Clinical trial NCT02263508
Conditions: Melanoma
Keywords: Talimogene Laherparepvec pembrolizumab KEYNOTE-034 MASTERKEY-265
Sponsor: Amgen
Start date: 2014-12-08; Completion date: 2021-03-11
Enrollment: 713 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of the Phase 1b part of the study are to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in adults with previously untreated, unresectable, stage IIIB to IVM1c melanoma.

The primary objective of Phase 3 are to evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response evaluation by blinded independent central review using modified Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) and overall survival (OS).

Detailed description:

Arms: arm 1: Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. arm 2: Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. arm 3: Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
Interventions: intervention 1: Talimogene Laherparepvec intervention 2: Pembrolizumab intervention 3: Placebo
Intervention descriptions: intervention 1: Talimogene laherparepvec administered by intratumoral injection intervention 2: Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes. intervention 3: Administered by intratumoral injection

Protocol documents:
Prot_000.pdf: 
Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 1 of 171 
CONFIDENTIAL 
 
 
Title:  A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in 
Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable 
Stage IIIB to IVM1c Melanoma (MASTERKEY-265) 
Amgen Protocol Number (Talimogene Laherparepvec) 20110265 
EudraCT number 2014-000185-22 
NCT number 02263508 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: +1-805-447-1000 
Key Sponsor Contacts: 
, MD 
Senior Medical Scientist 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 
 
Email:  
 
Date: 
01 April 2014 
Amendment 1 Date: 
15 May 2015 
Amendment 2 Date: 
25 September 2015 
Amendment 3 Date: 
12 April 2017 
Amendment 4 Date: 
24 January 2018 
Amendment 5 Date 
15 January 2020 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  United States sites, 1- 800-77-AMGEN, Canadian 
sites, 1-866-50-AMGEN; for all other countries, 1-805-447-1000.   
This protocol was developed, reviewed, and approved in accordance with 
Amgen’s standard operating procedures. 
Approved 
 
 
-
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 2 of 171 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1b/3, Multicenter, Trial of Talimogene 
Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of 
Unresectable Stage IIIB to IVM1c Melanoma, dated 15 January 2020, and agree to 
abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 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) 
Approved 
 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 3 of 171 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1b/3, Multicenter Trial of Talimogene Laherparepvec in Combination With 
Pembrolizumab (MK-3475) for Treatment of Unresectable, Stage IIIB to IVM1c Melanoma 
Study Phase:  Phase 1b/3 
Indication:  Unresectable Stage IIIB to IVM1c Melanoma (American Joint Committee on Cancer 
[AJCC] 7th Edition) 
Primary Objectives: 
Phase 1b:  To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of 
talimogene laherparepvec in combination with pembrolizumab in subjects with previously 
untreated, unresectable, stage IIIB to IVM1c melanoma. 
Phase 3:  To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus 
placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response 
evaluation by blinded independent central review using modified Response Evaluation Criteria in 
Solid Tumors 1.1 [RECIST]) and overall survival (OS). 
Secondary Objectives: 
The secondary objectives are: 
Phase 1b: 
 
To evaluate the efficacy of talimogene laherparepvec in combination with pembrolizumab as 
assessed by: 
 
Confirmed objective response rate (ORR), best overall response (BOR), durable 
response rate (DRR), duration of response (DOR), disease control rate (DCR), and PFS 
(response evaluation by investigator using modified Immune-related Response Criteria 
[irRC]) 
 
OS 
 
To evaluate the safety of talimogene laherparepvec in combination with pembrolizumab as 
assessed by incidence of treatment-emergent and treatment-related adverse events (AEs), 
and abnormal laboratory tests. 
Phase 3: 
 
To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo 
with pembrolizumab, as assessed by: 
 
Complete response rate (iCRR) by blinded independent central assessed modified 
immune-related response criteria simulating response evaluation criteria in solid tumors 
(modified irRC-RECIST) 
 
iPFS by blinded independent central assessed modified irRC-RECIST 
 
OS in subjects excluding stage IVM1c per case report form (CRF) 
 
ORR, BOR, DRR, DOR, and DCR (response evaluation by blinded independent central 
review assessed using modified RECIST 1.1), and iORR, iBOR, iDRR, iDOR, and iDCR 
(response evaluation by blinded independent central review assessed using modified 
irRC-RECIST) 
 
To evaluate the safety of talimogene laherparepvec with pembrolizumab versus placebo with 
pembrolizumab, as assessed by incidence of treatment-emergent and treatment-related AEs, 
and abnormal laboratory tests. 
 
To evaluate patient reported outcomes (PRO) in phase 3 as assessed by the European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 
Core 30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) subscale. 
Approved 
 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 4 of 171 
CONFIDENTIAL 
 
 
Hypotheses: 
Phase 1b:  
Talimogene laherparepvec in combination with pembrolizumab will be safe and well tolerated in 
subjects with previously untreated, unresectable, stages IIIB to IVM1c melanoma. 
Phase 3: 
Two clinical hypotheses will be evaluated independently in the phase 3.  The first clinical 
hypothesis is that talimogene laherparepvec with pembrolizumab compared to placebo with 
pembrolizumab will improve PFS as evaluated by blinded independent central review using 
modified RECIST 1.1.  The second clinical hypothesis is that talimogene laherparepvec with 
pembrolizumab compared to placebo with pembrolizumab will improve OS. 
Primary Endpoints: 
Phase 1b: 
 
Incidence of DLT 
Phase 3: 
 
PFS (response evaluation by blinded independent central review assessed using modified 
RECIST 1.1) and OS 
Secondary Endpoints: 
Phase 1b: 
 
Confirmed ORR (Complete response [CR]+partial response [PR]) (response evaluation by 
investigator using modified irRC) 
 
BOR, DRR, DOR, PFS, and DCR (response evaluation by investigator using modified irRC) 
 
OS 
 
Incidence of treatment-emergent and treatment-related AEs (all AEs, grade ≥ 3 AEs, serious 
adverse events, fatal AEs, AEs defined as events of interest), and abnormal laboratory tests 
Phase 3: 
 
iCRR by blinded independent central review using modified irRC-RECIST 
 
iPFS by blinded independent central review using modified irRC-RECIST 
 
OS in subjects excluding stage IVM1c per CRF 
 
ORR (CR + PR), BOR, DRR, DOR, and DCR (response evaluation by blinded independent 
central review assessed using modified RECIST 1.1), and iORR (iCR + iPR), iBOR, iDRR, 
iDOR, and iDCR (response evaluation by blinded independent central review assessed using 
modified irRC-RECIST) 
 
Incidence of treatment-emergent and treatment-related AEs (all AEs, grade ≥ 3 AEs, serious 
adverse events, fatal AEs, and AEs defined as events of interest), and abnormal laboratory 
tests 
 
Changes in EORTC QLQ-C30 GHS/QoL subscale. 
Study Design: 
This is a phase 1b/3, multicenter clinical trial.  The study will be conducted in 2 parts (phase 1b 
and phase 3) as described below. 
Phase 1b: 
Phase 1b is an open-label, multicenter, single-arm study.  Talimogene laherparepvec will be 
administered in combination with pembrolizumab to approximately 20 subjects with previously 
untreated, unresectable, stage IIIB to IVM1c melanoma to evaluate the safety of talimogene 
laherparepvec in combination with pembrolizumab.  In addition, phase 1b will evaluate potential 
blood and 
 that associate with response or resistance to talimogene 
laherparepvec in combination with pembrolizumab.  
Approved 
 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 5 of 171 
CONFIDENTIAL 
 
 
Subjects will be treated with talimogene laherparepvec in combination with pembrolizumab until 
24 months from the date of the first dose of pembrolizumab or end of treatment for other reasons 
as described in Section 3.1.1.1, whichever occurs first. 
The DLT evaluation by the dose level review team (DLRT) will be based on the initial 6 to 
9 subjects meeting the DLT evaluation criteria as outlined in Section 3.1.1.1.  The DLRT will 
recommend either to enroll more subjects for DLT evaluation in phase 1b, to prematurely stop 
enrollment into phase 1b, or to declare that the combination is tolerable and whether to open 
phase 3.  However, the enrollment will not be halted while the DLT evaluation is still ongoing.  
Additional subjects, up to a total of approximately 20, will be enrolled in the phase 1b portion of 
the trial to address the secondary objective exploring the relationship between 
 
and response to treatment.  The DLRT will review additional safety data from subjects enrolled in 
phase 1b beyond the 6 to 9 DLT evaluable subjects to further assess the overall safety profile of 
talimogene laherparepvec in combination with pembrolizumab. 
Phase 3: 
The phase 3 study is a multicenter, double-blind, placebo-controlled, randomized trial to evaluate 
the efficacy, as assessed by PFS and OS of talimogene laherparepvec with pembrolizumab 
versus placebo with pembrolizumab in subjects with unresectable, stage IIIB to IVM1c melanoma.  
Approximately 660 subjects will be randomized 1:1 to receive the following: 
 
Arm 1:  talimogene laherparepvec plus pembrolizumab 
 
Arm 2:  placebo plus pembrolizumab  
Randomization will be stratified by stage of disease:  less advanced stages (IIIB, IIIC, and IVM1a) 
versus more advanced stages (IVM1b and IVM1c) and by prior serine/threonine protein kinase  
B-Raf (BRAF) inhibitor therapy:  no prior BRAF inhibitor versus BRAF inhibitor with or without 
MEK inhibitor. 
Subjects will be treated with talimogene laherparepvec in combination with pembrolizumab 
(arm 1) or placebo in combination with pembrolizumab (arm 2) until 24 months from the date of 
the first dose of pembrolizumab or end of treatment for other reasons as described in 
Section 3.1.2, whichever occurs first.   
A Data Monitoring Committee (DMC) will be responsible to review interim safety, the ORR and 
DCR futility analyses, interim efficacy and futility OS analysis, and the PFS primary analysis.  
Planned safety monitoring will occur when approximately 20 and 100 subjects have had the 
opportunity to be on treatment for at least 6 weeks from the initial dosing of study treatment in 
phase 3 and have received at least 1 dose of study therapy and approximately every 6 months 
after the DMC meeting to review the futility analysis for ORR and DCR until the later of the study 
team's unblinding or the primary analysis of OS. 
The futility analysis based on iORR and iDCR per blinded independent central review using 
modified irRC-RECIST is planned to include the first 160 subjects (80 per arm) that have been 
enrolled and have had an opportunity to be followed for the tumor assessment scheduled at 
week 24.  Interim OS analyses are planned at the time of the primary analysis of PFS, after 
282 OS events are observed, and after 315 OS events are observed.  A non-binding futility 
analysis of OS will be conducted at the 282 OS event interim analysis if the first and second 
interim OS analyses do not meet their respective criterion for statistical significance.  However, if 
282 death events are observed prior to the 407th PFS event, then the first OS interim analysis will 
occur with 282 events and include a PFS interim analysis with all PFS events.  In this case, the 
second OS interim analysis using all events will be performed at the PFS primary analysis.  For 
more details see Section 10.4.1.4. 
Safety Follow-up: 
Subjects enrolled in phase 1b and phase 3 have a safety follow-up visit approximately 
30 (+7) days after the last dose of all study treatment.  Serious adverse events observed by the 
investigators or reported by the subjects that occur within 90 (+7) days after the cessation of all 
study treatment or 30 (+7) days following cessation of treatment if the subject initiates new 
Approved 
 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 6 of 171 
CONFIDENTIAL 
 
 
anticancer therapy, whichever is earlier, will be reported, followed, and recorded as described in 
Section 9.2.1.2. 
Long-Term Follow-up: 
Subjects enrolled in phase 1b and phase 3 will be followed for survival, subsequent anticancer 
therapies, and suspected injected investigational product-related AEs approximately every 
12 weeks (± 28 days) for approximately 60 months after the last subjects are randomized in 
phase 3. 
For additional information about the study design of phase 1b and phase 3, please refer to the 
study schema at the end of protocol synopsis and Section 3.1. 
Sample Size:  Approximately 680 subjects (20 subjects will enroll in phase 1b and 660 subjects 
will enroll in phase 3). 
Summary of Subject Eligibility Criteria:  
Key Inclusion Criteria –  
Phase 1b and Phase 3: 
Male or female age ≥ 18 years with histologically confirmed diagnosis of melanoma and stage IIIB 
to IVM1c for whom surgery is not recommended.  Subjects must have measurable disease and 
be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal 
lesions.  Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 or 1, and adequate hematologic, hepatic, renal, and coagulation function.   
Phase 1b only: 
Subjects enrolled in phase 1b must be treatment naïve (ie, must not have received any prior 
systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy) 
given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma.  Subjects who 
received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to, 
radiotherapy, interferon, limb infusion/perfusion, or use of investigational agents in the adjuvant 
setting) with the exception that prior adjuvant therapy with inhibitors of programmed cell 
death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) is not allowed.  However, if the subject 
received adjuvant therapy, the subject must have completed therapy at least 3 months prior to 
enrollment.   
Phase 3 only: 
Subjects enrolled in phase 3 with serine/threonine protein kinase B-Raf V600 (BRAFV600) 
wild-type tumors must not have received any prior systemic anticancer treatment consisting of 
chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for 
unresectable stage IIIB to IVM1c melanoma.  Subjects enrolled in phase 3 with BRAFV600 
mutated tumors who have received prior BRAF inhibitor therapy either alone or in combination 
with MEK inhibitor as their only prior systemic therapy are eligible for the phase 3 of this study.  
Subjects with BRAFV600 mutant melanoma or unknown BRAFV600 mutation status who have not 
received a BRAF inhibitor are also eligible for the phase 3 of this study as first-line treatment if 
they meet the following criteria:  lactate dehydrogenase (LDH) < upper limit of normal (ULN), no 
clinically significant tumor related symptoms, and absence of rapidly progressing metastatic 
melanoma.  Subjects (BRAF mutant, wildtype and UNK) who received prior adjuvant therapy for 
melanoma will not be excluded (including, but not limited to, interferon, ipilimumab, limb 
infusion/perfusion, or use of investigational agents in the adjuvant setting) with the exception that 
prior adjuvant therapy with inhibitors of PD-1 or PD-L1 is not allowed.  However, if the subject 
received adjuvant therapy, the subject must have completed therapy at least 28 days prior to 
enrollment.  Subjects must have a tumor sample (archival sample or newly obtained biopsy) that 
is adequate for PD-L1 assessment prior to randomization. 
Approved 
 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 7 of 171 
CONFIDENTIAL 
 
 
Key Exclusion Criteria –  
Phase 1b and Phase 3: 
Subjects must not have clinically active cerebral metastases and/or carcinomatous meningitis.  
Subjects with up to 3 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 not requiring steroids, for at least 2 months prior to enrollment.  
Carcinomatous meningitis is excluded regardless of clinical stability.  Subjects must not have 
primary uveal or mucosal melanoma, history or evidence of melanoma associated with 
immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia), or 
history of other malignancy within the past 3 years with the exceptions of the prior malignancies 
noted in Section 4.1.2.  Subjects may not have been previously treated with talimogene 
laherparepvec, any other oncolytic virus, pembrolizumab, or any other inhibitor of PD-1, PD-L1, or 
programmed cell death ligand 2 (PD-L2).  Prior treatment with other immunotherapies 
(eg, anti-CD137, or cytotoxic T-lymphocyte associated antigen 4 [CTLA-4] inhibitor, or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) is allowed 
only in the adjuvant setting.  Subjects must not have history or evidence of symptomatic 
autoimmune glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented 
history of autoimmune disease or syndrome requiring systemic treatment in the past 2 years 
(ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo 
or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression.  
Subjects must not have active herpetic skin lesions or prior complications of herpetic infection 
(eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic treatment with 
an antiherpetic drug (eg, acyclovir), other than intermittent topical use. 
For a full list of eligibility criteria for phase 1b and phase 3, please refer to Section 4.1. 
Investigational Product 
Amgen Investigational Product Dosage and Administration: 
Talimogene laherparepvec (or placebo in phase 3) will be administered by intralesional injection 
into injectable cutaneous, subcutaneous, and nodal lesions with or without image ultrasound 
guidance.  Investigational product must not be administered into visceral organ metastases.  
See Section 6.2.1 for additional information regarding dosage and administration information. 
Phase 1b: 
The initial dose of talimogene laherparepvec is up to 4.0 mL of 106 plaque-forming units 
(PFU)/mL.  The second dose up to 4.0 mL of 108 PFU/mL talimogene laherparepvec should be 
administered 21 (+3) days after the initial dose.  Subsequent doses up to 4.0 mL of 108 PFU/mL 
talimogene laherparepvec should be given in phase 1 every 2 weeks (± 3) days until week 9 and 
every 3 weeks (± 3) days thereafter.  When talimogene laherparepvec and pembrolizumab are 
administered on the same day, talimogene laherparepvec should be administered first, if possible. 
Phase 3: 
The initial dose of double-blind treatment is up to 4.0 mL of 106 PFU/mL talimogene 
laherparepvec or placebo (talimogene laherparepvec formulation excipients as described in the 
Talimogene Laherparepvec Investigator’s Brochure).  The second dose up to 4.0 mL of 
108 PFU/mL talimogene laherparepvec or placebo should be administered 21 (+3) days after the 
initial dose.  Subsequent doses up to 4.0 mL of 108 PFU/mL talimogene laherparepvec or 
placebo should be given every 2 weeks (± 3) days until week 9 and every 3 weeks (± 3) days 
thereafter.  When double-blind treatment and pembrolizumab are administered on the same day, 
double-blind treatment should be administered first, if possible. 
Non-Amgen Investigational Product Dosage and Administration:   
Phase 1b: 
Pembrolizumab at a dose of 200 mg will be administered intravenously every 2 weeks (± 3 days). 
Approved 
 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 8 of 171 
CONFIDENTIAL 
 
 
Phase 3: 
Pembrolizumab at a dose of 200 mg will be administered intravenously every 3 weeks (± 3 days).  
The second dose of pembrolizumab will be administered 21 (+3) days after the initial dose.   
See Section 6.2.2 or additional information regarding dosage and administration of 
pembrolizumab. 
Procedures:  
Screening: 
Phase 1b and 3: 
The following procedures are to be completed during the screening period within 28 days of 
enrollment/randomization (unless otherwise noted) at time points designated in the Schedule of 
Assessments (Table 5 and Table 6): 
 
Confirmation that the Informed Consent Form has been signed, followed by medical and 
surgical history, demographic data, vital signs, ECOG performance status, physical 
examination including body weight as per standard of care, and electrocardiogram (ECG) 
 
Local laboratory assessments:  Hematology panel, chemistry panel, lactate dehydrogenase 
(LDH), coagulation tests, thyroid function tests, urinalysis and reflexive microscopic exam 
only for any abnormal urinalysis, serum or urine pregnancy test for female subjects of 
childbearing potential 
 
Clinical, radiographic, and photographic tumor assessment.  Note:  When a tumor lesion can 
be accurately evaluated by both radiographic imaging and clinical examination or 
photographs, radiographic imaging evaluations should be undertaken. 
 
Reporting of serious adverse events and documentation of concomitant medications 
 
Review of inclusion and exclusion criteria and registration and/or randomization in Interactive 
Voice Response system (IVRS).  
Phase 3 only: 
 
Archived tumor tissue for PD-L1 expression status testing, BRAFV600 mutation testing and 
 analyses. 
 
Biopsy for PD-L1 expression status testing, BRAFV600 mutation testing, and 
 
analyses:  Archived tumor tissue may be substituted for newly obtained fresh biopsy, if the 
archival biopsy was performed within 3 months prior to day 1 of treatment, and no systemic 
anticancer therapies were given since the archival biopsy was done.  Subjects with an 
unevaluable archival sample for PD-L1 expression testing and BRAFV600 mutation testing 
may obtain a new biopsy.  If the subject is ready to be randomized and treated after obtaining 
the new biopsy, randomization and start of treatment may proceed. 
Treatment Procedures: 
The following procedures will be completed during the treatment (at the times designated in the 
Schedule of Assessments (Table 5 and Table 6). 
 
Vital signs, physical examination, and ECOG performance status 
 
Local laboratory assessments:  hematology panel, chemistry panel, blood sample for total 
IgG, thyroid function tests, coagulation tests if clinically indicated, urinalysis and reflexive 
microscopic exam only for any abnormal urinalysis results.  Note:  Additional (eg, monthly) 
on-treatment pregnancy testing should be conducted as required per local laws and 
regulations, where applicable.   
Approved 
 
 
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AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 9 of 171 
CONFIDENTIAL 
 
 
 
Clinical, radiographic, and photographic tumor assessments, and tumor response 
assessments using modified irRC (phase 1b) or modified irRC-RECIST (phase 3).   
Note:  When a lesion can be accurately evaluated by both radiographic imaging and clinical 
examination or photographs, radiographic imaging evaluations should be undertaken. 
 
Completion of patient report outcome (PRO) questionnaires 
 
Reporting adverse events, serious adverse events, and pembrolizumab Events of Clinical 
Interest (ECI) and documentation of concomitant medications 
 
Administration of study treatment (refer to Section 6) 
Safety Follow-up Procedures: 
Upon permanent discontinuation from the study treatment for any reason, and including subjects 
who ended radiographic imaging or started new anticancer therapy, the following procedures will 
be performed approximately 30 (+7) days after the last dose of talimogene laherparepvec or the 
last dose of pembrolizumab, whichever is later, as described in the Schedule of Assessments 
(Table 5 and Table 6): 
 
Vital signs, physical examination including body weight as per standard of care, and ECOG 
performance status assessment, and ECG 
 
Local laboratory assessments:  hematology panel, chemistry panel, thyroid function tests, 
urinalysis and reflexive microscopic exam only for any abnormal urinalysis, serum or urine 
pregnancy test for female subjects of childbearing potential 
 
Clinical, radiographic, and photographic tumor assessments, and tumor response 
assessments using modified irRC (phase 1b) or modified irRC-RECIST (phase 3).  Note:  
When a tumor lesion can be accurately evaluated by both radiographic imaging and clinical 
examination or photographs, radiographic imaging evaluations should be undertaken. 
 
Completion of PRO questionnaires 
 
Reporting of nonserious adverse events (up to safety follow-up visit), serious adverse events 
(within 90 [+7] days after the cessation of all study treatment or 30 (+7) days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier), 
and documentation of concomitant medications 
Note:  If an end of treatment decision occurs > 30 (+7) days after the last treatment date, then the 
safety follow-up visit should be performed as soon as possible (eg, within a week of the end of 
treatment decision). 
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, initiation of additional 
melanoma therapy, and whether any injected investigational product-related AE has occurred.  
Contact for all subjects will be attempted every 12 weeks (± 28 days) following the safety 
follow-up visit until death, subject withdraws full consent, or up to 60 months after the end of 
randomization of phase 3.  The sponsor may request survival status to be assessed at additional 
time points during the course of the study. 
Clinical, radiographic, photographic tumor assessments, and tumor response assessment per 
modified irRC (phase 1b) or modified irRC-RECIST (phase 3) and completion of PRO 
questionnaires will be performed every 12 weeks (+1 week) until a documented confirmed 
progressive disease (PD) per modified irRC (phase 1b) or iPD per modified irRC-RECIST 
(phase 3), start of new anticancer treatment, death, or end of study, whichever occurs first.  For 
subjects with progressive disease (see footnote cc of Table 6), QLQ-C30 will no longer be 
collected, and EuroQoL-5D-3 Level (EQ-5D-3L) will be collected through the long-term follow-up. 
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Blood for anti-pembrolizumab antibody and blood for PK of pembrolizumab will be collected at 
3 and 6 months after study discontinuation or up until the subject starts new anticancer therapy, 
whichever occurs first.  Antibody and PK sample collection may be discontinued if ongoing 
antibody and PK results from this study continue to be consistent with existing data from other 
pembrolizumab melanoma clinical trials.  
All subjects treated with talimogene laherparepvec (all subjects in phase 1b and those who 
received talimogene laherparepvec in phase 3) and who permanently discontinue study will be 
eligible to continue follow-up for survival under an ongoing separate registry protocol that is in 
place for the long-term follow-up of subjects treated with talimogene laherparepvec in clinical 
trials.  The registry protocol, including for phase 1b subjects, will not apply until the end of the 
study or 5 years after the last subject is enrolled in phase 3, whichever comes first.  The registry 
protocol will also monitor for late and long-term adverse events thought to be potentially related to 
talimogene laherparepvec. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 5 and Table 6). 
Statistical Considerations: 
Phase 1b: 
Sample size considerations: 
For phase 1b, 6 to 9 evaluable subjects will be required to assess the DLT profile of talimogene 
laherparepvec in combination with pembrolizumab.  Additional subjects, to a total of 20, will be 
enrolled in the phase 1b portion of the trial to address the secondary objective exploring the 
relationship between 
 and response to treatment. 
Planned method of analyses: 
The efficacy and safety data will be summarized separately for phase 1b and phase 3. 
The phase 1b safety analysis is planned when there are 6 to 9 DLT evaluable subjects. 
For phase 1b, besides a summary of the incidence of DLTs, descriptive statistics will be provided 
for demographics, safety, efficacy, and 
 as appropriate.   
Treatment effects in efficacy endpoints in phase 3 will be according to the treatment group as 
randomized.  Frequency and percent of subjects for binary and categorical efficacy endpoints will 
be summarized by treatment arm.  Proportions and 95% confidence interval using a normal 
approximation will also be provided.  Treatment comparisons will be based on 
Cochran-Mantel-Haenszel test.  Exact tests will be used for subgroup analyses when cell sizes 
are too small.  Analysis of time-to-event endpoints will be based on K-M estimation.  Hazard 
ratios (HRs) will be estimated using Cox proportional hazards (PH) model. 
Phase 3: 
Sample size considerations: 
There are 2 primary endpoints, PFS and OS, in phase 3.  The hypothesized reduction of 
1/3 hazard for PFS (talimogene laherparepvec and pembrolizumab / pembrolizumab and 
placebo) is equivalent to an HR of 0.67 and the hypothesized HR for OS is 0.70.  Initial allocation 
of significance level, overall 2-sided 0.05, is 2-sided 0.005 for PFS and 2-sided 0.045 for OS.  
The event goal for PFS to achieve 90% power at 2-sided 0.005 is 407.  The event goal for OS 
adjusted for 4 group sequential analyses to achieve 90% power at a 2-sided 0.045 is 346.  The 
sample size is 660 subjects (ie, 330 per arm) based on an estimate of 346 death events occurring 
within 5 years (60 months). 
Planned method of analyses: 
The primary analysis of PFS will be based on tumor assessments per the blinded independent 
central review using modified RECIST 1.1.  For analyses of the 2 primary endpoints PFS and OS, 
a stratified log-rank test will be used as the primary method for testing the null hypothesis of no 
treatment difference.  The stratification factors will include randomization factors per IVRS and 
PD-L1 status at baseline (positive vs not positive).  Hazard ratios will be estimated using the Cox 
proportional hazards (PH) model stratified by randomization factors per IVRS and the baseline 
PD-L1 status (positive vs not positive).  Multiple statistical testing for the dual primary endpoints 
Approved 
 
 
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Date:  15 January 2020 
Page 11 of 171 
CONFIDENTIAL 
 
 
and the 3 secondary endpoints of iCRR, iPFS, and OS in subjects excluding disease stage IVM1c 
will follow a graphic-based, multiple group sequential hypotheses testing procedure  
(Maurer and Bretz, 2013) to ensure a strong control of an overall Type I error of 0.05 (see 
Section 10.5).  The information fraction will be based on the number of events included in the 
respective analysis for all time to event endpoints, and it will be based on the number of subjects 
with potential follow-up of at least 36 weeks for iCRR.  The nominal alpha will be transitioned to 
test hypotheses for the 3 secondary endpoints if either the primary endpoint of PFS or OS is 
statistically significant. 
Two interim safety analyses are planned to evaluate the safety of talimogene laherparepvec in 
combination with pembrolizumab in the target population for the phase 3.  Planned safety 
monitoring will occur when approximately 20 and 100 total subjects, respectively, have had the 
opportunity to be on treatment for at least 6 weeks from the initial dosing of study treatment in 
phase 3 and have received at least 1 dose of study therapy.   
The Bayesian method will be used for the futility analysis when assessing iORR and iDCR by 
blinded independent central review using modified irRC-RECIST.  The iORR futility criterion will 
be a posterior probability < 0.65 of at least a 6% absolute iORR increase (pembrolizumab and 
talimogene laherparepvec arm – placebo plus pembrolizumab arm), and the iDCR futility criterion 
will be a posterior probability < 0.75 of at least a 10% absolute DCR increase.  The interim futility 
analysis will be reviewed by the DMC, and the DMC will declare the combination therapy futile if 
both the iORR and iDCR futility criteria are met; however, the DMC’s recommendation will be 
non-binding and therefore the sponsor will make the final decision to terminate the study 
prematurely.  
At the time of the PFS primary analysis, an interim efficacy OS analysis will be performed.  The 
second interim OS analysis is planned after 282 events for efficacy and futility.  The interim OS 
futility analysis will be non-binding and define futility as a conditional power < 10% assuming a 
constant treatment effect; however, futility will also be similarly defined by considering a possible 
non-constant treatment effect that increases over time.  The order for the event-driven OS interim 
and PFS primary analyses may not be as anticipated due to incorrect design assumptions.  If 
282 OS events are observed prior to 407 PFS events, the first event-driven analysis will be an OS 
interim with 282 OS events and a PFS interim using all events.  The third interim OS analysis 
for efficacy is planned after 315 events are observed. 
The remaining secondary endpoints of ORR, iORR, DCR, iDCR, DRR, and iDRR will be 
summarized by treatment arm with associated 95% CI.  DOR and iDOR among responders will 
be estimated by treatment group using the Kaplan-Meier method.  Analyses of response 
endpoints will be performed first according to the blinded independent central review assessment 
using modified RECIST and modified irRC-RECIST, respectively.  Following the intent-to-treat 
principle, subjects who do not have any follow up tumor assessments will be determined as 
non-completeresponders.  Analysis for the PRO related endpoints will be descriptive.  Safety data 
including laboratory test results, vital signs and treatment-emergent adverse events will be 
summarized by treatment arms. 
 
  The analyses of exploratory PRO endpoints are described in Section 10.5.5.  
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   
 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 12 of 171 
CONFIDENTIAL 
 
 
Phase 1b Study Design and Treatment Schema 
E
N
R
O
L
L
M
E
N
T
Talimogene 
laherparepvec 
Monotherapy
For 2 Cycles
S
C
R
E
E
N
I
N
G
S
A
F
E
T
Y
F
O
L
L
O
W
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p
 
               
        
                  
28 Days
                
   
           30 (+7) days     Every 12                                                
     
       after end of Rxb      weeksc                                                 
/__________/  /_____________________________________________________________________/ /________________________________________________________________/  /___________//  /______ _//
Talimogene 
laherparepvec 
+
Pembrolizumab
Cycle 3 and 
beyond
Treatment until CR,
no injectable lesion (T-VEC 
only), PD, AE, or 
up to 24 months
B
A
S
E
L
I
N
  E a
L
O
N
G
T
E
R
M  
F
O
L
L
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Consent, Screening                                                    
 Treatment                  
             
                      
     Follow-up Phase             
Enrollment
/__________/   /_______________________________________________________________________________________________________________________________/  /_______________________/
 
AE = adverse event requiring permanent discontinuation of study treatment; CR = complete response; PD = progressive disease; Rx = treatment; 
T-VEC = talimogene laherparepvec 
a Subject will undergo clinical, photographic, and radiographic tumor assessments after 2 cycles of talimogene laherparepvec and prior to start of 
pembrolizumab. 
b Subjects will be followed up for SAEs until 90 (+ 7) days after the last dose of talimogene laherparepvec or the last dose of pembrolizumab, whichever is 
later. 
c Long-term follow-up every 12 weeks (± 28 days) until approximately 60 months after last subject enrolled in phase 3. 
 
Approved 
 
 
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i 
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q: 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 13 of 171 
CONFIDENTIAL 
 
 
Phase 3 Study Design and Treatment Schema 
 
 
 
AE = adverse event requiring permanent discontinuation of study treatment; CR = complete response; PD = progressive disease; Rx = treatment; 
T-VEC = talimogene laherparepvec 
a Subjects will be followed up for SAEs until 90 (+ 7) days after the last dose of talimogene laherparepvec or the last dose of pembrolizumab, whichever is 
later. 
b Long-term follow-up every 12 weeks (± 28 days) until approximately 60 months after last subject enrolled in phase 3. 
 
Approved 
 
 
Consent, 
Screening, 
Randomization 
-
--
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R 
A 
s 
N 
C 
D 
R 
0 
E i-. M ~ 
E 
I 
N 
z 
I 
A 
N 
T 
G 
I 
0 
N 
.... 
-
--
28 Days 
Arm 1 
Talimogene 
laherparepvec 
+ 
Pembrolizumab 
Arm 2 
Pembrolizumab 
+ 
Placebo 
Treatment 
Treatment until CR, 
no injectable lesions, PD, 
AE, or up to 24 months 
E 
N 
D 
0 
F 
T 
R 
E 
A 
T 
M 
Treatment until CR, no 
E 
injectab le lesions, PD, AE, 
N 
or up to 
T 
24 months 
Follow-up Phase 
s 
A 
F 
E 
T 
y 
F 
~ 
0 
L 
L 
0 w 
u 
p 
30 (+ 7) days 
atter end of Rx" 
L 
0 
N 
G 
T 
E 
R 
M 
F 
0 
L 
L 
0 w 
u 
p 
Every 12 
weeks' 
____ / / ____________________________________ //. ______________ _ 
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 14 of 171 
 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term Definition/Explanation 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ALT 
alanine aminotransferase  
AST  
aspartate aminotransferase   
BRAFV600 
serine/threonine protein kinase B-Raf V600 
BOR 
best overall response 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CRF  
case report form 
CNS 
central nervous system 
CR 
complete response 
CRR 
complete response rate 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte associated antigen 4 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DLRT 
Dose Level Review Team 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
DRR 
durable response rate 
ECG 
electrocardiogram 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
End of Follow-up 
defined as when the last subject completes the last protocol-specified 
safety or long-term follow-up assessment in the study, whichever is later   
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are conducted 
for an individual subject 
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CONFIDENTIAL 
 
 
Abbreviation or Term Definition/Explanation 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for the primary endpoint(s), for the purpose of conducting 
the primary analysis, whether the study concluded as planned in the 
protocol or was terminated early. 
End of Study (end of 
trial) 
defined as the date when the last subject across all sites is assessed or 
receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up), 
as applicable.   
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-3L 
EuroQoL-5D-3 Level 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GHS 
Global Health Status 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
GMI 
Growth Modulation Index 
H 
hypothesis 
HR 
hazard ratio 
HSU 
health state utility 
HSV, HSV-1 
herpes simplex virus, herpes simplex virus type 1 
iBOR 
best overall response (by modified irRC-RECIST) 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
iCR 
complete response (by modified irRC-RECIST) 
iCRR 
complete response rate (by modified irRC-RECIST) 
iDCR 
disease control rate (by modified irRC-RECIST) 
iDOR 
duration of response (by modified irRC-RECIST) 
iDRR 
durable response rate (by modified irRC-RECIST) 
ILD 
interstitial lung disease 
INR 
international normalization ratio 
iORR 
objective response rate (by modified irRC-RECIST) 
iPD 
progressive disease (by modified irRC-RECIST) 
iPFS 
progression-free survival (by modified irRC-RECIST) 
IPIM 
Investigational Product Instruction Manual 
iPR 
partial response (by modified irRC-RECIST) 
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CONFIDENTIAL 
 
 
Abbreviation or Term Definition/Explanation 
irAE 
immune-related adverse event 
IRB/IEC 
institutional review board/independent ethics committee 
irRC 
Immune-related Response Criteria 
irRC-RECIST 
Immune-related Response Criteria (irRC) simulating Response 
Evaluation Criteria in Solid Tumors (RECIST)  
iSD 
stable disease (by modified irRC-RECIST) 
iUE 
unevaluable (by modified irRC-RECIST) 
Interactive Voice 
Response (IVR) 
telecommunication technology that is linked to a central computer in real 
time as an interface to collect and process information.   
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
MRI 
magnetic resonance imaging 
mOS 
median overall survival 
MPR 
minor partial response 
MTD 
maximum tolerated dose 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed cell death-1 ligand 1 
PD-L2 
programmed cell death-1 ligand 2 
PET 
positron emission tomography 
PES 
polyethersulfone 
PFS 
progression-free survival 
PFU 
plaque-forming unit 
PK 
pharmacokinetics 
PR 
partial response 
PRO 
patient reported outcome 
PT 
prothrombin time 
PTT/aPTT 
partial thromboplastin time/activated partial thromboplastin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QoL 
quality of life 
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CONFIDENTIAL 
 
 
Abbreviation or Term Definition/Explanation 
QLQ-C30 
Quality of Life Questionnaire Core 30 
qPCR 
real-time polymerase chain reaction 
RECIST 
Response Evaluation Criteria in Solid Tumor 
RBC 
red blood cell 
SAE 
serious adverse event 
SD 
stable disease 
Source Data 
information from an original record or certified copy of the original record 
containing patient information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in 
source documents (original records or certified copies).  (ICH Guideline 
[E6]).  Examples of source data include subject identification, 
randomization identification, and stratification value. 
SPD 
the sum of the products of the two largest perpendicular diameters 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol required therapies is/are administered to the subject 
T3 
triiodothyronine 
TID 
Trial Integrity Document 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
UE 
unevaluable 
USA 
United States of America 
VAS 
visual analogue scale 
WBC 
white blood cell 
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CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Phase 1b Study Design and Treatment Schema ........................................................... 12 
Phase 3 Study Design and Treatment Schema ............................................................. 13 
Study Glossary .............................................................................................................. 14 
1. 
OBJECTIVES ....................................................................................................... 24 
1.1 
Primary ..................................................................................................... 24 
1.2 
Secondary ................................................................................................. 24 
1.3 
Exploratory ................................................................................................ 25 
2. 
BACKGROUND AND RATIONALE ...................................................................... 26 
2.1 
Melanoma and Programmed Cell Death 1 (PD-1) Receptor 
Inhibitor ..................................................................................................... 26 
2.2 
Talimogene Laherparepvec Background ................................................... 27 
2.3 
Pembrolizumab Background ..................................................................... 30 
2.4 
Rationale for Combination Therapy of Talimogene 
Laherparepvec and Pembrolizumab .......................................................... 32 
2.5 
Clinical Hypotheses ................................................................................... 34 
3. 
EXPERIMENTAL PLAN ........................................................................................ 35 
3.1 
Study Design ............................................................................................. 35 
3.1.1 
Phase 1b Study Design ............................................................. 35 
3.1.1.1 
Rules for DLT Evaluation in Phase 1b ..................... 36 
3.1.1.2 
Definition of DLT in Phase 1b .................................. 37 
3.1.2 
Phase 3 Study Design ............................................................... 38 
3.1.3 
Tumor Response Assessment ................................................... 40 
3.1.3.1 
Phase 1b Tumor Response Assessment ................. 41 
3.1.3.2 
Phase 3 Tumor Response Assessment................... 42 
3.1.3.3 
Subject Management After Radiographic 
Progression During Phase 3 .................................... 44 
3.1.4 
Follow-up ................................................................................... 46 
3.1.4.1 
Safety Follow-up ..................................................... 46 
3.1.4.2 
Long-term Follow-up ............................................... 46 
3.2 
Number of Sites ........................................................................................ 47 
3.3 
Number of Subjects ................................................................................... 47 
3.4 
Replacement of Subjects .......................................................................... 48 
3.5 
Estimated Study Duration .......................................................................... 48 
3.5.1 
Study Duration for Subjects ....................................................... 48 
3.5.2 
End of Study .............................................................................. 48 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 49 
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4.1 
Inclusion and Exclusion Criteria ................................................................ 49 
4.1.1 
Inclusion Criteria ........................................................................ 49 
4.1.1.1 
Inclusion Criteria for Phase 1b and 
Phase 3 ................................................................... 49 
4.1.1.2 
Inclusion Criteria Specific to Phase 1b .................... 50 
4.1.1.3 
Inclusion Criteria Specific to Phase 3 ...................... 51 
4.1.2 
Exclusion Criteria – Phase 1b and Phase 3 ............................... 52 
5. 
SUBJECT ENROLLMENT .................................................................................... 55 
5.1 
Randomization During Phase 3 ................................................................. 55 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 56 
6. 
TREATMENT PROCEDURES .............................................................................. 57 
6.1 
Classification of Products .......................................................................... 57 
6.2 
Investigational Products ............................................................................ 57 
6.2.1 
Amgen Investigational Product:  Talimogene 
Laherparepvec or Placebo ........................................................ 57 
6.2.1.1 
Talimogene Laherparepvec or Placebo 
Dosage, Administration, and Schedule .................... 57 
6.2.1.2 
Talimogene Laherparepvec or Placebo 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 60 
6.2.2 
Non-Amgen Investigational Product:  Pembrolizumab ............... 62 
6.2.2.1 
Pembrolizumab Dosage, Administration, 
and Schedule .......................................................... 62 
6.2.2.2 
Pembrolizumab Dosage Adjustments, 
Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ................... 64 
6.2.2.3 
Rescue Medications and Supportive Care 
Guidelines for Pembrolizumab ................................ 69 
6.2.2.4 
Diet and Other Considerations While 
Taking Pembrolizumab ............................................ 72 
6.3 
Other Protocol-required Therapies ............................................................ 72 
6.4 
Concomitant Therapy ................................................................................ 73 
6.5 
Other Treatment Procedures ..................................................................... 73 
6.6 
Medical Devices ........................................................................................ 74 
6.7 
Product Complaints ................................................................................... 74 
6.8 
Excluded Treatments and/or Procedures During Study Period .................. 74 
7. 
STUDY PROCEDURES ....................................................................................... 75 
7.1 
Schedule of Assessments ......................................................................... 75 
7.2 
General Study Procedures ........................................................................ 88 
7.2.1 
Screening, Enrollment (Phase 1b) and Randomization 
(Phase 3) .................................................................................. 89 
7.2.2 
Treatment Period ....................................................................... 92 
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7.2.3 
Safety Follow-up Visit ................................................................ 99 
7.2.4 
Long-term Follow-up ................................................................ 102 
7.2.5 
Reporting Unintended Exposure to Talimogene 
Laherparepvec in Phase 1b and Phase 3 ................................ 103 
7.3.1 
Blood Samples ........................................................................ 104 
7.3.2 
Archived Tumor Tissue Sample ............................................... 104 
..... 104 
7.4 
Pharmacogenetic Studies ....................................................................... 104 
7.5 
Sample Storage and Destruction ............................................................. 104 
7.6 
Patient Reported Outcomes .................................................................... 106 
7.6.1 
EORTC QLQ-C30 ................................................................... 106 
7.7 
Health State Utility Estimates .................................................................. 106 
7.7.1 
EQ-5D-3L ................................................................................ 106 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ................ 107 
8.1 
Subjects’ Decision to Withdraw ............................................................... 107 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion .................................... 108 
8.3 
Reasons for Removal From Treatment, or Study .................................... 108 
8.3.1 
Reasons for Removal From Treatment .................................... 108 
8.3.2 
Reasons for Removal From Study ........................................... 109 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ..................... 109 
9.1 
Definition of Safety Events ...................................................................... 109 
9.1.1 
Adverse Events ....................................................................... 109 
9.1.2 
Serious Adverse Events .......................................................... 110 
9.2 
Safety Event Reporting Procedures ........................................................ 110 
9.2.1 
Adverse Events ....................................................................... 110 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria .......................... 110 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ................................................................... 112 
9.3 
Pregnancy and Lactation Reporting ........................................................ 113 
9.4 
Reporting of Unintended Exposure to Talimogene 
Laherparepvec or Placebo ...................................................................... 114 
9.5 
Pembrolizumab Events of Clinical Interest (ECI) ..................................... 115 
9.6 
Definition of an Overdose of Pembrolizumab for This Protocol 
and Reporting of Pembrolizumab Overdose ............................................ 116 
10. 
STATISTICAL CONSIDERATIONS .................................................................... 116 
10.1 
Study Endpoints, Analysis Sets, and Covariates ..................................... 116 
10.1.1 
Study Endpoints ...................................................................... 116 
10.1.1.1 
Primary Endpoints ................................................. 116 
10.1.1.2 
Secondary Endpoints ............................................ 116 
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CONFIDENTIAL 
 
 
10.1.1.3 
Exploratory Endpoints ........................................... 117 
10.1.2 
Analysis Sets ........................................................................... 117 
10.1.3 
Covariates and Subgroups ...................................................... 118 
10.2 
Sample Size Considerations ................................................................... 119 
10.2.1 
Sample Size Considerations for Phase 1b ............................... 119 
10.2.2 
Sample Size Considerations for Phase 3 ................................. 120 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ........................................................................................... 122 
10.4 
Planned Analyses ................................................................................... 123 
10.4.1 
Interim Analyses ...................................................................... 123 
10.4.1.1 
DLT Safety Analysis (Phase 1b) ............................ 123 
10.4.1.2 
Interim Safety Analysis (Phase 3) .......................... 123 
10.4.1.3 
Interim iORR and iDCR Futility Analysis 
(Phase 3) .............................................................. 123 
10.4.1.4 
Interim Efficacy and Futility Analysis 
(Phase 3) .............................................................. 124 
10.4.2 
Dose Level Review Team (DLRT) ........................................... 129 
10.4.3 
Data Monitoring Committee (DMC) .......................................... 129 
10.4.4 
Primary Analysis ...................................................................... 129 
10.4.4.1 
Primary Analysis Phase 1b .................................... 129 
10.4.4.2 
Primary Analysis Phase 3...................................... 130 
10.4.5 
Final Analysis .......................................................................... 130 
10.5 
Planned Methods of Analysis .................................................................. 130 
10.5.1 
Multiple Hypothesis Testing Procedures and 
Multiplicity Adjustment ............................................................. 131 
10.5.2 
Primary Endpoint ..................................................................... 132 
10.5.2.1 
Phase 1b ............................................................... 132 
10.5.2.2 
Phase 3 ................................................................. 132 
10.5.3 
Secondary Efficacy Endpoints ................................................. 133 
10.5.4 
Safety Endpoints ..................................................................... 133 
10.5.5 
Patient Reported Outcome Endpoints and Analyses ............... 134 
10.5.6 
Health State Utility Estimates .................................................. 135 
11. 
REGULATORY OBLIGATIONS .......................................................................... 135 
11.1 
Informed Consent .................................................................................... 135 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 136 
11.3 
Subject Confidentiality ............................................................................. 136 
11.4 
Investigator Signatory Obligations ........................................................... 137 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 137 
12.1 
Protocol Amendments and Study Termination ........................................ 137 
12.2 
Study Documentation and Archive .......................................................... 137 
12.3 
Study Monitoring and Data Collection ..................................................... 138 
12.4 
Investigator Responsibilities for Data Collection ...................................... 139 
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12.5 
Language ................................................................................................ 140 
12.6 
Publication Policy .................................................................................... 140 
12.7 
Compensation ......................................................................................... 141 
13. 
REFERENCES ................................................................................................... 142 
14. 
APPENDICES .................................................................................................... 146 
List of Tables 
Table 1.  Imaging and Treatment After First Evidence of iPD ........................................ 45 
Table 2.  Talimogene Laherparepvec or Placebo Injection Volume Guideline 
Based on Tumor Size ............................................................................. 59 
Table 3.  Pembrolizumab-related Adverse Event Management ..................................... 64 
Table 4.  Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines .............................................................................................. 70 
Table 5.  Schedule of Assessments for Phase 1b .......................................................... 76 
Table 6.  Schedule of Assessments for Phase 3 – Arms 1 and 2 ................................... 82 
Table 7.  Laboratory Analytes ........................................................................................ 88 
Table 9.  Timing of Primary Analysis for PFS (at 407 events) and OS 
(at 346 events)...................................................................................... 121 
Table 10.  Hypothesized Effect Sizes and Hypothesis Test Powers ............................ 122 
Table 11.  Study Analyses and Possible Hypothesis Tests .......................................... 126 
Table 12.  Analysis Timing, Nominal Significance Levels, and Boundary 
Properties ............................................................................................. 128 
Table 13.  Definition of Measurable Tumor Response ................................................. 159 
Table 14.  Matrix for Determining the Overall Response at Each Assessment 
Point ..................................................................................................... 160 
Table 15.  Definition of Measurable Tumor Response (Baseline Target and 
New, Measurable Lesions) ................................................................... 167 
Table 16.  Matrix for Determining the Overall Response at Each Assessment 
Point ..................................................................................................... 168 
List of Figures 
Figure 1.  Progression-free Survival ............................................................................ 120 
Figure 2.  Overall Survival ........................................................................................... 121 
Figure 3.  Initial Graph of Maurer-Bretz Multiple Testing Procedure ............................. 132 
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List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 147 
Appendix B.  Sample Serious Adverse Event Report Form ......................................... 148 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 153 
Appendix D.  Modified Immune-related Response Criteria (irRC) for Review 
of Disease Response in Phase 1b ........................................................ 155 
Appendix E.  Eastern Cooperative Oncology Group Performance Status 
Scale .................................................................................................... 162 
Appendix F.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response in Phase 3 ............................................................................ 163 
Appendix G.  Modifications to Conventional RECIST Guidelines for 
Assessment of Disease Response in Phase 3 ...................................... 171 
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1. 
OBJECTIVES 
1.1 
Primary 
The primary objectives are: 
Primary Objectives: 
Phase 1b:   
 
To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of 
talimogene laherparepvec in combination with pembrolizumab in subjects with 
previously untreated, unresectable, stage IIIB to IVM1c melanoma. 
Phase 3: 
 
To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus 
placebo with pembrolizumab, as assessed by progression-free survival (PFS) 
(response evaluation by blinded independent central review using modified 
Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival 
(OS). 
1.2 
Secondary 
The secondary objectives are: 
Phase 1b: 
 
To evaluate the efficacy of talimogene laherparepvec in combination with 
pembrolizumab as assessed by: 
 
Confirmed objective response rate (ORR), best overall response (BOR), durable 
response rate (DRR), duration of response (DOR), disease control rate (DCR), 
and PFS (response evaluation by investigator using modified immune-related 
Response Criteria [irRC]) 
 
OS 
 
To evaluate the safety of talimogene laherparepvec in combination with 
pembrolizumab as assessed by incidence of treatment-emergent and 
treatment-related adverse events, and abnormal laboratory tests. 
Phase 3: 
 
To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus 
placebo with pembrolizumab, as assessed by: 
 
Complete response rate (iCRR) by blinded independent central assessed 
modified immune-related response criteria simulating response evaluation criteria 
in solid tumors (modified irRC-RECIST) 
 
iPFS by blinded independent central assessed modified irRC-RECIST 
 
OS in subjects excluding stage IVM1c per case report form (CRF) 
 
ORR, BOR, DRR, DOR, and DCR (response evaluation by blinded independent 
central review assessed using modified RECIST 1.1), and iORR, iBOR, iDRR, 
iDOR, and iDCR by blinded independent central review assessed using modified 
irRC-RECIST) 
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 
To evaluate the safety of talimogene laherparepvec with pembrolizumab versus 
placebo with pembrolizumab, as assessed by incidence of treatment-emergent and 
treatment-related adverse events, and abnormal laboratory tests. 
 
To evaluate patient reported outcomes (PRO) in phase 3 as assessed by the 
European Organization for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life 
(GHS/QoL) subscale. 
1.3 
Exploratory 
The exploratory objectives are: 
Phase 1b: 
 
To evaluate whether talimogene laherparepvec induces changes in PD-L1 
expression by immunohistochemistry (eg, negative to positive) in injected and 
non-injected lesions after starting talimogene laherparepvec in subjects whose 
tumors are PD-L1-negative prior to receiving talimogene laherparepvec in phase 1b. 
Phase 3: 
 
iORR, iBOR, iDRR, iDOR, iDCR, and iPFS (response evaluation by 
investigator-assessed modified irRC-RECIST). 
 
To evaluate the incidence of anti-pembrolizumab antibodies when pembrolizumab is 
administered in combination with talimogene laherparepvec or placebo. 
 
To evaluate the pharmacokinetics (PK) of pembrolizumab when administered in 
combination with talimogene laherparepvec or placebo. 
 
To evaluate PROs as assessed by the EORTC QLQ-C30 subscales. 
 
To estimate health state utility (HSU) values using the EuroQoL-5D-3 Level 
(EQ-5D-3L). 
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2. 
BACKGROUND AND RATIONALE 
2.1 
Melanoma and Programmed Cell Death 1 (PD-1) Receptor Inhibitor 
In adults, cutaneous melanoma is the fifth most common cancer in men and the seventh 
most common cancer in women in the United States of America (USA), with an 
estimated 76,100 new cases and 9,710 deaths expected in 2014 (Siegel et al, 2014).  In 
Europe, the annual incidence of melanoma is somewhat lower than that in the USA, with 
a crude rate of approximately 13.5 per 100,000 as compared with 21.9 per 100,000 in 
the USA, but is the seventh most common cancer among women (Ferlay et al, 2013; 
Siegel et al, 2014).  In Europe as a whole, approximately 100,442 new cases were 
diagnosed in 2012 (Ferlay et al, 2013).  The incidence of melanoma is increasing rapidly 
worldwide, with a 270% increase in the USA between 1973 and 2002.  This increase is 
the most rapid of any cancer with the exception of lung cancer in women 
(Jemal et al, 2006; Ries et al, 2000). 
Cancer has developed multiple mechanisms to successfully avoid recognition by the 
immune-system and resultant antitumor effector functions, thus limiting the benefits of 
cancer immunotherapies (Whiteside, 2006).  Therapeutic strategies have recently been 
developed to overcome a tumor’s ability to protect itself from targeted immune response.  
Antibodies that block the inhibitory receptor cytotoxic T-lymphocyte associated antigen 
4 (CTLA-4), such as ipilimumab, have been shown to release one of these negative 
immune regulatory pathways, leading to durable responses in a subgroup of patients 
with metastatic melanoma and an OS benefit in patients with metastatic melanoma 
(Robert et al, 2011; Hodi et al, 2010). 
The programmed cell death-1 (PD-1) receptor is another inhibitory receptor 
expressed by T cells.  Its primary ligand, programmed cell death-1 ligand 1 (PD-L1), 
is frequently expressed within the tumor microenvironment, including cancer cells and 
tumor-infiltrating macrophages.  The PD-1 receptor has a second ligand, programmed 
cell death-1 ligand 2 (PD-L2), which is preferentially expressed by antigen-presenting 
cells (Pardoll, 2012).  In tumor models, PD-1 negatively regulates the effector phase of 
T-cell responses after ligation of PD-L1 expressed by the tumor (Blank et al, 2004).  It 
has been postulated that antibodies that block the interaction between PD-1 and PD-L1 
in tumors may preferentially release the cytotoxic function of tumor-specific T cells 
with fewer systemic toxic effects than those that are seen with other immune 
checkpoint inhibitors (Pardoll, 2012; Ribas; 2012; Okazaki and Honjo, 2007).  Inhibitory 
antibodies targeted to PD-1 and PD-L1 have demonstrated objective responses in 
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multiple tumor types including melanoma (Robert et al, 2015; Hamid et al, 2013; 
Brahmer et al, 2012; Topalian et al, 2012).  Anti-PD-1 antibodies have also been 
shown to improve overall survival in melanoma (Larkin et al, 2019;  
Robert et al, 2019).  The combination of PD-1 blockade with nivolumab and CTLA-4 
blockade with ipilimumab has resulted in significantly longer progression free survival 
and overall survival than ipilimumab but was associated with a high rate of grade 3 or 
4 adverse events (Larkin et al, 2019; Larkin et al, 2015). 
2.2 
Talimogene Laherparepvec Background 
Talimogene laherparepvec is an intralesionally delivered oncolytic immunotherapy 
comprised of a genetically engineered herpes simplex virus type 1 (HSV-1) that 
selectively replicates in tumor tissue (Talimogene Laherparepvec Investigator’s 
Brochure).  The genes encoding neurovirulence factor ICP34.5 and ICP47 are 
functionally deleted in the virus, while the gene for human granulocyte macrophage 
colony-stimulating factor (GM-CSF) is inserted. 
The ICP34.5 functional deletion allows the virus to replicate selectively in tumors.  The 
deletion of ICP47 prevents its function of blocking the transporter associated with 
antigen processing 1 and 2 and subsequent antigen presentation on major 
histocompatibility complexes I and II.  ICP47 deletion 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. 
In the open-label, randomized, phase 3 study of talimogene laherparepvec versus 
subcutaneously administered GM-CSF in stage IIIB, IIIC, and IV unresectable 
melanoma, talimogene laherparepvec or GM-CSF was administered until complete 
response (CR), clinically significant PD, intolerable side effects, 12 months of therapy 
without an objective response, or withdrawal of consent (OPTiM study, Study 005-05).  
The primary endpoint of the study was DRR, defined as the rate among subjects with an 
objective response (CR or partial response [PR]) lasting continuously for 6 months and 
starting any time within 12 months of initiating therapy.  Primary analysis of the OPTiM 
study showed a statistically significant difference between the rate of durable response 
among subjects treated with talimogene laherparepvec (16%; 95% confidence interval 
[CI]:  12%, 21%) versus those treated with GM-CSF (2%; 95% CI:  0%, 5%) (p-value 
< 0.0001).  Responses were seen in injected, non-injected, and visceral lesions.  A 
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difference in the secondary endpoint of OS was also seen with a hazard ratio (HR) of 
0.79 (95% CI:  0.62-1.00), p = 0.051.  Median OS of subjects treated with talimogene 
laherparepvec was 4.4 months longer than those treated with GM-CSF (23.3 months for 
talimogene laherparepvec versus 18.9 months for GM-CSF) (Kaufman et al, 2014).  
Survival at 1, 2, 3, and 4 years in the talimogene laherparepvec arm was estimated to be 
74%, 50%, 39% and 33%, respectively, and 69%, 40%, 30% and 21% in the GM-CSF 
arm, respectively.  Median (range) time to response among the 78 subjects in the 
talimogene laherparepvec arm with a response was 4.1 (1.2 to 16.7) months, whereas 
among the 8 in the GM-CSF arm with a response, it was 3.7 (1.9 to 9.1) months.  
Fifty-four percent of talimogene laherparepvec objective responders and 48% of 
talimogene laherparepvec durable responders exhibited “interval progression”, which is 
transient locoregional or distant progression including appearance of new lesions, before 
ultimately achieving response (Ross et al, 2014; Kaufman et al, 2013).  Subjects with 
HSV-1 seronegative or seropositive status at baseline had similar ORR (23.7 vs 28.6%), 
DRR (13.4 vs 17.7%, respectively), and OS HR ratio (0.79 vs 0.81) with talimogene 
laherparepvec (Kaufman et al, 2014; Andtbacka et al, 2013; data on file).  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%) (all treatment-emergent).  
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%]; 
GM-CSF, n =1[< 1%]).  Of 10 fatal adverse events in the talimogene laherparepvec arm, 
8 were attributable to disease progression.  The remaining 2 fatal adverse events 
(sepsis in the setting of salmonella infection; myocardial infarction) were not considered 
treatment-related per investigator (Andtbacka et al, 2013).  Subjects with HSV-1 
seronegative or seropositive status at baseline had similar incidence of grade 3 and 
4 (20.4 vs 17.7%) and serious adverse events (25.5 vs 28.0%) on talimogene 
laherparepvec (Andtbacka et al, 2013; data on file).  
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.  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 one dose of talimogene laherparepvec.  There were 
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no reported DLT during the DLT evaluation period (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.  Two subjects (11%) 
experienced possible immune-related grade 3 or 4 adverse events attributed either 
ipilimumab or the combination of ipilimumab and talimogene laherparepvec.  There were 
no unexpected adverse events attributable to the combination therapy that have not 
been seen previously with either ipilimumab or talimogene laherparepvec individually.  
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 time of 15.6 months revealed 
9 objective responses (50%) with 4 confirmed CRs (33%) and DRR 44% by 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.  Primary 
analysis of the phase 2 portion of the study was recently reported (Chesney et al, 2017).  
198 patients were randomized:  98 in the talimogene laherparepvec + ipilimumab arm 
and 100 in the ipilimumab arm.  Baseline characteristics were generally balanced 
between the 2 arms.  Thirty eight patients (39%) in the combination arm and 18 patients 
(18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI:  1.5 to 
5.5; p = 0.002).  Responses were not limited to injected lesions.  Visceral lesion 
decreases were observed in 51 patients (52%) in the combination arm and 23 patients 
(23%) in the ipilimumab arm.  Of 183 patients in the safety set (93 in the combination 
arm and 90 in the ipilimumab arm), the incidences of grade 3/4 treatment related 
adverse events were 45% in the combination arm and 35% in the ipilimumab arm.  The 
most frequently occurring adverse events included fatigue (combination: 59%, 
ipilimumab: 42% respectively), chills (53%, 3%), diarrhea (42%, 35%), pruritus (40%, 
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36%), rash (39%, 28%) and nausea (38%, 24%).  Three patients in the combination arm 
had fatal adverse events that were not treatment related. 
Refer to the Talimogene Laherparepvec Investigator’s Brochure for additional 
information related to safety and efficacy of talimogene laherparepvec 
(Talimogene Laherparepvec Investigator’s Brochure). 
2.3 
Pembrolizumab Background 
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 intravenous 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 Investigator brochure (Pembrolizumab Investigator’s Brochure). 
A phase 3 registration trial (KEYNOTE-006) of pembrolizumab versus ipilimumab in 
ipilimumab-naive subjects with advanced melanoma has been published 
(clinicaltrials.gov identifier NCT01866319, Schachter et al, 2007).  This is a 3-arm study 
to evaluate the safety and efficacy of two dosing schedules of pembrolizumab compared 
to ipilimumab for the treatment of ipilimumab-naïve participants with unresectable or 
metastatic melanoma.  Subjects are randomized 1:1:1 to receive pembrolizumab 
10 mg/kg every 2 weeks for up to 2 years or pembrolizumab 10 mg/kg every 3 weeks for 
up to 2 years or ipilimumab 3 mg/kg for a total of 4 doses.  Primary endpoints of this 
study are progression free survival (PFS) and overall survival (OS).  At an interim 
analysis with 834 subjects enrolled and median duration of follow-up 7.9 months (range 
6.1-11.5 months), the response rate for pembrolizumab every 2 weeks was 33.7% and 
every 3 weeks was 32.9% as compared with ipilimumab at 11.9% (p < 0.001 for both 
comparisons) (Robert et al, 2015).  The PFS hazard ratio was 0.58 (P < 0.001 for both 
pembrolizumab regimens versus ipilimumab), and the hazard ratio for death for 
pembrolizumab every 2 weeks was 0.63 (P = 0.0005) and 0.69 for pembrolizumab every 
3 weeks (P = 0.0036) versus ipilimumab.  Rates of treatment-related adverse events of 
grade 3 to 5 were lower in the pembrolizumab groups (13.3% and 10.1%) than in the 
ipilimumab group (19.9%) (Robert et al, 2015).  The overall survival benefit of 
pembrolizumab versus ipilimumab continued to hold after a median follow-up of 
57.7 months (range 56.7 to 59.2 months).  The median overall survival (mOS) was 
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32.7 months in the combined pembrolizumab groups and 15.9 months in the 
ipilimumab group (hazard ratio  0.73, 95% confidence interval of 0.61 to 0.88,  
P  0.00049) (Robert et al, 2019). 
The dose of pembrolizumab planned to be studied in this trial is 200 mg, as approved in 
the United States.  Information on the rationale for selecting 200 mg every 3 weeks in 
the phase3 part of this trial is summarized below. 
KEYNOTE-001 is an open-label Phase I study conducted to evaluate the safety, 
tolerability, PK and pharmacodynamics, and anti-tumor activity of pembrolizumab when 
administered as monotherapy.  The dose escalation portion of this trial evaluated 3 dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) and dose 
expansion cohorts evaluated 2 mg/kg every 3 weeks (Q3W) and 10 mg/kg Q3W in 
subjects with advanced solid tumors.  All dose levels were well tolerated and no 
dose-limiting toxicities 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 maximum tolerated dose (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 monoclonal antibodies, 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 
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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, non small cell 
lung cancer (NSCLC), and other tumor types support a lack of meaningful difference in 
PK exposures obtained at 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. 
2.4 
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.  
Talimogene laherparepvec combined with ipilimumab in a phase 1b study demonstrated 
response rates of 50% by irRC with 22% confirmed CR and was tolerable with no 
unexpected adverse events (AEs) (Puzanov et al, 2015).  
A prior concurrent regimen of nivolumab, a PD-1 inhibitor, with ipilimumab, a CTLA-4 
inhibitor has yielded higher response rates (57.5%, 95% CI 52.0 to 63.2) and median 
progression free survival (11.5 months, 95% CI 8.9 to 16.7) in advanced melanoma than 
ipilimumab (Larkin et al, 2015).  Updated results also showed a longer mOS for the 
combination (mOS  60 months) versus ipilimumab (mOS = 19.9 months)  
(Larkin et al, 2019), suggesting that immune therapies can be given concurrently to 
improve efficacy.  However, toxicity was also increased with 55% having grade 3 or  
4 adverse events for combination versus 16.3% for nivolumab and 27.3% for ipilimumab.  
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As both pembrolizumab and talimogene laherparepvec have had relatively low toxicity 
as single agents, it is possible that the overall incidence of severe adverse events would 
remain low when they are combined as has been seen with the talimogene 
laherparepvec and ipilimumab combination. 
This phase 1b/3, multicenter, study is intended to provide confirmation that a regimen of 
an oncolytic immunotherapy (talimogene laherparepvec) and an immune checkpoint 
inhibitor (pembrolizumab) is safe and tolerable, and that the combination treatment might 
enhance the clinical efficacy shown when pembrolizumab is administered alone to 
subjects with unresectable, stage IIIB to IVM1c melanoma. 
As this is the first use of talimogene laherparepvec with pembrolizumab, the phase 1b 
study is necessary to evaluate the safety of talimogene laherparepvec in combination 
with pembrolizumab.  In addition, the phase 1b part of the study will evaluate potential 
blood and 
 that associate with response or resistance to talimogene 
laherparepvec in combination with pembrolizumab.  During phase 1b, talimogene 
laherparepvec will be started 5 weeks preceding pembrolizumab administration and 
continuing during pembrolizumab administration.  This dosing schedule will allow for 
correlative 
 studies to be performed before and after talimogene laherparepvec 
is combined with pembrolizumab. 
An analysis of the phase 1b portion of the study was recently completed 
(Ribas et al, 2017).  Twenty one patients with advanced melanoma were treated with 
talimogene laherparepvec followed by pembrolizumab.  Median follow-up was 18.6 (17.7 
to 20.8) months.  Therapy was generally well tolerated.  No dose-limiting toxicities 
occurred.  The most frequent adverse events were fatigue (62%), fever (43%), chills 
(48%), and rash (33%).  One event of grade 1 cytokine-release syndrome was described 
as possibly related to the combination.  The other serious adverse events were 
attributed solely to pembrolizumab and included grade 3 autoimmune hepatitis, grade 3 
aseptic meningitis and grade 4 pneumonitis (one patient each).  The confirmed objective 
response rate (ORR) was 62% with a complete response (CR) rate of 33% per  
immune-related response criteria.  Responses occurred across all substages of 
melanoma.  Median PFS and OS were not reached at the time of last follow-up.  
Response to the combination therapy did not appear to be associated with baseline 
CD8+ T cell infiltration or IFN-gamma signature.  Patients who responded to the 
combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression as 
well as IFN-gamma gene expression on several cell subsets in the tumors after 
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talimogene laherparepvec treatment.  These findings suggest that 
talimogene laherparepvec may improve the efficacy of pembrolizumab by changing the 
tumor microenvironment. 
In both phases of the study, pembrolizumab will be administered at a fixed dose of 
200 mg either every 2 weeks in phase 1 or every 3 weeks in phase 3.  A 2 mg/kg Q3W 
dose is approved for metastatic melanoma in some countries. 
The dosing schedule will be changed from Q2W in phase 1 to Q3W in phase 3 to align 
with the FDA-approved schedule for pembrolizumab and in consideration of the data.  
Talimogene laherparepvec will be Q2W starting with the second dose but will switch to 
Q3W at week 9.  The Q2W schedule for talimogene laherparepvec between weeks 3 
and 9 will allow for more optimal delivery of talimogene laherparepvec during the period 
when it is likely that most subjects will have lesions to inject but switch to Q3W at week 9 
in order to allow for synchronization of talimogene laherparepvec and pembrolizumab 
schedules to minimize treatment visits for the subjects still requiring talimogene 
laherparepvec treatment.  The median number of talimogene laherparepvec doses 
received during phase 1b of the 20110264 study in combination with ipilimumab was six 
(Puzanov et al, 2014).  Although a Q3W schedule for talimogene laherparepvec have 
not been compared directly against a Q2W schedule in melanoma, clinical activity has 
been observed in early phase head and neck and pancreatic cancer studies using a 
Q3W schedule (Chang et al, 2012; Harrington et al, 2010). 
2.5 
Clinical Hypotheses 
Phase 1b:  
Talimogene laherparepvec in combination with pembrolizumab will be safe and well 
tolerated in subjects with previously untreated, unresectable, stage IIIB to IVM1c 
melanoma. 
Phase 3: 
Two clinical hypotheses will be evaluated independently in the phase 3.  The first clinical 
hypothesis is that talimogene laherparepvec with pembrolizumab compared to placebo 
with pembrolizumab will improve PFS as evaluated by a blinded independent central 
review using modified RECIST 1.1.  The second clinical hypothesis is that talimogene 
laherparepvec with pembrolizumab compared to placebo with pembrolizumab will 
improve OS. 
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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 1b/3, multicenter, clinical trial.  The study will be conducted in 2 parts 
(phase 1b and phase 3) as described below.   
3.1.1 
Phase 1b Study Design 
Phase 1b is an open-label, multicenter, single-arm study.  Talimogene laherparepvec will 
be administered in combination with pembrolizumab to approximately 20 subjects with 
previously untreated, unresectable, stage IIIB to IVM1c melanoma to evaluate the safety 
of talimogene laherparepvec in combination with pembrolizumab.  In addition, phase 1b 
will evaluate potential blood and 
 that associate with response or 
resistance to talimogene laherparepvec in combination with pembrolizumab. 
Subjects enrolled in phase 1b will receive talimogene laherparepvec 5 weeks before the 
initiation of pembrolizumab treatment to evaluate changes in the blood and 
 
 in individuals who receive talimogene laherparepvec monotherapy prior to 
the addition of pembrolizumab.  The start of talimogene laherparepvec will be defined as 
week -5.  The start of pembrolizumab will be defined as week 0.  When talimogene 
laherparepvec and pembrolizumab are administered on the same day, talimogene 
laherparepvec should be administered first, if possible. 
Talimogene laherparepvec will be administered as an intralesional injection up to 4 mL 
of 106 PFU/mL at day 1 of week -5 followed by up to 4 mL of 108 PFU/mL at day 1 of 
week -2 (ie, 21 days later [+3 days]), at day 1 of week 0 (± 3 days), and every 2 weeks 
(± 3 days) thereafter until disappearance of injectable lesions, CR, confirmed PD per 
modified immune-related Response Criteria (irRC; Wolchok et al, 2009; Appendix D), 
intolerance of study treatment, 24 months from the date of the first dose of 
pembrolizumab, or end of study, whichever occurs first.  Due to the mechanism of action, 
subjects may experience growth in existing tumors or the appearance of new tumors 
prior to maximal clinical benefit of talimogene laherparepvec.  Therefore, talimogene 
laherparepvec dosing should continue provided that the subject has no evidence of 
confirmed PD per modified irRC (Appendix D) and is able to tolerate the treatment.   
Pembrolizumab will be administered at a dose of 200 mg, as an intravenous infusion 
over approximately 30 minutes every 2 weeks (± 3 days) starting at day 1 week 0 
(ie, at the time of the third dose of talimogene laherparepvec).  Pembrolizumab dosing 
will continue until confirmed PD per modified irRC, intolerance to treatment, 24 months 
from the date of the first dose of pembrolizumab, or end of study, whichever occurs first.  
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For subjects who have attained a confirmed CR, discontinuation of treatment may be 
considered if the subjects have been treated for at least 24 weeks with pembrolizumab 
and had at least 2 treatments with pembrolizumab beyond the date when the initial CR 
was declared. 
3.1.1.1 
Rules for DLT Evaluation in Phase 1b 
A Dose Level Review Team (DLRT) consisting of the Amgen study team, including at 
least one clinician, safety representative, and biostatistician, at least one representative 
of the Merck study team, and at least one investigator participating in the study who has 
recruited subjects into the phase 1b part of the study, was to review the safety data to 
evaluate possible drug effects and DLT.  This team was to recommend either to enroll 
more subjects for DLT evaluation in phase 1b, to prematurely stop enrollment into 
phase 1b, or to declare that the combination is tolerable and whether to open phase 3. 
The DLT evaluation period is 6 weeks from the initial administration of pembrolizumab.  
To be evaluable for a DLT, subjects must have had the opportunity to be on treatment 
for at least 6 weeks from the initial dosing of pembrolizumab and have received at least 
2 doses of talimogene laherparepvec and 2 doses of pembrolizumab in combination 
(ie, on the same day) or otherwise experienced a DLT within 6 weeks after starting the 
combination therapy.  Subjects could be replaced if they were not evaluable for DLT 
(eg, a subject did not receive study treatment, permanently discontinued talimogene 
laherparepvec prior to receiving the first dose of pembrolizumab for any reason, or 
ended the study treatment before completion of DLT evaluation period for a reason other 
than experiencing a DLT). 
The DLRT was to initially meet when 6 subjects are evaluable for DLT.  The DLRT was 
to declare the combination of talimogene laherparepvec and pembrolizumab tolerable if 
the incidence of DLT is < 33% during the DLT evaluation period subject to the following 
rules: 
 
If ≤ 1 subject among the initial 6 evaluable subjects in phase 1b experienced a DLT 
during the DLT evaluation period, then the combination of talimogene laherparepvec 
and pembrolizumab would be declared as safe and enrollment in phase 3 would 
open. 
 
If 2 subjects among the initial 6 evaluable subjects in phase 1b experienced a DLT 
during the DLT evaluation period, an additional 3 evaluable subjects would be 
enrolled in phase 1b. 
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 
If  2 subjects among the expanded cohort of 9 evaluable subjects in phase 1b 
experienced a DLT during the DLT evaluation period, then the combination of 
talimogene laherparepvec and pembrolizumab would be declared as safe and 
enrollment in phase 3 would open. 
 
If  3 subjects among the initial 6 evaluable subjects or among the expanded cohort 
of 9 evaluable subjects in the phase 1b experienced a DLT during the DLT 
evaluation period, then the combination of talimogene laherparepvec and 
pembrolizumab would be declared not safe, the enrollment in phase 1b would end, 
and phase 3 would not be opened for enrollment. 
The DLT evaluation would be based on the initial 6 to 9 subjects meeting the DLT 
evaluation criteria as outlined above.  However, the enrollment would not be halted while 
the DLT evaluation was still ongoing.  Additional subjects, up to a total of approximately 
20, would be enrolled in the phase 1b portion of the trial to address the secondary 
objective exploring the relationship between 
 and response to 
treatment.  The DLRT would review additional safety data from subjects enrolled in 
phase 1b beyond the 6 to 9 DLT evaluable subjects during the DLT review meeting or 
request an ad hoc review if deemed necessary to further assess the overall safety profile 
of talimogene laherparepvec in combination with pembrolizumab and would decide 
whether DLT evaluation of these subjects beyond the first 6 to 9 should be 
recommended prior to initiating phase 3. 
A DLRT meeting was conducted on 19 May 2015 to review safety data after 6 subjects 
had been treated for at least 6 weeks past the first dose of combination therapy.  There 
were no DLTs in the first 6 subjects.  Following review of the cumulative safety data for 
all subjects enrolled into the phase 1b portion of the study, the DLRT voting attendees, 
including Amgen and Merck study team members and 4 investigators on the study, 
unanimously agreed that the reviewed data did not present any safety concerns and that 
the study can proceed to opening the next phase (data on file). 
3.1.1.2 
Definition of DLT in Phase 1b 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 (Appendix A). 
The occurrence of any of the following toxicities during DLT evaluation period 
(ie, 6-week period from the initial administration of pembrolizumab) will be considered a 
DLT, if judged by the investigator to be related to the administration of talimogene 
laherparepvec and/or pembrolizumab: 
 
Grade 4 non-hematologic toxicity 
 
Grade 3 or higher pneumonitis  
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 
Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care 
 
Grade 3 fatigue will not be classified as DLT, irrespective of duration 
 
Any grade 3 or higher non-hematologic laboratory value if: 
 
medical intervention is required, or 
 
the abnormality leads to hospitalization, or 
 
the abnormality persists for > 1 week 
 
Febrile neutropenia grade 3 or grade 4: 
 
Grade 3 is defined as absolute neutrophil count (ANC) < 1.0 x 109/L with a  
single temperature of > 38.3ºC (101 ºF) 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 > 38.3 ºC 
(101ºF) or sustained temperature of ≥ 38ºC (100.4ºF) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated 
 
Thrombocytopenia < 25 x 109/L if associated with:  
 
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 
 
Grade 5 toxicity (ie, death) 
 
Any other intolerable toxicity leading to permanent discontinuation of talimogene 
laherparepvec or pembrolizumab  
If a subject experiences a DLT during the DLT evaluation period, study treatments will 
be discontinued for that subject. 
3.1.2 
Phase 3 Study Design 
The phase 3 study is a double-blind, placebo-controlled, multicenter, randomized trial to 
evaluate the efficacy, as assessed by PFS and OS of talimogene laherparepvec with 
pembrolizumab versus placebo with pembrolizumab in subjects with unresectable, 
stage IIIB to IVM1c melanoma.  Approximately 660 subjects will be randomized 1:1 to 
receive the following: 
 
Arm 1:  talimogene laherparepvec plus pembrolizumab 
 
Arm 2:  placebo plus pembrolizumab  
Randomization will be stratified by stage of disease:  less advanced stages (IIIB, IIIC, 
and IVM1a) versus more advanced stages (IVM1b and IVM1c) and by prior 
serine/threonine protein kinase B-Raf BRAF inhibitor therapy:  no prior BRAF inhibitor 
versus prior BRAF inhibitor with or without MEK inhibitor. 
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Talimogene laherparepvec/placebo and pembrolizumab treatment will be initiated 
simultaneously.  When talimogene laherparepvec/placebo and pembrolizumab are 
administered on the same day, talimogene laherparepvec/placebo should be 
administered first, if possible. 
Talimogene laherparepvec/placebo will be administered as an intralesional injection up 
to 4 mL of 106 PFU/mL at day 1 of week 0 followed by up to 4 mL of 108 PFU/mL at 
day 1 of week 3 (ie, 21 days later [+3 days]), and every 2 weeks (± 3 days) until the  
fifth injection of talimogene laherparepvec/placebo (week 9) and then be dosed 
synchronously with pembrolizumab thereafter every 3 weeks (± 3 days).  Talimogene 
laherparepvec/placebo should be administered until disappearance of injectable lesions, 
iCR, documented confirmed progressive disease (iPD) per modified irRC-RECIST 
(Appendix F), intolerance of study treatment, 24 months from the date of the first dose of 
talimogene laherparepvec/placebo, or end of study, whichever occurs first.  Due to the 
mechanism of action, subjects may experience growth in existing tumors or the 
appearance of new tumors prior to maximal clinical benefit of talimogene laherparepvec.  
Therefore, dosing should continue provided that the subject has no evidence of 
confirmed iPD per modified irRC-RECIST (Appendix F) and is able to tolerate the 
treatment. 
Pembrolizumab will be administered at a dose of 200 mg, as an intravenous infusion 
over approximately 30 minutes on day 1 of week 0, day 1 of week 3 (ie, 21 days later 
[+3 days]), and every 3 weeks (± 3 days) thereafter until confirmed iPD per modified 
irRC-RECIST (Appendix F), intolerance to treatment, 24 months from the date of the  
first dose of pembrolizumab, or end of study, whichever occurs first.  For subjects who 
have attained a confirmed iCR, discontinuation of treatment may be considered if the 
subjects have been treated for at least 24 weeks with pembrolizumab and had at least 
2 treatments with pembrolizumab beyond the date when the initial CR was declared.   
The first two interim analyses of safety are planned to evaluate the safety of talimogene 
laherparepvec in combination with pembrolizumab in the target population for phase 3.  
Planned safety monitoring will occur when approximately 20 and 100 total subjects, 
respectively, have had the opportunity to be on treatment for at least 6 weeks from the 
initial dosing of study treatment in phase 3 and have received at least 1 dose of study 
treatment.  Safety monitoring by the Data Monitoring Committee (DMC) will occur 
approximately every 6 months after the DMC meeting to review the futility analysis for 
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iORR and iDCR until the primary analysis of OS.  Enrollment will not be halted while the 
interim analysis of safety is ongoing. 
Additional interim safety analyses may be performed if warranted based on results from 
the planned safety and/or interim analyses or if requested by the clinical study team or 
the DMC.  The futility analysis based on iORR and iDCR using modified irRC-RECIST 
per blinded independent central review is planned to include the first 160 subjects 
(80 per arm) that have been enrolled and have had an opportunity to be followed for the 
tumor assessment scheduled at week 24.  This futility analysis will be based on 
Bayesian methods.  The talimogene laherparepvec plus pembrolizumab arm is 
considered to be futile if the posterior probability that at least 6% absolute increase for 
iORR (at least 10% for iDCR) from the pembrolizumab is < 0.65 (< 0.75 for iDCR).  A 
DMC will be responsible to review interim safety and non-binding futility analyses for 
iORR and iDCR.  The DMC is also responsible to review the results from the primary 
analysis of PFS by blinded independent central review using modified RECIST 1.1 and 
all interim OS analyses performed by an external independent biostatistics group.  At the 
time of PFS primary analysis, an interim OS efficacy analysis will be performed by the 
external biostatistics group and reviewed by the DMC.  The second interim OS analysis 
is planned after 282 events have occurred.  If OS is not declared statistically significant 
at the second interim analysis, a non-binding futility analysis will be performed.  
However, if 282 OS events are observed prior to the event goal for the primary PFS, 
then the first OS interim will be the event-driven (ie, 282 events) and a PFS interim will 
be conducted with all PFS events at the time of the 282 OS events interim analysis.  In 
this case, the second OS interim analysis will be performed at the PFS primary analysis 
with all OS events.  The third interim OS analysis for efficacy is planned after 
315 events have occurred.  Refer to Section  10.4.1.4 for additional information. 
3.1.3 
Tumor Response Assessment 
Immunotherapy agents such as talimogene laherparepvec and pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune 
responses.  The response patterns seen with such approaches may extend beyond the 
typical time course of responses seen with cytotoxic agents, and can manifest as a 
clinical response after an initial increase in tumor burden or even the appearance of new 
lesions.  Therefore, irRC and modified irRC-RECIST will be used in the phase 1b and 
phase 3, respectively, to account for the unique tumor response characteristics seen 
with talimogene laherparepvec and pembrolizumab.  The irRC, which uses 
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bidimensional measurements, was found to be highly concordant to a version of irRC 
using unidimensional measurements (Nishino et al, 2013).  Moreover, the concordance 
between irRC-RECIST 1.0 and 1.1 was also high (Nishino et al, 2014). 
3.1.3.1 
Phase 1b Tumor Response Assessment 
irRC (Wolchok et al, 2009) will be used for the determination of the ORR endpoints in 
the phase 1b part of the study.  Clinical measurements of cutaneous, subcutaneous, and 
palpable nodal tumor lesions by calipers, photographic imaging of up to 5 (maximum 
5 per organ) visible (ie, visible protrusion from skin surface) cutaneous and 
subcutaneous tumor lesions, and radiographic imaging (computed tomography [CT] 
scan, positron emission tomography [PET/CT] scan, magnetic resonance imaging, [MRI], 
or ultrasound [US], if applicable) of all other disease, will be performed according to the 
schedule of assessment and procedures for phase 1b (refer to Table 5, Section 7.1 and 
Section 7.2).  Note:  When a lesion can be accurately evaluated by both radiographic 
imaging and clinical examination or photographs, radiographic imaging evaluations 
should be undertaken. 
irRC will also be used by the investigator during the phase 1b to determine eligibility and 
to make treatment decisions. 
Up to 5 measurable cutaneous lesions and 10 measurable visceral lesions (maximum 
5 per organ) will be selected as index lesions at baseline and will be followed and 
measured at each subsequent tumor assessment visit.  In addition, up to 5 new 
measurable cutaneous lesions and 10 new measurable visceral lesions (maximum 5 per 
organ) will be followed, measured, and added to the tumor burden calculations for each 
subject.  If tumor assessments (clinical, photographic, radiographic) show initial 
response (CR or PR), tumor assessments must be repeated ≥ 4 weeks later in order to 
confirm the response by the investigator.  If a tumor assessment (clinical, photographic, 
radiographic) after the first dose of pembrolizumab shows initial PD, tumor assessments 
must be repeated ≥ 4 weeks later in order to confirm PD by the investigator.  Subjects 
will have the option of continuing assigned study treatment while awaiting confirmation of 
PD.  If repeat clinical, photographic, and radiographic assessments show a reduction in 
the tumor burden compared to the initial assessments demonstrating PD, treatment may 
be continued.  If repeat clinical, photographic, and radiographic assessments confirm 
PD, subjects will be discontinued from study treatment.  In determining whether or not 
the tumor burden has increased or decreased, investigators should consider all index 
lesions and new measurable lesions as well as non-index lesions and new 
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non-measurable lesions.  Additional information for tumor response assessments is 
provided in Appendix D. 
In subjects who have initial evidence of PD, it is at the discretion of the investigator to 
continue a subject on study treatment until repeat imaging is obtained a minimum of 
4 weeks later.  This clinical judgment decision should be based on the subject’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data.  
Subjects will receive treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
 
Absence of signs and symptoms indicating PD 
 
No decline in the Eastern Cooperative Oncology Group (ECOG) performance status 
 
Absence of rapid progression of disease 
 
Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
When feasible, subjects should not be discontinued until PD is confirmed.  Subjects who 
are reported by the investigator as being clinically unstable and not meeting the above 
criteria for clinical stability are not required to have repeated clinical, photographic, and 
radiographic assessments for confirmation of PD. 
3.1.3.2 
Phase 3 Tumor Response Assessment 
RECIST 1.1 (Eisenhauer et al, 2009), which includes the following modifications will be 
used by a blinded independent central review for determination of primary endpoint and 
some of the secondary tumor response-related endpoints in the phase 3 part of the 
study (summarized in Appendix G with additional details provided in the independent 
central review charter):  
 
Increased total target lesions to a maximum of 10 (up to a maximum of 5 per 
organ). 
 
Lesions not measurable on CT or MRI will be considered as non-target only. 
A modified version of the irRC-RECIST defined by (Nishino et al, 2014) (Appendix F), 
will be employed in phase 3 to account for unique tumor response characteristics 
observed with immunotherapies and enable treatment beyond progression and to 
simplify the irRC to unidimensional measurements.  The modified irRC-RECIST criteria 
will be used by the investigator during the phase 3 to determine eligibility, make 
treatment decisions and evaluation of some response-related secondary endpoints 
based on the investigator review of the clinical photographic and radiographic data. 
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Photographic imaging of visible (ie, visible protrusion from skin surface) cutaneous and 
subcutaneous tumor lesions, and radiographic imaging (CT scan, PET/CT scan, or MRI) 
of all other disease, must be performed during the phase 3 part of the study according to 
the schedule of assessments and procedures (refer to Table 6, Sections 7.1 and 7.2) 
and submitted to a blinded independent imaging vendor for evaluation of primary and 
some of the secondary response-related endpoints by the blinded independent central 
review.  Note:  When a lesion can be accurately evaluated by both radiographic imaging 
and clinical examination or photographs, radiographic imaging evaluations must be 
undertaken.  When a lesion/lesions cannot be evaluated by radiographic imaging, but 
can be accurately evaluated by both clinical examinations and photographs, 
photographs must be undertaken.  Radiographic images and/or photography (if 
applicable), should be submitted to the imaging vendor.  Additional information will be 
included in the Site Imaging Manual. 
irRC-RECIST is a modification of the RECIST 1.1 criteria that includes the revised 
guidelines for definition of measurable lesion, number of target lesions, measurement of 
lymph nodes, and cutoff values of percent changes in tumor burden for PR and PD as 
described in RECIST 1.1 in addition to the following (See Appendix F): 
 
Lesions not measurable on CT or MRI will be considered as non-target only. 
 
Up to 10 (maximum 5 per organ) unidimensional measurable lesions (≥ 10 mm 
longest diameter for non-nodal lesions and ≥ 15 mm of short axis for lymph nodes) 
will be selected as target lesions at baseline and will be followed and measured at 
each subsequent tumor assessment visit.  All other lesions, including measurable 
lesions not selected as target lesions and truly non-measurable lesions, will be 
followed as non-target lesions.   
 
At each subsequent tumor assessment, the sum of the diameter of the baseline 
target lesions and the sum of the diameter of new measurable lesions (up to 10 new 
measurable lesions [maximum 5 per organ] per time point) are added together to 
provide the total tumor burden.  New nodal lesions must be ≥ 15 mm in short axis to 
be measurable. 
 
At each subsequent tumor assessment follow-up the cutoff values defined in 
RECIST 1.1 are used to determine response.  iPR requires a ≥ 30% reduction in 
tumor burden compared to baseline while iPD requires ≥ 20% increase in tumor 
burden for iPD compared to the nadir.  iCR requires disappearance of all non-nodal 
lesions, while all nodal lesions must achieve a short axis < 10 mm. 
 
If tumor assessments (clinical, photographic, and/or radiographic) by investigator 
show initial iCR or iPR, tumor assessments (clinical, photographic, and/or 
radiographic) must be repeated ≥ 4 weeks (28 days) later in order to confirm iCR or 
iPR by the investigator. 
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 
If tumor assessments (clinical, photographic, and/or radiographic) by investigator 
show initial iPD, tumor assessments (clinical, photographic, and/or radiographic), 
must be repeated ≥ 4 weeks later in order to confirm iPD by the investigator unless 
the subject is clinically unstable (Section 3.1.3.1) as indicated by the investigator, in 
which case confirmation is not necessary for initial iPD.  At the discretion of the 
investigator, subjects with PD may continue on treatment as described in 
Section 3.1.3.3. 
 
A ≥ 20% increase in total tumor burden (ie, the sum of the diameter 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 will be considered 
confirmed iPD (with the date of progression considered to be the time of the initial 
evaluation showing iPD). 
Note:  Unequivocal progression of non-measureable lesions only does not result in 
overall iPD. 
Refer to Appendix F for additional instructions regarding tumor response assessments 
using modified irRC-RECIST guidelines. 
3.1.3.3 
Subject Management After Radiographic Progression During 
Phase 3 
 
If, following initial iPD, repeat clinical, photographic, and/or radiographic 
assessments show stable disease (SD), iPR, or iCR treatment may be continued as 
per treatment schedule and the prior evaluation will not be considered as a 
progression event. 
 
If, following initial iPD, repeat clinical, photographic, and/or radiographic 
assessments confirm iPD without reduction in tumor burden compared to previous 
time-point, subjects will be discontinued from study treatment unless granted 
exception as stated in the note section below. 
 
A ≥ 20% increase in total tumor burden (ie, the sum of the diameter of target lesions 
identified at baseline and up to 10 [maximum 5 per organ] new measurable lesions 
per time point) compared to the nadir at two consecutive time points at least 4 weeks 
(28 days) apart will be considered confirmed iPD.  Additional information for tumor 
response assessments is provided in Appendix F. 
The decision to continue study treatment after the first evidence of iPD is at the 
investigator’s discretion based on the clinical status of the subject as described in 
Table 1. 
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Table 1.  Imaging and Treatment After First Evidence of iPD 
 
Clinically Stable 
Clinically Unstable 
 
Assessments 
Treatment 
Assessments 
Treatment 
1st clinical, 
photographic, 
and/or 
radiographic 
evidence of iPD 
Repeat clinical, 
photographic, 
and/or 
radiographic 
assessments 
≥ 4 week at site 
to confirm iPD  
May continue 
study treatment 
at the 
investigator’s 
discretion while 
awaiting 
confirmatory 
assessments by 
the site 
Repeat clinical, 
photographic, 
and/or 
radiographic 
assessments 
≥ 4 week at site 
to confirm iPD 
per investigator’s 
discretion only 
Discontinue 
study treatment 
Repeat clinical, 
photographic, 
and/or 
radiographic 
assessments 
confirm iPD (no 
reduction in 
tumor burden 
from prior 
assessments) 
No additional 
clinical 
photographic, 
and/or 
radiographic 
assessments 
required 
Discontinue 
study treatment 
unless granted 
exception as 
stated in the 
note section 
below. 
No additional 
clinical 
photographic, 
and/or 
radiographic 
assessments 
required 
Discontinue 
study treatment 
Repeat clinical, 
photographic, 
and/or 
radiographic 
assessments do 
not confirm iPD 
(reduction in 
tumor burden 
from prior 
assessments) 
May continue 
regularly 
scheduled 
clinical 
photographic, 
and/or 
radiographic 
assessments 
after medical 
monitor 
consultation 
May continue 
study treatment 
after 
consultation with 
the sponsor 
medical monitor 
May continue 
regularly 
scheduled 
clinical 
photographic, 
and/or 
radiographic 
assessments 
after medical 
monitor 
consultation 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
investigator’s 
and medical 
monitor’s 
discretion 
Repeat clinical, 
photographic, 
and/or 
radiographic 
assessments 
show iSD, iPR, 
or iCR 
Continue 
regularly 
scheduled 
clinical 
photographic, 
and/or 
radiographic 
assessments 
Continue study 
treatment at the 
investigator’s 
discretion 
Continue 
regularly 
scheduled 
clinical 
photographic, 
and/or 
radiographic 
assessments 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
investigator’s 
discretion 
iCR = complete response; iPD = progressive disease; iPR = partial response; iSD = stable disease 
Confirmatory clinical, photographic, and/or radiographic assessments may be performed 
as early as 4 weeks (28 days) later; alternatively, the assessments at the next schedule 
tumor response assessment visit (every 12 weeks +7) may be used for confirmation of 
iPD.  The clinical judgment decision should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data.  
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Subjects will receive treatment while waiting for confirmation of iPD if they are clinically 
stable as defined by all of the following criteria: 
 
Absence of signs and symptoms (including worsening of laboratory values) indicating 
iPD 
 
No decline in the Eastern Cooperative Oncology Group (ECOG) performance status 
 
Absence of rapid progression of disease 
 
Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
Subjects exhibiting intolerable toxicity from the study treatment may not continue to 
receive study treatment. 
Note:  If a subject with confirmed iPD (ie, two consecutive tumor assessments at least 
4 weeks [28 days] apart demonstrating iPD) is clinically stable or clinically improved, and 
there is no further increase in tumor burden at the confirmatory assessments (assessed 
by the investigator and site radiologist, if applicable), an exception may be considered to 
continue treatment upon consultation with the sponsor medical monitor. 
3.1.4 
Follow-up 
3.1.4.1 
Safety Follow-up 
Subjects enrolled in phase 1b and phase 3 will be followed for safety approximately 
30 (+7) days after the last dose of study treatment.  If an end of treatment decision 
occurs > 30 (+7) days after the last treatment date, then the Safety follow-up should be 
performed as soon as possible (eg, within a week of the end of treatment decision).  
Applicable safety follow-up procedures should occur even if the subject has initiated new 
anticancer therapy.  Serious adverse events observed by the investigators or reported 
by the subjects that occur within 90 (+7) days after the cessation of all study treatment or 
30 (+7) days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, will be reported, followed, and recorded as described in 
Section 9.2.1.2. 
3.1.4.2 
Long-term Follow-up 
Subjects enrolled in phase 1b and phase 3 will be followed for survival, subsequent 
anticancer therapies, and injected investigational product-related adverse events for 
every 12 weeks (± 28 days) for approximately 60 months after the last subject is 
randomized in phase 3. 
For subjects who discontinue study treatment without documented PD, every effort 
should be made to continue monitoring tumor response status by clinical, photographic, 
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and radiographic assessments, and to complete PRO questionnaires every 12 weeks 
(+1 week) until documented confirmed PD per modified irRC in phase 1b (Appendix D) 
or iPD per modified irRC-RECIST in phase 3 (Appendix F), start of new anticancer 
treatment, death, or end of study, whichever occurs first.  For subjects with PD (see 
footnote cc of Table 6), QLQ-C30 will no longer be collected, and EQ-5D-3L will be 
collected through the long-term follow-up.  Subjects who have reached a confirmed CR 
may increase their interval of radiographic assessments up to 6 months (26 weeks) after 
the first 2 years beyond confirmed CR and up to 12 months (52 weeks) after the  
first 5 years beyond confirmed CR as long as CR is maintained.  For subjects with PD, 
EQ-5D-3L may be collected via telephone. 
Subjects who have received talimogene laherparepvec (all subjects in phase 1b and 
those who received talimogene laherparepvec in phase 3) and completed the 
protocol-specified follow-up period for a reason other than death or withdrawal of full 
consent will be eligible to continue follow-up in a separate ongoing registry protocol 
which is in place for the long-term survival follow-up of subjects treated with talimogene 
laherparepvec in clinical trials.  The registry protocol, including for phase 1b subjects, will 
not apply until the end of the study or 5 years after the last subjects enrolled in phase 3, 
whichever comes first.  The registry protocol will also monitor for late and long-term 
adverse events thought to be potentially related to talimogene laherparepvec. 
The overall study design of phase 1b and phase 3 is described by study schemas at the 
end of the protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
The study will be conducted at approximately 175 sites in Australia, Europe, North 
America, and other regions.  Additional sites and countries may be added. 
Sites that do not enroll subjects within approximately 4 months of site initiation may be 
closed.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Approximately 680 subjects will be enrolled in this study:  approximately 20 subjects will 
be enrolled in phase 1b and approximately 660 subjects will be enrolled in phase 3. 
Refer to Section 10.2 for sample size considerations. 
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3.4 
Replacement of Subjects 
Subjects enrolled in phase 1b may be replaced if they are not evaluable for DLT (eg, did 
not receive study treatment, permanently discontinued talimogene laherparepvec prior to 
receiving the first dose of pembrolizumab for any reason, or ended the study treatment 
before completion of DLT evaluation period for a reason other than experiencing a DLT).   
Subjects enrolled in phase 3 who are withdrawn or removed from treatment or from the 
study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The duration for the study from the initiation of phase 1b is approximately 8 years 
(96 months).  The duration of screening for each subject will be approximately 28 days.  
The subject accrual period for phase 1b is planned for approximately 6 months from the 
initiation of phase 1b.  The subject accrual period for phase 3 is planned for 
approximately 20 months (depending on average per month enrollment rates) from the 
initiation of phase 3.  The duration of treatment will vary for each subject.  Subjects 
enrolled in phase 1b and phase 3 parts of the study will be treated for up to 
approximately 24 months.  Subjects will be followed for safety approximately 
30 (+7) days after the last dose of study treatment and for serious adverse event 
reporting approximately 90 (+7) days after the cessation of all study treatment or 
30 (+7) days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier.  If an end of treatment decision occurs > 30 (+7) days after 
the last treatment date, then the Safety follow-up should be performed as soon as 
possible (eg, within a week of the end of treatment decision).  Subjects will be followed 
for survival for approximately 60 months after the last subject is randomized in phase 3. 
The end of study for each subject is defined as the date the subject withdraws full 
consent from the study, completes the safety follow-up visit or the long-term survival 
follow-up, whichever is later, or death. 
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s). 
The primary completion date is the date when data for the primary endpoint(s) are last 
collected for the purpose of conducting the primary analysis. 
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If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up), as 
applicable. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1). 
4.1 
Inclusion and Exclusion Criteria  
4.1.1 
Inclusion Criteria 
4.1.1.1 
Inclusion Criteria for Phase 1b and Phase 3 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures 
102 
Male or female age ≥ 18 years at the time of informed consent 
103 
Histologically confirmed diagnosis of melanoma 
104 
Disease stage defined as one of the following (per the seventh edition of the 
American Joint Committee on Cancer [AJCC] Cancer Staging Manual):  
Subject with unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c melanoma 
107 
Candidate for intralesional therapy defined as either one of the following: 
 
at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion 
≥ 10 mm in longest diameter 
 
multiple injectable melanoma lesions that in aggregate have a longest 
diameter of ≥ 10 mm injectable disease 
108 
ECOG performance status of 0 or 1 
109 
Adequate organ function determined within 14 days prior to enrollment, defined 
as follows: 
 
Hematological 
o ANC  1.5 x 109/L 
o platelet count  100 x 109/L 
o hemoglobin  9 g/dL (without need for hematopoietic growth factor or 
transfusion support) 
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 
Renal 
o serum creatinine  1.5 x upper limit of normal (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). 
 
Hepatic 
o serum bilirubin  1.5 x ULN OR direct bilirubin ≤ ULN for a subject with 
total bilirubin level > 1.5 x ULN 
o aspartate aminotransferase (AST)  2.5 x ULN OR  5 x ULN for subject 
with liver metastases 
o alanine aminotransferase (ALT)  2.5 x ULN OR  5 x ULN for subject 
with liver metastases 
 
Coagulation 
o international normalization ratio (INR) or prothrombin time (PT) 
 1.5 x ULN unless the subject is receiving anticoagulant therapy as long 
as PT and partial thromboplastin time (PTT)/activated PTT (aPTT) is 
within therapeutic range of intended use of anticoagulants 
110 
Female subject of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to enrollment.  If the urine pregnancy test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
4.1.1.2 
Inclusion Criteria Specific to Phase 1b 
105 
Prior therapy for melanoma inclusion requirement:  Treatment naïve:  Must not 
have received any prior systemic anticancer treatment consisting of 
chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant 
setting for unresectable stage IIIB to IVM1c melanoma 
Note:  Subjects who received prior adjuvant therapy for melanoma will not be 
excluded (including, but not limited to radiotherapy, interferon, limb 
infusion/perfusion, or use of investigational agents in the adjuvant setting).  
However, if the subject received a course of adjuvant therapy, the subject must 
have ended therapy at least 3 months prior to enrollment.  If adjuvant therapy 
was not completed due to intolerance, the subject must have ended therapy at 
least 3 months prior to enrollment.  No prior pembrolizumab, other anti-PD-1, 
anti-PD-L1, anti-PD-L2, anti-CD137, ipilimumab, other CTLA-4 inhibitor, 
talimogene laherparepvec, tumor vaccine, or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways is allowed, 
even if given in the adjuvant setting. 
106 
Measurable disease:  defined as either one of the following: 
 
at least 1 visceral or nodal/soft tissue melanoma lesion (including lymph 
nodes) that can be accurately and serially measured in at least 2 dimensions 
and for which the longest diameter is ≥ 10 mm as measured by CT scan or 
MRI 
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 
at least 1 superficial cutaneous or subcutaneous melanoma lesion that can 
be accurately and serially measured in at least 1 dimension and for which the 
longest diameter is ≥ 10 mm as measured by calipers 
4.1.1.3 
Inclusion Criteria Specific to Phase 3 
105 
BRAFV600 wild-type:  Subjects with BRAFV600 wild-type tumors must not have 
received any prior systemic anticancer treatment consisting of chemotherapy, 
immunotherapy, or targeted therapy given in a non-adjuvant setting for 
unresectable stage IIIB to IVM1c melanoma. 
BRAFV600 mutation:  Subjects with BRAFV600 mutated tumors who have received 
prior BRAF inhibitor therapy either alone or in combination with MEK inhibitor as 
their only prior line of systemic therapy are eligible for this study.  However, the 
subject must have ended BRAF inhibitor therapy either alone or in combination 
with MEK inhibitor at least 14 days prior to enrollment and have adequately 
recovered from any treatment-related adverse events (ie, ≤ Grade 1 or baseline).   
Subjects with BRAFV600 mutant melanoma or unknown BRAFV600 mutation status 
who have not received a BRAF inhibitor are also eligible for the phase 3 of this 
study as first-line treatment if they meet the following criteria:  lactate 
dehydrogenase (LDH) < ULN, no clinically significant tumor related symptoms, 
and absence of rapidly progressing metastatic melanoma. 
Note:  Subjects (BRAF mutant, wildtype and UNK) who received prior adjuvant 
therapy for melanoma will not be excluded (including, but not limited to 
radiotherapy, interferon, limb infusion/perfusion, ipilimumab, or use of 
investigational agents in the adjuvant setting).  However, the subject must have 
ended therapy at least 28 days prior to enrollment.  No prior anti-CD137, 
ipilimumab or other CTLA-4 inhibitor, talimogene laherparepvec, tumor vaccine, 
or any other oncolytic viruses or drugs specifically targeting T-cell co-stimulation 
or checkpoint pathways are allowed in a non-adjuvant setting.  No prior 
pembrolizumab or any other inhibitor of PD-1, PD-L1, or PD-L2 are allowed in 
any setting. 
106 
Measurable disease defined as: 
 
at least 1 visceral or nodal/soft tissue melanoma lesion that can be accurately 
and serially measured in at least 1 dimension and for which the longest 
diameter is ≥ 10 mm as measured by CT scan or MRI.  Lymph nodes must 
measure ≥ 15 mm in their short axis to be considered measurable by 
CT scan or MRI 
111 
Subject has a tumor sample (archival sample obtained within 3 months prior to 
day 1 and no systemic therapy given 3 months prior to archival biopsy or newly 
obtained biopsy) that is submitted for PD-L1 assessment prior to randomization.  
Subject must submit the tumor sample during screening for PD-L1 expression 
testing at a central laboratory.  Subjects will be eligible to participate regardless 
of the level of PD-L1 expression.  Subjects with an unevaluable archival sample 
for PD-L1 expression testing and BRAFV600 mutation testing may obtain a new 
biopsy and subjects with an unevaluable newly obtained biopsy may undergo 
re-biopsy at the discretion of the investigator.  If repeat sample is also 
unevaluable and the subject is otherwise eligible, the investigator may enroll the 
subject with or without a second re-biopsy.  Subjects with an unevaluable newly 
obtained biopsy may undergo re-biopsy at the discretion of the investigator.  If 
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the subject is ready to be randomized and treated after re-biopsy, randomization 
and start of treatment may proceed. 
4.1.2 
Exclusion Criteria – Phase 1b and Phase 3 
201 
Clinically active cerebral melanoma metastases and/or carcinomatous 
meningitis.  Subjects with up to 3 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 not 
requiring steroids for at least 2 months prior to enrollment.  Carcinomatous 
meningitis is excluded regardless of clinical stability. 
202 
Primary uveal or mucosal melanoma 
203 
History or evidence of melanoma associated with immunodeficiency states 
(eg, hereditary immune deficiency, organ transplant, or leukemia) 
204 
History of other malignancy within the past 3 years with the following exceptions: 
 
malignancy treated with curative intent and with no known active disease 
present and has not received chemotherapy for  3 years before enrollment 
and felt to be at low risk for recurrence by the treating physician 
 
adequately treated non-melanoma skin cancer without evidence of disease at 
the time of enrollment 
 
adequately treated cervical carcinoma in situ without evidence of disease at 
the time of enrollment 
 
adequately treated breast ductal carcinoma in situ without evidence of 
disease at the time of enrollment 
 
prostatic intraepithelial neoplasia without evidence of prostate cancer at the 
time of enrollment 
 
adequately treated superficial or in-situ carcinoma of the bladder without 
evidence of disease at the time of enrollment 
205 
Prior therapy with talimogene laherparepvec or any other oncolytic viruses 
206 
Prior therapy with tumor vaccine (unless administered in the adjuvant setting) 
207 
Prior therapy with pembrolizumab or any other inhibitor of PD-1, PD-L1 or PD-L2.  
Prior therapy in a non-adjuvant setting with anti-CD137, or anti-CTLA-4 antibody 
(including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways). 
208 
Prior mAb therapy within 28 days prior to enrollment or who has not recovered 
(ie, ≤ grade 1 or at baseline) from adverse events due to agents administered 
more than 28 days earlier 
209 
Currently receiving treatment in another investigational device or drug study, or 
less than 28 days since ending treatment on another investigational device or 
drug study 
210 
Expected to require other cancer therapy while on study with the exception of 
local radiation treatment to the site of bone and other metastasis for palliative 
pain management 
211 
Other investigational procedures while participating in this study. 
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212 
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. 
213 
Evidence of clinically significant immunosuppression such as the following: 
 
diagnosis of immunodeficiency 
 
concurrent opportunistic infection 
 
receiving systemic immunosuppressive therapy (> 2 weeks) or within 7 days 
prior to the first dose of study treatment, including oral steroid doses 
> 10 mg/day of prednisone or equivalent except for management of adverse 
events and central nervous system (CNS) metastases during the course of 
the study.  Subjects that require intermittent use of bronchodilators or local 
steroid injection will not be excluded from the study. 
214 
Active herpetic skin lesions or prior complications of herpetic infection 
(eg, herpetic keratitis or encephalitis) 
215 
Require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), 
other than intermittent topical use 
216 
Known human immunodeficiency virus (HIV) disease 
217 
Known acute or chronic hepatitis B or hepatitis C infection 
218 
Received live vaccine within 28 days prior to enrollment 
219 
Female subject is pregnant or breast-feeding, or planning to become pregnant 
during study treatment and through 3 months after the last dose of talimogene 
laherparepvec or 4 months after the last dose of pembrolizumab, whichever is 
later 
220 
Female subject of childbearing potential who is unwilling to use acceptable 
method(s) of effective contraception during study treatment and through 
3 months after the last dose of talimogene laherparepvec or 4 months after the 
last dose of pembrolizumab, whichever is later.  Note:  Women not of 
childbearing potential are defined as:   
 
postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle 
stimulating hormone [FSH] level in the postmenopausal range may be used 
to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  In the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
 
have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
screening; 
OR 
 
has a congenital or acquired condition that prevents childbearing. 
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Note:  Acceptable methods of effective contraception are defined in the informed 
consent form.  Where required by local laws and regulations, additional 
country-specific contraception requirements may be outlined in a country-specific 
protocol supplement at the end of the Appendix Section of the protocol. 
221 
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.  
Additional country-specific contraception requirements may be defined in a 
country-specific protocol supplement at the end of the Appendix Section of 
protocol as required by local laws and regulations. 
222 
Subject has known sensitivity to any of the products or components to be 
administered during dosing 
223 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge 
224 
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 physician, if consulted, 
would pose a risk to subject safety or interfere with the study evaluation, 
procedures or completion 
225 
Is or has an immediate family member (eg, spouse, parent/legal guardian, 
sibling, or child) who is investigational site or sponsor staff directly involved in the 
this trial, unless prospective institutional review board (IRB)/independent ethics 
committee (IEC) approval (by chair or designee) is given allowing exception to 
this criterion for a specific subject 
226 
Sexually active subjects and their partners unwilling to use a male or female latex 
condom to avoid potential viral transmission during sexual contact while 
on-treatment and within 30 days after treatment with talimogene laherparepvec.  
For those with latex allergies, polyurethane condoms may be used 
227 
Subject who is unwilling to minimize exposure with his/her blood or other body 
fluids to individuals who are at higher risks for HSV-1 induced complications 
(immunosuppressed individuals, HIV-positive individuals, pregnant women, or 
children under the age of 1 year) during talimogene laherparepvec treatment and 
through 30 days after the last dose of talimogene laherparepvec 
228 
Has undergone prior allogeneic hematopoietic stem cell transplantation within the 
last 5 years.  (Subjects who have had a transplant greater than 5 years ago are 
eligible as long as there are no symptoms of Graft versus Host Disease.) 
229 
Has a known history of active Bacillus tuberculosis 
230 
Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis 
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5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written IRB/IEC approval of the protocol, informed consent 
form, and all other subject information and/or recruitment material, if applicable 
(see Section 11.2).  All subjects must personally sign and date the informed consent 
form before commencement of study-specific activities/procedures. 
Each subject who enters into the screening period for the study (defined as the point 
when the subject signs the informed consent) receives a unique subject identification 
number before any study-related activities/procedures are performed.  The subject 
identification number will be assigned by the interactive voice response system (IVRS).  
The subject identification number will not be the same as the randomization number 
assigned for subjects participating in phase 3.  This subject identification number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject. 
Subjects who are determined not eligible after screening must be screen-failed in the 
IVRS 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 informed consent form is signed within 28 days of 
enrollment or randomization.  Subjects who are determined not eligible after rescreen 
must be screen-failed in the IVRS and the reason for the screen-failure provided.  
Subjects only may be enrolled or randomized once into this study.   
Upon confirmation of eligibility, the site staff will use the IVRS to enroll or randomize a 
subject.  The investigator is to document this decision and date, in the subject’s medical 
record and in/on the enrollment CRF.  For the phase 1b portion, the subjects will be 
considered enrolled upon being registered as enrolled in the IVRS.  For the phase 3 
portion subjects will be considered enrolled upon randomization in the IVRS.  The 
subject identification number must remain constant throughout the entire clinical study; it 
must not be changed after initial assignment, including if a subject is rescreened. 
5.1 
Randomization During Phase 3 
Upon confirmation of eligibility, the site staff will use the IVRS to randomize a subject. 
The IVRS will assign a randomization number.  Approximately 660 subjects will be 
stratified according to stage of disease:  less advanced stages (IIIB, IIIC, and IVM1a) 
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versus more advanced stages (IVM1b and IVM1c) and by prior BRAF inhibitor therapy:  
no prior BRAF inhibitor versus prior BRAF inhibitor with or without MEK inhibitor, and 
randomized with a 1:1 ratio to receive the following: 
 
Arm 1:  talimogene laherparepvec plus pembrolizumab 
 
Arm 2:  placebo plus pembrolizumab  
Following randomization via the IVRS, study treatment must commence within 5 days. 
Eligible subjects must be registered as randomized subjects in the IVRS before the 
administration of protocol-specified therapy. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
The subject, site personnel, and Amgen study personnel and designees are blinded to 
the randomization treatment group assignment unless otherwise specified in this 
protocol.  Refer to Section 10.3 for details on when and how the randomization code 
may be unblinded. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
Talimogene laherparepvec or placebo may be supplied as open label or blinded product.  
Where talimogene laherparepvec or placebo is supplied open label, the site pharmacist 
or designee will need to be unblinded to prepare blinded talimogene 
laherparepvec/placebo.  However, all precaution and efforts, including independent 
monitoring and tracked records, will be taken to ensure the Sponsor and blinded site 
personal will remain blinded to the study treatment.   
 
For talimogene laherparepvec or placebo supplied as open-label investigational 
medicinal product IVRS will confirm to the unblinded site pharmacist or designee 
from which lot number(s) vials must be selected for a patient visit.  In no 
circumstances should an unblinded pharmacist reveal the treatment assignment to 
other site staff. 
 
For talimogene laherparepvec or placebo supplied as blinded investigational 
medicinal product IVRS will confirm to the site pharmacist or designee from which 
box number(s) vials must be selected for a patient visit.  All site personnel will be 
blinded to study treatment. 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study and/or for 
determining eligible treatment options outside of the trial after the subject discontinues 
study treatment due to documented disease progression.  In the event that a subject’s 
treatment assignment must be unblinded by the investigator using the IVRS unblinding 
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module, the subject will require review by the medical monitor to determine if they will be 
allowed to receive any further investigational product.  Unblinding at the study site for 
any other reason will be considered a protocol deviation. 
The principal investigator is strongly encouraged to contact the sponsor before 
unblinding any subject’s treatment assignment, but must do so within 1 working day after 
the event and must document the unblinding in the subject’s electronic case report form. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products 
The Amgen investigational product used in this study:  talimogene laherparepvec or 
placebo. 
The Non-Amgen investigational product used in this study:  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 Products 
6.2.1 
Amgen Investigational Product:  Talimogene Laherparepvec or 
Placebo 
Talimogene laherparepvec and placebo will be manufactured and packaged by Amgen 
Inc. and distributed using Amgen clinical study drug distribution procedures.  The supply 
for the 106 PFU/mL concentration will be packaged separately from the supply for the 
108 PFU/mL concentration. 
Placebo (talimogene laherparepvec formulation excipients as described in the 
Talimogene Laherparepvec Investigator’s Brochure) will be supplied as sterile frozen 
liquid is the same presentation, packaging and with blinded labelling as for talimogene 
laherparepvec. 
6.2.1.1 
Talimogene Laherparepvec or Placebo Dosage, Administration, and 
Schedule 
Talimogene laherparepvec or placebo must be prepared and administered by a qualified 
healthcare professional.  Subjects should be assessed clinically for adverse 
events/toxicity prior to each dose using the CTCAE version 4 (Appendix A).  Complete 
blood count with differential and chemistry panels including liver function laboratory tests 
(ALT, AST, and total bilirubin) and thyroid function tests (triiodothyronine [T3] or free T3 
[FT3] per local standard, free thyroxine [FT4], and thyroid stimulating hormone [TSH]) 
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should be obtained according to the Schedule of Assessments (up to 3 days before 
dosing, see Table 5 and Table 6) and the results should be checked prior to the 
administration of scheduled dose of study drugs.  Dosing will occur only if these test 
values are acceptable, per Section 6.2.1.2. 
Note:  Thyroid function tests must be collected, but if there are no symptoms of 
hypothyroidism or hyperthyroidism, study treatment can be initiated prior to the reporting 
of the laboratory results. 
Talimogene laherparepvec or placebo will be administered by intralesional injection only 
into injectable cutaneous, subcutaneous, and nodal tumors, with or without image 
ultrasound guidance.  Talimogene laherparepvec or placebo must not be administered 
into visceral organ metastases. 
The first cycle of talimogene laherparepvec or placebo will be 21 (+3) days.  Subsequent 
cycles should be given in phase 1 every 2 weeks (± 3) days and in phase 3 every 
2 weeks (± 3) days until week 9 and every 3 weeks (± 3) days thereafter.  On day 1 of 
cycle 1 the first dose of talimogene laherparepvec will be up to 4.0 mL of 106 PFU/mL or 
placebo.  The second injection up to 4.0 mL of 108 PFU/mL should be administered 
21 (+3) days after the initial injection (ie, no sooner than day 22 but should not be 
delayed more than 3 days after the 21-day time point).   
The treatment cycle interval may be increased due to toxicity as described in 
Section 6.2.1.2.  When talimogene laherparepvec or placebo injections and 
pembrolizumab are administered on the same day, talimogene laherparepvec or placebo 
should be administered first, if possible. 
The maximum volume of talimogene laherparepvec or placebo administered at any dose 
is 4.0 mL for any individual lesion.  The maximum dose in any treatment is 4.0 mL.  
Investigators are encouraged to use the maximum amount whenever lesions’ properties 
allow.  Dose reduction for adverse events is not allowed.  However, if in the course of 
administration of talimogene laherparepvec or placebo the subject cannot tolerate the 
full dose due to an injection-related adverse event such as pain, the total volume given 
should be recorded, and the reason for intolerance should be documented as an 
adverse event. 
The recommended volume of talimogene laherparepvec or placebo to be injected into 
the tumor(s) is dependent on the size of the tumor(s) and should be determined 
according to the injection volume guideline in Table 2. 
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Table 2.  Talimogene Laherparepvec or Placebo Injection Volume Guideline 
Based on Tumor Size 
Tumor Size (longest dimension) 
Maximum Injection Volume 
> 5.0 cm 
4.0 mL 
> 2.5 cm to 5.0 cm 
2.0 mL 
> 1.5 cm to 2.5 cm 
1.0 mL 
> 0.5 cm to 1.5 cm 
0.5 mL 
≤ 0.5 cm 
0.1 mL 
For subjects enrolled in phase 1b:  At baseline, if there are ≥ 2 lesions, one lesion 
(ie, the lesion considered lowest priority for injection) amenable for biopsy should be left 
uninjected at least until it is biopsied at time of initial PR, confirmed disease progression, 
or week 24 for subjects with stable disease (SD), whichever comes first.   
For subjects randomized to phase 3:  At baseline, if there are ≥ 2 lesions, one lesion 
(ie, the lesion considered lowest priority for injection) amenable for biopsy should be left 
uninjected at least until it is biopsied at week 5 (see Section 7.2.2).  Aside from leaving 
one lesion uninjected, all other reasonably injectable lesions (cutaneous, subcutaneous 
and nodal disease that can be injected with or without ultrasound guidance) should be 
injected with the maximum dosing volume available on an individual dosing occasion 
(Table 2).  On each treatment day, prioritization of injections is recommended as follows: 
 
any tumor that does not correspond to the uninjected lesion reserved for biopsy until 
week 24 (phase 1b) or week 5 (phase 3) 
 
any new injectable tumor that has appeared since the last injection 
 
by tumor size, beginning with the largest tumor  
 
any previously uninjectable tumor(s) that is now injectable  
It is recommended that each lesion should receive the maximum amount possible to 
inject due to tumor properties at each visit before moving on to the next lesion, using the 
prioritization model above and the injection volume guideline based on tumor size per 
Table 2.  Lesions should be injected until the maximum volume per day (4.0 mL) has 
been reached or there are no further injectable lesions, whichever comes first. 
For phase 1b and phase 3, subjects will be treated with talimogene laherparepvec until 
subjects have achieved a CR, all injectable tumors have disappeared, confirmed PD per 
modified irRC in phase 1b (Appendix D) or iPD per modified irRC-RECIST in phase 3 
(Appendix F), intolerance of study treatment, 24 months from the date of the first dose of 
pembrolizumab, or end of study, whichever occurs first.  Due to the mechanism of 
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action, subjects may experience growth in existing tumors or the appearance of new 
tumors prior to maximal clinical benefit of talimogene laherparepvec.  Therefore, 
talimogene laherparepvec or placebo dosing should continue provided that the subject 
has no evidence of confirmed PD per modified irRC in phase 1b (Appendix D) or iPD per 
modified irRC-RECIST in phase 3 (Appendix F) and is able to tolerate the treatment.The 
dose, start date, and lot/box number of talimogene laherparepvec/placebo are to be 
recorded on the electronic CRF as per the recommendation found in the electronic CRF 
completion guidelines. 
6.2.1.2 
Talimogene Laherparepvec or Placebo Dosage Adjustments, Delays, 
Rules for Withholding or Restarting, Permanent Discontinuation  
If talimogene laherparepvec/placebo 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.  Dose reductions of talimogene laherparepvec or placebo are not 
permitted, other than with respect to a reduction in the volume injected due to a disease 
response. 
If a subject experiences any of the following treatment-related toxicities, talimogene 
laherparepvec/placebo administration should be delayed until the toxicity has resolved to 
at least CTCAE grade 1 or baseline: 
 
grade 2 or greater immune-mediated adverse events, with the exception of vitiligo 
 
grade 2 or greater allergic reactions 
 
any other grade 3 or greater hematologic or non-hematologic toxicity  
Subjects who are receiving talimogene laherparepvec or placebo may not receive 
systemic antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir), but may receive a 
topically administered antiherpetic drug more than 20 cm from a talimogene 
laherparepvec or placebo injection site.  Dosing should be permanently discontinued if, 
in the opinion of the investigator, the subject develops clinical evidence of any systemic 
herpes infection (such as encephalitis or disseminated infection).   
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) 
for pembrolizumab or talimogene laherparepvec/placebo related toxicities, talimogene 
laherparepvec or placebo dosing must be withheld until the corticosteroid dose has 
decreased to 10 mg or < 10 mg prednisone daily (or equivalent). 
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All necessary supportive therapies except for those listed in Section 6.8 shall be 
available to subjects.  Talimogene laherparepvec or placebo treatment should be 
continued based on the potential benefit/risk assessment of the subject. 
If talimogene laherparepvec or placebo dosing is delayed by more than 4 weeks from 
the date of the planned dose (ie, approximately 6 weeks or 7 weeks depending whether 
the patient is receiving Q2W or Q3W dosing from the previous dose) due to the 
occurrence of an adverse event that is considered related to talimogene laherparepvec, 
the subject must be permanently withdrawn from talimogene laherparepvec treatment.   
If talimogene laherparepvec or placebo dosing is delayed by more than 4 weeks from 
the date of the planned dose (ie, approximately 6 weeks or 7 weeks depending whether 
the patient is receiving Q2W or Q3W dosing 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 or placebo doses may be 
given no less than 8 days apart (eg, day 1 and day 9), if needed, for the purpose of  
re-aligning dosing schedules for talimogene laherparepvec or placebo injections and 
pembrolizumab after a dose delay.  The 8 day dosing should only be used for re-aligning 
the talimogene laherparepvec or placebo and pembrolizumab schedule.  It should not be 
utilized to bring doses back to schedule.  The allowable protocol dosing windows should 
be used for this purpose. 
Talimogene laherparepvec or placebo is to be permanently discontinued for subjects 
meeting any of the following criteria: 
 
Phase 1b subject developed DLT during the DLT evaluation period. 
 
The subject, for any reason, requires treatment with another anticancer therapeutic 
agent for treatment of the study disease (other than the exceptions noted in 
Section 6.8).  In this case, discontinuation from the treatment occurs immediately 
upon introduction of the new agent. 
 
Confirmed PD occurs as defined per the modified irRC in phase 1b (Appendix D) or 
iPD per modified irRC-RECIST in phase 3 (Appendix F).  
 
A grade 2 or greater immune-mediated adverse event (with the exception of vitiligo) 
or allergic reactions attributed to talimogene laherparepvec that would require a dose 
delay of greater than 4 weeks from the date of the planned dose (ie, approximately 
6 weeks from the previous dose). 
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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 4 weeks from the date of the planned dose 
(ie, approximately 6 weeks from the previous dose). 
 
The subject develops clinical evidence of any systemic herpes infection (such as 
encephalitis or disseminated infection). 
 
A female subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception (for those subjects who are able to conceive).   
 
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. 
For additional information related special warnings and precautions for the use of 
talimogene laherparepvec please refer to the latest version of the Talimogene 
Laherparepvec Investigator’s Brochure. 
6.2.2 
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 intravenous infusion. 
Additional details regarding the pembrolizumab product are provided in the IPIM. 
6.2.2.1 
Pembrolizumab Dosage, Administration, and Schedule 
Pembrolizumab must be prepared and administered by a qualified healthcare 
professional.  Subjects should be assessed clinically for adverse events/toxicity prior to 
each dose using the CTCAE version 4 (Appendix A).  Complete blood count with 
differential and chemistry panels including liver function laboratory tests (ALT, AST, and 
total bilirubin) and thyroid function tests (triiodothyronine [T3] or FT3 per local standard, 
free thyroxine [FT4], and thyroid stimulating hormone [TSH]) should be obtained 
according to the Schedule of Assessments (up to 3 days before dosing, see Table 5 and 
Table 6) and the results should be checked before each applicable treatment.  Dosing 
will occur only if these test values are acceptable, per Section 6.2.2.2. 
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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. 
In phase 1b, pembrolizumab at a dose of 200 mg will be administered intravenously 
every 2 weeks (± 3 days).  In phase 3 pembrolizumab at a dose of 200 mg will be 
administered intravenously every 3 weeks (± 3 days).  In phase 3, the second dose of 
pembrolizumab will be administered 21 (+3) days after the initial dose.  The treatment 
cycle interval may be increased due to toxicity as described in Section 6.2.2.2.  When 
talimogene laherparepvec and pembrolizumab are administered on the same day, 
talimogene laherparepvec should be administered first, if possible.   
For phase 1b and phase 3, pembrolizumab dosing will continue until confirmed PD per 
the modified irRC in phase 1b (Appendix D) or iPD per modified irRC-RECIST in 
phase 3 (Appendix F), intolerance to treatment, 24 months from the date of the first dose 
of pembrolizumab, or end of study, whichever occurs first.  For subjects who have 
attained a confirmed CR, discontinuation of treatment may be considered if the subjects 
have been treated for at least 24 weeks with pembrolizumab and had at least 
2 treatments with pembrolizumab beyond the date when the initial CR was declared. 
Pembrolizumab infusion will be administered as a 30-minute intravenous infusion.  
Investigators should make every effort to target infusion timing to be as close to 
30 minutes as possible.  However, given the variability of infusion pumps from site to 
site, a window of -5 and +10 minutes is permitted (ie, infusion time is 
30 minutes:  -5 min/+10 min).  A central catheter is not required for infusion; however if a 
subject has a central venous catheter in place, it is recommended that it be used for the 
infusion.  A 0.2 or 0.22 µm in-line filter made of polyethersulfone (PES) must be used 
during administration to remove any adventitious particles.  If the infusion set does not 
contain a 0.2 or 0.22 µm in-line filter, it is recommended to use an extension line 
containing the filter.  Details on the preparation and administration are provided in the 
IPIM. 
The dose, start date, and lot number of pembrolizumab are to be recorded on the 
electronic CRF. 
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6.2.2.2 
Pembrolizumab Dosage Adjustments, Delays, Rules for Withholding 
or Restarting, Permanent Discontinuation 
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment.  
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening 
AEs as per Table 3 below  See Section 6.2.2.3 for supportive care guidelines, including 
use of corticosteroids. 
Table 3.  Pembrolizumab-related Adverse Event Management 
General instructions: 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered.  Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
For severe and life-threatening irAEs, intravenous corticosteroid should be initiated first followed by oral 
steroid.  Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids. 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and 
follow-up 
Pneumonitis 
Grade 2 
Withhold 
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Monitor 
participants for 
signs and 
symptoms of 
pneumonitis 
Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
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Table 3.  Pembrolizumab-related Adverse Event Management 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and 
follow-up 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
Administer 
corticosteroids (initial 
dose of  
1-2 mg/kg
prednisone or
equivalent) followed
by taper
Monitor 
participants for 
signs and 
symptoms of 
enterocolitis 
(ie, diarrhea, 
abdominal pain, 
blood or mucus 
in stool with or 
without fever) 
and of bowel 
perforation 
(ie, peritoneal 
signs and ileus) 
Participants with 
≥ Grade 2 
diarrhea 
suspecting colitis 
should consider  
GI consultation 
and performing 
endoscopy to 
rule out colitis  
Participants with 
diarrhea/colitis 
should be 
advised to drink 
liberal quantities 
of clear fluids.  If 
sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes 
should be 
substituted via 
IV infusion 
Grade 4 
Permanently 
discontinue 
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Table 3.  Pembrolizumab-related Adverse Event Management 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and 
follow-up 
AST/ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer 
corticosteroids (initial 
dose of 0.5 - 1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Monitor with liver 
function tests 
(consider weekly or 
more frequently until 
liver enzyme value 
returned to baseline 
or is stable 
Grade 3 or 4 
Permanently 
discontinue 
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of  
-cell failure 
Withhold 
Initiate insulin 
replacement therapy 
for participants with 
T1DM  
Administer  
anti-hyperglycemic in 
participants with 
hyperglycemia  
Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.  
Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal 
insufficiency)  
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hyperthyroidism 
Grade 2 
Continue 
Treat with  
non-selective  
beta-blockers  
(eg, propranolol) or 
thionamides as 
appropriate  
Monitor for signs 
and symptoms of 
thyroid disorders  
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
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Table 3.  Pembrolizumab-related Adverse Event Management 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and 
follow-up 
Hypothyroidism 
Grade 2-4 
Continue 
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
Monitor for signs 
and symptoms of 
thyroid disorders 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold 
Administer 
corticosteroids 
(prednisone  
1 – 2 mg/kg or 
equivalent) followed 
by taper. 
Monitor changes 
of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
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Table 3.  Pembrolizumab-related Adverse Event Management 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and 
follow-up 
All other  
immune-related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
Based on type and 
severity of AE 
administer 
corticosteroids  
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:   
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
1 Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.   
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when adverse event resolves to ≤ Grade 2 and is controlled 
with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 
For myocarditis, in certain circumstances, pembrolizumab may be resumed at grade 1 only if the 
investigator believes that the myocarditis has clinically resolved and the investigator has obtained written 
permission from the medical monitor to resume therapy.   
Page 5 of 5 
AE = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = common terminology criteria for adverse events; irAE = immune-related adverse events 
Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (eg, elective surgery, unrelated medical events, 
patient vacation, and/or holidays).  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 patient's study 
record. 
Subjects enrolled in the phase 1b who develop DLT during the DLT evaluation period 
will permanently discontinue pembrolizumab. 
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6.2.2.3 
Rescue Medications and Supportive Care Guidelines for 
Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator including, but not limited, to the items outlined in Table 3. 
Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined in Table 3.  Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other 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 the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined in Table 3).  Refer to 
Section 6.2.1.2 for dose modification. 
It may be necessary to perform additional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. 
6.2.2.3.1 
Dose Modification and Toxicity Management of Infusion Reactions 
Related to Pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion reaction including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  Dose modification and toxicity management guidelines on  
pembrolizumab-associated infusion reaction are provided in Table 4. 
 
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Table 4.  Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion interruption but 
responds promptly to symptomatic treatment (eg, 
antihistamines, non-steroidal anti-inflammatory drugs 
[NSAIDs], narcotics, intravenous [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 participant 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 (eg, from 100 mL/hr to  
50 mL/hr.). Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment. 
 
Participant may be premedicated 1.5 h 
(± 30 minutes) prior to infusion of _____ with: 
Diphenhydramine 50 mg po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg po (or equivalent dose 
of analgesic). 
Page 1 of 2 
 
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Table 4.  Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grades 3 or 4 
 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial 
improvement; hospitalization indicated for other 
clinical sequelae (eg, renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or ventilator 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 participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from further 
study drug treatment. 
 
No subsequent dosing 
Page 2 of 2 
** 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 v4.0 (CTCAE) at http://ctep.cancer.gov 
 
 
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6.2.2.4 
Diet and Other Considerations While Taking Pembrolizumab 
6.2.2.4.1 
Diet During Treatment With Pembrolizumab 
Subjects should maintain a normal diet unless modifications are required to manage 
adverse events such as diarrhea, nausea, or vomiting. 
6.2.2.4.2 
Contraception Requirement 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 220 and 221) from the 
day of pembrolizumab initiation (or 14 days prior to the initiation of pembrolizumab for 
oral contraception) throughout the study period up to 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. 
6.2.2.4.3 
Use of Pembrolizumab in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The outcome of the pregnancy will 
be reported to Amgen and followed as described in Section 9.3 (Pregnancy and 
Lactation Reporting). 
6.2.2.4.4 
Use of Pembrolizumab in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, female subjects who are breast-feeding are not eligible for enrollment in 
this study. 
6.3 
Other Protocol-required Therapies 
All other protocol-required therapies including, topical anesthetic or an injectable local 
anesthetic medications used for pretreatment of the talimogene laherparepvec/placebo 
injection site and oral or systemic steroids for management of pembrolizumab irAEs that 
are commercially available are not provided or reimbursed by Amgen (except if required 
by local regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies. 
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Additional details regarding these protocol-required therapies are provided in the IPIM. 
6.4 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 
All prescription and nonprescription concomitant medication administered up to 28 days 
prior to enrollment/randomization, on an ongoing basis at enrollment/randomization, as 
well as changes in such concomitant medication, and, any new concomitant medication 
taken while the subject is on study, should be recorded on the appropriate CRF through 
30 (+7) days after the last dose of talimogene laherparepvec/placebo or pembrolizumab, 
whichever is later.  Concomitant medications administered 30 (+7) days after last dose 
of talimogene laherparepvec/placebo or pembrolizumab for serious adverse events 
should for recorded as defined in Section 9.2.  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. 
6.5 
Other Treatment Procedures  
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 
cutaneous or subcutaneous lesions for tumor analysis during the study.  However, 
resection of lesions may occur only following tumor assessment.  If a subject undergoes 
resection of the lesion, the investigator or designee should notify the sponsor medical 
monitor as soon as possible.  Tumor biopsies of the resected lesion are to be collected 
for 
 analysis. 
Local radiation treatment to the site of bone and other metastasis will be permitted for 
palliative pain management at any time during the study.  If a subject undergoes local 
radiation, the investigator or designee should notify the sponsor’s medical monitor as 
soon as possible. 
If a subject demonstrates evidence of new or worsening CNS metastases, all study 
treatments should be withheld and the investigator or designee should notify the 
sponsor’s medical monitor as soon as possible.  Subjects may be allowed to remain on 
study after discussion between the sponsor’s medical monitor and the investigator to 
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determine the appropriateness of treatment resumption provided CNS lesions can be 
treated with stereotactic radiotherapy, Gamma Knife, or craniotomy.  After approval is 
obtained from the sponsor’s medical monitor, subjects may be allowed to reinitiate 
talimogene laherparepvec/placebo and/or pembrolizumab treatment per Sections 6.2.1.1 
and 6.2.2.1, respectively, following stereotactic radiotherapy only when dosing of 
corticosteroid is below 1.5 mg dexamethasone, 10 mg prednisone or equivalent.  If 
higher doses of corticosteroid are used, talimogene laherparepvec/placebo and/or 
pembrolizumab must be held until that dose level is reached during the period of steroid 
tapering. 
6.6 
Medical Devices 
Medical devices (eg, 0.2 or 0.22 μm in-line filter made of polyethersulfone, intravenous 
administration set, infusion pump syringes, sterile needles, alcohol prep pads) that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.   
6.7 
Product Complaints 
A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of any investigational or non-investigational product(s) or device(s). 
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.8 
Excluded Treatments and/or Procedures During Study Period  
Subjects must not use any of the following therapies during the screening or treatment 
period, unless indicated otherwise: 
 
other investigational agents or procedures 
 
concurrent experimental or approved antitumor therapies other than study drugs and 
radiation therapy required for palliation.   
 
immunosuppressive agents (with the exception of treatment for adverse events [see 
Sections 6.2.1.2, 6.2.2.2, and 6.2.2.3] and CNS metastases [see Section 6.5]) 
 
any live vaccine therapies used for the prevention of infectious disease within 
28 days prior to enrollment and during the treatment period  
 
antiherpetic drugs, other than if topically administered > 20 cm from a talimogene 
laherparepvec injection site 
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 
any surgery or radiotherapy for melanoma (other than the exceptions noted in 
Section 6.5) 
 
Subjects must not schedule any elective surgeries (other than the exceptions noted 
in Section 6.5) during the treatment period and for at least 30 days after the last 
administration of study drugs.  If a subject undergoes any unexpected surgery during 
the course of the study, all study treatments must be withheld and the investigator or 
designee should notify the sponsor’s medical monitor as soon as possible.  A subject 
may be allowed to resume study drugs if both the investigator and sponsor’s medical 
monitor agree to restart study therapy. 
The exclusion criteria describe other medications and procedures which are prohibited in 
this study (refer to Sections 4.1.2).  The investigator or their designee must consult with 
the sponsor’s medical monitor about subjects in the post-treatment follow up period who 
have not demonstrated confirmed disease progression, clinical instability 
(Section 3.1.3.1), or intolerance to pembrolizumab and/or talimogene laherparepvec 
prior to starting any experimental or approved antitumor therapies. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
For Schedule of Assessments for phase 1b, phase 3 arm 1, and phase 3 arm 2 refer to 
Table 5 and Table 6, respectively. 
 
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Table 5.  Schedule of Assessments for Phase 1b 
 
Screening 
Study Treatment d 
(week number) 
Follow-up 
Study Procedures 
≤ 28 
days a 
≤ 14 
days b 
≤ 72 
hour c -5 
-2 
0 
2 
4 6 
8 
10 
12 
14 
16 
18 
20 
22 
24 z 
> 24 
weeksdd 
Safety e 
Survival f 
General Assessments 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical, Surgical 
and Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recording of Concomitant 
Medicationi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xaa 
Vital Signs g 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Physical Exam Including Body 
Weight 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG Performance Status 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead electrocardiogram (ECG) h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Review of AEs and SAEs i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xf 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Local Laboratory Tests 
Chemistry j 
 
X 
 
X 
X 
X  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Hematology k 
 
X 
 
X 
X 
X  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Total Immunoglobulin G (IgG) 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis cc 
 
X 
 
 
 
X  
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Lactate Dehydrogenase (LDH) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT or INR and PTT or aPTT bb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4, TSH l 
 
X 
 
 
 
X  
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Urine or Serum Pregnancy Test m 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 2 
Footnotes defined on last page of table. 
 
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Table 5.  Schedule of Assessments for Phase 1b 
 
Screening 
Study Treatment d 
(week number) 
Follow-up 
Study Procedures 
≤ 28 
days a 
≤ 14 
days b 
≤ 72 
hour c 
-5 -2 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 z 
> 24 
weeksdd 
Safety e 
Survival f 
Central Laboratory Tests 
Swab of Herpetic Lesion for 
Real-Time Polymerase Chain 
Reaction (qPCR) s 
 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
 
Response Assessments 
Clinical Tumor Assessment t 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Photographs of Visible Cutaneous & 
Subcutaneous Tumor Lesions u 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Radiographic (CT, PET/CT, MRI, or 
US) Scans & Tumor Assessment v,w 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Treatment Administration 
Talimogene laherparepvec x 
 
 
 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pembrolizumab y 
 
 
 
 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Reporting Exposure to Talimogene Laherparepvec 
Exposure of Healthcare Provider 
or Close Contact 
 
 
 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Page 2 of 2 
Footnotes defined on next page.  
 
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Note:  Subjects enrolled in the phase 1b will receive talimogene laherparepvec 5 weeks before the initiation of pembrolizumab treatment.  The start of talimogene 
laherparepvec will be defined as week -5.  The start of pembrolizumab will be defined as week 0. 
a Procedures to be performed ≤ 28 days prior to enrollment. 
b Procedures to be performed ≤ 14 days prior to enrollment. 
c Procedures to be performed ≤ 72 hours prior to enrollment. 
d Talimogene laherparepvec treatment should begin as soon as possible after enrollment via IVRS but no later than 5 days after enrollment.  During treatment, 
assessments and procedures will be performed within ± 3 days of the planned visit unless indicated otherwise. 
e Safety follow-up will be performed approximately 30 (+7) days after the last dose of talimogene laherparepvec or the last dose of pembrolizumab, whichever is later.  
If an end of treatment decision occurs > 30 (+7) days after the last treatment date, then the safety follow-up should be performed as soon as possible (eg, within a 
week of the end of treatment decision). 
f Subjects will be followed for survival every 12 weeks (± 28 days) from the date of the safety follow-up visit (or from the planned visit date if the safety follow-up visit 
does not occur) up to 60 months after the last subject randomized in phase 3.  Subsequent cancer treatments for melanoma and talimogene laherparepvec-related 
adverse events will be collected as part of the long-term follow-up survival assessment.   
g Vital signs (systolic/diastolic blood pressure, heart beat, respiration rate, and temperature) must be performed prior to the study treatment (talimogene laherparepvec 
and/or pembrolizumab) administration at week -5, -2, 0, then every 4 weeks, and at the safety follow-up. 
h A single 12-lead ECG will be performed ≤ 28 days before enrollment and the safety follow-up visit. 
i All SAEs that occur after the subject has signed the main informed consent through 90 (+7) days after the cessation of all study treatment or 30 (+7) days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, whichever is later, will be reported to Amgen and recorded in the CRF.  
SAEs must be reported to Amgen within 24 hours of the investigator knowledge of the event.  All non-serious AEs that occur after first dose of talimogene 
laherparepvec or pembrolizumab and concomitant medications that are administered after enrollment through 30 (+7) days after the last dose of talimogene 
laherparepvec or the last dose of pembrolizumab, whichever is later, will be recorded in the case report form.  Selected non-serious and serious AEs known as 
pembrolizumab Events of Clinical Interest that occurs after the first dose of pembrolizumab through 90 (+7) days after the last dose of pembrolizumab, or 
30 (+7) days after initiation of a new anticancer therapy, whichever is earlier, must be reported to Amgen within 24 hours of the investigator’s knowledge of the event 
regardless of attribution to pembrolizumab.  AEs and concomitant medications should be assessed on an ongoing basis and recorded at each subject visit. 
j Blood samples for chemistry will be collected at screening.  During treatment blood samples will be collected prior to study treatment administration at day 1 (-3 days) 
of weeks -5, -2, 0, then every 4 weeks until end of study treatment.  Results should be reviewed prior to the administration of scheduled dose of study drugs.  Blood 
sample will also be collected at the safety follow-up visit (-3 days). 
k Blood samples for hematology will be collected at screening.  During treatment blood samples will be collected prior to study treatment administration at day 1 
(-3 days) of weeks -5, -2, 0, then every 4 weeks until end of study treatment.  Results should be reviewed prior to the administration of scheduled dose of study 
drugs.  Blood sample will also be collected at the safety follow-up visit (-3 days). 
l Blood samples for thyroid function tests (T3 [or FT3 per local standard], FT4, and TSH) will be collected at screening.  Samples will be collected prior to study 
treatment administration on Day 1 (- 3 days) every 6 weeks until end of study treatment.  Blood sample will also be collected at the safety follow-up visit (-3 days).    
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.  A urine pregnancy test should be performed within 72 hours prior to enrollment 
and at the safety follow-up visit.  If urine pregnancy test result is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  Note:  
Additional (eg, monthly) on-treatment pregnancy testing should be conducted as required per local laws and regulations, where applicable. 
 
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s Swab of any lesion of herpetic origin for qPCR testing of talimogene laherparepvec DNA:  Upon notification of a suspected herpetic lesion by the subject, the subject 
should be instructed to 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 collected, stored, and ultimately tested for the 
detection of talimogene laherparepvec DNA using qPCR.   
t Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions by caliper and response assessment per modified irRC (Appendix D).  The 
screening clinical measurements must be done within 28 days prior to enrollment.  During treatment, the clinical tumor assessments will performed independent of 
treatment cycle at week 0 (after 2 cycles of talimogene laherparepvec and prior to start of pembrolizumab), week 12 (+1 week) and every 12 weeks (+1 week) 
thereafter or more frequently if clinically indicated until confirmed PD per modified irRC (Appendix D) or start of new anticancer treatment.  The schedule of clinical 
assessment of tumor lesions should not be adjusted for cycle initiation delays and performed according to the calendar.  Response or progression should be by 
repeated clinical assessment ≥ 4 weeks after the first indication of response or progression.  Tumor assessment is required at the safety follow up visit if the subject 
ended treatment prior to confirmed PD and has not had clinical tumor assessments performed within 4 weeks (+1 week) of the visit.  For subjects who discontinued 
treatment for any reason other than confirmed PD, every effort should be made to complete clinical tumor assessments every 12 weeks (+1 week) or more frequently 
if clinically indicated during the long-term follow-up until documentation of confirmed PD per modified irRC (Appendix D), start of new anticancer treatment, if present, 
whichever occurs first.  Note:  When a lesion can be accurately evaluated by both radiographic imaging and clinical examination, radiographic imaging evaluations 
should be undertaken. 
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u Photographs of up to 5 (maximum 5 per organ) visible (ie, visible protrusion from skin surface) cutaneous and subcutaneous measurable tumor lesions which are 
selected as index lesions will be performed at screening within 28 days prior to enrollment.  During treatment, the photographs of visible cutaneous and 
subcutaneous index tumor lesions and of new visible lesion cutaneous and subcutaneous lesions, if present, will be performed independent of treatment cycle at 
week 0 (after 2 cycles of talimogene laherparepvec and prior to start of pembrolizumab), week 12 (+1 week) and every 12 weeks (+1 week) thereafter or more 
frequently if clinically indicated until confirmed PD per modified irRC (Appendix D) or start of new anticancer treatment.  The schedule of photograph of tumor lesions 
should not be adjusted for cycle initiation delays and performed according to the calendar.  Response or progression should be confirmed by repeated photographs  
≥ 4 weeks after the first indication of response or progression.  Photographs of visible cutaneous and subcutaneous index tumor lesions and of new visible cutaneous 
and subcutaneous lesions, if present, is required at the safety follow up visit if the subject ended treatment prior to confirmed PD and has not had photographs 
performed within 4 weeks (+1 week) of the visit.  For subjects who discontinued treatment for any reason other than PD, every effort should be made to complete 
photographs of visible cutaneous and subcutaneous index lesions and of new visible cutaneous and subcutaneous lesions, if present, every 12 weeks (+1 week) or 
more frequently if clinically indicated during the long-term follow-up until documentation of confirmed PD per modified irRC (Appendix D), start of new anticancer 
treatment, or end of study, whichever occurs first.  The photographic images will collected and held for possible supportive retrospective review of tumor response by 
a blinded independent central review committee.  Note:  When a lesion can be accurately evaluated by both radiographic imaging and photographs, radiographic 
imaging evaluations should be undertaken. 
v Radiographic imaging (CT, PET/CT, or MRI) of the chest, abdomen, and pelvis, and CT or MRI of the brain are required at screening.  Tumor assessments must also 
include all other sites of disease.  The screening scans must be done within 28 days prior to enrollment.  During treatment, radiographic imaging (CT or MRI) of the 
abdomen, pelvis, and chest, along with tumor assessments of all other sites of disease, (and CT or MRI of the brain if a subject has symptoms or signs suggestive of 
CNS metastases), will be performed independent of treatment cycle at week 0 (after 2 cycles of talimogene laherparepvec and prior to start of pembrolizumab), 
week 12 (+1 week), and then every 12 weeks (+1 week) or more frequently if clinically indicated until confirmed PD per modified irRC (Appendix D) or start of new 
anticancer treatment.  Imaging should not be adjusted for cycle initiation delays and performed according to the calendar.  The imaging modality selected (eg, CT or 
MRI) should remain constant for any individual subject.  Response or progression should be confirmed by repeated radiographic imaging ≥ 4 weeks after the first 
indication of response or progression.  Radiographic imaging is required at the safety follow up visit if the subject ended treatment prior to confirmed PD and has not 
had radiographic tumor imaging performed within 4 weeks (+1 week) of the visit.  For subjects who discontinued treatment for any reason other than confirmed PD, 
every effort should be made to complete radiographic assessments every 12 weeks (+1 week) or more frequently if clinically indicated during the long-term follow-up 
until documentation of confirmed PD per modified irRC (Appendix D), start of new anticancer therapy, or end of study, whichever occurs first.  Subjects who have 
reached a confirmed CR may increase their interval of radiographic assessments up to 6 months after the first 2 years beyond confirmed CR and up to 12 months 
after the first 5 years beyond confirmed CR as long as CR is maintained.  The radiographic images will be collected and held for possible supportive retrospective 
review of tumor response by a blinded independent central review committee. 
w Response (CR, or PR) or PD to be confirmed by second consecutive response assessment no less than 4 weeks from the date of the first documented response or 
PD. 
x Talimogene laherparepvec will be administered to subjects randomized on day 1 of week -5, day 1 of week -2 (+3 days), day 1 of week 0 (± 3 days) and every 
2 weeks (± 3 days) thereafter.  The initial dose of talimogene laherparepvec is up to 4.0 mL of 106 PFU/mL.  Subsequent doses of talimogene laherparepvec are up 
to 4.0 mL of 108 PFU/mL.  Dosing of talimogene laherparepvec should be continued until CR, disappearance of injected lesion, confirmed PD per modified irRC 
(Appendix D), intolerance of study treatment, 24 months from the first dose of talimogene laherparepvec, or end of study, whichever occurs first.  Due to the 
mechanism of action, subjects may experience growth in existing tumors or the appearance of new tumors prior to maximal clinical benefit of talimogene 
laherparepvec.  Therefore, dosing should be continued provided that the subject has no evidence of confirmed PD per modified irRC (Appendix D) and is able to 
tolerate the treatment.  Assessments and procedures are to be performed within 3 days of the planned visit and results available prior to study drug administration, 
unless otherwise specified.  It is recommended that dosing occur on the same day of the week (eg, if first dose is administered on a Monday, all subsequent doses 
should be administered on a Monday), however, a ± 3 day dosing window is allowed. 
 
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y Pembrolizumab will be administered intravenously to subjects randomized at a dose of 200 mg every 2 weeks (± 3-days) starting at day 1 of week 0 (at the time of the 
third dose of talimogene laherparepvec) until confirmed PD per modified irRC (Appendix D), intolerance to pembrolizumab, 24 months from the first dose of 
pembrolizumab, or end of study, whichever occurs first.  When talimogene laherparepvec and pembrolizumab are administered on the same day, talimogene 
laherparepvec should be administered first, if possible.   
z Repeat week 24 procedures and assessments until end of study treatment unless otherwise indicated. 
aa Only subsequent treatment for melanoma will be recorded. 
bb Blood sample for coagulation will be collected at screening.  During treatment, blood samples should be collected for coagulation as clinically indicated. 
cc Urine samples for urinalysis will be collected at screening.  During treatment urine samples will be collected prior to study treatment administration at day 1 of 
weeks 0, 8, 16 then every 8 weeks until end of study treatment.  Results should be reviewed prior to the administration of scheduled dose of study drugs.  Urine 
sample will also be collected at the safety follow-up visit.  Reflexive microscopy should be obtained for any abnormal urinalysis result. 
dd  > 24 study treatment week number pertains to all the study procedures required beyond week 24.  To determine the frequency of each study procedure, please refer 
to the footnote associated with that particular study procedure. 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 82 of 171 
CONFIDENTIAL 
 
 
Table 6.  Schedule of Assessments for Phase 3 – Arms 1 and 2 
 
Screening 
Study Treatment d 
(week number) 
Follow-up 
Study Procedures 
≤ 28 days a ≤ 14 days b ≤ 72 hour c 
0 
3 
5 
6 
7 
9 
12 
15 
18 
21 
24y 
> 24 
weeksee
Safety e 
Survival f 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical, Surgical and 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recording of Concomitant Medication i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X Z 
Vital Signs g 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Physical Exam Including Body Weight 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG Performance Status 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Review of AEs and SAEs i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xf 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
QLQ-C30 Questionnaire cc 
 
 
 
X 
X 
 
X 
  
X 
X 
 
X 
  
X 
X 
X 
X 
EQ-5D-3L dd 
 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Local Laboratory Tests 
Chemistry j 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Hematology k 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Total Immunoglobulin G (IgG) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis bb 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
LDH 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
PT or INR and PTT or aPTT aa 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4, TSH l 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Urine or Serum Pregnancy Test m 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 2 
Footnotes defined on last page of table.  
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 83 of 171 
CONFIDENTIAL 
 
 
Table 6.  Schedule of Assessments for Phase 3 – Arms 1 and 2 
 
Screening 
Study Treatment d 
(week number) 
Follow-up 
Study Procedures 
≤ 28 days a ≤ 14 days b ≤ 72 hour c 0 
3 
5 
6 
7 
9 
12 
15 
18 
21 
24y 
> 24 
weeksee 
Safety e 
Survival 
f 
Central Laboratory Tests 
Swab of Herpetic Lesion for qPCR s 
 
 
 
Within 3 days of occurrence of suspected lesion of herpetic origin 
 
 
Response Assessments 
Photographs of Visible Cutaneous & 
Subcutaneous Tumor Lesions t 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Radiographic (CT, PET/CT, or MRI) 
Scans & Tumor Assessment u,v 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Treatment Administration 
Talimogene laherparepvec or placebow 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pembrolizumab x 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Reporting Exposure to Talimogene Laherparepvec or Placebo 
Exposure of Healthcare Provider 
or Close Contact 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Page 2 of 2 
Footnotes defined on next page. 
 
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Date:  15 January 2020 
Page 84 of 171 
CONFIDENTIAL 
 
 
a Procedures to be performed ≤ 28 days prior to enrollment. 
b Procedures to be performed ≤ 14 days prior to enrollment. 
c Procedures to be performed ≤ 72 hours prior to enrollment. 
d Treatment should begin as soon as possible after randomization via IVRS but no later than 5 days after randomization.  During treatment, assessments and 
procedures will be performed within ± 3 days of the planned visit unless indicated otherwise. 
e Safety follow-up will be performed approximately 30 (+7) days after the last dose of talimogene laherparepvec or placebo or the last dose of pembrolizumab, 
whichever is later.  If an end of treatment decision occurs > 30 (+7) days after the last treatment date, then the safety follow-up should be performed as soon as 
possible (eg, within a week of the end of treatment decision). 
f Subjects will be followed for survival every 12 weeks (± 28 days) from the date of the safety follow-up visit (or from the planned visit date if the safety follow-up visit 
does not occur) until death, subject withdraws full consent, or up to 60 months after the last subjects randomized in phase 3.  Subsequent cancer treatments for 
melanoma and any injected investigational product-related adverse events and EQ-5D-3L (every 12 weeks) will be collected as part of the long-term follow-up survival 
assessment.   
g Vital signs (systolic/diastolic blood pressure, heart beat, respiration rate, and temperature) must be performed prior to the study treatment (talimogene laherparepvec 
and/or pembrolizumab) administration at week 0, 3, 6, 12 and every 6 weeks thereafter, and at the safety follow-up. 
h  A single 12-lead ECG will be performed ≤ 28 days before enrollment and the safety follow-up visit. 
i All SAEs that occur during screening through 90 (+7) days after the cessation of all study treatment or 30 (+7) days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, will be reported to Amgen and recorded in the CRF.  SAEs must be reported to Amgen within 24 hours of the 
investigator knowledge of the event.  All non-serious AEs that occur after first dose of talimogene laherparepvec or pembrolizumab and concomitant medications that 
are administered after randomization through 30 (+7) days after the last dose of talimogene laherparepvec or placebo or the last dose of pembrolizumab, whichever is 
later, will be recorded in the CRF.  Selected non-serious and serious AEs known as pembrolizumab Events of Clinical Interest that occur after the first dose of 
pembrolizumab through the safety follow up period, or 30 (+7) days after initiation of a new anticancer therapy, whichever is earlier, must be reported to Amgen within 
24 hours of the investigator’s knowledge of the event regardless of attribution to pembrolizumab.  AEs and concomitant medications should be assessed on an ongoing 
basis and recorded at each subject visit.  Talimogene laherparepvec/placebo-related AEs will be collected following the long term safety follow-up period until end of 
study. 
j Blood samples for chemistry will be collected at screening.  During treatment blood samples will be collected prior to study treatment administration at day 1 (-3 days) 
of week 0, day 1 of week 3, 6, 12 and then every 6 weeks until end of study treatment.  Results should be reviewed prior to the administration of scheduled dose of 
study drugs.  Blood sample will also be collected at the safety follow-up visit (-3 days). 
k Blood samples for hematology will be collected at screening.  During treatment blood samples will be collected prior to study treatment administration at day 1 
(-3 days) of week 0, day 1 of week 3, 6, 12 and then every 6 weeks until end of study treatment.  Results should be reviewed prior to the administration of scheduled 
dose of study drugs.  Blood sample will also be collected at the safety follow-up visit (-3 days). 
l Blood samples for thyroid function tests (T3 [or FT3 per local standard], FT4, and TSH) will be collected at screening.  Samples will be collected prior to study 
treatment administration on day 1 (- 3 days) every 6 weeks until end of study treatment.  Blood sample will also be collected at the safety follow-up visit (-3 days).  
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.  A urine pregnancy test should be performed within 72 hours prior to enrollment 
and at the safety follow-up.  If urine pregnancy test result is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  Note:  Additional 
(eg, monthly) on-treatment pregnancy testing should be conducted as required per local laws and regulations, where applicable. 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 85 of 171 
CONFIDENTIAL 
s Swab of any lesion of herpetic origin for qPCR testing of talimogene laherparepvec DNA:  Upon notification of a suspected herpetic lesion by the subject, the subject
should be instructed to 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 collected, stored, and ultimately tested for the detection of
talimogene laherparepvec DNA using qPCR.
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 86 of 171 
CONFIDENTIAL 
 
 
t Photographs of all visible (ie, visible protrusion from skin surface) cutaneous and subcutaneous tumor lesions not detectable on radiographic imaging must be 
performed at screening within 28 days prior to enrollment for the purposes of documentation of baseline lesion data.  It is critical that baseline photography is captured 
for subjects with visible cutaneous and subcutaneous tumor lesions in order to allow for follow up of these lesions during the treatment phase.  During treatment, the 
photographs of all visible cutaneous and subcutaneous tumor lesions not detectable on radiographic imaging, including new visible lesion cutaneous and subcutaneous 
lesions, if present, must be performed independent of treatment cycle at Day 1 of week 12 (+1 week) and every 12 weeks (+1 week) thereafter or more frequently if 
clinically indicated until confirmed iPD per modified irRC-RECIST (Appendix F) or start of new anticancer treatment.  Photographs must also be taken for previously 
visible cutaneous and subcutaneous tumor lesions that have resolved at subsequent tumor assessment visits.  The schedule of photograph of tumor lesions should not 
be adjusted for cycle initiation delays and performed according to the calendar.  Response or progression should be confirmed by repeated photographs ≥ 4 weeks 
after the first indication of response or progression.  Photographs of all visible cutaneous and subcutaneous tumor lesions not detectable on radiographic imaging, 
including new visible cutaneous and subcutaneous lesions, if present, is required at the safety follow-up visit if the subject ended treatment prior to confirmed iPD and 
has not had photographs performed within 4 weeks (+1 week) of the visit.  For subjects who discontinued treatment for any reason other than iPD, every effort should 
be made to complete photographs of all visible cutaneous and subcutaneous lesions not detectable on radiographic imaging, including new visible cutaneous and 
subcutaneous lesions, if present, every 12 weeks (+1 week) or more frequently if clinically indicated during the long-term follow-up until documentation of confirmed 
iPD per modified irRC-RECIST (Appendix F), start of new anticancer treatment, or end of study, whichever occurs first.  Subjects who have reached a confirmed iCR 
may increase their interval of radiographic assessments up to 6 months after the first 2 years beyond confirmed iCR and up to 12 months after the first 5 years beyond 
confirmed iCR as long as iCR is maintained.  The photographic images will be collected for review of tumor response by a blinded independent central review 
committee.  Photographed lesions not appearing on radiographic imaging should only be considered non-target lesions and not target lesions.  Note:  When a lesion 
can be accurately evaluated by both radiographic imaging and photographs, radiographic imaging evaluations must be undertaken.  When a lesion/lesions can not be 
evaluated by radiographic imaging, but can be accurately evaluated by both clinical examination and photographs, photographs must be undertaken. 
u Radiographic imaging (CT, PET/CT, or MRI) of the chest, abdomen, and pelvis, and CT or MRI of the brain are required at screening.  Tumor assessments must also 
include all other sites of disease.  The screening scans must be done within 28 days prior to enrollment.  During treatment, radiographic imaging (CT or MRI) of the 
abdomen, pelvis, and chest, along with tumor assessments of all other sites of disease, (and CT or MRI of the brain if a subject has symptoms or signs suggestive of 
CNS metastases), will be performed independent of treatment cycle at week 12 (+1 week), and then every 12 weeks (+1 week) or more frequently if clinically indicated 
until confirmed iPD per modified irRC-RECIST (Appendix F) or start of new anticancer treatment.  Imaging should not be adjusted for cycle initiation delays and 
performed according to the calendar.  The imaging modality selected (eg, CT or MRI) should remain constant for any individual subject.  Response or progression 
should be confirmed by repeated radiographic imaging ≥ 4 weeks after the first indication of response or progression.  Radiographic imaging is required at the safety 
follow up visit if the subject ended treatment prior to confirmed iPD and has not had radiographic tumor imaging performed within 4 weeks (+1 week) of the visit.  For 
subjects who discontinued treatment for any reason other than confirmed iPD, every effort should be made to complete radiographic assessments every 12 weeks 
(+1 week) or more frequently if clinically indicated during the long-term follow-up until documentation of confirmed iPD per modified irRC-RECIST (Appendix F), start of 
new anticancer therapy, or end of study whichever occurs first.  The radiographic images will be collected for review of tumor response by a blinded independent 
central review committee. 
v Response (iCR, or iPR) or iPD to be confirmed by second consecutive response assessment no less than 4 weeks from the date of the first documented response or 
PD. 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 87 of 171 
CONFIDENTIAL 
 
 
w Talimogene laherparepvec or placebo will be administered on day 1 of week 0, day 1 of week 3 (+3 days), then every 2 weeks (± 3 days) until week 9, and thereafter 
every 3 weeks (± 3 days) synchronously with pembrolizumab.  The initial dose of talimogene laherparepvec is up to 4.0 mL of 106 PFU/mL.  Subsequent doses of 
talimogene laherparepvec are up to 4.0 mL of 108 PFU/mL.  Dosing of talimogene laherparepvec or placebo should be continued until CR, disappearance of injected 
lesion, documented confirmed iPD per modified irRC-RECIST (Appendix F), intolerance of study treatment, 24 months from the first dose of talimogene laherparepvec 
or placebo, or end of study, whichever occurs first.  Due to the mechanism of action, subjects may experience growth in existing tumors or the appearance of new 
tumors prior to maximal clinical benefit of talimogene laherparepvec.  Therefore, dosing should be continued provided that the subject has no evidence of confirmed 
iPD per modified irRC-RECIST (Appendix F) and is able to tolerate the treatment.  Assessments and procedures are to be performed within 3 days of the planned visit 
and results available prior to study drug administration, unless otherwise specified.  It is recommended that dosing occur on the same day of the week (eg, if first dose 
is administered on a Monday, all subsequent doses should be administered on a Monday), however, a ± 3 day dosing window is allowed. 
x Pembrolizumab will be administered at a dose of 200 mg starting at day 1 of week 0, day 1 of week 3 (+3 days), and every 3 weeks (± 3 days) thereafter until 
documented confirmed iPD per modified irRC-RECIST (Appendix F), intolerance to pembrolizumab, 24 months from the first dose of pembrolizumab, or end of study, 
whichever occurs first.  When talimogene laherparepvec or placebo injections and pembrolizumab are administered on the same day, talimogene laherparepvec or 
placebo should be administered first, if possible. 
y Repeat week 24 procedures and assessments until end of study treatment, unless otherwise indicated. 
z Only subsequent treatment for melanoma will be recorded. 
aa Blood sample for coagulation will be collected at screening.  During treatment, blood samples should be collected for coagulation as clinically indicated. 
bb Urine samples for urinalysis will be collected at screening.  During treatment urine samples will be collected prior to study treatment administration at day 1 of 
weeks 0, 6, 12, 18, 24, then every 12 weeks until end of study treatment.  Results should be reviewed prior to the administration of scheduled dose of study drugs.  
Urine sample will also be collected at the safety follow-up visit.  Reflexive microscopy should be obtained for any abnormal urinalysis result. 
cc The QLQ-C30 questionnaire will be completed prior to study treatment administration at day 1 of weeks 0, 3, 6, 9, 12, then every 6 weeks until end of study 
treatment, and at the safety follow-up visit.  For subjects who discontinued treatment for any reason other than confirmed PD, every effort should be made to complete 
the EQ-5D-3L and QLQ-C30 questionnaires every 12 weeks (+1 week) during the long-term follow-up until documentation of confirmed iPD per modified irRC-RECIST 
(Appendix F), start of new anticancer therapy, or end of study whichever occurs first. 
dd The EQ-5D-3L questionnaire will be completed prior to study treatment administration at day 1 of weeks 0, 3, 6, 9, and 12, and then every 6 weeks, and at the time 
of disease progression (confirmed iPD or unconfirmed iPD with clinical deterioration), safety follow-up, and then every 12 weeks (± 1 to 3 weeks) thereafter during the 
long term follow-up visits.  If patients are too ill to self-complete, proxy completion by a named person (eg, a relative or health care provider) should be performed.  At 
least 2 assessments completed by both the patient and the named proxy-respondent at the same time should be made (eg, at a pre-progression visit [ie, week 0] and 
the first assessment after disease progression). 
ee > 24 study treatment week number pertains to all the study procedures required beyond week 24.  To determine the frequency of each study procedure, please refer 
to the footnote associated with that particular study procedure. 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 88 of 171 
CONFIDENTIAL 
 
 
Refer to the applicable supplemental laboratory and imaging manuals for detailed 
collection and handling procedures.   
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.  It is recommended that dosing occur on the same day of the week (eg, if 
first dose is administered on Monday, all subsequent doses should be administered on a 
Monday), however a ± 3-day dosing and study procedure window is allowed. 
The following laboratory analytes in Table 7 will be assessed at various times throughout 
the study. 
Table 7.  Laboratory Analytes 
Chemistry 
Coagulation 
Thyroid Function Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Calcium 
Magnesium 
Phosphorus 
Uric acid 
Total protein 
Albumin 
BUN/Urea 
Creatinine 
Total bilirubin 
Alkaline- 
phosphatase 
AST 
ALT 
Glucose 
PT or INR 
PTT or aPTT 
TSH 
T3 (or FT3 per 
local standard) 
FT4 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differential* 
 Neutrophils 
 Eosinophils 
 Basophils 
 Lymphocytes 
 Monocytes 
Pregnancy 
LDH 
Urinalysis 
 Blood 
 Glucose 
 Protein 
 Specific gravity 
 Microscopic exam 
(only reflexively for 
abnormal urinalysis 
results) 
qPCR for talimogene 
laherparepvec DNA 
HSV-1 antibody 
Anti-pembrolizumab 
antibody 
Pembrolizumab PK 
 
Total IgG 
 Blood 
 Archived tumor tissue 
* 3-part differential if 5-part unable to be performed 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 89 of 171 
CONFIDENTIAL 
 
 
All tests (except for qPCR, antibody, PK, and 
 are to be performed at a local 
laboratory and test results are to be fully and routinely recorded on the CRFs.  Missed 
tests that are not done must be reported as such on the CRFs.  The qPCR, antibody, PK 
and 
 will be performed at a central laboratory and results will not be 
recorded on the CRFs. 
Other on-study tests deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion as long as 
the subject remains active in the clinical study. 
Where required by local laws or regulations, additional assessments are defined in a 
country-specific protocol supplement at the end of the Appendix Section of protocol. 
7.2.1 
Screening, Enrollment (Phase 1b) and Randomization (Phase 3) 
The following procedures are to be completed during the screening period within 
28 days of enrollment/randomization (unless otherwise noted) at time points designated 
in the Schedule of Assessments (Table 5 and Table 6): 
Phase 1b and 3: 
 
Confirmation that the Informed Consent Form has been signed 
 
Review of eligibility criteria 
 
Demographic data including sex, age or date of birth, race, and ethnicity will be 
collected in order to study their possible association with subject safety and 
treatment effectiveness. 
 
Vital signs (systolic/diastolic blood pressure, heart rate, respiration rate, 
temperature):  Subject must be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
as possible.  The position selected for a subject should be the same that is used 
throughout the study and documented on the vital sign CRF.  Record all 
measurements on the vital signs CRF. 
 
Medical, surgical and medication history  
 
Physical examination including body weight as per standard of care  
 
Documentation of concomitant medications 
 
ECOG performance status assessment 
 
A 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. 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
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Date:  15 January 2020 
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CONFIDENTIAL 
 
 
 
Local Laboratory Assessments  
 
within ≤ 14 days prior to enrollment/randomization 
o hematology panel:  hemoglobin, hematocrit, white blood cell (WBC) count 
with 5-part differential (3-part differential if 5-part unable to be performed), red 
blood cell (RBC) count, platelets  
o chemistry panel:  sodium, potassium, chloride, calcium, magnesium, 
phosphorous, uric acid, total protein, albumin, blood urea nitrogen (BUN), 
creatinine, total bilirubin, alkaline phosphatase, AST, ALT, glucose  
o LDH 
o coagulation:  PT or INR and PTT or aPTT 
o thyroid function tests:  T3 (or FT3 per local standard), FT4, TSH  
o urinalysis (blood, glucose, protein, specific gravity) and reflexive microscopic 
exam only for any abnormal urinalysis result 
o serum or urine pregnancy test for female subjects of childbearing potential 
(urine pregnancy test should be performed within 72 hours prior to 
enrollment).   
 
Radiographic tumor imaging (including CT scan, positron emission tomography 
[PET]/CT scan, magnetic resonance imaging [MRI]) of the chest, abdomen, pelvis, 
and all other sites of disease, and CT scan or MRI of the brain, to be used as 
baseline imaging 
 
Recording of serious adverse events that occur after subject signs informed consent.  
Serious adverse events will be reported to Amgen within 24 hours following the 
investigator’s knowledge of the event 
 
Review of inclusion and exclusion criteria 
 
Registration and/or randomization in IVRS 
Phase 1b only: 
 
Clinical tumor assessments, including clinical measurement of cutaneous, 
subcutaneous, and palpable nodal tumor lesions by caliper to be used as baseline 
assessment.  Note:  When a tumor lesion can be accurately evaluated by both, 
radiographic imaging and clinical examination, radiographic imaging evaluations 
should be undertaken. 
 
Photographs of visible (ie, visible protrusion from skin surface) cutaneous and 
subcutaneous tumor lesions: 
- Photographs of visible cutaneous and subcutaneous measurable tumor lesions 
(up to 5; maximum 5 per organ) which are selected as index lesions will be 
performed. 
- Note:  When a tumor lesion can be accurately evaluated by both, radiographic 
imaging and photographs, radiographic imaging evaluations should be 
undertaken. 
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Product:  Talimogene Laherparepvec 
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Date:  15 January 2020 
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 
Tumor biopsy for PD-L1 expression, BRAFV600 mutation, and 
 analyses: 
- One lesion will be biopsied within 28 days prior to enrollment (archived 
formalin-fixed paraffin-embedded tumor biopsy tissue may be substituted if 
biopsy was performed within 3 months prior to Day 1, and no systemic anticancer 
therapies were given since the archival biopsy was performed). 
Subjects with an unevaluable archival sample for PD-L1 expression testing and 
BRAFV600 mutation testing may obtain a new biopsy and subjects with an 
unevaluable newly obtained biopsy may undergo re-biopsy at the discretion of 
the investigator.  If repeat sample is also unevaluable and the subject is 
otherwise eligible, the investigator may enroll the subject with or without a 
second re-biopsy.   
Subjects with an unevaluable newly obtained biopsy may undergo re-biopsy at 
the discretion of the investigator.  If the subject is ready to be randomized and 
treated after re-biopsy, randomization and start of treatment may proceed. 
In the case of an unevaluable BRAF mutation status, the subject must have LDH 
< ULN, no clinically significant tumor related symptoms in the judgment of the 
investigator, and have absence of rapidly progressing metastatic melanoma in 
the judgment of the investigator. 
Phase 3 only: 
 
Archived tumor tissue for PD-L1 expression, BRAFV600 mutation testing, and 
 analyses: 
- PD-L1 expression testing:  Subject must submit the tumor sample during 
screening for PD-L1 expression testing at a central laboratory.  Subjects with an 
unevaluable archival sample may obtain a new biopsy during screening as 
described below. 
- BRAFV600 mutation testing must be performed prior to randomization if a subject 
meets any of the following criteria: 
o LDH > ULN 
o Presence of clinically significant tumor related symptoms in the judgment of 
the investigator 
o Presence of rapidly progressing metastatic melanoma in the judgment of the 
investigator 
- BRAFV600 mutation testing may be obtained in a number of ways as listed below:  
o Previously Known BRAFV600 Tumor Status:  BRAFV600 tumor status result, 
obtained prior to screening for this study, from a local laboratory will be 
acceptable.  The local laboratory report supporting the local BRAFV600 tumor 
testing result should be available at the site within 4 weeks prior to 
randomization if the subject meets any of the above criteria or within 4 weeks 
after randomization if the subject does not meet any of the above criteria. 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
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CONFIDENTIAL 
 
 
o Previously Unknown BRAFV600 Tumor Status:  Archived formalin-fixed 
paraffin-embedded tumor tissue (block or unstained tumor slide) from either 
the primary tumor or a metastatic lesion should be analyzed at a local 
laboratory or submitted to the central laboratory within 4 weeks prior to 
randomization if the subject meets any of the above criteria or within 4 weeks 
after randomization if the subject does not meet any of the above criteria.  
Subjects with an unevaluable archival sample for BRAFV600 testing may 
obtain a new biopsy during screening as described below. 
 
Tumor biopsy for PD-L1 expression, BRAFV600 mutation, and 
 analyses: 
- One lesion will be biopsied within 28 days prior to enrollment (archived 
formalin-fixed paraffin-embedded tumor biopsy tissue may be substituted if 
biopsy was performed within 3 months prior to day 1, and no systemic anticancer 
therapies were given since the biopsy was done). 
Subjects with an unevaluable archival sample for PD-L1 expression testing and 
BRAFV600 mutation testing may obtain a new biopsy.  If the subject is ready to be 
randomized and treated after obtaining the new biopsy, randomization and start 
of treatment may proceed. 
Subjects with an unevaluable newly obtained biopsy may undergo re-biopsy at 
the discretion of the investigator.  If the subject is ready to be randomized and 
treated after re-biopsy, randomization and start of treatment may proceed.   
In the case of an unevaluable BRAF mutation status, the subject must have LDH 
less than ULN, no clinically significant tumor related symptoms in the judgment of 
the investigator, and have absence of rapidly progressing metastatic melanoma 
in the judgment of the investigator. 
 
Local laboratory assessments 
- Chemistry assessments:  BUN/urea 
 
Photographs of visible (ie, visible protrusion from skin surface) cutaneous and 
subcutaneous tumor lesions: 
- Photographs of all visible cutaneous and subcutaneous tumor lesions not 
detectable on radiographic imaging must be performed for the purposes of 
baseline tumor lesion documentation to be used for subsequent tumor 
assessments.   
- Note:  When a tumor lesion can be accurately evaluated by both, radiographic 
imaging and photographs, radiographic imaging evaluations must be undertaken.  
When a lesion/lesions can not be evaluated by radiographic imaging, but can be 
accurately evaluated by both clinical examination and photographs, photographs 
must be undertaken. 
7.2.2 
Treatment Period 
Treatment begins when the first dose of protocol-required therapies is administered to a 
subject. 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 5 and Table 6).  Study treatment 
should begin as soon as possible after enrollment via IVRS but no later than 5 days after 
Approved 
 
 
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enrollment/randomization.  Study treatment is to be administered after all other 
procedures are completed, unless otherwise stated during each visit that it is required. 
Phase 1b and 3: 
 
Local laboratory assessments:  Screening laboratory values may be used for 
treatment initiation assessment if completed within 3 days of study treatment 
initiation.  On treatment tests can be performed within 3 days of the planned visit.  
Results should be reviewed prior to the administration of study treatment. 
 
Coagulation:  PT or INR and PTT or aPTT – as clinically indicated 
 
Serum or urine pregnancy test for female subjects of childbearing potential:  
Additional (eg, monthly) on-treatment pregnancy testing should be conducted as 
required per local laws and regulations, where applicable. 
 
Central laboratory assessments: 
 
Swab of cold sore, vesicles and other lesions suspected to be herpetic in origin 
(if any) for qPCR testing of talimogene laherparepvec DNA: 
o Upon notification of a suspected herpetic lesion by the subject, the subject 
should return to the clinic within 3 days of the occurrence of a reportable 
lesion suspected to be herpetic in origin.  The lesion should be evaluated by 
the investigator and swabbed if HSV infection is suspected.  A qPCR analysis 
will be performed on the swab sample to evaluate whether the talimogene 
laherparepvec DNA is detectable in the sample. 
 
Recording of adverse events at each visit 
 
Recording of serious adverse events at each visit.  Serious adverse events will be 
reported to Amgen within 24 hours following the investigator’s knowledge of the 
event.   
 
For subject treated with pembrolizumab:  Selected non-serious and serious adverse 
events known as pembrolizumab Events of Clinical Interest must be reported to 
Amgen within 24 hours of the investigator’s knowledge of the event regardless of 
attribution to pembrolizumab (see Section 9.5) 
 
Documentation of concomitant medications at each visit 
Phase 1b: 
 
Vital signs (systolic/diastolic blood pressure, heart rate, respiration rate, 
temperature):  Subject must be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
possible.  The position selected for a subject should be the same that is used 
throughout the study and be documented on the vital signs CRF. 
 
day 1 of weeks -5, -2, 0, 4, 8, 12 and then every 4 weeks until end of study 
treatment 
 
Physical examination including body weight, as per standard of care 
 
day 1 of weeks -5 and 0 
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 
ECOG performance status 
 
day 1 of weeks -5 and 0 
 
Local laboratory assessments:  Screening laboratory values may be used for 
treatment initiation assessment if completed within 3 days of study treatment 
initiation.  On treatment tests can be performed within 3 days of the planned visit.  
Results should be reviewed prior to the administration of study treatment. 
 
Hematology panel:  hemoglobin, hematocrit, WBC with 5-part differential (3-part 
differential if 5-part unable to be performed), RBC, platelet 
o day 1 of weeks -5, -2, 0, 4, 8, 12 and then every 4 weeks until end of study 
treatment 
 
Chemistry panel:  sodium, potassium, chloride, calcium, magnesium, 
phosphorus, uric acid, total protein, albumin, BUN, creatinine, total bilirubin, 
alkaline phosphatase, AST, ALT, glucose 
o day 1 of weeks -5, -2, 0, 4, 8, 12 and then every 4 weeks until the end of 
study treatment 
 
Blood sample for total immunoglobulin G (IgG) 
o day 1 of week 0 
 
Thyroid function tests:  T3 (or FT3 per local standard), FT4, TSH 
o day 1 every 6 weeks until the end of study treatment  
 
Urinalysis (blood, glucose, protein, specific gravity) and reflexive microscopic 
exam only for any abnormal urinalysis result 
o day 1 of weeks 0, 8, 16, week 24 and then every 8 weeks until end of study 
treatment 
 
Central laboratory assessments: 
 
Blood for anti-pembrolizumab antibody (immunogenicity): 
o day 1 of weeks 0, 2, 8, 16, 24 and every 12 weeks (6 cycles) starting with 
week 36.   
o Note:  All samples should be drawn within 24 hours before infusion of 
pembrolizumab and at the same time as the pre-dose trough blood collection 
for the PK sample. 
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Date:  15 January 2020 
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 
Blood for PK of pembrolizumab: 
o pre-dose trough and post-dose peak PK samples will be collected on day 1 of 
week 0.  A one-time PK sample should be drawn between 48 to 168 hours 
after week 0.  Pre-dose trough samples only will be collected at week 2, 8, 
16, 24 every 12 weeks (6 cycles) starting with week 36. 
o Note:  All trough samples should be drawn within 24 hours before infusion of 
pembrolizumab.  Peak sample should be drawn within 30 minutes after the 
end of the infusion. 
 
Archived tumor tissue for BRAFV600 mutation testing: 
- BRAFV600 mutation testing for may be obtained in a number of ways as listed 
below:  
o Previously Known BRAFV600 Tumor Status:  BRAFV600 tumor status result, 
obtained prior to screening for this study, from a local laboratory will be 
acceptable.  The local laboratory report supporting the local BRAFV600 tumor 
testing result should be available at the site within 4 weeks after enrollment. 
o 
Previously Unknown BRAFV600 Tumor Status:  Archived formalin-fixed 
paraffin-embedded tumor tissue (block or unstained tumor slide) from either 
the primary tumor or a metastatic lesion should be analyzed at a local 
laboratory or submitted to the central laboratory within 4 weeks after 
enrollment. 
 
Radiographic tumor imaging assessments must include CT scan, PET/CT, or MRI of 
the abdomen, pelvis, and chest and all other sites of disease.  In addition, CT scan 
or MRI of the brain will only be performed if signs or symptoms suggestive of CNS 
metastasis are present.  Imaging will be performed independent of treatment cycle at 
day 1 of week 0, day 1 of week 12 (+1 week), and then every 12 weeks (+1 week) or 
more frequently if clinically indicated until confirmed PD per modified irRC 
(Appendix D), or start of new anticancer treatment.  Imaging should not be adjusted 
for cycle initiation delays and performed according to the calendar.  The imaging 
modality selected (eg, CT or MRI) should remain constant for any individual subject. 
 
Photographs of visible cutaneous and subcutaneous:  
- Photographs of visible cutaneous and subcutaneous index tumor lesions and of 
new visible lesion cutaneous and subcutaneous, if present, will be performed 
independent of treatment cycle at day 1 of week 0, day 1 of week 12 (+1 week) 
and every 12 weeks (+1 week) thereafter or more frequently if clinically indicated 
until confirmed PD per modified irRC (Appendix D) or start of new anticancer 
treatment.  The scheduled photography of tumor lesions should not be adjusted 
for cycle initiation delays and performed according to the calendar.   
- Note:  When a tumor lesion can be accurately evaluated by both, radiographic 
imaging and photographs, radiographic imaging evaluations should be 
undertaken. 
Approved 
 
 
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Protocol Number:  20110265 
Date:  15 January 2020 
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 
Clinical tumor assessments 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. 
 
Tumor response will be assessed using the modified irRC (Appendix D), at day 1 of 
week 0, day 1 of week 12 (+1 week) and every 12 weeks (+1 week) thereafter or 
more frequently if clinically indicated until confirmed PD or start of new anticancer 
treatment.  Response (CR, or PR) or PD occurring after the first dose of 
pembrolizumab to be confirmed by second consecutive response assessment no 
less than 4 weeks from the date of the first documented response or PD. 
 
Talimogene laherparepvec administration 
 
day 1 of weeks -5, -2, week 0, and every 2 weeks thereafter until end of study 
treatment 
 
Note:  on days when co-administered, talimogene laherparepvec should be 
administered first, if possible. 
 
Pembrolizumab administration 
 
day 1 of weeks 0, 2, 4, 6, 8, 10, 12 and every 2 weeks thereafter until end of 
study treatment 
Phase 3: 
 
Vital signs (systolic/diastolic blood pressure, heart rate, respiration rate, 
temperature):  Subject must be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
possible.  The position selected for a subject should be the same that is used 
throughout the study and be documented on the vital signs CRF. 
 
day 1 of weeks 0, 3, 6, 12 and every 6 weeks until end of study treatment 
 
Physical examination including body weight, as per standard of care 
 
day 1 of week 0 
 
ECOG performance status 
 
day 1 of week 0 
 
Local laboratory assessments:  Screening laboratory values may be used for 
treatment initiation assessment if completed within 3 days of study treatment 
initiation.  On treatment tests can be performed within 3 days of the planned visit.  
Results should be reviewed prior to the administration of study treatment. 
 
Hematology panel:  hemoglobin, hematocrit, WBC with 5-part differential (3-part 
differential if 5-part unable to be performed), RBC, platelet 
o day 1 of weeks 0, 3, 6, 12 and then every 6 weeks until end of study 
treatment  
 
Chemistry panel:  sodium, potassium, chloride, calcium, magnesium, 
phosphorus, uric acid, total protein, albumin, BUN/urea, creatinine, total bilirubin, 
alkaline phosphatase, AST, ALT, glucose 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 97 of 171 
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o day 1 of weeks 0, 3, 6, 12 and then every 6 weeks until end of study 
treatment 
– LDH 
o day 1 of weeks 0, 3, 6, 12 and then every 6 weeks until end of study 
treatment 
 
Blood sample for total immunoglobulin G (IgG) 
o day 1 of week 0 
 
Thyroid function tests:  T3 (or FT3 per local standard), FT4, TSH 
o day 1 every 6 weeks until end of study treatment 
 
Urinalysis (blood, glucose, protein, specific gravity) and reflexive microscopic 
exam only for any abnormal urinalysis result 
o day 1 of weeks 0, 6, 12, 18, 24 and then every 12 weeks until end of study 
treatment 
 
Central laboratory assessments: 
 
Blood for anti-pembrolizumab antibody (immunogenicity): 
o day 1 of weeks 0, 3, 12, 27, 39 and every 12 weeks (4 cycles) thereafter.  
Anti-pembrolizumab antibody sample collection and analyses in phase 3 may 
be discontinued if ongoing antibody results from this study continue to be 
consistent with existing antibody data from other pembrolizumab melanoma 
clinical trials. 
o Note:  All samples should be drawn within 24 hours before infusion of 
pembrolizumab and at the same time as the pre-dose trough blood collection 
for the PK sample. 
 
Blood for PK of pembrolizumab: 
o Pre-dose trough and post-dose peak PK samples will be collected at week 0 
(ie, pembrolizumab cycle 1).  Pre-dose trough PK samples will be collected 
on day 1 of weeks 3, 12, 27, 39 and every 12 weeks (4 cycles) thereafter.  
Pembrolizumab PK sample collection and analyses in phase 3 may be 
discontinued if ongoing PK results from this study continue to be consistent 
with existing PK data from other pembrolizumab melanoma clinical trials. 
o Note:  All trough samples should be drawn within 24 hours before infusion of 
pembrolizumab.  Peak sample should be drawn within 30 minutes after the 
end of the infusion. 
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 
Tumor response will be assessed using modified irRC-RECIST (Appendix F), at 
day 1 of week 12 (+1 week) and every 12 weeks (+1 week) thereafter or more 
frequently if clinically indicated until confirmed iPD or start of new anticancer 
treatment.  Response (iCR, or iPR) or iPD to be confirmed by second consecutive 
response assessment no less than 4 weeks from the date of the first documented 
response or iPD.  Subjects who have reached a confirmed iCR may increase their 
interval of radiographic assessments up to 6 months after the first 2 years beyond 
confirmed iCR and up to 12 months after the first 5 years beyond confirmed iCR as 
long as iCR is maintained.   
 
Radiographic tumor imaging assessments must include CT scan, PET/CT, or 
MRI of the abdomen, pelvis, and chest and all other sites of disease.  In addition, 
CT scan or MRI of the brain will only be performed if signs or symptoms 
suggestive of CNS metastasis are present.  Imaging will be performed 
independent of treatment cycle at day 1 of week 0 (phase 1b only), day 1 of 
week 12 (+1 week), and then every 12 weeks (+1 week) or more frequently if 
clinically indicated until confirmed iPD per modified irRC-RECIST (Appendix F), 
or start of new anticancer treatment.  Imaging should not be adjusted for cycle 
initiation delays and performed according to the calendar.  The imaging modality 
selected (eg, CT or MRI) should remain constant for any individual subject. 
 
Photographs of visible cutaneous and subcutaneous:  
o Photographs of all visible (ie, visible protrusion from skin surface) cutaneous 
and subcutaneous tumor lesions not detectable on radiographic imaging must 
be performed at screening within 28 days prior to enrollment for the purposes 
of documentation of baseline lesion data.  It is critical that baseline 
photography is captured for subjects with visible cutaneous and 
subcutaneous tumor lesions in order to allow for follow up of these lesions 
during the treatment phase.   
During treatment, the photographs of all visible cutaneous and subcutaneous 
tumor lesions not detectable on radiographic imaging, including new visible 
cutaneous and subcutaneous lesions, if present, must be performed 
independent of treatment cycle at day 1 of week 12 (+1 week) and every 
12 weeks (+1 week) thereafter or more frequently if clinically indicated until 
confirmed iPD per modified irRC-RECIST (Appendix F) or start of new 
anticancer treatment.  Photographs must also be taken for previously visible 
cutaneous and subcutaneous tumor lesions that have resolved at subsequent 
tumor assessment visits.  The schedule of photograph of tumor lesions 
should not be adjusted for cycle initiation delays and performed according to 
the calendar.  Response or progression should be confirmed by repeated 
photographs ≥ 4 weeks after the first indication of response or progression.   
Photographs of all visible cutaneous and subcutaneous tumor lesions not 
detectable on radiographic imaging, including new visible cutaneous and 
subcutaneous lesions, if present, is required at the safety follow-up visit if the 
subject ended treatment prior to confirmed iPD and has not had photographs 
performed within 4 weeks (+1 week) of the visit.  For subjects who 
discontinued treatment for any reason other than iPD, every effort should be 
made to complete photographs of all visible cutaneous and subcutaneous 
lesions not detectable on radiographic imaging, including new visible 
cutaneous and subcutaneous lesions, if present, every 12 weeks (+1 week) 
or more frequently if clinically indicated during the long-term follow-up until 
documentation of confirmed iPD per modified irRC-RECIST (Appendix F), 
start of new anticancer treatment, or end of study, whichever occurs first. 
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Protocol Number:  20110265 
Date:  15 January 2020 
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o The photographic images will be collected for review of tumor response by a 
blinded independent central review committee.  Photographed lesions not 
appearing on radiographic imaging should only be considered non-target 
lesions.   
Note:  When a lesion can be accurately evaluated by both radiographic 
imaging and photographs, radiographic imaging evaluations must be 
undertaken.  When a lesion/lesions can not be evaluated by radiographic 
imaging, but can be accurately evaluated by both clinical examination and 
photographs, photographs must be undertaken. 
○ Photographs must also be taken for previously visible cutaneous and 
subcutaneous tumor lesions that have resolved at subsequent tumor 
assessment visits. 
 
Completion of PRO (EQ-5D-3L and QLQ-C30) questionnaires (PRO questionnaires 
will be administered to subjects where translations are available): 
 
prior to study treatment administration at day 1 of weeks 0, 3, 6, 9, 12, then every 
6 weeks until end of study treatment. 
 
For subjects with progressive disease, QLQ-C30 will no longer be collected, and 
EQ-5D-3L will be collected through the long-term follow-up. 
 
Talimogene laherparepvec or placebo administration 
 
day 1 of weeks 0, 3, 5, 7, 9, and every 3 weeks thereafter until end of study 
treatment 
 
Note:  on days when co-administered, talimogene laherparepvec should be 
administered first, if possible. 
 
Pembrolizumab administration 
 
day 1 of weeks 0, 3, 6, 9, and every 3 weeks thereafter until end of study 
treatment 
7.2.3 
Safety Follow-up Visit 
Upon permanent discontinuation from the study treatment for any reason, the following 
procedures will be performed approximately 30 (+7) days after the last dose of 
talimogene laherparepvec or the last dose of pembrolizumab, whichever is later.  If an 
end of treatment decision occurs > 30 (+7) days after the last treatment date, then the 
safety follow-up should be performed as soon as possible (eg, within a week of the end 
of treatment decision).  Applicable safety follow-up procedures should occur even if the 
subject has initated new anticancer therapy. 
Phase 1b and 3: 
 
Vital signs (systolic/diastolic blood pressure, heart rate, respiration rate, 
temperature):  Subject must be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position 
possible.  The position selected for a subject should be the same that is used 
throughout the study and be documented on the vital sign CRF. 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 100 of 171 
CONFIDENTIAL 
 
 
 
Physical examination including body weight as per standard of care 
 
ECOG performance status assessment 
 
A 12-lead ECG.  The ECG must include the following measurements:  heart rate, 
PR, QRS, QT and QTc intervals. 
 
Local laboratory Assessments:  Tests can be performed within 3 days of the planned 
visit. 
 
hematology panel:  hemoglobin, hematocrit, WBC count with 5-part differential 
(3-part differential if 5-part unable to be performed), RBC count, platelets 
 
chemistry panel:  sodium, potassium, chloride, calcium, magnesium, phosphorus, 
uric acid, total protein, albumin, BUN (phase 1b only), BUN/urea (phase 3), 
creatinine, total bilirubin, alkaline phosphatase, AST, ALT, glucose 
 
LDH test (phase 3 only) 
 
thyroid function tests:  T3 (or FT3 per local standard), FT4, TSH 
 
serum or urine pregnancy test for female subjects of childbearing potential 
 
urinalysis (blood, glucose, protein, specific gravity) and reflexive microscopic 
exam only for any abnormal urinalysis results 
 
Central laboratory assessments: 
 
Swab of cold sore, vesicles and other lesions suspected to be herpetic in origin 
(if any) for qPCR testing of talimogene laherparepvec DNA: 
o Upon notification of a suspected herpetic lesion by the subject, the subject 
should return to the clinic within 3 days of the occurrence of a reportable 
lesion suspected to be herpetic in origin.  The lesion should be evaluated by 
the investigator and swabbed if HSV infection is suspected.  A qPCR analysis 
will be performed on the swab sample to evaluate whether the talimogene 
laherparepvec DNA is detectable in the sample.   
– Blood for anti-pembrolizumab antibody (immunogenicity).  Anti-pembrolizumab 
antibody sample collection and analyses in phase 3 may be discontinued if 
ongoing antibody results from this study continue to be consistent with existing 
antibody data from other pembrolizumab melanoma clinical trials. 
– Blood for PK pembrolizumab:  sample taken at the same time as blood sample 
for anti-pembrolizumab antibody.  Pembrolizumab PK sample collection and 
analyses in phase 3 may be discontinued if ongoing PK results from this study 
continue to be consistent with existing PK data from other pembrolizumab 
melanoma clinical trials. 
 
Recording of adverse events 
 
Recording of serious adverse events:  Serious adverse events that occur within 
90 (+7) days after the cessation of all study treatment or 30 (+7) days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier, will be reported within 24 hours following the investigator’s knowledge of the 
event. 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
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 
For subjects treated with pembrolizumab:  Selected non-serious and serious adverse 
events known as pembrolizumab Events of Clinical Interest (ECI) must be reported 
to Amgen within 24 hours of the investigator’s knowledge of the event regardless of 
attribution to pembrolizumab (see Section 9.5). 
 
Documentation of concomitant medications 
 
Completion of PRO (EQ-5D-3L and QLQ-C30) questionnaires 
Phase 1b: 
 
Radiographic tumor imaging, clinical tumor assessment, photographic assessment, 
and tumor response assessments are to be performed if the subject ended study 
treatment prior to confirmed PD per modified irRC (Appendix D) and has not had 
assessments performed within 4 weeks (+1 week) of the visit. 
– Radiographic tumor imaging assessments must include CT scan, PET/CT, or 
MRI of the abdomen, pelvis, and chest along with all other sites of disease.  In 
addition, CT scan or MRI of the brain will only be performed if signs or symptoms 
suggestive of CNS metastasis are present.   
– Photographic imaging assessments of visible cutaneous and subcutaneous 
lesions: 
o Photographs of visible cutaneous and subcutaneous index tumor lesions and 
of new visible lesion cutaneous and subcutaneous, if present. 
o Note:  When a tumor lesion can be accurately evaluated by both, 
radiographic imaging and photographs, radiographic imaging evaluations 
should be undertaken. 
– Clinical tumor assessments 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. 
– Tumor response will be assessed using the modified irRC.  Response (CR or 
PR) or PD to be confirmed by second consecutive response assessment no less 
than 4 weeks from the date of the first documented response or PD. 
Phase 3: 
 
Radiographic tumor imaging, clinical tumor assessment, photographic assessment, 
and tumor response assessments are to be performed if the subject ended study 
treatment prior to confirmed iPD per modified irRC-RECIST (Appendix F) and has 
not had assessments performed within 4 weeks (+1 week) of the visit. 
– Radiographic tumor imaging assessments must include CT scan, PET/CT, or 
MRI of the abdomen, pelvis, and chest along with all other sites of disease.  In 
addition, CT scan or MRI of the brain will only be performed if signs or symptoms 
suggestive of CNS metastasis are present.   
– Photographic imaging assessments of visible cutaneous and subcutaneous 
lesions: 
o Photographs of all visible (ie, visible protrusion from skin surface) cutaneous 
and subcutaneous tumor lesions not detectable on radiographic imaging must 
be performed. 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
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o Note:  When a tumor lesion can be accurately evaluated by both, 
radiographic imaging and photographs, radiographic imaging evaluations 
must be undertaken.  When a lesion/lesions can not be evaluated by 
radiographic imaging, but can be accurately evaluated by both clinical 
examination and photographs, photographs must be undertaken.  
Photographs must also be taken for previously visible cutaneous and 
subcutaneous tumor lesions that have resolved at subsequent tumor 
assessment visits. 
– Tumor response will be assessed using modified irRC-RECIST (Appendix F).  
Response (CR or PR) or iPD to be confirmed by second consecutive 
response assessment no less than 4 weeks from the date of the first 
documented response or iPD. 
The Safety Follow-up visit is not required for those subjects who are randomized, but do 
not receive any doses of investigational product. 
7.2.4 
Long-term Follow-up 
All subjects who permanently discontinue study drug for any reason other than withdraw 
of full consent will be contacted by clinic visit or telephone to assess survival, initiation of 
additional melanoma therapy, and whether any injected investigational product-related 
adverse events has occurred. 
Contact for all subjects will be attempted every 12 weeks (± 28 days) following the safety 
follow-up visit until death, subject withdraws full consent, or up to 60 months after the 
end of randomization of phase 3.  The sponsor may request survival status to be 
assessed at additional time points during the course of the study. 
For subjects discontinuing study treatment without a documented confirmed PD, clinical 
tumor assessment (phase 1b only), radiographic imaging, photographic imaging, and 
tumor response assessment as detailed in Section 7.2.2 and PRO (EQ-5D-3L and 
QLQ-C30) questionnaires will be performed every 12 weeks (+1 week) or more 
frequently if clinically indicated until documented confirmed PD per modified irRC in 
phase 1b (Appendix D) or iPD per modified irRC-RECIST in phase 3 (Appendix F), start 
of new anticancer treatment, death, or end of study, whichever occurs first.  For subjects 
with progressive disease, QLQ-C30 will no longer be collected, and EQ-5D-3L will be 
collected through the long-term follow-up.  Subjects who have reached a confirmed CR 
may increase their interval of radiographic assessments up to 6 months after the first  
2 years beyond confirmed CR and up to 12 months after the first 5 years beyond 
confirmed CR as long as CR is maintained. 
Approved 
 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 103 of 171 
CONFIDENTIAL 
Blood for anti-pembrolizumab antibody and blood for PK of pembrolizumab will be 
collected at 3 and 6 months after study discontinuation or up until the subject starts new 
anticancer therapy, whichever occurs first.  Anti-pembrolizumab antibody and 
pembrolizumab PK sample collection and analyses in phase 3 may be discontinued if 
ongoing antibody and PK results from this study continue to be consistent with existing 
antibody and PK data from other pembrolizumab melanoma clinical trials. 
All subjects treated with talimogene laherparepvec (all phase 1b subjects and those who 
received talimogene laherparepvec in phase 3) and who permanently discontinue study 
will be eligible to continue follow-up for survival under an ongoing separate registry 
protocol that is in place for the long-term follow-up of subjects treated with talimogene 
laherparepvec in clinical trials.  The registry protocol, including for phase 1b subjects, will 
not apply until the end of the study or 5 years after the last subject is enrolled in phase 3, 
whichever comes first.  The registry protocol will also monitor for late and long-term 
adverse events thought to be potentially related to talimogene laherparepvec. 
7.2.5 
Reporting Unintended Exposure to Talimogene Laherparepvec in 
Phase 1b and Phase 3  
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 or who has had signs or symptoms suspected to be herpetic in origin or 
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. 
Approved
AMGEN® 


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 104 of 171 
CONFIDENTIAL 
 
 
7.3.1 
Blood Samples 
Blood samples are to be collected for 
 development as described in 
Sections 7.2.2 and 7.2.3. 
7.3.2 
Archived Tumor Tissue Sample 
A block of formalin-fixed paraffin-embedded tumor tissue collected prior to the study is to 
be sent to the central laboratory along with the corresponding pathology report (if 
available) as described in Section 7.2.1.  The tumor block is to be carefully selected by a 
pathologist or a skilled experienced histology associate to include generous tumor tissue 
using the Pathology Report as a guide.  In lieu of a block, approximately 20 unstained 
sections on charged slides from the same block can be submitted.  When the samples of 
tumor tissues are available, analyses of tumor specific mutations or epigenetic changes 
may be performed (eg, somatic mutations).   
7.4 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of cancer and/or to identify 
subjects who may have positive or negative responses to talimogene laherparepvec 
and/or pembrolizumab.  No additional samples are collected for this part of the study.  
For subjects who consent to this/these analysis/analyses, DNA may be extracted. 
7.5 
Sample Storage and Destruction 
Any blood, tumor, or swab samples collected according to the Schedule of Assessments 
(Table 5 and Table 6) can be analyzed for any of the tests outlined in the protocol and 
for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability.   
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All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
cancer,  the dose response and/or prediction of response to talimogene laherparepvec 
and/or pembrolizumab, characterize antibody response, and characterize aspects of the 
molecule (eg, mechanism of action/target, metabolites).  Results from these analyses 
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 qPCR testing of talimogene laherparepvec DNA from swabs of cold sores, 
vesicles, and other lesions suspected to be herpetic in origin are not expected to be 
available in time to benefit the subject directly or to alter the treatment course, the results 
of qPCR testing will not be provided unless requested by the investigator or the subject.  
Results may not be available until the end of the study.  The evaluations of 
pharmacogenetic, 
 or other exploratory studies are not expected 
to benefit the subject directly or to alter the treatment course.  The results of 
pharmacogenetic,
 or other exploratory studies are not placed in 
the subject’s medical record and are not to be made available to the subject, members 
of the family, the personal physician, or other third parties, except as specified in the 
informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood and tumor samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
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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. 
7.6 
Patient Reported Outcomes 
PROs will be assessed using the following questionnaires:  the EQ-5D-3L and QLQ-C30.  
The two questionnaires are commonly used, uniformly accepted and validated 
instruments to evaluate health outcomes in subjects with cancer.  PRO questionnaires 
will be administered to subjects where translations are available.  PRO questionnaires 
will be collected via pen and paper.  During long term follow-up for subjects who have 
progressed, EQ-5D-3L may be collected via the telephone. 
7.6.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 Version 3 is a 2-page, self-reporting 30-item generic instrument 
for use in cancer subjects across tumor types (Bjordal et al, 2000).  It assesses 
15 domains consisting of 5 functional domains (physical, role, emotional, cognitive, 
social), 9 symptom domains (fatigue, nausea and vomiting, pain, dyspnea, insomnia, 
appetite loss, constipation, diarrhea, financial difficulties), and a Global Health 
Status-Quality of Life (GHS-QOL) subscale (Aaronson et al, 1993). 
7.7 
Health State Utility Estimates 
Health state utility estimates for the purpose of inclusion in a health economic model will 
be derived using the EQ-5D-3L. 
7.7.1 
EQ-5D-3L 
The EQ-5D-3L questionnaire is a 2-page, generic preference-based QoL measure 
comprised of a 5-item health status measure and a visual analogue scale (VAS)  
(Rabin and de Charro, 2001; Kind, 1996) and is used to generate 2 scores.  The  
EQ-5D-3L utility score is based on answers to 5 questions that evaluate mobility,  
self-care, usual activities, pain/discomfort, and anxiety/depression.  The EQ-5D-3L VAS 
generates a single health status index and the analogue scale ranges from 0 to 100 in 
which subjects are asked to rate their current health state by drawing a line from a box 
marked, "Your health today." 
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8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 5 and 
Table 6) including different options for follow-up (eg, in person, by phone/email, through 
family/friends, in correspondence/communication with other treating physicians, the 
review of medical records) and collection of data, including endpoints and adverse 
events.  Subjects that have discontinued investigational product and/or protocol required 
therapies or procedures should not be automatically removed from the study.  Whenever 
safe and feasible, it is imperative that subjects remain on study to undergo safety 
surveillance and/or collection of outcome data.  The investigator must document the 
change to the Schedule of Assessments (Table 5 and Table 6) and the level of follow-up 
that is agreed to by the subject (eg, in person, by telephone/mail, through family/friends, 
in correspondence/communication with other physicians, from review of the medical 
records). 
For subjects who discontinue investigational product without documented 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, and 
to complete PRO questionnaires as described in Table 6. 
Those subjects who discontinue investigational product should continue into the 
long-term follow-up.  Subjects will be followed for survival and subsequent anticancer 
therapies every 12 weeks (± 28 days) for approximately 60 months after the last subject 
is enrolled in phase 3.  In addition, talimogene laherparepvec- or placebo-related 
adverse events that occur through the end of the long-term follow-up will be reported. 
For those subjects who are randomized but do not receive any doses of investigational 
product, every effort should be made to continue monitoring tumor response status by 
clinical and radiographic tumor assessments as described in Table 6.  They should 
continue into the long-term follow-up and be followed for survival and subsequent 
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anticancer therapies every 12 weeks (± 28 days) for approximately 60 months after the 
last subject is enrolled in phase 3. 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject from investigational 
products 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 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment, or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational products or procedural 
assessments include any of the following: 
 
completed study treatment 
 
Phase 1b and phase 3:  completed 24 months of treatment with talimogene 
laherparepvec/placebo and/or pembrolizumab.  Note:  For phase 1b, 24 months of 
study treatment is calculated from the date of first dose of pembrolizumab. 
 
subject request 
 
safety concern (eg, due to an adverse event)  
 
ineligibility determined  
 
protocol deviation  
 
non-compliance  
 
requirement for alternative therapy  
 
pregnancy 
 
death 
 
lost to follow-up 
 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
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 
decision by investigator (other than subject request, safety concern, lost to follow-up) 
 
confirmed PD per modified irRC in phase 1b (Appendix D) or iPD per modified 
irRC-RECIST (Appendix F) 
 
Note:  A subject may be granted an exception to end treatment for nonconfirmed 
PD if deterioration of health status requires discontinuation of treatment 
(see Section 3.1.3.1 and Appendix D for phase 1b or Section 3.1.3.3 and 
Appendix F for phase 3). 
 
other protocol-specified criteria (see Sections 6.2.1.2, 6.2.2.2, and 6.2.2.3). 
 
subject’s treatment assignment is unblinded during the double-blind phase of the 
study via IVRS for the future management of the subject, and subject is not allowed 
to continue treatment (see Section 5.2) 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
full withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
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 what would be expected, and/or has an association with a 
significantly worse outcome than expected.  A pre-existing condition that has not 
worsened more than anticipated (ie, more than usual fluctuation of disease) during the 
study or involves an intervention such as elective cosmetic surgery or a medical 
procedure while on study, is not considered an adverse event. 
For situations when an adverse event or serious adverse event is due to melanoma, 
report all known signs and symptoms.  Death due to disease progression in the absence 
of signs and symptoms should be reported as the primary tumor type (eg, melanoma). 
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Note:  The term “disease progression” should not be used to describe the adverse event. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, or events that necessitate 
an emergency room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures 
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of talimogene 
laherparepvec/placebo or pembrolizumab through the safety follow-up visit 
(ie, 30 [+7] days after the last dose of talimogene laherparepvec/placebo or 
pembrolizumab, whichever is later, are reported using the applicable CRF (eg, Adverse 
Event Summary).  In addition, injected investigational product-related adverse events 
that occur during the long term safety follow-up period until the end of study should also 
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be captured in the Adverse Event CRF although these events will not be considered 
treatment-emergent adverse events. 
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
 
Dates of onset and resolution (if resolved), 
 
Severity [and/or toxicity per protocol], 
 
Assessment of relatedness to injected investigational product and/or pembrolizumab, 
and 
 
Action taken. 
The adverse event grading scale used will be the CTCAE version 4.0.  The grading 
scale used in this study is described in Appendix A.  The investigator must assess 
whether the adverse event is possibly related to injected investigational product 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 
injected investigational product and/or pembrolizumab?   
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity and/or procedure (including any screening procedures).  This 
relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity and/or 
procedure”?  
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
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 Adverse 
Event Summary CRF.  The investigator is expected to follow reported adverse events 
until stabilization or reversibility. 
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9.2.1.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 90 (+7) days after the cessation of all study treatment or 30 (+7) days 
following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier, are recorded in the subject’s medical record and are submitted to Amgen.  All 
serious adverse events must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the applicable CRF.   
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours following 
the investigator’s knowledge of the event.  Serious adverse events reported outside of 
the protocol-required reporting period will be captured within the safety database as 
clinical trial cases for the purposes of expedited reporting.   
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
serious adverse event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet /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 eSAE 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 
injected investigational product and/or pembrolizumab.  This relationship is indicated by 
a “yes” or “no” response to the question:  Is there a reasonable possibility that the event 
may have been caused by the injected investigational product and/or pembrolizumab? 
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”?  Relatedness means that there are facts or 
reasons to support a relationship between investigational product and the event.  
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The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable CRF (eg, Adverse 
Event Summary CRF). 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements. 
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.   
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other reports received from Amgen, in accordance with local procedures 
and statutes. 
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 3 months after the last dose of talimogene 
laherparepvec or 4 months after the last dose of pembrolizumab (or 30 days following 
cessation of pembrolizumab if the subject initiates a new anticancer therapy, whichever 
is earlier).   
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The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, 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 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 
3 months after the last dose of talimogene laherparepvec or 4 months after the last dose 
of pembrolizumab (or 30 days following cessation of pembrolizumab if the subject 
initiates a new anticancer therapy, whichever is earlier). 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
9.4 
Reporting of Unintended Exposure to Talimogene Laherparepvec or 
Placebo 
If a household member, caregiver, or healthcare provider who has had close contact 
with a subject treated with talimogene laherparepvec or placebo on this study is 
suspected to have been exposed to talimogene laherparepvec or placebo (eg, have or 
who have had signs or symptoms suspected to be herpetic in origin or who have been 
accidentally exposed to talimogene laherparepvec or placebo), while the subject is 
taking talimogene laherparepvec or placebo, report the exposure to Amgen as specified 
below.  In addition to reporting an unintended exposure case during the study treatment, 
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investigators should monitor for potential exposure cases that occur after the last dose of 
talimogene laherparepvec or placebo through 30 (+7) days after the last dose of 
talimogene laherparepvec or placebo. 
Any potential or known unintended exposure should be reported to Amgen within 
24 hours of the investigator’s knowledge of the event of exposure.  Amgen will seek to 
follow up with the exposed individual, if necessary, to collect more information about the 
exposed individual contact with clinical trial subject, signs and/or symptoms related to 
the exposure, medical history, and/or outcome of the exposure.  If the exposed individual 
is reporting sign or symptoms suspected to be related to talimogene laherparepvec or 
placebo exposure, the exposed individual may be asked to have a swab taken to 
evaluate for the presence of talimogene laherparepvec DNA in the lesion. 
9.5 
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. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, 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, placebo treatment, or a procedure. 
For the time period beginning at treatment allocation/randomization 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 Events of Clinical Interest for this trial include: 
 
an overdose of pembrolizumab, as defined in Section 9.6 
 
an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, 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. 
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9.6 
Definition of an Overdose of Pembrolizumab for This Protocol and 
Reporting of Pembrolizumab Overdose 
For the purpose of this trial, an overdose of pembrolizumab will be defined as > 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. 
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 9.2.1.1 and 9.2.1.2, 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 9.5. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoints 
Phase 1b: 
 
Incidence of DLT 
Phase 3: 
 
Progression-free Survival by blinded independent central review using modified 
RECIST (PFS):  Time from randomization to the date of disease progression 
(response evaluation by blinded independent central review using modified 
RECIST 1.1) or death, whichever occurs earlier. 
 
Overall Survival (OS):  Time from randomization date to the date of death from any 
cause. 
10.1.1.2 
Secondary Endpoints 
Phase 1b: 
 
Confirmed ORR (CR+PR) (response evaluation by investigator using modified irRC). 
 
BOR, DRR (duration of response for 6 months or longer), DOR (the time from date of 
the initial confirmed response to the date of the first documented PD or death), DCR, 
and PFS (response evaluation by investigator using modified irRC). 
 
OS. 
 
Incidence of treatment-emergent and treatment-related adverse events (all AEs, 
grade ≥ 3 AEs, SAEs, fatal AEs, AEs defined as events of interest), and abnormal 
laboratory tests. 
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Phase 3: 
 
iCRR by blinded independent central review using modified irRC-RECIST 
 
iPFS by blinded independent central review using modified irRC-RECIST 
 
OS in subjects excluding stage IVM1c per CRF 
 
ORR (CR + PR), BOR, DRR, DOR (the time from date of the initial confirmed 
response to the date of the first documented PD or death), and DCR (response 
evaluation by blinded independent central review using modified RECIST 1.1), and 
iORR (iCR + iPR), iBOR, iDRR, iDOR, and iDCR response evaluation by blinded 
independent central review using modified irRC-RECIST). 
 
Incidence of treatment-emergent and treatment-related adverse events (all AEs, 
grade ≥ 3 AEs, SAEs, fatal AEs, and AEs defined as events of interest), and 
abnormal laboratory tests. 
 
Changes in EORTC QLQ-C30 GHS/QoL subscale. 
10.1.1.3 
Exploratory Endpoints 
 
iORR (iCR + iPR), iBOR, iDRR, iDOR, and iPFS (response evaluation by 
investigator using modified irRC-RECIST). 
 
Changes in the EORTC QLQ-C30 subscales. 
 
Changes in HSU estimates derived via EQ-5D-3L. 
 
Incidence of anti-pembrolizumab antibodies. 
 
Descriptive statistics of trough and peak levels of pembrolizumab (MK-3475). 
10.1.2 
Analysis Sets 
DLT Analysis Set 
The DLT analysis set will include DLT-evaluable subjects enrolled in phase 1b who have 
had the opportunity to be on treatment for at least 6 weeks from the initial dosing of 
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pembrolizumab and received at least 2 doses of talimogene laherparepvec and 2 doses 
of pembrolizumab in combination (ie, on the same day) or otherwise experienced a DLT 
within 6 weeks after starting the combination therapy. 
Full Analysis Set 
The primary analysis of all efficacy endpoints for phase 3 part of the study, unless noted 
otherwise, will be conducted on the full analysis set defined as all randomized subjects.  
All subjects will be analyzed according to treatment to which they are randomized. 
Safety Analysis Set 
The safety analysis set will include all subjects who received at least 1 dose of 
talimogene laherparepvec or pembrolizumab.  The safety analysis set will be defined 
separately for the phase 1b and phase 3.  For phase 3 all subjects will be analyzed 
according to the treatment they received. 
PRO Population 
The PRO population includes the subset of the subjects in the full analysis set 
who had received at least 1 dose of study therapy and had at least 1 PRO 
assessment.  A PRO assessment will be defined as completed if at least 1 
subscale/domain can be calculated from the questionnaire.  Patient reported 
outcome populations will be defined separately for each questionnaire (EORTC 
QLQ-C30 and EQ-5D-3L) and for the secondary endpoint of EORTC QLQ-C30 
GHS/QoL. 
10.1.3 
Covariates and Subgroups 
Randomization will be stratified by stage of disease:  less advanced stages (IIIB, IIIC, 
and IVM1a) versus more advanced stages (IVM1b and IVM1c) and by prior BRAF 
inhibitor therapy:  no prior BRAF inhibitor versus prior BRAF inhibitor with or without 
MEK inhibitor. 
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The following baseline covariates and randomization stratification factors may be used to 
examine efficacy in subgroups or in multivariate analyses: 
 
Region, if applicable (USA or non-USA) 
 
Age:  < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 
 
Individual disease stage:  IIIB vs IIIC vs IVM1a vs IVM1b vs IVM1c 
 
Grouped disease stage:  IIIB/C-IVM1a vs IVM1b/c (CRF and IVRS) 
 
Grouped disease stage:  IIIB/C-IVM1b vs IVM1c 
 
LDH:  ≤ ULN vs > ULN 
 
Sex (female vs male) 
 
ECOG performance status (0 vs 1) 
 
HSV-1 serostatus (positive vs negative) 
 
The sum of longest, or shortest for nodal, diameters of target lesions (SLD) 
determined by blinded independent central review (will be dichotomized based 
on median) 
 
Baseline PD-L1 status (positive vs not positive) 
 
Prior BRAF inhibitor (none vs BRAF inhibitor alone vs BRAF and MEK inhibitors in 
combination):  if subjects included in each of the 2 BRAF related category represent 
≥ 10% of the study population (CRF) 
 
Prior BRAF inhibitor (yes versus no BRAF inhibitor with or without MEK inhibitors) 
(IVRS) 
 
Baseline of BRAFV600 mutation:  yes vs no vs missing/unknown 
10.2 
Sample Size Considerations 
10.2.1 
Sample Size Considerations for Phase 1b 
Six to nine DLT-evaluable subjects will be required to assess the DLT profile of 
talimogene laherparepvec in combination with pembrolizumab for phase 1b.  The 
sample size of approximately 6 to 9 subjects is determined empirically and is consistent 
with those used in 6+3 phase 1 designs to evaluate the safety of a single dose of each 
agent assuming a true incidence rate of DLT is 11 to 33%.  Additional subjects, up to a 
total of 20, will be enrolled in the phase 1b portion of the trial to address the secondary 
objective exploring the relationship between 
 and response to 
treatment. 
Approved 
 
 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 122 of 171 
CONFIDENTIAL 
 
 
modified irRC-RECIST, and OS in the disease subgroup excluding IVM1c, will be 
performed.  Table 10 shows event goals (or analysis time) based on hypothesized effect 
sizes and simulated powers for testing 5 endpoints, where PFS and iPFS refer to the 
modified RECIST 1.1 and modified irRC-RECIST criterion, respectively.  The simulated 
powers are based on the Maurer-Bretz graphic-based multiple testing procedure 
(Maurer and Bretz, 2013) assuming a 1-time analysis.  Details of the multiple testing 
procedure are described in Section 10.5. 
Table 10.  Hypothesized Effect Sizes and Hypothesis Test Powers 
Hypothesis 
Effect Size 
Primary  
Analysis Timing 
Simulated 
Powera 
H1 (OS) 
HR = 0.70 
346 events 
91% 
H2 (PFS) 
HR = 0.67 
407 events 
90% 
H3 (iPFS) 
HR = 0.60 
256 events 
94% 
H4 (iCRR) 
OR = 3.9 
DCO for PFS PA 
97% 
H5 (OS subgroup) 
HR = 0.60 
Earlier of 208 events or 
5 years minimum 
follow-up 
90% 
DCO = data cutoff at event goal; H = hypothesis; HR = hazard ratio; iCRR = complete response rate (by 
modified irRC-RECIST); iPFS = progression free survival (by modified irRC-RECIST); OR = odds ratio;  
OS = overall survival; PA = primary analysis; PFS = progression free survival 
A CRR (95% CI) of 24% (8-47), per modified irRC, was observed in phase 1b subjects of 
the study with 36 weeks minimum follow-up time (Long et al, 2016).  It is also reported 
that CRR in pembrolizumab, per RECIST, was 5% (3-8) from KEYNOTE-006  
(Joseph et al, 2014) and 3% (1-10), per irRC, from KEYNOTE-001 (Robert et al, 2015).  
Assuming 6% CRR in pembrolizumab and 20% in the combination arm, then the odds 
ratio of 3.9 is hypothesized for iCRR in the phase 3 part of the study. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
To guard against actual or perceived bias due to subjective decisions made by Amgen 
or Designee in light of potentially unblinding data captured during phase 3 of the study, 
the study team will comply with Amgen standard operating procedures that govern 
restricted and potential unblinding data access.  Subject-level unblinding data will be 
available to an external independent biostatistics group that supports the DMC safety 
and efficacy reviews.  The external DMC will be the primary reviewer of the unblinding 
results for interim safety, efficacy, and futility analyses prior to the primary analysis of OS 
(see Section 10.4.3).  If the DMC recommends to stop the study due to safety concerns 
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Date:  15 January 2020 
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CONFIDENTIAL 
 
 
or declares that an efficacy or futility criterion has been met, then the sponsor may 
unblind a restricted study team as deemed necessary.  
Unblinding and potentially unblinding information for subjects and investigators should 
not occur prior to the study being unblinded for the primary analysis of OS except as 
specified (eg, Section 5.2, Section 9.2.1.2, and Section 10.4.3).   
10.4 
Planned Analyses 
10.4.1 
Interim Analyses 
A DLT interim safety analysis was planned and conducted by the study team for 
phase 1b.  Data were reviewed by a DLRT. 
All analyses prior to the primary OS analysis will be conducted by an external 
independent biostatistics group and reviewed by the DMC per the DMC charter.  The 
analyses will include safety monitoring, ORR/DCR and OS futility, primary and possibly 
interim PFS1, and interim OS analyses.  The study team is responsible for conducting 
the primary analysis of OS and all subsequent analyses. 
10.4.1.1 
DLT Safety Analysis (Phase 1b) 
An interim safety analysis in phase 1b to evaluate DLT included 6 subjects who were 
eligible for DLT evaluation (see Section 10.1.2 for definition of DLT-evaluable subjects in 
the DLT Analysis Set).  Data were reviewed by a DLRT as summarized in 
Section 3.1.1.1.  Rules for determination of DLTs are described in Section 3.1.1.1. 
10.4.1.2 
Interim Safety Analysis (Phase 3) 
Planned safety monitoring in phase 3 will first occur after approximately 20 and 
100 subjects, respectively, have been enrolled in phase 3 and have had an opportunity 
to be followed for at least 6 weeks after receiving study treatment and approximately 
every 6 months after the DMC meeting for the futility analysis for ORR and DCR has 
been completed until the later of the study team's unblinding or the primary analysis of 
OS.  Monitoring guidelines for futility will be provided to the DMC.  Additional ad hoc 
safety and/or efficacy data reviews may be requested by the DMC as needed. 
10.4.1.3 
Interim iORR and iDCR Futility Analysis (Phase 3) 
An interim futility analysis of iORR and iDCR per blinded independent central review 
using modified irRC-RECIST is planned to include the first 160 subjects 
(ie, approximately 80 per arm) that have had a chance to be followed for the tumor 
assessment scheduled at week 24.  The analysis will include the first 160 subjects 
enrolled.  All tumor response data will be included up to 26 weeks from the date of  
first dose of study therapy for the 160th enrolled subject (or randomization date if subject 
is not dosed).  The futility criterion will be based on the Bayesian method.   
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Beta (8.75, 16.25) and Beta (12.5, 12.5) prior distributions are assumed for the true 
placebo plus pembrolizumab arm (arm 2) iORR and iDCR in the trial population with 
means equal to 0.35 and 0.50, respectively, and both with the precision equal to a 
sample size of 25.  Beta (10.08, 10.92) and (14.91, 6.09) prior distributions are assumed 
for the iORR and iDCR for the combination of pembrolizumab and talimogene 
laherparepvec (arm 1) with means equal to 0.48 and 0.71, respectively, and both with a 
concentration parameter of 21.  The priors for the combination correspond to the results 
from a 24-week minimum follow-up analysis of the 21 subjects in the phase 1b part of 
the study. 
Beta posterior distributions for the iORR and iDCR will be calculated for each arm based 
on the corresponding prior distribution and the observed study iORR and iDCR results.  
The iORR futility criterion will be a posterior probability < 0.65 of at least a 6% absolute 
iORR increase (Arm 1 – Arm 2), and the iDCR futility criterion will be a posterior 
probability < 0.75 of at least a 10% absolute iDCR increase.  The DMC will declare the 
combination therapy futile if both the iORR and iDCR futility criteria are met; however, 
the DMC’s recommendation will be non-binding and therefore the sponsor will make the 
final decision to terminate the study prematurely. 
10.4.1.4 
Interim Efficacy and Futility Analysis (Phase 3) 
There are 5 planned analysis time points for hypothesis testing, including primary and/or 
interim analyses of the 5 hypotheses (H):  H1, associated with OS; H2, PFS by blinded 
independent central review assessed modified RECIST 1.1; H3, iPFS by blinded 
independent central review assessed modified irRC-RECIST; H4, iCRR by blinded 
independent central review assessed modified irRC-RECIST; and H5, OS subgroup 
excluding IVM1c (Table 10).  The analysis times are defined by the following 
event-driven time points with the DMC responsible for Analyses #1, #2, and #3. 
1. OS interim analysis and PFS primary analysis at 407 PFS events (DMC). 
2. OS interim analysis at 282 events (including a futility analysis) (DMC). 
3. OS interim analysis at 315 events (DMC). 
4. OS primary analysis at 346 events. 
5. OS subgroup primary analysis at earlier of 208 events in subgroup or 5 years 
minimum follow-up. 
Note that there is no sequential order in these 5 analysis times (with the exception that 
Analysis #2 is before Analysis #3, and Analysis #3 before Analysis #4).  Each analysis 
time may also include interim or primary analyses for the other endpoints.  Endpoints to 
be analyzed, and the type of analysis (ie, interim or primary), are presented in Table 11 
and are dependent on which hypotheses have been rejected.  For example, testing for 
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iCRR and iPFS at an analysis time point will be conditional upon previously rejecting 
either H1 or H2.  O'Brien-Fleming group sequential boundaries based on the Lan-DeMets 
approach (O'Brien and Fleming, 1979) will be used for testing endpoints with interim 
analyses.  Multiple testing procedures will utilize the graphic-based Maurer-Bretz 
approach (Section 10.5). 
The information fractions will be based on the events included at the time of analysis for 
testing of all time to event endpoint null hypotheses (ie, H1, H2, H3, and H5) and it will be 
based on the number of subjects with potential follow-up time of at least 36 weeks for 
testing the iCRR null hypothesis (ie, H4).  The maximum information for testing iCRR is 
all randomized subjects.  Each analysis time will have a corresponding database 
snapshot; however, there will not be a separate snapshot for each endpoint tested at the 
same analysis time. 
1. The initial alpha allocation for testing the hypothesis of PFS (H2) is 0.5% and 4.5% 
for OS (H1).  There will not be a nominal alpha passed back to H2 after rejecting H1 
or other hypotheses at any analysis. 
2. An interim OS analysis will be performed at Analysis #1 with all death events, 
regardless if H2 is rejected.  In the event when Analysis #2 occurs prior to Analysis 
#1, then it will include an interim analysis to test H2 for PFS (using all PFS events) 
and, if H2 is not rejected, it will be tested again at the planned time for Analysis #1.  
However, if the projected time for achieving 407 PFS events is within 4 months 
from the projected 282 OS events time, then Analysis #2 will be combined with 
Analysis #1 and be performed at Analysis #1 using all death events with PFS times 
censored after the 407th PFS event. 
3. At each of the 5 planned analysis times, it will be considered an interim analysis of 
iCRR and iPFS, rather than the primary analysis, if the maximum information has 
not been reached for the respective endpoint at that time.  For example, if H3 is 
tested in an analysis that includes fewer than 256 iPFS events, then it will be an 
interim analysis of iPFS that includes all observed events; otherwise, it will be the 
primary analysis with all iPFS times censored after the date of the 256th event.  If 
all randomized subjects do not have at least 36 weeks follow-up in an analysis, 
then it will be an interim analysis for iCRR only including those subjects with at 
least 36 weeks follow-up; otherwise, it will be the primary analysis and include all 
randomized subjects.  With the exception of PFS, the hypothesis for an endpoint 
may be re-tested after its primary analysis using its primary analysis data if alpha is 
subsequently propagated to it from the rejection of another hypothesis. 
4. Assuming Analysis #1 is before Analysis #2, and at Analysis #1 the null hypothesis 
of PFS (H2) is rejected, the hypotheses H3 and H4 will be tested.  H1 will be tested 
at Analysis #1 regardless of whether H2 is rejected.  The iPFS (H3) and iCRR (H4) 
can be tested if H2 is not rejected but H1 is significant.  Likewise, OS subgroup (H5) 
can be tested at Analysis #1 if any of the following set of hypotheses are rejected:  
(1) H2 and H3; (2) H2 and H4; (3) H1 and H3; or (4) H1 and H4. 
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5. If projections indicate 256 iPFS events will occur in the same timeframe as either 
Analysis #1 or Analysis #2, then the option will be considered to extend the data 
cutoff to include all 256 iPFS events.  In this event, Analysis #1 will have PFS times 
censored after the 407th PFS event and Analysis #1 or #2 will include all OS 
events. 
6. The OS hypothesis (H1) will be tested at Analyses #1-4 with all (Analysis #1) or 
required number (Analysis #2, Analysis #3, and Analysis #4) of events in the 
absence of its prior rejection (or futility at Analysis #2). 
7. The OS subgroup hypothesis (H5) will be tested at the first and all subsequent 
analysis times when alpha can be propogated to it from the rejection of H1 or H2 
followed by H3 and/or H4.  All OS events in the subgroup at the end of 5 years 
follow-up will be used if 208 events have not been observed.  If H1 is not rejected 
by Analysis #4, it will be tested again using events at Analysis #4 if alpha can be 
propogated from the rejection of H5 at Analysis #5.   
8. Likewise, H3 and H4 may be re-tested if not rejected by their primary analysis using 
their respective primary analysis data if H1 is subsequently rejected. 
Table 11 illustrates possible hypothesis tests at the 5 planned analyses. 
Table 11.  Study Analyses and Possible Hypothesis Tests 
 
 
Hypothesis Tested 
(Analysis Type) 
Analysis 
Timing 
H1 
(OS) 
H2 
(PFS) 
H3 
(iPFS) 
H4 
(iCRR) 
H5 
(OS 
subgroup) 
#1 
407 PFS events 
 
(IA) 
(PA) 
If reject H1 or H2 
(IA if < 256 
events) 
If reject H1 or H2 
(IA if includes 
fewer than all 
random-ized) 
If reject H2 and 
either H3 or H4, 
or reject H1 and 
either H3 or H4 
(IA if < 208 
events) 
#2 
282 OS events 
(IA) 
n/a 
(IA if 
Analysis 
#2 is 
performed 
first) 
If reject H1 or H2 
(PA on first 256 
events) 
If reject H1 or H2 
(PA if includes all 
random-ized) 
If reject H2 and 
either H3 or H4, 
or reject H1 and 
either H3 or H4 
(IA if < 208 
events) 
#3 
315 OS events 
(IA) 
n/a 
If reject H1 or 
H2 
(PA on first 
256 events) 
If reject H1 or H2 
(PA if includes 
all randomized) 
If reject H2 and 
either H3 or H4, 
or reject H1 
and either H3 
or H4 (IA if 
< 208 events) 
#4 
346 OS events 
(PA) 
n/a 
See Analysis #2 
and #3 above 
See Analysis #2 
and #3 above 
See Analysis 
#2 and #3 
above 
Page 1 of 2 
Footnotes defined on next page of table 
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Date:  15 January 2020 
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CONFIDENTIAL 
 
 
Table 11.  Study Analyses and Possible Hypothesis Tests 
 
 
Hypothesis Tested 
(Analysis Type) 
Analysis 
Timing 
H1 
(OS) 
H2 
(PFS) 
H3 
(iPFS) 
H4 
(iCRR) 
H5 
(OS 
subgroup) 
#5 
Earlier of  
208 OS events 
in subgroup or 
5 years 
minimum 
follow-up 
If reject H2 
previously 
and H5  
(PA at first 
346 events) 
n/a 
See Analysis #2 
and #3 above 
See Analysis #2 
and #3 above 
See Analysis 
#2 and #3 
above 
(PA) 
Page 2 of 2 
H = hypothesis; IA = interim analysis; iCRR = complete response rate (by modified irRC-RECIST);  
iPFS = progression free survival (by modified irRC-RECIST); n/a = not applicable; OS = overall survival;  
PA = primary analysis; PFS = progression free survival 
Futility Analysis for OS 
At the 282 OS events interim analysis (ie, Analysis #2), if hypothesis H1 is not rejected, 
then an OS futility analysis will be evaluated by the DMC.  The interim OS futility 
analysis will be non-binding and define futility as a conditional power < 10% assuming a 
constant treatment effect (Denne, 2001); the corresponding OS futility boundary is  
0.89, assuming a constant HR = 0.70.  OS futility will also be evaluated by the DMC 
considering a possible non-constant treatment effect that increases over time (eg, a 
2-interval model with a cutpoint between 4-8 months and constant treatment effect in 
each interval, where the second interval has a larger effect than the first one).  To limit 
the probability of futility < 0.02, the futility boundary for the observed HR at 282 OS 
events analysis will be 0.93.  Guidelines for this possible late effect will be provided in 
the DMC charter amendment.  Operating characteristics of the primary analysis of PFS 
and sequential tests of OS are shown in Table 12 based on the OS events expected at 
Analysis #1. 
 
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Table 12.  Analysis Timing, Nominal Significance Levels, and Boundary Properties 
 
Analysis 
Data 
cut-off 
(mon) 
Endpoint 
(scenario) 
Event 
(% goal) 
Efficacy 
nominal 
2-sided  
Futile HR b 
Prob. Futile b 
Efficacy 
HR 
Power total 
H0 
H1 
 
PFS PA  
48 
PFS 
407 (100) 
0.0050 
 
 
 
0.76 
90% 
 
OS IA1 
48 
OS (PFS-) 
OS (PFS+) 
252 (73)a 
0.0150 
0.0173 
 
 
 
0.74 
0.74 
66% 
67% 
 
OS IA2 
52 
OS (PFS-) 
OS (PFS+) 
282 (82) 
0.0187 
0.0212 
0.89 
0.89 
84% 
83% 
2% 
2% 
0.76 
0.76 
76% 
77% 
 
OS IA3 
61 
OS (PFS-) 
OS (PFS+) 
315 (91) 
0.0261 
0.0292 
 
 
 
0.78 
0.78 
84% 
85% 
 
OS PA 
75 
OS (PFS-) 
OS (PFS+) 
346 (100) 
0.0336 
0.0372 
 
 
 
0.80 
0.80 
90% 
90% 
IA = interim analysis; H0 = null hypothesis; H1 = alternative hypothesis; HR = hazard ratio; OS = overall survival; PFS = progression free survival; PA = primary 
analysis. O’Brien-Fleming spending α for OS; futility if conditional power < 10%; H0:  HR = 1 and H1:  HR = 0.67 (PFS) and 0.70 (OS).  Testing OS at an overall 2-sided 
0.045 if PFS is not significant at 2-sided 0.005 (eg, PFS-); testing OS at 0.05 when all other null hypotheses are rejected (eg, PFS+). 
 
 
a The events for OS IA1 are not pre-determined; the estimates shown are the number expected at the time of PFS PA. 
b The futile HR and probabilities are shown for the conditional power criterion only which assumes a constant OS effect. 
 
 
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10.4.2 
Dose Level Review Team (DLRT) 
A DLRT consisting of the Amgen study team, including at least one clinician, safety 
representative, and biostatistician, at least one representative from the Merck study 
team, and at least one investigator participating in the study who has recruited subjects 
into phase 1b, reviewed the safety data to evaluate possible DLT.  This team will 
recommend either to enroll more subjects for DLT evaluation in phase 1b, to prematurely 
stop enrollment into phase 1b, or to declare that the combination is tolerable and 
whether to open the phase 3.  The DLRT will review additional safety data from subjects 
enrolled in phase 1b beyond the 6 to 9 DLT evaluable subjects to further assess the 
overall safety profile of talimogene laherparepvec in combination with pembrolizumab. 
10.4.3 
Data Monitoring Committee (DMC) 
An independent  DMC which includes two clinicians and a biostatistician who are 
external to Amgen and Merck will review data from the phase 3 interim analyses prior to 
the primary analysis of OS (see Section 10.4.1 interim analysis for details).  All available 
safety data from the phase 1b part of the study will also be provided to DMC at the time 
of the first planned interim safety analysis (ie, at 20 subjects trigger) in phase 3.  The 
DMC will be governed by a detailed DMC charter.  Additional DMC safety analyses may 
be performed if recommended by the DMC based on results from the planned analyses 
or if requested by the clinical study team. 
10.4.4 
Primary Analysis 
This section describes the timing of the primary analysis of phase 1b and 3, respectively.  
The clinical study report (CSR) will be written based on the results from the OS primary 
analysis for phase 3, which will also include safety data from subjects in phase 1b.  
However, a CSR will be prepared should there be a decision for unblinding the study 
team based on early stopping for safety, efficacy, or futility (Section 10.4.1).  Amgen 
senior management will make the decision to unblind the study team based on the 
DMC’s recommendations; however, only a subset of the study team will be unblinded 
prior to the OS primary analysis. 
10.4.4.1 
Primary Analysis Phase 1b 
The goal of the primary analysis is to determine the safety and tolerability of talimogene 
laherparepvec in combination with pembrolizumab as assessed by incidence of DLT.  
The primary analysis will occur when the last subject enrolled in the phase 1b has had 
the opportunity to be on treatment for at least 6 weeks from the initial dosing of 
pembrolizumab.  To evaluate secondary objectives, the phase 1b will be re-analyzed 
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after the last subject has had a chance to be followed for 24 weeks from the initiation of 
pembrolizumab and at the time of the phase 3 OS primary analysis. 
10.4.4.2 
Primary Analysis Phase 3 
Phase 3 will evaluate the efficacy as assessed by PFS and OS of talimogene 
laherparepvec with pembrolizumab versus placebo with pembrolizumab in subjects with 
unresectable, stage IIIB to IVM1c melanoma.  The timing of the primary analyses for 
PFS and OS of phase 3 will be triggered when 407 PFS events and 346 OS events have 
occurred, respectively. 
10.4.5 
Final Analysis 
The final analysis will occur approximately 5 years (60 months) after the last subject has 
been enrolled in phase 3.  A separate, final analysis CSR will be drafted with the 
updated results from the final analysis at the completion of the study. 
10.5 
Planned Methods of Analysis 
The DLT analysis set will be used to summarize the subject incidence of DLT for the 
phase 1b part of the study and the safety analysis set will be used for all other analyses 
of safety including incidence of treatment-emergent and treatment-related adverse 
events (all AEs, grade ≥ 3 AEs, SAEs, fatal AEs and AEs defined as events of interest). 
For phase 1b, descriptive statistics for ORR, BOR, DCR, DRR, DOR, PFS, and OS will 
be provided where tumor response evaluations are based on investigator assessments 
using modified irRC.  The analysis will include data from phase 1b subjects in the Safety 
Analysis Set. 
For phase 3, the efficacy analyses will be conducted on the Full Analysis Set.  Treatment 
effects on efficacy endpoints will be evaluated according to the treatment as 
randomized.  Formal treatment comparisons will be performed on the dual primary 
endpoints and the 3 key secondary endpoints. 
In principle, summary statistics including mean, standard deviation, median, first and 
third quartiles, will be provided for continuous variables.  Frequency and percentage will 
be summarized by treatment arm for binary and categorical variables.  Proportions and 
the corresponding 95% confidence intervals will be based on normal approximations and 
the treatment comparison will be based on Cochran-Mantel-Haenszel test.  Exact tests 
will be considered for subgroup analyses when the cell size is too small.  Time-to-event 
endpoints will be estimated using the Kaplan-Meier (KM) estimation.  Kaplan-Meier 
estimates and the 95% confidence intervals for within each treatment arm and 
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differences between treatment arms by time point will be provided.  Standard errors of 
estimated treatment differences by time point will be calculated using Greenwood's 
formula (Kalbfleisch and Prentice, 1980).  Confidence intervals for the KM quartiles will 
be provided by treatment arm (Brookmeyer and Crowley, 1982).  Log-rank test statistics 
and associated p-values will also be calculated.  Hazard ratios will be estimated using 
Cox PH models. 
10.5.1 
Multiple Hypothesis Testing Procedures and Multiplicity Adjustment 
Multiple statistical hypothesis tests will be conducted which include testing for primary 
endpoints of PFS and OS and the 3 secondary endpoints (iCRR, iPFS, and OS in the 
subgroup excluding disease stage IVM1c) at multiple analysis time points.  To control 
the study-level overall Type I error, a graphic-based multiple testing procedure for group 
sequential tests for multiple endpoints will be utilized (Maurer and Bretz, 2013).  No 
updated information will be used when a hypothesis is re-tested at a later time point after 
its primary analysis.  A hypothesis can be re-tested repeatedly with a different nominal 
level that is propagated from rejecting other hypothesis test(s).  The following figure 
illustrates the Maurer-Bretz multiple testing procedure with initial 2-sided α allocation 
specified as a fraction used for each hypothesis test.  Each hypothesis is represented by 
a circle.  A 0 fraction in the circle indicates a hypothesis that is tested conditional on 
rejection of another hypothesis.  The fractions in the square on the directed arrows 
connecting 2 hypotheses indicate the proportion of α propogated to the next hypothesis 
test(s) when the current hypothesis is rejected. 
Approved 
 
 
AMGEN® 


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


Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 133 of 171 
CONFIDENTIAL 
 
 
PD-L1 status (positive vs not positive).  Kaplan-Meier (KM) time to event curves will be 
presented by the randomized treatment group.   
Statistical testing of a treatment effect for PFS and OS will follow the multiple hypothesis 
testing procedure as described in Section 10.5.   
Subgroups and covariates for analyses of PFS and OS will include, but not limited to, 
disease stage (IIIB/C to IVM1a, IVM1b/c), known PD-L1 status (positive, negative) and 
prior treatment with BRAF inhibitor. 
10.5.3 
Secondary Efficacy Endpoints 
All secondary endpoints of phase 1b will be descriptive.  
Phase 3 analyses of iPFS and OS excluding the disease stage IVM1c subgroup will 
follow the analysis described for PFS.  iCRR by blinded independent central review per 
modified irRC-RECIST will be treated as a binary endpoint and will be analyzed with a 
stratified Cochran-Mantel-Haenszel test using the same stratification variables used by 
the PFS analysis.  Following the intent-to-treat principle, subjects who do not have any 
follow up tumor assessments will be determined to be non-complete responders.  
Hypothesis testings for iPFS, iCRR, and OS subgroup are described in multiple testing 
procedures in Section 10.5.  Analyses of remaining secondary endpoints in phase 3 will 
be descriptive. 
ORR, DCR, and DRR per modified RECIST and iORR, iDCR, and iDRR per modified 
irRC-RECIST by blinded independent central review will be summarized by treatment 
arm as randomized (phase 3).  Subjects who do not have any follow up tumor 
assessments will be classified as not having a response, disease control, or a durable 
response.  DOR (defined as the time from date of the initial response to the date of the 
initial PD per response criterion or death) will be analyzed among responders and will be 
estimated using the Kaplan-Meier method.   
10.5.4 
Safety Endpoints 
Treatment emergent adverse events are defined as adverse events that occur after 
receiving the first dose of study therapy through 30 days after the last dose of study 
therapy.  Subject incidence rates of treatment-emergent adverse events (including all 
AEs, grade ≥ 3 AEs, SAEs, adverse events of interest and events requiring the 
discontinuation of study drug, local effects on the tumor [ie, pain, inflammation and 
ulceration]) will be summarized.  Medical Dictionary for Regulatory Activities (MedDRA) 
will be used to code adverse events to a system organ class (SOC) and a preferred term 
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within the SOC.  The CTCAE version 4.0 will be used to grade severity of adverse 
events.  Adverse events reported beyond 30 days after the last dose will be analyzed 
separately. 
The analyses of safety laboratory endpoints and vital signs will include summary 
statistics over time by treatment group.  Shifts in grades of safety laboratory values 
between the baseline and the worst on-study value will be tabulated by treatment group. 
Summary statistics will also be provided for concomitant medications, dose delay, study 
treatment discontinuation, overall exposure, and changes in ECOG performance status.  
Tables and/or narratives of deaths through either the 30 days after the last dose of 
talimogene laherparepvec or pembrolizumab, whichever is later, will be provided. 
The ECG measurements from this clinical study will performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data, summaries and 
statistical analyses of ECG measurements are not planned, and these data would not be 
expected to be useful for meta-analysis with data from other trials. 
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 descriptively.  The incidence and percentage of subjects who develop 
anti-pembrolizumab antibodies (binding and if positive, neutralizing) at any time will be 
tabulated. 
Potential or known unintended exposure to talimogene laherparepvec, related suspected 
signs or symptoms, and detection of talimogene laherparepvec in a subject’s household 
member, caregiver, or healthcare provider will be reported. 
10.5.5 
Patient Reported Outcome Endpoints and Analyses 
The PRO analyses will be conducted for subjects in the PRO population.  Summary 
scores at each assessment and changes from baseline of PROs as assessed by 
EQ-5D-3L and the QLQ-C30 questionnaires will be reported.  Changes from baseline 
will be summarized and at specified time points of interest, differences between 
treatment groups for each defined score will be analyzed.  For the EORTC QLQ-C30 
questionnaire, each of the 5 functional scales, 9 symptom scales, and a GHS/QoL 
subscale (secondary endpoint) will be summarized similarly.  For the EQ-5D-3L 
questionnaire, 2 scores will be estimated:  the utility score calculated from the  
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5 domains using a scoring algorithm, and the VAS score based on the 0 to 
100 feeling thermometer.  Details of all the PRO analyses will be provided in the PRO 
supplemental statistical analysis plan. 
10.5.6 
Health State Utility Estimates 
For the EQ-5D-3L questionnaire, 2 scores will be estimated:  the utility score calculated 
from the 5 domains using a scoring algorithm, and the VAS score based on the 
0-100 feeling thermometer.  The calculation of scores and methods for handling missing 
data will be based on the questionnaire's standard scoring guidelines.  Details for 
deriving the HSU estimates will be provided in the statistical analysis plan. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject 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 products are administered. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician are to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject. 
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If a potential subject is illiterate or visually impaired, the investigator must provide an 
impartial witness to read the informed consent form to the subject and must allow for 
questions.  Thereafter, both the subject and the witness must sign the informed consent 
form to attest that informed consent was freely given and understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by 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 AE 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 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guidelines, it is required that the investigator and 
institution permit authorized representatives of the company, of the regulatory agency(s), 
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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 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 
talimogene laherparepvec by an extension protocol or as provided for by the local 
country’s regulatory mechanism.  However, Amgen reserves the unilateral right, at its 
sole discretion, to determine whether to supply Amgen investigational product 
talimogene laherparepvec and by what mechanism, after termination of the study and 
before the product is available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
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Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the IVRS captures the following data points and these are considered 
source data:  subject identification number and randomization number. 
CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data). 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list. 
 
Study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen. 
 
Investigational product-related correspondence including Proof of Receipts (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, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen clinical monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
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research.  The clinical monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process and/or data queries are created in the EDC system database for site 
resolution and subsequently closed by the EDC system or by an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that investigator inspected or reviewed the 
data on the CRF and the data queries, and agrees with the content. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 5 and Table 6), the investigator can search publicly 
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. 
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12.5 
Language 
CRFs must be completed in English.  TRADENAMES (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 
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 may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the 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.  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 
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institution, investigator, and Amgen will detail the procedures for, and timing of, Amgen’s 
review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for Research 
and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use in international 
clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-376. 
American Joint Committee on Cancer (AJCC) cancer staging manual (7th ed). New 
York, NY: Springer; 2010. 
Andtbacka RHI, Collichio FA, Amatruda T, et al.  OPTiM:  a randomized phase III trial of 
talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage 
colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and 
IV melanoma.  J Clin Oncol.  2013;31(suppl).  Abstract LBA9008. 
Bjordal K, de Graeff A, Fayers PM, et al.  A 12 country field study of the EORTC  
QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC  
QLQ-H&N35) in head and neck patients.  EORTC Quality of Life Group.  Eur J Cancer.  
2000;36(14):1796-807. 
Blank C, Brown I, Peterson AC, et al.  PD-L1/B7H-1 inhibits the effector phase of tumor 
rejection by T cell receptor (TCR) transgenic CD8+ T cells.  Cancer Res.  
2004;64:1140-1145. 
Brahmer JR, Tykodi SS, Chow LQ, et al.  Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer.  N Engl J Med 2012; 366:2455-2465. 
Brookmeyer R and Crowley J.  A Confidence Interval for the Median Survival Time.  
Biometrics.  1982;38:29-41. 
Chang KJ, Senzer NN, Binmoeller K, et al.  Phase I dose-escalation study of talimogene 
laherparepvec (T-VEC) for advanced pancreatic cancer (ca).  J Clin Oncol.  2012; 
30(suppl).  Abstract e14546. 
Chesney J, Puzanov I, Collichio F, et al.  Randomized open-label phase II study 
evaluating the efficacy and safety of talimogene laherparepvec in combination with 
ipilimumab versus ipilimumab alone in patients with advanced unrespectable melanoma. 
J Clin Oncol. 2017; 35 [Epub ahead of pring] 
Clopper, CJ. and Pearson, ES.  The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial.  Biometrika,1934; 26, 404–413 
Denne JS.  Sample size recalculation using conditional power.  Stat Med.  
2001;20:2645-2660. 
Eisenhauer EA, Therasse P, Bogarets J, et al.  New response evaluation criteria in solid 
tumours:  Revised RECIST guideline (version 1.1).  Eur J Cancer.  2009;45:228-247. 
Ferlay J, Soerjomataram I, Ervik M, et al.  GLOBOCAN 2012 v1.0, Cancer Incidence 
and Mortality Worldwide:  IARC Cancer Base No.  11 [Internet].  Lyon, France:  
International Agency for Research on Cancer; 2013.  http://globocan.iarc.fr 
Hamid O, Robert C, Daud A, et al.  Safety and tumor responses with lambrolizumab 
(anti-PD-1) in melanoma.  N Engl J Med.  2013;369:134-144. 
Harrington K, Hingorani M, Tanay M, et al.  Phase I/II study of oncolytic HSVGM-CSF in 
combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell 
cancer of the head and neck.  Clin Can Res.  2010; 16:4005-4015. 
Hodi FS, O'Day SJ, McDermott DF, et al.  Improved survival with ipilimumab in patients 
with metastatic melanoma.  N Engl J Med.  2010;363:711-723. 
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Jemal A, Siegel R, Ward E, et al.  Cancer statistics, 2006.  CA Cancer J Clin.  
2006;56:106-130. 
Joseph RW, Elassaiss-Schaap J, Wolchock JD, et al.  Baseline tumor size and PD-L1 
expression are independently associated wtih clinical outcomes in patients with 
metastatic melanoma treated with pembrolizumab (MK-3475).  Pigment Cell Melanoma 
Res.  2014;27:1188. 
Kalbfleisch JD and Prentice RL.  The statistical analysis of failure time data.  New York:  
John Wiley & Sons.  1980. 
Kaufman HL, Andtbacka RH, Collichio FA, et al.  Primary overall survival (OS) from 
OPTiM, a randomized phase 3 trial of talimogene laherparepvec (T-VEC) versus 
subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the 
treatment (tx) of unresected stage IIIB/C and IV melanoma.  J Clin Oncol.  2014;32:5s 
(suppl; abstr 9008a). 
Kaufman HL, Andtbacka HI, Collichio F, et al.  Interim OS subset analyses in OPTiM, a 
randomized phase 3 trial of intralesional talimogene laherparepvec vs.  subcutaneous 
granulocyte macrophage-colony stimulating factor in stage IIIB-IV melanoma.  Society 
for Melanoma Research; 2013. 
Kaufman HL, Kim DW, DeRaffele, G, Mitcham J, Coffin RS, Kim-Schulze S.  Local and 
distant immunity induced by intralesional vaccination with an oncolytic herpes virus 
encoding GM-CSF in patients with stage IIIc and IV melanoma.  Ann Surg Oncol.  
2010;17(3):718-730. 
Kind P.  The EuroQoL Instrument:  An Index of Health-Related Quality of Life.  In:  
Spilker B, ed.  Quality of Life and Pharmacoeconomics in Clinical Trials, Second Edition.  
Philadelphia, PA:  Lippincott-Raven Publishers, 1996:191-201.   
Lachin J, and Foulkes M.  Evaluation of sample size and power for analyses of survival 
with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and 
stratification.  Biometrics.  1986;42:507-519. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al.  Five-year survival with combined 
nivolumab and ipilimumab in advanced melanoma.  N Engl J Med.  
2019;381(16):1535-1546. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al.  Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma.  N Engl J Med.  2015; 373:23-34 
Long GV et al.  A phase 1/3 multicenter trial of talimogene laherparepvec in combination 
with pembrolizumab for unresected, stage IIIB-IV melanoma (MASTERKEY-265).  J Clin 
Oncol 34, 2016 (suppl; abstr TPS9598). 
Maurer W, Bretz F.  Multiple Testing in Group Sequential Trials Using Graphical 
Approaches.  Statistics in Biopharmaceutical Research.  2013;5(4):311-320. 
Nishino M, Gargano, M, Suda M, Ramaiya NH, Hodi FS.  Optimizing immune-related 
tumor response assessment:  does reducing the number of lesions impact response 
assessment in melanoma patients treated with ipilimumab.  J Immunother Cancer.  
2014;2(17);1-12. 
Nishino M, Giobbe-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS.  Developing a 
common language for tumor response to immunotherapy:  immune-related response 
criteria using unidimensional measurements.  Clin Cancer Res.  2013;19(14);3936-3943. 
O'Brien PC, and Fleming TR.  A multiple testing procedure for clinical trials.  Biometrics.  
1979;35(3):549-556. 
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Okazaki T, Honjo T.  PD-1 and PD-1 ligands:  from discovery to clinical application.  
Int Immunol.  2007;19:813-824. 
Pardoll DM.  The blockade of immune checkpoints in cancer immunotherapy.  Nat Rev 
Cancer.  2012;12:252-264. 
Pembrolizumab (MK-3475) Investigator’s Brochure, Edition 6.0.  Whitehouse Station, 
NJ.  Merck Sharp & Dohme Corp, a Subsidiary of Merck & Co, Inc; 31 August 2015. 
Puzanov I, Milhem MM, Andtbacka RHI, et al.  Primary analysis of a phase 1b 
multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) 
and ipilimumab (ipi) in previously untreated, unresected, Stage IIIB-IV melanoma.  J Clin 
Oncol.  2014;32:5s (suppl; abstr 9029). 
Puzanov I, Milhem M, Andtbacka R, et al.  Survival, safety, and response patterns in a 
phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in 
previously untreated, unresected stage IIIB-IV melanoma.  J Clin Oncol.  2015;33 (suppl; 
abstr 9063) 
Rabin R, de Charro F.  EQ-5D:  a measure of health status from the EuroQol Group.  
Ann Med.  2001;33(5):337-343.   
Ribas A.  Tumor immunotherapy directed at PD-1.  N Engl J Med.  2012;366:2517-2519. 
Ribas A, Dummer R, Puzanov I, et al.  Oncolytic virotherapy promotes intratumoral T cell 
infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170:1109-1119. 
Ries LA, Wingo PA, Miller DS, et al.  The annual report to the nation on the status of 
cancer, 1973-1997, with a special section on colorectal cancer.  Cancer.  
2000;88:2398-2424. 
Robert C, Ribas A, Schachter J, et al.  Pembrolizumab versus ipilimumab in 
advanced melanoma (KEYNOTE-066):  post-doc 5-year results from an open-label, 
multicenter, randomised, controlled, phase 3 study.  Lancet Oncol.  
2019;20(9):1239-1251. 
Robert C, Thomas L, Bondarenko I, et al.  Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma.  N Engl J Med.  2011;364:2517-2526. 
Robert C, Schachter J, Long GV, et al.  Pembrolizumab versus ipilimumab in advanced 
melanoma.  N Engl J Med.  2015; 372:2521-2532. 
Robert C, Long GV, Brady B, et al.  Nivolumab in previously untreated melanoma 
without BRAF mutation.  N Engl J Med.  2015; 372:320-330. 
Ross M, Andtbacka R, Puzanov I, et al.  Patterns of durable response (DR) with 
intralesional talimogene laherparepvec (T-VEC) from a phase 3 trial in patients with 
Stage IIIB-IV melanoma.  American Society of Clinical Oncology Annual Meeting 2014.  
Abstract 9026. 
Schachter J, Ribas A, Long GV, et al.  Pembrolizumab versus ipilimumab for advanced 
melanoma:  final overall survival results of a multicentre, randomised, open-label phase 
3 study (KEYNOTE-006). Lancet. 2007;390(10105);1853-1862. 
Siegel R, Ma J, Zou Z, Jemal A.  Cancer statistics, 2014.  CA Cancer J Clin.  
2014;64:9-29. 
Talimogene Laherparepvec Investigator’s Brochure, Edition 10.0.  Woburn, MA.  BioVEX 
(a wholly owned subsidiary of Amgen); 17 January 2014. 
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Topalian SL, Hodi FS, Brahmer JR, et al.  Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer.  N Engl J Med.  2012;366:2443-2454. 
Whiteside TL.  Immune suppression in cancer:  effects on immune cells, mechanisms 
and future of therapeutic intervention.  Semin Cancer Biol.  2006;16:3-15. 
Wolchok JD, Hoos A, O’Day S, et al.  Guidelines for the evaluation of immune therapy 
activity in solid tumors:  immune-related response criteria.  Clin Cancer Res.  
2009;15(23):7412-7420. 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 is available 
at the following location:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
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Appendix B.  Sample Serious Adverse Event Report Form 
 
Approved 
 
 
Com letion Instructions - Electronic Adverse Event Conlin 
or use for dinicaJ trial studies usin Electronic Data 
NOTE: This fonn is to be used under restricted conditions ouUined on page 1 below. If you ,must fax an event report to 
Amgen, you must also enter that event into the EDC system (eg, Rave) when it becomes available. 
General Instructions 
The protoc.ol will prov·ide instruction on what types of events to report for the study. This form is to be used ONLY to 
~eport events that must be captured in the Amgen safety database. •·indicates a mandatory fie ld. 
Types of Events to be re ported on this form 
Seri,ous. Adverse Events (regardless of causal relationship to IPI 
1. Site lnfonnation 
Site Number' - Enter your assig ned site number for this sludy 
Investigator", Country", Reporter", Phone No., and Fax No. - Enter information requested 
2. Subject Information 
Subject ID Number" - Enter the enlire number assigned to the subject 
Age at event onset, Sex, and Race - Enter the subjecf s demographic informa ·on 
End of Study date- If the subject has already compleled the study or terminated the study early, enter lfle End of Study 
date 
ff you are submitting follow-up information to a previous report, provide the serious adverse event term for the 
previous report as well as the start date for the initial event. 
l. Serious Adverse Event 
Provide the date the lnve.stigator became aware of this Information 
Serious Adverse Event Diagnosis or Syndrome• -
► If the diagnosis is known, it should be entered. Do not list all signs/symploms if they are included in lfle diagnosis. 
► If a diagnosis is not known , the relevant signs/symptoms should be e/ltered. 
► If the event is fatal, the cause of dealfl should be entered and autopsy results should be submitted, when availab e. 
Date Started'" - Enter date lfle adverse event first started (not the date on 1vhich ttl e event met serious criteria )rather lflan 
the date of diagnosis or hospitalizion .. This is a mandatory field. 
Date Ended - Enter date the adverse event ended and not the date wh en tile event no longer met serious criteria. If the 
event has not ended at lfle time of the initial report, a follow-up report should be comple ed when the end dale is known . If 
the event is fatal, enter the date of death as the ,end dale. 
If event occurred before the first dose of lnvestigational Pmd11ct (IP)/drug under study, add a check mark in the 
corresponding box. 
Is event serious?• - Indicate Yes or No. This is a mandatory field. 
Serious Criteria Code• - This is a mandatory field for seriou s events. Enter all reasons why the reported event has met 
serious criteria: 
► Immediately life-threatening - Use only if the subject was at immediate risk of death from lfle ev,ent as it occurred. 
Emergency treatment is often required to sustain life in this situation. 
► If the investigator decides an event should be reported in an expedited manner, but it does not me-et other serious 
criteria, "Other Medically Important Serious Eve/lt" may be the appropriate serious criterion. 
Relationship to IP - The Investigator must determine and enter lfle relationship of the evenl to the IP at the time lfle event is 
initially reported. This is a mandatory field. 
Relationship to Amgen device' - The Investigator must determine and enter the rela ·onship of the event to the Amgen 
device (e.g. prefilled syringe, auto-injector) at lfle time lfle event is inilially reporled. If tile study involves an Amgen device, 
this is a mandatory field. This question does not apply to non-Amgen devices used in the study (e.g. heating pads, 
infusion pumps) 
Outcome of Event" - Enter lfle code for the outcome of lfle event at lfle time lfle form is completed. This is a mandatory 
field. 
► Resolved - End dafe is !:ncwn 
► No.t resolved I Unknovm - End date is unknovm 
► F efal - Event led to death 
If event is related to a study procedure, such as a biopsy, radiolflerapy or withdrawal of a current drug tr,eabn ent during a 
wash'-Oul period, add a check mark to the corresponding box. This does not include relationship to IP or concomitant 
medication - only diagnostic tests or activities mandated by tile protocol. 
4. Hospitalization 
If the subject was hospitalized, e/lter admission and discharge dales. Hospitalization is any in-patient hospital admission for 
medical reasons, including an overnight stay in a healthcare facility, regardless of duration. A pre-existing condition that did 
not worsen while on study which involved a hospitalization for an elective lreatmellt, is not considered an adverse event. 
Protocol specified hospitalizations are exempt. 
FORM--056006 
lnatruoooos Page 1 of2 
ve,s;on 7.0 
Elfeclive Da!e: 1 February 2016 
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Date:  15 January 2020 
Page 149 of 171 
CONFIDENTIAL 
 
 
 
Approved 
 
 
Completion Instructions - Electronic Adverse Event Conting_e'lfddeport Form 
(for use for Studies using Electronic Data Capture[ 
) 
Note, t!hi.s form is to be used under restricted conditions outlined on page 1 of the form. If you must fax an event report 
to Amgen, you must also enter that event into the EDC system (eg, Rave) when it becomes available. 
I At the top of Page 2, provide vour Site Number and the Subiect ID Number in the designated section. 
5. IIP Admini.stration including lot# and Serial# when known / available. 
Blinded or open-label - If applicable, indicate whether the investigational product is blinded or open-label 
Initial! Start Date - Enter dale the product was first adminislered, regardless of dose. 
!late of !lose Prior to or at tile time of tile Event - Enter date the product was last adminislered prior to, or at the time ot, 
the onset of th e event. 
!lose, Route, and Frequency at or prior to the event - Enler the appropriate information for the dose, route and frequency 
at, or prior to, the onset of the event. 
Action Taken with Product- Enter the status of the product administration. 
6. Concomitant Medications 
Indicate if there are any medications. 
Medication Name, Start Date, Stop Date, Do,se, Route, and Frequency - Enter information for any oth er medications tile 
subject is taking. Include any study drugs not included in section 5 (Producl Administration) such as chemotherapy, whtcfl 
may be considered co-suspect. 
Co-suspect- Indicate it the medication is co.suspect in the event 
Continuing, - Indicate if the subject is still taking the medication 
Event Treatment - lndicale if th e medication was used to tr-eat the event 
7. Relevant Medical History 
Enter medical history that is relevant to the reported event, not the event description. This may include pre-existing conditions 
thal contributed o the event allergies and any relevant prior therapy, such as radiation. Include dales if available. 
8. Relevant laboratory Tests 
Indicate if there are any relevant laboratory values. 
For each test type, enter the test name, units, date the I.est was run and the results. 
9. Other Relevant Tests 
Indicate if there are any tests, including any diagnostics or procedures. 
for each test type, enter the dale, name, results arid units (if applicable). 
!At the top of Page 31 provide your Site Number and the Subiect ID Number in the designated section.l 
1 0. Case llesc ription 
Describe Event-Enter summary of the event. Provide narrative details of Ille evenls listed in section 3. Include any 
therapy administered , such as radiotherapy; (excluding medications, wflich will be captur-ed in section 6). If riec-essary, 
provide additio rial pages to Amgen. 
Complete the signature section at the bottom of page 3 and fax the form to Amgen. If the reporler is not the investigator, 
designee must be identified on the Delegation of Authority form. 
FORM--056006 
lnstruclioos Page 2 of 2 
Vers,ion 7.0 Effedive Date: 1 February 2016 
AMGEN® 


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Protocol Number:  20110265 
Date:  15 January 2020 
Page 150 of 171 
CONFIDENTIAL 
 
 
 
Approved 
 
 
~ 
Study# 20110265 
T alimog"""' laherparepvec 
Electronic Serious Adverse Event Contingency Report Fonn 
For Restricted Use 
Reason for reporting this event via fax 
The Clinical Trial Database (eg. Rave): 
Is not available due to internet outage at my site 
Is not yet available for this study 
Has been closed for this study 
«For completion by COM prior to providing to sites: SELECT OR TYPE IN A FAX#>> 
1. SITE INFORMATION 
1S?.rr·1 
lt111es1i!lator 
I 
Co,m!ry 
Reporter 
Prone Numher 
I (axNumher 
( 
) 
) 
2. SUBJECT INFORMATION 
Si.il:jectllDN..,-.ba-
I 
Age at event oosel 
Sex 
I~,. 
w awli::all~ l'ft"id• &,d cl Sl!ldy 
I I I I I I I I I I 
U F UM 
date 
If this is a follow-up lo an event reported in lhe EDC system (eg, Rave~ provide lhe adverse evenl term: 
and start date: Day __ I.lo, __ Ye-;,, ___ 
3. SERIOUS ADVERSE EVENT 
Provide the date the Investigator became aware of this information: Day 
klonfh 
Year 
5erioos Adv-ert1& Ev811t diagnoaia or ayndrome 
ct,,:k ·-
~ 
outcome r~--:' 
lf diagnoaie ia unknown~ Bl1f&r it:igna. / eymptoma 
entyij 
"' 
oner 
Is tn:re a rea:Dnallte p1:.sblrj ttl3111E:::1iicnt alEvecrt 
gi 
re~b 
and proville dlagnooia, when known, in a fol c,w-
e. .. 
0 
5erioue 
m3)' ttaJe tle:n irai:ei:1 try 
-:iib:J~ .,,,, 
up report 
Date Started 
Date Ended 
cw.med 
·.;; 
Qm:, 
IP or an Amgen ,i:l!!\i:e U:ed to idrrJnttE:r ttie &J!1"tl,.J f"""3',. 
list on~ era,t per .wie. If eve11tis fat,!, e,fer ~ 
lle!co, 
:: 
coli, 
IP? 
,re!,I 
11:s, oo,e 1 
'It "'"' 
eg,ti<pS) 
cav.seofee3fh. Entryof·a.._c.atn·is.rro:t a~;ble., 
of IP 
/..e 
as this i's aNootco.me. 
COil& 
l!)ay Monti, 
Year il'ay Monti, 
Year 
.!!l 
t""') l llllml:l;a,tll• ·- --
r.it.n:11r.~ • -- -- -- ,_ -
[Pe 
o,, 
[Pe 
o,, 
[Pe 
o,, 
Serious 
01 Fatal 
03 Requi""1'prolooged hasj:i:-aliza1ion 
OS Conl!"'Jr.-al anomaly I birth <!,elect 
Criteria: 
02 ln;media'.:,Jy lit,e.;hre.a'.erw,g 
04 P.ersis.~em or significamt disability /incapacity 
0G Other n-.adicallv import3nt serious """111 
4. Was subject hospitalized or was a hospitalization prolonged due this event? UNo lJYes If yes. please complete all of Seclion 4 
Date Admitted 
I 
Date Discilarg.ed 
Dav 
Mo11th 
Year 
Dav 
Month 
Year 
I 
5. Was IP/drug under study administered/taken prior to this event? UNo UYes If yes, please complete el of Sectior, 5 
Prior to or at timei of Ev.en( 
Action Tak.., 
Date ofln ilial Dose 
Date of Dose 
Do!& 
Roo1'> 
Fraqu&J1cy 
witll Product 
01 Stilll:Eir,g 
,~mr,nisiered 
LoU and5ariali! 
02 FEm1aoenilJ 
disc011tinlled 
IP/Amgen Oevice: 
Dey Month 
Year Dey 
MOl\th 
Yee, 
031'/ill1keld 
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0 Unlr,o,'" 
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□umn.ii;tje / 
laheroarecwec 
D tilnde:1 □~ 131:El 
unu-i.a.·.n 
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~:: 
□ unn'i=il.:tle/ 
Pemb<orirurnab 
D tilnde:1 □~13 1:El 
U!llri.Cli'.f.l 
FORM--056006 
VetSIOtl 7.0 
Effective Date: 1 February 2016 
Page 1 of3 
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Date:  15 January 2020 
Page 151 of 171 
CONFIDENTIAL 
 
 
 
Approved 
 
 
Att1GBt 
Study# 20110265 
T alimogene laherparepvec 
Electronic Serious Adverse Event Contingency Report Fonn 
For Restricted Use 
Site Number 
I 
Subject ID Number 
I I I I I I I I 
I I I I I I 
6. CONCOMITANT MEDICATIONS (eg, chemotherapyl Anyl.ledications? U No U Yes If yes. please complete: 
Medication Name(s) 
Start Dato 
stop Dalo 
Co-&1.rape,cl 
Canfinuillg 
Dose 
Route 
Freq. 
Treatm .. ta,..i 
O"J 
lbdh 
y.,. 
°'-' 
l,.'ai!, 
v, .. tbl" : Yea✓ 
l'tb✓: 
Yea✓ 
·No,.,'" : v .. .,. 
: 
: 
: 
: 
: 
: 
7. RELEVANT MEDICAL HI STORY (include dates, allergies and any relevant prior therapy) 
8. RELEVANT LABORATORY VALUES (include baseline values) Any Relevant Laboraloryvalues? U No UYes If yes, please complete: 
Toot 
Unit 
Dato 
U"J 
.. , ... ... 
9. OTHER RELEVANT TESTS (diagnostics <tnd procedures) 
Any othe:r Relevant tests? 
UNo UYes If yes, please complete: 
Dalo 
Addition al T est:s 
Resu lts 
Units 
D"J ~-
r..--
FORM-056006 
Vemon 7.0 
Effective Date: 1 February 2016 
Page2 of 3 
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Page 152 of 171 
CONFIDENTIAL 
 
 
 
Approved 
 
 
Att1GBt 
Study# 20110265 
T alimogene laherparepvec 
Electronic Serious Adverse Event Contingency Report Form 
For Restricted Use 
Site Number 
I 
Subject ID Number 
I I I I I I I I I 
I I I I I 
1 0. CA SE DESCRIPTION (Provide narrative details of events listed in section 3) Provide additional pages if necessary. For each 
event in section 3, where relationship=Yes, please provide raliona.le. 
Sigl'\Slure of lnvesfigetor or Oesignee -
Title 
Dale 
l confirm by signing this re.pa-rt thot the information on this form$ indudin.g seriousness ond 
rousality o=sments, is being provided to Amgett by the investigator for this stuol/, or b.y 
a Qu.ofified Medic of P.etson autha-rfz.e-e:I b-y the investigator for thjs study. 
FORM-056006 
Vemian 7.0 
EJfec#ve Date: 1 Februe,y 2016 
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Page 153 of 171 
CONFIDENTIAL 
 
 
Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Amgen Proprietary - Confidential 
A~N• Pregnancy Notification Form 
Study Design: ~ lnterventional 
D Observational (If Observational: D Prospective D Retrospective) 
2. Contact Information 
Investigator Name ______________________ 
Site # ____________ _ 
Phone 1-_ _,_ ________ _ 
Fax(_), _______ 
_ 
Email _____________ _ 
Institution ___________________________________________ _ 
Address 
4. Amgen Product Exposure 
Amgen Product 
Dose at time of 
Frequency 
Route 
conception 
Was the Amgen product (or study drug) discontinued? D Yes 
D No 
If yes, provide product (or study drug) stop date: mm __ /dd __ /yyyy __ 
Did the subject withdraw from the study? D Yes 
D No 
5. Pregnancy Information 
Pregnant female's last menstrual period (LMP) 
mm ____ / dd ___ / yyyy ___ _ 
Estimated date of delivery mm ___ / dd ___ 
/ yyyy __ 
If NIA, date of termination (actual or planned) mm ___ / dd_
/ yyyy _____ _ 
Has the pregnant female already delivered? D Yes 
D No D Unknown D NIA 
If yes, provide date of delivery: mm ___ 
/ dd ___ 
/ yyyy __ _ 
Was the infant healthy? D Yes 
D No 
D Unknown D N/A 
Start Date 
mm __ /dd __ 
/yyyy __ 
□Unknown 
□NIA 
If any Adverse Event was experienced by the infant, provide brief details: ________________ _ 
Form Comoleted bY 
Print Name: ________________ _ 
Title: ________________ _ 
Signature: _________________ _ 
Date: _________________ _ 
FORM-115199 
Version 1.0 
Effective Date: 24-Sept-2018 
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Date:  15 January 2020 
Page 154 of 171 
CONFIDENTIAL 
 
 
 
Approved 
 
 
Amgen Proprietary - Confidential 
ANGEN" Lactation Notification Form 
D Observational (If Observational: D Prospective D Retrospective) 
2. Contact Information 
Investigator Name ____________________ _ 
Site # ____________ _ 
Phone '-_ _,__ ________ _ 
Fax L__) ________ _ 
Email _____________ _ 
Institution __________________________________________ _ 
4. Amgen Product Exposure 
Amgen Product 
Dose at time of 
Frequency 
Route 
breast feeding 
Was the Amgen product (or study drug) discontinued? D Yes 
D No 
If yes, provide product (or study drug) stop date: mm __ 
/dd __ lyyyy __ 
Did the subject withdraw from the study? D Yes 
D No 
5. Breast Feeding Information 
Start Date 
mm __ /dd __ /yyyy __ 
Did the mother breastfeed or provide the infant with pumped breast milk while actively taking an Amgen product? D Yes 
D No 
If No, provide stop date: mm ___ 
/dd ___ lyyyy ___ _ 
Infant date of birth: mm ___ 
/dd ___ lyyyy __ _ 
Infant gender: D Female 
D Male 
Is the infant healthy? D Yes 
D No 
D Unknown D NIA 
If any Adverse Event was experienced by the mother or the infant. provide brief details: ________________ _ 
Form comoleted bv: 
Print Name: ________________ _ 
Title: _________________ _ 
Signature: _________________ _ 
Date: ________________ _ 
FORM-115201 
Version 1.0 
Effective Date: 24-Sept-2018 
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Page 155 of 171 
CONFIDENTIAL 
 
 
Appendix D.  Modified Immune-related Response Criteria (irRC) for Review of 
Disease Response in Phase 1b 
A systematic tumor response criteria designated immune-related response criteria (irRC) 
was defined by Wolchok et al, 2009, in an attempt to capture additional tumor response 
patterns observed with immunotherapy in advanced melanoma beyond those described 
by the Response Evaluation Criteria in Solid Tumors (RECIST) or the World Health 
Organization (WHO) criteria.  A modified version of the irRC will be employed in the 
phase 1b part of the study. 
Method of Measurement of Melanoma Tumor Lesions 
Clinical Examination Using Caliper:  All measurements will be determined using a ruler 
or calipers and reported in metric notation (mm) and will be recorded bi-dimensionally.  
Clinical lesions will only be considered measurable when they are superficial and can be 
accurately and serially measured in at least 2 dimensions and for which the longest 
diameter is ≥ 5 mm as assessed using calipers (eg, superficial cutaneous and 
subcutaneous melanoma lesions).  [Note:  When a lesion can be accurately evaluated 
by both, clinical examination and imaging, imaging evaluations should be undertaken 
since it is more objective]. 
Photographs:  Photographic imaging of up to 5 (maximum 5 per organ) visible (ie, visible 
protrusion from skin surface) cutaneous and subcutaneous measurable tumor lesions 
will performed to evaluate tumor response for cutaneous and subcutaneous lesions.  All 
measurements will be determined using a ruler or calipers and reported in metric 
notation (mm) and will be recorded bi-dimensionally.  Photographed cutaneous and 
subcutaneous lesions will only be considered measurable when they are visible 
(ie, visible protrusion from skin surface) and can be accurately and serially photographed 
and measured in at least 2 dimensions and for which the longest diameter is ≥ 5 mm as 
assessed using calipers.  [Note:  When a lesion can be accurately evaluated by both, 
radiographic imaging and photographs, radiographic imaging evaluations should be 
undertaken]. 
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.  MRI is acceptable to assess disease extent if used throughout the study. 
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The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  A 
switch from contrast enhanced CT to noncontrast CT or to MRI (or vice versa) should 
not preclude response assessment if, in the judgment of the site radiologist, there is no 
significant difference in the assessment by changing modalities.  This may occur if a 
subject has developed a medical contraindication to intravenous contrast for CT scans 
while on trial.  This change would require the preapproval of the sponsor medical 
monitor. 
Positron Emission Tomography (PET)/CT Scans:  If a combined PET/CT scan is 
performed at the discretion of the investigator, the CT portion of that exam should not be 
substituted for the dedicated CT exams required by this protocol.  The PET portion of the 
CT may introduce additional data which may bias the investigator assessment of 
response if it is not routinely or serially performed.  However, if the investigator or the 
site radiologist can document that the CT performed as part of a PET/CT is of identical 
diagnostic quality to a diagnostic CT (with intravenous and oral contrast) then the CT 
portion of the PET/CT can be used for tumor measurements.   
Ultrasound:  Ultrasound may be used to assess superficial palpable lymph nodes and 
subcutaneous lesions where ultrasound provides a more accurate measure than clinical 
measurement or CT.  In addition, ultrasound can be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.  However, 
if ultrasound is not useful in assessment of lesion size it must not be used to as a 
method of measurement.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. 
Measurement of Lesions 
Measurability is defined by the ability to measure a lesion bi-dimensionally with surface 
area determined by multiplying the longest diameter by the diameter perpendicular to the 
longest diameter as defined below.  An individual lesion measure is therefore provided 
by the product of a tumors longest diameter and the diameter perpendicular to that. 
All measurements will be determined using a ruler or calipers and reported in metric 
notation (mm) and will be recorded bi-dimensionally.   
Definitions of Measurable and Nonmeasurable Lesions 
At baseline, lesions are categorized as measurable or nonmeasurable according to the 
following definitions: 
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Measurable Lesions: 
Measurable lesions are defined at baseline as lesions that can be accurately and serially 
measured in at least 2 dimensions and for which the longest diameter is: 
 
 10 mm as measured by CT scan (CT scan slice thickness no greater than 5 mm) 
or MRI for visceral or nodal/soft tissue disease (including lymph nodes) 
 
 5 mm caliper measurement by clinical exam for superficial cutaneous or 
subcutaneous melanoma lesion as measured by caliper 
Nonmeasurable: 
All other lesions, including small lesions (longest diameter < 10 mm by CT/MRI for 
visceral or nodal/soft tissue disease [including lymph nodes] or < 5-mm caliper 
measurement by clinical exam or photographs for superficial cutaneous and 
subcutaneous melanoma lesions) and other truly nonmeasurable lesions are considered 
non-measurable and characterized as nonindex lesions.  Other examples of 
nonmeasurable lesions include some bone lesions, leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
the skin or (lymphangitis cutis/pulmonis), and groups of lesions that are small and 
numerous. 
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. 
 
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. 
 
Blastic bone lesions are not nonmeasurable.   
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) 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 noncystic lesions are present in the same subject, these are preferred for 
selection as index lesions. 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiate area, or an area subject to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
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Measureable Tumor Assessment/Burden: 
Baseline Documentation of “Index Lesions”: 
All baseline evaluations should be performed as close as to the enrollment or 
randomization and never more than 4 weeks (ie, 28 days) prior to 
enrollment/randomization. 
At baseline up to 5 cutaneous or subcutaneous lesions and 10 visceral lesions, a 
maximum of 5 per organ, will be chosen to measure over the course of therapy.  The 
distribution of these index lesions should be representative of the subject’s overall 
disease status.  Index lesions should be selected on the basis of their size (lesions with 
longest bi-dimensionally perpendicular diameters) and suitability for accurate repeated 
measurements by imaging techniques (CT, MRI or US) and/or other method such as 
clinical exam or photographs, if tumor lesions cannot be accurately evaluated by imaging 
techniques. 
The sum of the products of the two largest of perpendicular diameters (SPD) of all index 
lesions will be calculated and reported. 
Baseline Documentation of “Non-index Lesions”:  All other lesions (or sites of 
disease), including any measurable lesions beyond the maximum number of 
5 cutaneous lesions and 10 visceral lesions (maximum 5 lesions per organ) that that 
were not chosen as index lesions will be identified as nonindex lesions.  Measurable 
nonindex lesions should also be recorded and assessed qualitatively over the course of 
therapy. 
Follow-up: 
At each subsequent tumor assessment, the SPD of the index lesions and of new, 
measurable lesions (accurately and serially measured in at least 2 dimensions and for 
which the longest diameter is ≥ 10 mm) are added together to provide the total tumor 
burden.  A maximum of up to 5 new cutaneous or subcutaneous lesions and 10 visceral 
lesions (maximum 5 new lesions per organ) may be identified.  If measurable new 
lesions are present exceeding the organ-specific or total maximum, the lesions should 
be selected on the basis of their size (lesions with longest bi-dimensionally perpendicular 
diameters) and suitability for accurate repeated measurements by imaging techniques 
(CT, MRI or US) and/or other method such as clinical exam or photographs. 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions. 
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Non-measurable nonindex disease measurements are not required and these lesions 
should be followed as “present”, “absent”, or in rare cases “unequivocal progression”. 
For index and new measurable nodal lesions < 10 mm, the measurement should 
be recorded as the 0 x 0 mm instead of the actual measurement. 
Response Criteria 
Evaluation of Objective Response Rate: 
The subject response will be assessed based on the response of the index lesions and 
the presence or absence of new measurable lesions, and, in the case of CR, the 
presence or absence of nonindex lesions.  The overall response is derived from 
time-point response assessments (based on tumor burden) as described in Table 13 
and Table 14. 
Table 13.  Definition of Measurable Tumor Response 
Complete Response (CR): 
Complete disappearance of all lesions (whether measurable or 
not, and no new lesions) confirmation by a repeat, consecutive 
assessment no less than 4 weeks (28 days) from the date first 
documented. 
Partial Response (PR): 
Decrease in tumor burden ≥ 50% relative to baseline confirmed 
by a consecutive assessment at least 4 weeks (28 days) after 
first documentation. 
Progressive Disease (PD): 
Increase in tumor burden ≥ 25% 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): 
Not meeting criteria for CR or PR, in absence of PD. 
Unevaluable (UE): 
Any lesion present at baseline which was not assessed or was 
unable to be evaluated leading to an inability to determine the 
status of that particular tumor for that time point. 
Not Applicable (NA) 
No index lesions were identified at baseline 
Not Done (ND) 
Radiographic image, photographic image or clinical 
measurement were not performed at this time point to evaluate 
the index lesions 
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Table 14.  Matrix for Determining the Overall Response at Each Assessment Point 
Measurable Response 
Non-measurable Response 
Overall 
Response 
Index and new, 
measurable lesions 
(tumor burden)a, % 
Non-index 
New, non-measurable 
lesions 
Using irRC 
↓100 
Absent/NAd 
Absent 
CRb 
↓100 
Present/ND/UE 
Any 
PRb 
↓100 
Unequivocal progression 
Any 
PRb 
↓≥ 50 
Absent/Present/NAd/ND/UE Any 
PRb 
↓≥ 50 
Unequivocal progression 
Any 
PRb 
↓< 50 to < 25↑ 
Absent/Present/NAd/ND/UE Any 
SD 
↓< 50 to < 25↑ 
Unequivocal progression 
Any 
SD 
≥ 25 
Any 
Any 
PDb 
UE 
Any 
Any 
UE 
ND 
Any 
Any 
UE 
NAc 
Any 
Any 
UE 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; 
UE = unevaluable; ND = not done; NA = not applicable.   
a Decrease disease relative to baseline, including new measurable lesions only (> 5x5mm). 
b Assuming response (CR or PR) or progression are confirmed by a second, consecutive assessment at 
least 4 weeks (28 days) apart. 
c No index lesions identified at baseline.  When a patient has only nonmeasurable disease (ie, no index 
lesions identified at baseline) the response will be unevaluable. 
d No non-index lesions identified at baseline. 
Determination of irRC BOR 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 SD even if new lesions were present, as long as 
they met the respective thresholds of response as described in Table 14. 
Response Confirmation 
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 (fine needle aspirate/biopsy) to confirm the CR 
status. 
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If a subject is classified as having PD at a post baseline tumor assessment, then 
confirmation of PD by a second consecutive assessment in the absence of clinical 
instability (Section 3.1.3.1) is required.  The definition of confirmation of progression 
represents an increase in tumor burden ≥ 25% compared with the nadir at two 
consecutive time points at least 4 weeks (28 days) apart. 
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 classified as “nonconfirmed PD.”  In this case PD cannot be 
assigned at the time as the overall objective tumor response.  Every effort should be 
made to document the objective progression even after discontinuation of treatment. 
A best overall response of SD requires a visit response of SD or better no earlier than 
84 days after the date of enrollment; otherwise the overall response will be UE. 
Subjects who have had a procedure to completely/partially resect a lesion will be 
evaluated as follows: 
The procedure itself and all post-procedure lesion assessments should always be 
recorded in the CRF.  A completely resected lesion should be assigned a default code of 
0 x 0 mm (for index and new measurable lesions) or “absent” (for non-index and new 
non-measurable lesions).  A partially resected lesion should be assigned its 
measurement post-procedure (for index or new measurable lesions) or “present” (for 
non-index or new non-measurable lesions).  If the resected lesion contained no 
melanoma 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 melanoma 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. 
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Appendix E.  Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, ie, light housework or office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about > 50% of waking hours. 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of waking 
hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead 
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Appendix F.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response in Phase 3 
Immune-related Response Criteria (irRC) simulating Response Evaluation Criteria in 
Solid Tumors version (RECIST) 1.1 [irRC-RECIST] defined by Nishino et al, 2014 will 
employed in the phase 3 to account for unique tumor response characteristics observed 
with immunotherapies to enable treatment beyond progression, if the subject is clinically 
stable.  These criteria are modified to increase the total number of target lesions to 
10 with a maximum of 5 target lesions per organ.  Similarly the total number of new 
measurable lesions is also increased to 10 with a maximum of 5 target lesions per 
organ.  Target lesions are be measurable by CT or MRI only.  Otherwise, these 
guidelines will follow irRC simulating RECIST 1.1 defined by Nishino et al, 2014. 
Method of Measurement of Melanoma Tumor Lesions: 
Photographs:  Photographs of all (ie, visible protrusion from skin surface) cutaneous and 
subcutaneous tumor lesions not detectable on radiographic imaging will performed to 
evaluate tumor response for non-target cutaneous and subcutaneous lesions.  
Photographed cutaneous and subcutaneous lesions will not need to be measured and 
will be considered non-target.  [Note:  When a lesion can be accurately evaluated by 
both photographs and radiographs, radiographic imaging and photographs, radiographic 
imaging evaluations should be undertaken]. 
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.  MRI is acceptable to assess disease extent if used throughout the study. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  A 
switch from contrast enhanced CT to noncontrast CT or to MRI (or vice versa) should 
not preclude response assessment if, in the judgment of the site radiologist, there is no 
significant difference in the assessment by changing modalities.  This may occur if a 
subject has developed a medical contraindication to intravenous contrast for CT scans 
while on trial.  This change would require the preapproval of the sponsor medical 
monitor. 
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Positron Emission Tomography (PET)/CT Scans:  If a combined PET/CT scan is 
performed at the discretion of the investigator, the CT portion of that exam should not be 
substituted for the dedicated CT exams required by this protocol.  The PET portion of the 
CT may introduce additional data which may bias the investigator assessment of 
response if it is not routinely or serially performed.  However, if the investigator or the 
site radiologist can document that the CT performed as part of a PET/CT is of identical 
diagnostic quality to a diagnostic CT (with intravenous and oral contrast) then the CT 
portion of the PET/CT can be used for tumor measurements.   
Ultrasound is not appropriate for measurement of target lesions due to higher variability 
in measurement technique compared to CT or MRI.  Any new lesions identified by 
ultrasound will need to be confirmed by CT or MRI.  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. 
Scan slices should be 3 to 5 mm and not exceed 5 mm.  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 Tumor Lesions:  
Indeterminate lesions which may or may not be cancer should not be considered 
non-measurable tumor lesions.  These lesions must all be considered cancer.  All other 
lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 mm but < 15 mm short axis) and other truly non-measurable lesions are 
considered non-measurable and characterized as non-target lesions.  This will include 
any measurable lesions beyond the maximum number of 10 total or 5 per organ at each 
time point that were not chosen as target lesions.  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. 
*Bone Lesions: 
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 
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. 
 
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. 
 
Blastic bone lesions should not be selected as non-measurable at baseline since 
many blastic bone lesions might be benign.  However, if new blastic lesions 
appear and are clearly progressing, they may be considered as new 
non-measurable 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 cancerous cystic lesion has both cystic and solid components, the entire 
lesion should be measured across both components without excluding the cystic 
component. 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area, or an area subject to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion. 
Baseline Documentation of “Target” and “Non-Target” Lesions: 
Baseline evaluations will be used to prospectively identify all sites of disease present as 
close as possible to the enrollment and never more than 4 weeks before the enrollment 
date.  Sites of disease will be characterized as either target or non-target lesions. 
Baseline Documentation of Target Lesions: 
Up to 10 target lesions (a maximum of 5 per organ) will be chosen to measure over the 
course of therapy.  Pathological lymph nodes that are defined as measurable must meet 
the criterion of a short axis of ≥ 15 mm by CT scan in order to be identified as target 
lesions.  Lesions that only appear on photography and not on radiographic imaging 
should not be selected 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 
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techniques.  There may be circumstances where the larger lesions are not appropriate 
for accurate repeated measurements (eg, proximity to diaphragm that may lead to 
variability between scans depending on respiratory changes), and smaller lesions that 
are measurable and more accurately assessed may need to be selected for target 
lesions. 
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, cutaneous and subcutaneous lesions on appearing on 
photography and not radiographic images, and pathological lymph nodes with short axis 
≥ 10 mm but < 15 mm, should be identified as non-target lesions.  Measurable 
non-target lesions (ie, those that exceed the maximum 10 target lesions overall or 
maximum 5 target lesions per organ) should also be recorded and assessed qualitatively 
over the course of therapy.  Non-target disease measurements are not performed, but 
should be evaluated as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’  If 
a significant partial response occurs in a non-target lesion, this should be documented in 
the comments section. 
Follow-up Assessment of Tumor Lesions: 
At each subsequent tumor assessment, the sum of diameters of target lesions identified 
at baseline plus the sum of diameters of up to 10 (maximum 5 per organ) new 
measurable lesions per time point (ie, and for which the longest diameter is ≥ 10 mm for 
non-nodal lesions or the short axis is ≥ 15 mm for 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 given time point, the new measurable lesions should be selected 
on the basis of their size and suitability for accurate repeated measurements by imaging 
techniques (CT or MRI).  If there are lesions beyond of the new measurable lesion limit 
during the course of the study for one subject, the additional lesions would be 
considered new non-measurable lesions. 
Tumor Burden = sum of diameter of target lesions + sum of diameter of 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”. 
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For target lesions that become too small to measure, a value of 5 mm will be assigned.  
If an actual measurement is able to be provided, that should be recorded, even if it is 
< 5 mm.  If it is in the opinion of the radiologist that the non-nodal lesion has likely 
disappeared, the measurement should be recorded as “0 mm”.  Nodal disease should 
always have the actual short axis measurement recorded even if the nodes regress to 
below 10 mm on study.  For iCR, each node must achieve a short axis <10 mm. 
Non-target lesions photographed at baseline should continue to be photographed at 
subsequent time points if not detected via radiographic imaging. 
Response Evaluation: 
Evaluation of Objective Response: 
The subject response will be assessed based on tumor burden (the sum of diameters of 
target lesions plus the sum of up to 10 [maximum 5 per organ] new measurable lesions 
per time point), and, in the case of iCR, 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 15 and Table 16. 
Table 15.  Definition of Measurable Tumor Response (Baseline Target and New, 
Measurable Lesions)  
Complete Response (iCR): 
Disappearance of all lesions (whether measurable or not and 
whether baseline or new) and confirmation by a repeat, 
consecutive assessment no less than 4 weeks (28 days) from the 
date first documented.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (iPR): 
Decrease in tumor burdena ≥ 30% relative to baseline confirmed 
by a consecutive assessment at least 4 weeks (28 days) after first 
documentation  
Progressive Disease (iPD): 
Increase in tumor burdena ≥ 20 % and at least 5 mm absolute 
increase relative to nadir (minimum recorded tumor burden) 
confirmation by a repeat, consecutive assessment no less than 
4 weeks (28 days) from the date first documented iPD.   
Stable Disease (iSD): 
Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient 
increase to qualify for iPD. 
Unevaluable (iUE): 
Any lesion present at baseline or a new measureable lesion 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.  Exception:  when iPD is documented based on a 
partial assessment. 
Page 1 of 2 
Footnotes defined on next page of table 
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Table 15.  Definition of Measurable Tumor Response (Baseline Target and New, 
Measurable Lesions) 
Not Applicable (NA) 
No target lesions were identified at baseline 
Not Done (ND) 
Radiographic image, photographic image or clinical measurement 
were not performed at this time point to evaluate the response of 
measurable lesions 
Page 2 of 2 
a Tumor Burden = sum of diameter of target lesions + sum of diameter of up to 10 (maximum 5 per organ) 
new, measurable lesions.  Diameters used: 
 
For nodal disease, shortest axis 
 
For non-nodal disease, longest diameters 
Table 16.  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, non-measurable 
lesions 
Using modified 
irRC-RECIST 
↓100e 
Absent/NAd 
Absent 
iCRb 
↓100 
Present/ND/iUE 
Any 
iPRb 
↓100 
Unequivocal progression 
Any 
iPRb 
↓≥ 30 
Absent/Present/NAd/ND/iUE Any 
iPRb 
↓≥ 30 
Unequivocal progression 
Any 
iPRb 
↓< 30 to ↑< 20 
Absent/Present/NAd/ND/iUE Any 
iSD 
↓< 30 to ↑< 20 
Unequivocal progression 
Any 
iSD 
↑≥ 20f 
Any 
Any 
iPDb 
iUE 
Any 
Any 
iUE 
ND 
Any 
Any 
iUE 
NAc 
Any 
Any 
iUE 
iCR = complete response (per modified irRC-RECIST); iPR = partial response (per modified 
irRC-RECIST); iSD = stable disease (per modified irRC-RECIST); iPD = progressive disease (per 
modified irRC-RECIST); iUE = unevaluable (per modified irRC-RECIST); ND = not done; NA = not 
applicable. 
a Decrease disease relative to baseline, including new measurable lesions only (> 10 mm). 
b iCR or iPR progression should be confirmed by a second, consecutive assessment at least 4 weeks 
(28 days) apart.  Rapid clinical deterioration is an exception for confirming initial iPD. 
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 iCR 
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 iPD.  If the tumor burden does not demonstrate ≥ 5 mm increase from nadir but 
tumor burden is increased ≥ 20% from the nadir, response should be recorded as iSD. 
Determination of best overall response is based on changes in total tumor burden from 
the baseline (nadir, for iPD) tumor assessment, regardless of any initial increase in 
baseline lesions or the appearance of new lesions. 
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Subjects are considered to have iPR or iSD even if new lesions were present, as long as 
they met the respective thresholds of response as described in Table 16. 
A best overall response of iSD requires a visit response of iSD or better no earlier than 
84 days after the date of enrollment; otherwise the overall response will be unevaluable 
(iUE). 
Confirmation of Response (iCR or iPR): 
To be assigned a status of iCR or iPR changes in tumor measurements must be 
confirmed by consecutive repeat assessments performed no less than 4 weeks 
(28 days) after the criteria for response are first met. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of iCR depends on this determination, it is recommended 
that the residual lesion be investigated (ie, biopsy) to confirm the iCR status. 
Confirmation of Disease Progression: 
If a subject is classified as having iPD at a post baseline tumor assessment, then 
confirmation of iPD by a second assessment ≥ 4 weeks (28 days) later in the absence of 
clinical instability (Section 3.1.3.1) is required.  The definition of confirmation of 
progression represents a ≥ 20% 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 per time point) and absolute increase of ≥ 5 mm in sum of diameters 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 iPD).  
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of iPD at the time should have the reason for 
treatment discontinuation classified as “clinically unstable” (Section 3.1.3.1).  Every effort 
should be made to document the objective progression even after discontinuation of 
treatment. 
Subjects who have had a procedure to completely/partially resect a lesion will be 
evaluated as follows: 
The procedure itself and all post-procedure lesion assessments should always be 
recorded in the CRF.  A completely resected lesion should be assigned a default code of 
0 mm (for target lesions) or “absent” (for non-target lesions).  A partially resected lesion 
should be assigned its measurement post-procedure (for target lesions) or “present” (for 
non-target lesions).  If the resected lesion contained no melanoma under pathology 
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evaluation, subsequent tumor assessments post-procedure may be used for tumor 
burden calculations and/or determination of response.  If the resected lesion contained 
melanoma 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 iUE for response except in the case of iPD. 
If the new tumor burden post-procedure is lower than the nadir before the procedure, 
then the new nadir will be set to the post-procedure tumor burden.  Otherwise, the 
previous pre-procedure nadir will be retained as the nadir.  Subsequent assessments for 
iPD 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.  Any lesion with measurement 0 mm that resulted from merging with 
another lesion(s) should be documented as lesions that were combined with and not 
truly disapearing lesions. 
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/new measurable 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.  
For more information, refer to "Follow-up Assessments of Tumor Lesions" in this same 
appendix.  Any new lesions that result from separating should be documented as lesions 
that were generated by separating and not truly new lesions. 
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Appendix G.  Modifications to Conventional RECIST Guidelines for Assessment of 
Disease Response in Phase 3 
 
Conventional RECIST 1.1 
Study 20110265 RECIST Modifications 
Measurable lesions 
o 
Non-lymph node longest 
axis ≥ 10mm (on CT, 
MRI, or calipers) 
o 
Non-lymph node longest 
axis ≥ 20mm (on X-ray) 
o 
Lymph node short axis 
≥ 15mm 
o 
Target lesions must be measurable 
on CT or MRI only 
o 
Lesions not measurable on CT or 
MRI are considered  
non-target 
Number of target 
lesions 
o 
Up to 2 per organ, 
maximum 5 total 
o 
Up to 5 per organ, maximum 
10 total 
Overall Response: 
 
 
CR 
o 
Confirmation of CR or PR 
is not required for RCTs 
o 
Disappearance of all 
lesions, except lymph 
node short axis < 10 mm 
 
PR 
o 
Confirmation of CR or PR 
not required 
o 
≥ 30% reduction in sum 
of diameters in target 
lesions  
 
SD 
o 
Neither sufficient 
shrinkage to qualify for 
CR or PR nor sufficient 
increase to qualify for PD 
 
PD from target 
lesions 
o 
Increase from nadir 
by ≥ 20%  
o 
 5 mm absolute 
increase above nadir 
 
PD from  
non-target lesions 
o 
Appearance of a new 
lesion (measurable or 
not) is a PD 
 
 
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Amendment 5 
Protocol Title:  A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in 
Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable Stage 
IIIB to IVM1c Melanoma (MASTERKEY-265) 
 
Amgen Protocol Number (Talimogene laherparepvec) 20110265 
EudraCT number 2014-000185-22 
NCT number 02263508 
 
Amendment Date: 
15 January 2020 
Rationale: 
This protocol is being amended to: 
 
Update statistical characteristics of the group sequential overall survival (OS) 
analyses and add in a third interim OS analysis for efficacy planned after 315 events.  
Based on the updated results from the CHECKMATE-067 trial (Larkin et al, 2019), a 
delay in the OS treatment effect could be present in the melanoma trial involving 
combination immunotherapy (ie, nivolumab plus ipilimumab versus nivolumab).  To 
optimize the opportunity to observe statistical significance prior to the OS primary 
analysis (PA) if there is a late survival effect that would not be achieved at OS interim 
anlaysis (IA)1 or OS IA2, an additional look at OS IA3 (n = 315) was added prior to 
the OS PA.  The trigger for 315 was selected to achieve approximately half the 
information gain between n = 282 and n = 346, and is halfway between the expected 
timings of OS IA2 and OS PA.  The protocol is amended to include this additional 
analysis prior to any formal evaluation of efficacy related to progression free survival 
or overall survival.  Appropriate alpha has been allocated for all of the efficacy 
analyses. 
 
Update the background to include the updated OS results from the KEYNOTE-006 
and CHECKMATE-067 trials. 
 
Update exploratory objectives to evaluate PROs as assessed by the EORTC 
QLQ-C30 and EuroQoL-5D-3L (EQ-5D-3L) subscales and add language for Patient 
reported outcome (PRO) population assessment. 
 
An exploratory endpoint of assessing lesion level response was added to explore the 
systemic effect of talimogene laherparevec at the lesion level. 
 
Clarify covariates for efficacy in subgroup or multivariate analyses. 
 
Clarify language for interim efficacy analyses including possible hypotheses tests at 
planned analyses and operating characteristics of the primary analysis of 
progression-free survival (PFS) and sequential tests of OS. 
 
Add text to clarify that in the phase 1b part of the study when nodal disease 
regresses to below 10 mm, the nodal lesion measurement should be recorded as 
0 x 0 mm instead of the actual measurement. 
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 
Clarify that no index lesions identified at baseline (footnote “d”) is associated with 
“Not applicable (NA)” instead of “Not done (ND) in Table 14 and Table 16.  Add 
“unevaluable (UE) or iUE (unevaluable by modified Immune-related Response 
Criteria [irRC] simulating Response Evaluation Criteria in Solid Tumors (RECIST) 
[irRC-RECIST]) for Table 14 or Table 16, respectively” following “ND” for  
non-measurable response (non-index or non-target). 
 
Clarify number of days after the date of enrollment for visit response of stable 
disease by modified irRC-RECIST (iSD) or better. 
 
Remove retired language for self-evident corrections. 
 
Administrative, typographical, and formatting changes were made throughout the 
protocol. 
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Description of Changes: 
Section:  Global 
Change:  Updated version date throughout document from 24 January 2018 to 
15 January 2020 
Section:  Global 
Change:  Editorial changes (including typographical, grammatical, and formatting) have 
been made throughout the document. 
Section:  Title page 
Add: 
Date: 
01 April 2014 
Amendment 1 Date: 
15 May 2015 
Amendment 2 Date: 
25 September 2015 
Amendment 3 Date: 
12 April 2017 
Amendment 4 Date: 
24 January 2018 
Amendment 5 Date: 
15 January 2020 
This protocol was developed, reviewed, and approved in accordance with 
Amgen’s standard operating procedures. 
Section:  Protocol Synopsis, Study Design, Phase 3, Paragraph 5 
Replace: 
The futility analysis based on iORR and iDCR per blinded independent central review 
using modified irRC-RECIST is planned to include the first 160 subjects (80 per arm) 
that have been enrolled and have had an opportunity to be followed for the tumor 
assessment scheduled at week 24.  Interim OS analyses are planned at the primary 
analysis of PFS and after 282 events are observed.  A non-binding futility analysis of OS 
will be conducted at the 282 OS event interim analysis if the first and second interim OS 
analyses do not meet their respective criterion for statistical significance.  However, if 
282 death events are observed prior to the 407th PFS event, then the first OS interim 
analysis will occur with 282 events and include a PFS interim analysis with all PFS 
events.  In this case, the second OS interim analysis using all events will be performed 
at the PFS primary analysis.  For more details see Section 10.4.1.4. 
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With: 
The futility analysis based on iORR and iDCR per blinded independent central review 
using modified irRC-RECIST is planned to include the first 160 subjects (80 per arm) 
that have been enrolled and have had an opportunity to be followed for the tumor 
assessment scheduled at week 24.  Interim OS analyses are planned at the time of the 
primary analysis of PFS, after 282 OS events are observed, and after 315 OS events 
are observed.  A non-binding futility analysis of OS will be conducted at the 282 OS 
event interim analysis if the first and second interim OS analyses do not meet their 
respective criterion for statistical significance.  However, if 282 death events are 
observed prior to the 407th PFS event, then the first OS interim analysis will occur with 
282 events and include a PFS interim analysis with all PFS events.  In this case, the 
second OS interim analysis using all events will be performed at the PFS primary 
analysis.  For more details see Section 10.4.1.4. 
Section:  Protocol Synopsis, Statistical Considerations, Phase 3, Planned method of 
analyses, Paragraph 4 
Replace: 
At the time of the PFS primary analysis, an interim efficacy OS analysis will be 
performed.  A second interim OS analysis is planned after 282 events for efficacy and 
futility.  The interim OS futility analysis will be non-binding and define futility as a 
conditional power < 10% assuming a constant treatment effect; however, futility will also 
be similarly defined by considering a possible non-constant treatment effect that 
increases over time.  The order for the event-driven OS interim and PFS primary 
analyses may not be as anticipated due to incorrect design assumptions.  If 282 OS 
events are observed prior to 407 PFS events, the first event-driven analysis will be an 
OS interim with 282 OS events and a PFS interim using all events. 
With: 
At the time of the PFS primary analysis, an interim efficacy OS analysis will be 
performed.  The second interim OS analysis is planned after 282 events for efficacy and 
futility.  The interim OS futility analysis will be non-binding and define futility as a 
conditional power < 10% assuming a constant treatment effect; however, futility will also 
be similarly defined by considering a possible non-constant treatment effect that 
increases over time.  The order for the event-driven OS interim and PFS primary 
analyses may not be as anticipated due to incorrect design assumptions.  If 282 OS 
events are observed prior to 407 PFS events, the first event-driven analysis will be an 
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OS interim with 282 OS events and a PFS interim using all events.  The third interim 
OS analysis for efficacy is planned after 315 events are observed. 
Section:  Study Glossary (new) 
Add: 
mOS 
median overall survival 
Section:  1.3, Exploratory, Phase 3, bullet 9 (new) 
Add: 
 
To evaluate the response rates (partial, complete, partial or complete) and 
maximum decrease in lesion size, separately for visceral, injected, and 
uninjected non-visceral lesions. 
Section:  2.1, Melanoma and Programmed Cell Death 1 (PD-1) Receptor Inhibitor, 
Paragraph 3 
Replace: 
It has been postulated that antibodies that block the interaction between PD-1 and  
PD-L1 in tumors may preferentially release the cytotoxic function of tumor-specific  
T cells with fewer systemic toxic effects than those that are seen with other immune 
checkpoint inhibitors (Pardoll, 2012; Ribas; 2012; Okazaki and Honjo, 2007).  Inhibitory 
antibodies targeted to PD-1 and PD-L1 have demonstrated objective responses in 
multiple tumor types including melanoma (Robert et al, 2015; Hamid et al, 2013; 
Brahmer et al, 2012; Topalian et al, 2012).  The combination of PD-1 blockade with 
nivolumab and CTLA-4 blockade with ipilimumab has resulted in longer progression free 
survival than either agent alone but was associated with a high rate of grade 3 or 
4 adverse events (Larkin et al, 2015). 
With: 
It has been postulated that antibodies that block the interaction between PD-1 and  
PD-L1 in tumors may preferentially release the cytotoxic function of tumor-specific  
T cells with fewer systemic toxic effects than those that are seen with other immune 
checkpoint inhibitors (Pardoll, 2012; Ribas; 2012; Okazaki and Honjo, 2007).  Inhibitory 
antibodies targeted to PD-1 and PD-L1 have demonstrated objective responses in 
multiple tumor types including melanoma (Robert et al, 2015; Hamid et al, 2013; 
Brahmer et al, 2012; Topalian et al, 2012).  Anti-PD-1 antibodies have also been 
shown to improve overall survival in melanoma (Larkin et al, 2019;  
Robert et al, 2019).  The combination of PD-1 blockade with nivolumab and CTLA-4 
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blockade with ipilimumab has resulted in significantly longer progression free survival 
and overall survival than ipilimumab but was associated with a high rate of grade 3 or 
4 adverse events (Larkin et al, 2019; Larkin et al, 2015). 
Section:  2.3, Pembrolizumab Background, Paragraph 2 
Replace: 
A phase 3 registration trial (KEYNOTE-006) of pembrolizumab versus ipilimumab in 
ipilimumab-naive subjects with advanced melanoma has been published 
(clinicaltrials.gov identifier NCT01866319, Schachter et al, 2007).  This is a 3-arm study 
to evaluate the safety and efficacy of two dosing schedules of pembrolizumab compared 
to ipilimumab for the treatment of ipilimumab-naïve participants with unresectable or 
metastatic melanoma.  Subjects are randomized 1:1:1 to receive pembrolizumab 
10 mg/kg every 2 weeks for up to 2 years or pembrolizumab 10 mg/kg every 3 weeks for 
up to 2 years or ipilimumab 3 mg/kg for a total of 4 doses.  Primary endpoints of this 
study are progression free survival (PFS) and overall survival (OS).  At an interim 
analysis with 834 subjects enrolled and median duration of follow-up 7.9 months (range 
6.1-11.5 months), the response rate for pembrolizumab every 2 weeks was 33.7% and 
every 3 weeks was 32.9% as compared with ipilimumab at 11.9% (p < 0.001 for both 
comparisons) (Robert et al, 2015).  The PFS hazard ratio was 0.58 (P < 0.001 for both 
pembrolizumab regimens versus ipilimumab), and the hazard ratio for death for 
pembrolizumab every 2 weeks was 0.63 (P = 0.0005) and 0.69 for pemrbolizumab every 
3 weeks (P = 0.0036) versus ipilimumab.  Rates of treatment-related adverse events of 
grade 3 to 5 were lower in the pembrolizumab groups (13.3% and 10.1%) than in the 
ipilimumab group (19.9%) (Robert et al, 2015). 
With: 
A phase 3 registration trial (KEYNOTE-006) of pembrolizumab versus ipilimumab in 
ipilimumab-naive subjects with advanced melanoma has been published 
(clinicaltrials.gov identifier NCT01866319, Schachter et al, 2007).  This is a 3-arm study 
to evaluate the safety and efficacy of two dosing schedules of pembrolizumab compared 
to ipilimumab for the treatment of ipilimumab-naïve participants with unresectable or 
metastatic melanoma.  Subjects are randomized 1:1:1 to receive pembrolizumab 
10 mg/kg every 2 weeks for up to 2 years or pembrolizumab 10 mg/kg every 3 weeks for 
up to 2 years or ipilimumab 3 mg/kg for a total of 4 doses.  Primary endpoints of this 
study are progression free survival (PFS) and overall survival (OS).  At an interim 
analysis with 834 subjects enrolled and median duration of follow-up 7.9 months (range 
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6.1-11.5 months), the response rate for pembrolizumab every 2 weeks was 33.7% and 
every 3 weeks was 32.9% as compared with ipilimumab at 11.9% (p < 0.001 for both 
comparisons) (Robert et al, 2015).  The PFS hazard ratio was 0.58 (P < 0.001 for both 
pembrolizumab regimens versus ipilimumab), and the hazard ratio for death for 
pembrolizumab every 2 weeks was 0.63 (P = 0.0005) and 0.69 for pembrolizumab every 
3 weeks (P = 0.0036) versus ipilimumab.  Rates of treatment-related adverse events of 
grade 3 to 5 were lower in the pembrolizumab groups (13.3% and 10.1%) than in the 
ipilimumab group (19.9%) (Robert et al, 2015).  The overall survival benefit of 
pembrolizumab versus ipilimumab continued to hold after a median follow-up of 
57.7 months (range 56.7 to 59.2 months).  The median overall survival (mOS) was 
32.7 months in the combined pembrolizumab groups and 15.9 months in the 
ipilimumab group (hazard ratio  0.73, 95% confidence interval of 0.61 to 0.88, 
P  0.00049) (Robert et al, 2019). 
Section:  2.4, Rationale for Combination Therapy of Talimogene Laherparepvec and 
Pembrolizumab, Paragraph 2 
Replace: 
A prior concurrent regimen of nivolumab, a PD-1 inhibitor, with ipilimumab, a CTLA-4 
inhibitor has yielded higher response rates (57.5%, 95% CI 52.0 to 63.2) and median 
progression free survival (11.5 months, 95% CI 8.9 to 16.7) in advanced melanoma than 
either agent as monotherapy (Larkin et al, 2015), suggesting that immune therapies can 
be given concurrently to improve efficacy.  However, toxicity was also increased with 
55% having grade 3 or 4 adverse events for combination versus 16.3% for nivolumab 
and 27.3% for ipilimumab.  As both pembrolizumab and talimogene laherparepvec have 
had relatively low toxicity as single agents, it is possible that the overall incidence of 
severe adverse events would remain low when they are combined as has been seen 
with the talimogene laherparepvec and ipilimumab combination. 
With: 
A prior concurrent regimen of nivolumab, a PD-1 inhibitor, with ipilimumab, a CTLA-4 
inhibitor has yielded higher response rates (57.5%, 95% CI 52.0 to 63.2) and median 
progression free survival (11.5 months, 95% CI 8.9 to 16.7) in advanced melanoma than 
ipilimumab (Larkin et al, 2015).  Updated results also showed a longer mOS for the 
combination (mOS  60 months) versus ipilimumab (mOS = 19.9 months) 
(Larkin et al, 2019), suggesting that immune therapies can be given concurrently to 
improve efficacy.  However, toxicity was also increased with 55% having grade 3 or  
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4 adverse events for combination versus 16.3% for nivolumab and 27.3% for ipilimumab.  
As both pembrolizumab and talimogene laherparepvec have had relatively low toxicity 
as single agents, it is possible that the overall incidence of severe adverse events would 
remain low when they are combined as has been seen with the talimogene 
laherparepvec and ipilimumab combination. 
Section:  3.1.2, Phase 3 Study Design, Paragraph 7 
Replace: 
Additional interim safety analyses may be performed if warranted based on results from 
the planned safety and/or interim analyses or if requested by the clinical study team or 
the DMC.  The futility analysis based on iORR and iDCR using modified irRC-RECIST 
per blinded independent central review is planned to include the first 160 subjects 
(80 per arm) that have been enrolled and have had an opportunity to be followed for the 
tumor assessment scheduled at week 24.  This futility analysis will be based on 
Bayesian methods.  The talimogene laherparepvec plus pembrolizumab arm is 
considered to be futile if the posterior probability that at least 6% absolute increase for 
iORR (at least 10% for iDCR) from the pembrolizumab is < 0.65 (< 0.75 for iDCR).  A 
DMC will be responsible to review interim safety and non-binding futility analyses for 
iORR and iDCR.  The DMC is also responsible to review the results from the primary 
analysis of PFS by blinded independent central review using modified RECIST 1.1 and 
all interim OS analyses performed by an external independent biostatistics group.  At the 
time of PFS primary analysis, an interim OS efficacy analysis will be performed by the 
external biostatistics group and reviewed by the DMC.  A second interim OS analysis is 
planned after 282 events have occurred.  If OS is not declared statistically significant at 
the second interim analysis, a non-binding futility analysis will be performed.  However, if 
282 OS events are observed prior to the event goal for the primary PFS, then the first 
OS interim will be the event-driven (ie, 282 events) and a PFS interim will be conducted 
with all PFS events at the time of the 282 OS events interim analysis.  In this case, the 
second OS interim analysis will be performed at the PFS primary analysis with all OS 
events.  Refer to Section 10.4.1.4 for additional information. 
With: 
Additional interim safety analyses may be performed if warranted based on results from 
the planned safety and/or interim analyses or if requested by the clinical study team or 
the DMC.  The futility analysis based on iORR and iDCR using modified irRC-RECIST 
per blinded independent central review is planned to include the first 160 subjects 
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(80 per arm) that have been enrolled and have had an opportunity to be followed for the 
tumor assessment scheduled at week 24.  This futility analysis will be based on 
Bayesian methods.  The talimogene laherparepvec plus pembrolizumab arm is 
considered to be futile if the posterior probability that at least 6% absolute increase for 
iORR (at least 10% for iDCR) from the pembrolizumab is < 0.65 (< 0.75 for iDCR).  A 
DMC will be responsible to review interim safety and non-binding futility analyses for 
iORR and iDCR.  The DMC is also responsible to review the results from the primary 
analysis of PFS by blinded independent central review using modified RECIST 1.1 and 
all interim OS analyses performed by an external independent biostatistics group.  At the 
time of PFS primary analysis, an interim OS efficacy analysis will be performed by the 
external biostatistics group and reviewed by the DMC.  The second interim OS analysis 
is planned after 282 events have occurred.  If OS is not declared statistically significant 
at the second interim analysis, a non-binding futility analysis will be performed.  
However, if 282 OS events are observed prior to the event goal for the primary PFS, 
then the first OS interim will be the event-driven (ie, 282 events) and a PFS interim will 
be conducted with all PFS events at the time of the 282 OS events interim analysis.  In 
this case, the second OS interim analysis will be performed at the PFS primary analysis 
with all OS events.  The third interim OS analysis for efficacy is planned after 
315 events have occurred.  Refer to Section 10.4.1.4 for additional information. 
Section:  3.5.2, End of Study, Primary Completion, Paragraph 1 
Delete: 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
Section:  3.5.2, End of Study, Primary Completion, Paragraph 2 
Add: 
The primary completion date is the date when data for the primary endpoint(s) are last 
collected for the purpose of conducting the primary analysis. 
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Section:  4.1.1.1, Inclusion Criteria for Phase 1b and Phase 3, Criterion #104 
Add: 
Disease stage defined as one of the following (per the seventh edition of the 
American Joint Committee on Cancer [AJCC] Cancer Staging Manual):  Subject 
with unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c melanoma 
Section:  7.1, Schedule of Assessments, Table 6, footnote “r” 
Replace: 
r Blood for PK of pembrolizumab:  Pre-dose trough will be collected at week 0 (ie, 
pembrolizumab cycle 1), week 3 (ie, pembrolizumab cycle 2), week 12 
(ie, pembrolizumab cycle 5), week 27 (ie, pembrolizumab cycle 9), week 39 (ie, 
pembrolizumab cycle 13) every 12 weeks (4 cycles) thereafter, at safety follow-up visit 
(30 [+7] days after discontinuation of study treatment), and again 3 months after study 
discontinuation or up until the subject starts new anticancer therapy, whichever occurs 
first.  Every effort should be taken to collect samples at 30 days and 3 months after end 
of pembrolizumab treatment.  All trough samples should be drawn within 24 hours before 
infusion of pembrolizumab.  Pembrolizumab PK sample collection and analyses in 
phase 3 may be discontinued if ongoing PK results from this study continue to be 
consistent with existing PK data from other pembrolizumab melanoma clinical trials. 
With: 
r Blood for PK of pembrolizumab:  Pre-dose trough and post-dose peak PK samples will 
be collected at week 0 (ie, pembrolizumab cycle 1).  Pre-dose trough samples only will 
be collected on day 1 of week 3 (ie, pembrolizumab cycle 2), week 12 
(ie, pembrolizumab cycle 5), week 27 (ie, pembrolizumab cycle 9), week 39 (ie, 
pembrolizumab cycle 13) every 12 weeks (4 cycles) thereafter, at safety follow-up visit 
(30 [+7] days after discontinuation of study treatment), and again 3 months after study 
discontinuation or up until the subject starts new anticancer therapy, whichever occurs 
first.  Every effort should be taken to collect samples at 30 days and 3 months after end 
of pembrolizumab treatment.  All trough samples should be drawn within 24 hours before 
infusion of pembrolizumab.  The peak sample should be drawn within 30 minutes after 
the end of the infusion.  Pembrolizumab PK sample collection and analyses in phase 3 
may be discontinued if ongoing PK results from this study continue to be consistent with 
existing PK data from other pembrolizumab melanoma clinical trials. 
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Section:  10.1.1.3, Exploratory Endpoints, bullet 5 
Replace: 
 
HSU estimates derived via EQ-5D-3L at each assessment in phase 3 and 
post-progression. 
With: 
 
Changes in HSU estimates derived via EQ-5D-3L 
Section:  10.1.1.3, Exploratory Endpoints, bullet 11 (new) 
Add: 
 
Response rates (partial, complete, partial or complete) and maximum decrease 
in lesion size, separately for visceral, injected, and uninjected non-visceral 
lesions. 
Section:  10.1.2, Analysis Sets, PRO Population 
Replace: 
PRO Analysis Sets 
PRO analysis set will include subset of subjects in the Full Analysis Set who had 
received at least one dose of study therapy and had at least one PRO assessment. 
With: 
PRO Population 
The PRO population includes the subset of the subjects in the full analysis set 
who had received at least 1 dose of study therapy and had at least 1 PRO 
assessment.  A PRO assessment will be defined as completed if at least 1 
subscale/domain can be calculated from the questionnaire.  Patient reported 
outcome populations will be defined separately for each questionnaire (EORTC 
QLQ-C30 and EQ-5D-3L) and for the secondary endpoint of EORTC QLQ-C30 
GHS/QoL. 
Section:  10.1.3, Covariates and Subgroups, Paragraph 2 
Delete: 
The following baseline covariates and randomization stratification factors may be used to 
examine all efficacy in subgroups or in multivariate analyses: 
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Section:  10.1.3, Covariates and Subgroups, Paragraph 2, bullets 10, 11, and 14 
Replace: 
 
The sum of longest, or shortest for nodal, diameters of target lesions (SLD) 
 
Pre-randomization PD-L1 status (positive, negative, indeterminant/unknown) 
 
Pre-randomization of BRAFV600 mutation:  yes vs no 
With: 
 
The sum of longest, or shortest for nodal, diameters of target lesions (SLD) 
determined by blinded independent central review (will be dichotomized based 
on median) 
 
Baseline PD-L1 status (positive vs not positive) 
 
Baseline of BRAFV600 mutation:  yes vs no vs missing/unknown 
Section:  10.2.2, Sample Size Considerations for Phase 3, Paragraph 2 
Replace: 
The overall Type I error for the dual primary endpoints is 2-sided 0.05.  The event goal 
for PFS to achieve 90% power at 2-sided 0.005 is 407 and that for OS to achieve 90% 
power at a 2-sided 0.045 is 346 after taking into account the group sequential interim OS 
analyses.  The OS event goal is not adjusted for the non-binding OS futility assessment 
at the second OS interim analysis.  The sample size is 660 (ie, 330 per arm) based on 
an estimate of 346 death events occurring within 5 years (60 months) with approximately 
48% of subjects censored.  Assuming a non-uniform subject accrual rate for which 50% 
of cumulative enrollment is accrued at 2/3 of expected total enrollment period (Lachin 
and Foulkes, 1986), and exponential distributions for loss to follow up for PFS and OS 
with an annual rate of 5% for OS and 10% for PFS, Table 9 displays estimated timing of 
analysis based on 2 scenarios of enrollment rates: 
With: 
The overall Type I error for the dual primary endpoints is 2-sided 0.05.  The event goal 
for PFS to achieve 90% power at 2-sided 0.005 is 407 and that for OS to achieve 90% 
power at a 2-sided 0.045 is 346 after taking into account the group-sequential interim OS 
analyses.  The OS event goal is not adjusted for the non-binding OS futility assessment 
at the second OS interim analysis.  The sample size is 660 (ie, 330 per arm) based on 
an estimate of 346 death events occurring within 5 years (60 months) with approximately 
48% of subjects censored.  Assuming a non-uniform subject accrual rate for which 50% 
of cumulative enrollment is accrued at 2/3 of expected total enrollment period 
(Lachin and Foulkes, 1986), and exponential distributions for loss to follow up for PFS 
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and OS with an annual rate of 5% for OS and 10% for PFS, Table 9 displays estimated 
timing of analysis based on the actual enrollment rate: 
Section:  10.2.2, Sample Size Considerations for Phase 3, Table 9 
Replace: 
Table 9.  Timing of Primary Analysis for PFS (at 407 events) and OS (at 346 events) 
Average 
Enrollment Rate 
Enrollment 
Duration 
(month) 
PFS PA DCO 
(month) 
OS Events (% event 
goal) at PFS PA 
DCO 
OS PA DCO 
(month) 
20/month 
33 
44 
240 (69%) 
62 
33/month 
20 
33 
222 (64%) 
53 
DCO = data cutoff at event goal; OS = overall survival; PA = primary analysis; PFS1 = progression free 
survival per blinded independent central review using modified RECIST 1.1. N = 660 
With: 
Table 9.  Timing of Primary Analysis for PFS (at 407 events) and OS (at 346 events) 
Enrollment 
Duration (month) 
PFS PA DCO 
(month) 
OS Events (% event goal) 
at PFS PA DCO 
OS PA DCO 
(month) 
26 
48 
252 (73%) 
75 
DCO = data cutoff at event goal; OS = overall survival; PA = primary analysis; PFS1 = progression free 
survival per blinded independent central review using modified RECIST 1.1. 
 
 
 
 
 
 
Section:  10.2.2, Sample Size Considerations for Phase 3, Table 10, footnote a 
Add: 
 
Section:  10.4.1.4, Interim Efficacy and Futility Analysis (Phase 3), Paragraphs 1 and 2 
Replace: 
There are 4 planned analysis time points for hypothesis testing, including primary and/or 
interim analyses of the 5 hypotheses (H):  H1, associated with OS; H2, PFS by blinded 
independent central review assessed modified RECIST 1.1; H3, iPFS by blinded 
independent central review assessed modified irRC-RECIST; H4, iCRR by blinded 
independent central review assessed modified irRC-RECIST; and H5, OS subgroup 
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excluding IVM1c (Table 10).  The analysis times are defined by the following 
event-driven time points with the DMC responsible for Analyses #1 and #2. 
1. PFS primary analysis at 407 events (DMC). 
2. OS interim analysis at 282 events (including a futility analysis) (DMC). 
3. OS primary analysis at 346 events. 
4. OS subgroup primary analysis at earlier of 208 events in subgroup or 5 years 
minimum follow-up. 
Note that there is no sequential order in these 4 analysis times (with the exception that 
Analysis #2 is before Analysis #3).  Each analysis time may also include interim or 
primary analyses for the other endpoints.  Endpoints to be analyzed, and the type of 
analysis (ie, interim or primary), are presented in Table 11 and are dependent on which 
hypotheses have been rejected.  For example, testing for iCRR and iPFS at an analysis 
time point will be conditional upon previously rejecting either H1 or H2.  O'Brien-Fleming 
group sequential boundaries based on the Lan-DeMets approach (O'Brien and Fleming, 
1979) will be used for testing endpoints with interim analyses.  Multiple testing 
procedures will utilize the graphic-based Maurer-Bretz approach (Section 10.5). 
With: 
There are 5 planned analysis time points for hypothesis testing, including primary and/or 
interim analyses of the 5 hypotheses (H):  H1, associated with OS; H2, PFS by blinded 
independent central review assessed modified RECIST 1.1; H3, iPFS by blinded 
independent central review assessed modified irRC-RECIST; H4, iCRR by blinded 
independent central review assessed modified irRC-RECIST; and H5, OS subgroup 
excluding IVM1c (Table 10).  The analysis times are defined by the following 
event-driven time points with the DMC responsible for Analyses #1, #2, and #3. 
1. OS interim analysis and PFS primary analysis at 407 PFS events (DMC). 
2. OS interim analysis at 282 events (including a futility analysis) (DMC). 
3. OS interim analysis at 315 events (DMC). 
4. OS primary analysis at 346 events. 
5. OS subgroup primary analysis at earlier of 208 events in subgroup or 5 years 
minimum follow-up. 
Note that there is no sequential order in these 5 analysis times (with the exception that 
Analysis #2 is before Analysis #3, and Analysis #3 before Analysis #4).  Each analysis 
time may also include interim or primary analyses for the other endpoints.  Endpoints to 
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be analyzed, and the type of analysis (ie, interim or primary), are presented in Table 11 
and are dependent on which hypotheses have been rejected.  For example, testing for 
iCRR and iPFS at an analysis time point will be conditional upon previously rejecting 
either H1 or H2.  O'Brien-Fleming group sequential boundaries based on the Lan-DeMets 
approach (O'Brien and Fleming, 1979) will be used for testing endpoints with interim 
analyses.  Multiple testing procedures will utilize the graphic-based Maurer-Bretz 
approach (Section 10.5). 
Section:  10.4.1.4, Interim Efficacy and Futility Analysis (Phase 3), Paragraph 3, 
bullets 3, 6, and 7 
Replace: 
3. At each of the 4 planned analysis times, it will be considered an interim analysis of 
iCRR and iPFS, rather than the primary analysis, if the maximum information has not 
been reached for the respective endpoint at that time.  For example, if H3 is tested in 
an analysis that includes fewer than 256 iPFS events, then it will be an interim 
analysis of iPFS that includes all observed events; otherwise, it will be the primary 
analysis with all iPFS times censored after the date of the 256th event.  If all 
randomized subjects do not have at least 36 weeks follow-up in an analysis, then it 
will be an interim analysis for iCRR only including those subjects with at least 
36 weeks follow-up; otherwise, it will be the primary analysis and include all 
randomized subjects.  With the exception of PFS, the hypothesis for an endpoint 
may be re-tested after its primary analysis using its primary analysis data if alpha is 
subsequently propagated to it from the rejection of another hypothesis. 
6. The OS hypothesis (H1) will be tested at Analyses #1-3 with all (Analysis #1) or 
required number (Analysis #2 and Analysis #3) of events in the absence of its prior 
rejection (or futility at Analysis #2). 
7. The OS subgroup hypothesis (H5) will be tested at the first and all subsequent 
analysis times when alpha can be propogated to it from the rejection of H1 or H2 
followed by H3 and/or H4.  All OS events in the subgroup at the end of 5 years 
follow-up will be used if 208 events have not been observed.  If H1 is not rejected by 
Analysis #3, it will be tested again using events at Analysis #3 if alpha can be 
propogated from the rejection of H5 at Analysis #4. 
With: 
3. At each of the 5 planned analysis times, it will be considered an interim analysis of 
iCRR and iPFS, rather than the primary analysis, if the maximum information has not 
been reached for the respective endpoint at that time.  For example, if H3 is tested in 
an analysis that includes fewer than 256 iPFS events, then it will be an interim 
analysis of iPFS that includes all observed events; otherwise, it will be the primary 
analysis with all iPFS times censored after the date of the 256th event.  If all 
randomized subjects do not have at least 36 weeks follow-up in an analysis, then it 
will be an interim analysis for iCRR only including those subjects with at least 
36 weeks follow-up; otherwise, it will be the primary analysis and include all 
randomized subjects.  With the exception of PFS, the hypothesis for an endpoint 
may be re-tested after its primary analysis using its primary analysis data if alpha is 
subsequently propagated to it from the rejection of another hypothesis. 
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6. The OS hypothesis (H1) will be tested at Analyses #1-4 with all (Analysis #1) or 
required number (Analysis #2, Analysis #3, and Analysis #4) of events in the 
absence of its prior rejection (or futility at Analysis #2). 
7. The OS subgroup hypothesis (H5) will be tested at the first and all subsequent 
analysis times when alpha can be propogated to it from the rejection of H1 or H2 
followed by H3 and/or H4.  All OS events in the subgroup at the end of 5 years 
follow-up will be used if 208 events have not been observed.  If H1 is not rejected by 
Analysis #4, it will be tested again using events at Analysis #4 if alpha can be 
propogated from the rejection of H5 at Analysis #5. 
Section:  10.4.1.4, Interim Efficacy and Futility Analysis (Phase 3), Paragraph 4 and 
Table 11 
Replace: 
Table 11 illustrates possible hypothesis tests at the 4 planned analyses. 
Table 11.  Study Analyses and Possible Hypothesis Tests 
 
 
Hypothesis Tested 
(Analysis Type) 
Analysis 
Timing 
H1 
(OS) 
H2 
(PFS) 
H3 
(iPFS) 
H4 
(iCRR) 
H5 
(OS 
subgroup) 
#1 
407 PFS 
events 
 
(IA) 
(PA) 
If reject H1 or 
H2 
(IA if  
< 256 events) 
If reject H1 or 
H2 
(IA if includes 
fewer than all 
randomized) 
If reject H2 
and either H3 
or H4, or 
reject H1 and 
either H3 or 
H4 
(IA if < 208 
events) 
#2 
282 OS 
events 
(IA) 
n/a 
(IA if Analysis 
#2 is 
performed 
first) 
If reject H1 or 
H2 
(PA on first 
256 events) 
If reject H1 or 
H2 
(PA if includes 
all random-
ized) 
If reject H2 
and either H3 
or H4, or 
reject H1 and 
either H3 or 
H4 
(IA if  
< 208 events) 
#3 
346 OS 
events 
(PA) 
n/a 
See Analysis 
#2 above 
See Analysis 
#2 above 
See Analysis 
#2 above 
#4 
Earlier of 208 
OS events in 
subgroup or 
5 years 
minimum 
follow-up 
If reject H2 
previously 
and H5  
(PA at first 
346 
events) 
n/a 
See Analysis 
#2 above 
See Analysis 
#2 above 
See Analysis 
#2 above 
(PA) 
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With: 
Table 11 illustrates possible hypothesis tests at the 5 planned analyses. 
Table 11.  Study Analyses and Possible Hypothesis Tests 
 
 
Hypothesis Tested 
(Analysis Type) 
Analysis 
Timing 
H1 
(OS) 
H2 
(PFS) 
H3 
(iPFS) 
H4 
(iCRR) 
H5 
(OS 
subgroup) 
#1 
407 PFS 
events 
 
(IA) 
(PA) 
If reject H1 or 
H2 
(IA if  
< 256 events) 
If reject H1 or 
H2 
(IA if includes 
fewer than all 
random-ized) 
If reject H2 
and either H3 
or H4, or 
reject H1 and 
either H3 or 
H4 
(IA if  
< 208 events) 
#2 
282 OS 
events 
(IA) 
n/a 
(IA if 
Analysis #2 
is performed 
first) 
If reject H1 or 
H2 
(PA on first 
256 events) 
If reject H1 or 
H2 
(PA if includes 
all random-
ized) 
If reject H2 
and either H3 
or H4, or 
reject H1 and 
either H3 or 
H4 
(IA if 
 < 208 events) 
#3 
315 OS 
events 
(IA) 
n/a 
If reject H1 
or H2 
(PA on first 
256 events) 
If reject H1 or 
H2 
(PA if 
includes all 
randomized) 
If reject H2 
and either H3 
or H4, or 
reject H1 and 
either H3 or 
H4 (IA if 
< 208 events) 
#4 
346 OS 
events 
(PA) 
n/a 
See Analysis 
#2 and #3 
above 
See Analysis 
#2 and #3 
above 
See Analysis 
#2 and #3 
above 
#5 
Earlier of 208 
OS events in 
subgroup or 
5 years 
minimum 
follow-up 
If reject H2 
previously 
and H5  
(PA at first 
346 events) 
n/a 
See Analysis 
#2 and #3 
above 
See Analysis 
#2 and #3 
above 
See Analysis 
#2 and #3 
above 
(PA) 
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Section:  10.4.1.4, Futility Analysis for OS 
Delete: 
At the 282 OS events interim analysis (ie, Analysis #2), if hypothesis H1 is not rejected, 
then an OS futility analysis will be evaluated by the DMC.  The interim OS futility 
analysis will be non binding and define futility as a conditional power < 10% assuming a 
constant treatment effect (Denne, 2001); the corresponding OS futility boundary is 0.89, 
assuming a constant HR = 0.70.  OS futility will also be evaluated by the DMC 
considering a possible non constant treatment effect that increases over time (eg, a 2 
interval model with a cutpoint between 4 8 months and constant treatment effect in each 
interval, where the second interval has a larger effect than the first one).  To limit the 
probability of futility < 0.02, the futility boundary for the observed HR at 282 OS events 
analysis will be 0.93.  Guidelines for this possible late effect will be provided in the DMC 
charter amendment.  Operating characteristics of the primary analysis of PFS and 
sequential tests of OS are shown in Table 12 based on the OS events expected at 
Analysis #1 based on 2 enrollment scenarios shown in Table 9. 
 
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Section:  10.4.1, Futility Analysis for OS, Table 12 
Replace: 
Table 12  Analysis Timing, Nominal Significance Levels, and Boundary Properties by Average Enrollment 
Average 
enrollment 
Analysis 
Data 
cut-off 
(mon) 
Endpoint 
(scenario) 
Event (% 
goal) 
Efficacy 
nominal 
2-sided  
Futile HR b 
Prob. Futile b 
Efficacy 
HR 
Power total 
H0 
H1 
20/month 
PFS PA  
44 
PFS 
407 (100) 
0.0050 
 
 
 
0.76 
90% 
 
OS IA1 
44 
OS (PFS-) 
OS (PFS+) 
240 (69)a 
0.0123 
0.0143 
 
 
 
0.72 
0.73 
60% 
62% 
 
OS IA2 
50 
OS (PFS-) 
OS (PFS+) 
282 (82) 
0.0194 
0.0219 
0.89 
0.89 
84% 
83% 
2% 
2% 
0.76 
0.76 
76% 
77% 
 
OS PA 
62 
OS (PFS-) 
OS (PFS+) 
346 (100) 
0.0376 
0.0416 
 
 
 
0.80 
0.80 
90% 
91% 
33/month 
PFS PA  
33 
PFS 
407 (100) 
0.0050 
 
 
 
0.76 
90% 
 
OS IA1 
33 
OS (PFS-) 
OS (PFS+) 
222 (64)a 
0.0088 
0.0103 
 
 
 
0.70 
0.71 
52%  
54%  
 
OS IA2 
41 
OS (PFS-) 
OS (PFS+) 
282 (82) 
0.0203 
0.0230 
0.89 
0.89 
84% 
83% 
2% 
2% 
0.76 
0.76 
76% 
77%  
 
OS PA 
53 
OS (PFS-) 
OS (PFS+) 
346 (100) 
0.0377 
0.0417 
 
 
 
0.80 
0.80 
90% 
91% 
N = 660 
IA = interim analysis; H0 = null hypothesis; H1 = alternative hypothesis; HR = hazard ratio; OS = overall survival; PFS = progression free survival; PA = primary 
analysis. 
O’Brien-Fleming spending α for OS; futility if conditional power < 10%; H0:  HR = 1 and H1:  HR = 0.67 (PFS) and 0.70 (OS).  Testing OS at an overall 2-sided 0.045 if 
PFS is not significant at 2-sided 0.005 (eg, PFS-); testing OS at 0.05 when all other null hypotheses are rejected (eg, PFS+).  
 
Approved 
 
 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 20 of 30 
CONFIDENTIAL 
 
 
With: 
Table 12  Analysis Timing, Nominal Significance Levels, and Boundary Properties 
Analysis 
Data cut-off 
(mon) 
Endpoint 
(scenario) 
Event (% 
goal) 
Efficacy 
nominal 
2-sided  
Futile HR b 
Prob. Futile b 
Efficacy HR 
Power total 
H0 
H1 
PFS PA  
48 
PFS 
407 (100) 
0.0050 
 
 
 
0.76 
90% 
OS IA1 
48 
OS (PFS-) 
OS (PFS+) 
252 (73)a 
0.0150 
0.0173 
 
 
 
0.74 
0.74 
66% 
67% 
OS IA2 
52 
OS (PFS-) 
OS (PFS+) 
282 (82) 
0.0187 
0.0212 
0.89 
0.89 
84% 
83% 
2% 
2% 
0.76 
0.76 
76% 
77% 
OS IA3 
61 
OS (PFS-) 
OS (PFS+) 
315 (91) 
0.0261 
0.0292 
 
 
 
0.78 
0.78 
84% 
85% 
OS PA 
75 
OS (PFS-) 
OS (PFS+) 
346 (100) 
0.0336 
0.0372 
 
 
 
0.80 
0.80 
90% 
90% 
IA = interim analysis; H0 = null hypothesis; H1 = alternative hypothesis; HR = hazard ratio; OS = overall survival; PFS = progression free survival; PA = primary 
analysis. O’Brien-Fleming spending α for OS; futility if conditional power < 10%; H0:  HR = 1 and H1:  HR = 0.67 (PFS) and 0.70 (OS).  Testing OS at an overall 2-sided 
0.045 if PFS is not significant at 2-sided 0.005 (eg, PFS-); testing OS at 0.05 when all other null hypotheses are rejected (eg, PFS+). 
 
 
 
 
Approved 
 
 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 21 of 30 
CONFIDENTIAL 
 
 
Section:  10.5.5, Patient Reported Outcome Endpoints and Analyses 
Replace: 
10.5.5 PRO Endpoints 
The PRO analyses will be conducted for subjects in the PRO Analysis Sets.  Summary 
scores at each assessment and changes from baseline of PROs as assessed by 
EQ-5D-3L and the QLQ-C30 questionnaires will be reported.  Changes from baseline 
will be summarized and at specified time points of interest, differences between 
treatment groups for each defined score will be analyzed.  For the EORTC QLQ-C30 
questionnaire, each of the 5 functional scales, 9 symptom scales, and a GHS/QoL 
subscale (secondary endpoint) will be summarized similarly.  The calculation of scores 
and methods for handling missing data will be based on the questionnaire’s standard 
scoring guidelines.  Details of all the PRO analyses will be provided in the statistical 
analysis plan. 
With: 
10.5.5 Patient Reported Outcome Endpoints and Analyses 
The PRO analyses will be conducted for subjects in the PRO population.  Summary 
scores at each assessment and changes from baseline of PROs as assessed by 
EQ-5D-3L and the QLQ-C30 questionnaires will be reported.  Changes from baseline 
will be summarized and at specified time points of interest, differences between 
treatment groups for each defined score will be analyzed.  For the EORTC QLQ-C30 
questionnaire, each of the 5 functional scales, 9 symptom scales, and a GHS/QoL 
subscale (secondary endpoint) will be summarized similarly.  For the EQ-5D-3L 
questionnaire, 2 scores will be estimated:  the utility score calculated from the 5 
domains using a scoring algorithm, and the VAS score based on the 
0 to 100 feeling thermometer.  Details of all the PRO analyses will be provided in the 
PRO supplemental statistical analysis plan. 
Section:  12.3, Study Monitoring and Data Collection, Paragraph 6 
Delete: 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
Approved 
 
 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 22 of 30 
CONFIDENTIAL 
 
 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout. 
Section:  13, References 
Add: 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al.  Five-year survival with combined 
nivolumab and ipilimumab in advanced melanoma.  N Engl J Med.  
2019;381(16):1535-1546. 
Robert C, Ribas A, Schachter J, et al.  Pembrolizumab versus ipilimumab in 
advanced melanoma (KEYNOTE-066):  post-doc 5-year results from an open-label, 
multicenter, randomised, controlled, phase 3 study.  Lancet Oncol.  
2019;20(9):1239-1251. 
Approved 
 
 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 23 of 30 
CONFIDENTIAL 
 
 
Section:  14, Appendix C, Pregnancy and Lactation Notification Worksheets 
Replace: 
 
Approved 
 
 
Ald(;EN" Pregnancy Notification Worksheet 
Fax Completed Form to the Country-respective Safety Fax Une 
SB.ECT OR TYPE IN ,llt. FNtJ# 
...:.J 
Study Design: ii lntervenliona1 
Observaliooal ,(tf 0bsetVationa1: □ Prospective □ Re.trospecmre) 
2. Contact Information 
Investigator Name ___________________ _ 
Site# ___________ 
_ 
Phone ,__ _ _._ ________ _ 
Fax ,__ _ _,_ ________ _ 
Emall ____________ _ 
lnstifution _______________________________________ _ 
Address _______________________________________ _ 
4. Amgen Product Exposure 
Am@,n Product 
Dose at time of 
Fre~"ncy 
Route 
Stan Date 
co.nc,e;ption 
rrm ...:JJ'dd ...:J1ym_ 
Was 1he Amgen product (or study drug,) disoonlinu ed'? 
Yes 
D 
o 
If yes. pll>Vide prod'ucl (or study drugt sklp da e:: mm 
...:J1ctd 
...:J1yyyy __ 
Did 1he sul>jecl wilhdraw from !he study? D Yes 
No, 
5. Pregnancy lnfonmrtion 
Pregnant fema1e·s U.IP 
mm. 
...:J I dd. ..:Ji YYY'/.___ D Unknown 
Estimated date of delivery mm 
..=J I dd 
..=Ji yyyy__ D Unknown 
NIA 
If WA. dali! ,of termination (actual or planned!) mm 
...:J I dd 
...:JI Yffl. __ 
_ 
Has the p!l<'Qnanl female reooy de,weredr? D Yes D No, D Unknown D NIA 
If yecs, pro,,id'e dale of deliveiry. mm 
...:J1 
dd 
...:JI Yffl. __ 
_ 
W85 lhe infan; healmy? 
Yes O o O Un:kru>,m O NIA 
If any Adverse Event was eooperienoed by the mt:anl provide brie.f details: _______________ _ 
I 
JFo_nn Completed by: 
Pn nl Name.-==--------------
Signature: _______________ _ 
TIiie: _______________ _ 
Date: _______________ _ 
6.'fecfive Date: Maim 27, 2(Jc11 
Page 1 cf 1 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 24 of 30 
CONFIDENTIAL 
 
 
 
Approved 
 
 
Print Form 
AhGN° Lactation Notification Worksheet 
Fax Compfeted Fann to the Cou.llfly•respective Safety Fax Line 
SBLECT OR TYPE IN A FAX# ... 
le_n_te_<_fa_x_n_u_m_'b_er ____ ....,..., 
Study Design: 0 lnterven1ion.a1 
Observational ,(If Observalion.a1: D Pro.speclie,e D Re1rospective) 
2. Contact Information 
ln.vestil)ilto. lName ___________________ 
_ 
Site# ___________ _ 
IPhone ~ -
~ ---------
Fax~- ~ --------
Email ____________ _ 
llnsfifution _______________________________________ _ 
4. Amgen Product Exposure 
Amg"n Product 
Oose at time of 
bn>as,t feeding 
Freqµency 
Was the Amgen l>fO(luct (or study drug~ discontinued? D Yes 
0 
Rouie 
I yes. pn,vide product (orsiudy drug) stop date: rrm __ lcld __ 
/ym __ 
Did the S\Jbj:ecl vrilhdraw from the study? D Yes 
No 
5. Breast Feediing Information 
Start Date 
lffll __ 
/d:l __ !Ym __ 
Did the mother breastfeed or p,ovide the mfan; with pcmiped breast mllk 
ile acti"llely taking, an Amgen product? 
Yes 
No 
If No, p,ovide slop date: mm ___ 
!dd ___ /ym ___ _ 
lnfan; dale of birth: mm ___ 
lcld ___ 
/YY'iY __ _ 
lnfan; gender: D FenD e 
Male 
Is the infant healthy? 
Yes 
□No , 
llnknown 
NIA 
If any i',jve,,;e Event was experienced by the mother or 1he infant. provide brief c!elsits: _______________ _ 
I 
IFonn Completed by: 
IPrint Name.: _______________ 
_ 
SignatLa"e: ________________ _ 
r,o.,, ----------------
D<ate: ----------------
6.ieciive Date: OJ.April 2012. """""' 2. 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 25 of 30 
CONFIDENTIAL 
 
 
With:
Approved 
 
 
Amgen Proprietary - Confidential 
A"'9(3EN" 
Pregnancy Notification Form 
Study Design: e:J lnterventional 
0 Observational (If Observational: 0 Prospective D Retrospective) 
2. Contact Information 
Investigator Name _____________________ _ 
Site# ____________ _ 
Phone ~ -
~ ---------
Fax ~ -
~ ---------
Email _____________ _ 
Institution __________________________________________ _ 
Address 
4. Amgen Product Exposure 
Amgen Product 
Dose at time of 
Frequency 
Route 
conception 
Was the Amgen product (or study drug) discontinued? D Yes 
D No 
If yes, provide product (or study drug) stop dale: mm __ 
/dd __ /yyyy __ 
Did the subject withdraw from the study? D Yes 
D No 
5. Pregnancy Information 
Pregnant female's last menstrual period (LMP) 
mm ____ / dd ___ / yyyy ___ _ 
Estimated date of delivery mm ___ / dd ___ / yyyy __ 
If NIA, date of termination (actual or planned) mm ___ / dd_
/ yyyy _____ _ 
Has the pregnant female already delivered? D Yes 
D No D Unknown D N/A 
If yes, provide date of delivery: mm ____ / dd ____ / yyyy ___ _ 
Was the infant healthy? D Yes 
D No 
O Unknown D N/A 
Start Date 
mm __ /dd __ 
/yyyy __ 
□U n known 
O N/A 
If any Adverse Event was experienced by the infant, provide brief details: ________________ _ 
Form Comoleted bY 
Print Name: ________________ _ 
Title: _________________ _ 
Signature: _________________ _ 
Date: _________________ _ 
FORM-11 5199 
Version 1.0 
Effective Date: 24-Sept-2018 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 26 of 30 
CONFIDENTIAL 
 
 
 
Approved 
 
 
Amgen Proprietary - Confidential 
ANGEN" Lactation Notification Form 
D Observational (If Observational: D Prospective D Retrospective) 
2. Contact Information 
Investigator Name _____________________ _ 
Site# ____________ _ 
Phone (__J _________ _ 
Fax L__) ________ _ 
Email _____________ _ 
Institution __________________________________________ _ 
Address 
4. Amgen Product Exposure 
Amgen Product 
Dose at time of 
Frequency 
Route 
Start Date 
breast feeding 
mm __ 
/dd __ /Y'f'IY __ 
Was the Amgen product (or study drug) discontinued? D Yes 
□ No 
If yes, provide product (or study drug) stop date: mm __ 
/dd __ /yyyy __ 
Did the subject withdraw from the study? D Yes 
□ No 
5. Breast Feeding Information 
Did the mother breastfeed or provide the infant with pumped breast milk while actively taking an Amgen product? D Yes 
D No 
If No, provide stop date: mm ___ 
/dd ___ /yyyy ___ _ 
Infant date of birth: mm ___ 
/dd ___ /yyyy __ 
_ 
Infant gender: D Female 
D Male 
Is the infant healthy? D Yes 
D No 
D Unknown 
D NIA 
If any Adverse Event was experienced by the mother or the infant, provide brief details:. ________________ _ 
Form ComPleted bv: 
Print Name: ________________ _ 
Title: _________________ _ 
Signature: _________________ _ 
Date: _________________ _ 
FORM-115201 
Version 1.0 
Effective Date: 24-Sept-2018 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 27 of 30 
CONFIDENTIAL 
 
 
Section:  14, Appendix D, Modified Immune-related Response Criteria (irRC) for Review 
of Disease Response in Phase 1b, Follow-up, Paragraph 1 
Replace: 
At each subsequent tumor assessment, the SPD of the index lesions and of new, 
measurable lesions (accurately and serially measured in at least 2 dimensions and for 
which the longest diameter is ≥ 5 mm) are added together to provide the total tumor 
burden. 
With: 
At each subsequent tumor assessment, the SPD of the index lesions and of new, 
measurable lesions (accurately and serially measured in at least 2 dimensions and for 
which the longest diameter is ≥ 10 mm) are added together to provide the total tumor 
burden. 
Section:  14, Appendix D, Modified Immune-related Response Criteria (irRC) for Review 
of Disease Response in Phase 1b, Follow-up, Paragraph 3 
Add: 
For index and new measurable nodal lesions < 10 mm, the measurement should 
be recorded as the 0 x 0 mm instead of the actual measurement. 
Approved 
 
 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 28 of 30 
CONFIDENTIAL 
 
 
Section:  14, Appendix D, Modified Immune-related Response Criteria (irRC) for Review 
of Disease Response in Phase 1b, Evaluation of Objective Response Rate:, Table 14 
Replace: 
Measurable Response 
Non-measurable Response 
Overall 
Response 
Index and new, 
measurable lesions 
(tumor burden)a, % 
Non-index 
New, non-measurable 
lesions 
Using irRC 
↓100 
Absent/NAd 
Absent 
CRb 
↓100 
Present/ND 
Any 
PRb 
↓100 
Unequivocal progression 
Any 
PRb 
↓≥ 50 
Absent/Present/NA/ND d 
Any 
PRb 
↓≥ 50 
Unequivocal progression 
Any 
PRb 
↓< 50 to < 25↑ 
Absent/Present/NA/ND d 
Any 
SD 
↓< 50 to < 25↑ 
Unequivocal progression 
Any 
SD 
≥ 25 
Any 
Any 
PDb 
UE 
Any 
Any 
UE 
ND 
Any 
Any 
UE 
NAc 
Any 
Any 
UE 
With: 
Measurable Response 
Non-measurable Response 
Overall 
Response 
Index and new, 
measurable lesions 
(tumor burden)a, % 
Non-index 
New, non-measurable 
lesions 
Using irRC 
↓100 
Absent/NAd 
Absent 
CRb 
↓100 
Present/ND/UE 
Any 
PRb 
↓100 
Unequivocal progression 
Any 
PRb 
↓≥ 50 
Absent/Present/NAd/ND/UE Any 
PRb 
↓≥ 50 
Unequivocal progression 
Any 
PRb 
↓< 50 to < 25↑ 
Absent/Present/NAd/ND/UE Any 
SD 
↓< 50 to < 25↑ 
Unequivocal progression 
Any 
SD 
≥ 25 
Any 
Any 
PDb 
UE 
Any 
Any 
UE 
ND 
Any 
Any 
UE 
NAc 
Any 
Any 
UE 
Approved 
 
 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 29 of 30 
CONFIDENTIAL 
 
 
Section:  14, Appendix D, Modified Immune-related Response Criteria (irRC) for Review 
of Disease Response in Phase 1b, Response Confirmation, Paragraph 5 
Replace: 
A best overall response of SD requires a visit response of SD or better no earlier than 
77 days after the date of enrollment; otherwise the overall response will be UE. 
With: 
A best overall response of SD requires a visit response of SD or better no earlier than 
84 days after the date of enrollment; otherwise the overall response will be UE. 
Section:  14, Appendix F, Modified irRC-RECIST Guidelines for Assessment of Disease 
Response in Phase 3, Evaluation of Objective Response:, Table 16 
Replace: 
Measurable Response 
Non-measurable Response 
Overall 
Response 
Target and new, 
measurable lesions 
(tumor burden)a, % 
Non-target 
New, non-measurable 
lesions 
Using modified 
irRC-RECIST 
↓100e 
Absent/NAd 
Absent 
iCRb 
↓100 
Present/ND 
Any 
iPRb 
↓100 
Unequivocal progression 
Any 
iPRb 
↓≥ 30 
Absent/Present/NA/ND d 
Any 
iPRb 
↓≥ 30 
Unequivocal progression 
Any 
iPRb 
↓< 30 to ↑< 20 
Absent/Present/NA/ND d 
Any 
iSD 
↓< 30 to ↑< 20 
Unequivocal progression 
Any 
iSD 
↑≥ 20f 
Any 
Any 
iPDb 
iUE 
Any 
Any 
iUE 
ND 
Any 
Any 
iUE 
NAc 
Any 
Any 
iUE 
Approved 
 
 
AMGEN® 


Product:  Talimogene laherparepvec 
Protocol Number:  20110265 
Date:  15 January 2020 
Page 30 of 30 
CONFIDENTIAL 
 
 
With: 
Measurable Response 
Non-measurable Response 
Overall 
Response 
Target and new, 
measurable lesions 
(tumor burden)a, % 
Non-target 
New, non-measurable 
lesions 
Using modified 
irRC-RECIST 
↓100e 
Absent/NAd 
Absent 
iCRb 
↓100 
Present/ND/iUE 
Any 
iPRb 
↓100 
Unequivocal progression 
Any 
iPRb 
↓≥ 30 
Absent/Present/NAd/ND/iUE Any 
iPRb 
↓≥ 30 
Unequivocal progression 
Any 
iPRb 
↓< 30 to ↑< 20 
Absent/Present/NAd/ND/iUE Any 
iSD 
↓< 30 to ↑< 20 
Unequivocal progression 
Any 
iSD 
↑≥ 20f 
Any 
Any 
iPDb 
iUE 
Any 
Any 
iUE 
ND 
Any 
Any 
iUE 
NAc 
Any 
Any 
iUE 
Section:  Appendix F, Modified irRC-RECIST Guidelines for Assessment of Disease 
Response in Phase 3, Evaluation of Objective Response:, Paragraph 4 
Replace: 
A best overall response of iSD requires a visit response of iSD or better no earlier than 
77 days after the date of enrollment; otherwise the overall response will be unevaluable 
(iUE). 
With: 
A best overall response of iSD requires a visit response of iSD or better no earlier than 
84 days after the date of enrollment; otherwise the overall response will be unevaluable 
(iUE). 
Approved 
 
 
AMGEN® 


Product:  Talimogene Laherparepvec
Protocol Number:  20110265
Date:  24 January 2018
Page 1 of 104
CONFIDENTIAL
Amendment 4
Protocol Title:  A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in 
Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable 
Stage IIIB to IVM1c Melanoma (MASTERKEY-265)
Amgen Protocol Number Talimogene Laherparepvec 20110265
EudraCT number 2014-000185-22
NCT Number 02263508
Amendment Date:
24 January 2018
Rationale:
The rationale for the major changes in this protocol are as follows:

Replace the Dose Modification Guidelines for Pembrolizumab Related Adverse 
Events Table with the Pembrolizumab-related Adverse Event Management table to 
incorporate the new myocarditis risk and management;

Replace the information and table regarding management of infusion reactions 
related to pembrolizumab to incorporate the most updated guidelines for grading, 
treatment and premedication at subsequent dosing;

Remove redundant and outdated information about management of 
pembrolizumab-related adverse events from Section 6.2.2.3 to consolidate the dose 
modification and adverse event management into one table for easy reference;

Add thyroid testing up to three days before dosing and explain that study treatment 
can be administered before the results are reported, as long as the subject is 
asymptomatic to facilitate study conduct at sites where thyroid testing results are not 
immediately available.
Other minor changes to the protocol for administrative and clarification purposes are as 
follows:

Update the Key Sponsor Contact information

Add clarity surrounding the response evaluation criteria used for Phase 1b and 
Phase 3 and the respective endpoints

Clarify the collection of archival biopsy

Clarify when subjects should undergo safety follow-up procedures

Allow survival status to be assessed at additional time points not specifically outlined
in the Schedule of Assessments
Approved 
 
 
AMCHN® 


Product:  Talimogene Laherparepvec
Protocol Number:  20110265
Date:  24 January 2018
Page 2 of 104
CONFIDENTIAL

Clarify that for subjects with progressive disease QLQ-C30 is not collected in the 
long-term follow-up; however, EQ-5D-3L will be collected through the long-term 
follow-up

Clarify the timing of the beginning of the registry protocol

Update the primary completion and end of trial dates

Update talimogene laherparepvec background information based on recent 
published results

Update pembrolizumab background information based on recent published results

Update the rationale for combination therapy

Clarify the timing of safety monitoring by the data monitoring committee

Clarify that both clinical and photographic evaluations must be done for lesions which 
cannot be evaluated by radiographic imaging

Clarify that prior tumor vaccines are allowable if administered in the adjuvant setting

Allow subjects with latex allergies to use polyurethane condoms

Clarify that the investigator should instruct the subject to return to the clinic within 
3 days after notification of a suspected herpetic lesion

Clarify that photographs of all visible lesions must be done at baseline to allow for 
follow-up of lesions during treatment

Clarify that laboratory assessment up to 3 days prior to administration of study 
treatment is allowed

Clarify which subjects will be included in the patient reported outcome analysis set

Clarify how the futility analysis of overall survival for a non-constant treatment effect 
will be performed

Update the references

Update Appendix B to the most recent versions of the forms

Update the matrix for determining the overall response at each assessment point for 
phase 1b and hase 3

Make editorial, typographical, and formatting changes throughout the document
Approved 
 
 
AMCHN® 


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Approved 
 
 
Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  25 September 2015 
Page 1 of 140 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in 
Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable 
Stage IIIB to IVM1c Melanoma (MASTERKEY-265) 
Talimogene Laherparepvec 
Amgen Protocol Number (Talimogene Laherparepvec) 20110265 
 
Amendment 2 Date: 
25 September 2015 
 
Rationale: 
The protocol is amended primarily so that an injectable placebo may be added to 
pembrolizumab in the control arm and to convert the study from open-label to 
double-blind in phase 3.  This is necessary in order to reduce the bias of having 
intralesional injections in only 1 arm of the study. 
The following key changes have been incorporated into protocol amendment 2: 
• 
Changed phase 3 portion of study to be double-blind and added placebo to the 
pembrolizumab arm. The placebo and talimogene laherparepvec will not be initially 
available as blinded investigational medicinal product. Until talimogene 
laherparepvec or placebo is available as blinded investigational medicinal product, 
the site pharmacist or designee will need to be unblinded to prepare blinded 
talimogene laherparepvec/placebo.  The subject, Amgen study personnel, and all 
other site personnel and designees will be blinded to the randomization treatment 
group. 
• 
Reordered sections to separate phase 1b and phase 3 in the synopsis, inclusion 
criteria, and general study procedures sections in order to more clearly delineate 
which sections are specific to each phase of the study. 
• 
Updated background information for talimogene laherparepvec and pembrolizumab 
to reflect recent publications or presentations. 
• 
Added results of the completed dose level review team (DLRT) evaluation for 
phase 1b. 
• 
Allowed for more flexibility in frequency of radiographic follow-up for subjects who 
have reached a confirmed clinical response (CR) in long term follow-up. Subjects 
who have reached a confirmed CR may need less radiographic imaging per 
investigator discretion after prolonged periods of CR. 
• 
Updated contraception language for exclusion criterion and also sections related to 
pembrolizumab. This is to align with other pembrolizumab protocols. 
• 
Shortened period from ending prior adjuvant therapy from 3 months to 28 days prior 
to enrollment as 28 days should be adequate time for washout of the previous 
therapy. 
AMGEN® 


Approved 
 
 
Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  25 September 2015 
Page 2 of 140 
CONFIDENTIAL 
 
 
• 
Prior ipilimumab as adjuvant therapy is now allowed. There may have been subjects 
that had disease recurrence following adjuvant ipilimumab for melanoma, and these 
subjects should not necessarily be excluded because ipilimumab has been received 
prior to pembrolizumab by many subjects in other studies and in clinical practice. 
• 
Added exclusion criteria for allogeneic hematopoietic stem cell transplantation and 
for active tuberculosis in order to align with other pembrolizumab protocols. 
• 
Updated text related to pembrolizumab events of clinical interest, rescue 
medications, dose adjustment, overdose, and supportive care guidelines to align with 
other pembrolizumab protocols. Immune-related adverse events are no longer 
considered pembrolizumab events of interest, but diffuse liver injury and 
pembrolizumab overdose are still events of clinical interest. 
• 
Combined the tables for the schedule of assessments for phase 3; arms 1 and 2, 
since the study procedures will be identical for both arms of the study. 
• 
Injectable investigational product-related adverse events during the long-term 
follow-up period will be collected. Although there is a talimogene laherparepvec 
registry protocol capturing reporting of any long-term talimogene 
laherparepvec-related adverse events, the subjects would not be eligible to enroll in 
this registry protocol until after they have ended their participation on this study. 
Subjects may be in long-term follow-up for many years prior to participation in the 
registry, and this change will allow for reporting of long-term talimogene 
laherparepvec-related adverse events during the long-term follow up period between 
the safety follow-up period and the time that the subjects can enroll on the registry 
protocol. 
• 
Updated pregnancy and lactation reporting language to align with other talimogene 
laherparepvec and pembrolizumab protocols. 
• 
Updated text for interim analysis and interim objective response rate (ORR) futility 
analysis in phase 3. In the event that futility is declared on ORR at the interim futility 
analysis, disease control rate (DCR) would also need to have futility declared. This is 
to prevent the study treatment being declared futile when the ORR may not be 
adequately improved but the DCR is at the time of the interim analysis. 
• 
Updated text pertaining to the analysis for the secondary endpoint of 
progression-free survival (PFS) per immune-related response criteria simulating 
Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (phase 3) and 
including text regarding multiplicity adjustment for further clarification. 
• 
Removed from modified RECIST 1.1 criteria used for blinded independent central 
review the modification that new skin lesions will be considered in the overall 
non-target lesion assessment but will not automatically result in a timepoint response 
of progressive disease (PD) in order to more closely follow conventional RECIST 1.1. 
• 
Updated language to clarify the modified response criteria in the appendices (eg, the 
maximum number of new measurable lesions that may be added, how to evaluate 
resected lesions). 
AMGEN® 


Superseded 
 
 
Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 May 2015 
Page 1 of 189 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase 1b/3, Multicenter, Open-label Trial of Talimogene 
Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of 
Unresected, Stage IIIB to IVM1c Melanoma (MASTERKEY) 
 
Talimogene Laherparepvec 
Amgen Protocol Number 20110265 
 
 
Amendment Date: 
15 May 2015 
 
Rationale: 
The protocol has been amended to adequately power the study to evaluate the efficacy 
of talimogene laherparepvec in combination with pembrolizumab in subjects with 
unresected, stage IIIB to IVM1c melanoma to support approval of talimogene 
laherparepvec in combination with pembrolizumab in this patient population. 
The following are the key changes incorporated into protocol amendment 1: 
• 
Changed the phase 2 part of study to phase 3 
• 
Included 2 primary endpoints, progression-free survival (PFS) and overall survival 
(OS), in phase 3.  The primary end of PFS will be based on tumor evaluation by an 
independent blinded central review using modified RECIST 1.1. 
• 
RECIST 1.1 including the following modifications will be used by a blinded 
independent central review for determination of primary endpoint and some of the 
secondary tumor response-related endpoints in the phase 3 part of the study:  
1. increased total target lesions to a maximum of 10 (up to a maximum of 5 per 
organ).  
2. because appearance of new skin lesions may not necessarily correlate with 
clinically relevant disease progression, new skin lesions will be considered in 
the overall non-target lesion assessment, but will not automatically result in a 
timepoint response of progressive disease 
• 
Removed cross-over combination treatment (Phase 2 Part 2) for subjects who 
progress on the pembrolizumab control arm in the randomized portion in order to 
better study the primary endpoint of OS. 
• 
Increased sample size of phase 3 from 90 to 660 subjects to formally test for PFS 
and OS as 2 primary endpoints 
AMGEN® 


Superseded 
 
 
Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 May 2015 
Page 2 of 189 
CONFIDENTIAL 
 
 
• 
Revised the treatment schedule of pembrolizumab during the phase 3 to 200 mg 
every 3 weeks in phase 3. This was due to data from comparisons of every 2 week 
to every 3 week dosing of pembrolizumab which showed comparable efficacy, 
safety, and pharmacokinetics between the two groups. 
• 
Revised the phase 3 treatment schedule of talimogene laherparepvec to up to 4 mL 
106 PFU/mL at week 0, followed by up to 4 mL of 108 PFU/mL at weeks 3, 5, 7, 9, 
and then every 3 weeks. The every 2 week schedule weeks 3-9 is preserved in order 
to allow for more optimal delivery of talimogene laherparepvec during the period 
when most subjects will have lesions to inject, but increased to every 3 weeks after 
week 9 in order to synchronize the schedules of talimogene laherparepvec for longer 
term dosing.   
• 
Updated the prior therapy inclusion criteria in phase 3 as described below to account 
for the increasing use of BRAF inhibitor regimens in the first line for BRAFV600 mutant 
melanoma : 
− 
Subjects with BRAFV600 wild-type tumors must not have received any prior 
systemic anticancer treatment consisting of chemotherapy, immunotherapy, or 
targeted therapy for unresected stage IIIB to IVM1c melanoma. 
− 
Subjects with BRAFV600 mutated tumors who have received prior BRAF inhibitor 
therapy either alone or in combination with MEK inhibitor as their only prior 
systemic therapy are eligible for this study.  However, the subject must have 
ended BRAF inhibitor therapy either alone or in combination with MEK inhibitor at 
least 14 days prior to enrollment.  At the discretion of the investigator, subjects 
with BRAFV600 mutant melanoma or those subjects whose BRAFV600 mutation 
status is unknown at the time of randomization who have not received a BRAF 
inhibitor are also eligible for the phase 3 of this study as first-line treatment if they 
meet the following criteria: LDH < ULN, no clinically significant tumor related 
symptoms in the judgment of the investigator, and absence of rapidly progressing 
metastatic melanoma in the judgment of the investigator. 
− 
Subjects who received prior adjuvant therapy for melanoma will not be excluded 
(including, but not limited to, interferon, limb infusion/perfusion, or use of 
investigational agents in the adjuvant setting).  However, the subject must have 
ended therapy at least 3 months prior to enrollment. 
− 
No prior pembrolizumab, other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
ipilimumab, other CTLA-4 inhibitor, talimogene laherparepvec, tumor vaccine, or 
any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways is allowed, even if given in the adjuvant setting. 
• 
For treatment decisions and secondary endpoints, sed immune-related response 
criteria simulating-RECIST (irRC-RECIST) in phase 3 which reduces tumor 
measurements to a single dimension like conventional RECIST but can account for 
unique tumor response characteristics observed with immunotherapies to enable 
treatment beyond disease progression (PD), if the subject is clinically stable, until PD 
is confirmed at least 4 weeks after initial progression as a secondary endpoint.  
• 
Given that subjects who have initial progression before response might still have 
clinical benefit from treatment and might be different between the two arms in phase 
3, more formal testing of irRC-RECIST as a secondary endpoint is planned. An 
event-driven analysis of the secondary PFS endpoint based on irRC-RECIST per 
investigator will be tested at the earlier of the following outcomes: (1) a statistically 
significant improvement in the primary PFS endpoint with testing at a 2-sided 0.005 
AMGEN® 


Superseded 
 
 
Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 May 2015 
Page 3 of 189 
CONFIDENTIAL 
 
 
level, or (2) an interim or primary analysis statistically significant improvement in OS 
with testing at a 2-sided 0.045 level. 
• 
Updated the measurable disease inclusion criteria in phase 3 as described below:   
− 
Measurable disease defined as either one of the following to better match 
RECIST criteria: 
• 
at least 1 visceral or nodal/soft tissue melanoma lesion that can be accurately 
and serially measured in at least 1 dimension and for which the longest 
diameter is ≥ 10 mm as measured by CT scan or MRI.  Lymph nodes must 
measure ≥ 15 mm in their short axis to be considered measurable by CT 
scan or MRI 
• 
Updated the inclusion criteria in phase 3 to require subjects to attempt collection of 
tumor samples (archival sample or newly obtained biopsy) that are adequate for 
PD-L1 assessment prior to randomization up to two times.   
• 
Skin photographs and radiographs performed during the 3 part of the study will be 
collected and submitted to a blinded independent imaging vendor for evaluation of 
primary endpoint of PFS and secondary response-related endpoints by central 
review. 
• 
Removed the option for retreatment (second-course phase) for subjects who initially 
stopped talimogene laherparepvec or pembrolizumab treatment after attaining 
investigator-confirmed complete response (CR) and later experienced an 
investigator-determined PD as evaluating retreatment after progression is not an 
objective of this study. 
• 
The phase 1b will be re-analyzed after the last subject has had a chance to be 
followed for 24 weeks from the initiation of pembrolizumab and at the time of the 
phase 3 primary analysis in order to provide a interim review of efficacy data 
between the phase 1b and phase 3 primary analyses. 
• 
Added 2 interim safety, 1 interim ORR futility, 1 interim efficacy, and 1 interim 
analysis for OS during the phase 3. 
• 
Utilized an independent, external to Amgen and Merck, data monitoring committee 
(DMC) in phase 3 to monitor safety and evaluate futility. 
• 
Updated the pembrolizumab-related pneumonitis toxicity management guidelines to 
incorporate instruction for management of interstitial lung disease (ILD) as described 
in the Dear Investigator Letter, dated 24 October 2014, and the Pembrolizumab 
Event of Clinical Interest and Immune-Related Adverse Events Guidance document 
version 3.0. 
• 
Updated the tumor sample collection schedule during phase 3 as described below: 
− 
The following tumor samples will be to obtained from all subjects enrolled in 
phase 3: 
• 
A biopsy will be performed during screening 
• 
A formalin-fixed paraffin-embedded (FFPE) tumor tissue will collected during 
screening.  No repeat tumor biopsy would be needed provided the (FFPE) 
AMGEN® 


Superseded 
 
 
Product:  Talimogene Laherparepvec 
Protocol Number:  20110265 
Date:  15 May 2015 
Page 4 of 189 
CONFIDENTIAL 
 
 
tumor tissue was obtained within 3 months of enrollment and there was no 
intervening therapy.  
• 
At least a single post-treatment biopsy will be collected at week 5 from an 
uninjected lesion (preferred) or an injected lesion if there are no uninjected 
lesions available for biopsy. 
− 
The following tumor tissue samples will be to obtained from approximately 
200 subjects (100 per arm) enrolled in phase 3 at select sites: 
• 
At least a single post-treatment biopsy will be collected at the time of 
confirmed disease progression. 
• 
Revised the schedule of safety laboratory assessments (hematology, chemistry, 
thyroid function test, and urinalyses), patient-reported outcomes assessments 
(EQ-5D and EORTC QLQ-C30), pembrolizumab PK analyses, and 
anti-pembrolizumab antibody analyses to align with revised pembrolizumab 
treatment schedule during phase 3.  The blood sample collection for pembrolizumab 
PK analyses and anti-pembrolizumab antibody analyses in phase 3 may be 
discontinued if ongoing PK and antibody results from this study continue to be 
consistent with existing PK and antibody data from other pembrolizumab melanoma 
clinical trials. 
• 
The secondary objectives evaluating anti-pembrolizumab antibodies and 
pharmacokinetics of pembrolizumab as well as changes in PD-L1 expression in 
injected and non-injected lesions after starting talimogene laherparepvec have been 
converted into exploratory objectives so that there would be more emphasis on 
efficacy and safety objectives. The overall analysis for these objectives will not 
change. 
• 
Ordinal categorical response score and deep response rate were removed as 
endpoints since they may be derived from objective response rate. 
• 
Moved evaluation of patient reported outcomes (PRO) in the randomized phase from 
an exploratory to secondary objective for greater emphasis. 
• 
Additional language is provided to clarify the responsibilities of the Dose Level 
Review Team (DLRT) in providing recommendations in phase 1b, but there are no 
changes in the DLRT responsibilities. 
• 
Increased follow-up of subjects from 36 months to 60 months after the last subject is 
enrolled in order to ensure enough events would be captured for the overall survival 
endpoint.  
• 
Changed the reporting period for pembrolizumab Events of Clinical Interest from 
90 (+7) days after the last dose of pembrolizumab to 90 (+7) after the last of dose of 
pembrolizumab or 30 (+7) days after initiation of a new anticancer therapy, 
whichever is earlier, and changed the reporting period for serious adverse events 
from 90 (+7) days after the cessation of all study treatment to 90 (+7) days after the 
cessation of all study treatment or 30 (+7) days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, to align with other 
pembrolizumab protocols. 
Other changes and administrative corrections were made throughout the protocol.  Refer 
to the subsequent sections of this document for description of the changes incorporated 
in protocol amendment 1. 
AMGEN® 

SAP_001.pdf: 
Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 1 
STATISTICAL ANALYSIS PLAN 
A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination With 
Pembrolizumab (MK-3475) for Treatment of Unresectable Stage IIIB to IVM1c 
Melanoma (MASTERKEY-265) 
Protocol Number: 
20110265 
Version: 
Version 4.0 
Date: 
16 January 2020 
Authors: 
 
 
 
 
NCT Number: NCT02263508
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov
--
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 2 
 
Table of Contents 
1. 
Introduction ............................................................................................................. 8 
2. 
Objectives ............................................................................................................... 8 
2.1 
Primary ....................................................................................................... 8 
2.2 
Secondary ................................................................................................... 9 
2.3 
Exploratory ................................................................................................ 10 
3. 
Study Overview .................................................................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.1.1 
Phase 1b ................................................................................... 10 
3.1.2 
Phase 3 ..................................................................................... 11 
3.1.3 
Second Course (Retreatment) ................................................... 12 
3.1.4 
Follow-up ................................................................................... 12 
3.1.4.1 
Safety Follow-up ..................................................... 12 
3.1.4.2 
Long-term Follow-up ............................................... 12 
3.2 
Sample Size .............................................................................................. 12 
3.2.1 
Sample Size Considerations for Phase 1b ................................. 12 
3.2.2 
Sample Size Considerations for Phase 3 ................................... 13 
4. 
Study Endpoints and Covariates ........................................................................... 13 
4.1 
Study Endpoints ........................................................................................ 13 
4.1.1 
Primary Endpoint(s) ................................................................... 13 
4.1.1.1 
Phase 1b ................................................................. 13 
4.1.1.2 
Phase 3 ................................................................... 13 
4.1.2 
Secondary Endpoints ................................................................ 13 
4.1.3 
Exploratory Endpoints ............................................................... 14 
4.2 
Planned Covariates ................................................................................... 14 
5. 
Hypotheses and/or Estimations ............................................................................ 15 
6. 
Definitions ............................................................................................................. 15 
7. 
Analysis Subsets .................................................................................................. 27 
7.1 
DLT Analysis Set ....................................................................................... 27 
7.2 
Full Analysis Set (FAS) ............................................................................. 27 
7.3 
Safety Analysis Set ................................................................................... 27 
7.4 
PD-L1 Negative Analysis Set .................................................................... 28 
7.5 
PD-L1 Positive Analysis Set ...................................................................... 28 
7.6 
qPCR Suspicious Lesion Swab Analysis Set ............................................. 28 
7.7 
Per Protocol Analysis Set .......................................................................... 28 
7.8 
Retreatment Analysis Set .......................................................................... 29 
7.9 
Subgroup Analyses ................................................................................... 29 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 3 
 
8. 
Interim Analysis and Early Stopping Guidelines .................................................... 31 
8.1 
Interim Analyses........................................................................................ 31 
8.1.1 
DLT Safety Analysis (Phase 1b) ................................................ 31 
8.1.2 
Interim Safety Analysis (Phase 3) .............................................. 31 
8.1.3 
Interim iORR and iDCR Futility Analysis (Phase 3) .................... 32 
8.1.4 
Interim Efficacy and Futility Analysis (Phase 3) ......................... 33 
9. 
Data Screening and Acceptance ........................................................................... 37 
9.1 
General Principles ..................................................................................... 37 
9.2 
Data Handling and Electronic Transfer of Data ......................................... 37 
9.3 
Handling of Missing and Incomplete Data ................................................. 37 
9.4 
Detection of Bias ....................................................................................... 37 
9.5 
Outliers ..................................................................................................... 37 
9.6 
Distributional Characteristics ..................................................................... 38 
9.7 
Validation of Statistical Analyses ............................................................... 38 
10. 
Statistical Methods of Analysis.............................................................................. 38 
10.1 
General Principles ..................................................................................... 38 
10.2 
Subject Accountability ............................................................................... 40 
10.3 
Important Protocol Deviations ................................................................... 40 
10.4 
Demographic and Baseline Characteristics ............................................... 41 
10.5 
Efficacy Analyses ...................................................................................... 41 
10.5.1 
Phase 3 ..................................................................................... 42 
10.5.1.1 
Analyses of Primary Efficacy Endpoint(s) ................ 42 
10.5.1.2 
Analyses of Secondary Efficacy 
Endpoint(s) .............................................................. 43 
10.5.1.3 
Agreement of Blinded Independent Central 
Review (BICR) and Investigator Reported 
Endpoints ................................................................ 44 
10.5.2 
Phase 1b ................................................................................... 44 
10.5.2.1 
Analyses of Primary Endpoint ................................. 44 
10.5.2.2 
Analyses of Secondary Efficacy Endpoint ............... 44 
10.5.3 
Analyses of Exploratory Endpoints ............................................ 44 
10.5.3.1 
PD-L1 Induction ...................................................... 44 
10.5.3.3 
iORR, iBOR, iDRR, iDOR, iPFS (response 
evaluation by investigator using modified 
irRC-RECIST) ......................................................... 45 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 4 
 
10.5.4 
Sensitivity Analyses ................................................................... 45 
10.5.4.1 
PFS and iPFS Sensitivity Analyses ......................... 46 
10.5.4.2 
OS Sensitivity Analyses .......................................... 47 
10.5.5 
Additional Summaries ................................................................ 48 
10.6 
Safety Analyses ........................................................................................ 48 
10.6.1 
Adverse Events ......................................................................... 48 
10.6.2 
Laboratory Test Results ............................................................ 49 
10.6.3 
Vital Signs ................................................................................. 49 
10.6.4 
Electrocardiogram (ECG) .......................................................... 49 
10.6.5 
Antibody Formation ................................................................... 50 
10.6.6 
Exposure to Investigational Product .......................................... 50 
10.6.7 
Exposure to Concomitant Medication ........................................ 50 
10.6.8 
ECOG Performance Status ....................................................... 50 
10.7 
Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Analysis .................................................................................................... 50 
10.8 
Analyses for Retreatment Phase ............................................................... 50 
10.9 
Incidence of Detection of Talimogene Laherparepvec DNA in 
Lesions Suspected to be Herpetic in Origin ............................................... 51 
11. 
Changes From Protocol-specified Analyses.......................................................... 51 
12. 
Literature Citations / References ........................................................................... 52 
13. 
Data not Covered by This Plan ............................................................................. 53 
14. 
Appendices ........................................................................................................... 54 
List of Tables 
Table 1.  Matrix of Determining BOR per Modified irRC ................................................. 17 
Table 2.  Matrix of Determining iBOR per Modified irRC-RECIST .................................. 19 
Table 3.  Study Analyses and Possible Hypothesis Tests .............................................. 35 
Table 4.  Analysis Timing, Nominal Significance Levels, and Boundary 
Properties ............................................................................................... 36 
Table 5.  Example 2-sided Nominal Significance Levels at the OS Interim 
Analysis 1 or PFS PA (ie, 407 PFS) With Partial or Full 
Information for All Remaining Hypotheses .............................................. 66 
Table 6.  Example of Nominal P-values and Significance Levels at PFS PA.................. 70 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 5 
 
List of Figures 
Figure 1.  Initial Graph of Maurer-Bretz Multiple Testing Procedure ............................... 43 
Figure 2.  Maurer-Bretz Sequential Rejection Testing Procedure: The First 
Tier Endpoints (OS and PFS) ................................................................. 59 
Figure 3.  Maurer-Bretz Sequential Rejection Testing Procedure: The Second 
Tier Endpoints (iPFS and iCRR) ............................................................. 60 
Figure 4.  Maurer-Bretz Sequential Rejection Testing Procedure: The Third 
Tier Endpoint (OS subgroup) .................................................................. 63 
Figure 5.  Maurer-Bretz Sequential Rejection Testing Procedure: Potential 
Re-testing of the Hypothesis Given Alpha Is Subsequently 
Propagated to It From the Rejection of Another Hypothesis.................... 65 
 
List of Appendices 
Appendix B.  Nominal Significance Levels for Maurer-Bretz Multiple Testing ................ 57 
Appendix C.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ...................................................... 71 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 6 
 
Table of Abbreviations 
Abbreviation/Acronym 
Definition 
AE 
adverse event 
BICR 
blinded independent central review 
BRAFV600 
serine/threonine protein kinase B-Raf V600 
BOR 
best overall response 
BQL 
below quantification limit 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CT 
computerized tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DILI 
drug induced liver injury 
DLRT 
dose level review team 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee 
DMP 
data management plan 
DOR 
duration of response 
DpR 
depth of response 
DRT 
data review team 
DRR 
durable response rate 
DTP 
data transfer plan 
eCRF 
electronic case report form 
ECI 
events of clinical interest 
EOI 
event of interest (Amgen) 
EQ5D 
EuroQoL-5D 
HLA 
human leukocyte antigen 
HR 
hazard ratio 
HSU 
health state utility 
HSV, HSV-1 
herpes simplex virus, herpes simplex virus type 1 
IA 
interim analysis 
iBOR 
best overall response (by modified irRC-RECIST) 
iCR 
complete response (by modified irRC-RECIST) 
iCRR 
complete response rate (by modified irRC-RECIST) 
iDCR 
disease control rate (by modified irRC-RECIST) 
iDOR 
duration of response (by modified irRC-RECIST) 
iDRR 
durable response rate (by modified irRC-RECIST) 
iORR 
objective response rate (by modified irRC-RECIST) 
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Abbreviation/Acronym 
Definition 
IP 
investigational product 
iPD 
progressive disease (by modified irRC-RECIST) 
IPD 
Important protocol deviation 
iPFS 
progression-free survival (by modified irRC-RECIST) 
iPR 
partial response (by modified irRC-RECIST) 
irRC 
Immune-related Response Criteria 
irRC-RECIST 
Immune-related Response Criteria (irRC) simulating Response 
Evaluation Criteria in Solid Tumors (RECIST) 
iSD 
stable disease (by modified irRC-RECIST) 
iUE 
unevaluable (by modified irRC-RECIST) 
IVRS 
Interactive Voice Response System 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
ND 
not done 
NN 
non-CR/non-PD 
OR 
objective response (CR or PR) 
ORR 
objective response rate 
OS 
overall survival 
PA 
primary analysis 
PD 
progressive disease 
PFS 
progression free survival 
PFU 
plaque-forming unit 
PRO 
patient reported outcome 
PT 
preferred term 
qPCR 
real-time polymerase chain reaction 
RECIST 
response Evaluation Criteria in Solid Tumor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SMQ 
standardized MedDRA Queries 
SOC 
system organ class 
SOP 
standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
QLQ-C30 
Quality of Life Questionnaire Core 30 
UE 
unevaluable for tumor evaluation 
WHODRUG 
World Health Organization Drug Dictionary 
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Product:  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 Talimogene Laherparepvec 
Study 20110265 (Amendment 5 dated 15 January 2020).  The scope of this plan 
includes the interim, primary and the final analyses that are planned and will be 
executed by the Biostatistics department unless otherwise specified. 
The clinical study report (CSR) will be written based on the results of the primary 
analysis of Overall Survival (OS) for phase 3.  Analysis of changes in PD-L1 expression 
by immunohistochemistry (eg, negative to positive) introduced by talimogene 
laherparepvec (for phase 1b) will also be included.  A separate final analysis CSR will be 
drafted with the updated results from the final analysis at the completion of the study.  
Analysis of patient reported outcomes (PRO) endpoints will be described separately in a 
supplemental SAP (SSAP).  
 
  
Data collected and analyzed in Amgen-owned databases and systems will adhere to 
approved Data Element Standards and International Case Report Form (CRF) 
Standards established by Biomedical Data Stewardship Governance (BDSG). 
2. 
Objectives 
2.1 
Primary 
The primary objectives are: 
Phase 1b: To evaluate the safety, as assessed by incidence of dose limiting toxicity 
(DLT), of talimogene laherparepvec in combination with pembrolizumab in subjects with 
previously untreated, unresectable, stage IIIB to IVM1c melanoma.  
Phase 3: To evaluate the efficacy of talimogene laherparepvec with pembrolizumab 
versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) 
(response evaluation by blinded independent central review (BICR) using modified 
Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival (OS).  
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Product:  Talimogene Laherparepvec 
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Date:  16 January 2020 
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2.2 
Secondary 
The secondary objectives are: 
Phase 1b: 
• 
To evaluate the efficacy of talimogene laherparepvec in combination with 
pembrolizumab as assessed by: 
− 
Confirmed objective response rate (ORR), best overall response (BOR), durable 
response rate (DRR), duration of response (DOR), disease control rate (DCR), 
and PFS (response evaluation by investigator using modified immune-related 
Response Criteria [irRC]) 
− 
OS 
• 
To evaluate the safety of talimogene laherparepvec in combination with 
pembrolizumab as assessed by incidence of treatment-emergent and 
treatment-related adverse events (AEs), and abnormal laboratory tests. 
Phase 3: 
• 
To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus 
placebo with pembrolizumab, as assessed by: 
− 
Complete response rate (iCRR) by blinded independent central assessed 
modified immune-related response criteria simulating response evaluation criteria 
in solid tumors (modified irRC-RECIST) 
− 
iPFS by blinded independent central assessed modified irRC-RECIST 
− 
OS in subjects excluding stage IVM1c per case report form (CRF) 
− 
ORR, BOR, DRR, DOR, and DCR (response evaluation by blinded independent 
central review assessed using modified RECIST 1.1), and iORR, iBOR, iDRR, 
iDOR, and iDCR (response evaluation by blinded independent central review 
assessed using modified irRC-RECIST) 
• 
To evaluate the safety of talimogene laherparepvec with pembrolizumab versus 
placebo with pembrolizumab, as assessed by incidence of treatment-emergent and 
treatment-related adverse events, and abnormal laboratory tests. 
• 
To evaluate patient reported outcomes (PRO) in phase 3 as assessed by the 
European Organization for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life 
(GHS/QoL) subscale. 
AMGEN® 


Product:  Talimogene Laherparepvec 
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Date:  16 January 2020 
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2.3 
Exploratory 
The exploratory objectives are: 
Phase 1b: 
• 
To evaluate whether talimogene laherparepvec induces changes in PD-L1 
expression by immunohistochemistry (eg, negative to positive) in injected and 
non-injected lesions after starting talimogene laherparepvec in subjects whose 
tumors are PD-L1-negative prior to receiving talimogene laherparepvec in phase 1b. 
Phase 3: 
• 
iORR, iBOR, iDRR, iDOR, iDCR and iPFS (response evaluation by  
investigator-assessed modified irRC-RECIST) 
• 
To evaluate the incidence of anti-pembrolizumab antibodies when pembrolizumab is 
administered in combination with talimogene laherparepvec or placebo. 
• 
To evaluate the pharmacokinetics (PK) of pembrolizumab when administered in 
combination with talimogene laherparepvec or placebo. 
• 
To evaluate PROs as assessed by the EORTC QLQ-C30 subscales. 
• 
To estimate health state utility (HSU) values using the EuroQoL-5D-3 Level 
(EQ-5D-3L). 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1b/3, multicenter, clinical trial. The study will be conducted in 2 parts 
(phase 1b and phase 3) as described below.   
3.1.1 
Phase 1b  
Phase 1b is an open-label, multicenter, single-arm study to evaluate the safety of 
talimogene laherparepvec in combination with pembrolizumab.  Two doses (5 weeks) of 
talimogene laherparepvec will be administered first prior to addition of pembrolizumab to 
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Product:  Talimogene Laherparepvec 
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Date:  16 January 2020 
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approximately 20 subjects with previously untreated, unresectable, stage IIIB to IVM1c 
melanoma until disappearance of injectable lesions, CR, confirmed PD per modified 
immune-related Response Criteria (irRC; Wolchok et al, 2009; protocol Appendix D), 
intolerance of study treatment, 24 months from the date of the first dose of 
pembrolizumab, or end of study, whichever occurs first. In addition, phase 1b will 
evaluate potential blood and 
 that associate with response or 
resistance to talimogene laherparepvec in combination with pembrolizumab. 
The DLRT was to initially meet when 6 subjects are evaluable for DLT. The DLRT was to 
declare the combination of talimogene laherparepvec and pembrolizumab tolerable if the 
incidence of DLT is < 33% during the DLT evaluation period. Refer to protocol  
section 3.1.1.1. for more details. 
3.1.2 
Phase 3 
The phase 3 is a double-blind, placebo-controlled, multicenter randomized trial to 
evaluate the efficacy, as assessed by PFS and OS of talimogene laherparepvec with 
pembrolizumab versus placebo with pembrolizumab in subjects with unresectable, stage 
IIIB to IVM1c melanoma.  
Approximately 660 subjects will be randomized 1:1 to receive the following: 
• 
Arm 1:  talimogene laherparepvec plus pembrolizumab 
• 
Arm 2:  placebo plus pembrolizumab 
Randomization will be stratified by stage of disease: less advanced stages (IIIB, IIIC, 
and IVM1a) versus more advanced stages (IVM1b and IVM1c) and by prior 
serine/threonine protein kinase B-Raf (BRAF) inhibitor therapy: no prior BRAF inhibitor 
versus prior BRAF inhibitor with or without MEK inhibitor. 
Talimogene laherparepvec/placebo and pembrolizumab treatment will be initiated 
simultaneously. 
Talimogene laherparepvec/placebo will be administered until disappearance of injectable 
lesions, iCR, documented confirmed progressive disease (iPD) per modified 
irRC-RECIST (protocol Appendix F), intolerance of study treatment, 24 months from the 
date of the first dose of talimogene laherparepvec/placebo, or end of study, whichever 
occurs first. 
Pembrolizumab will be administered until confirmed iPD per modified irRC-RECIST 
(protocol Appendix F), intolerance to treatment, 24 months from the date of the first dose 
AMGEN® 


Product:  Talimogene Laherparepvec 
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Date:  16 January 2020 
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of pembrolizumab, or end of study, whichever occurs first. Discontinuation of treatment 
may be considered for subjects who have attained a confirmed iCR and have been 
treated for at least 24 weeks with pembrolizumab and had at least 2 treatments with 
pembrolizumab beyond the date when the initial CR was declared.  
At least seven interim analyses for safety, efficacy and futility are planned to be 
reviewed by a Data Monitoring Committee (DMC). Refer to Section 8 for details on 
interim analyses.   
3.1.3 
Second Course (Retreatment) 
Subjects enrolled in phase 1b who ended talimogene laherparepvec and/or 
pembrolizumab because they reached a CR but then subsequently progressed may be 
eligible for a second course treatment (retreatment) with talimogene laherparepvec 
and/or pembrolizumab are eligible to receive for up to 12 additional months at the 
investigator’s discretion as long as the phase 3 remains open for treatment (ie, all 
subjects enrolled in phase 3 have not yet completed treatment).   
3.1.4 
Follow-up 
3.1.4.1 
Safety Follow-up 
Subjects enrolled in phase 1b and phase 3 will be followed for safety approximately 
30 (+7) days after the last dose of study treatment.  If an end of treatment decision 
occurs > 30 (+7) days after the last treatment date, then the Safety follow-up should be 
performed as soon as possible (eg, within a week of the end of treatment decision). 
Applicable safety follow-up procedures should occur even if the subject has initiated new 
anticancer therapy.  Serious adverse events observed by the investigators or reported 
by the subjects that occur within the earlier time of 90 (+7) days after the cessation of all 
study treatment or 30 (+7) days following cessation of treatment if the subject initiates 
new anticancer therapy will be reported. 
3.1.4.2 
Long-term Follow-up 
Subjects enrolled in phase 1b and phase 3 will be followed for survival and subsequent 
anticancer therapies, and injected investigational product-related adverse events for 
every 12 weeks (± 28 days) for approximately 60 months after the last subject is 
randomized in phase 3. 
3.2 
Sample Size 
3.2.1 
Sample Size Considerations for Phase 1b 
See protocol Section 10.2.1. 
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Product:  Talimogene Laherparepvec 
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Date:  16 January 2020 
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3.2.2 
Sample Size Considerations for Phase 3 
See protocol Section 10.2.2. 
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
4.1.1 
Primary Endpoint(s) 
4.1.1.1 
Phase 1b 
Incidence of DLT (protocol section 3.1.1.2). 
4.1.1.2 
Phase 3 
• 
Progression-free Survival by BICR using modified RECIST 1.1 
• 
Overall Survival (OS) 
4.1.2 
Secondary Endpoints 
Phase 1b: 
• 
Confirmed ORR (response evaluation by investigator using modified irRC). 
• 
BOR, DCR, DRR, DOR and PFS (response evaluation by investigator using modified 
irRC) 
• 
OS. 
• 
Incidence of treatment-emergent and treatment-related adverse events (all AEs, 
grade ≥ 3 AEs, SAEs, fatal AEs, and AEs defined as events of interest), and 
abnormal laboratory tests. 
Phase 3: 
• 
iCRR by BICR using modified irRC-RECIST 
• 
iPFS by BICR using modified irRC-RECIST 
• 
OS in subjects excluding stage IVM1c per CRF 
• 
ORR (CR + PR), BOR, DRR, DOR, and DCR (response evaluation by BICR using 
modified RECIST 1.1) and iORR (iCR + iPR), iBOR, iDRR, iDOR, and iDCR 
response evaluation by BICR using modified irRC-RECIST). 
• 
Incidence of treatment-emergent and treatment-related adverse events (all AEs, 
grade ≥ 3 AEs, SAEs, fatal AEs, and AEs defined as events of interest, and 
abnormal laboratory tests. 
• 
Changes in EORTC QLQ-C30 GHS/QoL subscale. 
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Product:  Talimogene Laherparepvec 
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Date:  16 January 2020 
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4.1.3 
Exploratory Endpoints 
Phase 1b: 
• 
Changes in PD-L1 expression by immunohistochemistry (eg, negative to positive) in 
injected and non-injected lesions after starting talimogene laherparepvec in subjects 
whose tumors are PD-L1-negative prior to receiving talimogene laherparepvec in 
phase 1b. 
Phase 3: 
• 
iORR, iBOR, iDRR, iDOR, iDCR and iPFS (response evaluation by investigator using 
modified irRC-RECIST) 
• 
Changes in the EORTC QLQ-C30 subscales. 
• 
Changes in HSU estimates derived via EQ-5D-3L. 
• 
Incidence of anti-pembrolizumab antibodies 
• 
Descriptive statistics of trough and peak levels of pembrolizumab (MK-3475) 
4.2 
Planned Covariates 
The following baseline covariates, including the stratification factors (phase 3) will be 
used to examine efficacy individually:  
• 
Region, if applicable (USA or non-USA) 
• 
Age: < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 
• 
Individual disease stage: IIIB vs IIIC vs IVM1a vs IVM1b vs IVM1c 
• 
Grouped disease stage:  IIIB/C-IVM1a vs IVM1b/c (CRF) 
• 
Grouped disease stage:  IIIB/C-IVM1a vs IVM1b/c (IVRS) 
• 
Grouped disease stage:  IIIB/C-IVM1b vs IVM1c 
• 
LDH: ≤ ULN vs > ULN  
• 
Sex (female vs male) 
• 
ECOG performance status (0 vs 1) 
• 
Herpes simplex virus type 1 (HSV-1) serostatus (positive vs negative) 
• 
The sum of longest, or shortest for nodal, diameters of baseline target lesions (SLD) 
determined by BICR (will be dichotomized based on median) 
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• 
Baseline PD-L1 status (positive vs not positive) 
• 
Prior BRAF inhibitor (none vs BRAF inhibitor alone vs BRAF and MEK inhibitors in 
combination): if subjects included in each of the 2 BRAF related categories represent 
≥ 10% of the study population 
• 
Prior BRAF inhibitor (yes versus no BRAF inhibitor with or without MEK inhibitors) 
(IVRS) 
• 
Baseline BRAFV600 mutation (yes vs no vs missing/unknown) 
5. 
Hypotheses and/or Estimations 
Phase 1b: 
Talimogene laherparepvec in combination with pembrolizumab will be safe and well 
tolerated in subjects with previously untreated, unresectable, stages IIIB to IVM1c 
melanoma. 
Phase 3: 
Two clinical hypotheses will be evaluated independently in the phase 3. The first clinical 
hypothesis is that talimogene laherparepvec with pembrolizumab compared to placebo 
with pembrolizumab will improve PFS as evaluated by BICR using modified RECIST 1.1. 
The second clinical hypothesis is that talimogene laherparepvec with pembrolizumab 
compared to placebo with pembrolizumab will improve OS.   
6. 
Definitions 
Definitions described in this section apply to data points derived by the study team 
including investigator-determined endpoints, unless stated otherwise.  The BICR Charter 
details the specifications for the data points provided by BICR.  
Actual Follow-Up Time 
Actual follow-up time for a subject is calculated from the randomization date (Phase 3) or 
first dose date (Phase 1b) to the last on-study date (ie death date, or date last known to 
be alive for subjects still alive). 
Baseline 
Baseline in general refers to study day 1. The baseline value of a parameter (eg, vital 
signs, laboratory tests, and tumor measurement) is considered to be the latest value 
prior to receiving any study drug (ie, on or prior to the first date of dosing) in the 
respective phase of the study. If the measurement is done on the same day as the first 
dose of any study drug and the exact measurement time relative to the first dose of any 
study drug is unknown, it will be assumed that the measurement is done before the 
administration of the first dose of any study drug.  If a subject does not receive any study 
drug, baseline is the closest recorded measurement on or before the 
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enrollment/randomization date.  BRAF mutational status, which is not sensitive to 
treatment, will be considered baseline regardless of the timing of ascertainment.  For 
phase 1b, talimogene laherparepvec starts 5 weeks before pembrolizumab, therefore 
Week -5 is used as baseline.  
 
   
Best overall response (BOR) per modified irRC (Phase 1b) 
BOR of complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD) or unevaluable (UE) will be derived based on investigator 
assessment per modified irRC.  Overall visit response assessments occurring on or 
after the start of the first subsequent anticancer therapy, including complete or partial 
removal/reduction of any index lesion which contained melanoma on pathology 
evaluation or pathology results were unknown, will not be included. The timepoint 
responses after initial confirmation of PD will not be used to derive BOR. 
Confirmation of CR, PR, and PD is required as noted in the individual definitions for CR, 
PR and PD per modified irRC (refer to protocol Appendix D). For the derivation of BOR, 
the overall visit response will be considered SD if it is an unconfirmed CR or PR, and UE 
if it is either SD earlier than 84 days after the date of enrollment or an unconfirmed PD 
when confirmation of PD is required (ie, initial PD without clinical instability). As indicated 
in Table 1, BOR is defined as the best overall visit response in the following order:  CR, 
PR, SD, PD, or UE. 
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Table 1.  Matrix of Determining BOR per Modified irRC 
Visit Overall 
Response 
Sequence 
Examples 
Best 
Overall 
Response 
Specifications 
*, CR, CR,* 
PR, CR, CR 
CR, CR, PD 
CR 
A confirmatory CR must be at least 4 weeks 
(28 days) later; a subsequent CR within 
28 days will not be valid for confirmation 
and will be ignored; the CR will also not be 
confirmed if there is a subsequent 
PR/SD/PD at any time prior to the next CR. 
*, PR, PR, * 
 
*, PR, CR/PR, 
non-CR, * 
 
PR, PR, PD 
PR, CR, PD 
 
CR, PR, PD 
PR 
Criteria for BOR=CR not met. 
A 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 ≥ 84 days from date of 
enrollment; however, this is not required for 
an unconfirmed CR/PR. 
*,PD, PD, * 
 
*, PDci, * 
 
PD, PD 
PD, SD, PD, PD 
PD, UE, PD 
PDci 
PD 
Criteria for BOR= CR, PR, or SD not met. 
A consecutive confirmatory PD  must be no 
less than 4 weeks (28 days) later unless 
the initial progression qualified for PDci.; 
PDci = the last available PD with 
“Nonconfirmed Disease Progression with 
Clinical Instability” as the reason for ending 
radiographic follow-up. 
*, SD, * 
 
PD 
SD 
UE, SD 
PD 
UE, PD 
UE 
Criteria for BOR=CR, PR, SD, or PD not 
met. 
SD must be < 84 days from date of 
enrollment. 
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Product:  Talimogene Laherparepvec 
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Date:  16 January 2020 
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Best overall response (iBOR) per modified irRC-RECIST (Phase 3) 
iBOR of complete response (iCR), partial response (iPR), stable disease (iSD), 
progressive disease (iPD) or unevaluable (iUE) will be derived per modified  
irRC-RECIST based on investigator assessment and BICR assessment, respectively.  
Overall visit response assessments occurring on or after the start of the first subsequent 
anticancer therapy, including complete or partial removal/reduction of any target lesion 
which contained melanoma on pathology evaluation or pathology results were unknown, 
will not be included. The timepoint responses after initial confirmed iPD will not be 
used to derive BOR. Confirmation of iCR, iPR, and iPD is required as noted in the 
individual definitions for iCR, iPR and iPD per modified irRC-RECIST (refer to protocol 
Appendix F). For the derivation of iBOR, the overall visit response will be considered iSD 
if it is an unconfirmed iCR or iPR, and iUE if it is either iSD earlier than 84 days after the 
date of randomization or an unconfirmed iPD when confirmation of iPD is required (ie, 
initial iPD without clinical instability). As indicated in Table 2, iBOR is defined as the best 
overall visit response in the following order:  iCR, iPR, iSD, iPD, or iUE. 
 
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Table 2.  Matrix of Determining iBOR per Modified irRC-RECIST 
Visit Overall 
Response 
Sequence 
Examples 
Best 
Overall 
Response 
Specifications 
*, iCR, iCR,* 
iPR, iCR, iCR 
iCR, iCR, iPD 
iCR 
A confirmatory iCR must be at least  
4 weeks (28 days) later; a subsequent iCR 
within 28 days will not be valid for 
confirmation and will be ignored; the iCR 
will also not be confirmed if there is a 
subsequent iPR/iSD/iPD at any time prior to 
the next iCR. 
*, iPR, iPR, * 
 
*, iPR, iCR/iPR, non-
iCR, * 
 
iPR, iPR, iPD 
iPR, iCR, iPD 
iCR, iPR, iPD 
iPR 
Criteria for iBOR=iCR not met. 
A confirmatory iPR/iCR   must be no less 
than 4 weeks (28 days) later; a subsequent 
iPR/iCR within 28 days will not be valid for 
confirmation and will be ignored; the iPR 
will also not be confirmed if there is a 
subsequent iSD/iPD at any time prior to the 
next iPR/iCR. 
*, iSD, * 
 
*,iCR, non-iPR/iCR, 
* 
 
*,iPR, non-iPR/iCR, 
* 
iCR 
iPD, iCR 
iPR 
iPD, iPR, iSD 
iSD 
iPD,iSD,iPD 
iSD 
Criteria for iBOR=iCR or iPR not met. 
iSD must be ≥ 84 days from date of 
randomization; however, this is not required 
for an unconfirmed iCR/iPR. 
*,iPD, iPD, * 
 
*, iPDci, * 
 
iPD, iPD 
iPD, iSD, iPD, 
iPD 
iPD, iUE, iPD 
iPDci 
iPD 
Criteria for iBOR= iCR, iPR, or iSD not met. 
A consecutive confirmatory iPD  must be no 
less than 4 weeks (28 days) later unless 
the initial progression qualified for iPDci.; 
iPDci = the last available iPD with 
“Nonconfirmed Disease Progression with 
Clinical Instability” as the reason for ending 
radiographic follow-up. 
*, iSD, * 
 
iPD 
iSD 
iUE, iSD 
iPD 
iUE, iPD 
iUE 
Criteria for iBOR=iCR, iPR, iSD, or iPD not 
met. 
iSD must be < 84 days from date of 
randomization. 
 
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Best overall response (BOR) per modified RECIST 1.1 (Phase 3) 
BORs will be derived based on modified RECIST 1.1 (Eisenhauer et al. 2009) 
utilizing response evaluations obtained from BICR. Per RECIST 1.1,  a 
confirmation of CR or PR by a consecutive subsequent tumor assessment will not 
be required for the derivation of BOR. Overall visit response assessments 
occurring on or after the start of the first subsequent anticancer therapy, 
including complete or partial removal/reduction of any target lesion which 
contained melanoma on pathology evaluation or pathology results were unknown, 
will not be included. The timepoint responses after initial PD will not be used to 
derive BOR. A timepoint response report of Non-CR/Non-PD (NN), a valid 
timepoint response for a subject who has been identified by BICR to have only 
non-target disease per RECIST 1.1, will be reported as is for analysis purposes.  
For the derivation of BOR, the overall visit response will be considered UE if it is 
SD earlier than 84 days after the date of randomization.  BOR is defined as the 
best overall visit response up to and including the first overall visit response of 
PD in the following order:  CR, PR, SD, NN, PD or UE. 
Complete response rate (iCRR) per modified irRC-RECIST (Phase 3) 
Complete response rate (iCRR) per modified irRC-RECIST is defined as the incidence of 
an iBOR of iCR per modified irRC-RECIST in the respective analysis set.  
Disease control rate (DCR) per modified irRC (Phase 1b) 
Disease control rate (DCR) per modified irRC is defined as the incidence of a BOR of 
CR, PR or SD in the respective analysis set.  
Disease control rate (iDCR) per modified irRC-RECIST (Phase 3) 
Disease control rate (iDCR) per modified irRC-RECIST is defined as the incidence of an 
iBOR of iCR, iPR or iSD in the respective analysis set.  
Disease control rate (DCR) per modified RECIST 1.1 (Phase 3) 
Disease control rate (DCR) per modified RECIST 1.1 is defined as the incidence of a 
BOR of CR, PR or SD in the respective analysis set. 
Duration of response (DOR) per modified irRC (Phase 1b) 
Duration of response (DOR) is defined as the time from the date of an initial response 
that is subsequently confirmed to the earlier of PD (see definition of BOR per modified 
irRC) or death.  Subjects who have not ended their response at the time of analysis will 
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be censored at their last evaluable tumor assessment before start of the first subsequent 
anticancer therapy.  
Duration of response (iDOR) per modified irRC-RECIST (Phase 3) 
Duration of response (iDOR) is defined as the time from the date of an initial response 
that is subsequently confirmed to the earlier of iPD (see definition of BOR per modified 
irRC-RECIST) or death.  Subjects who have not ended their response at the time of 
analysis will be censored at their last evaluable tumor assessment before the start of the 
first subsequent anticancer therapy.  
Duration of response (DOR) per modified RECIST 1.1 
Duration of response (DOR) is defined as the time from the date of an initial response of 
CR or PR to the earlier of PD (see definition of BOR per modified RECIST 1.1) or death.  
Subjects who have not ended their response at the time of analysis will be censored at 
their last evaluable tumor assessment date before start of the first subsequent 
anticancer therapy. 
Durable response rate (DRR) per modified irRC (Phase 1b) 
DRR is defined as the percent of subjects with a CR or PR per modified irRC with a 
DOR ≥ 6 months. One month will be calculated based on 365.25 days per year. 
Durable response rate (iDRR) per modified irRC-RECIST (Phase 3) 
iDRR is defined as the percent of subjects with an iCR or iPR per modified irRC-RECIST 
with a DOR ≥ 6 months. One month will be calculated based on 365.25 days per year. 
Durable response rate (DRR) per modified RECIST 1.1 (Phase 3) 
DRR is defined as the percent of subjects with a CR or PR per modified RECIST 1.1 
with a DOR ≥ 6 months. One month will be calculated based on 365.25 days per year. 
Measurable Tumor Burden  
Measurable 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.  The measurable tumor burden 
will be censored at the start of the first subsequent anticancer therapy, or at the 
time of complete or partial removal/reduction of any target lesion which contained 
melanoma on pathology evaluation or pathology results were unknown, 
whichever occurs first. 
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Depth of Response (DpR)  
DpR is defined based on the maximum post-baseline measurable tumor burden 
decrease from baseline measurable tumor burden where maximum post  
baseline-measurable tumor burden decrease is categorized as:  G0 = no shrinkage 
or increase, G1 = >0 ≤25%, G2 = >25-50%, G3 = >50-75%, G4 = >75- < 100%, and  
G5 = 100%.   
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the purposes of final collection of data 
for the primary endpoint(s).. The primary completion date is the date when data for the 
primary endpoints are last collected for the purpose of conducting the primary analysis. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long term follow-up), as 
applicable. 
Evaluable tumor assessment 
An overall visit response other than iUE or UE. 
Event of Interest (EOI) and Events of Clinical Interest (ECI) 
EOIs are defined in version-controlled search strategies maintained by Global 
Regulatory Affairs and Safety (GRAAS) at Amgen for talimogene laherparepvec and 
those for ECIs for pembrolizumab will be provided by Merck before the analysis.   
Investigational product (IP) 
Investigational product (IP) refers to talimogene laherparepvec/placebo (also known as 
“Amgen IP”) and Pembrolizumab (also known as “non-Amgen IP”) in this study.  IP is 
also referred as study drug, or study therapy. 
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Last date known to be alive 
For subjects not known to have died, their last date known to be alive will be determined 
as the latest date associated with clinic visits including, for example, but not limited to 
the following: 
1. Survival status: Last subject status date if status of subject is “Alive”  
2. End of study date if the primary reason for ending study is not “Lost to follow-up” 
or “Death” 
3. Any Subsequent anti‐tumor therapy initialization date 
4. AE start or end date 
5. Procedure and concomitant medication start/end date  
6. Date of tumor assessments 
7. Date of herpetic lesion swabbing 
8. Visit date of vital signs; physical exam; ECOG; local lab and central lab  
9. Date of last investigational product administration 
Objective response rate (ORR) per modified irRC (Phase 1b) 
ORR is defined as the incidence of a BOR of CR or PR per modified irRC in the 
respective analysis set. Subjects who do not have any post-baseline tumor assessments 
will be regarded as non-responders. 
Objective response rate (iORR) per modified irRC-RECIST (Phase 3) 
iORR is defined as the incidence of an iBOR of iCR or iPR per modified irRC-RECIST in 
the respective analysis set. Subjects who do not have any post baseline tumor 
assessments will be regarded as non-responders. 
Objective response rate (ORR) per modified RECIST 1.1 (Phase 3) 
ORR is defined as the incidence of a BOR of CR or PR per modified RECIST 1.1 in the 
respective analysis set.  Subjects who do not have any post-baseline tumor 
assessments will be regarded as non-responders. 
Overall Survival (OS) 
Overall survival is defined as the interval from randomization (phase 3) or first dose 
(phase 1b) to death from any cause. Subjects without an event will be censored at the 
last known to be alive date. 
Progression-free survival (PFS) per modified irRC (Phase 1b) 
PFS per modified irRC is defined as the interval from first dose (phase 1b) to the earlier 
event of PD or death from any cause. Subjects without an event will be censored at their 
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last evaluable tumor assessment if available; otherwise will be censored on Study 
Day 1. 
Progression-free survival (iPFS) per modified irRC-RECIST (Phase 3) 
iPFS per modified irRC-RECIST is defined as the interval from randomization (phase 3) 
to the earlier event of iPD or death from any cause. Subjects without an event will be 
censored at their last evaluable tumor assessment if available; otherwise will be 
censored on randomization date. 
Progression-free survival (PFS) per modified RECIST 1.1 (Phase 3) 
PFS per modified RECIST 1.1 is defined as the interval from randomization to the earlier 
event of PD per modified RECIST 1.1 or death from any cause. Subjects without an 
event will be censored at their last evaluable tumor assessment if available; otherwise 
will be censored on randomization date.  
Safety follow-up visit 
Safety follow-up visit will be performed approximately 30 (+7) days after the last dose of 
IP.  In addition, serious adverse events will be reported that occur through 90 (+7) days 
after the cessation of all study treatment or 30 (+7) days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier. 
Serious adverse events (SAE) 
Serious adverse events (SAE) are defined as any adverse event categorized as serious 
as determined by investigator per protocol defined criteria. 
Study day 
For phase 3, study day is calculated from the first day IP is administered (ie, non-zero 
dosing) to the subject. Study day = visit date – first dose date +1 if visit date is on or after 
the first dose date. Study day = visit date – first dose date, if visit date is before the first 
dose date.   
For phase 1b, study day is calculated from the first day pembrolizumab is administered 
(ie, non-zero dosing) to the subject. Study day = visit date – first pembrolizumab dose 
date +1 if visit date is on or after the first dose date. Study day = visit date – first 
pembrolizumab dose date, if visit date is before the first dose date. 
Study Week 0 
For phase 3, the start of IP administration (ie, non-zero dosing) to the subject is study 
week 0. Study day 1 is corresponding to study week 0. 
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For phase 1b, the start of pembrolizumab  is study week 0.  Study day 1 is 
corresponding to study week 0. 
Study Week -5 
In phase 1b, the start of talimogene laherparepvec is study week -5. 
Treatment period 
Treatment period is defined as the period between the first date of study therapy 
administration and 30 days after the last study therapy administration. 
Treatment-emergent Adverse Events (TEAE) 
Treatment-emergent adverse events are defined as any adverse event occurring after 
initiation of the first dose of study therapy through 30 days after the last administration of 
study therapy.  Adverse events that occur on the same day as the first dose date of 
study therapy 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 indicating prior to the first dose of study therapy is checked 
on eCRF, then the event will not be counted as a treatment-emergent AE).   
Treatment-emergent serious adverse events (TESAE) 
Treatment-emergent serious adverse events are defined as any serious adverse event 
occurring after initiation of the first dose of study therapy through 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 treatment-emergent serious adverse event). 
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7. 
Analysis Subsets 
7.1 
DLT Analysis Set 
The DLT analysis set will include DLT-evaluable subjects enrolled in phase 1b who  
have had the opportunity to be on treatment for at least 6 weeks from the initial dosing of 
pembrolizumab and received at least 2 doses of talimogene laherparepvec and 2 doses 
of pembrolizumab in combination (ie, on the same day) or those who otherwise 
experience a DLT within 6 weeks after starting the combination therapy. 
7.2 
Full Analysis Set (FAS) 
The primary analysis of all efficacy endpoints for phase 3 part of the study, unless noted 
otherwise, will be conducted on the full analysis set defined as all randomized subjects.  
All subjects will be analyzed according to treatment to which they are randomized. 
7.3 
Safety Analysis Set 
The safety analysis set will include all subjects who received at least 1 dose of 
talimogene laherparepvec (or placebo in phase 3) or pembrolizumab. The safety 
analysis set will be defined separately for the phase 1b and phase 3. All subjects will be 
analyzed according to the treatment they received. Subjects will be classified in the 
talimogene laherparepvec and pembrolizumab arm for safety analyses if they received 
at least one dose of talimogene laherparepvec at any time during the treatment period. 
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7.4 
PD-L1 Negative Analysis Set 
The PD-L1 negative analysis set will include all subjects that are PD-L1 negative prior to 
randomization (phase 3) /first IP dose (phase 1b). 
7.5 
PD-L1 Positive Analysis Set 
The PD-L1 positive analysis set will include all subjects that are PD-L1 positive prior to 
randomization (phase 3) /first IP dose (phase 1b). 
7.6 
qPCR Suspicious Lesion Swab Analysis Set 
The qPCR Suspicious Lesion Swab Analysis Set will include subjects who are enrolled 
(phase 1b) or in the FAS (phase 3), receive at least one dose of talimogene 
laherparepvec / placebo, and have at least one swab sample evaluable result from 
lesions suspicious to be herpetic in origin during the study. Evaluable samples are 
sample with either positive, below quantification limit (BQL), or not detected results. 
7.7 
Per Protocol Analysis Set 
The Per Protocol Analysis Set is a subset of the Full Analysis Set (phase 3) which 
includes subjects who do not have important protocol deviations (IPDs) that are 
considered to have an impact on efficacy outcomes.  
Subjects with any of the following eligibility criteria IPDs will be removed from the Per-
Protocol Analysis Set: 
• 
Subject does not have histologically confirmed diagnosis of melanoma  
• 
Subject does not have unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c 
melanoma 
• 
Subject is not a candidate for intralesional therapy 
Additionally, subjects assigned to the talimogene laherparepvec arm, but who did not 
receive the first two consecutive doses of talimogene laherparepvec, will be excluded 
from the Per Protocol Analysis Set 
For purposes of the Per-Protocol sensitivity analyses, subjects who (a) received the 
investigational product not matching the subject’s randomized treatment group, or (b) 
have been identified to have an IPD under the category of prohibited concomitant 
medications during treatment, all event data collected after the first occurrence of the 
violation will be excluded from the analysis, and the endpoints analyzed as time-to-event 
will be censored at the time of the first violation for subjects who have not had an event 
prior to the violation date. 
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7.8 
Retreatment Analysis Set 
The retreatment analysis set will include subjects receiving second-course of treatment 
in retreatment phase. The option of retreatment is available only for subjects in phase 1b 
as documented in country-specific protocols.  
7.9 
Subgroup Analyses 
Efficacy analyses specified for the Full Analysis Set for phase 3 will be repeated within 
the following subgroups:  
• 
PD-L1 status (positive, not positive) at baseline 
• 
Disease stage (less advanced [stage IIIB/C-IVM1a], more advanced [stage IVM1b/c]) 
at baseline (IVRS) 
• 
Prior treatment with BRAF inhibitor (IVRS) 
• 
Region, if applicable (USA or non-USA) 
• 
Age: < 65, ≥ 65; < 75, ≥ 75 years 
• 
LDH: ≤ ULN vs > ULN  
• 
Sex (female vs male) 
• 
ECOG performance status (0 vs 1) 
• 
HSV-1 serostatus (positive vs negative vs missing/unknown) 
• 
The sum of longest, or shortest for nodal, diameters of baseline target lesions (SLD) 
determined by BICR (≤ median of SLD vs > median of SLD) 
• 
Baseline BRAFV600 mutation (yes vs no vs missing/unknown) 
The sum of longest, or shortest for nodal, diameters of baseline target lesions (SLD) will 
be dichotomized into two groups based on the median calculated at the time of analysis. 
These subgroups will be re-examined for appropriateness and may be re-categorized or 
omitted (due to small sample size, for example, if there are < 10% of subjects within a 
subgroup) before unblinding.  The analyses of these subgroups will be exploratory in 
nature.   
The treatment effects in subgroups will be estimated using stratified odds ratio for binary 
endpoints; and stratified HR for time to event endpoints. Stratification factors in the 
analysis model will include the randomization stratification factors as well as PD-L1 
status at baseline (positive vs not positive).  In the case of a subgroup analysis of one of 
the stratification factors, only the other two stratification factors will be included in the 
models. To evaluate the efficacy of talimogene laherparepvec in combination with 
pembrolizumab in subgroups defined by the stratification factors and key covariates, the 
treatment effect will be investigated using the Gail and Simon quantitative and qualitative 
interaction tests (1985).  Post hoc power for a nominal 2-sided 5% significance level test 
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may be calculated to help aid in the assessment (see code fragment in Appendix C). 
The adjusted hazard ratio of the treatment effect with the corresponding 95% confidence 
interval and p-value adjusting for each of the subgroup variables listed above, using the 
stratified Cox proportional hazards (PH) model, as well as adjusting for all subgroup 
variables simultaneously in a multiple regression analysis, will be presented. 
Subgroup analysis of exposure by age (< 65 vs ≥ 65, < 75 vs ≥ 75 years), gender and 
race (white vs non-white) will be presented.  Subgroup analysis of adverse events by 
age, gender, and race will also be presented. 
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8. 
Interim Analysis and Early Stopping Guidelines 
8.1 
Interim Analyses 
A DLT interim safety analysis was planned and conducted for phase 1b. Data were 
reviewed by a DLRT.  
All analyses prior to the primary OS analysis will be conducted by an external 
independent biostatistics group (IBG) and reviewed by the DMC per the DMC charter. 
The analyses will include safety monitoring, iORR/iDCR futility, primary and possibly 
interim PFS, and interim OS (including OS futility) analyses. The study team is 
responsible for conducting the primary analysis of OS and all subsequent analyses. 
8.1.1 
DLT Safety Analysis (Phase 1b) 
An interim safety analysis in phase 1b to evaluate DLT included 6 subjects who were 
eligible for DLT evaluation. A DLRT consisting of the Amgen study team, including at 
least one clinician, safety representative, and biostatistician, at least one representative 
from the Merck study team, and at least one investigator participating in the study who 
recruited subjects into the phase 1b, was to review the safety data to evaluate possible 
DLTs.  This team was to recommend either to enroll more subjects for DLT evaluation in 
the phase 1b, to prematurely stop enrollment into the phase 1b, or to declare that the 
combination is tolerable and open the phase 3.  The DLRT would review additional 
safety data from subjects enrolled in the phase 1b beyond the 6 DLT evaluable subjects 
to further assess the overall safety profile of talimogene laherparepvec in combination 
with pembrolizumab.   
8.1.2 
Interim Safety Analysis (Phase 3) 
An independent Data Monitoring Committee (DMC) will review interim safety analyses to 
evaluate the safety of talimogene laherparepvec in combination with pembrolizumab in 
the target population for the phase 3. The first two safety analyses occurred after 
approximately 20 and 100 total subjects had enrolled in phase 3, respectively, who had 
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the opportunity to be followed for at least 6 weeks after initiating study treatment. 
Additional safety review meetings may occur every 6 months after the interim iORR and 
iDCR futility review meeting (Section 8.1.3) until the primary analysis of OS. Unblinded 
safety tables and listings by treatment arm will be prepared for the DMC by IBG 
according to the DMC charter. All available safety data from the phase 1b part of the 
study was provided to DMC at the time of the first planned interim safety analysis (ie, at 
20 subjects trigger) in phase 3. 
8.1.3 
Interim iORR and iDCR Futility Analysis (Phase 3) 
An interim futility analysis of iORR and iDCR per BICR using modified irRC-RECIST is 
planned when approximately 160 subjects (ie, 80 per arm) have been enrolled and have 
had a chance to be followed for at least 24 weeks (+2 weeks). This interim futility 
analysis will be conducted by the DMC with support from an IBG. The analysis will be 
limited to those subjects who had the potential to be followed for at least 24 weeks 
(+ 2 weeks). All tumor response data will be included up to 26 weeks from the date of 
first dose of study therapy for the 160th enrolled subject (or randomization date if subject 
is not dosed).  
Beta (8.75, 16.25) and Beta (12.5, 12.5) prior distributions are assumed for the true 
placebo plus pembrolizumab arm (arm 2) iORR and iDCR in the trial population with 
means equal to 0.35 and 0.50, respectively, and both with the precision equal to a 
sample size of 25. Beta (10.08, 10.92) and (14.91, 6.09) prior distributions are assumed 
for the iORR and iDCR for the combination of pembrolizumab and talimogene 
laherparepvec (arm 1) with means equal to 0.48 and 0.71, respectively, and both with a 
concentration parameter of 21. The priors for the combination correspond to the results 
from a 24-week minimum follow-up analysis of the 21 subjects in the phase 1b part of 
the study.   
Beta posterior distributions for the iORR and iDCR will be calculated for each arm based 
on the corresponding prior distribution and the observed study iORR and iDCR results. 
The iORR futility criterion will be a posterior probability < 0.65 of at least a 6% absolute 
iORR increase (Arm 1 – Arm 2), and the iDCR futility criterion will be a posterior 
probability < 0.75 of at least a 10% absolute iDCR increase. The DMC will declare the 
combination therapy futile if both the iORR and iDCR futility criteria are met; however, 
the DMC’s recommendation will be non-binding and therefore the sponsor will make the 
final decision to terminate the study prematurely. 
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8.1.4 
Interim Efficacy and Futility Analysis (Phase 3) 
There are 5 planned analysis time points for hypothesis testing, including primary and/or 
interim analyses of the 5 hypotheses (H):  H1, associated with OS; H2, PFS by BICR 
assessed modified RECIST 1.1; H3, iPFS by BICR assessed modified irRC-RECIST; H4, 
iCRR by BICR assessed modified irRC-RECIST; and H5, OS subgroup excluding IVM1c. 
The analysis times are defined by the following event-driven timepoints with the DMC 
responsible for Analyses #1, #2, and #3. 
1. OS interim analysis and PFS primary analysis at 407 PFS events (DMC). 
2. OS interim analysis at 282 events (including a futility analysis) (DMC). 
3. OS interim analysis at 315 events (DMC). 
4. OS primary analysis at 346 events. 
5. OS subgroup primary analysis at earlier of 208 events in subgroup or 5 years 
minimum follow-up. 
Note that there is no sequential order in these 5 analysis times (with the exception that 
Analysis #2 is before Analysis #3 and Analysis #3 is before analysis #4) and the 
analyses may be combined.  Each analysis time may also include interim or primary 
analyses for the other endpoints.  Endpoints to be analyzed, and the type of analysis (ie, 
interim or primary), are presented in Table 3 and are dependent on which hypotheses 
have been rejected.  For example, testing for iCRR and iPFS at an analysis timepoint 
will be conditional upon previously rejecting either H1 or H2.  O'Brien-Fleming group 
sequential boundaries based on the Lan-DeMets approach (O'Brien and Fleming, 1979) 
will be used for testing endpoints with interim analyses. Multiple testing procedures will 
utilize the graphic-based Maurer-Bretz approach (Section 10.5.1.1). 
The information fractions will be based on the observed events included at the time of 
analysis for testing of all time to event endpoint null hypotheses (ie, H1, H2, H3, and H5) 
and it will be based on the number of subjects with potential follow-up time of at least  
36 weeks for testing the iCRR null hypothesis (ie, H4).  The maximum information for 
testing iCRR is all randomized subjects.  Each analysis time will have a corresponding 
database snapshot; however, there will not be a separate snapshot for each endpoint 
tested at the same analysis time. 
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1. The initial alpha allocation for testing the hypothesis of PFS (H2) is 0.5% and 4.5% 
for OS (H1).  There will not be a nominal alpha passed back to H2 after rejecting H1 
or other hypotheses at any analysis. 
2. An interim OS analysis will be performed at Analysis #1 with all observed death 
events, regardless if H2 is rejected.  In the event when Analysis #2 occurs prior to 
Analysis #1, then it will include an interim analysis to test H2 for PFS (using all PFS 
events) and, if H2 is not rejected, it will be tested again at the planned time for 
Analysis #1.  However, if the projected time for achieving 407 PFS events is within 
4 months from the projected 282 OS events time, then Analysis #2 will be 
combined with Analysis #1 and be performed at Analysis #1 using all death events 
with PFS times censored after the 407th PFS event. 
3. At each of the 5 planned analysis times, it will be considered an interim analysis of 
iCRR and iPFS, rather than the primary analysis, if the maximum information has 
not been reached for the respective endpoint at that time.  For example, if H3 is 
tested in an analysis that includes fewer than 256 iPFS events, then it will be an 
interim analysis of iPFS that includes all observed events; otherwise, it will be the 
primary analysis with all iPFS times censored after the date of the 256th event.  If 
all randomized subjects do not have at least 36 weeks follow-up in an analysis, 
then it will be an interim analysis for iCRR only including those subjects with at 
least 36 weeks follow-up; otherwise, it will be the primary analysis and include all 
randomized subjects.  With the exception of PFS, the hypothesis for an endpoint 
may be re-tested after its primary analysis using its primary analysis data if alpha is 
subsequently propagated to it from the rejection of another hypothesis. 
4. Assuming Analysis #1 is before Analysis #2, and at Analysis #1 the null hypothesis 
of PFS (H2) is rejected, the hypotheses H3 and H4 will be tested.  H1 will be tested 
at Analysis #1 regardless of whether H2 is rejected.  The iPFS (H3) and iCRR (H4) 
can be tested if H2 is not rejected but H1 is significant.  Likewise, OS subgroup (H5) 
can be tested at Analysis #1 if any of the following set of hypotheses are rejected:  
(1) H2 and H3; (2) H2 and H4; (3) H1 and H3; or (4) H1 and H4. 
5. If projections indicate 256 iPFS events will occur in the same timeframe as either 
Analysis #1 or Analysis #2, then the option will be considered to extend the data 
cutoff to include all 256 iPFS events.  In this event, Analysis #1 will have PFS times 
censored after the 407th PFS event and Analysis #1 or #2 will include all OS 
events. 
6. The OS hypothesis (H1) will be tested at Analyses #1-4 with all (Analysis #1) or 
required number (Analysis #2, Analysis #3, and Analysis #4) of events in the 
absence of its prior rejection (or futility at Analysis #2). 
7. The OS subgroup hypothesis (H5) will be tested at the first and all subsequent 
analysis times when alpha can be propagated to it from the rejection of H1 or H2 
followed by H3 and/or H4.  All OS events in the subgroup at the end of 5 years 
follow-up will be used if 208 events have not been observed.  If H1 is not rejected 
by Analysis #4, it will be tested again using events at Analysis #4 if alpha can be 
propagated from the rejection of H5 at Analysis #5.   
8. Likewise, H3 and H4 may be re-tested if not rejected by their primary analysis using 
their respective primary analysis data if H1 is subsequently rejected. 
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Table 3 illustrates possible hypothesis tests at the 5 planned analyses. 
Table 3.  Study Analyses and Possible Hypothesis Tests 
 
 
Hypothesis Tested 
(Analysis Type) 
Analysis 
Timing 
H1 
(OS) 
H2 
(PFS) 
H3 
(iPFS) 
H4 
(iCRR) 
H5 
(OS 
subgroup) 
#1 
407 PFS 
events 
 
(IA) 
(PA) 
If reject H1 or 
H2 
(IA if < 256 
events) 
If reject H1 or 
H2 
(IA if includes 
fewer than all 
randomized) 
If reject H2 
and either H3 
or H4, or 
reject H1 and 
either H3 or 
H4 
(IA if < 208 
events) 
#2 
282 OS 
events 
(IA) 
n/a 
(IA if 
Analysis #2 
is 
performed 
first) 
If reject H1 or 
H2 
(PA on first 
256 events) 
If reject H1 or 
H2 
(PA if 
includes all 
randomized) 
If reject H2 
and either H3 
or H4, or 
reject H1 and 
either H3 or 
H4 
(IA if < 208 
events) 
#3 
315 OS 
events 
(IA) 
n/a 
 
If reject H1 
or H2 
(PA on first 
256 events) 
If reject H1 or 
H2 
(PA if 
includes all 
randomized) 
If reject H2 
and either 
H3 or H4, or 
reject H1 
and either 
H3 or H4 
(IA if < 208 
events) 
#4 
346 OS 
events 
(PA) 
n/a 
See Analysis 
#2 & #3 
above 
See Analysis 
#2 & #3 
above 
See Analysis 
#2 & #3 
above 
#5 
Earlier of 
208 OS 
events in 
subgroup or 
5 years 
minimum 
follow-up 
If reject H2 
previously 
and H5  
(PA at first 
346 
events) 
n/a 
See Analysis 
#2 & #3 
above 
See Analysis 
#2 & #3 
above 
See Analysis 
#2 & #3 
above 
(PA) 
iCRR = complete response rate (by modified irRC-RECIST); iPFS = progression free survival (by modified 
irRC-RECIST); H = hypothesis; IA = interim analysis; n/a = not applicable; OS = overall survival;  
PA = primary analysis; PFS = progression free survival 
Futility Analysis for OS 
At the 282 OS events interim analysis (ie, Analysis #2), if hypothesis H1 is not rejected, 
then an OS futility analysis will be evaluated by the DMC.  The interim OS futility 
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analysis will be non-binding and define futility as a conditional power < 10% assuming a 
constant treatment effect (Denne, 2001); the corresponding OS futility boundary is 0.89, 
assuming a constant HR = 0.70. OS futility will also be evaluated by the DMC 
considering a possible non-constant treatment effect that increases over time  
(eg, a 2 interval model with a cutpoint between 4 to 8 months and constant treatment 
effect in each interval, where the second interval has a larger effect than the first one). 
To limit the probability of futility < 0.02, the futility boundary for the observed HR at  
282 OS events analysis will be 0.93. Guidelines for this possible late effect are provided 
in the DMC charter amendment. Operating characteristics of the primary analysis of PFS 
and sequential tests of OS are shown in Table 4 based on the OS events expected at 
Analysis #1. 
Table 4.  Analysis Timing, Nominal Significance Levels, and Boundary Properties  
Analysis 
Data 
cut-off 
(mon) 
Endpoint 
(scenario) 
Event (% 
goal) 
Efficacy 
nominal 
2-sided α 
Futile 
HR b 
Prob. 
Futileb 
Power 
total 
H0 
H1 
PFS PA 
44 
PFS 
407 (100) 
0.0050 
 
 
 
90% 
OS IA1 
44 
OS (PFS-) 
OS (PFS+) 
252 (73)a 
0.0150 
0.0173 
 
 
 
66% 
67% 
OS IA2 
52 
OS (PFS-) 
OS (PFS+) 
282 (82) 
0.0187 
0.0212 
0.89 
0.89 
84% 
83% 
2% 
2% 
76% 
77%  
OS IA3 
61 
OS (PFS-) 
OS (PFS+) 
315 (91) 
0.0261 
0.0292 
 
 
 
84% 
85% 
OS PA 
75 
OS (PFS-) 
OS (PFS+) 
346 (100) 
0.0336 
0.0372 
 
 
 
90% 
90% 
IA = interim analysis; H0 = null hypothesis; H1 = alternative hypothesis; HR = hazard ratio; OS = overall 
survival; PFS = progression free survival; PA = primary analysis. 
O’Brien-Fleming spending α for OS; futility if conditional power < 10%; H0:  HR = 1 and H1:  HR = 0.67 
(PFS) and 0.70 (OS).  Testing OS at an overall 2-sided 0.045 if PFS is not significant at 2-sided 0.005 (eg, 
PFS-); testing OS at 0.05 when all other null hypotheses are rejected (eg, PFS+). 
 
 
 
 
 
a The events for OS IA1 are not pre-determined.  
b The futile HR and probabilities are shown for the conditional power criterion only which assumes a constant 
OS effect. 
 
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9. 
Data Screening and Acceptance 
9.1 
General Principles 
The objective of the data screening is to assess the quantity, quality and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
9.2 
Data Handling and Electronic Transfer of Data  
9.3 
Handling of Missing and Incomplete Data 
Every effort will be made to obtain complete data in the clinical study. Partial or missing 
dates of adverse events and concomitant medications will be imputed.  Adverse events 
with missing IP relatedness, seriousness, or CTCAE severity grades are included in 
TEAE as long as the events qualify for the reporting period.  Events with missing 
relatedness, seriousness, and severity grades will be excluded from treatment-related, 
serious, and with a CTCAE grade of 3 or higher AE analysis, respectively.  
 
 
   
9.4 
Detection of Bias 
Lack of protocol compliance may introduce potential bias in the estimation of protocol 
endpoints. All important protocol deviations (IPDs) will be reported, documented and 
stored in eClinical (a clinical trial management system).  IPD reports will be produced 
 by the study manager and will be regularly reviewed in the study team’s 
IPD review meetings as well as before analysis.  
Protocol compliance will be examined by tabulating subjects with IPDs. Bias will be 
evaluated, in part, by conducting sensitivity analyses using the Per Protocol Analysis Set 
(see Section 7.7).  
9.5 
Outliers 
Descriptive statistics will be used to identify potential outliers in key variables.  
Suspected outliers will be included in all analyses unless there is sufficient scientific 
justification to exclude them.  
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9.6 
Distributional Characteristics 
All binary endpoints will follow a binomial distribution. A beta prior is assumed in the 
Bayesian model for the interim iORR/iDCR futility analysis. The KM estimates for the 
probability of time-to endpoints are based on non-parametric methods. Treatment 
comparisons in time-to endpoints based on the Cox proportional hazards (PH) model are 
semi-parametric.  Assumption of proportionality in hazards will be examined graphically 
with the Schoenfeld residuals plot (see code fragment in Appendix C).  Comparisons 
based on the log-rank test are fully non-parametric.  
Should there be inferential statistics for continuous variables that rely on the normal 
distribution assumption, the assumption will be checked using a normal probability plot.  
If severe departure from normality is observed, a non-parametric method such as the 
Wilcoxon rank sum test will be employed.    
9.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System version 9.4 or later 
and qualified R.   
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
In general, the efficacy and safety analyses will be conducted separately for phase 1b 
and phase 3.  Data collected after the analysis data cutoff date at each analysis time will 
be excluded.   
For phase 1b, descriptive statistics for the confirmed ORR, BOR, DCR, DRR, DOR, 
PFS, and OS will be provided where tumor response evaluations are based on 
investigator assessments using modified irRC. The analysis will include data from phase 
1b subjects in the Safety Analysis Set.  
For phase 3, the efficacy analyses will be conducted on the Full Analysis Set. Treatment 
effects on efficacy endpoints will be evaluated and compared between the 2 treatment 
arms according to the treatment as randomized. Formal treatment comparisons will be 
performed on the dual primary endpoints and the 3 key secondary endpoints. 
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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.  For binary endpoints, proportions and the 
corresponding 95% confidence intervals, and p-values will be based on normal 
approximations and the treatment comparison (ratio of proportions, treatment over 
control) will be based on Cochran-Mantel-Haenszel test (see code fragment in  
Appendix C) stratified by randomization stratification factors and baseline PD-L1 status 
as the primary method.  Additionally, p-values from the stratified Mantel-Haenszel test 
for the common risk difference will also be calculated (see code fragment in  
Appendix C).  Exact confidence intervals (Clopper & Pearson 1934) (see code fragment 
in Appendix C) and Fisher exact tests (see code fragment in Appendix C) for binary 
endpoints will be considered for phase 1b and all subgroup analyses in phase 3. Logistic 
regression will be used to estimate the odds ratio, 95% CI for the odds ratio, and p-value 
(see code fragment in Appendix C). 
 time-to-event endpoints will be 
analyzed as follows.  Time to-event endpoints will be summarized descriptively by 
treatment group using the Kaplan-Meier (K-M) method.  Standard errors of estimated 
treatment differences by time point will be calculated using Greenwood's formula 
(Kalbfleisch and Prentice, 1980).  KM median estimates will be provided for each 
treatment arm along with KM estimates at appropriate times for each endpoint (eg, 
month 3, month 6, month 9, month 12, etc for PFS and 1 year, 2 year, 3 year etc. for 
OS). In addition, the point estimate of the adjusted risk difference (difference in  
Kaplan-Meier estimates at the time point of interest, treatment arm – control arm) and 
the corresponding 95% confidence interval will be provided using the inverse variance-
weighted method (see code fragment in Appendix C).  Stratified log-rank test statistics 
and associated p-values will also be used as the primary analysis method to assess the 
hypothesis of no treatment difference.  Hazard ratios will be estimated using stratified 
Cox proportional hazards (PH) models (see code fragment in Appendix C). 
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For stratified analyses, the stratification factors will include randomization stratification 
factors per IVRS and PD-L1 status at baseline (positive vs not positive). The criteria for 
PD-L1 status is as follows: 
• 
Any available PD-L1 positive result makes the subject a positive (irrespective of 
tissue analyzed and irrespective of the timing). 
• 
If there are more than one PD-L1 result, and none of them are positive, then 
choose the one from a fresh biopsy.  
Listings (eg, baseline characteristics, adverse events and exposure) of subjects in the 
Retreatment Analysis Set will be provided.  
10.2 
Subject Accountability 
The number of subjects enrolled will be tabulated by country and investigator site overall 
and by treatment group (when applicable).  Subject disposition (including the number 
enrolled, treated, ended treatment, ended radiographic follow-up and that completed the 
safety follow-up visit and the study) will be summarized separately for all enrolled 
subjects in phase 1b, and phase 3.  Subject accountability will be tabulated by 
respective treatment group when applicable.  Reasons for not receiving treatment, for 
ending treatment, ending radiographic follow-up and not completing the 30-day safety 
follow-up visit will be provided.  
Key study dates for the first subject enrolled, last subject enrolled, first subject treated in 
each respective portion of the study, and last subject’s end of study will be presented.  
In phase 3, the number and percent of subjects randomized (enrolled) will be tabulated 
by the randomization stratification factors overall and by randomized treatment. 
10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, sub-category codes and 
descriptions will be used during the course of the study.  
Eligibility deviations are defined in the protocol. Eligibility deviations that are defined as 
IPDs will be summarized in both the IPD and Eligibility Deviation table and IPD and 
Eligibility Deviation listings. 
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10.4 
Demographic and Baseline Characteristics 
Summary statistics of the following demographic and baseline disease characteristics 
will be tabulated using the Safety Analysis Set for phase 1b and Full Analysis Set for 
phase 3. 
• 
Region (USA or Non-USA) 
• 
Age at enrollment: <50, ≥ 50; < 65, ≥ 65; <75, ≥75 years 
• 
Sex (male or female) 
• 
ECOG performance status (0 vs 1) 
• 
LDH: ≤ ULN vs > ULN;  ≤ 2 x ULN vs > 2 x ULN  
• 
HSV-1 serostatus (positive vs negative vs missing/unknown) 
• 
Individual disease stage per eCRF (stage IIIB, IIIC, IVM1a, IVM1b, and IVM1c) 
• 
Grouped disease stage per IVRS and CRF (less advanced vs more advanced): 
IIIB/C-IVM1a vs IVM1b/c (CRF and IVRS) 
• 
Grouped disease stage:  IIIB/C-IVM1b vs IVM1c 
• 
Baseline PD-L1 status (positive, negative, vs indeterminate/unknown) 
• 
Interval from initial melanoma diagnosis and enrollment / randomization 
• 
The sum of longest, or shortest for nodal, diameters of target lesions (SLD) 
determined by BICR (both continuous and dichotomized group based on median 
will be presented) 
• 
BRAF mutation status (V600E/K mutation present, no mutation, or unknown) 
• 
Prior BRAF inhibitor (yes versus no BRAF inhibitor with or without MEK 
inhibitors) (IVRS) 
• 
Prior BRAF inhibitor (none, BRAF inhibitor alone, BRAF and MEK inhibitors in 
combination): if subjects included in each of the 2 BRAF related category 
represent ≥ 10% of the study population (CRF) 
• 
Baseline BRAFV600 mutation: yes vs no vs missing/unknown 
• 
Treated brain metastasis (yes vs no) 
• 
Liver metastasis (yes vs no) 
• 
In-transit metastases (yes vs no) 
• 
IVM1c with no visceral lesions (yes vs no) 
• 
BRAFv600 status (BRAF wild type vs BRAFv600 mutant, previous directed 
treatment vs BRAFv600 mutant, no previous directed treatment) 
• 
Previous adjuvant or neoadjuvant therapy (yes vs no) 
10.5 
Efficacy Analyses  
The following sections describe analyses of efficacy endpoints for phase 1b and 
phase 3, separately. Analysis sets used for efficacy endpoints will be specified 
accordingly. 
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10.5.1 
Phase 3 
Analysis of efficacy endpoints will be based on the Full Analysis Set. 
10.5.1.1 
Analyses of Primary Efficacy Endpoint(s) 
The primary analyses of the dual primary endpoints of PFS and OS will be triggered 
when 407 PFS events and 346 OS events have occurred, respectively, as well as OS 
interim analysis at 282 events (including a futility analysis) and at 315 events.  The final 
analysis will occur approximately 5 years (60 months) after the last subject has been 
enrolled in phase 3. 
• 
The analyses of primary efficacy endpoints will be based on stratified log-rank 
tests as a primary method for testing the null hypothesis of no treatment 
difference.  
In order to allow for the use of PD-L1 status in a stratified analysis, indeterminate and 
missing PD-L1 status will be classified together with the “negative” PD-L1 group and 
analyze in the categories of “positive” vs “not positive” PD-L1 group. 
Hazard ratios and corresponding two-sided 95% CI will be estimated using Cox PH 
models stratified by randomization stratification factors per IVRS (disease stage [IIIB-
IVM1a vs IVM1b/c] and prior BRAF inhibitor therapy [no vs yes]) and the baseline PD-L1 
status (positive vs not positive). KM time to event curves will be presented by the 
randomized treatment group. 
Multiple statistical hypothesis tests will be conducted which include testing for primary 
endpoints of PFS and OS and the 3 secondary endpoints (iCRR, iPFS, and OS in the 
subgroup excluding disease stage IVM1c) at multiple analysis time points. To control the 
study-level overall Type I error at an overall 2-sided 0.05 level, a graphic-based multiple 
testing procedure for group sequential tests for multiple endpoints will be utilized  
(Maurer and Bretz, 2013) (see code fragment in Appendix C). No updated information 
will be used when a hypothesis is re-tested at a later time point after its primary analysis. 
A hypothesis can be re- tested repeatedly with a different nominal level that is 
propagated from rejecting other hypothesis test(s). The following figure illustrates the 
Maurer-Bretz multiple testing procedure with initial 2-sided α allocation specified as a 
fraction used for each hypothesis test.  Each hypothesis is represented by a circle.  A 0 
fraction in the circle indicates a hypothesis that is tested conditional on rejection of 
another hypothesis. The fractions in the square on the directed arrows connecting 2 
hypotheses indicate the proportion of α propagated to the next hypothesis test(s) when 
the current hypothesis is rejected.  
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Figure 1.  Initial Graph of Maurer-Bretz Multiple Testing Procedure 
 
H1 α = 0.05 × 9/10 = 0.045 
H2 α = 0.05 × 1/10 = 0.005 
Due to the nature of the Maurer-Bretz multiple testing procedure, nominal levels used for 
testing the OS subgroup can range between 0.05% to 5%. 
Further details regarding the derivation of nominal significance levels for each 
hypothesis test at the planned analyses are provided in Appendix B. 
OS follow-up time will be assessed overall and by treatment arm.  The distribution of 
actual and potential follow up will be provided (eg, median, range, etc.). Clark’s 
completeness index (C) will be calculated (Clark, 2002) to quantify the actual relative to 
potential follow up (see code fragment in Appendix C).  Plots of actual follow-up time 
versus time of study entry will be provided overall and by treatment arm for all subjects 
to assess observed follow-up times relative to potential follow up, and will be repeated 
for the subset with censored OS. 
10.5.1.2 
Analyses of Secondary Efficacy Endpoint(s) 
Analysis of secondary efficacy endpoints will be based on the Full Analysis Set. 
Hypothesis testing for iPFS, iCRR, and OS subgroup are described in multiple testing 
procedures in section 10.5.1.1. 
iPFS and OS excluding disease stage IVM1c subgroup: The analysis for these 
endpoints will follow that described for PFS. 
ORR, DCR, DRR, iCRR, iORR, iDCR and iDRR: These endpoints will be analyzed as 
described in Section 10.1. In addition, Logistic regression with the same stratification 
variables used by the PFS analysis will be used to estimate a p-value and a 95% CI for 
the treatment odds ratio. A 95% CI for the between-arm difference will be estimated 
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using Wilson’s score method with continuity correction. (Newcombe 1998) (see code 
fragment in Appendix C).  
DOR and iDOR: DOR and iDOR among responders will be estimated using the KM 
method.   
BOR categories will be summarized (number and percent) by treatment arm as 
randomized. 
10.5.1.3 
Agreement of Blinded Independent Central Review (BICR) and 
Investigator Reported Endpoints  
To assess the agreement of the BICR and the investigator reported endpoints for iPFS 
and iCRR, two by two tables will be created (iPD vs non-iPD, and iCR vs non-iCR 
respectively) and the kappa coefficient with the 95% CI will be provided (see code 
fragment in Appendix C). 
10.5.2 
Phase 1b 
10.5.2.1 
Analyses of Primary Endpoint 
Subject incidence of DLT 
The subject incidence of DLT will be summarized as a binary variable using the DLT 
analysis set.  
10.5.2.2 
Analyses of Secondary Efficacy Endpoint 
Analysis of secondary efficacy endpoints will be based on the Phase 1b Safety Analysis 
Set. Analysis of phase 1b efficacy endpoints will be performed after the last subject has 
had a chance to be followed for 24 weeks from the initiation of pembrolizumab and at the 
time of the Phase 3 OS primary analysis. All tumor responses will be assessed by 
investigator per modified irRC for Phase 1b subjects. 
ORR, DCR, and DRR will be summarized with associated exact binomial 95% CI 
(Clopper & Pearson 1934). 
BOR categories will be summarized (number and percent).   
DOR, PFS, and OS: KM estimates of DOR among responders, PFS, and OS will be 
provided. 
10.5.3 
Analyses of Exploratory Endpoints  
10.5.3.1 
PD-L1 Induction 
PD-L1 expression from tumor biopsy tissue samples will be reported as positive or 
negative.  PD-L1 induction (ie, change of PD-L1 expression from negative to positive 
from paired biopsy samples taken before and after initiating talimogene laherparepvec) 
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will be tabulated overall and for injected and uninjected lesions.  The pairing will be 
based on lesion number.  Should there be multiple biopsies on the same lesion after 
initiating talimogene laherparepvec, and if there is any positive observation, the  
post-dose observation for PD-L1 will be considered positive.  The analysis will include 
subjects in the PD-L1 Negative Analysis Set in the Safety Set of Phase 1b.  
10.5.3.3 
iORR, iBOR, iDRR, iDOR, iPFS (response evaluation by investigator 
using modified irRC-RECIST) 
These endpoints will be analyzed in the similar manner to corresponding primary and 
secondary endpoints assessed by BICR. 
10.5.4 
Sensitivity Analyses 
Sensitivity analyses will be performed for the Phase 3 portion of the study utilizing the 
Full Analysis Set to assess the robustness of select primary and secondary endpoints as 
noted below. Primary analysis method for primary efficacy endpoints as well as the 
secondary efficacy endpoints will be repeated for the Per Protocol Analysis Set to 
assess the impact of IPDs. All p-values will be descriptive. 
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10.5.4.1 
PFS and iPFS Sensitivity Analyses 
The following set of analyses will be used to assess the robustness of the PFS and iPFS 
primary analysis given the potential for ascertainment or time bias due to skipped or 
unscheduled tumor assessments, or deaths in the absence of prior radiologic evidence 
of progression that are remote from the last evaluable tumor assessment, and also to 
assess the impact of subsequent anti-cancer therapy. 
• 
Stratified log-rank and Cox model analyses will be repeated in which PFS/iPFS 
times not associated with death in the absence of PD/iPD, that are outside of a  
+ 1 week scheduled assessment window, are moved to the next scheduled 
post-randomization assessment day on both treatment arms. Times will not be 
moved if the next scheduled assessment is beyond the date of death or the 
analysis data cutoff date This analysis will also be performed moving the same 
PFS/iPFS times to the closest assessment day. 
• 
Stratified log-rank and Cox model analyses will be repeated in which PFS/iPFS 
death events that occur more than 13 weeks (12 weeks + 1 week window) after 
the last evaluable radiologic tumor assessment will be censored at the time of the 
last evaluable radiologic tumor assessment (Dodd, 2008). 
• 
A complementary log-log model (Allison, 1997) will be used to estimate the 
hazard ratio of talimogene laherparepvec in combination with pembrolizumab 
compared to pembrolizumab alone adjusting for the randomization stratification 
factors as well as PD-L1 status at baseline (positive vs not positive) . The 
complementary log-log model is based on a Cox model for continuous time in 
that the data will be grouped into time intervals. Twelve-week time intervals will 
be used to match the tumor assessment schedule. 
• 
The impact of subsequent anti-cancer therapy on PFS/iPFS will be assessed by 
summarizing the incidence by treatment arm of selected anti-cancer therapies 
with potential PFS/iPFS benefit, the timing of such therapies among subjects that 
received it, and treatment HR estimates of time to first use among all subjects.  
Stratified log-rank and Cox model analyses will be repeated in which PFS/iPFS 
censoring at the last evaluable tumor assessment prior to the start of the first 
selected anti-cancer therapy.   
In the event of inadvertent Suspected Unexpected Serious Adverse Reaction (SUSAR) 
unblinding, an additional sensitivity analysis for PFS will performed to assess the 
potential effect of the unblinding, by removing all event data after the date of the SUSAR 
unblinding from the analysis. 
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For the iPFS endpoint, analyses will be repeated if applicable imputing an event at the 
time of a last overall visit response of iPD that was not confirmed as required per 
modified irRC-RECIST.   
Additionally, to assess the robustness of the PFS and iPFS primary and supportive 
analyses given the potential for bias related to potential informative censoring, the 
analyses noted for OS potential censoring in Section 10.5.4.2 will be repeated for PFS 
and iPFS.  Censoring times will be classified as (1) administrative (random) if within 
91 days (corresponding to maximum lag time allowable between tumor assessments) of 
the analysis data cutoff date or otherwise (2) informative. 
10.5.4.2 
OS Sensitivity Analyses 
The following set of analyses will be used to assess the robustness of the OS primary 
analysis given the potential for bias related to informative censoring, and also to assess 
the impact of subsequent anti-cancer therapy. 
• 
OS potential informative censoring will be assessed with a competing risks 
analysis utilizing the Fine-Gray proportional subdistribution hazards model 
(Fine, 1999; Gray, 1988) (see code fragment in Appendix C). Censoring times 
will be classified as (1) administrative (random) if within 140 days (corresponding 
to maximum lag time allowable between long term follow up assessments) of the 
analysis data cutoff date or otherwise (2) informative. Type (2) censoring will be 
defined as a competing risk event.  Gray’s test will be performed and the Fine-
Gray treatment HR with 95% CI will be calculated stratified as per dual primary 
efficacy endpoints.   
• 
The impact of subsequent anti-cancer therapy on OS will be assessed by 
summarizing the incidence by treatment arm of selected anti-cancer therapies 
with potential OS benefit, the timing of such therapies among subjects that 
received it, and K-M and treatment HR estimates of time to first use among all 
subjects. OS analyses will be repeated in which OS is censored at the first 
selected anti-cancer therapy.   
• 
Since this analysis may introduce bias due to dependent censoring, the OS effect 
will also be estimated with an inverse probability censoring weighting (IPCW) 
method (see code fragment in Appendix C) that incorporates a pre-specified 
covariate history (eg, grouped stage of disease (not IVRS), LDH, SLD, change in 
ECOG performance score, BRAF mutation (not IVRS), PD-L1, and time to 
progression per irRC-RECIST.) and outcomes up to the start of subsequent  
anti-cancer therapy (Robins et al., 2000)  
In the event of inadvertent SUSAR unblinding, an additional sensitivity analysis for OS 
will performed to assess the potential effect of the unblinding, by removing all event data 
after the date of the SUSAR unblinding from the analysis. 
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10.5.5 
Additional Summaries 
CR per BICR, and separately DpR per BICR, will be summarized for the Full 
Analysis Set.  The proportion of subjects in each response level (CR analysis 
response levels: CR vs non-CR; DpR analysis response levels: G4/G5 vs 
G0/G1/G2/G3) will be provided by treatment arm.  The between-treatment arm 
differences in proportions will calculated and 95% CIs will be estimated using 
Wilson’s score method for continuity correction.  
Additionally, OS will be summarized by CR response level (CR vs non-CR) per 
BICR and treatment arm as well as by DpR response level (G4/G5 vs G0/G1/G2/G3) 
per BICR and treatment arm for the Full Analysis Set.  The OS KM median 
estimates with the associated 95% CIs will be summarized for each level of the 
response within treatment arm.  
10.6 
Safety Analyses 
10.6.1 
Adverse Events 
Safety analyses will be conducted separately for phase 1b and phase 3.  The Medical 
Dictionary for Regulatory Activities (MedDRA) version 20.0 or later will be used to code 
all adverse events (AE) to a system organ class and a preferred term.  The CTCAE 
version 4.0 or later will be used to grade severity of adverse events.  In general, events 
with missing IP relatedness, seriousness, or CTCAE severity grades are included in the 
analysis of treatment emergent AE as long as the event is satisfied for a TEAE.  
However, analyses of treatment-related, SAE, or grade 3 or higher, or combination 
thereof will exclude events with missing relatedness, seriousness, and severity grades, 
respectively.    
The subject incidence of AEs will be summarized for all treatment-emergent AEs, 
serious AEs, AEs leading to withdrawal of investigational product, grade 3 or 4 AEs, fatal 
AEs, talimogene laherparepvec events of interest (EOI) and pembrolizumab events of 
clinical interest (ECI).  Subject incidence of EOIs and ECIs will be summarized by the 
EOI categories and ECI categories.  Preferred terms within each EOI and ECI category 
will also be summarized.  
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The subject incidence of all treatment-related AEs, serious AEs, AEs leading to 
withdrawal of investigational product, grade ≥ 3 AEs, and fatal AEs will be tabulated by 
system organ class and preferred term in descending order of frequency.   
Summaries of treatment-emergent and serious AEs occurring in at least 5% of the 
subjects by preferred term in any treatment arm will be provided in descending order of 
frequency.   
A listing of fatal AEs will be provided. A listing of SAEs/EOIs/ECIs reported in the clinical 
database with an event onset after 30 days since last dose of IP will be provided.  Listing 
of SAEs from consent and before first dose of study therapy will also be provided 
separately.  Listing of SAEs reported with event onset 90 days after the last dose of 
study therapy or 30 days after last dose of study therapy if the subject initiates new 
anticancer therapy, whichever is earlier, will be provided.  Additional listings of 
SAEs/EOIs/ECIs for subjects who received treatment by error that occur during the 
incorrect treatment period will be provided.   
Potential or known unintended exposure to talimogene laherparepvec, related suspected 
signs or symptoms, and detection of talimogene laherparepvec in a subject’s household 
member, caregiver, or healthcare provider will be summarized.  Listings of reported 
cases with available qPCR testing results will be provided.   
10.6.2 
Laboratory Test Results 
Shifts in grades of safety laboratory values between the baseline and the worst on-study 
value will be tabulated by treatment group.  Subject incidence of potential hepatotoxicity 
as identified by the Hy’s Law criteria (FDA guidance for Industry Drug Induced Liver 
Injury: pre-marketing evaluation, July 2009) as well as confirmed DILI events as reported 
by investigators will be presented.  
10.6.3 
Vital Signs 
Analysis of vital signs will not be performed as routine monitoring and collection of vital 
sign data is not sufficient for analysis.   
10.6.4 
Electrocardiogram (ECG) 
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; neither summaries nor 
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statistical analyses will be provided, and these data would not be expected to be useful 
for meta-analysis with data from other trials. 
10.6.5 
Antibody Formation 
The incidence and percentage of subjects who develop anti-pembrolizumab antibodies 
will be analyzed by Merck. 
10.6.6 
Exposure to Investigational Product 
Summary statistics for exposure to talimogene laherparepvec/placebo, including total 
doses administered, total volume administered, duration from the first to the last 
administration of talimogene laherparepvec/placebo, and the average volume received 
by subject per visit will be provided and will be separated by the first (concentration of 
106 PFU/ml) and subsequent doses (concentration of 108 PFU/ml).  Subject incidence 
rate and reasons for IP delay, dose change, withdrawal and/or injections with <4 ml will 
be tabulated. 
Exposure to pembrolizumab including total doses (in mg) administered, relative dose 
intensity, duration from the first to the last administration, and the average dose received 
by subject per visit will be provided.  Subject incidence rate and reasons for IP delay, 
dose change, withdrawal and/or receiving ≥ 300 mg of pembrolizumab will be examined.  
10.6.7 
Exposure to Concomitant Medication  
The number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term for each treatment group as coded by the World Health 
Organization Drug (WHODRUG) dictionary.    
10.6.8 
ECOG Performance Status 
ECOG performance status scores will be summarized for each treatment arm at each 
assessed time point. The change in scores from baseline to each assessed time point 
will also be summarized. 
10.7 
Pharmacokinetic or Pharmacokinetic/Pharmacodynamic Analysis 
The summary of the PK analysis performed by Merck will be provided in a separate 
document.  
10.8 
Analyses for Retreatment Phase 
Listings of all data collected in the retreatment course (eg, baseline characteristics, 
adverse events, exposure, tumor assessments, etc.) for subjects in the Retreatment 
Analysis Set will be provided. 
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10.9 
Incidence of Detection of Talimogene Laherparepvec DNA in 
Lesions Suspected to be Herpetic in Origin 
Phase 1b and Phase 3 
The number and proportion of subjects with positive qPCR for talimogene laherparepvec 
DNA detection in any swab of a lesion suspected to be herpetic in origin will be 
calculated based on the qPCR Suspicious Lesion Swab Analysis Set. 
Individual subjects having a positive qPCR results for talimogene laherparepvec DNA 
detection will be reviewed. 
11. 
Changes From Protocol-specified Analyses 
Not applicable. 
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12. 
Literature Citations / References 
Allison, PD. (1997) Survival Analysis Using the SAS System: A Practical Guide. SAS 
Institute Inc. 
Clark, T.G., Altman, D.G., and De Stavola, B.L. (2002) Quantification of the 
Completeness of Follow-up.  Lancet, 359, 1309–1310. 
Clopper, C. and Pearson, E. (1934) “The Use of Confidence or Fiducial Limits Illustrated 
in the Case of the Binomial,” Biometrika, 26, 404–413 
Denne JS.(2001) “Sample size recalculation using conditional power.” Statistics in 
Medicine, 20,2645-2660. 
Dodd, L.E, Korn, E.L., Freidlin, B., Jaffe, C.C., Rubinstein, L.V., Dancey, J., and 
Mooney, M.M.  (2008)  “Blinded Independent Central Review of Progression-Free 
Survival in Phase III Clinical Trials: Important Design Element or Unnecessary 
Expense?” J Clin Oncol, 26(22), 3791–3796. 
Eisenhauer, A., et al (2009) “New Response Evaluation in Solid Tumors: Revised 
RECIST Guideline (version 1.1)”, EJC, 45, 228-247.  
Fisher, L.D. and van Belle, G. (1993): New York: John Wiley & Sons. Biostatistics - A 
Methodology for the Health Sciences. P 322 
Fine, J.P. and Gray, R.J. (1999) “A Proportional Hazards Model for the Subdistribution of 
a Competing Risk.”, Journal of the American Statistical Association, 94, 496–509 
Gail, M. and Simon, R. (1985) “Testing for Qualitative Interactions Between Treatment 
Effects and Patient Subsets.” Biometrics,  41, 361-372. 
Gray, R.J. (1988)  “A Class of K-Sample Tests for Comparing the Cumulative Incidence 
of a Competing Risk.” The Annals of Statistics, 16(3), 1141-1154. 
Kalbfleisch, J.D. and Prentice, R.L. (1980) The Statistical Analysis of Failure Time Data, 
New York: John Wiley & Sons. 
Maurer, W., Bretz, F. (2013) Multiple Testing in Group Sequential Trials Using Graphical 
Approaches, Statistics in Biopharmaceutical Research, 5:4, 311-320 
Newcombe RG.  (1998) “Interval estimation for the difference between independent 
proportions: Comparison of eleven methods.”  Statistics in Medicine, 17(8), 873-890. 
O'Brien PC, and Fleming TR.(1979) “A multiple testing procedure for clinical trials.” 
Biometrics,35(3),549-556. 
Osgood C, Mulkey F, Mishra-Kalyani PS, et al. (2019) “FDA analysis of depth of 
response (DpR) and survival across 10 randomized controlled trials in patients with 
previously untreated unresectable or metastatic melanoma (UMM) by therapy 
type”. Presented at 2019 American Society of Clinical Oncology (ASCO) Annual 
Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9508. 
Robins, R., Hernan, M., and Brumback, B. (2000) Marginal Structural Models and 
Causal Inference in Epidemiology.  Epidemiology, 11(5), 550-560. 
Wolchok JD, Hoos A, and O’Day S, et al. (2009) “Guidelines for the evaluation of 
immune therapy activity in solid tumors: immune-related response criteria.” Clin Cancer 
Res, 15(23), 7412-7420. 
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13. 
Data not Covered by This Plan  
Analysis plans for 
 and PRO will be provided 
in separate SSAPs. 
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14. 
Appendices  
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Appendix B.  Nominal Significance Levels for Maurer-Bretz Multiple Testing 
Multiple testing will be conducted on primary endpoints (OS and PFS) and three 
secondary endpoints (iPFS, iCRR and OS subgroup excluding disease stage IVM1c) at 
5 planned analyses for the study: PFS PA or OS IA1 (407 PFS events), OS IA2 (282 
deaths), OS IA3 (315 deaths), OS PA (346 deaths), and OS in subgroup (208 deaths).  
At the time of 1st interim analysis, the nominal significant level depends on the 
information fractions observed where the spending function mimics the O’Brien-Fleming 
(OBF) boundaries: 
𝛼𝛼(𝛾𝛾, 𝑦𝑦) = 2 ቀ1 −Φ൫Φ−1(1 −𝛾𝛾/2)/ඥ𝑦𝑦൯ቁ 
Where 
𝛾𝛾 = 1-sided overall significance level 
y = information fraction at the analysis time point 
Φ = cumulative normal. 
Based on the progress of the study, the PFS PA will be the 1st analysis and thus, the 
information fraction is 100% for this endpoint.  At the time of PFS PA, it is likely that the 
information for hypotheses testing on OS, iPFS and OS subgroup will be partial and 
iCRR will be full information because all enrolled subjects will have been followed for 
more than 6 months.  
Figure 2 to Figure 5 below illustrate the Maurer-Bretz successive sequential testing 
procedure for (1) the initial test of primary endpoints; (2) testing secondary endpoints 
(iPFS and iCRR); (3) testing secondary endpoint (OS subgroup); (4) possible re-test of 
one of the primary endpoints, OS, when rejection of both PFS and OS subgroup 
endpoints occur (note PFS cannot be re-tested at PFS PA or any subsequent analyses).  
Table 5 provides the nominal significance levels for all possible scenarios at the PFS PA 
as illustrated in Figure 2 to Figure 5 under a set of information fractions assumed as: 
252/346 for OS, 100% for iPFS and iCRR, and 168/208 for OS subgroup. Note because 
nominal significance levels are very small, to avoid rounding error, the observed number 
of events out of the target number of events should be used to calculate information 
fractions for OS, iPFS, and OS subgroup.  Upon the PFS PA snapshot (lock), this table 
will be re-calculated for all possible significance levels for these endpoints by replacing 
the observed number of events for the 3 endpoints (OS, iPFS, and OS subgroup).  
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Figures will be re-created illustrating testing procedures and a table containing 
significance levels prior to each subsequent analysis (OS IA2, OS IA3, OS PA, and OS 
subgroup PA) based on the outcome of the previous analysis.  The rationale for this that 
(a) the previous analysis outcomes (eg, the rejection of PFS hypothesis) will significantly 
reduce the number of possible testing scenarios; and (b) a more precise set of 
information fractions can be applied for the remaining endpoints that did not achieve full 
information at the previous analysis.    
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Figure 2.  Maurer-Bretz Sequential Rejection Testing Procedure: The First Tier 
Endpoints (OS and PFS) 
Test: PFS and Initial OS 
 
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Figure 3.  Maurer-Bretz Sequential Rejection Testing Procedure: The Second Tier 
Endpoints (iPFS and iCRR) 
Test: iPFS or iCRR 
Rejected: OS, PFS 
Rejected: OS; ^Rejected: 
PFS 
Rejected: PFS; ^Rejected: OS 
 
 
 
• 
• 
• 
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Figure 3.  Maurer-Bretz Sequential Rejection Testing Procedure: The Second Tier 
Endpoints (iPFS and iCRR) 
Test: iCRR 
Rejected: OS, PFS, iPFS 
Rejected: OS, iPFS; 
^Rejected: PFS 
Rejected: PFS, iPFS; 
^Rejected: OS 
 
 
 
 
 
 
Figure 3.  Maurer-Bretz Sequential Rejection Testing Procedure: The Second Tier 
Endpoints (iPFS and iCRR) 
Test: iCRR 
Rejected: OS, PFS; 
^Rejected: iPFS 
Rejected: OS; ^Rejected: 
PFS, iPFS 
Rejected: PFS; ^Rejected: 
OS, iPFS 
 
 
 
 
 
 
Figure 3.  Maurer-Bretz Sequential Rejection Testing Procedure: The Second Tier 
Endpoints (iPFS and iCRR) 
Test: iPFS 
Rejected: OS, PFS, iCRR 
Rejected: OS, iCRR; 
^Rejected: PFS 
Rejected: PFS, iCRR; 
^Rejected: OS 
 
 
 
 
 
 
 
• 
• 
• 
•• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
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Figure 3.  Maurer-Bretz Sequential Rejection Testing Procedure: The Second Tier 
Endpoints (iPFS and iCRR) 
Test: iPFS 
Rejected: OS, PFS; 
^Rejected: iCRR 
Rejected: OS; ^Rejected: 
PFS; iCRR 
Rejected: PFS; ^Rejected: 
OS, iCRR 
 
 
 
 
 
 
 
 
• 
• 
• 
• 
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Figure 4.  Maurer-Bretz Sequential Rejection Testing Procedure: The Third Tier 
Endpoint (OS subgroup) 
Rejected: OS, PFS, iPFS, iCRR 
 
 
 
 
 
 
 
Figure 4.  Maurer-Bretz Sequential Rejection Testing Procedure: The Third Tier 
Endpoint (OS subgroup) 
Rejected: OS, PFS, iPFS; ^Rejected: iCRR 
Rejected: OS, PFS, iCRR; ^Rejected: iPFS 
 
 
 
 
 
 
 
 
Figure 4.  Maurer-Bretz Sequential Rejection Testing Procedure: The Third Tier 
Endpoint (OS subgroup) 
Rejected: OS, iPFS, iCRR; ^Rejected: PFS 
Rejected: PFS, iPFS, iCRR; ^Rejected: OS 
 
 
 
 
 
 
 
• 
• 
• 
• 
• • 
• 
• 
• 
• 
• 
• 
• 
• 
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Rejected: OS, iPFS; ^Rejected:  PFS, iCRR 
Rejected: OS, iCRR; ^Rejected: PFS, iPFS 
 
 
 
 
 
 
 
 
 
 
Rejected: PFS, iPFS; ^Rejected: OS, iCRR 
Rejected: PFS, iCRR; ^Rejected: OS, iPFS 
 
 
 
 
 
 
 
 
 
• 
• • 
• 
• 
• 
• 
1 
• 
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Figure 5.  Maurer-Bretz Sequential Rejection Testing Procedure: Potential 
Re-testing of the Hypothesis Given Alpha Is Subsequently Propagated to It From 
the Rejection of Another Hypothesis 
Re-test: OS 
Rejected: PFS, iPFS, iCRR, 
OS subgroup; ^Rejected: OS 
Rejected: PFS, iPFS, OS 
subgroup; ^Rejected: OS, 
iCRR 
Rejected: PFS, iCRR, OS 
subgroup; ^Rejected: OS, 
iPFS 
 
 
 
 
 
 
 
Table 5 summarizes nominal significance levels (2-sided) 𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) at the time of PFS 
PA (ie, with 407 PFS events) based on sequential testing, assuming overall (one-sided) 
significance level 𝛼𝛼 = 0.025, where a possible scenario of information fraction (y) is 
explored as described below. 
• 
• 
• 
• • • 
• • 
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Table 5.  Example 2-sided Nominal Significance Levels at the OS Interim Analysis 
1 or PFS PA (ie, 407 PFS) With Partial or Full Information for All Remaining 
Hypotheses 
 
OS 
PFS 
iPFS 
iCRR 
OS 
Subgroup 
Maximum information 
(events or subjects) 
346 
407 
256 
692 
208 
Number of events (subjects) 
252 
407 
256 
692 
168 
Information fraction, y 
252/346 
1.00 
1.00 
1.00 
168/208 
Rejected: None 
Initial 
test: OS 
Test: PFS 
 
𝑤𝑤𝑖𝑖(∙) 
9/10 
1/10 
0 
0 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
0.045 
0.005 
0 
0 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
0.0150 
0.0050 
NA 
NA 
NA 
Rejected: OS, PFS 
 
 
Test: iPFS or iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
81/100 
19/100 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.0405 
0.0095 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.0405 
0.0095 
NA 
Rejected: OS; ^Rejected: 
PFS 
 
 
Test: iPFS or iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
0.72 
9/50 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.036 
0.0090 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.0360 
0.0090 
NA 
Rejected: PFS; ^Rejected: 
OS 
 
 
Test: iPFS or iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
9/100 
1/100 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.0045 
0.0005 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.0045 
0.0005 
NA 
Rejected: OS, PFS, iPFS 
Test: iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
0.919 
0.081 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
0.04595 
0.00405 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
0.04595 
NA 
Rejected: OS, PFS; ^Rejected: iPFS 
Test: iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
19/100 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
0.0095 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
0.0095 
NA 
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Table 5.  Example 2-sided Nominal Significance Levels at the OS Interim Analysis 
1 or PFS PA (ie, 407 PFS) With Partial or Full Information for All Remaining 
Hypotheses 
 
OS 
PFS 
iPFS 
iCRR 
OS 
Subgroup 
Rejected: OS, iPFS; ^Rejected: PFS 
Test: iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
0.828 
9/125 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
0.0414 
0.0036 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
0.0414 
NA 
Rejected: OS; ^Rejected: PFS, iPFS 
Test: iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
9/50 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
0.0090 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
0.0090 
NA 
Rejected: PFS, iPFS; ^Rejected: OS 
Test: iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
91/1000 
9/1000 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
0.00455 
0.00045 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
0.00455 
NA 
Rejected: PFS; ^Rejected: OS, iPFS 
Test: iCRR 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
1/100 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
0.0005 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
0.0005 
NA 
Rejected: OS, PFS, iCRR 
Test: iPFS 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
0.981 
- 
0.019 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.04905 
- 
0.00095 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.04905 
- 
NA 
Rejected: OS, PFS; ^Rejected: iCRR 
Test: iPFS 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
81/100 
- 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.0405 
- 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.0405 
- 
NA 
Rejected: OS, iCRR; ^Rejected: PFS 
Test: iPFS 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
441/500 
- 
9/500 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.0441 
- 
0.0009 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.0441 
- 
NA 
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Table 5.  Example 2-sided Nominal Significance Levels at the OS Interim Analysis 
1 or PFS PA (ie, 407 PFS) With Partial or Full Information for All Remaining 
Hypotheses 
 
OS 
PFS 
iPFS 
iCRR 
OS 
Subgroup 
Rejected: OS; ^Rejected: PFS, iCRR 
Test: iPFS 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
0.72 
- 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.036 
- 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.0360 
- 
NA 
Rejected: PFS, iCRR; ^Rejected: OS 
Test: iPFS 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
99/1000 
- 
1/1000 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.00495 
- 
0.00005 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.00495 
- 
NA 
Rejected: PFS; ^Rejected: OS, iCRR 
Test: iPFS 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
9/100 
- 
0 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
0.0045 
- 
0 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
0.0045 
- 
NA 
Rejected: OS, PFS, iPFS, iCRR 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
1 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.05 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.0253 
Rejected: OS, PFS, iPFS; 
^Rejected: iCRR 
 
 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
0.081 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.00405 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.0012 
Rejected: OS, PFS, iCRR; 
^Rejected: iPFS 
 
 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
0.019 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.00095 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.0002 
Rejected: OS, iPFS, iCRR; ^Rejected: PFS 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
9/10 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.045 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.0222 
Page 3 of 5 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 69 
 
Table 5.  Example 2-sided Nominal Significance Levels at the OS Interim Analysis 
1 or PFS PA (ie, 407 PFS) With Partial or Full Information for All Remaining 
Hypotheses 
 
OS 
PFS 
iPFS 
iCRR 
OS 
Subgroup 
Rejected: PFS, iPFS, iCRR; ^Rejected: OS 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
1/10 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.005 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.0015 
Rejected: OS, iPFS; ^Rejected: PFS, iCRR 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
9/125 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.0036 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.0010 
Rejected: OS, iCRR; ^Rejected: PFS, iPFS 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
9/500 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.0009 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.0002 
Rejected: PFS, iPFS; ^Rejected: OS, iCRR 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
9/1000 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.00045 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.0001 
Rejected: PFS, iCRR; ^Rejected: OS, iPFS 
Test: OS subgroup 
𝑤𝑤𝑖𝑖(∙) 
- 
- 
- 
- 
1/1000 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
- 
- 
- 
- 
0.00005 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
- 
- 
- 
- 
0.000005 
Rejected: PFS, iPFS, iCRR, 
OS subgroup; ^Rejected: 
OS 
Re-test: 
OS 
 
𝑤𝑤𝑖𝑖(∙) 
1 
- 
- 
- 
- 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
0.05 
- 
- 
- 
- 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
0.0173 
- 
- 
- 
- 
Rejected: PFS, iPFS, OS 
subgroup; ^Rejected: OS 
 
 
𝑤𝑤𝑖𝑖(∙) 
0.909 
- 
- 
- 
- 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
0.04545 
- 
- 
- 
- 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
0.0152 
- 
- 
- 
- 
Page 4 of 5 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 70 
 
Table 5.  Example 2-sided Nominal Significance Levels at the OS Interim Analysis 
1 or PFS PA (ie, 407 PFS) With Partial or Full Information for All Remaining 
Hypotheses 
 
OS 
PFS 
iPFS 
iCRR 
OS 
Subgroup 
Rejected: PFS, iCRR, OS 
subgroup; ^Rejected: OS 
 
 
𝑤𝑤𝑖𝑖(∙) 
0.901 
- 
- 
- 
- 
𝑤𝑤𝑖𝑖(∙)𝛼𝛼 
0.04505 
- 
- 
- 
- 
𝛼𝛼𝑖𝑖,1
∗(𝑤𝑤𝑖𝑖(∙)𝛼𝛼) 
0.0150 
- 
- 
- 
- 
Page 5 of 5 
Table 6 provides an example of testing 5 endpoints at the time of PFS PA assuming the 
observed information fractions are: 252/346 for OS, 100% for PFS, iPFS, and iCRR, and 
168/208 for OS subgroup and observed nominal p-values are 0.03 for OS, 0.001 for 
PFS, 0.003 for iPFS, 0.011 for iCRR, and 0.01 for OS subgroup.  Because 𝑝𝑝2,1 (PFS 
endpoint) is less than 0.005, the PFS endpoint is significant and therefore, the two 
secondary endpoints (iPFS and iCRR) can be tested. Regardless of what happens to 
iCRR, because 𝑝𝑝3,1 is less than 0.0040, which is the significance level for iPFS when 
only PFS is significant, this endpoint is significant.  Because both PFS and iPFS are 
significant, iCRR is tested at 0.00455, which is not significant, and OS subgroup is 
tested at 0.0001, which is not significant.  
Table 6.  Example of Nominal P-values and Significance Levels at PFS PA 
Endpoint / 
Hypothesi
s 
𝒊𝒊 
Nomina
l 𝒑𝒑𝒊𝒊,𝟏𝟏 
𝜶𝜶𝒊𝒊,𝟏𝟏
∗(𝒘𝒘𝒊𝒊(𝟏𝟏, 𝟐𝟐, 𝟑𝟑, 𝟒𝟒, 𝟓𝟓)𝜶𝜶𝜶𝜶𝒊𝒊,𝟏𝟏
∗(𝒘𝒘𝒊𝒊(𝟑𝟑, 𝟒𝟒, 𝟓𝟓)𝜶𝜶𝜶𝜶𝒊𝒊,𝟏𝟏
∗(𝒘𝒘𝒊𝒊(𝟓𝟓)𝜶𝜶) 
Significanc
e at PFS PA 
OS 
1 
0.03 
0.0150 
- 
- 
Not 
significant 
PFS 
2 
0.001 
0.0050 
- 
- 
Significant 
iPFS 
3 
0.003 
0 
0.0045 
- 
Significant 
iCRR 
4 
0.011 
0 
0.00455 
- 
Not 
significant 
OS 
subgroup 
5 
0.01 
0 
NA 
0.0001 
Not 
significant 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 71 
 
Appendix C.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs 
 
C.1 
Cochran-Mantel-Haenszel (CMH) Statistics 
 
proc freq data=data1; 
tables <stratum> * trtgrp * response /cmh; 
run; 
 
 
C.2 
Mantal-Haenszel Common Risk difference 
 
ods output CommonPdiff=cpdiff2; 
proc freq data=data1; 
   tables Gender*Treatment*Response /riskdiff(common); 
   weight Count; 
run; 
 
data cpdiff_3; 
   set cpdiff2; 
   if method='Mantel-Haenszel'; 
   p_value=min(1, 2*(1-probnorm(abs(value/stderr)))); 
run; 
 
 
C.3 
Clopper-Pearson Exact Confidence Interval 
proc freq data=data1; 
   tables var1/ binomial(exact); 
   by trtgrp; 
run; 
 
 
C.4 
Fisher’s Exact Test 
proc freq data=data1; 
   tables var1 * trtgrp /exact; 
run; 
 
 
C.5 
Logistic Regression 
 
/* event=’1’: value 1 indicating an event/response observed */ 
proc logistic data=data1; 
   class trtgrp cov1 cov2 cov3; 
   model response (event='1') = trtgrp cov1; 
run; 
 
/* Stratified logistic regression */ 
proc logistic data=data1; 
   class <stratum> trtgrp cov1 cov2 cov3; 
   model response (event='1') = trtgrp cov1; 
   strata <stratum>; 
run; 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 72 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 73 
 
C.6 
Kappa Coefficient 
proc freq data=data1; 
   tables var1 * trtgrp /agree; 
run; 
 
 
C.7 
Wilcoxon Rank-sum Test on Continuous Response  
proc npar1way wilcoxon data=<data>; 
   class trtpxcd; 
   var <continuous endpoint>; 
run; 
 
 
C.8 
Fine-Gray Subdistribution Proportional Hazards Model 
/* The variable STATUS has three values: 0 for censored observations, 1 
for subjects with event of interest (e.g. local recurrence for LRFS), 
and 2 for patients who experienced competing risk. */ 
 
proc phreg data=dat1 ; 
   class TRTGRP (order=internal ref=first) param=glm; 
   model LRFS*STATUS(0)= TRTGRP x1 x2 / eventcode=1; 
   hazardratio 'Subdistribution Hazards' TRTGRP; 
   strata randomization_strata; 
   * Delete strata statement to assess overall proportional hazards; 
   * x1, x2 are covariates. 
run; 
 
 
C.9 
Assumption of Non-Proportionality Hazards: Schoenfeld Residuals Plot 
 
/* cnsr(1): value 1 indicating censored observations*/ 
proc phreg data=data1;   
    model OS * CNSR(1) = TRTGRP covariate1 covariate2 covariate3 
/ties=exact;   
    strata randomization_strata; 
    output out=outdata ressch= s_TRTGRP s_covariate1 s_covariate2 
s_covariate3;  
run;  
 
proc sgplot data=outdata;  
    scatter y=TRTGRP x=OS/ name="Schoenfeld_&CHECK";  
    loess y=TRTGRP x=OS /SMOOTH=.8 DEGREE=1 INTERPOLATION= CUBIC ;  
run; 
 
*Note:  Repeat proc gplot for other covariates (covar1, covar2, etc.)*; 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 74 
 
C.10 
Kaplan Meier Method:  Stratified Log-Rank Test and Standard Errors Using 
Greenwood's Formula  
 
/* cnsr(1): value 1 indicating censored observations */ 
proc lifetest data=data1; 
   time Days*cnsr(1); 
   strata <stratum> / group=TRTGRP; 
run; 
 
 
C.11 
Stratified multivariate Cox Proportional Hazards Model 
 
/* cnsr(1): value 1 indicating censored observations */ 
proc phreg data=dat1; 
   model OS * CNSR(1) = TRTGRP covariate1 covariate2 / ties=exact 
rl=pl; 
   strata <stratum>; 
run; 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 75 
 
C.13 
Inverse Probability Censoring Weighting (IPCW) 
 
*** Model 1: time-independent model 
*** model the probability of without subsequent anti-cancer therapy per 
each subject 
*** include the baseline covariates; 
proc sort data=adsl out=indep;by subther;run; 
proc genmod data=indep order=data; 
  class disstgi LDH brafmut PDL1; 
  model subther = disstgi LDH SLD brafmut PDL1 / dist=binomial 
link=logit ; 
  output out=num prob=num; 
run; 
 
*** Model 2: time-dependent model 
*** model the probability of without subsequent anti-cancer therapy per 
each subject-timeinterval 
*** include both baseline covariates and time-dependent covariates; 
proc sort data=all2 out=dep;by subther;run; 
proc genmod data=dep order=data; 
  class disstgi LDH brafmut PDL1   <time-dep categorical vars> ; 
  model subther = disstgi LDH SLD brafmut PDL1   <time-dep vars> / 
dist=binomial link=logit ; 
  output out=den prob=den; 
run; 
 
proc sort data=num ;by usubjid;run; 
proc sort data=den ;by usubjid;run; 
 
data wgt; 
retain <stratification factors> armcd usubjid subther   
       num den 
; 
  merge num den ; 
  by usubjid; 
run; 
 
*** calculate weights; 
data wgt2; 
  set wgt; 
  by usubjid; 
 
retain w_num w_den ; 
  if first.usubjid then do; 
 
w_num = 1; 
 
w_den = 1; 
  end; 
  w_num = w_num*num ; 
  w_den = w_den*den ; 
 
  if subther = 'y' then weights = (1-w_num)/(1-w_den); 
  else if subther = 'n' then weights = w_num/w_den; 
run; 
 
data os_wgt; 
  merge wgt2(in=a)  
        os(in=b) 
; 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 76 
 
  by usubjid; 
  if a and b; 
run; 
 
*** Inverse Probability Censoring Weighted Cox model ; 
proc phreg data=os_wgt; 
  class armcd(ref='PB_PEM'); 
  model aval*cnsr(1)=armcd; 
  strata <stratification factors>; 
  freq weights / notruncate; 
  hazardratio armcd / alpha=0.05 cl=wald diff=ref; 
  ods output hazardratios=hr_ci_ipcw; 
run; 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 77 
 
C.14 
Gail and Simon Quantitative and Qualitative Interaction Tests and  Post 
Hoc Power Test 
 
%macro int(ds     =,  /* Dataset                          */ 
           txvar  =,  /* Treatment indicator              */ 
           sgroup =,  /* Subgroup variable                */ 
           time   =,  /* Time to event variable           */ 
           censor =,  /* Censor var 1=observed 0=censored */ 
           covar  =,  /* Covariates for model             */  
           alpha  =,  /* 2-sided nominal alpha for power  */ 
           outf   =   /* SASname of results file          */ ); 
 
proc sort data=&ds out=&ds._d1; 
  by &sgroup; 
run; 
 
/* 
proc printto new print=&outf; run; 
*/ 
ods output ParameterEstimates=phfit; 
proc phreg data=&ds._d1; 
  model &time*&censor(0)=&txvar &covar 
  / rl ties=exact; 
  by &sgroup; 
 
data ph (keep=&sgroup estimate v rename=(estimate=b)); 
  set phfit (keep=&sgroup estimate stderr); 
  v=stderr**2; 
 
proc transpose data=ph prefix=b out=b (drop=_name_);  
  var b; 
proc transpose data=ph prefix=v out=v (drop=_name_);  
  var v; 
 
data t; merge b v; 
  label H='(GS)|Quant.|Test|Value'  
    ph='(GS)|Quant.|p-val' ph_p='(GS)|Quant.|Post Hoc|Power' 
    Q='(GS)|Qual.|Test|Value' pq='(GS)|Qual.|p-val' 
    pp='(PG)|Qual.|p-val' Qmin='(PG)|Qmin' Qmax='(PG)|Qmax' 
    alpha='Alpha|2-tail'; 
  alpha = &alpha+0; 
  array b b1-b30; 
  array v v1-v30; 
  g=0; do i=1 to 30; if b{i} ne . then g+1; end; 
 
  * (GS) Quantitative interaction test ; 
  n=0; d=0; 
  do i=1 to g; n=n + b{i}/v{i}; d=d + 1/v{i}; end; 
  Dbar=n/d; 
  H=0; 
  do i=1 to g; H=H + ((b{i}-Dbar)**2)/v{i}; end; 
  ph=1-probchi(H,g-1); 
 
  * Post hoc power ; 
  c_alpha = quantile('CHISQ', 1-alpha, g-1); 
  ph_p = 1 - probchi(c_alpha, g-1, H); 
 
  * (GS) Qualitative Interaction ; 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 78 
 
  Q=0; Qn=0; Qp=0; pq=0; 
  do i=1 to g; 
    Qn=Qn + ((b{i}**2)/v{i})*resolve(b{i}>0); 
    Qp=Qp + ((b{i}**2)/v{i})*resolve(b{i}<0); 
  end; 
  Q=min(Qn,Qp); 
  do i=1 to g-1; 
    pq=pq + (probbnml(.5,g-1,i)-probbnml(.5,g-1,i-1)) * 
            (1-probchi(Q,i)); 
  end; 
 
  * (PG) Qualitative Interaction ; 
  array r r1-r30; 
  do i=1 to g; 
    r{i}=b{i}/sqrt(v{i}); 
    if i=1 then do; Qmin=r{i}; Qmax=r{i}; end; 
    if r{i} lt Qmin then Qmin=r{i}; 
    if r{i} gt Qmax then Qmax=r{i}; 
  end; 
  if Qmin ge 0 then pp=.5; 
  else do; 
    c=min(abs(Qmin),abs(Qmax)); 
    pp=1 - (1-probnorm(-c))**(g-1); 
  end; 
run; 
 
proc print data=t noobs label split='|'; 
  var h ph ph_p q pq Qmin Qmax pp; 
run; 
%mend int; 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 79 
 
        
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 80 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 81 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 82 
 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 83 
 
C.16 
Wilson’s Score Method With Continuity Correction 
Macro and Sample Code for Wilson’s score method with continuity correction 
• 
S1 is the numerator and N1 is the demoninator for T-VEC; S2 is the numerator 
and N2 is the denominator for GM-CSF 
• 
There are variables P1, P2 , LL and UL. 
• 
The percentage difference is the P1-P2 and 95% CI is (LL, UL) 
 
%macro method11(ds=,  
                dsout=, 
                by=, 
                cc=0.80); 
 
  data &dsout; 
    length s1 n1 p1 s2 n2 p2 LL UL cc 8; 
    set &ds; 
    retain cc &cc; 
    array nn{2} n1 n2; 
    array s{2} s1 s2; 
    array p{2} p1 p2; 
    array q{2} _temporary_; 
    array np{2} _temporary_; 
    array nq{2} _temporary_; 
    array l{2} _temporary_; 
    array u{2} _temporary_; 
    ca2=probit(0.5 + cc/2); 
    ca2sq=ca2*ca2; 
    do i=1 to 2; 
      p{i}=s{i}/nn{i};; 
      q{i}=1-p{i};; 
      nq{i}=nn{i}*q{i}; 
      np{i}=nn{i}*p{i}; 
      if p{i}=0 then l{i}=0; 
      else l{i}=(((2*np{i})+(ca2sq-1))-(ca2*(sqrt((ca2sq-(2+(1/nn{i}))+ 
((4*p{i})*(nq{i}+1)))))))/(2*(nn{i}+ca2sq)) ; 
      if p{i}=1 then u{i}=1; 
      else u{i}=(((2*np{i})+(ca2sq+1))+(ca2*(sqrt((ca2sq+(2-(1/nn{i}))+ 
((4*p{i})*(nq{i}-1)))))))/(2*(nn{i}+ca2sq)) ; 
    end; 
    d=sqrt((p{1}-l{1})**2+(u{2}-p{2})**2); 
    e=sqrt((p{2}-l{2})**2+(u{1}-p{1})**2); 
    LL=p{1}-p{2}-d; 
    UL=p{1}-p{2}+e; 
  *  keep s1 n1 p1 s2 n2 p2 LL UL cc; 
    label s1='Number of Sample from Population 1' 
          n1='Number of Population 1' 
          p1='Proportion 1 = s1 / n1 ' 
          s2='Number of Sample from Population 2' 
          n2='Number of Population 2' 
          p2='Proportion 2 = s2 / n2' 
          ll='Lower limit of interval estimation for difference' 
          ul='Upper limit of interval estimation for difference' 
          cc='Confidence coefficient'; 
  run; 
 
  %if %length(&by)>0 %then %do; 
    proc sort data=&dsout; 
      by &by; 
    run; 
  %end; 
 
  title1 "Comparison of two independent proportions using continuity 
correction" ; 
  title2 'NEWCOMBER METHOD 11 : Example H '; 
  title3 "LL UL &cc% CI for Difference between Independent Proportions";  
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Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 84 
 
  proc print data=&dsout label; 
    var &by n1 s1 p1 n2 s2 p2 LL UL cc; 
  run; 
%mend method11; 
 
 
data dsin; 
  input n1 n2 s1 s2; 
cards; 
25 50 5 4.25; 
run; 
%method11(ds=dsin, dsout=dsout, by=, cc=0.95); 
 
C.17 
Clark’s Quantification of the Completeness of Follow-up 
%let cutdt = 02-OCT-18; 
 
proc univariate data=adamp.adtte noprint; 
where paramcd = "PFS" and cohort ne "PHASE 1B"; 
  var randdt; 
  output out=regmin min=randdt_min_ 
                    max=randdt_max_; 
 
data fuci1; 
  set adamp.adtte(keep=subjid saffl cohort trt01p aval cnsr paramcd 
randdt adt); 
  format obs_fu_dt date9.; 
  where paramcd = "PFS" and cohort ne "PHASE 1B"; 
  * Observed follow-up time = death time ; 
  obs_fu=aval; 
  obs_fu_dt=randdt + aval; 
 
  * Potential follow-up time ; 
  if cnsr=0 then po_fu=aval; 
  else po_fu="&cutdt"d - randdt; 
 
  * Time since survival time ; 
  lag = "&cutdt"d - obs_fu_dt; 
run; 
 
data fuci2; 
  drop randdt_min_ randdt_min; 
  merge fuci1 
        regmin; 
  retain randdt_min; 
  if _n_=1 then randdt_min=randdt_min_; 
  entry_day=randdt-randdt_min; 
 
  obs_fu = obs_fu/365.25; 
  po_fu = po_fu/365.25; 
run; 
 
proc univariate data=fuci2 noprint; 
  var obs_fu po_fu; 
  output out=f_all n=n1 n2 sum=t_obs_fu t_po_fu; 
run; 
 
data fu; 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 85 
 
  set f_all; 
  ci=100 * t_obs_fu / t_po_fu; 
  call symput('ci',trim(left(put(ci,8.0)))); 
run; 
 
proc print data=fu; 
  title 'Completion Index (CI)'; 
run; 
 
C.18 
Complementary log-log model with data grouped into 12-week time 
intervals 
data pfs_12wk; 
   set pfsdur; 
 
   /* convert duration into 12-week interval */ 
   duration_in12wk = ceil(duration/12);  
 
   do interval_12wk=1 TO duration_in12wk; 
   if interval_12wk=duration_in12wk and event=1 then PD=1; 
 
else PD=0; 
   output; 
   end; 
run; 
 
/* variable event:  1=event occurred 0=no event */ 
proc logistic data= pfs_12wk; 
   class interval_12wk;  
   model PD(event=’1’)=trtgrp strata1 strata2 strata3 interval_12wk 
/link=cloglog; 
run; 
AMGEN® 


Product:  Talimogene Laherparepvec 
Statistical Analysis Plan:  20110265 
Date:  16 January 2020 
Page 86 
 
AMGEN®