination with 
systemic IV administration of 
pembrolizumab, separately, for each 
non-HCC tumor type (hormone 
 
Part 2:  
ORR per modified irRC-RECIST with 
intralesional injection of talimogene 
laherparepvec into cutaneous, 
subcutaneous, lymph node, and liver 
tumors in combination with systemic 
IV administration of pembrolizumab 
separately by tumor type arm 


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receptor positive breast 
adenocarcinoma [BC], triple negative 
breast cancer [TNBC], colorectal 
adenocarcinoma [CRC], cutaneous 
squamous cell carcinoma [CSCC], 
basal cell carcinoma [BCC]) as well as 
primary HCC with and without viral 
hepatitis. 
(hormone receptor positive BC, 
TNBC, CRC, CSCC, BCC, and HCC 
with and without viral hepatitis) 
 
Part 2:  
To evaluate safety separately for each 
tumor type as assessed by subject 
incidence of treatment-emergent and 
treatment-related adverse events, 
including DLTs 
 
Part 2:  
Subject incidence, for each tumor type 
arm, of treatment-emergent and 
treatment-related adverse events, 
including DLTs 
Secondary Efficacy 
 
Part 1:  
To evaluate the efficacy separately by 
monotherapy versus combination for 
non-HCC tumors and HCC with and 
without viral hepatitis when applicable 
as assessed by: 
ORR, best overall response (BOR), 
durable response rate (DRR), duration 
of response (DOR), response in 
injected and uninjected lesions, 
disease control rate (DCR), 
progression-free survival (PFS), and 
overall survival (OS) 
 
Part 1:  
ORR, BOR, DRR, DOR, response in 
injected and uninjected lesions, DCR, 
PFS, and OS separately for non- HCC 
and HCC tumors in monotherapy and 
combination cohorts 
 
Part 2:  
To evaluate the efficacy in individual 
tumor types in the non-HCC group 
and HCC group with and without viral 
hepatitis as assessed by: BOR, DRR, 
DOR, response in injected and 
uninjected lesions, DCR, PFS, and 
OS by primary tumor type arm (TNBC, 
Hormone receptor positive BC, CRC, 
CSCC, BCC, and HCC with and 
without viral hepatitis) 
 
Part 2:  
BOR, DRR, DOR, response in 
injected and uninjected lesions, DCR, 
PFS, and OS by primary tumor type 
(hormone receptor positive BC, 
TNBC, CSCC, CRC, BCC and HCC 
with and without viral hepatitis)  
Secondary Safety (Parts 1 and 2) 
 
To evaluate the safety in each 
monotherapy and combination 
cohorts in Part 1 and each arm 
separately in Part 2, as assessed 
by subject incidence of treatment-
emergent and treatment-related 
adverse events 
 
Subject incidence of treatment-
related and treatment-emergent 
adverse events (each 
monotherapy and combination 
cohorts in Part 1, and each tumor 
type separately in Part 2, and 


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HCC with and without viral 
hepatitis) 
 
To estimate the incidence of 
detectable talimogene 
laherparepvec deoxyribonucleic 
acid (DNA) in blood and urine 
 
Subject incidence of detectable 
talimogene laherparepvec DNA in 
blood and urine 
 
To estimate the incidence of 
clearance of talimogene 
laherparepvec DNA from blood 
and urine 
 
Incidence of clearance of 
talimogene laherparepvec DNA 
from blood and urine 
 
To estimate the rate of detection 
(per sample) and incidence (per 
subject) of talimogene 
laherparepvec DNA and virus at 
the surface of talimogene 
laherparepvec injection site, the 
exterior of the occlusive dressing, 
and the oral mucosa 
 
Subject incidence (per subject) 
and rate of detection (per sample) 
of talimogene laherparepvec DNA 
and virus at the surface of 
injection site, the exterior of the 
occlusive dressing, and the oral 
mucosa 
 
To estimate the incidence of 
talimogene laherparepvec DNA 
detection in lesions suspected to 
be herpetic in origin 
 
Subject incidence of talimogene 
laherparepvec DNA detection in 
lesions suspected to be herpetic in 
origin 
 
Exploratory 
2.2 
Hypotheses and/or Estimations 
PART 1: 
Monotherapy cohorts 1-4: Talimogene laherparepvec injected intrahepatically into 
liver tumors will be safe in subjects with non-HCC with liver metastases and subjects 
with HCC without active viral hepatitis as assessed by subject incidence of DLTs. 
Combination cohorts 5 and 6: Talimogene laherparepvec injected intrahepatically 
into liver tumors in combination with systemically administered pembrolizumab 
will be safe in subjects with non-HCC with liver metastases and subjects with HCC with 
and without viral hepatitis as assessed by subject incidence of DLTs.  
PART 2: 


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Talimogene laherparepvec injected intratumorally in combination with systemic IV 
administration of pembrolizumab will demonstrate at least a 40% ORR in each tumor 
type and be safe in the individual non-HCC tumor types as well as primary HCC with and 
without viral hepatitis.  
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1b/2, multicenter, open-label, basket trial to evaluate the safety of 
talimogene laherparepvec injected intrahepatically into liver tumors alone and in 
combination with systemic IV administration of pembrolizumab, in subjects with 
non-HCC liver metastases from BC, CRC, GEC, melanoma, NSCLC, RCC in Part 1 
Group A, and subjects with HCC with and without viral hepatitis in Part 1 Group B (viral 
hepatitis is only applicable in combination setting), and to evaluate the efficacy and 
safety of intratumoral talimogene laherparepvec in combination with systemic 
pembrolizumab to treat subjects with advanced TNBC, hormone receptor positive breast 
cancer, CRC, CSCC, and BCC in Part 2 Group A and subjects with HCC with and 
without viral hepatitis in Part 2 Group B. The study consists of 2 parts and 2 groups and 
Part 2 includes 2 stages. 
The overall study design is described by a study design and treatment schema at the 
end of the protocol synopsis section. 
3.1.1 
Study Design for Part 1 
Part 1 is a dose escalation study to evaluate the safety of intrahepatic injection of 
talimogene laherparepvec into liver tumors alone and in combination with systemic IV 
administration of pembrolizumab for the non-HCC (Group A) and HCC (Group B) (with 
and without viral hepatitis; viral hepatitis is only applicable in combination setting) 
cohorts separately. For talimogene laherparepvec monotherapy cohorts (Cohorts 1-4), 
safety will be assessed for the non-HCC and HCC groups based on the “3+3” design. 
The initial concentration in all cohorts will always be 106 PFU/mL. Maximum total 
volumes (up to 4 mL or 8 mL) and subsequent concentrations (107 or 108 PFU/mL) to be 
administered will depend on the specific cohort. Combination cohorts (Cohorts 5 and 6) 
in Part 1 will determine the safety of administering intrahepatic injection of talimogene 
laherparepvec at 107 PFU/mL or 108 PFU/mL sequentially (volume up to 4 mL for both 
doses) in combination with systemic IV administration of pembrolizumab using a 
modified toxicity probability interval (mTPI) up-and-down design. 


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3.1.2 
Study Design for Part 2 (Non-HCC and HCC Groups) 
Part 2 is a 2-stage design to evaluate the efficacy and safety of talimogene 
laherparepvec in combination with systemic pembrolizumab separately by tumor type. 
The DLRT will consider prospective guidelines in the DLRT Charter to monitor safety in 
Part 2 separately by tumor type and, if introduced, talimogene laherparepvec total 
volumes > 4 mL within Group A and Group B. 
Part 2 (Group A) of the study will enroll subjects of non-HCC tumors (hormone receptor 
positive BC, TNBC, CSCC, CRC, BCC).  Subjects will be enrolled separately into each 
tumor type.  Stage 1 of Part 2 (Group A) will begin enrolling after MTC has been 
determined from Cohort 5 and 6 in Part 1. 
Part 2 (Group B) of the study will enroll subjects with HCC with and without viral 
hepatitis.  Stage 1 of Part 2 (Group B) will begin enrolling after MTC has been 
determined from Cohorts 5 and 6 in Part 1. 
Subject enrollment and study conduct during Part 2 of the study will progress 
independently in the non-HCC and HCC groups. 
During Stage 1 of Part 2, non-HCC and HCC groups will enroll approximately 
10 subjects for each tumor arm (5 tumor arms in Group A and 1 tumor arm in Group B 
with and without viral hepatitis).  Subjects enrolled in Part 2 will initially be administered 
up to 8 mL of talimogene laherparepvec MTC determined from Cohorts 5 or 6 in Part 1.  
Administration of up to 8 mL of talimogene laherparepvec was established from Part 1, 
cohort 3 of either group any newly enrolled subjects in Part 2 can be administered up to 
8 mL of talimogene laherparepvec.  No intrasubject concentration or volume escalation 
is allowed.  The primary analysis of efficacy will include subjects that receive any volume 
of talimogene laherparepvec (monotherapy cohorts) and subjects that receive any 
volume of talimogene laherparepvec and pembrolizumab (combination cohorts). Stage 1 
of a 2-stage efficacy assessment will occur once 10 subjects have been enrolled in a 
tumor type arm.  Stage 1 efficacy assessments will occur separately per tumor arm.  If 
efficacy is not futile, Stage 2 will open for that particular tumor arm where approximately 
an additional 11 treated subjects can be enrolled. 
For a full description of the protocol design, please refer to Section 3.1 of the protocol. 
3.2 
Sample Size 
Sample Size Considerations for Part 1 


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The sample size of approximately 3 to 6 subjects per monotherapy cohort is determined 
empirically and is consistent with those used in traditional “3+3” phase 1 designs to 
evaluate safety assuming a true DLT rate of less than 1/3.  There are up to 
4 monotherapy cohorts in Groups A / B in Part 1.  Subjects enrolled in a monotherapy 
cohort may be replaced if they are not evaluable for DLT (eg, did not receive talimogene 
laherparepvec or ended the study treatment before completion of the DLT evaluation 
period for a reason other than experiencing a DLT).    
Safety of the combination will be evaluated with the mTPI up-and-down design in Part 1 
to determine the talimogene laherparepvec MTC with a target DLT rate of 40%.  The 
maximum sample size in the combination cohorts 5 and 6 or 6a will be 28 (maximum of 
12 subjects evaluated at 6b).   Unless the cohort 5 is deemed too toxic, patients may be 
enrolled and assigned to appropriate doses until the maximum sample size is reached or 
minimum of 12 subjects are enrolled in Cohort 6 provided the mTPI outcome is not at a 
D or DU in cohort 6. If in Non HCC group, cohort 6b completes prior to cohorts 5 and 6a 
enrollment, and 6b is deemed safe, then cohorts 5 and 6a will close to enrollment. Full 
details of the mTPI will be specified in the DLRT Charter. 
Part 2 for non-HCC tumor types (Group A) or HCC (Group B) will open if the 
corresponding group MTC is selected at the end of Part 1. 
Sample Size Considerations for Part 2 
The recommended phase 2 dose from Part 1 (RP2D) for non-HCC (Group A) and HCC 
(Group B) will be evaluated in Part 2 independently for each tumor type arm for the 
combination of talimogene laherparepvec with systemic pembrolizumab.  Subjects that 
initiate treatment at the corresponding RP2D in Part 1 will not be included in the Part 2 
efficacy analysis according to their respective tumor type arm. 
The primary objective in Part 2 for each tumor type arm will be to evaluate the ORR per 
modified irRC-RECIST with a minimum potential follow-up of at least 29 weeks. The null 
hypothesis (H0) for each tumor type is an ORR ≤ 10% which, if true, would not warrant 
further evaluation in contrast to the alternative hypothesis (H1) of an ORR ≥ 40%. 
The following 2-stage design will be used to reject H0 at a ≤ 2.5% 1-sided significance 
level. The efficacy analysis will be based on the Full Analysis Set in part 2 only. A 
cumulative total of 10 subjects will be treated in Stage 1 and enrollment is planned to 
stop. If there are 2 or more responders (PR or CR no confirmation is needed), then a 
total of 11 additional subjects will be treated in Stage 2; otherwise, H0 will be accepted 


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and enrollment will be permanently discontinued. If the required number of responders to 
continue to Stage 2 is observed before the end of Stage 1 enrollment, then enrollment 
will not be suspended. 
H0 will be rejected after Stage 2 if there are ≥ 6 responders (with confirmation) in 21 
treated subjects, ie, the observed ORR is ≥ 28.6%. In the event precisely 21 subjects are 
not included in the analysis in total, H0 will be rejected if the lower limit of the 95% exact 
binomial CI is > 10% (Atkinson and Brown, 1985) (see code fragment in Appendix D.2). 
If exactly 10 and 11 subjects are included at Stage 1 and 2, respectively, the design 
achieves a 1-sided 1.3% significance level, 88.4% power, and the probability of stopping 
at Stage 1 if H0 (H1) is true is 73.6% (4.6%). 
For each tumor type that advances to Stage 2, a Bayesian framework may be utilized to 
assess evidence that the combination ORR exceeds that expected for pembrolizumab 
alone to aid in decision-making as to whether further evaluation is warranted. Given the 
observed ORR in the Full Analysis Set, the Bayesian posterior probability will be 
calculated that the true combination ORR exceeds the expected ORR for 
pembrolizumab by an absolute amount (delta).  Since the data is not available yet, the 
following is just an illustration how it will work. For example, the expected ORR for 
pembrolizumab in the study population of one of the tumor arm in part 2 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 ORR 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 of a delta increase from 0% to 30% in 5% increments 
for an observed ORR ranging from 14.3% (3/21) to 66.7% (14/21) in the example. It can 
be updated later once we have more information of pembrolizumab in the study 
population of one of the tumor arm. The calculation of a 90% credible region for delta are 
also provided (see Appendix E). 
 
Figure 1. Probability of a Combination Delta Absolute Objective Response Rate 
Increase Over Pembrolizumab 


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From 10 to 21 subjects per tumor type are expected to be treated at the RP2D for a total 
of 60 to 126 subjects. 
For Part 2, the DLRT will consider prospective guidelines in the DLRT Charter to monitor 
safety separately by tumor type arm and, if introduced, talimogene laherparepvec total 
volumes > 4 mL within Group A and Group B.   
The subject incidence of DLT in Part 2 will be based on the DLT Analysis Set with at 
least 6 weeks minimum potential follow-up. 
The maximum total sample size for Parts 1 and 2 will be approximately 3 to 242 subjects 
(approximately up to 116 subjects in Part 1; approximately 60 to 126 subjects in Part 2).  
This estimate includes approximately 126 Full Analysis Set subjects that receive the 
combination treatment in Parts 1, up to 48 DLT-evaluable subjects from Part 1 
monotherapy cohorts.  Dose-limiting toxicity non-evaluable subjects will not be replaced 
in Part 2. 
 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates and Subgroups 
The following covariates may be used whenever applicable to examine efficacy and 
safety in subgroups or in multivariate analyses: 


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• Region, if applicable (USA vs non-USA) 
• Age at baseline (< 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years) 
• Baseline LDH (≤ ULN vs > ULN) 
• Gender (Female vs Male) 
• Baseline ECOG (0 vs 1) 
• Baseline sum of lengths of measurable lesions 
• Baseline sums of lengths of measurable liver lesions 
• Prior exposure to chemotherapy (Yes vs No) 
• HSV-1 serostatus (Yes vs No) 
• Maximum talimogene laherparepvec volume at highest concentration per visit 
(≤ 4 mL vs > 4 mL) 
• Baseline HBV or HCV status  
• Baseline Microsatellite Instability status for CRC subjects 
4.2 
Subgroups 
N/A 
5. 
Definitions 
The definition of DLT is provided in Protocol Section 3.1.4.3. Additional definitions are as 
follows: 
DLT evaluation period  
- Monotherapy Cohorts: The DLT evaluation period for a given subject will consist of the 
period between the initial 106 PFU/mL dose of talimogene laherparepvec and 3 weeks 
following the initial 107 or 108 PFU/mL dose of talimogene laherparepvec. 
- Combination Cohorts: The DLT evaluation period for a given subject will consist of the 
period between the initial 106 PFU/mL concentration of talimogene laherparepvec and 3 
weeks following the initial 107 or 108 PFU/mL dose of talimogene laherparepvec. Any 
subject who has not received at least 2 doses of talimogene laherparepvec (106, and 107 
or 108 PFU/mL) and 2 doses of pembrolizumab, will not be considered DLT-evaluable 
unless they experience a DLT after the first dose. 
 
Maximum Tolerated Dose (MTD) 


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The MTD is the combination of the maximum tolerated volume (MTV) and the maximum 
tolerated concentration (MTC) determined from the dose limiting toxicity (DLT) 
evaluations in Part 1 per group. 
 
Enrollment date 
The date subject is enrolled to the study.  A subject will be considered enrolled when the 
investigator confirms that the subject has met all eligibility criteria and the subject is 
registered as enrolled in the interactive voice response system (IVRS). 
 
Investigational Product 
Investigational product (IP) refers to Amgen investigational product talimogene 
laherparepvec in Part 1 monotherapy cohorts, and refers to Amgen investigational 
product talimogene laherparepvec and non-Amgen investigational product 
pembrolizumab in Part 1 combination cohorts and Part 2. 
 
Last IP Dose Date  
Last IP Dose Date for each subject is defined as the latest date IP is administered in this 
study. 
 
End of IP Admin Date 
End of IP Admin for each subject is defined as the date the decision was made to end IP 
as recorded on the End of IP CRF page in this study. 
 
Screening Phase 
The screening phase is the time period after subject signing off the informed consent 
form and before enrollment when study-specific laboratory tests and procedures are 
performed, and medical history is reviewed to confirm subject eligibility for the study. 
 
Study Day 
Study day is calculated from the first day the study drug is administered 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. 
 


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Study Day 1 
Study day 1 is the first day that protocol-specified investigational products are 
administered to the subject.  The day before study day 1 is study day ‘-1’. 
 
Baseline 
Baseline in general refers to study day 1.  The baseline value of a parameter (e.g., vital 
signs, laboratory tests, and tumor measurement) is considered to be the latest value 
prior to receiving the study drug (i.e., on or prior to the first date of dosing). 
 
Best overall response (BOR) per Modified irRC-RECIST 
Best overall response (BOR) of complete response (CR), partial response (PR), stable 
disease (SD), progressive disease (PD) or un-evaluable (UE) will be derived based on 
investigator assessment using modified irRC-RECIST as defined in protocol Appendix D.   
Overall visit response assessments occurring after the start of the first subsequent 
anticancer therapy will not be included. With the exception of a PD observation, the 
overall visit response occurring on or after complete or partial removal/reduction of any 
target lesion which contained cancer on pathology evaluation or pathology results were 
unknown, will not be included. Consecutive confirmation of CR, PR, and PD is required 
where the second overall response must be at least 28 days from the first, the only 
exception being when the investigator reports that an initial PD cannot be confirmed due 
to rapid clinical deterioration. The following will be considered a confirmed PR: CR 
followed by PR or PR followed by CR. 
BOR is defined as the best visit response in the following order:  CR, PR, SD, PD, or UE 
(see Table 1). BOR is defined as SD if the best overall visit response is an unconfirmed 
CR or PR, and UE if it is either SD earlier than 77 days after first dose date or an 
unconfirmed PD when confirmation of PD is required (ie, initial PD without rapid clinical 
deterioration). 
 
Table 1.  Matrix of Determining BOR per Modified irRC-RECIST 
Visit Overall Response 
Sequence 
Examples 
Best 
Overall 
Response 
Confirmation specifications 
*, CR, CR,* 
PR, CR, CR 
CR, CR, PD 
CR 
The confirmatory CR must be at least 
4 weeks (28 days) later; a subsequent 
CR within 28 days will not be valid for 


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confirmation and will be ignored; the CR 
will also not be confirmed if there is a 
subsequent PR/SD/PD at any time prior 
to the next CR. 
*, PR, PR, * 
 
*, PR, CR/PR, non-CR, 
* 
 
*,CR, PR,* 
PR, PR, PD 
PR, CR, PD 
 
CR, PR, PD 
PR 
Criteria for BOR=CR not met. 
The confirmatory PR/CR   must be no 
less than 4 weeks (28 days) later; a 
subsequent PR/CR within 28 days will 
not be valid for confirmation and will be 
ignored; the PR will also not be 
confirmed if there is a subsequent 
SD/PD at any time prior to the next 
PR/CR. 
*, SD, * 
 
*,CR, non-PR/CR, * 
 
*,PR, non-PR/CR, * 
CR 
PD, CR 
PR 
PD, PR, SD 
SD 
PD,SD,PD 
SD 
Criteria for BOR=CR or PR not met. 
SD must be ≥ 77 days from the date of 
first dose; however, this is not required 
for an unconfirmed CR/PR. 
*,PD, PD, * 
 
*, PDr, * 
 
 
PDr = PD with 
concurrent or 
subsequent rapid 
clinical deterioration as 
the reason for ending 
radiographic follow-up. 
PD, PD 
PD, SD, PD, 
PD 
PDr 
PD 
Criteria for BOR= CR, PR, or SD not 
met. 
The confirmatory PD must be no less 
than 4 weeks (28 days) later unless 
there is rapid clinical deterioration; PDr 
does not require confirmation; a 
subsequent PD within 28 days will not be 
valid for confirmation and will be ignored. 
*, SD, * 
 
PD 
SD 
UE, SD 
PD 
UE, PD 
UE 
Criteria for BOR=CR, PR, SD, or PD not 
met. 
SD must be < 77 days from the date of 
first dose. 
 


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Duration of Response (DOR) 
Duration of response is defined as the time from the date of an initial response that is 
subsequently confirmed to the earlier of PD (see definition of BOR per modified  
irRC-RECIST) or death. Subjects who have not ended their response at the time of 
analysis will be censored at the last evaluable tumor assessment before start of the first 
subsequent anticancer therapy.    
 
Durable Response Rate (DRR) 
Durable response rate is defined as the percent of subjects with a CR or PR per 
modified irRC-RECIST with a DOR ≥ 6 months. One month will be calculated based on 
365.25 days per year.  
 
Disease Control Rate (DCR also called the Clinical benefit response rate)  
Disease control rate is the proportion of subjects that have a best overall response of 
confirmed CR/ PR or SD. 
 
Objective Response Rate (ORR) 
The incidence rate of either a confirmed CR or PR per Modified irRC-RECIST. Subjects 
who do not achieve confirmed CR or PR by the start date of subsequent anticancer 
therapy or the data cutoff date, whichever occurs earlier, are regarded as non-
responders. 
 
Baseline Lesion 
Baseline lesion is defined as the lesions identified on or before study day 1 with a 
positive tumor length. If a baseline lesion has a positive tumor length reported at more 
than one visit, then the length from the most recent visit will be selected as the baseline 
length.  
 
New Lesion 


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New lesion is defined as the lesions that first appear after study day 1 with a positive 
tumor length. “Baseline” (ie, initial) tumor length of a new lesion will be obtained from the 
earliest date with a positive tumor length. Lesions that split from other lesions will not be 
considered as new lesions. 
 
Lesion complete response (L-CR) 
Lesion complete response (L-CR) is a response at the lesion level in injected vs 
uninjected lesions and applies only to target lesions and new measurable lesions. For 
injected and uninjected lesions, L-CR is defined as complete disappearance of a non-
nodal or reduction in short axis to <10 mm for pathological lymph node with confirmation 
by a repeat consecutive assessment no less than 4 weeks (28 days) after first 
documented. 
 
Lesion partial response (L-PR) 
Lesion partial response (L-PR) is a response at the lesion level in injected vs uninjected 
lesions and applies only to target lesions and new measurable lesions and is defined as 
≥ 30% decrease in lesion length relative to baseline with confirmation by a repeat 
consecutive assessment no less than 4 weeks (28 days) from the date first documented. 
 
Lesion objective response rate (L-ORR) 
Lesion objective response rate (L-ORR) is a response rate at the lesion level in injected 
vs uninjected lesions and is defined as the incidence among a set of lesions analyzed of 
L-CR or L-PR.  
Response at the lesion-level will be censored at the earliest after the start of the first 
subsequent anticancer therapy, or on or after the event of merging with another 
lesion, or complete or partial removal/reduction of any target lesion which contained 
cancer on pathology evaluation or pathology results were unknown. If a lesion splits, the 
sum of the length of the split lesions will be added together prior to analysis. 
 
Maximum Tumor Burden Decrease 


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Tumor burden is defined as the sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions and up to 10 (maximum 5 per organ) 
new measurable lesions. Tumor burden ratio is defined as the ratio of the tumor burden 
at each assessment divided by the baseline tumor burden. The Maximum tumor burden 
decrease is defined as smallest tumor burden ratio among all assessments -1.  
The maximum tumor burden decrease at the subject-level will be censored at the 
earliest after the start of the first subsequent anticancer therapy, or on or after the 
event of complete or partial removal/reduction of any target lesion which contained 
cancer on pathology evaluation or pathology results were unknown. 
The maximum tumor burden decrease at the lesion-level will be censored at the earliest 
after the start of the first subsequent anticancer therapy, or on or after the event of 
merging with another lesion, or complete or partial removal/reduction of any target lesion 
which contained cancer on pathology evaluation or pathology results were unknown. If a 
lesion splits, the sum of the length of the split lesions will be added together prior to 
analysis. 
 
Overall Survival (OS) 
Overall survival (OS) is defined as the time from the date of first dose date to the date of 
death from any cause.  Death is the event of interest.  OS time will be censored at the 
last date the patient is known to be alive when the confirmation of death is absent or 
unknown. 
 
Evaluable tumor assessment 
An overall visit response other than unevaluable (UE) or not done (ND). 
  
Evaluable lesion 
A target lesion or a new measurable lesion with a baseline and at least subsequent non 
missing dimension. 
 
Progression-free survival (PFS)  


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PFS is defined as the interval from first dose date to the earlier event of confirmed PD or 
death from any cause.  Subjects without an event will be censored at the latter of their 
last evaluable tumor assessment if available; otherwise will be censored on Study Day 1. 
 
Treatment Period 
Treatment period is defined as the period between the first date of IP administration in 
the study and 30 days after the last IP administration in the study. 
 
Subject Incidence of Detectable Talimogene Laherparepvec in Blood and Urine 
This endpoint is the prevalence of subjects with detectable talimogene laherparepvec 
DNA per qPCR in the blood /urine after the administration of talimogene laherparepvec 
within the first 4 cycles and safety follow-up per time point. 
 
Clearance of Talimogene Laherparepvec DNA in Blood and Urine  
A subject will be considered to have cleared talimogene laherparepvec DNA in the 
blood/urine if the qPCR assay for a blood sample is tested as negative following a 
previous positive qPCR testing.  For example, the cycle 2 day 1 prior to injection sample 
will be used to consider clearance of a positive qPCR post injection from cycle 1. 
 
Rate of Talimogene Laherparepvec DNA Detection and Viral Detection on the 
Exterior of Occlusive Dressing 
The rate of detectable talimogene laherparepvec DNA per qPCR on the exterior of 
occlusive dressing is defined as the number of cases of detectable talimogene 
laherparepvec DNA per qPCR divided by all swabs collected on the exterior of occlusive 
dressing per time point.  The rate of viral detection on the exterior of occlusive dressing 
is defined as the number of cases of detectable talimogene laherparepvec virus (TCID50 
positive) divided by the number swabs collected on the exterior of occlusive dressing per 
time point. 
 
Rate of Talimogene Laherparepvec DNA Detection and Viral Detection at the Skin 
Surface of Injection   


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The rate of detectable talimogene laherparepvec DNA per qPCR at the skin surface of 
injected lesions is defined as the number of cases of detectable talimogene 
laherparepvec DNA per qPCR divided by all swabs collected at the skin surface of 
injected lesions per time point.  The rate of viral detection in injected lesions is defined 
as the number of cases of detectable talimogene laherparepvec virus (TCID50 positive) 
divided by the number of swabs collected at the skin surface of injected lesions per time 
point. 
 
Rate of Talimogene Laherparepvec DNA Detection and Viral Detection in Oral 
Mucosa 
The rate of detectable talimogene laherparepvec DNA per qPCR in oral mucosa is 
defined as the number of cases of detectable talimogene laherparepvec DNA per qPCR 
divided by all swabs collected in oral mucosa per time point.  The rate of viral detection 
in oral mucosa is defined as the number of cases of detectable talimogene 
laherparepvec virus (TCID50 positive) divided by the number of swabs collected in oral 
mucosa per time point. 
 
Rate of Detectable Talimogene Laherparepvec DNA per qPCR in Suspicious 
Lesions to be Herpetic in Origin 
The rate of detectable talimogene laherparepvec DNA per qPCR in suspicious lesions is 
defined as the number of cases of detectable talimogene laherparepvec DNA per qPCR 
from swabs collected from lesions that are suspected to be herpetic in origin divided by 
all swabs collected from these lesions per time point. 
 
Treatment-emergent Adverse Events (TEAE) 
Treatment-emergent adverse events are defined as any adverse events that occur after 
the first dose of talimogene laherparepvec or pembrolizumab through 30 days after the 
last dose of talimogene laherparepvec or pembrolizumab, whichever is later. Adverse 
events that occur on the same day as the first dose date of IP will be treated as 
treatment-emergent events unless indicated otherwise.  (For example, if an event occurs 
on the same date as the first administration of study therapy and the check box 


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indicating prior to the first dose of IP is checked, then the event will not be counted as a 
TEAE). 
 
Treatment-emergent Serious Adverse Events (TESAE) 
Treatment-emergent serious adverse events are defined as any serious adverse event 
occurring after initiation of the first dose of study therapy through 90 days after the last 
administration of study therapy or 30 days after the last administration of study therapy if 
the subject initiates new anticancer therapy, whichever is earlier.  Serious adverse 
events that occur on the same day as the first dose date of study therapy will be treated 
as treatment-emergent serious events unless indicated otherwise.  (For example, if an 
event occurs on the same date as the first administration of study therapy and the check 
box indicating prior to the first dose of study therapy is checked on eCRF, then the event 
will not be counted as a TESAE). 
 
On-study Surgery/procedure 
On study surgeries or procedures are defined as surgeries or procedures performed 
from the time of first drug exposure to end of the treatment period or death or end of 
study, whichever occurs first. 
 
On-study Death 
Deaths of all causes that occur any time during the study are defined as on-study 
deaths.  This may include deaths that occur beyond the end of the treatment period. 
Note that this study has a long-term survival follow-up after the safety follow-up, deaths 
that occur after the study long-term survival follow-up will be reported in study 20120139, 
which is the registry study for long-term follow up of clinical trial subjects who have 
completed talimogene laherparepvec treatment. 
 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
For efficacy analyses of talimogene laherparepvec monotherapy, the Full Analysis Set 
will be defined as all subjects who received at least 1 dose of talimogene laherparepvec 


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and no treatment with systemic pembrolizumab; and for efficacy analyses of talimogene 
laherparepvec in combination with systemic pembrolizumab, it will be defined as all 
subjects who received at least 1 dose of talimogene laherparepvec and at least 1 dose 
of pembrolizumab in combination. 
6.2 
Safety Analysis Set 
The Safety Analysis Set will be defined as all subjects who received study therapy.  For 
monotherapy cohorts, subjects will be included for analysis of safety if they received at 
least 1 dose of talimogene laherparepvec.  For the combination therapy cohorts or part 
2, subjects will be included for analysis of safety if they received at least 1 dose of 
talimogene laherparepvec or at least 1 dose of pembrolizumab. 
6.3 
DLT Analyses Set(s) 
DLT Analysis Set:  The DLT analysis set will include DLT-evaluable subjects enrolled in 
Part 1 and Part 2 defined as follows:   
 
Monotherapy Cohorts:  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 1 additional dose of talimogene laherparepvec 
 
Combination Cohorts:  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 pembrolizumab in combination  
 
Subjects experiencing a DLT:  Have a DLT during the DLT-evaluation period after 
at least 1 dose of talimogene laherparepvec (for monotherapy cohorts) and 
talimogene laherparepvec and pembrolizumab (for combination cohorts) 
6.5 
Reactive Swab Analysis Set 
Subjects who are enrolled, receive at least one dose of talimogene laherparepvec, and 
have at least one swab sample collected from lesions that are suspected to be herpetic 
in origin.  This analysis set is used to examine the number of subjects with a lesion 
suspected to be herpetic, and detection of talimogene laherparepvec DNA by qPCR in 
lesions suspected to be herpetic in origin. 


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6.6 
Blood and Urine Evaluable Analysis Sets 
Subjects who are enrolled, receive at least one dose of talimogene laherparepvec, and 
have at least one post dose blood sample (and urine sample, respectively) collected.  
The Blood and Urine Analysis Sets will be used for examining the biodistribution of 
talimogene laherperapvec in the blood and urine, respectively. 
6.7 
Blood and Urine Clearance Analysis Sets 
Subjects who are enrolled, receive at least one dose of talimogene laherparepvec, and 
have at least 2 post dose blood/urine samples collected within the same dosing cycle.  In 
addition, subjects included in the Blood/Urine Clearance Analysis Set must have at least 
1 positive talimogene laherparepvec DNA sample and at least 1 subsequent sample at 
any time during the cycle (including the sample collected prior to the next dose of 
investigational product, if applicable).  A subject will be defined as having cleared 
talimogene laherparepvec if a negative qPCR in a sample is obtained following a prior 
positive test and if there are no subsequent positive test results in the same cycle.  The 
Blood/Urine Clearance Analysis Set will be used to evaluate the subject incidence of 
clearing talimogene laherparepvec DNA in the blood and urine over time in the first three 
cycles. 
6.8 
Exterior of Occlusive Dressing Evaluable Analysis Sets 
Subjects who are enrolled, receive at least one dose of talimogene laherparepvec, and 
have at least one swab collected from the exterior of the occlusive dressing.  This 
analysis set is used to examine the detection of talimogene laherparepvec DNA and 
virus in the exterior of the occlusive dressing. 
6.9 
Skin Surface of Injections Evaluable Analysis Sets 
Subjects who are enrolled, receive at least one dose of talimogene laherparepvec, and 
have at least one swab collected from the skin surface of injections.  This analysis set is 
used to examine the detection of talimogene laherparepvec DNA and virus at the skin 
surface of in injections. 
6.10 
Oral Mucosa Evaluable Analysis Sets 
Subjects who are enrolled, receive at least one dose of talimogene laherparepvec, and 
have at least one swab collected from oral mucosa.  This analysis set is used to 
examine the detection of talimogene laherparepvec DNA. 


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6.11 
Lesion Analysis Sets 
The Injected Lesion Analysis Set includes any target lesion and new measurable lesion 
that was ever injected and the uninjected lesion analysis set includes any target lesion 
and new measurable lesion that was never injected among subjects in Full Analysis Set. 
The Injected Lesion Evaluable and Uninjected Lesion Evaluable analysis sets will 
include the corresponding subset of target lesions and new measurable 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 partial or 
complete resection and pathology indicates absence of malignant cells). If a lesion splits, 
the sum of the length of the split lesions will be added together prior to analysis. 
 
7. 
Planned Analyses 
7.1 
Interim Analysis 
Dose-limiting toxicities interim safety analyses will be performed to support the 
evaluation of safety and determination of the MTC and MTV of talimogene 
laherparepvec administered as monotherapy and in combination with systemic 
pembrolizumab. Interim efficacy analysis for part 1 will be performed as needed. Interim 
safety and efficacy futility analyses are planned for this study in Part 2 separately for 
each tumor type arm. 
7.1.1 DLT Safety Analysis (Part 1) 
The planned interim safety data reviews for monotherapy cohorts in Part 1 to evaluate 
the subject incidence of DLTs will be conducted according to timing/rules described in 
Protocol Section 3.1.1. Data will be reviewed by a DLRT.  The DLRT will recommend 
either to declare the cohort dose intolerable, to reassess safety after 3 additional DLT-
evaluable subjects, or to declare the cohort dose tolerable and to apply the same 
evaluation rules to subsequent cohorts.  For combination cohorts in Part 1, the DLRT will 
recommend according to the DLRT Charter whether it is safe to continue enrollment 
based on the mTPI up-and-down design. The database will be cleaned, and a database 
snapshot will be used in the analysis. 
7.1.2 Interim Safety Analysis (Part 2) 
An interim safety data review will occur for each tumor type separately after 
approximately 10 subjects have been treated in Part 2 with the specific tumor type and 
have had an opportunity to be followed up for at least 6 weeks. 


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 At the discretion of the DLRT, 2 additional safety analyses may be conducted as 
warranted during Part 2 after a target of approximately 6 and 16 DLT-evaluable subjects. 
A total volume > 4 mL of talimogene laherparepvec may be allowed in Part 2 with 
systemic pembrolizumab if it is declared safe without pembrolizumab in Part 1. In 
this event, the DLRT will also monitor safety in Part 2 separately among subjects 
in non-HCC (Group A) and HCC (Group B) arms that receive at least 1 dose of 
talimogene laherparepvec with a total volume > 4 mL at the combination MTC with 
systemic pembrolizumab. Subjects will be included in the safety assessment of 
> 4 mL with at least 3 weeks follow-up from an initial total volume > 4 mL at the 
combination MTC.  
Safety analyses will be performed at the time of the planned analyses for each tumor 
type or more frequently at the DLRTs discretion. The database will be cleaned, and a 
database snapshot will be used in the analysis. 
7.1.3 Interim Futility Analysis (Part 2) 
One interim efficacy futility analysis will occur after 10 subjects have been treated with 
the combination in Part 2 by tumor type and have had an opportunity to be followed up 
for at least 20 weeks. Enrollment will be suspended for the specific tumor type arm 
pending the outcome of the interim analysis. If there are 2 or more responders (CR or 
PR confirmation not required), then a total of 11 additional subjects will be treated; 
otherwise, further enrollment of the tumor type will be permanently discontinued. If at 
least 2 responders are observed by the enrollment of the 10th treated subject, then 
enrollment will not be suspended. The database will be cleaned, and a database 
snapshot will be used in the analysis. 
7.1.4 Dose Level Review Team (DLRT) 
A DLRT consisting of the Amgen study team, including at least one medical clinician, 
safety representative and biostatistician, at least one representative of the Merck study 
team, and at least one participating investigator who has recruited subjects into 
Part 1, will review the safety data to evaluate possible DLTs. Representative(s) from 
Merck will participate in DLRT meetings for all cohorts (voting member only for 
Cohorts 5 and 6 of Part 1 and all cohorts of Part 2). The DLRT will make 
recommendations in Part 1 and 2 according to a DLRT Charter. The DLRT Charter 
will include guidelines to monitor safety in Part 2 separately by tumor type arm and, if 
introduced, talimogene laherparepvec total volumes > 4 mL within Group A and Group 


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B. In Part 2, the DLRT may consider reducing the RP2D talimogene laherparepvec 
concentration and/or discontinuation of total volumes > 4 mL, if introduced. The 
database will be cleaned, and a database snapshot will be used in the analysis. 
7.2 
Primary Analysis 
One clinical study report (CSR) will be written based on the results of the primary 
analyses across Part 1 and Part 2. 
The primary analysis for each combination cohort from Part 2 will occur 
independently when all subjects in each tumor type arm have a minimum potential 
follow-up of ≥ 29 weeks. The primary analysis for part 1 will occur after all 
subjects have a minimum potential follow-up of ≥ 29 weeks. The database will be 
cleaned, and a locked database will be used in the analysis. 
7.3 
Final Analysis 
The final analysis will occur when all subjects have discontinued the study treatment and 
have had the opportunity to complete the long-term survival follow-up visit. One CSR will 
be written with the updated results from the final analyses at the completion of the study. 
The database will be cleaned, and a locked database will be used in the analysis. 
8. 
Data Screening and Acceptance 
8.1 
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. 
8.2 
Data Handling and Electronic Transfer of Data 
 
 
, HSV 
antibody serostatus samples, and swab samples collected from lesions suspected to be 
herpetic in origin, will be processed and analyzed by a vendor of Amgen.  
 
8.3 
Handling of Missing and Incomplete Data 
Adverse events with missing severity, seriousness, and/or possible relationship to 
talimogene laherparepvec will be included in all AE analyses, except by severity grade 
and treatment-related analyses. 


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Partial or missing dates of adverse events and concomitant medications will be imputed.  
 
  Every effort will be made to obtain complete dates for deaths. 
 
 
8.4 
Detection of Bias 
NA 
8.5 
Outliers 
The database will be subject to edit checks outlined in the protocol-specific Data 
Management Plan (DMP).  Data with inconsistencies and suspicious values will be 
queried and resolved before the database lock. 
8.6 
Distributional Characteristics 
NA 
8.7 
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. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
In Part 1, the efficacy and safety analyses will be conducted separately in monotherapy 
and combination cohorts.  The DLT analysis set will be used to summarize the subject 
incidence of DLT for the study and the Safety Analysis Set will be used for all other 
analyses of safety endpoints (including but not limited to all adverse events, grade ≥ 3 
adverse events, serious adverse events, fatal adverse events, adverse events requiring 
discontinuation of study drug, and AEs defined as events of interest).  The efficacy 
analysis will be conducted using the Full Analysis Set unless otherwise specified.  All the 
analysis may be conducted overall or by cohort/ group if appropriate. 
In Part 2, the efficacy and safety analyses will be conducted separately by each tumor 
type arm. The efficacy analysis will be conducted using the Full Analysis Set unless 


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otherwise specified. The Safety Analysis Set will be used for all other analyses of safety 
endpoints. 
In principle, mean, standard deviation, median, first and third quartiles, minimum and 
maximum will be calculated for continuous variables; frequency count and percent will 
be calculated for binary and categorical variables.  The analysis of response variant 
endpoints will be based on investigator assessments per modified irRC-RECIST as 
described in the protocol unless otherwise specified. 
9.2 
Subject Accountability 
The number of subjects enrolled will be tabulated by investigator sites.  Subject 
disposition including screened, enrolled, treated and ended treatment, and completed 
safety follow-up visit will be summarized for all enrolled subjects in part 1 and part 2 
separately. Reasons for discontinuation of study drug, reason for not completing the 
study, and the reason for not completing safety follow-up will also be summarized overall 
or by cohort/part/tumor type arm/group if appropriate. Key study dates for the first 
subject enrolled, last subject enrolled, last subject’s end of study, last subject’s end of 
investigational product, and data cut-off date will be presented. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory 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.  An IPD and an Eligibility Deviation listing will be 
provided.  The number of subjects with at least one IPD during study will be tabulated. 
9.4 
Demographic and Baseline Characteristics 
Summary statistics of the following demographic, baseline characteristics, and disease 
characteristics described in 4.1 will be tabulated.  These will also be used whenever 
applicable to examine efficacy and safety in subgroups or in multivariate analyses. 
9.5 
Efficacy Analyses 
The efficacy analysis will be conducted separately for Part 1 and Part 2, using the Full 
Analysis Set. The efficacy analysis in Part 1 will be conducted overall and by 
group/cohort.  The efficacy analysis in Part 2 will be performed overall and by 
group/tumor type, unless otherwise specified. 


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Table 9-1.  Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if FAS 
is Not Used) 
Sensitivity Analysis 
Part 2: 
• ORR per modified 
irRC-RECIST with 
intratumoralinjection of 
talimogene 
laherparepvec into 
cutaneous, 
subcutaneous, lymph 
node, or liver tumors in 
combination with 
systemic IV 
administration of 
pembrolizumab 
separately by tumor 
type. 
The 2-stage design will be used to 
evaluate the ORR per the modified 
irRC-RECIST. The null hypothesis 
of a 10% ORR for a given tumor 
type that continued to Stage 2 will 
be rejected if an exact binomial 
95% CI for the ORR is above 10% 
(Atkinson and Brown, 1985).  
N/A 
Table 9-2.  Secondary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if FAS 
is Not Used) 
Sensitivity Analysis 
Part 1: 
• ORR, BOR, DRR, 
DOR, response in 
injected and uninjected 
lesions, DCR, PFS, and 
OS separately for non-
HCC and HCC tumors 
in monotherapy and 
combination cohorts 
 
 
For Part 1, the ORR/DRR/DCR 
will be estimated with the 
associated 95% CI (Clopper 
and Pearson, 1934).  
 
A listing of efficacy endpoints 
will be provided for whichever 
combination cohort is not the 
RP2D, if applicable. 
 
Kaplan-Meier (K-M) estimates 
of landmarks (e.g., 1-, 2-, and 
3-year rates) and quartiles for 
DOR/PFS/OS will be provided 
(Kaplan and Meier, 1958). 
Greenwood’s formula 
(Kalbfleisch and Prentice, 1980) 
for standard error will be used 
to calculate CIs for landmark K-
M rates.  CIs for K-M quartiles 
will be estimated (Brookmeyer 
and Crowley, 1982).  
 
Waterfall plots for maximum 
tumor burden decrease in the 
lesion diameter at subject-level 
and lesion-level will also be 
provided. 
N/A 
Part 2: 
• BOR, DRR, DOR, 
response in injected 
 
The BOR, DRR, DOR, 
response in injected and 
uninjected lesions, DCR, PFS 
and OS will be summarized by 
N/A 


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Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if FAS 
is Not Used) 
Sensitivity Analysis 
and uninjected lesions, 
DCR, PFS, and OS by 
primary tumor type. 
primary tumor type. The 
ORR/DRR/DCR will be 
estimated with the associated 
95% CI. Tumor response 
endpoints may also be 
evaluated based on modified 
RECIST v 1.1 for historical 
comparison for each tumor type 
that continues to Stage 2 of 
Part 2. 
 
Kaplan-Meier (K-M) estimates 
of landmarks (e.g., 1-, 2-, and 
3-year rates) and quartiles for 
DOR/PFS/OS will be provided 
(Kaplan and Meier, 1958). 
Greenwood’s formula 
(Kalbfleisch and Prentice, 1980) 
for standard error will be used 
to calculate CIs for landmark K-
M rates.  CIs for K-M quartiles 
will be estimated (Brookmeyer 
and Crowley, 1982). 
 
Waterfall plots for maximum 
tumor burden decrease in the 
lesion diameter at subject-level 
and lesion-level will also be 
provided. 
 
Analysis for response rate in 
injected vs. uninjected lesions 
may show the evidence of 
systemic effect separately in 
Part 2. Analysis of response at 
lesion-level will be conducted 
by lesion type (injected vs. 
uninjected and liver vs. non-
liver), and overall, if 
appropriate.  Wilson’s score 
method with continuity 
correction (Newcombe, 1998) 
will be used to calculate an 
approximate exact CI for 
between-group differences in 
binary rates if appropriate. 
 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
Part 2: 
• ORR per modified irRC-RECIST with intrahepatic injection of talimogene 
laherparepvec into liver tumors in combination with systemic IV administration 


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of pembrolizumab separately by tumor type (hormone receptor positive BC, TNBC, 
CRC, CSCC, BCC, without viral hepatitis) 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Part 1: 
• ORR, BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and 
OS separately for non-HCC and HCC tumors in monotherapy and combination 
cohorts  
Part 2: 
• BOR, DRR, DOR, response in injected and uninjected lesions, DCR, PFS, and 
OS by primary tumor type arm 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Part 1 and Part 2: 
Table 9-4.  Safety Endpoint Summary Table 
Endpoint 
Primary Summary and 
Analysis Method (Specify 
Analysis Set if FAS is Not 
Used) 
Sensitivity Analysis 
Part 1: 
Monotherapy cohorts 1-4: Subject 
incidence of DLTs with intrahepatic 
injection of talimogene laherparepvec 
into liver tumors in subjects with non-
HCC with liver metastases and 
subjects with HCC without active viral 
hepatitis. 
Combination cohorts 5 and 6: Subject 
incidence of DLTs with intrahepatic 
injection into liver tumors of 
talimogene laherparepvec in 
combination with systemic IV 
administration of pembrolizumab in 
subjects with non-HCC with liver 
metastases and subjects with HCC 
with and without viral hepatitis. 
The subject incidence of 
DLT will be summarized as a 
binary variable using the 
DLT analysis set. 
N/A 


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Part 2:  
Subject incidence, for each tumor 
type arm, of treatment-emergent and 
treatment-related adverse events, 
including DLTs. 
The subject incidence of 
DLT will be summarized as a 
binary variable using the 
DLT analysis set. 
N/A 
 
9.6.2 
Adverse Events and Disease-related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 or later will be 
used to code all events categorized as adverse events, disease-related events to a 
system organ class and a preferred term. The CTCAE version 4.03 will be used to grade 
severity of AEs. All the safety analysis of adverse events will be evaluated in each 
monotherapy and combination cohorts in Part 1 (by cohort/group) and each tumor type 
separately in Part 2 (by tumor type arm/group). 
The subject incidence of adverse events will be summarized for all treatment-emergent, 
treatment-related adverse events within the following categories: grade 3, grade 4, 
grades 3 or 4, serious adverse events, adverse events leading to withdrawal of 
investigational product, and fatal adverse events. 
Additional subject incidence tables will be presented to describe the treatment-emergent 
and treatment-related adverse events (including all adverse events, grade > 3 adverse 
events, serious adverse events, fatal adverse events, adverse events of interest, 
adverse events requiring permanent discontinuation of study therapy, and local effects 
on the tumor[i.e., pain, inflammation and ulceration]).  Summaries of treatment-emergent 
and serious AEs by preferred term will be provided in descending order of frequency.  
The subject incidence summaries will be provided in 2 ways: within system organ class 
(SOC) subset by preferred term, and by decreasing order of preferred term frequency.  
In addition, adverse events and treatment-related adverse events will be tabulated by 
worst grade within SOC subset by preferred term. 
A summary of deaths after initiation of the study through 90 days since the last dose of 
talimogene laherparepvec or pembrolizumab, whichever is discontinued last will be 
provided. 
Listings will be provided for treatment-emergent and treatment-emergent, treatment-
related adverse events (including all adverse events, serious adverse events, fatal 
adverse events, and adverse events requiring permanent discontinuation of protocol 


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drug).  In addition, screening SAEs prior to study Day 1 and all AEs > 30 (+/-7) days from 
last dose of study drug will be listed. 
Adverse Events of Interest 
Adverse events of interest are defined in a version-controlled Product Safety Analysis 
Plan (PSAP) for talimogene laherparepvec.  The search terms of each event of interest 
(EOI) will be extracted based on the most recent version of the PSAP prior to the 
database snapshot for the analysis.  Versions of the PSAP and MedDRA used for the 
EOI analysis will be documented in clinical study report(s). All the safety analysis of 
talimogene laherparepvec adverse events of interest (EOI) and pembrolizumab events 
of clinical interest (ECI) will be evaluated in each monotherapy and combination cohorts 
in Part 1 (by cohort/group) and each tumor type separately in Part 2 (by tumor 
type/group). The subject incidence of treatment-emergent and treatment-emergent, 
treatment-related EOIs and ECIs (including all events of interest, serious events of 
interest, non-serious events of interest) according to the EOI search strategy categories 
and ECI categories will be summarized. 
In addition, EOI and ECI may be tabulated by worst grade within EOI category and ECI 
category by preferred term respectively.  A table summarizing the incidence of all 
treatment-emergent adverse events of interest will also be provided by EOI category and 
ECI category as a high level summary. 
Subject Incidence of Detectable Talimogene Laherparepvec in Blood and Urine 
The analysis will be based on the Blood Evaluable Analysis Set in which proportions of 
subjects that meet the criteria of detectable (defined as positive result by qPCR analysis) 
DNA in blood will be calculated.  The point-wise exact 95% confidence intervals for 
binomial proportions using the F-distribution (Leemis and Trivedi, et al, 1996) from SAS® 
PROC FREQ procedure with the binomial option will also be calculated.  Similar analysis 
of incidence of talimogene laherparepvec DNA detected in the urine will be repeated 
using the Urine Evaluable Analysis Set. 
A detailed listing of qPCR results for subjects with detectable talimogene laherparepvec 
DNA per qPCR timepoints during the first 4 cycles and safety follow-up will be provided. 
The analysis will be based on available cases; that is, subjects who do not have blood 
sample (or urine sample for respective analysis) collected at the respective time points 
will be excluded from the analysis for that time point. 


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Incidence of Clearance of Talimogene Laherparepvec DNA in Blood and Urine 
The number and proportion of subjects with undetectable talimogene laherparepvec 
DNA per qPCR in blood among subjects with sample collected in each cycle will be 
presented.  Incidence of clearance of talimogene laherparepvec DNA from Cycle 1, 2 
and 3 in blood will be calculated by cycle.  The exact 95% CI for the binomial proportions 
using the F-distribution will be calculated.  The analysis of clearance of talimogene 
laherparepvec in the blood will include subjects in the Blood Clearance Analysis Set.  
The analysis will be repeated using the Urine Clearance Analysis Set to evaluate 
clearance in the urine. 
In addition, the analysis of incidence of clearance at Day 8 ((± 2 days) of each cycle for 
cycles 1, 2, and 3 will be repeated by baseline HSV-1 serostatus (i.e., seropositive and 
seronegative) among subjects with known HSV-1 status at baseline.  The difference in 
clearance rate at Day 8 for cycles 1, 2, and 3 will be provided.  The corresponding 95% 
confidence interval will be based on the Wilson’s score method with continuity correction 
(Newcombe, 1998). 
Rate and Subject Incidence of Talimogene Laherparepvec DNA Detection and Viral 
Detection on the Exterior of Occlusive Dressing 
The subject incidence of positive qPCR and subsequent positive plaque testings will be 
evaluated from swabs of occlusive dressings.  The number and proportion of subjects 
who have at least 1 positive qPCR result from the exterior of occlusive dressing swabs 
and the number and proportion of subjects exhibiting detectable virus from subsequent 
plaque testings will be presented.  Numeric results of positive qPCR, and separately for 
positive plaque analysis, will be summarized as a continuous variable.   
A detailed listing of qPCR and subsequent plaque results for subjects having a positive 
qPCR testing will be provided. 
The analysis of this endpoint will be based on the Exterior of Occlusive Dressing 
Evaluable Analysis Set. 
Rate and Subject Incidence of Talimogene Laherparepvec DNA Detection and Viral 
Detection at the Skin Surface of Injections 
The subject incidence of positive qPCR and subsequent positive plaque assays will be 
evaluated from swabs of skin surface of injections.  The number and proportion of 
subjects who have at least 1 positive qPCR result from at the skin surface of the injected 


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lesions and the number and proportion of subjects exhibiting detectable virus from 
subsequent plaque testings will be presented.  Numeric results of positive qPCR 
testings, and separately for positive plaque analysis, will be summarized as a continuous 
variable.   
A detailed listing of qPCR and subsequent plaque results for subjects having a positive 
qPCR testing will be provided. 
Analysis of this endpoint will be based on the skin surface of the Injected Lesion 
Evaluable Analysis Set. 
Rate and Subject incidence of Talimogene Laherparepvec DNA Detection and Viral 
Detection in Oral Mucosa 
The subject incidence of positive qPCR and subsequent positive plaque assays will be 
evaluated from swabs of oral mucosa.  The number and proportion of subjects who have 
at least 1 positive qPCR result from oral mucosa and number and proportion of subjects 
exhibiting detectable virus from subsequent plaque testings will be presented.  Numeric 
results of positive qPCR, and separately for plaque analysis, will be summarized as a 
continuous variable.   
A detailed listing of qPCR and subsequent plaque results for subjects having a positive 
qPCR testing will be provided. 
Analysis of this endpoint will be based on the Oral Mucosa Evaluable Analysis Set. 
Rate and Subject Incidence of Detectable Talimogene Laherparepvec DNA per 
qPCR in Suspicious Lesions to be Herpetic in Origin 
This rate will be calculated based on the Reactive Swab Analysis Set. 
The subject incidence will be reported for positive qPCR for talimogene laherparepvec 
DNA detection in any swab of a lesion suspected to be herpetic in origin.  The analysis 
will be based on the Reactive Swab Analysis Set.  A detailed listing of qPCR results for 
subjects having a positive qPCR testing will be provided.  In addition, a listing for all 
subjects in the Reactive Swab Analysis Set will be provided with reported treatment-
emergent adverse events (including preferred term, verbatim term, start and end dates, 
duration, grade, seriousness, and relationship to IP), and qPCR result (Y/N). 
Reporting of Suspected or Known Unintended Exposure to Talimogene 
Laherparepvec and Herpetic Illness in Close Contacts and Healthcare Providers 


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Potential or known unintended exposure to talimogene laherparepvec, and any related 
suspected signs or symptoms in a subject’s close physical contact, household member, 
caregiver, or healthcare provider will be reported.  If consent of a close contact or 
healthcare provider is provided, the exposed individual may be asked to have a swab 
taken to evaluate for the presence of talimogene laherparepvec in suspicious lesions.  
The positive qPCR for talimogene laherparepvec DNA detection from suspicious lesions 
will be reported.  These individual cases in secondary contacts will be reported with 
separate ID numbers to distinguish them from subjects’ data.  More details will be 
provided in a program-level SSAP for unintended exposure to talimogene 
laherparepvec. 
Disease-related Events 
A sensitivity analysis of treatment-emergent adverse events will be conducted that 
considers any disease-related events as an adverse event if the disease-related event 
was reported in the study for any subject as a treatment-emergent adverse event. 
Subject incidence of disease-related events will be summarized for all treatment-
emergent disease-related events, fatal disease-related events, serious disease-related 
events, disease-related events leading to withdrawal from study drug, and significant 
disease-related events will be provided separately as a sensitivity analysis. 
9.6.3 
Laboratory Test Results 
Lab-defined lower and upper limits of normal ranges will be used for chemistry, 
hematology, coagulation, immunology, and toxicology laboratory tests.  NCI Common 
Toxicity Criteria (CTC) version 4.03 grading will be used.  Laboratory results will be 
summarized with descriptive statistics at baseline and selected time points.  Grade shifts 
in important laboratory results from baseline to worst on-protocol value will be presented.  
The incidence of post-baseline laboratory abnormalities will be provided. 
9.6.4 
Vital Signs 
Descriptive analyses of temperature, blood pressure, respiratory rate, and heart rate will 
be conducted at baseline and selected time points. 
9.6.5 
Physical Measurements 
Descriptive analyses of temperature, blood pressure, respiratory rate, and heart rate will 
be conducted at baseline and selected time points. 


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9.6.6 
Exposure to Investigational Product 
In Part 1, descriptive statistics will be produced to describe the exposure to Amgen 
investigational product talimogene laherparepvec and non-Amgen investigational 
product pembrolizumab by cohort/group (non-HCC vs HCC vs overall). Subjects in 
cohort 1 to cohort 4 will be exposure to monotherapy treatment. 
In Part 2, descriptive statistics will be produced to describe the exposure to Amgen 
investigational product talimogene laherparepvec and non-Amgen investigational 
product pembrolizumab by tumor type/group (non-HCC vs HCC vs overall). 
Summary statistics for exposure to talimogene laherparepvec or/and pembrolizumab, 
including total doses administered, total volume administered, treatment visits with IP 
MTV <= 4ml, treatment visits with MTV volume > 4ml, 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.  The subject incidence rate and reasons for IP delays, missed 
treatment, and withdrawal will be tabulated. 
9.6.7 
Exposure to Other Protocol-required Therapy 
Summary statistics for subjects in the Full Analysis Set who undergo on-protocol surgery 
including any surgery/procedure performed, type of procedure, and intent of surgery 
(e.g., palliative) will be provided. 
9.6.8 
Exposure to Concomitant Medication 
Concomitant medications include all medications received during the treatment period 
other than the protocol drug. The number and proportion of subjects receiving any 
concomitant medications during the treatment period will be summarized by preferred 
term as coded by the World Health Organization Drug (WHO DRUG) dictionary.  A list of 
selected medications and their groupings are provided. 
9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
A separate SSAP will be prepared for the exploratory endpoints and this analysis may 
be reported separately. 
Enter Analyses of Health Economic Endpoints 


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10. 
Changes From Protocol-specified Analyses 
N/A 
11. 
Literature Citations / References 
Clopper, C.; Pearson, E. S. The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika.  1934:26:404–413. 
Kaplan and Meier. Nonparametric Estimation from Incomplete Observations Journal of 
the American Statistical Association.  1958:53 457- 481 
Brookmeyer, R. and Crowley, J.  A Confidence Interval for the Median Survival Time.  
Biometrics.  1982:38:29–41. 
Kalbfleisch, J.D. and Prentice, R.L. The Statistical Analysis of Failure Time Data, New 
York: John Wiley & Sons. 1980 
Leemis LM, Trivedi, KS.  A comparison of approximate interval estimates for the 
Bernoulli parameter.  The American Statistician.  1996;50:63-68. 
Newcombe RG.  Interval estimation for the difference between independent proportions: 
comparison of eleven methods.  Stat Med.  1998:17:873-890. 
Atkinson AN and Brown BW. Confidence Limits for Probability of Response in Multistage 
Phase II Clinical Trials. Biometrics. 1985;41 : 741-744. 
 
12. 
Prioritization of Analyses 
N/A 
 
13. 
Data Not Covered by This Plan 
N/A 


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14. 
Appendices 
Appendix A.  Reference Values/Toxicity Grades 
CTCAE v. 4 grading scale will be used for adverse event coding: 
1 – Mild 
2 – Moderate 
3 – Severe 
4 – Life-threatening 
5 – Death 
 
Enter Appendix Concomitant Medications 


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Appendix C.  Wilson’s Score Method with Continuity Correction in Calculating the 
95% Confidence Intervals for Difference in 2 Independent Proportions 
 
The following formula of interval estimation is extracted from Newcombe 1998 paper: 
Assuming  
.
,...,
2
,1
),
(
~
1
.
..
m
i
where
Bernoulli
X
d
i
i
i


 
.
,...,
2
,1
),
(
~
2
.
.
.
n
j
where
Bernoulli
Y
d
i
i
j


 
2






 
.
/
/
ˆ
1
m
a
m
x
m
i
i





 
.
/
/
ˆ
1
2
n
b
n
y
n
j
j




 
Then the 100(1- α)% confidence interval for 
n
b
m
a
/
/
ˆ
ˆ
ˆ









, with continuity 
correction is 
}
)
/
(
)
/
{(
2
2
2
1
n
b
u
l
m
a





 
}
)
/
(
)
/
{(
2
2
2
1
l
n
b
m
a
u




 
1l and 
1u  delimit the interval 
}
/)
1(
)
2
/(
1
|
/
|:
{
1
m
z
m
m
a















and  
2l and 
2
u  delimit the interval 
}
/)
1(
)
2
/(
1
|
/
|:
{
2
2
1
2
2
n
z
n
n
b











. 
 
 
 
 


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Appendix D.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs 
 
D.1 
Sample Posterior Probability Calculation 
%macro bayb1s (as    = ,    /* Standard beta a                */ 
               bs    = ,    /* Standard beta b                */ 
 
 
  ce    =,   /* Exp beta precision             */ 
 
 
  delta =,   /* Exp mean - std mean            */ 
 
 
  n     =,  /* 1-arm study sample size        */ 
 
 
  x     =,   /* # responders                   */  
               dmin  = 0,   /* Plot delta min                  */ 
 
 
  dmax  = 30,  /* Plot delta max                  */ 
 
 
  dby   = 5,   /* Plot delta increment            */ 
 
 
  alpha =0.10 /* 100-alpha credible intervals    */); 
 
*** Prior distributions for standard and experimental ***; 
data _null_; 
  * Prior for standard (s) ; 
  as    = &as; 
  bs    = &bs; 
  ms    = as/(as+bs);    * mean of single agent ; 
  Bsc   = beta(as,bs); 
 
  * Prior for experimental (e) ; 
  ce    = &ce;           * Concentration parameter (sample size) ; 
  delta = &delta;        * Absolute rate increase over standard ; 
  ae    = ce*(ms + delta/2); 
  be    = ce*(1 - (ms + delta/2)); 
  me    = ae/(ae+be);    * Mean of experimental ; 
 
  call symput('ms',trim(left(put(ms,6.4)))); 
  call symput('Bsc',Bsc); 
  call symput('ae',trim(left(put(ae,6.4)))); 
  call symput('be',trim(left(put(be,6.4)))); 
  call symput('me',trim(left(put(me,6.4)))); 
run; 
 
 
*** Experimental posterior distribution ***; 
data combo_post; 
  ae_p=&ae+&x;  
  be_p=&be+&n-&x; 
  me_p=ae_p/(ae_p+be_p); 
 
  * 95% credible interval for experimental ORR ; 
  cr_ll=betainv(0.025,ae_p,be_p); 
  cr_ul=betainv(0.975,ae_p,be_p); 
 
  call symput('ae_p',trim(left(put(ae_p,6.2)))); 
  call symput('be_p',trim(left(put(be_p,6.2)))); 
  call symput('me_p',trim(left(put(me_p,6.4)))); 
run; 
 
proc print data=combo_post noobs; 
  var ae_p be_p me_p cr_ll cr_ul; 
  title1 "Prior standard Beta(&as,&bs), mean=&ms; Prior experimental 
Beta(&ae,&be), mean=&me"; 
  title1 "Experimental posterior ORR 95% Credible Region"; 
  title2 "N=&n, X=&x"; 
run; 
 


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*** Plot of experimental prior and posterior ***; 
data plot; 
  * Prior ; 
  lab='Prior    '; 
  Bec = beta(&ae,&be); 
  do x=0 to 1 by .001; 
    if x le 1 then f=(x**(&ae-1)) * ((1-x)**(&be-1))/Bec; 
    output; 
  end; 
  * Posterior ; 
  lab='Posterior'; 
  Bec_p = beta(&ae_p,&be_p); 
  do x=0 to 1 by .001; 
    if x le 1 then f=(x**(&ae_p-1)) * ((1-x)**(&be_p-1))/Bec_p; 
    output; 
  end; 
run; 
 
axis1 minor=none value=(h=2.25) length=65 
  label=(a=90 h=2.5 'Beta Density'); 
axis2 label=(h=2.5 'Objective Response Rate') minor=none value=(h=2.25) 
  order=(0 to 1 by .1); 
symbol1 v=none w=2 i=spline line=1 c=blue; 
symbol2 v=none w=2 i=spline line=2 c=black; 
legend1 label=none value=(h=2.25 j=l) down=2 mode=share  
  position=(inside top middle); 
title; footnote; 
 
data _null_; 
  set combo_post; 
  call symput('cr_ll',trim(left(put(cr_ll,6.2)))); 
  call symput('cr_ul',trim(left(put(cr_ul,6.2)))); 
run; 
 
filename gf   "&prefix.Exp_prior_post.emf"; 
proc gplot data=plot; 
  plot f * x = lab 
    / vaxis=axis1  
      haxis=axis2 noframe 
      legend=legend1; 
  note h=2.25  
    move=(70,73) 'Prior' 
    move=(70,70) "Beta (&ae, &be)" 
    move=(70,67) "Mean = &me" 
    move=(70,61) 'Posterior' 
    move=(70,58) "Beta (&ae_p, &be_p)" 
    move=(70,55) "Mean = &me_p" 
    move=(70,52) "95% CR: &cr_ll, &cr_ul"; 
run; quit; 
 
 
*** Calculate posterior prob. exp ORR >= std ORR + delta ***; 
%macro suba; 
data inc; 
  retain rec 0; 
  do c=&dmin to &dmax by &dby; 
    d=c/100; 
    rec+1; 
    output; 
  end; 
run; 
%macro n_obs(ds    =, /* Dataset                 */ 
             whr   =, /* Where clause            */ 
             n_var =  /* Name of output variable */ ); 


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%global &n_var; 
data n_obs_; 
  set &ds 
    %if &whr ne %then %do; 
     (where=(&whr)) 
 
%end; ; 
data _null_; 
  dsid=open("n_obs_"); 
  nobs=attrn(dsid,"nobs"); 
  call symput("&n_var",trim(left(put(nobs,8.0)))); 
run; 
%mend n_obs; 
%n_obs(ds=inc,whr=,n_var=n_obs); 
 
%do i=1 %to &n_obs; 
  data _null_; 
    set inc (where=(rec=&i)); 
    call symput('d',trim(left(put(d,6.4)))); 
    call symput('ul',trim(left(put(1-d,6.4)))); 
  run; 
 
  proc iml; 
    start fun(x);  
      v = (1-probbeta(x+&d,&ae_p,&be_p)) * (x**(&as-1)) * ((1-x)**(&bs-
1))/&Bsc; 
      return(v); finish;  
 
    * Prob. Exp ORR >= Std + delta ; 
    lim = {0 &ul}; 
    call quad(pr,"fun",lim);  
 
    create p1 from pr  [colname='pr_d']; append from pr; close p1; 
  quit; 
  data t; set p1; d=&d+0; n=&n+0; x=&x+0; rate=x/n; run; 
 
  %if &i=1 %then %do; 
    data prs; set t; run; 
  %end; 
  %else %do; 
 
data prs; set prs t; run; 
  %end; 
%end; 
 
proc print data=prs noobs label split='\'; 
  var d pr_d; 
  title 'Posterior probability Exp ORR >= Std ORR + delta'; 
  label d='Delta' pr_d='Prob\Exp-Std ORR\>=Delta'; 
  format pr_d 8.3; 
run; 
%mend suba; 
%suba; 
 
 
*** Posterior mean and equal-tail credible interval for delta ***; 
data dat; 
  arm=2; n=&n+0; y=&x+0; 
run; 
 
ods output PostIntervals=PostInt PostSummaries=PostSum; 
*ods listing gpath="&gpath" image_dpi=150; 
*ods graphics on / imagefmt=wmf imagename="Post" reset=index width=4.5in 
height=3in;  
proc mcmc data=dat outpost=post 
    seed=11810 nbi=1000 mintune=4 maxtune=24 ntu=2000 
    nmc=50000 thin=1  


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    monitor=(_parms_ pe_pc) diagnostics=all 
    stats(alpha=&alpha)=all 
    /*plots=(trace autocorr density)*/; 
 
  parms pc pe; 
  prior pc ~ beta(&as, &bs); 
  prior pe ~ beta(&ae, &be); 
 
  pe_pc = pe - pc; 
 
  if arm=1 then llike=lpdfbin(y,n,pc);        * logL of standard *; 
  else if arm=2 then llike=lpdfbin(y,n,pe);   * logL of experimental *; 
  
  model general(llike);  
run; 
*ods graphics off; 
 
data post; 
  merge postint (where= (parameter='pe_pc') keep=parameter alpha CredibleLower 
CredibleUpper) 
        postsum (where= (parameter='pe_pc') keep=parameter mean); 
  by parameter; 
  n=&n+0; x=&x+0; rate=x/n;  
data _null_; 
  call symput('cr',trim(left(put(100-&alpha*100,8.0) ))); 
run; 
proc print data=post noobs label; 
  var parameter mean alpha CredibleLower CredibleUpper; 
  title "Delta &cr% Credible Interval"; 
run; 
%mend bayb1s; 
 
D.2 Two Stage Confidence Interval by Atkinson and Brown 
%macro cal (n1=10, /*first stage sample size*/ 
            n=, /*total number of subjects enrolled*/ 
 
 
 
c1=2, /*critical value for rejection in the first stage */ 
 
 
 
c=, /*the total number of responses observed */ 
 
 
 
alpha=0.05 /*100-alpha credible intervals*/); 
 
data m1; 
n1=&n1; 
n2=&n-n1; 
c1=&c1; 
do theta =0 to 1 by 0.0001; 
   do j= c1 to &c; 
     if j=c1 then do; y1=cdf('BINOM', c1, theta, n1); 
 
 output; 
 
 end; 
      else   do; 
      do i=c1+1 to j; 
          y1=pdf('BINOM', i, theta, n1)*pdf('BINOM', j-i, theta, n2); 
 
      output; 
 
 end; 
 
 end; 
   end; 
  end; 
run; 
 
proc sql ; 
create table sum as  
select distinct n1, n2, c1, theta, sum(y1) as sum1 
from m1  


Product:  Talimogene Laherparepvec 
Protocol Number:  20140318 
Date:  26 January 2022   
     
 
 
 
 
            Page 50 of 
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CONFIDENTIAL  
 
 
Internal Use Only General Business 
group by theta  
having calculated sum1 >= &alpha/2 
order by  theta desc 
; 
create table sum2 as  
select distinct n1, n2, c1, theta, sum(y1) as sum2 
from m1  
where j ne 5  
group by theta  
having  calculated sum2 <= (1-&alpha/2) 
; 
 
data _null_; 
set sum ; 
if _n_=1 then call symput ("Upper_Limit", theta); 
run; 
 
data _null_; 
set sum2 ; 
if _n_=1 then call symput ('Low_Limit', theta); 
run; 
 
%put &Low_Limit &Upper_Limit; 
%mend;