A Phase II Study of Talimogene Laherparepvec (T-VEC) Administered Concurrently With the Anti-PD1 Monoclonal Antibody Pembrolizumab in Patients With Metastatic and/or Locally Advanced Sarcoma
Phase: PHASE2
Conditions: Sarcoma, Epithelioid Sarcoma, Cutaneous Angiosarcoma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
 
 
MSK PROTOCOL COVER SHEET 
Phase II study of talimogene laherparepvec (T-VEC) administered concurrently with 
the anti-PD1 monoclonal antibody pembrolizumab in patients with metastatic and/or 
locally advanced sarcoma. 
Principal Investigator/Department: Ciara Kelly, MBBCh BAO / Medicine/Sarcoma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
Page 1 of 118 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 2 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 6 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 9 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 17 
4.1 
Design ........................................................................................................................... 17 
4.2 
Intervention .................................................................................................................... 20 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 20 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 34 
6.1 
Subject Inclusion Criteria ............................................................................................... 34 
6.2 
Subject Exclusion Criteria .............................................................................................. 35 
7.0 
RECRUITMENT PLAN ..................................................................................................... 37 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 37 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 38 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .................................................. 43 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................ 54 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 80 
13.0 CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 88 
14.0 BIOSTATISTICS ............................................................................................................... 91 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES .... 97 
15.1 Research Participant Registration .................................................................................. 97 
15.2 Randomization............................................................................................................... 97 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 97 
16.1 Quality Assurance ......................................................................................................... 98 
16.2 Data and Safety Monitoring ........................................................................................... 98 
17.0 PROTECTION OF HUMAN SUBJECTS ......................................................................... 100 
17.1 Privacy ........................................................................................................................ 101 
17.2 Serious Adverse Event (SAE) Reporting ...................................................................... 101 
17.2.1 Safety Reporting to Amgen by MSKCC ................................................................ 102 
18.0 INFORMED CONSENT PROCEDURES ......................................................................... 103 
19.0 REFERENCES ............................................................................................................... 105 
20.0 APPENDICES ................................................................................................................. 109 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
Page 3 of 118 
 
 
A phase II study of talimogene laherparepvec (T-VEC) administered concurrently with 
the anti-PD1 monoclonal antibody pembrolizumab in patients with metastatic and/or 
locally advanced sarcoma. 
 
Sarcomas comprise a very diverse group of malignancies including more than 50 subtypes of 
bone and soft tissue origin. Despite optimal approach, approximately 25-50% of patients will 
develop recurrent and metastatic disease after receiving initial therapy with curative intent. In 
this setting, responses to standard cytotoxic chemotherapy occur in 10-30% of the cases and 
median survival is 10-18 months. 
Sarcomas are immunogenic neoplasms with a need for more therapeutic options. Prior 
immunotherapeutic agents have shown promise in select sarcoma patients. Using a 
combination of talimogene laherparepvec (T-VEC) administered intralesionally concurrently 
with the anti-PD1 monoclonal antibody pembrolizumab to treat patients with sarcomas and 
our planned scientific correlates, we believe we can assess the safety and efficacy of immune 
activating therapy and better understand the effects of combined therapy in antitumoral 
immune response. 
This is a single-center, phase II study to evaluate the efficacy of the oncolytic herpes virus 
talimogene laherparepvec, given in combination with pembrolizumab for patients with 
metastatic and/or locally advanced sarcomas. 
 
Patients will initiate treatment with talimogene laherparepvec given intralesionally and 
pembrolizumab. Talimogene laherparepvec treatment will be given at Day 1 Week 1, 4, and 
every 3 weeks thereafter. (Table 1). Pembrolizumab will be given at Day 1 week 1 and every 
3 weeks thereafter (Table 1). Patients will be reassessed at week 8 and every 8 weeks 
thereafter. Treatment will be repeated until the patient develops progressive disease, 
unacceptable toxicity or for up to 12 months. 
 
Table 1. Study design and treatment plan 
Design 
Talimogene 
laherparepvec 
Pembrolizumab 
One stage design 
Intralesionally: 
Up to 4mL at 106 pfu/mL 
at Week 1 
Up to 4mL at 108 
pfu/mL starting at Week 
4 and every 3 weeks. 
Dose: 200mg/dose at Week 1, 
and every 3 weeks thereafter. 
 
This phase II study will be conducted using a one-stage design, based on the exact binomial 
test. 
 
The primary objective of this study is to evaluate the efficacy, as assessed by the best 
objective response rate (complete response + partial response) at 24 weeks by RECIST 1.1, 
of talimogene laherparepvec in combination with pembrolizumab in patients with metastatic 
and/or locally advanced sarcoma. Secondary objectives are to assess the safety/tolerability 
of the treatment, to determine PFS rate at 24 weeks and OS and to evaluate the efficacy, as 
assessed by irRECIST. The study will accrue a maximum of 20 patients in a single stage 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
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design, with sequential monitoring for predefined treatment-related toxicities. Toxicity will be 
recorded using CTCAE v.4.03. 
 
All patients enrolled in this study will undergo biopsies at baseline and week 8 where feasible. 
Optional biopsies at progression will be offered. Biopsies will be done of both the lesion 
injected with talimogene laherparepvec and one additional target lesion, if technically feasible. 
Serial blood samples will be obtained at baseline, during, and after treatment. The trial 
schema is outlined below (Figure 1). 
 
Exploratory objectives include: 
 
I. 
To investigate the rate of seroconversion in patients HSV seronegative at baseline 
after initial intralesional infusion of talimogene laherparepvec 
II. 
To evaluate associations between selected biomarkers measured in serial 
peripheral blood and with clinical efficacy, including immunophenotyping and 
Functional Analyses, evaluation of serum levels of chemokines, cytokines and 
other immune mediators, and characterization of T-cell receptor clonality in 
peripheral blood. 
III. 
To assess the potential effect of talimogene laherparepvec cell lysis and 
pembrolizumab on selected biomarker expression measured in pre- and post- 
treatment tumor tissue and the association between these biomarkers and with 
clinical outcome, including characterization of PD-1/PD-L1 expression, tumor 
infiltrating lymphocytes (TILs) and tumor antigens, gene expression profiling, and 
characterization of T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL). 
IV. 
To evaluate the association between baseline tumor mutational burden and 
neoantigen production with clinical efficacy of the study therapy. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
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Figure 1A. Trial overview. 
 
 
 
Additional Cohorts: 
 
Following enrollment of the first 20 patients on this study additional cohorts will open. The 
additional cohorts will evaluate the efficacy and safety of T-VEC in combination with 
pembrolizumab in an additional 40 patients. The additional cohorts will enrich for sarcoma 
histological subtypes where the combination study therapy demonstrated activity in the 
initial 20 patients enrolled on the study including cutaneous angiosarcoma, epithelioid 
sarcoma, undifferentiated pleomorphic sarcoma and myxofibrosarcoma. The additional 
cohorts will consist of 3 cohorts of 10 patients. A metastatic/inoperable locally advanced 
sarcoma group (n=30) will consist of 3 cohorts of 10 patients each, based on histological 
subtype including epithelioid sarcoma (n=10), cutaneous angiosarcoma (n=10) and 
UPS/MFS (n=10) 
 
Patients enrolled metastatic/locally advanced cohort with inoperable disease will be treated 
in the same way as outlined above for the original 20 patients who were enrolled on the 
study. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Objectives 
Primary objective: To evaluate the efficacy, as assessed by the best objective response rate 
(complete response + partial response) at 24 weeks by RECIST 1.1, of talimogene 
laherparepvec in combination with pembrolizumab in patients with advanced sarcoma. 
 
Secondary objectives: 
1. To assess the feasibility of pembrolizumab in combination with talimogene 
laherparepvec as determined by study completion to facilitate efficacy assessment 
without early termination due to excessive treatment-related toxicities. 
2. To assess the safety of talimogene laherparepvec in combination with pembrolizumab 
in patients with advanced sarcoma using CTCAE v4.03 criteria for toxicity assessment 
3. To determine the progression free survival (PFS) rate at 24 weeks by RECIST 1.1 and 
irRECIST, and overall survival (OS) for patients treated with talimogene laherparepvec 
in combination with pembrolizumab. 
 
4. To evaluate the efficacy, as assessed by the best objective response rate (complete 
response + partial response) at 24 weeks by immune-related response criteria 
(irRECIST), of talimogene laherparepvec in combination with pembrolizumab in 
patients with advanced sarcoma. 
Exploratory objectives and correlative studies: 
I. 
To investigate the rate of seroconversion in patients HSV seronegative at baseline 
after initial intralesional infusion of talimogene laherparepvec 
II. 
To evaluate associations between selected biomarkers measured in serial peripheral 
blood with clinical efficacy, including immunophenotyping and functional analyses, 
evaluation of serum levels of chemokines, cytokines and other immune mediators, and 
characterization of T-cell receptor clonality in peripheral blood. 
III. 
To assess the potential effect of talimogene laherparepvec cell lysis and 
pembrolizumab on selected biomarker expression measured in pre- and post- 
treatment tumor tissue and the association between these biomarkers and with clinical 
outcome, including characterization of PD-1/PD-L1 expression, tumor infiltrating 
lymphocytes 
(TILs) 
and 
tumor 
antigens, 
gene 
expression 
profiling, 
and 
characterization of T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL). 
IV. 
To evaluate the association between baseline tumor mutational burden and 
neoantigen production with clinical efficacy of the study therapy. 
 
 
Additional Cohorts: Primary and Secondary Objectives 
 
Locally advanced/metastatic cohorts 
Primary objective: To estimate the efficacy, as assessed by the best objective response rate 
(complete response + partial response) at 24 weeks by RECIST 1.1, of talimogene 
laherparepvec in combination with pembrolizumab in each sarcoma subtype-specific cohort 
[(i) UPS/myxofibrosarcoma, (ii) epithelioid sarcoma and (iii) cutaneous angiosarcoma] 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
Page 7 of 118 
 
 
Secondary objectives: 
1. To assess the safety of talimogene laherparepvec in combination with pembrolizumab 
in patients with advanced sarcoma using CTCAE v4.03 criteria for toxicity assessment 
 
2. To determine the progression free survival (PFS) rate at 24 weeks by RECIST 1.1 and 
irRECIST and overall survival (OS) for patients in each sarcoma subtype-specific 
cohort treated with talimogene laherparepvec in combination with pembrolizumab.. 
 
3. To evaluate the efficacy, as assessed by the best objective response rate (complete 
response + partial response) at 24 weeks by immune-related response criteria 
(irRECIST), of talimogene laherparepvec in combination with pembrolizumab in each 
sarcoma-subtype specific cohort. 
 
Additional Cohorts: Exploratory Objectives 
Exploratory objectives: 
1. To evaluate associations between selected biomarkers measured in serial peripheral 
blood with clinical efficacy, including immunophenotyping and functional analyses, 
evaluation of serum levels of chemokines, cytokines and other immune mediators, and 
characterization of T-cell receptor clonality in peripheral blood. 
 
2. To assess the potential effect of talimogene laherparepvec cell lysis and 
pembrolizumab on selected biomarker expression measured in pre- and post- 
treatment tumor tissue and the association between these biomarkers and with clinical 
outcome, including characterization of PD-1/PD-L1 expression, tumor infiltrating 
lymphocytes (TILs) and tumor antigens, gene expression profiling, bulk RNA 
sequencing to define the immune infiltrate, single cell RNA sequencing of TILs, and 
characterization of T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL). 
 
3. To evaluate the association between baseline tumor mutational burden and 
neoantigen production with clinical efficacy of the study therapy. 
 
4. To evaluate the potential for noninvasive imaging modalities including photography, 
confocal microscopy, optical coherence tomography, and ultrasound for the purposes 
of monitoring and/or predicting response to therapy in patients with cutaneous disease 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Sarcomas – unmet need for new therapies. 
Sarcomas correspond to a heterogeneous group of mesenchymal neoplasms of bone and 
soft tissue origin characterized by more than 50 distinct subtypes. Approximately 13,000 
cases of soft tissue and bone sarcomas are diagnosed annually in the US. Surgery is the 
mainstay of therapy for localized sarcoma, and adjuvant radiation therapy and chemotherapy 
are used in very particular situations. Despite primary combined modality therapy, between 
25-50% of patients develop recurrent and/or metastatic disease.1,2 Complete responses to 
chemotherapy for recurrent or metastatic sarcoma are rare, and median survival in the 
metastatic setting is 10-18 months.3,4  Standard cytotoxic chemotherapy agents such as 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
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doxorubicin, ifosfamide, and dacarbazine result in objective responses in 10-30% of the 
patients, and this is significantly influenced by histologic variant.5 The development of novel 
and effective therapies is desperately needed for patients with advanced/metastatic 
sarcomas. 
 
3.2 Sarcoma: an immunogenic tumor 
Immunotherapeutic strategies may be a promising approach to treating this disease. The role 
of the immune system as a mechanism of cancer therapy was first observed in a sarcoma 
patient who had a response after an erysipelas infection.6 Sarcomas are more common in 
patients who are immunosuppressed.7 Infiltration of lymphocytes has been demonstrated in 
sarcomas.8 Furthermore, tumor-infiltrating lymphocytes have been associated with improved 
survival in Ewing’s sarcoma and GIST.9-12 Spontaneous regression of primary tumors have 
been seen in desmoid tumors and osteosarcomas.13,14 There have been multiple clinical trials 
evaluating the role of immune stimulants such as IL-2, interferon, and liposomal-muramyl 
tripeptide phosphatidylethanolamine showing some benefit in sarcoma patients.15-21 T cells 
genetically engineered to target NY-ESO-1 expressing synovial sarcoma have shown some 
promise.22 In patients with GIST, tyrosine kinase inhibitors such as imatinib can have 
stimulating effects on multiple immune cells.12 
3.3 Oncolytic immunotherapy in sarcomas: inducing direct antitumoral effect through 
cell lysis and stimulating antigen-directed immune response. 
Although the role of viruses in treatment of cancer has long been studied, only recently the 
incorporation of gene engineering techniques has allowed significant improvements in the 
antitumoral activity of replicating viruses. Advances in molecular biology and recombinant 
DNA technology allowed for the development of viruses with genetically altered, highly 
specific cytolytic properties. As a result, oncolytic virotherapy has led to promising results in 
the management of several malignancies.23-25 In addition to direct cytopathic effects caused 
by intracellular viral replication (oncolysis); genetic manipulation has allowed the development 
of strains capable of increasing cytotoxic activity and enhancing antitumoral immune 
responses mediated by transcription products from engineered viral genome. Furthermore, 
both cellular and humoral immune responses have been documented following administration 
of oncolytic viruses.26-29 In the preclinical setting, direct intratumoral injections of oncolytic 
viruses have been shown to induce tumor regression in a variety of syngeneic and xenograft 
ed rodent tumor models. Interestingly, unilateral injection of oncolytic herpesvirus in mice 
bearing bilateral tumors resulted in regression of distant lesions and further resistance to 
subsequent tumor inoculation, coupled with the expression of cell-specific cytotoxic T 
lymphocytes.30-31 To further develop this concept, a variety of strains have been engineered 
to express different immunostimulatory molecules, including cytokines (IL-2, IL-12, GM-CSF), 
tumor-associated antigens, co-stimulatory proteins (CD80 and CD40 ligand) and chemokines. 
Following the documentation of antitumoral activity in neural neoplasms, ovarian cancer, 
melanoma and other epithelial malignancies, 25 oncolytic viruses were also studied in sarcoma 
tumor cells. Different strains of adenovirus, herpesvirus, vaccinia and RNA viruses have been 
shown to be able to infect sarcoma cells and result in antitumoral effect.25, 32, 33 For example, 
studies with adenoviruses showed their ability to infect and replicate in multiple bone and soft 
tissue sarcoma cell lines32 and it was recently shown to be well tolerated in a Phase I trial of 
patients with advanced solid tumors including sarcomas.33 Ewing sarcoma panels were 
tested for adenoviral receptors and were found to be receptive to adenoviral replication and 
cytotoxicity.34, 35 After Phase I studies confirmed safety,36 Phase II studies were designed with 

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IRB Number: 16-1534 A(20) 
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concurrent chemotherapy and confirmed in vivo viral replication and anti-tumor activity in 
sarcoma patients.37 Similar findings were reported in studies with Vaccinia, Reovirus and 
other RNA viruses.38, 39 
In this setting, herpesviruses showed some potential advantages. Herpes simplex virus-1 
(HSV) is a large, double-strand DNA, enveloped virus. Modern engineering techniques 
allowed the genetic manipulation of HSV and elimination of the ICP34.5 gene responsible for 
neurovirulence, without compromising its infectivity and replication capabilities.40 Its large 
genome makes it more amenable to incorporation of therapeutic transgenes. In vitro, HSV 
strains G207 and NV1020 were capable of infecting multiple sarcoma cell lines, including 
malignant fibrous histiocytoma, rhabdomyosarcoma and osteosarcoma, 41 and also were able 
to induce complete cytopathic effects in specific subsets. Further investigations revealed that 
similarly designed viruses induced regression in rhabdomyosarcoma xenografts, 42 with 
enhanced antitumoral activity when combined with vincristine, and in malignant peripheral 
nerve sheath tumors (MPNST).43 
As previously shown, engineered oncolytic herpesviruses have been tested and showed 
activity in sarcoma cell lines and xenograft models and are currently under clinical 
development.44 
 
3.4 Talimogene laherparepvec: an oncolytic immunotherapy derived from HSV-1 with 
documented activity in other malignancies. 
 
3.4.1 A brief overview of talimogene laherparepvec 
Talimogene laherparepvec (T-VEC, formerly named OncoVEX) is an intralesionally delivered 
oncolytic immunotherapy derived from herpes simplex virus type-1 (HSV-1) that is deleted for 
the neurovirulence factor ICP34.5. The genes encoding ICP34.5 are replaced by the coding 
sequence for human GM-CSF, resulting in its ability to selectively replicate within tumors and 
to produce GM-CSF to enhance systemic antitumor immune responses after virus 
replication.45, 46 Since herpes simplex viruses have the advantage of induced direct cytolytic 
effect, talimogene laherparepvec exhibits a unique mechanism that combines direct lysis of 
tumor cells with adaptive immune system stimulation. 
3.4.2 Clinical experience with talimogene laherparepvec (IMLYGIC®) 
In a phase I trial with multiple refractory malignancies (melanoma, breast, gastrointestinal and 
head and neck), intralesional talimogene laherparepvec resulted in HSV-antigen-associated 
tumor necrosis and disease stabilization, including 2 patients with melanoma.47 Treatment 
was well tolerated and most side effects were reactions at the injected tumor sites. Pyrexia 
and flu-like constitutional symptoms were also reported. The promising results prompted a 
phase II trial to investigate the clinical efficacy of talimogene laherparepvec in patients with 
stage IIIC and IV melanoma. Intratumoral talimogene laherparepvec was administered at a 
dose of 4ml of 106 pfu/ml followed 3 weeks later by up to 4ml of 108 pfu/ml and then every 2 
weeks, up to 24 treatments (infusions). The overall response rate was 26%, including 8 
complete responses and 5 partial responses. Interestingly, responses occurred in both 
injected and distant metastatic sites, including liver, lungs and lymph nodes. Treatment was 
well tolerated.48 
In an open-label, randomized, phase III trial initially presented at ASCO 2013, talimogene 
laherparepvec compared to GM-CSF resulted in significant antitumoral activity in 436 
patients with advanced melanoma.49 Talimogene laherparepvec was administered 
intralesionally (subcutaneously or intranodally). The primary outcome measure was durable 

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response rates (DRR) defined as the percentage of patients with response rates lasting 6 
months or more at any time in their treatment course. This trial met its primary endpoint of a 
statistically significant improvement in durable response rates; 26% of the patients achieved 
objective responses, including 11% with complete responses and 16 % who had durable 
responses. Responses occurred in injected, non-injected and visceral lesions. Initial survival 
analysis of the OPTiM trial were recently presented; although the difference did not reach 
statistical significance, an increase of 4.4 mos in overall survival with talimogene 
laherparepvec was observed (p =0.051; HR 0.787). Median OS was 23.3mos with 
talimogene laherparepvec vs 18.9mos with GM-CSF. The most common side effects in the 
OPTiM study were chills (talimogene laherparepvec, 49%; GM-CSF, 9%), pyrexia (43%; 
9%), injection-site pain (28%; 6%), nausea (36%; 20%), influenza-like illness (30%; 15%), 
and fatigue (50%; 36%).Grade ≥ 3 adverse events occurred in 36% of subjects receiving 
talimogene laherparepvec and 21% of subjects receiving GM-CSF. The only grade 3/4 
adverse events occurring in ≥ 5 subjects was cellulitis (talimogene laherparepvec, n=6 
[2.1%]; GM-CSF, n=1 [<1%]). Of 10 fatal adverse events in the talimogene laherparepvec 
arm, eight were attributable to disease progression. The remaining two fatal adverse events 
(sepsis in the setting of salmonella infection; myocardial infarction) were not considered 
treatment-related per investigator 49Final planned overall survival analysis suggested a 
trend towards improved survival, although the difference did not reach statistical significance 
(median OS 23.3m vs 18.9m; p=0.0494).49 
Additional insights into the mechanism of talimogene laherparepvec induced response 
provide 
further 
basis 
for 
the 
combination 
of 
talimogene 
laherparepvec 
with 
immunomodulatory agents. In a secondary analysis of the phase II clinical trial published by 
Kaufman and colleagues, the analysis of effector T cells in tumor samples of melanoma 
patients treated in the phase II talimogene laherparepvec trial suggested an antigen-specific 
effector T cell response induced by talimogene laherparepvec. CD8+ T cells derived from 
peripheral blood specimens revealed a significant increase in MART-1 response, indicating 
development of systemic antigen-specific antitumor immunity. In addition, vaccination 
induced downregulation of regulatory T lymphocytes at the tumor sites of responding 
patients.50 In addition it has been demonstrated in vitro that GM-CSF induces production of 
proinflammatory cytokines, by human T lymphocytes and antigen presenting cells, including 
IL-12, TNFα and IFN-γ. It is also associated with recruitment and expansion of dendritic cells, 
macrophages and granulocytes and differentiation of monocytes into dendritic cells.51, 52 
As a result, antigen release and proinflammatory effects induced by GM-CSF production by 
talimogene laherparepvec could be further amplified by concurrent administration of immune 
checkpoint inhibitors and enhance antitumoral activity in a synergistic mechanism. 
3.5 Tackling different steps in the immune activation cascade to enhance antitumoral 
immune responses: a possible role for combining oncolytic therapy with immune 
checkpoint blockade. 
As highlighted before, lysis of cells infected by oncolytic viruses not only leads to direct 
antitumoral effects, but also results in the exposure of tumor-associated antigens to circulating 
antigen-presenting cells,53 suggesting a conceptual model in which oncolytic viruses in 
association with immune checkpoint blockers could further enhance the anti-tumoral 
activity.54-61 In mouse models, infection of cells by HSV-1716 resulted in increased 
expression of molecules associated with dendritic cells maturation and increased cross- 
presentation of antigens.53 

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A key issue in T-cell mediated antitumoral effect is redirecting immune activity against specific 
antigens and allowing a synergistic interaction to enhance immune responses. Since the first 
step in the activation of anticancer immune responses involves the processing of tumoral 
neoantigens by dendritic cells,62 antigens release by tumor cells could initiate or reinitiate a 
self-sustaining process in the setting of immune checkpoint blockade. 
T cell activation requires a dual signaling.63, 64 the binding of the T cell receptor to antigens 
presented by antigen presenting cells via major histocompatibility complex I and II is the first 
required signal in T cell activation. Subsequently, the second signal is generated by specific 
molecules which bind to co-stimulatory receptors in T cells. This signaling leads to T cell 
proliferation, cytokine release and upregulation of the immune response. As a result of T cell 
activation, several negative regulators of T cells become overexpressed as a mechanism to 
prevent autoimmunity and tolerance to self antigens. Cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are examples of inhibitory T cell 
receptors. Blockade of CTLA-4 and PD-1 has shown promising results in the treatment of 
melanoma and other malignancies, with clinical trials demonstrating antitumoral activity and 
durable responses.65-67 
Strategies combining different steps of the immune activation cascade have been proved a 
promising and safe approach. Using melanoma murine models, Zamarin et al. demonstrated 
that intralesional injection of a oncolytic Newcastle disease virus (NDV) in combination with 
systemic CTLA-4 blockade was able to induce lymphocytic infiltrates and antitumor effects in 
distant (non-virally injected) lesions mediated by infiltration by CD8+ and CD4+ effector T 
cells.68 In a randomized phase II trial, the ant-CTLA-4 antibody ipilimumab combined with 
subcutaneous GM-CSF resulted in improved overall survival (HR 0.65; stratified log rank 
p1=0.016, p2=0.033) in patients with melanoma.69 Interestingly, a trend toward improved 
tolerability was noted in the combination arm versus ipilimumab monotherapy. talimogene 
laherparepvec has also been combined with ipilimumab in patients with advanced melanoma. 
In a phase 1b/2 trial presented at the ASCO meeting in 2014, talimogene laherparepvec was 
given by intralesional injection to 18 patients at weeks 1, 4 and then every 2 weeks in 
association with ipilimumab every 3 weeks starting at week 6 (clinical trial number 
NCT01740297).70 Only 2 patients had possible immune-related grade 3 or 4 adverse events. 
Correlative studies showed increased activated CD8+ T-cells during talimogene 
laherparepvec + Ipilimumab treatment.70 
As previously mentioned, PD-1 receptor is another promising potential immunological target. 
Similar to ipilimumab, this is an immune checkpoint receptor that is expressed by activated T 
cells. PD-1 is a member of the CD28 family of T-cell costimulatory receptors that also includes 
CD28, CTLA-4, ICOS and BTLA.71 PD-1 is expressed on activated T cells, B cells and myeloid 
cells.72 There are 2 ligands, programmed cell death ligands 1 and 2 (PD-L1 and PD-L2) that 
are specific for PD-1; PD-L1 is frequently expressed within the tumor microenvironment. 
Once they bind to PD-1, down-regulation of T-cell activation occurs.73, 74 When the PD-1 ligand 
binds to the receptor, the T cell activation is blocked. If this interaction is interrupted, the 
checkpoint is turned off and antitumor T-cell activation may get enhanced. Indeed, inhibitory 
antibodies targeting PD-1 and PD-L1 have demonstrated objective responses in multiple 
tumor types including melanoma. In a study that enrolled and treated 296 patients with 
nivolumab, a monoclonal antibody targeting PD-1, response rates were 18%, 28% and 27% 
in patients with non-small cell lung cancer, melanoma and renal cell carcinoma, 
respectively.75 There was initial evidence that PD-L1 expression could correlate with clinical 
activity of PD-1 blockade, suggesting PD-L1 expression as one possible biomarker of 
response. These data prompted interest in exploring PD-L1 expression in sarcoma. Our 

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group has demonstrated very high PD-L1 expression in nearly 65% of sarcoma cell lines 
tested, including synovial sarcoma, Ewing sarcoma, rhabdomyosarcoma, liposarcoma, 
malignant peripheral nerve sheath tumors, desmoplastic small round cell, osteosarcoma and 
chondrosarcoma. We then evaluated PD-L1 expression in 50 sarcoma tumor specimens of 
various subtypes. Immunohistochemistry (IHC) was performed on tumor specimens using a 
Qualtek monoclonal antihuman PD-L1 antibody (clone 28-8) and an automated assay 
developed by Dako. We identified ≥1% PDL-1 expression in 6/50 (12%) of samples. There 
was evidence of macrophage and lymphocyte infiltration both within the tumor and in its 
surrounding tissue. In a recent study presented at ASCO, Movva and colleagues reported 
high rates of PD-L1 in liposarcomas and chondrosarcomas.76 
The combination of talimogene laherparepvec and the anti-PD-1 inhibitory antibody, 
pembrolizumab, has been explored in the phase Ib setting of patients with unresectable, stage 
IIIB/IV, treatment naive melanoma. talimogene laherparepvec (≤4mL) was injected into 
cutaneous, subcutaneous, or nodal lesions: 106 PFU/mL day 1, 108 PFU/mL day 22 then 
every 2 weeks thereafter. Pembrolizumab was added from day 36 at 200mg IV every 2 weeks. 
The trial enrolled 21 patients. No dose limiting toxicities were reported. All 21 patients 
experienced a treatment-related adverse event (TEAE). The TEAE rate was 19%; G3 TEAE 
rate was 29%, there were no G4 TEAEs. The most common TEAEs were rash (57%), pyrexia 
(38%), fatigue (29%), chills (24%), nausea (19%), pruritis (19%), diarrhea (19%), vomiting 
(14%), headache (14%), and arthralgia (14%). The only G3 TEAEs occurring in >1 patient 
were anemia (n=2) and rash (n=2; 1 macular and 1 general rash, both following first 
pembrolizumab). One patient experienced a G1 cytokine release syndrome (attributed to 
combination treatment). One death occurred on study due to septic shock that was not 
deemed to be treatment related. No patients discontinued therapy due to adverse events. 
Ultimately, this study conveyed that the combination therapy is safe and well tolerated at full 
dose.91 The findings of this phase Ib trial support the initiation of the randomized phase III part 
of the study that aims to evaluate the efficacy and safety of the combination therapy compared 
to pembrolizumab alone (clinical trial number NCT 02263508). The combination will also be 
explored in an ongoing phase Ib/III multicenter, randomized open-label trial in patients with 
recurrent or metastatic squamous cell carcinoma of the head and neck (clinical trial number 
NCT02626000). 
3.6 
Pembrolizumab – a monoclonal antibody targeting PD-1 
3.6.1 A brief overview of pembrolizumab 
Pembrolizumab (previously named lambrolizumab and MK-3475), is a highly selective 
humanized monoclonal IgG4–kappa isotype antibody against PD-1 currently approved by the 
Food and Drug Administration (FDA) for the treatment of patients with advanced melanoma 
at a dose of 2mg/kg given every 3 weeks.77-80 
 
3.6.2 Summary of clinical experience with pembrolizumab 
The first dose-escalation phase 1 study involving patients with solid tumors showed that 
pembrolizumab was safe across 3 tested dose levels (1mk/kg; 3mg/kg and 10mg/kg) 
administered every 2 weeks; of note, the maximum tolerated dose was not reached and 
clinical responses were observed at all of the dose levels.77 Subsequent studies confirmed 
the clinical activity of pembrolizumab. Hamid et al. initially investigated pembrolizumab at 
doses of 2mg/kg every 3 weeks and 10mg/kg given every 2 or 3 weeks in a melanoma-only 

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cohort in a non-randomized fashion in the KEYNOTE-001 trial.78 Objective responses 
occurred in 38% of 135 included patients. Grade 3 or 4 adverse events occurred in only 13% 
of the patients. In a subsequent cohort of the same KEYNOTE-001 phase I trial, 79 173 
patients with advanced melanoma were randomized to receive pembrolizumab at 2mg/kg 
every 3 weeks or 10mg/mg every 3 weeks. ORR was 26% at both doses after a median follow 
up of 8 months, with no difference in OS between different doses (estimated OS at 1 year 
58% vs 63%, 95% CI 0.68-1.75). In the expansion cohort of the same trial including a total of 
411 patients, pembrolizumab resulted in objective responses in 40% untreated patients.80 
3.7 Identifying predictive biomarkers for response to immunotherapy 
One major challenge to harnessing immune checkpoint inhibitors in sarcomas is identifying 
patients who have the highest chance of benefiting from this modality of therapy. To address 
this question, lessons can be extrapolated from other tumor types and applied to sarcomas. 
We believe the heterogeneity inherent to sarcomas makes them an ideal group of tumors to 
validate a prospective biomarker for response to immune activating agents. 
It is unclear how best to predict which patients will benefit from immune checkpoint inhibitors. 
While the initial phase I trial of nivolumab suggested tumors expressing PD-L1 by 
immunohistochemistry (IHC) may benefit more frequently from PD-1 blockade,75 more recent 
data from the combination ipilimumab plus nivolumab trial has cast doubt on the theory that 
PD-L1 expression is necessary for therapeutic benefit. Among patients that received 
combination therapy, responses were seen both in patients with PD-L1 expression (6/13) or 
those without PD-L1 expression (9/22.) 
At the ASCO 2014 meeting, there were data presented in multiple malignancies 
demonstrating benefit to PD-1/PD-L1 blockade for patients regardless of their PD-L1 
expression. It is known that PD-L1 expression remains a dynamic marker that can change 
over time and under different conditions in the microenvironment. Tumor heterogeneity can 
also contribute to varied PD-L1 expression.81 These data suggest that PD-L1 expression may 
change as a result of therapy with immune checkpoint inhibitors or that other mechanisms 
underlie the response to immune checkpoint blockade. There remains the need to define a 
better biomarker predictive of response to PD-1 blockade. 
3.7.1 Tumor Neoantigens May Underlie Response to Immune Checkpoint Inhibition 
Recently, a report by van Rooij et al associated a response to ipilimumab in a patient with 
melanoma with T cell recognition of a tumor-specific mutant protein, termed a ‘neoantigen’.82 
To do this, they performed whole exome sequencing of the melanoma tumor tissue and tumor 
infiltrating lymphocytes (TILs) and identified >1000 tumor-specific mutations. They then 
utilized NetMHC, an online predictor of Class I major histocompatibility complex (MHC)- 
specific affinities for specific sequences of 9-11 amino acids, to narrow the mutant sequences 
to 448 peptides predicted to bind with medium to high affinity to the patient’s CD8+ T cells.83 
These peptides were screened for binding with patient TILs, and they identified 3.3% of all 
patient CD8+ T cells reacted with a specific mutated epitope in the ataxia-telangiectasia and 
Rad3-related protein (ATR) pathway, suggesting this resulted in the clinical benefit seen in 
this patient. 
Further support for neoantigen-specific immune surveillance has come from in vivo models of 
sarcoma. In a murine model of chemically-induced sarcomas arising in immune-deficient 
Rag2-/- mice, Matsushita et al reported that implantation into an immunocompetent murine 

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host resulted in “immune editing” of the tumor, and tumors with a greater neoantigen load 
were frequently rejected by the new host.84 Similar results were seen in a conditional Kras- 
p53 knockout mouse model. Whereas the work of van Rooij et al and Matsushita et al 
suggests that certain key mutations predict response, DuPage et al and other authors imply 
that a higher overall mutational load and resulting neoantigen burden may lead to efficacy.85 
The Chan lab at MSKCC has proprietary data supporting the association between this patient- 
specific neoantigen analysis in melanoma with individual clinical benefit from ipilimumab and 
tremelimumab. Whole exome sequencing was performed on tumor tissue and matched blood 
samples from 64 patients with melanoma who were treated with anti-CTLA-4 blockade 
(ipilimumab or tremelimumab). A neoantigen signature incorporating both mutational load 
and patient-specific neoantigens was shown to separate patients with prolonged clinical 
benefit from patients with progressive disease. They then validated this signature in another 
set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. In this 
validation set predicted neoantigens activated T cells from patients treated with ipilimumab. 
This work defines a genetic basis for benefit to anti-CTLA-4 blockade in melanoma and 
provides strong rationale for examining exomes of patients receiving other immunotherapies 
to similarly see if a genetic basis can be defined for response or resistance to these 
immunotherapies.96 
Sarcoma is an ideal tumor subtype in which to test this hypothesis prospectively. The Singer 
laboratory at MSKCC has shown that different histologies show markedly different amounts 
of genetic alteration.86 It is perhaps not surprising that a previous pilot study of ipilimumab in 
synovial sarcomas, a translocation-positive, genetically “simpler” tumor, produced no clinical 
responses.87 There are currently no published whole exome mutation studies in sarcoma, 
which underscores how important this research will be to the sarcoma community. 
 
3.8 
Summary statement 
Hence, there is strong rationale supporting the concept that, besides the antineoplastic effects 
of direct oncolysis, immune stimulation induced by GM-CSF and increased local antigen 
release induced by the oncolytic immunotherapy talimogene laherparepvec combined with 
immune checkpoint blockade using the anti-PD1 agent pembrolizumab could result in 
synergistic antitumoral antigen-specific activity in patients with metastatic and/or locally 
advanced sarcomas. The safety of this combination therapy has been explored in a phase 
Ib study in the setting of patients with treatment naïve, unresectable stage IIIB/IV melanoma. 
Ultimately, this study conveyed that the combination therapy is safe and well tolerated at full 
dose.91 Therefore, it is reasonable to now explore the efficacy of this combination therapy in 
a phase II study in patients with advanced/metastatic sarcoma. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
This is a single-center, single-arm phase II clinical trial with additional cohorts to evaluate 
efficacy, as assessed by response rate, of the oncolytic herpes virus talimogene 
laherparepvec given in combination with the anti-PD1 monoclonal antibody pembrolizumab 
for patients with metastatic and/or locally advanced sarcomas. 
Patients will initiate treatment with talimogene laherparepvec given intralesionally and 
pembrolizumab. Talimogene laherparepvec treatment will be given at Day 1 Week 1, and 
every 3 weeks thereafter. (Table 1). Pembrolizumab will be given at Day 1 week 1 and every 

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3 weeks thereafter (Table 1). Patients will be reassessed at week 8 and every 8 weeks 
thereafter. 
 
Patients will be evaluated radiographically at baseline, week 8 (+/- 7 days) and every 8 
weeks (+/- 7 days) subsequently until week 56 and then every 12 weeks thereafter or as per 
the discretion of the treating investigator. Response will be assessed using RECIST v1.1 
(primary response assessment) and immune-related response criteria (irRECIST) 
(secondary response assessment). 
 
The study will be sequentially monitored for pre-defined treatment-related toxicity events 
based on an early stopping rule as detailed in section 11. All study participants where feasible 
will undergo mandatory tumor biopsies, at baseline and week 8, of a distant site of disease. 
A site not intended to be injected is preferred for biopsy where feasible. Optional biopsies at 
progression will be offered. Serial blood samples will be obtained at baseline, during, and 
after treatment. Talimogene laherparepvec and pembrolizumab dosing should continue 
provided that the subject has no evidence of confirmed PD within 8 weeks of initial PD per 
RECIST, has no clear clinical deterioration and is able to tolerate the treatment. Treatment 
beyond progression will be allowed as long as patient is clinically benefitting, is tolerating the 
drug well and continues to meet all study treatment criteria. 
 
Subjects with a CR or complete disappearance of the injectable lesion may stop intralesional 
injections of talimogene laherparepvec, but treatment with pembrolizumab will be continued 
for a maximum of 35 cycles of study therapy, unless one of the criteria for treatment 
discontinuation is met. Therapy will be discontinued due to confirmed progression of disease 
or clinical progression, disappearance of injectable lesions (talimogene laherparepvec only), 
intercurrent illness that prevents further administration of treatment, intolerance of study 
treatment or 24 months of treatment. Patients who discontinue study therapy after a 
maximum of 35 cycles of study therapy will be allowed to resume study therapy for an 
additional 17 cycles in the setting of progression of disease off study therapySafety data will 
be collected for up to 30 days following the last dose of the study drugs. 
 
Study personnel will attempt to collect survival status for all patients who have confirmed 
disease progression after the end-of-study visit every 12 weeks (± 14 days) via telephone, 
email, or another method for up to 12 months after the end of treatment. 
 
Patients who complete the study with a PR or CR per RECIST criteria will be followed every 
12 weeks (± 14 days) until confirmed disease progression with the following assessments: 
 
o Standard imaging including CT chest (with or without contrast), CT abdomen/pelvis 
(with contrast where renal function permits) and/or MRI abdomen/pelvis (with and 
without contrast) in addition to imaging of the affected area if deemed necessary by 
the study investigator 
o Routine laboratory tests including CBC with differential, comprehensive serum 
chemistry panel (including glucose, blood urea nitrogen, creatinine, sodium, 
potassium, chloride, bicarbonate, calcium, total protein, albumin, serum bilirubin, 
alkaline phosphatase, ALT, and AST) and TSH 
o MD visit (physical examination) 

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Following enrolment of the first 20 patients on this study additional cohorts will open. In the 
initial 20 patients enrolled on this study, the ORR overall was 35% and the ORR at 24 
weeks was 30%. Objective response was observed in 5 histological subtypes including 
UPS, myxofibrosarcoma, cutaneous angiosarcoma, epithelioid sarcoma and undifferentiated 
sarcoma not otherwise specified. The additional cohorts will include a total of 40 patients 
and will be divided into 4 cohorts. Thirty patients with inoperable, locally 
advanced/metastatic sarcoma will be enrolled onto one of 3 cohorts based on sarcoma- 
specific subtype [i) UPS/myxofibrosarcoma, ii) epithelioid sarcoma, iii) cutaneous 
angiosarcoma]. Each cohort will enroll 10 patients. Patients with inoperable, locally 
advanced/metastatic sarcoma will be treated following the study design as highlighted 
above. 
 
In the metastatic/locally advanced cohort, patients who achieve a CR or complete 
disappearance of the injectable lesion may stop intralesional injections of talimogene 
laherparepvec, but treatment with pembrolizumab will be continued. Study therapy may 
continue for a total of 35 cycles in the absence of confirmed progression of disease or clinical 
progression, disappearance of injectable lesions (talimogene laherparepvec only), 
intercurrent illness that prevents further administration of treatment, or intolerance of study 
treatment. Patients who discontinue study therapy after a maximum of 35 cycles of study 
therapy will be allowed to resume study therapy for an additional 17 cycles in the setting of 
progression of disease off study therapy. In the neoadjuvant setting, TVEC and 
pembrolizumab will continue for up to 8 cycles prior to surgical resection. On completion of 
surgery pembrolizumab alone will continue as tolerated for a total of 17 cycles (neoadjuvant 
and adjuvant therapy). Safety data will be collected for up to 30 days following surgical 
resection. 
 
4.2 
Intervention 
Patients will be treated with intralesional injections of talimogene laherparepvec on Week 1 
and every three weeks thereafter and intravenous pembrolizumab on Week 1 and every three 
weeks thereafter, for up to 35 cycles. Patients who discontinue study therapy after a 
maximum of 35 cycles of study therapy will be allowed to resume study therapy in the setting 
of progression of disease off study therapy.In the additional neoadjuvant cohort, patients will 
receive up to 8 cycles of study therapy beginning on Week 1. On completion of surgery, 
pembrolizumab alone will continue as tolerated for a total of 17 cycles (neoadjuvant and 
adjuvant therapy). 
Talimogene laherparepvec will be administered intralesionally into injectable cutaneous, 
subcutaneous, accessible superficial or deep soft tissue and nodal lesions with or without 
ultrasound guidance. Talimogene laherparepvec must not be administered into visceral organ 
metastases. The initial dose of talimogene laherparepvec is up to 4.0 mL of 106 plaque- 
forming units (PFU)/mL on Week 1. Subsequent doses of talimogene laherparepvec are up 
to 4.0 mL of 108 PFU/mL on Week 4 and subsequent doses thereafter. When talimogene 
laherparepvec and pembrolizumab are administered on the same day, talimogene 
laherparepvec will be administered first. 
Pembrolizumab at a dose of 200mg/dose will be administered intravenously at Week 1 and 
every 3 weeks (±3 days) thereafter. Pembrolizumab infusion should be administered in 30 
minutes, with a window of -5 and +10 minutes, using an infusion pump. 

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5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1. 
Talimogene laherpevec (T-VEC) 
5.1.1 Mechanism of action 
Talimogene laherparepvec is an attenuated herpes simplex virus type 1 (HSV-1) derived by 
functional deletion of 2 genes, ICP34.5 and ICP47, and insertion of coding sequence for 
human granulocyte macrophage colony stimulating factor (GM-CSF). Deletion of ICP34.5 
allows talimogene laherparepvec replication in tumor tissue; normal cells are able to protect 
against talimogene laherparepvec infection as they contain intact anti-viral defense 
mechanisms. Deletion of ICP47 prevents down-regulation of antigen presentation molecules 
and increases the expression of HSV US11 gene, which enhances viral replication in tumor 
cells. GM-CSF recruits and activates antigen presenting cells which can process and present 
tumor-derived antigens to promote an effector T-cell response. 
5.1.2 Preclinical experience with talimogene laherparepvec 
Talimogene laherparepvec has been tested for efficacy in a variety of in vitro (cell line) and in 
vivo murine tumor models and has been shown to eradicate tumors or substantially inhibit 
their growth at doses comparable to those used in clinical studies. Nonclinical evaluation has 
also confirmed that GM-CSF enhances the immune response generated; enhancing both 
injected and uninjected tumor responses. 
 
5.1.2.1 Preclinical pharmacology – talimogene laherparepvec 
 
Nonclinical pharmacology studies, including in vitro studies of cytopathic effects and in vivo 
studies of efficacy in numerous tumor types, have been conducted with talimogene 
laherparepvec and its murine analog, OncoVEXmouseGM-CSF. Talimogene laherparepvec 
lyses a variety of in vitro human tumor cell lines in culture including colorectal cancer (HT29), 
breast 
cancer 
(MDA-MB-231), 
glioblastoma 
astrocytoma 
(U-87 
MG), 
prostate 
adenocarcinoma (LNCaP), and malignant melanoma (SK-MEL-28) tested at a multiplicity of 
infection (MOI) between 0.1 and 5; essentially all tumor cells were killed less than 48 hours 
following infection in vitro. Talimogene laherparepvec affects not only the tumors into which it 
is injected, but also distant non-injected tumors, demonstrating a systemic beneficial effect 
from local administration. Talimogene laherparepvec suppresses tumor recurrence upon re- 
challenge with the same tumor type, and remains effective when animals have undergone 
previous exposure to wild-type HSV or are immunosuppressed with cyclosporin. Talimogene 
laherparepvec has been tested to evaluate the combined effects of either radiation or 
chemotherapy in preclinical studies. Both combinations were tolerated could support potential 
clinical studies with these other agents for the treatment of cancer. 
 
5.1.2.2 
Preclinical 
safety 
pharmacology 
and 
toxicology 
– 
talimogene 
laherparepvec 
 
Toxicology – Talimogene laherparepvec 
 
The toxicology program evaluated the safety of talimogene laherparepvec in a number of 
preclinical animal models. These pivotal single- and repeat-dose toxicology and embryo-fetal 
development studies were performed in accordance with Good Laboratory Practice (GLP) 
regulations, and Office of Economic Cooperation and Development standards. High and 
multiple doses of talimogene laherparepvec, up to 107 PFU/animal, were well tolerated in 

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immune competent mice following SC, IV, or intralesional injection. Key findings following 
repeated SC administration of talimogene laherparepvec included reversible inflammation at 
the injection site; increased total white blood cells, neutrophils and lymphocytes (all 
reversible); and evidence of transient immune activation (enlargement and increased 
germinal centers in the spleen, lymphoid hyperplasia in spleen and bone marrow). These 
effects are consistent with the normal response of animals to administration of a virus, and 
development of normal anti-viral immunity. As a general rule, mice treated with talimogene 
laherparepvec tended to seroconvert and develop anti-HSV-1 antibodies. No evidence of 
overt toxicity to any cell type or organ, and no evidence of virally-associated 
neuropathology/neurovirulence were observed in animals treated with talimogene 
laherparepvec. Intravenous injection of talimogene laherparepvec at doses of 105, 106, or 107 
PFU/dose on gestation days 6, 9, 12, and 15 had no impact on embryo-fetal viability and 
development, or skeletal variations or malformations as assessed on gestation day 18. 
Assessment of maternal blood demonstrated a dose-dependent increase in viral DNA 
concentration. Systemic infection and lethality in nude mice treated with talimogene 
laherparepvec was observed at doses that are 10- to 100-fold higher than those that result in 
100% lethality in nude mice treated with wild-type HSV-1, indicating that talimogene 
laherparepvec is attenuated for causing systemic infection. These data indicate an important 
role of host defenses, including both T and B cell function, in the immune response to 
talimogene laherparepvec and HSV-1 viruses. Talimogene laherparepvec was also shown in 
preclinical studies to be sensitive to anti-viral therapy. For additional information, refer to the 
talimogene laherparepvec Investigator’s Brochure. 
Biodistribution – talimogene laherparepvec 
 
The biodistribution of talimogene laherparepvec in blood and all other tissues was evaluated 
using a validated quantitative polymerase chain reaction (qPCR) assay conducted in naïve or 
tumor-bearing BALB/c mice. 
 
The biodistribution of talimogene laherparepvec was predominantly restricted to tumor, blood, 
and tissues likely associated with immune-mediated viral clearance (i.e., spleen, lymph node, 
liver). Overall, the available data align with results previously reported in other biodistribution 
studies. For additional information, refer to the talimogene laherparepvec Investigator’s 
Brochure. 
 
5.1.3 Summary of clinical experience with talimogene laherparepvec 
Talimogene laherparepvec is approved in multiple regions and countries for the 
treatment of unresectable melanoma that is regionally or distantly metastatic. 
 
Analyses of efficacy have been conducted for studies with talimogene laherparepvec 
administered as monotherapy for various tumors (001/01, 002/03, 002/03-E, 005/04, 
005/05, and 005/05-E) and for studies of talimogene laherparepvec administered as 
combination therapy for various tumors (004/04, 006/09, 20110264, 20110265, and 
20130232). Key results are briefly summarized below and further details can be found in the 
investigator brochure for talimogene laherparepvec : 
 
Talimogene laherparepvec demonstrated initial biological activity as monotherapy 
(doses as low as 106 PFU/mL) in subjects with advanced solid tumors with 

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metastases in the skin or SC tissue as evidenced by necrosis or apoptosis in tumor 
biopsies (Study 001/01). 
 
Talimogene laherparepvec resulted in an improvement in durable response rate 
(DRR), a primary endpoint of Study 005/05 (defined as complete response [CR] or 
partial response maintained for 
6 months continuously and which had its onset on 
the first 12 months of treatment) compared with GM-CSF. At the primary analysis of 
overall survival (OS), a secondary endpoint of Study 005/05, median OS was 
23.3 (95% CI: 19.5, 29.6) months in the talimogene laherparepvec arm and 
18.9 (95% CI: 16.0, 23.7) months in the GM-CSF arm (hazard ratio [HR] 
0.79; 95% CI: 0.62, 1.00; p = 0.051). At final analysis, with an additional follow-up of 
5 months (median 49 months [range, 37–63]), median OS remained 4.4 months 
longer for talimogene laherparepvec compared with GM-CSF (23.3 months, 
95% CI: 19.5 to 29.6 vs 18.9 months, 95% CI: 16.0, 23.7; HR 0.79, 95% CI: 0.62, 
1.00, p = 0.0494, descriptive). Results from the phase 2 study in melanoma (002/03) 
also support the efficacy of talimogene laherparepvec for the treatment of melanoma. 
The high proportion of tumors that decreased in size and high rate of 
histopathological response at surgery suggested clinical activity with talimogene 
laherparepvec in combination with cisplatin and radiation in subjects with SCCHN 
(Study 004/04). Further investigations in a larger sample set were planned in the 
phase 3 study (006/09); however, this phase 3 study was terminated in July 2011 in 
light of emerging evidence regarding the influence of human papillomavirus status 
and smoking on prognosis following chemoradiation, and effects of these factors on 
the likelihood of study success. 
In the phase 2 portion of Study 20110264, a phase 1b/2 study evaluating the 
combination of talimogene laherparepvec and ipilimumab, treatment with talimogene 
laherparepvec and ipilimumab resulted in a statistically significant improvement in 
the primary endpoint of ORR (as evaluated by the investigator using modified 
immune-related response criteria [irRC]) compared with ipilimumab (38.8% vs 
18.0%; unadjusted odds ratio 2.9, 95% CI: 1.5, 5.5; p-value = 0.002). Median 
progression-free survival (PFS) time was 8.2 months in the talimogene 
laherparepvec and ipilimumab group and 6.4 months in the ipilimumab group 
(HR 0.83, 95% CI: 0.56, 1.23; p = 0.348). 
In the phase 1b portion of Study 20110265, a phase 1b/3 study evaluating the 
combination of talimogene laherparepvec and pembrolizumab (Long et al, 2016), 
21 subjects received talimogene laherparepvec and pembrolizumab in combination. 
At the time of the primary analysis, the confirmed ORR and complete response rate 
were 57.1% and 23.8%, respectively, per irRC. The unconfirmed objective response 
rate and complete response rate were 66.7% and 28.6%, respectively. Median PFS 
was not reached, with 71% of subjects progression free at 6 months. Further 
follow-up is ongoing. 
In the phase 1b portion of Study 20130232, a phase 1b/3 study evaluating the 
combination of talimogene laherparepvec and pembrolizumab in subjects with 
HNSCC, 36 subjects received talimogene laherparepvec and pembrolizumab in 
combination. The unconfirmed objective response rate was 15.6% (95% CI: 5.3, 
32.8) and the confirmed objective response rate was 9.4% (95% CI: 2.0, 25.0), per 
irRC. 

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Pharmacodynamics and Pharmacokinetics of talimogene laherparepvec in Humans 
 
Five clinical studies were conducted to characterize the dosing regimen, kinetics, viral 
shedding, clearance, anti-HSV-1 serostatus, and GM-CSF expression in tumor tissue of 
talimogene laherparepvec in subjects with metastatic melanoma and other cancer types 
including the first-in-human study92 and 4 other studies primarily designed to evaluate efficacy 
and safety but provided supportive data (clinical trial number NCT02574260, phase I/II study 
in SCCHN93, a phase II study in melanoma50 and a phase III study in melanoma.49 Of these 
4 studies, 2 evaluated subjects with metastatic melanoma (and 005/05).50,49, The other 2 
studies evaluated subjects in other indications (pancreatic cancer, clinical trial number NCT 
00402025,and cancer of the head and neck).93 
 
Clinical Biodistribution and Shedding Results – talimogene laherparepvec 
 
Data from the assessment of viral biodistribution of talimogene laherparepvec in humans are 
available from a number of clinical studies.92, 93, 50 All biodistribution data were based on qPCR 
and not viral culture; therefore, the potential for infectivity was not evaluable by this method. 
In summary, the biodistribution pattern of talimogene laherparepvec in blood and urine 
demonstrated consistently across studies that low copy numbers of viral DNA were 
sporadically detected in blood samples from 33% of subjects and urine samples from 22% of 
subjects from 1 hour to 1 week after intralesional injection. Blood and urine samples were 
negative by 2 weeks post-injection in those subjects for whom additional samples were 
available. The copy numbers of virus detected in blood and urine in all subjects at all collection 
time points was far lower than those present in the doses administered during treatment. 
Viral shedding was assessed by the collection of swab samples from the surface of 
injected tumors and the exterior dressing. The samples were analyzed by a plaque 
assay or 50% tissue culture infective dose (TCID50; Study 20120324 only) to determine if 
any infectious virus was present and to assess whether the occlusive dressings provided 
adequate containment for virus present at the tumor surface. The infectivity assays did 
not distinguish between wild-type HSV-1 and talimogene laherparepvec. It was 
assumed that a positive assay result indicated the presence of talimogene 
laherparepvec since the probability that wild-type HSV-1 was present on the surface of 
injected tumors and/or dressings would be very low. 
Investigative swab samples were collected after each injection in Studies 001/01 and 
004/04 and after the first injection in Study 002/03. In all studies (with the exception of 
pancreatic cancer Study 005/04), “reactive” swabs were collected from herpes labialis or 
other non-injected lesions that arose during treatment and that were suspected to be 
herpetic in origin, and from injected tumors that were oozing or weeping. 
The most comprehensive set of samples (ie, in terms of the number of time points 
tested) was obtained from Study 001/01. Overall, at any time point, a low percentage of 
subjects (13% [4 of 30]) had swabs that were positive for virus at the tumor site. These 
samples were further tested by a specific custom polymerase chain reaction (PCR) 
assay to distinguish between talimogene laherparepvec and wild-type HSV; it was 
determined that the virus detected in 3 of the swab samples was talimogene 
laherparepvec and not wild-type HSV. 
Results from Studies 002/03 and 004/04 were consistent with those from Study 001/01. 
Investigative swabs collected from the first 28 subjects in Study 002/03 (before the 

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protocol amendment removed this testing) showed that only a single subject (4%) had a 
positive investigative swab sample from the tumor site and 3/17 subjects (18%) in 
Study 004/04 had investigative swabs that were positive at the tumor site. Combined 
with results from Study 001/01, viral shedding was observed in 11% of subjects across the 3 
studies. The longest time that infectious virus was detected in these injection site 
swabs was 2 weeks post-injection. 
All swabs of the exterior of the dressing were negative at all time points tested across all 
studies. Thus, it appeared that the dressings were used effectively and prevented 
shedding of any virus from the tumors into the environment. 
In Study 005/05, 18 “reactive” swabs from oozing or weeping lesions as described 
earlier were collected from 12 subjects. Of these 18 swabs, 11 were collected from a 
tumor that had been previously injected with talimogene laherparepvec, 4 were collected 
from non-injected melanoma lesions, and 3 were collected from other sites or an 
unknown site. None of the 18 samples tested positive for infectious HSV (ie, talimogene 
laherparepvec or wild-type) using the plaque assay. 
In first-in-human study (001/01), staining of tumor biopsies with anti-HSV antibody 
indicated that talimogene laherparepvec antigens co-located with tumor necrosis. In the 
phase1/2 study of talimogene laherparepvec in the treatment of subjects with locally 
advanced SCCHN (004/04), needle biopsy tumor tissue samples were obtained for 
qPCR analysis from injected and neighboring uninjected neck nodes in 16 subjects prior 
to neck dissection. Detection of viral DNA was observed in the injected tumors of 
7 subjects and in the uninjected tumors of 1 subject. Additional biodistribution and shedding 
data were collected in Study 20120324. The 
final analysis of this phase 2, multicenter, single-arm study to investigate the 
biodistribution and shedding of talimogene laherparepvec in 50 subjects with 
unresected, stage IIIB to IVM1c melanoma has been conducted. Blood and urine 
samples were collected in addition to swabs from the surface of injected lesions, exterior 
of occlusive dressings, oral mucosa, anogenital regions, and lesions of suspected 
herpetic origin to test for the presence of talimogene laherparepvec DNA by qPCR test. 
In addition, swabs with detectable talimogene laherparepvec DNA were tested for the 
presence of infective virus by the TCID50 assay. 
Talimogene laherparepvec DNA was detected with the lowest frequency in samples from 
the oral mucosa (1% of samples in 13% of subjects), the anogenital area (2% of 
samples in 19% of subjects, with almost all detected at a concentration below the lower 
limit of quantification of the assay), and from urine (3% of samples in 32% of subjects). 
In contrast, and consistent with the method of administration, talimogene laherparepvec 
DNA was detected with the greatest frequency in swabs of injected lesions (49% of samples 
in 100% of subjects) and in blood (35% of samples in 98% of subjects). Most 
of the positive samples were obtained during cycle 2 when talimogene laherparepvec 
was administered at a concentration of 108 PFU/mL for the first time. 
Among the swabs of the surface of injected lesions, the incidence of viral infectivity via 
TCID50 assay was low (8/740 samples [1%]). Seven of these samples were from 
cycle 1, and 1 positive sample was from cycle 2; no swabs tested positive for viral 
activity by TCID50 testing after cycle 2. Live virus was never detected among 
1085 swabs of the exterior of occlusive dressings. Of 37 swabs from lesions of 
suspected herpetic origin taken from 19 subjects, 4 swabs from 3 subjects had 
detectable talimogene laherparepvec DNA, but all were negative for viral infectivity by 
TCID50 assay. 

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For additional information, refer to the talimogene laherparepvec Investigator’s Brochure. 
 
Human GM-CSF Expression – talimogene laherparepvec 
 
Human GM-CSF expression was measurable in the fine needle aspirates of injected tumors 
in 11 of the 13 samples tested in the first-in-human study during the single-dose phase.92 The 
level of human GM-CSF expression was dependent on the dose of talimogene laherparepvec. 
Higher levels of GM-CF were expressed in seronegative subjects than in seropositive 
subjects. Human GM-CSF levels in serum samples, as assessed by enzyme-linked 
immunosorbent assay (ELISA), were below the limit of detection of the assay at all time points 
tested. For additional information, refer to the talimogene laherparepvec Investigator’s 
Brochure. 
Immune Response in Clinical Studies – talimogene laherparepvec 
 
For initial serostatus testing, 69% of all subjects entering talimogene laherparepvec clinical 
studies were positive for the HSV-1 antibody. For the follow-up serostatus testing, all previous 
seronegative subjects converted to seropositive status, a 100% conversion rate. HSV-1 
serostatus was determined using indirect ELISA for HSV-1 antibody status. For most subjects, 
seroconversion occurred during the 3 weeks after the first injection of talimogene 
laherparepvec. After the second injection of talimogene laherparepvec all subjects 
experienced seroconversion.92, 93, 50 No difference in efficacy or safety was seen between 
subjects who were seropositive for HSV-1 versus those who were seronegative for HSV-1 at 
baseline. For additional information, refer to the talimogene laherparepvec Investigator’s 
Brochure. 
 
Efficacy of Talimogene Laherparepvec in Humans – talimogene laherparepvec 
Analyses of efficacy have been conducted for 4 studies92, 49, 50 with talimogene laherparepvec 
as monotherapy for various tumors and for 2 studies with talimogene laherparepvec as 
combination therapy for head and neck cancers (clinical trial number NCT01161498).93 these 
are briefly summarized below: 
 
• Talimogene laherparepvec demonstrated initial biological activity as monotherapy 
(doses as low as 106 PFU/mL) in subjects with advanced solid tumors with metastases 
in the skin or SC tissue as evidenced by necrosis or apoptosis in tumor biopsies .92 
 
• Talimogene laherparepvec resulted in an improvement in durable response rate 
(DRR), a primary endpoint of the phase III study investigating the efficacy of talimogene 
laherparepvec in patients with unresectable advanced melanoma(defined as complete 
response [CR] or partial response [PR] maintained for ≥ 6 months continuously and 
which had its onset on the first 12 months of treatment) compared with GM-CSF.49 At 
the primary analysis of overall survival (OS), a secondary endpoint of this study , 
median OS was 23.3 (95% CI: 19.5, 29.6) months in the talimogene laherparepvec 
arm and 18.9 (95% CI: 16.0, 23.7) months in the GM-CSF arm (HR 0.79; 95% CI: 0.62, 

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1.00; p = 0.051). Results from the phase 2 study in melanoma also support the efficacy 
of talimogene laherparepvec for the treatment of melanoma.50 
 
• The high proportion of tumors that decreased in size and high rate of histopathological 
response at surgery suggested clinical activity with talimogene laherparepvec in 
combination with cisplatin and radiation in subjects with SCCHN .94 Further 
investigations in a larger sample set were planned in the phase 3 study ( clinical trial 
number NCT01161498); however, this phase 3 study was terminated in July 2011 in 
light of emerging evidence regarding the influence of human papillomavirus status and 
smoking on prognosis following chemoradiation, and effects of these factors on the 
likelihood of study success. 
Safety of Talimogene Laherparepvec in Humans – talimogene laherparepvec 
 
At the time of the study-specific data cutoff dates, 486 subjects have received talimogene 
laherparepvec (with doses from 104 to 108 PFU/mL) across 15 studies. 
 
Overall, most adverse events reported in subjects administered talimogene laherparepvec 
are non-serious and primarily include flu-like symptoms and injection site reactions. Most fatal 
adverse events reported in subjects administered talimogene laherparepvec were reported in 
the setting of disease progression. 
 
The most common side effects in the OPTiM study were chills (talimogene 
laherparepvec, 49%; GM-CSF, 9%), pyrexia (43%; 9%), injection-site pain (28%; 6%), 
nausea (36%; 20%), influenza-like illness (30%; 15%), and fatigue (50%; 36%).Grade ≥ 3 
adverse events occurred in 36% of subjects receiving talimogene laherparepvec and 21% of 
subjects receiving GM-CSF. The only grade 3/4 adverse events occurring in ≥ 5 subjects 
was cellulitis (talimogene laherparepvec, n=6 [2.1%]; 
GM-CSF, n=1 [<1%]). Of 10 fatal adverse events in the talimogene laherparepvec arm, 
eight were attributable to disease progression. The remaining two fatal adverse events 
(sepsis in the setting of salmonella infection; myocardial infarction) were not considered 
treatment-related per investigator.49 
Additional identified risks, potential risks and adverse drug reactions associated to talimogene 
laherparepvec are described in detail in section 11.2. 
 
5.1.4 Formulation, Storage and Packaging – talimogene laherparepvec 
Talimogene laherparepvec will be manufactured by Amgen 
Talimogene laherparepvec will be presented as a sterile frozen liquid in a single-use 2.0cc 
Crystal Zenith vial with a gray Fluorotec®-coated chlorobutyl elastomer stopper, aluminum 
seal, and polypropylene cap. Each vial contains a minimum of 1.0 mL talimogene 
laherparepvec at either 106 PFU/mL or 108 PFU/mL concentrations. The supply for the 106 
PFU/mL concentration will be packaged separately from the supply for the 108 PFU/mL 
concentration. 
Talimogene Laherparepvec will be stored, prepared and handled as per Amgen’s Pharmacy 
Information guide and local institutional guidelines. 
 
Please refer to the Pharmacy Information Guide and local institutional guidelines for additional 
information regarding the formulation and packaging of talimogene laherparepvec. 

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5.1.5 Preparation and administration of talimogene laherparepvec 
Preparation of Talimogene Laherparepvec: 
• 
Amgen’s pharmacy information guide and Local institutional guidelines will be followed 
with regards to the preparation of talimogene laherparepvec 
Administration: 
Talimogene laherparepvec must be prepared and administered by a qualified healthcare 
professional. 
 
The total volume of talimogene laherparepvec to be prepared will be based on investigator 
evaluation of injectable lesions and estimation of the total volume needed based on the 
talimogene laherparepvec Injection Volume Guideline Based on Tumor Size Table 3 (detailed 
information described in Pharmacy Information Guide). Prescribe the estimated total volume 
by rounding up to the nearest 1.0 mL. 
The maximum volume of talimogene laherparepvec administered at any dose is 4.0 mL for 
any individual lesion. The maximum dose in any one treatment is 4.0 mL. Use the maximum 
amount whenever lesions allow. 
Table 3. Talimogene laherparepvec Injection Volume Guideline Based on Tumor Size* 
 
Tumor Size (longest dimension) 
Maximum Injection Volume 
> 5.0 cm 
4.0 mL 
> 2.5 cm to 5.0 cm 
2.0 mL 
> 1.5 cm to 2.5 cm 
1.0 mL 
> 0.5 cm to 1.5 cm 
0.5 mL 
≤ 0.5 cm 
0.1 mL 
Talimogene laherparepvec should be injected into viable tissue if available and 
direct injection into necrotic tumor tissue should be avoided. 
• Personal protective equipment (PPE) as per the local institutional guidelines for 
talimogene laherparepvec is required during preparation and administration. 
 
Drug Administration: Administer by intralesional injection into cutaneous, subcutaneous, 
and/or nodal lesions that are visible, palpable, or detectable by ultrasound 
First dose: Inject up to 4 mL at a concentration of 106 (1 million) PFU/mL. Where clinically 
appropriate and feasible inject largest lesion(s) first; where feasible inject remaining lesion(s) 
based on lesion size until maximum injection volume is reached or all lesions have been 
treated. 
 
Second dose and all subsequent doses (every three weeks after first dose): Inject up to 4 mL 
at a concentration of 108 (100 million) PFU/mL. All reasonably injectable lesions (cutaneous, 
subcutaneous and nodal disease that can be injected with or without ultrasound [US] 
guidance) should be injected with the maximum dosing volume available on an individual 

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dosing occasion. On each treatment day, prioritization of injections is recommended as 
follows where clinically appropriate and feasible: 
• any new injectable tumor that has appeared since the last injection 
• by tumor size, beginning with the largest tumor any previously un-injectable tumor(s) 
that is now injectable 
Within the guidelines of the algorithm in Table 3, and the prioritization model above it is 
recommended that each lesion receive the maximum amount possible at each visit before 
moving on to the next lesion, subject to tumor-specific limitations (such as inability to inject 
the full amount into the lesion). 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. 
 
Manufacturer’s and Local institutional guidelines for the preparation and administration of 
talimogene laherparepvec and the management of talimogene laherparepvec contaminated 
materials or surfaces will be followed. 
 
5.2 
Pembrolizumab 
Information 
extracted 
from 
Pembrolizumab 
Prescribing 
Information, 
available 
at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf 
 
5.2.1 Mechanism of action - Pembrolizumab 
Pembrolizumab (formerly known as MK-3475 or lambrolizumab), is a highly selective 
humanized monoclonal IgG4–kappa isotype antibody against PD-1, that acts by blocking its 
interaction with PD-L1 and PD-L2. Pembrolizumab is currently approved by the FDA for the 
treatment of patients with advanced melanoma and disease progression following ipilimumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits 
T cell proliferation and cytokine production. Upregulation of PD-1 ligands occur in some 
tumors and signaling through this pathway can contribute to inhibition of active T-cell immune 
surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 
receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the anti-tumor immune response. In syngeneic 
mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. 
 
The theoretical molecular weights of the heavy and light chains derived from the amino acid 
sequences, excluding glycosylation, are 49.4 kDa and 23.7 kDa, respectively. The antibody 
is heterogeneously glycosylated at asparagine 297 within the Fc domain of each heavy chain, 
yielding molecular weights typically ranging between 148.9 and 149.5 kDa, depending on the 
attached glycan chains. 
 
5.2.1 Non-clinical pharmacology - Pembrolizumab 
Pembrolizumab is a potent and highly selective humanized mAb designed to block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab potently blocks 
binding to both ligands with half maximal inhibitory concentration (IC50) values below1 nM. 
Pembrolizumab enhances T cell responses in human donor blood cell cultures with an EC50 
of ~0.1 to 0.3 nM. Pembrolizumab binds to cynomologus PD-1 with similar affinity, blocking 

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activity, and demonstrates equivalent enhancement of cynomologus T cell responses. It does 
not cross-react with rodent PD-1. 
 
Pembrolizumab strongly enhances T lymphocyte immune responses in cultured blood cells 
from healthy human donors, cancer patients, and primates. The antibody potentiates existing 
immune responses only in the presence of antigen-receptor stimulation and does not 
nonspecifically activate all T cells. Using an anti-mouse PD- 1 analog antibody, PD-1 blockade 
is demonstrated to significantly inhibit tumor growth in a variety of syngeneic murine tumor 
models. In experiments in mice, anti- PD-1 therapy is synergistic with chemotherapeutic 
agents, such as gemcitabine and 5-FU and this combination therapy results in increased 
efficacy, as well as complete regression rates in vivo. 
 
The dissociation constants (KD) of pembrolizumab binding to human and cynomologus 
monkey PD-1 were determined by measurement of kinetic rate constants (on/off) in a solid 
phase format (ForteBiobiolayer-interferometry [BLI]). BLI measurements demonstrated that 
format (ForteBiobiolayer-interferometry [BLI]). BLI measurements demonstrated that 
pembrolizumab binds human PD-1 with a fast association rate, dissociates very slowly, and 
has a high affinity of 29 pM (Table 2). The ability of pembrolizumab to block the binding of 
PD-1 ligands, PD-L1 and PD-L2, to human or cynomologus monkey PD-1 was measured 
using a competitive binding assay and detection by fluorometric microvolume assay 
technology (FMAT). Pembrolizumab potently blocks binding to both PD-1 ligands with IC50 
values below 1 nM. 
 
5.2.2 
Non-clinical toxicology - Pembrolizumab 
Animal Toxicology and/or Pharmacology 
In animal models, inhibition of PD-1 signaling resulted in an increased incidence of infections 
and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit 
markedly decreased survival compared with wild-type controls, which correlated with 
increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout 
mice have also shown decreased survival following infection with lymphocytic 
choriomeningitis virus (LCMV). Administration of pembrolizumab in chimpanzees with 
naturally occurring chronic hepatitis B infection resulted in two out of four animals with 
significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 
month after discontinuation of pembrolizumab. 
 
In the 1-month and 6-month toxicology study in cynomologus monkeys, pembrolizumab 
administered once a week and once every other week respectively, intravenously up to 200 
mg/kg resulted in no adverse treatment related effects. The exposure multiple based on a 
predicted AUC 0-tau of 4464 μg.day/mL at the maximum anticipated human clinical dose of 
10 mg/kg Q2W or Q3W is 15-fold at 200 mg/kg, the NOAEL for the 6-month monkey study. 
Additionally, in the tissue cross-reactivity study of pembrolizumab with human and monkey 
tissues demonstrated the expected on-target staining of the membranes of mononuclear 
leukocytes in both species. Off-target cross-reactivity staining was also noted in both species 
but was limited to cytoplasm of various cell types/tissues and the stroma (extracellular 
connective tissue matrix), and was considered related to the experimental method artifacts, 

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i.e. tissue processing for IHC, that are well recognized limitations of tissue cross-reactivity 
studies and, thus not considered toxicologically relevant. 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
No studies have been performed to test the potential of pembrolizumab for carcinogenicity or 
genotoxicity. Fertility studies have not been conducted with pembrolizumab. In 1-month and 
6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male 
and female reproductive organs; however, most animals in these studies were not sexually 
mature. 
 
5.2.3 Pharmacokinetics - Pembrolizumab 
The pharmacokinetics of pembrolizumab was studied in 479 patients who received doses of 
1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on a population 
pharmacokinetic analysis, the mean [% coefficient of variation (CV%)] clearance (CL) is 0.22 
L/day (28%) and the mean (CV%) elimination half-life (t1/2) is 26 days (24%). Steady-state 
concentrations of pembrolizumab were reached by 18 weeks of repeated dosing with an every 
3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration 
(Cmax), trough concentration (Cmin), and area under the plasma concentration versus time 
curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose 
range of 2 to 10 mg/kg every 3 weeks. 
Specific Populations: The effects of various covariates on the pharmacokinetics of 
pembrolizumab were assessed in population pharmacokinetic analyses. The CL of 
pembrolizumab increased with increasing body weight; the resulting exposure differences 
were adequately addressed by the administration of a weight-based dose. The following 
factors had no clinically important effect on the CL of pembrolizumab: age (range 18-94 
years), gender, renal impairment, mild hepatic impairment, and tumor burden. The effect of 
race could not be assessed due to limited data available in non-White patients. 
 
Renal Impairment: The effect of renal impairment on the CL of pembrolizumab was evaluated 
by population pharmacokinetic analyses in patients with mild (eGFR 60 to 89 mL/min/1.73 
m2; n=210), moderate (eGFR 30 to 59 mL/min/1.73m2; n=43), or severe (eGFR 15 to 29 
mL/min/1.73m2; n=2) renal 
impairment compared to patients with normal (eGFR greater than or equal to 90 
mL/min/1.73m2; n=221) renal function. No clinically important differences in the CL of 
pembrolizumab were found between patients with renal impairment and patients with normal 
renal function [see Use in Specific Populations (8.6)]. 
Hepatic Impairment: The effect of hepatic impairment on the CL of pembrolizumab was 
evaluated by population pharmacokinetic analyses in patients with mild hepatic impairment 
(TB less than or equal to ULN and AST greater than ULN or TB between 1 and 1.5 times ULN 
and any AST; n=59) compared to patients with normal hepatic function (TB and AST less than 
or equal to ULN; n=410). No clinically important differences in the CL of pembrolizumab were 
found between patients with mild hepatic impairment and normal hepatic function. 
KEYTRUDA has not been studied in patients with moderate (TB greater than 1.5 to 3 times 
ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment 
[see Use in Specific Populations (8.7)]. 

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5.2.4 Summary of clinical experience with pembrolizumab 
The efficacy of pembrolizumab was investigated in a multicenter, open-label, randomized 
(1:1), dose-comparative, activity-estimating cohort. Key eligibility criteria were unresectable 
or metastatic melanoma with progression of disease; refractory to two or more doses of 
ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; 
and disease progression within 24 weeks following the last dose of ipilimumab. The trial 
excluded patients with autoimmune disease; a medical condition that required 
immunosuppression; and a history of severe immune-mediated adverse reactions with 
ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 
3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent 
dose) for greater than 12 weeks. Patients were randomized to receive 2 mg/kg (n=89) or 10 
mg/kg (n=84) of pembrolizumab every 3 weeks until unacceptable toxicity or disease 
progression that was symptomatic, was rapidly progressive, required urgent intervention, 
occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat 
imaging. Assessment of tumor status was performed every 12 weeks. The major efficacy 
outcome measures were confirmed overall response rate (ORR) according to Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central 
review and duration of response. Among the 173 patients enrolled, the median age was 61 
years (36% age 65 or older); 60% male; 97% White; and 66% and 34% with an ECOG 
performance status 0 and 1, respectively. Disease characteristics were BRAF V600 mutation 
(17%), elevated lactate dehydrogenase (39%), M1c (82%), brain metastases (9%), and two 
or more prior therapies for advanced or metastatic disease (73%). The ORR was 24% (95% 
confidence interval: 15, 34) in the 2 mg/kg arm, consisting of 1 complete response and 20 
partial responses. Among the 21 patients with an objective response, 3 (14%) had 
progression of disease 2.8, 2.9, and 8.2 months after initial response. The remaining 18 
patients (86%) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, 
which included 8 patients with ongoing responses of 6 months or longer. One additional 
patient developed two new asymptomatic lesions at the first tumor assessment concurrent 
with a 75% decrease in overall tumor burden; Pembrolizumab was continued and this 
reduction in tumor burden was durable for 5+ months. There were objective responses in 
patients with and without BRAF V600 mutation-positive melanoma. Similar ORR results were 
observed in the 10 mg/kg arm. 
 
As of 18-Oct-2013, 1,000 patients have been treated with pembrolizumab at several dose- 
schedules, including 10 mg/kg every 2 weeks. Pembrolizumab has been generally well 
tolerated, as expected based on preclinical findings and other anti-PD- 1 monoclonal 
antibodies. As of 18-Oct-2013 no serious infusions reactions had been reported, however, 
since the potential exists in anti-PD-1 monoclonal antibodies, investigators should be vigilant 
to this possibility. There is no contraindication to further clinical investigation with 
pembrolizumab. Pharmacokinetics were as expected, based on pembrolizumab being an IgG 
mAb and based on preclinical data, which support dosing once every 2 or 3 weeks. 
Pembrolizumab monotherapy induces an ORR of 25%/27% in patients with ipilimumab- 
exposed melanoma by central independent RECIST and oncology review/investigator 
assessed irRECIST, respectively. Pembrolizumab monotherapy induces an ORR of 
39%/43% in patients with ipilimumab-naive melanoma by central independent RECIST and 
oncology review/investigator assessed irRECIST, respectively. These responses are 
remarkably durable. The preliminary 1-year survival rate for patients, many of whom have had 
multiple therapies, including ipilimumab, who receive pembrolizumab is 81%. Pembrolizumab 

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monotherapy induces an ORR of 21%/24% in patients with previously-treated NSCLC by 
central independent RECIST/investigator assessed irRECIST, respectively, with these 
responses also remarkably durable. Preliminary data suggest higher levels of PD-L1 
expression in tumors of NSCLC are associated with increased activity (ORR 67% by 
investigator assessed irRECIST/57% by central independent RECIST); additional data are 
required to define the optimal PD-L1 cut point. The most commonly reported treatment 
emergent AEs experienced are fatigue (43.8%), nausea (26.7%), cough (25.3%), pruritus 
(24.6%), diarrhea (22.3%) and rash (21.5%). Immune-related adverse events were reported 
in 21.4% of melanoma patients; most of these events (15.8%) were considered drug-related 
by the 
investigator. The most commonly reported, immune-related adverse events across the 
dose-schedules are rash (3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), 
arthralgia (2.2%), diarrhea (2.2%), and pneumonitis (1.9%). Review of the overall benefit:risk 
ratio of pembrolizumab favors enrollment of eligible patients into clinical trials of 
pembrolizumab. The preliminary data suggest that a dose of pembrolizumab at 2 mg/kg Q3W 
is appropriate for patients with melanoma. 
 
No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. 
 
Additional identified risks, potential risks and adverse drug reactions associated to 
pembrolizumab are described in detail in section 11.3. 
5.2.3 Formulation, Storage and Packaging - Pembrolizumab 
Pembrolizumab will be manufactured by Merck. 
 
Pembrolizumab is supplied as pembrolizumab 50 mg lyophilized powder in a single-use vial 
for reconstitution or as Pembrolizumab 100 mg/4ml Solution for Injection 
 
Reconstituted and diluted solutions of pembrolizumab should be stored either: 
 
• At room temperature for no more than 4 hours from the time of reconstitution. This 
includes room temperature storage of reconstituted vials, storage of the infusion 
solution in the IV bag, and the duration of infusion. 
• Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the 
time of reconstitution. If refrigerated, allow the diluted solution to come to room 
temperature prior to administration. 
 
Product should not be frozen. 
 
5.2.4 Administration of pembrolizumab 
Pembrolizumab must be prepared and administered by a qualified healthcare professional. 
 
Pembrolizumab at a dose of 200 mg will be administered intravenously on Week 1 and every 
3 weeks (±3 days) thereafter. When talimogene laherparepvec and pembrolizumab are 
administered on the same day, talimogene laherparepvec must be administered first. 

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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 (i.e., 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. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
Describe the characteristics of the patient/subject population. 
6.1 
Subject Inclusion Criteria 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
• Male or female age ≥ 18 years at the time of informed consent. 
• Be willing and able to provide written informed consent/assent for the trial. 
• Be willing to comply with treatment protocol 
• Subjects must have a histologically confirmed metastatic and/or locally advanced 
inoperable sarcoma (metastatic/locally advanced cohort) 
• For histology specific additional metastatic cohorts, patients must have undifferentiated 
pleomorphic 
sarcoma/myxofibrosarcoma, 
epithelioid 
sarcoma 
or 
cutaneous 
angiosarcoma. 
• Subjects must have at least 1 injectable cutaneous, subcutaneous (superficial or deep) 
soft tissue or nodal lesion ≥ 10 mm in longest diameter. Of note, bone lesions are not 
eligible for injection unless there is a soft tissue component that is amenable to injection. 
Injectable lesions must not be chosen from a previously irradiated field unless there has 
been radiographically and/or pathologically documented tumor progression in that lesion 
prior to enrollment. Subjects with locally advanced/metastatic sarcoma must have at least 
one prior line of systemic therapy (e.g. chemotherapy, immunotherapy, targeted or 
biological therapy) An exception to this criterion will be made for patients with sarcoma 
histological subtypes for which there is no known standard systemic therapy 
(e.g.,epithelioid sarcoma). Treatment naïve patients may be enrolled if they have refused 
standard systemic treatment. Prior adjuvant therapy will not count provided it was 
completed more than 6 months previously. 
• Adequate performance status: ECOG 0 or 1/KPS 100-70% 
• Adequate organ function determined within 3 weeks of treatment initiation, defined as 
follows: 
I. Hemoglobin ≥ 8.0 g/dl 
II. Absolute neutrophil count ≥ 1,000/mm3 (1.0 x 109/L) 
III. Platelet count ≥ 75,000/mm3 (75 x 109/L) 
IV. Serum bilirubin  1.5 x ULN OR direct bilirubin ≤ ULN for a subject 
with total bilirubin level > 1.5 x ULN 

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V. Aspartate aminotransferase (AST)  2.5 x ULN OR  5 x ULN for 
subjects with liver metastases 
VI. Alanine aminotransferase (ALT)  2.5 x ULN OR  5 x ULN for 
subjects with liver metastases 
VII. Alkaline Phosphatase < 5 x ULN 
VIII. Albumin ≥2.5mg/dL 
IX. Serum creatinine ≤ 1.5 x ULN or a measured or calculateda creatinine 
clearance ≥ 60mL/min for subject with creatinine levels > 1.5 x 
institutional ULN (Note: Creatinine clearance need not be determined 
if the baseline serum creatinine is within normal limits. GFR can also 
be used in place of creatinine or CrCl) 
X. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 
X  ULN  unless  subject  is  receiving  anticoagulant  therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
XI. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless 
subject is receiving anticoagulant therapy as long as PT and PTT is 
within therapeutic range of intended use of anticoagulants 
 
aCreatinine clearance should be calculated per institutional standard 
 
 
• 
Female subject of childbearing potential should have a negative serum pregnancy testing 
at screening visit and within 72 hours prior to the first dose of study medication. 
6.2 
Subject Exclusion Criteria 
Patients who fulfil any of the following criteria are not eligible for admission to the study: 
 
• Uncontrolled intercurrent illness including active infection requiring systemic therapy 
or symptomatic congestive heart failure within 6 months 
• Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability. 
• Evidence of clinically significant immunosuppression such as the following: 
- 
Primary immunodeficiency state such as Severe Combined 
Immunodeficiency Disease 
- 
Concurrent opportunistic infection 

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- 
Receiving systemic immunosuppressive therapy (> 2 weeks) including oral 
steroid doses > 10 mg/day of prednisone or equivalent within 7 days prior 
to enrollment. However, in the setting of non-immune mediated indications 
for use, chronic/active low dose steroid use may be permitted at the 
discretion of the principal investigator. 
• Known history of human immunodeficiency virus (HIV) disease. 
• History or evidence of symptomatic autoimmune disease (e.g., pneumonitis, 
glomerulonephritis, vasculitis, or other), or history of active autoimmune disease that 
has required systemic treatment (i.e., use of corticosteroids, immunosuppressive 
drugs or biological agents used for treatment of autoimmune diseases) in past 2 
years prior to enrollment. Replacement therapy (e.g., thyroxine for hypothyroidism, 
insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency) is not considered a form of systemic treatment for autoimmune 
disease. 
• Active herpetic skin lesions or prior complications of herpetic infection 
• Require intermittent or chronic treatment with an intravenous or oral antiherpetic drug 
(e.g., acyclovir), other than intermittent topical use 
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
• Received live vaccine or live-attenuated vaccine within 30 days prior to enrollment. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
• Has a known history of active TB  (Bacillus Tuberculosis) 
• Female subject is pregnant or breast-feeding, or planning to become pregnant or male 
subject is planning to father a child within the projected duration of the trial, starting 
with the pre-screening or screening visit, 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. 
• Male and female subjects of childbearing potential who are unwilling to use 
acceptable method(s) of effective contraception during study treatment and through 
3 months after the last dose of talimogene laherparepvec and 4 months after the last 
dose of pembrolizumab. (Note: Women not of childbearing potential are defined as: 
Any female who is post-menopausal [age > 55 years with cessation of menses for 12 
or more months or less than 55 years but not spontaneous menses for at least 2 
years or less than 55 years and spontaneous menses within the past 1 year, but 
currently amenorrhoeic (e.g., spontaneous or secondary to hysterectomy), and with 
postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating 
hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or 
according to the definition of "postmenopausal range" for the laboratory involved] or 
who have had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). 
• Sexually active subjects and their partners unwilling to use male or female latex 
condom or polyurethane condoms for patients with latex allergies to avoid potential 
viral transmission during sexual contact while on treatment and within 30 days after 
treatment with talimogene laherparepvec. 
• Subject who is unwilling to minimize exposure with his/her blood or other body fluids 

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to individuals who are at higher risks for HSV-1 induced complications such as 
immunosuppressed individuals, individuals known to have HIV infection, pregnant 
women, or children under the age of 1 year, during talimogene laherparepvec 
treatment and through 30 days after the last dose of talimogene laherparepvec. 
• Known previous history of sensitivity to talimogene laherparepvec or any of its 
components to be administered during dosing (e.g. sorbitol, myo-inositol) 
• Hypersensitivity to pembrolizumab or any of its excipients. 
• 
Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or 
has current pneumonitis/interstitial lung disease. 
• 
Prior therapy with talimogene laherparepvec, tumor vaccine. 
• Prior chemotherapy, radiotherapy, biological cancer therapy, targeted small molecule 
therapy or major surgery within 21 days prior to study Day 1 or who has not recovered 
(i.e., to CTCAE ≤ grade 1 or at baseline) from adverse events due to previously 
administered therapy. Note: Subjects with ≤ grade 2 neuropathy and alopecia are an 
exception to this criterion and may qualify for the study. Note: If subject received major 
surgery, they must have recovered adequately from the toxicity and/or complications 
from the intervention prior to starting therapy. 
• Is currently participating and receiving study therapy with another investigational 
device or study drug or has participated in a study of an investigational agent and 
received study therapy or used an investigational device within 3 weeks of the first 
dose of treatment. 
• 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
• 
The presence of any other concurrent active malignancy. 
7.0 
RECRUITMENT PLAN 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
The clinical trial will be listed on the clinicaltrials.gov website and on the websites of 
participating institutions. Patients will be identified through internal referrals and external 
referrals by Medical and Surgical Oncologists, nationally and internationally. Patients will be 
recruited through the Sarcoma Disease Management Team of the Memorial Sloan Kettering 
Cancer Center. The Sarcoma Service and the Sarcoma Disease Management Team each 
hold weekly interdepartmental meetings to identify study participants for open clinical trials. 
We will also discuss the trial and patient recruitment with several Sarcoma patient support 
groups. The principal investigator will be available to all patients for further questions and 
information through a contact number, which will be provided on the consent form. 
 
7.1 Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process, registering individuals will be required to 
complete a protocol-specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. 

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8.0 
Informed Consent Procedures 
 
The consent form/research authorization meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent 
form will include the following: 
 
1. The nature, objectives, potential risks, and benefits of the intended study. 
 
2. The length of study, what it entails, and the likely follow-up required. 
 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
 
4. The name of the investigator(s) responsible for the protocol. 
 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
 
6. How the participants’ data will be protected, who will have access to their PHI, 
and what data will be disclosed for research purposes 
 
Prior to inclusion in the study and before protocol-specified procedures are carried out, the 
consenting professionals will explain the details of the protocol as outlined in the consent and 
research authorization to the participants/LARs. The participant/LAR will also be informed that 
they are free to withdraw from the study at any time. The consent discussion may occur in 
person or remotely via teleconference, telephone, or videoconference. 
 
All participants/LARs must sign an IRB/PB-approved consent form/research authorization 
indicating their consent to participate. Each participant/LAR and consenting professional will 
sign and date the consent form. The participant/LAR must receive a copy of the signed 
informed consent form. 
 
9.0 
PRETREATMENT EVALUATION 
Screening 
All aspects of the screening evaluation should be completed prior to entering the study, unless 
otherwise noted: 
Within 30 days of study start: 
- 
Confirmation of disease: documented presence of metastatic and/or inoperable, 
locally advanced sarcoma with at least one palpable lesion deemed suitable for 
direct intralesional injection of talimogene laherparepvec and at least one target 
lesion. The palpable lesion may be used as the target lesion for RECIST assessment 
if it meets the RECIST 1.1 criteria for a target lesion and no other appropriate target 
lesion exists. 
- 
All patients enrolled in this study will undergo a new baseline biopsy where feasible 
- 
Informed Consent 

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Within 3 weeks of study start: 
- 
Full medical history, physical exam, assessment of performance status by KPS or 
ECOG status 
- 
Review of concomitant medications 
- 
Complete vital signs (pulse, blood pressure, temperature, respiratory rate) as well as 
weight and height. Height may be documented at any time prior to registration. 
- 
Standard baseline imaging with CT scan of the chest (with or without contrast), 
abdomen and pelvis (with contrast where renal function permits) and MRI if 
applicable. Additional imaging for research purposes may also be performed where 
clinically appropriate. 
- 
12-lead electrocardiogram (EKG) 
- 
Serum β-HCG pregnancy test for women with child-bearing potential. (within 72 
hours) 
- 
Complete blood count with differential, including lymphocyte and eosinophil count. 
- 
Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, sodium, 
potassium, chloride, bicarbonate, calcium, total protein, albumin, serum bilirubin, 
alkaline phosphatase, ASL, AST), phosphorus, magnesium, TSH, T4 free, amylase, 
lipase. 
- 
Review of inclusion and exclusion criteria 
Please refer to Study Calendar in Section 10 for additional information. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 
Study drugs 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in section 11.0. Modifications and dose delays due to toxicity are 
described further in section 11.3. The schedule of evaluations and interventions is described 
in Section 10. 
Patients will be treated with up to 4mL at 106 pfu/mL of talimogene laherparepvec given on 
Week 1 and up to 4mL at 108 pfu/mL starting at Week 4 every 3 weeks thereafter. 
Pembrolizumab at 200mg/dose will be given on Week 1 and every 3 weeks thereafter for up 
to 35 cycles. Patients will be reassessed at week 8 and then every 8 weeks until week 56 
and then every 12 weeks thereafter or as per the discretion of the treating investigator . 
Talimogene laherparepvec will be administered by intralesional injection into injectable 
lesions with or without image ultrasound guidance. The initial dose (Week 1) of talimogene 
laherparepvec is up to 4.0 mL of 106 plaque-forming units (PFU)/mL. Subsequent doses of 
talimogene laherparepvec are up to 4.0 mL of 108 PFU/mL. When talimogene laherparepvec 
and pembrolizumab are administered on the same day, talimogene laherparepvec must be 
administered first. 
 
Pembrolizumab at a dose of 200mg will be administered intravenously on Week 1 and every 
3 weeks (±3 days). Pembrolizumab infusion should be administered in 30 minutes, with a 
window of -5 and +10 minutes, using an infusion pump. 
No additional investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient’s malignancy. 

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9.1.1 Dose rationale 
The toxicity profile of talimogene laherparepvec used as single agent based on the same 
proposed dose was well studied in early phase clinical trials as well as in a large, randomized 
phase III trial in patients with melanoma.51, 49, 50 In a phase 1b/2 trial also in patients with 
melanoma using the same doses of talimogene laherparepvec in combination with 
ipilimumab, although Grade 3/4 adverse events occurred in 32% of the patients, only 2 
patients had possible immune-related grade 3 or 4 adverse events and no DLTs were 
reported.71 In addition, a Phase Ib/II study of the combination of talimogene laherparepvec 
and pembrolizumab in patients with melanoma has recently completed accrual. In this study, 
talimogene laherparepvec was administered five weeks prior to initiating pembrolizumab. 
Patients were given intratumoral talimogene laherparepvec injection at doses up to 4 mL per 
treatment (106 PFU/mL on day 1, then 108 PFU/mL on day 22 and every 2 weeks thereafter. 
Intravenous pembrolizumab was given at a dose of 200mg from Day 36 in phase 1b (n = 20) 
and Day 1 in phase 2 (n = 90) and then every two weeks thereafter. The combination 
appeared to be safe and well tolerated.92.[2] The FDA has now approved pembrolizumab, 
administered intravenously at a dose of 2mg/kg every 3 weeks, for the treatment of patients 
with unresectable and metastatic melanoma. Intralesional injection of talimogene 
laherparepvec, also known as IMLYGIC®, has been approved by the United States Food and 
Drug Administration (FDA) for the local treatment of unresectable cutaneous, subcutaneous, 
and nodal lesions in adult patients with melanoma recurrent after initial surgery. However, it 
has not been shown to increase OS or have an effect on metastases to internal organs 
including the liver and lungs. 
The suggested treatment plan is summarized in Table 4.  Patients will be offered an optional 
biopsy at the time of progression of disease. 
 
Table 4. Study design and treatment plan 
 
Talimogene 
laherparepvec 
Pembrolizumab 
One stage design 
based on the 
exact binomial 
test 
Intratumoral 
administration 
(injection): : 
Up to 4mL at 106 
pfu/mL at Week 1 
Up to 4mL at 108 
pfu/mL at Week 4 
and every 3 weeks 
thereafter. 
Dose: 200mg/dose at 
Week 1, and every 3 
weeks thereafter. 
 
Toxicities will be assessed using the NCI CTCAE (version 4.03) unless otherwise specified 
and discussed in detail in section 11.0. 

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9.2 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment with intralesional 
talimogene laherparepvec may continue until one of the following criteria applies: 
 
- 
Disappearance of injectable lesions 
- 
Complete response 
- 
Confirmed progression of disease (detailed in section 13) or clinical progression 
- 
Intercurrent illness that prevents further administration of treatment 
- 
Intolerance of study treatment (detailed in section 11.1) 
- 
Completion of 35 treatments (approximately 2 years) with pembrolizumab 
o Note: The number of treatments is calculated starting with the first 
dose. Participants who stop the combination or pembrolizumab after receiving 35 
doses may be eligible for retreatment if they progress after stopping study treatment 
provided they meet the requirements detailed in Section 9.2.1. Participants may be 
retreated in the Second Course Phase (Retreatment) for up to an additional 17 
cycles (approximately 1 year). 
 
- 
Patient is lost to follow-up 
- 
Physician’s decision to withdraw a patient from the study for a reason not listed 
- 
Patient decides to withdraw from the study 
- 
End of study, whichever occurs first. 
 
In the absence of treatment delays due to adverse events, treatment with pembrolizumab 
may continue until one of the following criteria applies: 
 
- 
Confirmed progression of disease (detailed in section 13) or clinical progression 
- 
Intercurrent illness that prevents further administration of treatment 
- 
Intolerance of study treatment (detailed in section 11.1) 
- 
Patient is lost to follow-up 
- 
Completion of 35 treatments (approximately 2 years) with pembrolizumab 
o Note: The number of treatments is calculated starting with the first 
dose. Participants who stop the combination or pembrolizumab after receiving 35 
doses may be eligible for retreatment if they progress after stopping study treatment 
provided they meet the requirements detailed in Section 9.2.1. Participants may be 
retreated in the Second Course Phase (Retreatment) for up to an additional 17 
cycles (approximately 1 year). 
- 
Physician’s decision to withdraw a patient from the study for a reason not listed 
- 
Subject is lost to follow-up 
- 
Patient decides to withdraw from the study 
- 
End of study, whichever occurs first. 

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Subjects with a complete response (CR) may stop injections of talimogene laherparepvec, 
but treatment with pembrolizumab will be continued unless one of the criteria for treatment 
discontinuation is met. This is discussed in again in section 13.0. 
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 and 
pembrolizumab. The patient may be allowed to continue study treatment after initial RECIST 
1.1 defined progression if they are assessed by the treating physician to be deriving clinical 
benefit and tolerating study treatment. The treating physician may consult with the overall 
study PI for help with assessing the patient. Such patients should discontinue study therapy 
upon further evidence of progression. 
9.2.1 Second Course 
All participants in the inoperable, locally advanced/metastatic cohort who stop study 
treatment with SD or better may be eligible for up to an additional 17 cycles (approximately 1 
year) of pembrolizumab and talimogene laherparepvec treatment if they progress after 
stopping study treatment from the initial treatment phase and have lesions that are eligible for 
injection as defined in the inclusion criteria. This retreatment is termed the Second Course 
Phase of this study and is only available if the study remains open and the participant meets 
the following conditions: 
Either 
• 
Stopped initial treatment with study treatment after attaining an 
investigator-determined confirmed CR based on RECIST 1.1, and 
o Was treated with at least 8 cycles of study treatment before discontinuing 
treatment, and 
o Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared 
OR 
• Had SD, PR, or CR and stopped study treatment after completion of 
35 administrations (approximately 2 years) of study treatment for reasons other than 
disease progression or intolerability 
AND 
• Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 after stopping initial treatment, and 
o Have at least 1 injectable cutaneous, subcutaneous (superficial or deep) soft 
tissue or nodal lesion ≥ 10 mm in longest diameter as defined in the inclusion 
criteria. 
o No new anticancer treatment was administered after the last dose of study 
treatment, and 
o The participant meets all of the safety parameters listed in the inclusion criteria 
and none of the safety parameters listed in the exclusion criteria, and 

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o The study is ongoing 
An objective response or disease progression that occurs during the Second Course 
Phase for a participant will not be counted as an event for the primary analysis of either 
endpoint in this study. 
*Note: patients must have measurable disease at the start of protocol treatment to be 
eligible for this provision. 
 
9.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Supportive Care: Best supportive care and treatment will be given as appropriate to 
each subject as per Clinical Center and ASCO guidelines 
(antiemetics, antibiotics, packed red blood cell and platelet 
transfusions, nutritional support, non-radiation palliative treatment 
for pain). 
Steroids: 
Doses up to 10mg of prednisone daily (or equivalent) will be 
allowed concurrently with continuous treatment with talimogene 
laherparepvec and/or pembrolizumab. If the subject requires 
corticosteroid dosing of >10 mg prednisone daily (or equivalent) 
and/or other immunosuppressive medication for related toxicities, 
talimogene laherparepvec and pembrolizumab dosing must be 
held until the corticosteroid dose has decreased to ≤10 mg 
prednisone daily (or equivalent) and the administration of the other 
immunosuppressive medication has discontinued. In the setting 
of non-immune mediated indications for use, chronic/active low 
dose steroid use ( at doses >10 mg prednisone daily) may be 
permitted at the discretion of the principal investigator. 
Radiation: 
Radiation therapy is only allowed during the study if required for 
palliation of symptoms due to underlying sarcoma. 
Surgery: 
Subjects must not schedule any elective surgeries during 
the treatment period and for at least 30 days after the last 
administration of study drugs. If a subject undergoes any 
unexpected surgery during the course of the study, all study 
treatments must be withheld and the investigator or designee 
should report the event per their institutional guidelines. A 
subject may be allowed to resume study drugs per PI’s 
discretion. 
 
Other supportive measures and specific treatments/guidelines recommended for the 
management of toxicities are detailed in Appendix A. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
10.1 – Pre-treatment diagnosis confirmation 
All patients will have histological confirmation of their diagnosis prior to treatment. Baseline 
clinical and radiologic evaluations are to be conducted within 3 weeks of starting protocol 
therapy. In addition, a mandatory baseline biopsy will be performed within 30 days of first 
dose of the study drugs for all patients enrolled in the study where feasible. 

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10.2 – Standard evaluations 
Locally advanced/metastatic cohort 
Evaluations at clinic visits will occur at weeks 1 and 4 (± 3 days), and then prior to every 
scheduled treatment (± 3 days) thereafter. Patients who achieve response/stability of disease 
lasting for at least 12 months and come off study therapy will be followed every 2 months (± 
2 weeks) thereafter. Imaging studies will be performed at baseline, week 8 and every 8 weeks 
subsequently (± 1 week window) until 56 weeks, and then every 12 weeks thereafter or as 
per the discretion of the treating investigator. The clinical evaluations are delineated further 
in the study calendar (Table 6) and include: 
- 
Full medical history, physical exam, assessment of performance status by 
KPS or ECOG status 
- 
Review of concomitant medications 
- 
 
Complete vital signs (pulse, blood pressure, temperature, respiratory rate)  as 
well as weight and height. Height may be documented at any time prior to 
registration. 
All patients will undergo a baseline staging CT scan of the chest (with or without contrast), 
abdomen and pelvis (with contrast where renal function permits), and MRI abdomen/pelvis 
(with and without contrast) if deemed necessary by the treating physician. Response 
evaluations will occur at week 8 and every 8 weeks subsequently (± 1 week window) until 56 
weeks, and then every 12 weeks thereafter or as per the discretion of the treating investigator. 
EKGS will also be performed at baseline, week 8 and every 8 weeks thereafter to evaluate 
the heart during the study. 
Routine/standard blood samples will be obtained at screening, weeks 1, 4 and then prior to 
every scheduled treatment (±3 days) thereafter. All routine blood samples should be obtained 
prior to the daily dose talimogene laherparepvec and/or pembrolizumab. These samples will 
be used for routine tests and are part of standard of care. The following analyses will be 
assessed at various time points during the study: 
- 
Hematology: Complete blood count with differential, including lymphocyte and 
eosinophil count. 
- 
Chemistry: phosphorus, magnesium 
- 
Serum β-HCG pregnancy test for women with child-bearing potential (NOTE: for 
women of child bearing potential a negative urine or serum pregnancy at screening 
and within 72 hours prior to first dose of study medication is required. 
- 
Comprehensive metabolic panel (sodium, potassium, chloride, bicarbonate, calcium, 
glucose, blood urea nitrogen, creatinine, total protein, albumin, serum bilirubin, 
alkaline phosphatase, ALT, AST) 
- 
TSH, T4 free. 
- 
Additional tests if clinically indicated. 
 
 
10.2.1 Required Laboratory Parameters for Treatment 
 
A new dose of therapy may be initiated provided that the patient meets the following criteria 
within 72 hours of treatment: 
• ANC ≥ 1,000/μL 

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• Platelets > 75,000/μL 
• All grade ≥ 2 non-hematologic adverse events (except for fatigue, 
nausea and vomiting, or laboratory values that are not clinically 
significant) must have resolved to CTCAE grade ≤ 1 
• No evidence of infection/necrosis or local complications in the injection 
site. 
 
10.3 – Tumor and blood samples for correlative/companion studies 
All patients enrolled on this study will undergo paired biopsies/blood samples for research 
purposes (correlative/companion studies) 
 
Metastatic/inoperable, locally advanced cohort: 
Blood samples for research purposes will be obtained at week 1, 4, 7, 13, 19, 22 and at the 
date of the off study visit (± 7 days). This is detailed in Table 6 (Study calendar). 
Biopsies for research purposes will be done at baseline (within 30 days of the first dose of 
talimogene laherparepvec and/or pembrolizumab) and at Week 8 in all patients enrolled in 
this study where feasible. Biopsy of a distant site of disease at each biopsy timepoint will be 
obtained. A site not intended to be injected is preferred for biopsy where feasible. Up to 6 
cores from each tumor biopsy site should be taken where feasible and safe to do so. A goal 
of 6 cores should be obtained with a minimum of one formalin-fixed, one fresh and one flash 
frozen in liquid nitrogen. Biopsy procedures will otherwise be performed in accordance with 
institutional guidelines and the biopsy guideline outlined in Appendix F. An optional biopsy of 
a distant site of disease will be offered to all patients at the time of progression. 
Neoadjuvant cohort: 
Blood samples for research purposes will be obtained at week 1, 4, and week 6 and 12 (where 
applicable) prior to surgical resection. For patients receiving additional cycles of treatment, 
additional blood samples will be drawn prior to each cycle. 
Mandatory biopsies for research purposes will be done at baseline (within 30 days of the first 
dose of talimogene laherparepvec and/or pembrolizumab) and at Week 4 prior to the 
administration of study therapy. For patients receiving additional cycles of treatment, 
additional core biopsies may be obtained prior to each additional treatment (ie. week 7 and 
week 10, etc.) 
An open excisional biopsy or up to 6 cores from each tumor biopsy site should be taken where 
feasible and safe to do so. A goal of 6 cores should be obtained with a minimum of one 
formalin-fixed, one fresh and one flash frozen in liquid nitrogen. Biopsy procedures will 
otherwise be performed in accordance with institutional guidelines and the biopsy guideline 
outlined in Appendix F. 
 
Tumor Based Biomarkers 
Interrogation of immune responses within the tumor microenvironment of sarcomas 
before and after treatment with talimogene laherparepvec and PD-1 checkpoint 
blockade. 
For each resected specimen, up to 6 cores of tissue will be obtained for tumor immune 
correlative studies. 

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a) Density of immune infiltration and immune checkpoint expression of 
sarcomas: IHC will be used to assess the number and composition of immune 
infiltrates in order to define the immune cell subsets present within the tumor and 
PD-L1 protein expression by IHC before and after exposure to talimogene 
laherparepvec and pembrolizumab. 
 
The IHC assays will be performed using but are not limited to the following markers: 
CD3, CD4, CD8, CD25, CD28 CD45RA, CD68, CD69, CCR7, PD-L1, PD-1, 
CD137, FOXP3, LAG-3, TIM-3, and ICOS. 
 
PD-L1 expression by immunohistochemistry staining of archival tumor specimens 
will be performed with using a QualTek immunohistochemistry-based assay. 
b) Phenotype and function of TIL in human sarcomas: 
Multiparameter flow cytometry (MFC) performed on freshly dissociated tumor tissue 
will be used to characterize the tissue T cell populations. We will study the 
functional significance of PD-1 expression on T cells isolated from sarcomas. Using 
intracellular cytokine staining (ICS) and MFC analysis on freshly isolated TIL, we 
will identify the T cell cytokine profiles in accordance to their immune checkpoint 
expression profile (PD-1, LAG-3, TIM-3). A range of cytokines representing key 
lymphocyte subgroups (e.g., Th1, 2 or 17) such as IL-2, TNF- , IFN- IL-17 among 
other inflammatory mediators will be assessed. Functional T cell markers including 
granzyme B and perforin as well as activation markers such as CD62L, CD44, 
CD69 will be also included in our analysis. 
 
c) Tumor Biopsy gene expression profiling: Fresh tumor biopsy will be examined 
for RNA gene and protein expression by NanoString technology (nCounter® RNA: 
Protein, PanCancer Immune Profiling Panel) and/or qRT-PCR to detect expression 
of immune related genes. This panel includes 770 immune related genes including: 
109 genes related to cell surface markers for 24 different immune cell types and 
populations, 30 genes for commonly studied cancer/testis (CT) antigens, over 500 
genes for measuring immune response and 40 reference genes. 
 
d) Neoantigen analysis: Massively parallel sequencing of the whole exome of the 
tumor tissue and normal blood will be performed for patients who opt in. Genomic 
DNA will be captured via solution-based hybrid selection and sequenced on the 
Illumina HiSeq platform by the Genomics Core at MSKCC. The sequencing data 
will be aligned by the Bioinformatics Core Tumor, using Somatic Sniper, Somatic 
Indel Detector and Mutect softwares. 

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e) Next generation sequencing for T-cell receptor clonality in tumor-infiltrating 
lymphocytes (TIL): Samples will be analyzed using high throughput sequencing 
of the variable β-chain of the T cell receptor (TCR) to characterize the expansion 
and clonality of the T-cell repertoire in TILs. 
 
f) Tumor Biopsy Analyses: Tissue microarrays (TMA) will be created using biopsy 
tissue mounted on poly-L-lysine coverslips, done by central pathology. Deidentified 
TMAs will be shipped to Enable Medicine for imaging analysis. 
 
Role of Enable Medicine as a Participating Site is as Follows: 
• Specimens will be labeled with deidentified study IDs, to only indicate cohort 
identification and patient subsets. 
• Documents will be sent with a simple packing sheet providing an inventory list 
of the material being sent. 
• No participant identifiers will be shared. 
• Specimens will be shipped to Enable Medicine, located at 3499 Edison Way, 
Menlo Park, CA 94025. 
• Specimens will be shipped at ambient temperature. 
• Specimens are being tracked in a secure MS Excel that has been locked. 
• 
Specimens should be received during normal business hours, M-F. 
• Enable Medicine’s primary contact is as follows, and will be notified when 
shipments go out – and to confirm shipment receipt 
o Archit Sheth-Shah (archit@enablemedicine.com) 
• Preferred Courier is FedEx 
g)  
 
 
Peripheral blood studies 
 
Blood samples will be taken prior to initiation of study therapy and on designated time points 
post-treatment. Research blood collection procedures will be performed as outlined in 
Appendix F. 
These samples will be analyzed for: 
 
 
a.) Immunophenotyping and Functional Analyses: 
1. Samples will be analyzed by flow cytometry to study the effects of talimogene 
laherparepvec and pembrolizumab on various peripheral blood immune cell 
subsets including, but not limited to T cell subsets (activated, memory and 
regulatory T cells). 
2. To explore whether PD-1 blockade will restore T cell activation and function, 
peripheral blood mononuclear cells (PBMCs) will be isolated and cryopreserved. 

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Assays of the functional status of effector T cells will be performed, including, but 
not limited to assays for interferon-gamma (IFN-γ) and granzyme B. This assay 
will use a non-specific stimulus including but not limited to anti-CD3 and anti-CD28 
and would allow for the comparison of the effect of nivolumab on T cell function. 
 
b.) Soluble Factors: Baseline and on-treatment serum levels of chemokines, 
cytokines and other immune mediators will be assessed by techniques that may 
include but are not limited to ELISA or multiplex assays. Analytes may include, but 
are not limited to IFN-γ, IL-12, IL-10, soluble MICA, C-reactive protein, soluble PD- 
1 and soluble PD-L1. 
 
c.) Next generation sequencing for T-cell receptor clonality in peripheral blood: 
Samples will be analyzed using high throughput sequencing of the variable β-chain 
of the T cell receptor (TCR) to characterize the expansion and clonality of the T-cell 
repertoire in peripheral blood mononuclear cells. 
 
Table 5. Exploratory Biomarkers 
Biomarker name 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
Peripheral Blood Cells 
1. Flow cytometric analyses 
to evaluate activated 
(HLA-DR+) and memory 
(CD45RA-) T cells 
2. Flow cytometric analyses 
to evaluated peripheral 
blood leucocytes including 
CD4/CD25/FoxP3, 
CD4/CD8/CD45RA/CCR7, 
CD4/CD8/LAG3/PD-1/PD- 
L1, CD4/CD8/CD137 
3. Functional Status of 
effector T cells assays for 
interferon-gamma and 
granzyme B. 
4. T-cell subsets and their 
activation status (CD8+ 
Teff/Treg ratio and ICOS 
expression 
Metastatic/locally advanced cohort: 
Blood (Weeks, 1,4, 7, , 13, 19, 22 
and off-study) 
Neoadjuvant cohort: blood (weeks 
1, 4, 6 and 12 where applicable) 
and prior to all cycles of therapy 
Soluble Factors, Serum 
Treatment modulation of serum 
levels of chemokines, cytokines 
and other immune mediators by 
ELISA or other multiplex-based 
assay methods. Primary analysis 
includes interferon-gamma and IL- 
10. 
Metastatic/locally advanced cohort: 
Blood Serum (Weeks 1,4, 7, , 13, 
19, 22 and off-study) 
Neoadjuvant cohort: blood (weeks 
1, 4, 6 and 12 where applicable) 
and prior to all cycles of therapy 
Characterization of Tumor 
infiltrating lymphocytes 
1. IHC to assess number 
and composition of 
Metastatic/locally advanced cohort: 

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immune infiltrates to 
define immune cell 
subsets present within 
tumor before and after 
exposure to treatment. 
CD3, CD4, CD8 and 
FOXP3 will be evaluated. 
2. Immune cell phenotyping 
of freshly isolated TIL to 
evaluate Treg/Teff ratio 
(CD8+/FoxP3+ cells) and 
activations markers 
(ICOS, PD-1, CD69). 
Tumor biopsy at: 
Baseline 
Week 8 
Progression (optional) 
Neoadjuvant cohort: 
Tumor biopsy at: 
Baseline 
Week 4 
Week 7 and/or 10 if applicable 
(optional) 
Surgical specimen 
PD-L1 expression by IHC 
Qualtek immunohistochemistry- 
based assay for PD-L1 
Metastatic/locally advanced cohort: 
Tumor biopsy at: 
Baseline 
Week 8 
Progression (optional) 
Neoadjuvant cohort: 
Tumor biopsy 
Baseline 
Week 4 
Week 7 and/or 10 if applicable 
(optional) 
Surgical specimen 
Tumor Biopsy neoantigen 
analysis 
Fresh frozen tumor biopsy will be 
utilized for massively parallel 
whole exome sequencing. 
Available databases such as SNP 
effect 
(http://snpeff.sourceforge.net/will 
be used to determine which 
mutations are in coding regions 
and will affect amino acid 
sequence. NetMHC and the 
Immune Epitope Database will be 
utilized to predict MHC Class I 
binding and T cell interactions, 
respectively. 
Tumor biopsies at baseline 
Paired normal peripheral blood 
mononuclear cells at baseline 
T-cell receptor sequencing 
High throughput sequencing of the 
variable β chain of the T-cell 
receptor. 
Metastatic/locally advanced cohort: 
Tumor biopsy at: 

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Baseline 
Week 8 
Progression (optional) 
Neoadjuvant cohort: 
Tumor biopsy at: 
Baseline 
Week 4 
Week 7 and/or 10 if applicable 
(optional) 
Surgical specimen 
10.4 – Imaging studies for exploratory analysis of diagnosis and non-invasive, 
monitoring of disease during therapy 
 
In addition to invasive interrogation of immune responses within the tumor 
microenvironment, imaging studies are planned to evaluate the potential for 
noninvasive monitoring of disease and disease progression in patients with cutaneous 
disease. All imaging modalities are FDA approved or have been granted FDA 
exemption and are believed to involve minimal risk to participants. 
RECIST 1.1 criteria for cutaneous disease currently relies on caliper measurements and 
clinical photography with rulers to monitor disease response to therapy. For each patient with 
cutaneous disease, imaging will be performed of the injected and distant sites of metastasis 
(if accessible) for the purposes of correlative studies both at baseline and at regular intervals. 
These imaging techniques will be performed prior to biopsy for the purposes of correlative 
studies and in order to decrease the possible effect on the biopsies on imaging results. 
Imaging to include reflectance confocal microscopy, optical coherence tomography, and 
ultrasonography if feasible (as determined by the investigator) will be performed. These 
imaging modalities are intended both to enhance our understanding of the tumor response to 
therapy and to provide a much-needed addition to the literature 
 
 
Briefly, confocal microscopy uses light that is back-scattered from the tissue. The penetration 
depth can be limited which is why combination with optical coherence tomography or 
ultrasonography may be important for identifying tumor volumes or morphology. While CLSM 
provides higher resolution and cellular level detail than OCT, the images can be difficult to 
interpret because of their en face orientation and lack of structural context (e.g., epidermis 
versus dermis). Thus, the addition of OCT and/or ultrasonography is anticipated to facilitate 
interpretation of our CSLM images. In the long term, we expect that addition of OCT and 
ultrasonography to CLSM will enable noninvasive and real-time monitoring of sarcoma 
response to immunotherapy. High frequency ultrasonography with Doppler based 
assessment of tissue blood flow and elastography will be attempted if available on a case by 
case basis to further enhance our understanding of tumor response to therapy. 

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Table 6. Study calendar 
 
A. Metastatic/locally advanced cohort 
 
 
Screening 
Week 1 
Week 4 
Week7 Week 8 
Week 
10 
Week13 
and every 
3 weeks 
up to 24 
months 
Off 
study 
visit10 
Talimogene 
laherparepvec1 
X 
X 
X 
X 
X 
Pembrolizumab1 
X 
X 
X 
X 
X 
Informed consent 
X 
Review of concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
Review of adverse 
events 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
Routine laboratory tests6 
X 
X 
X 
X 
X 
X 
X 
Research blood 4, 
X 
X 
X 
X4 
X 
Hepatitis B, C and HSV 
screen9 
X 
Pregnancy Test7 
X 
X 
X 
EKG3 
X 
X3 
X 
CT and/or MRI2 
X 
X2 

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Additional imaging for 
research purposes11 
X 
X 
Biopsy 
X 
X5 
Reporting Exposure to 
talimogene 
laherparepvec (subject’s 
household member or 
caregiver or healthcare 
provider)8 
X 
X 
X 
X 
X 
X 
X 
Swab collection from 
suspected herpes 
infected lesions for T- 
VEC DNA qPCR testing 
X 
X 
X 
X 
X 
X 
X 
1. Talimogene laherparepvec and pembrolizumab will be given at the assigned doses. 
2. Standard Imaging studies will be performed at baseline, week 8 and every 8 weeks subsequently (± 1 
week window) and will include CT of chest (with or without contrast) , CT of abdomen/pelvis (with 
contrast where renal function permits) and/or MRI abdomen/pelvis (with and without contrast), in 
addition to imaging of the affected area if deemed necessary by the study investigator. 
3. An EKG will be performed at baseline, week 8 and every 8 weeks subsequently (± 1 week window). 
4. Research blood samples will be collected at week 1,4, 7, 13, 19, 22 and at the date of the off study 
visit (± 7 days). 
5. Mandatory tumor tissue biopsies, of a distant site of disease, preferably a site not intended to be 
injected with talimogene laherparepvec where feasible, will be required at baseline and at week 8 (± 7 
days). An optional biopsy at time of progression of disease will also be offered. 
6. Routine laboratory tests include: cbc with differential, PT/INR and aPTT, comprehensive serum 
chemistry panel (including glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, 
bicarbonate, calcium, total protein, albumin, serum bilirubin, alkaline phosphatase, ALT, AST, 
phosphorus, magnesium, TSH, T4 free) urinalysis 
7. Serum β-HCG (Female subject of childbearing potential should have a negative serum pregnancy at 
screening and within 72 hours prior to first dose of both study drugs and at the off study visit). 
8. Exposure cases to be reported during the duration of the study and for 30 days post treatment. If the 
exposed individual is reporting signs or symptoms suspected to be related to talimogene laherparepvec 
exposure, the exposed individual may be asked to have a swab taken at baseline, during treatment and 
in follow-up to evaluate for the presence of talimogene laherparepvec DNA in the suspected herpetic 
lesion by qPCR testing. 
9. Hepatitis serology includes testing for HCV antibody, HBV core antibody and HBV surface antigen. 
10. The off study visit will take place 30 days (+7 days) after the last dose of talimogene laherparepvec or 
the last dose of pembrolizumab, whichever is later . 
11. Additional imaging for research purposes will be performed in patients with cutaneous disease. 
Research imaging techniques will be performed at baseline and prior to treatment biopsies and then 
regularly in conjunction with the schedule when standard cross sectional imaging is performed. 
11.0 TOXICITIES/SIDE EFFECTS 
Toxicity will be assessed using the NCI CTCAE (version 4.03). 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value must be followed until resolution or stabilization of the 
event. As described in section 11.1, a dose delay >9 weeks may require the patient to be 
discontinued from the study, with exception of patients who undergo surgery. 

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11.1 Adverse Event Characteristics and Definitions 
 
11.1.1 Definitions of Treatment Related Toxicity Events (TRTE) and decisions based 
on TRTEs: 
Subjects are considered evaluable for feasibility and toxicity assessments if they receive at 
least one dose of the protocol-assigned dose(s). The treatment related toxicity events that 
determine feasibility and early-stopping results are defined as those that result in: 
i) study drug(s) discontinuation or 
ii) delay in study drug administration more than 9 weeks from the date of the planned 
dose (i.e., approximately 12 weeks since the previous dose) 
TRTE will be evaluable throughout the study period. The events will only be considered 
TRTE if judged by the investigator to be related to the administration of talimogene 
laherparepvec and/or pembrolizumab. 
Examples include 
- 
Grade 4 non-hematologic toxicity 
- 
Grade 3 or greater immune-mediated adverse events (except skin). 
- 
Any grade plasmacytoma at or near the injection site or evidence of impaired wound 
healing at the injection site 
- 
Grade 3 or greater allergic reactions considered at least possibly related to talimogene 
laherparepvec or pembrolizumab. 
- 
Grade 3 or higher pneumonitis 
- 
Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care 
- 
Any grade 3 or higher non-hematologic laboratory value if: 
o medical intervention is required, or 
o the abnormality leads to hospitalization, or 
o the abnormality persists for > 1 week 
- 
Febrile neutropenia grade 3 or grade 4. 
- 
Thrombocytopenia < 25 x 109/L 
- 
Grade 5 toxicity (i.e., death) 
 
The following herpetic events: 
• Serious herpetic events such as herpetic encephalitis, encephalomyelitis or 
disseminated herpetic infection 
• For any herpetic events confirmed due to talimogene laherparepvec that require 
treatment with acyclovir or similar anti-viral agent, treatment with talimogene 
laherparepvec should be suspended if anti-viral treatment is required with systemic 
acyclovir or other anti-virals, and if ongoing anti-viral treatment is required, treatment 
with talimogene laherparepvec should be permanently discontinued 

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Herpetic events due to wild-type HSV-1 or wild-type HSV-2 which require acyclovir and are 
not due to talimogene laherparepvec (as confirmed by PCR testing) should not be 
considered as treatment related toxicity event caused by talimogene laherparepvec. 
Subjects may be replaced if they are not evaluable for feasibility and treatment related events 
(e.g., a subject did not receive both study drugs or permanently discontinued talimogene 
laherparepvec prior to receiving the first dose of pembrolizumab for any reason). 
 
If dosing is delayed by more than 9 weeks from the date of the planned dose (i.e., 
approximately 12 weeks since the previous dose) due to the occurrence of an adverse 
event that is considered related to talimogene laherparepvec and/or pembrolizumab, then 
the subject should be taken off study treatment(s) that the adverse event is deemed to have 
been related to (see section 11.4.1). 
 
11.1.2 Definition of an AE 
Any untoward medical occurrence in a subject or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medicinal product. For marketed medicinal products, this also includes failure to 
produce expected benefits, abuse, or misuse. Examples of events meeting the definition of 
an AE include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition 
• New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE). 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
11.1.3 Definition of a SAE 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization 

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• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not 
considered an SAE. 
SAE reporting is required as soon as the participant starts investigational treatment. SAE 
reporting is required for 30-days after the participant’s last investigational treatment. Any 
event that occur after the 30-day period that is unexpected and at least possibly related to 
protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
 
 
11.1.4 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and 
SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements) including 
those that worsen from baseline, and events felt to be clinically significant in the medical and 
scientific judgment of the investigator are to be recorded as an AE or SAE, in accordance with 
the definitions provided. 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject's 
condition, are not to be reported as AEs or SAEs. 
 
11.1.5 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
SAEs 
Disease Related Events are events (serious or non-serious) anticipated to occur in the study 
population due to the underlying disease. These could include overall disease progression 
or pain or discomfort caused by growing tumors. Such events do not meet the definition of 
an Adverse Event unless assessed to be more severe than expected for the subject’s 
condition. 
An event which is part of the natural course of the disease under study (i.e., disease 
progression) does not need to be reported as an SAE. Deaths and hospitalizations related to 
disease (other than for study procedures) during the study period and 30 days after 
completion must be reported as SAEs. 
Disease Related Events that would qualify as an Adverse Event or Serious Adverse Event: 

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• An event based on the underlying disease that is worse than expected as assessed by 
the investigator for the subject’s condition 
• The investigator believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol required therapies and disease worsening 
11.2 – Risks, toxicities and adverse drug reactions – talimogene laherparepvec 
Talimogene laherparepvec dosing likely will produce side effects, and not all side effects may 
be known. Specific identified risks and potential risks are highlighted below, as well as 
adverse drug reactions observed in clinical trials. 
As of 26 April 2018, an estimated 1253 subjects (727.1 subject-years) have been 
exposed to talimogene laherparepvec in Amgen-sponsored clinical studies since the 
beginning of the development program. Overall, most adverse events reported in subjects 
administered talimogene laherparepvec are non-serious and primarily include flu-like 
symptoms and injection site reactions. Most fatal adverse events reported in subjects 
administered talimogene 
laherparepvec were reported in the setting of disease progression. Please refer to talimogene 
laherparepvec investigational brochure (Appendix A) for additional information. 
 
 
11.2.1 –Important Identified risks – talimogene laherparepvec 
Disseminated herpetic infection in severely immunocompromised individuals (those with any severe 
congenital or acquired cellular and/or humoral immune deficiency) 
Talimogene laherparepvec has not been studied in immunocompromised subjects. 
Based on animal data, subjects who are severely immunocompromised (eg, subjects 
with severe congenital or acquired cellular and/or humoral immune deficiency) may be at 
an increased risk of disseminated herpetic infection and should not be treated with 
talimogene laherparepvec [see Section 2.0: Contraindications and Section 7.0 of the 
Investigator’s Brochure]. Disseminated herpetic infection may also occur in 
immunocompromised subjects (such as those with HIV/AIDS, leukemia, lymphoma, 
common variable immunodeficiency, or who require chronic high-dose steroids or other 
immunosuppressive agents). Consider the risks and benefits of treatment before 
administering talimogene laherparepvec to these subjects. 
• 
Accidental exposure of healthcare providers (HCP) to Talimogene Laherparepvec 
Accidental exposure may lead to transmission of talimogene laherparepvec and herpetic 
infection. Healthcare providers and close contacts (household members, caregivers, 
sex partners or persons sharing the same bed), pregnant women and neonates should 
avoid direct contact with injected lesions or body fluids of treated subjects. Accidental 
needle stick and splash back have been reported in healthcare providers during 
preparation and administration of talimogene laherparepvec. Subjects should be 
advised to avoid touching or scratching injection sites as this could lead to inadvertent 
transfer of talimogene laherparepvec to other areas of their body. Close contacts who 
are pregnant or immunocompromised should not change the subject’s dressings or 
clean their injection sites. 
Caregivers should be advised to wear protective gloves when assisting subjects in 
applying or changing dressings and to observe safety precautions for disposal of used 
dressings and cleaning materials [see Special Instructions for Use and Handling of the 
investigational brochure]. 
In the event of an accidental exposure to talimogene laherparepvec, exposed individuals 
should be advised to clean affected area thoroughly with soap and water and/or a 

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disinfectant. If signs or symptoms of herpetic infection develop, they should contact their 
healthcare provider. Talimogene laherparepvec is sensitive to acyclovir. 
Obstructive airway disorder 
Obstructive airway disorder has been reported following talimogene laherparepvec 
treatment. Use caution when injecting lesions close to major airways. 
• 
Immune-mediated adverse events 
In clinical studies, immune-mediated events including glomerulonephritis, vasculitis, 
pneumonitis, worsening psoriasis, and vitiligo have been reported in subjects treated 
with talimogene laherparepvec. 
Consider the risks and benefits of talimogene laherparepvec before initiating treatment in 
subjects who have underlying autoimmune disease or before continuing treatment in 
subjects who develop immune-mediated events. 
• 
Plasmacytoma at the injection site 
Plasmacytoma has been reported in proximity to the injection site after administration of 
talimogene laherparepvec. Consider the risks and benefits of talimogene laherparepvec in 
subjects with multiple myeloma or in whom plasmacytoma develops during treatment. 
• 
Cellulitis at site of injection 
Necrosis or ulceration of tumor tissue may occur during talimogene laherparepvec 
treatment. Cellulitis and systemic bacterial infection have been reported. Careful wound 
care and infection precautions are recommended, particularly if tissue necrosis results in 
open wounds. 
• 
Arterial hemorrhage 
Fatal carotid arterial hemorrhage (carotid blowout syndrome) has been reported 
following administration of talimogene laherparepvec in the setting of recurrent 
squamous cell carcinoma of the head and neck (SCCHN). Subjects with tumor(s) in 
direct contact or encasing a major blood vessel with ulceration and/or fungation onto the skin 
surface, and subjects with history of re-irradiation to a field which involves the carotid arteries 
may be at increased risk for arterial hemorrhage. Consider the risks and 
benefits of treatment before administering talimogene laherparepvec to these subjects. 
• 
Herpetic infection 
In clinical studies, herpetic infections (including cold sores and herpes keratitis) have 
been reported in subjects treated with talimogene laherparepvec. Subjects who develop 
herpetic infections should be advised to follow standard hygienic practices to prevent 
viral transmission. 
Talimogene laherparepvec is sensitive to acyclovir. Consider the risks and benefits of 
talimogene laherparepvec treatment before administering acyclovir or other anti-viral 
agents indicated for management of herpetic infection. These agents may interfere with the 
effectiveness of talimogene laherparepvec 
• 
Impaired healing at the injection site 
In clinical studies, impaired healing at the injection site has been reported. Talimogene 
laherparepvec may increase the risk of impaired healing in subjects with underlying risk 

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factors (eg, previous radiation at the injection site or lesions in poorly vascularized 
areas). Consider the risks and benefits of talimogene laherparepvec before continuing 
treatment if persistent infection or delayed healing develops. 
11.2.3 Herpetic Events and qPCR Testing 
• 
Any cases of suspected herpetic events in treated subjects or of suspected 
secondary transmission in a close contact or HCP with signs or symptoms should 
be reported to Amgen within 24 hours of sponsor awareness. 
• 
All reporting is done over the phone to Amgen at (855-465-9442). Refer to Appendix 
C and table 12 for reporting suspected herpetic events, and a sample form with the 
information to be reported to Amgen. Patients will be tested if they develop suspected 
herpetic lesions in order to allow detection of DNA specific to talmogene 
laherparepvec. 
o Any suspected herpetic lesion should be evaluated by the investigator and 
swabbed 
o Swabs of cold sores, vesicles or any other lesions suspected to be herpetic in 
origin should be obtained. 
o Follow the instructions provided by the qPCR test manual provided for sample 
collection, shipping, and handling process, (appendix B) 
o Amgen does not require qPCR or other testing for wild type HSV 1. A 
commercially available test should be ordered if the investigator believes it is 
clinically indicated. 
o Principal investigator/clinical research team should report confirmed (by qPCR 
as described) herpetic events to local institutions Infection Control 
Department. 
• 
Patients will be provided with a letter detailing exposure, prevention, and who to 
contact if a family member, care giver, or close contact experiences symptoms that 
may be related to talimogene laherparepvec. 
 
11.2.4 - Adverse Drug Reactions – talimogene laherparepvec 
The most commonly reported adverse reactions (≥ 25%) in talimogene laherparepvec -treated 
subjects were fatigue, chills, pyrexia, nausea, influenza like illness, and injection site pain. 
Most adverse reactions reported were mild or moderate in severity and generally resolved 
within 72 hours. The most common grade 3 or higher adverse reaction was cellulitis. Pyrexia, 
chills, and influenza like illness can occur any time during talimogene laherparepvec treatment, 
but were reported more frequently during the first 3 months of treatment, particularly in 
subjects who were HSV-1 negative at baseline. 
 
Adverse drug reactions observed in talimogene laherparepvec clinical trials are listed below 
in table 7. 

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Table 7. ADRs Observed in talimogene laherparepvec Clinical Trials 
 

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11.3 – Risks, toxicities and adverse drug reactions – Pembrolizumab 
Pembrolizumab dosing likely will produce side effects, and not all side effects may be known. 
Specific identified risks and potential risks are highlighted below, as well as adverse drug 
reactions observed in clinical trials: 
Information extracted from Pembrolizumab Prescribing Information, available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf 
11.3.1 – Identified risks - Pembrolizumab 
Risk: Immune-Mediated Pneumonitis 

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Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases 
in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving pembrolizumab. The median time 
to development of pneumonitis was 5 months (range 0.3 weeks-9.9 months). The median 
duration was 4.9 months (range 1 week-14.4 months). Five of eight patients with Grade 2 and 
the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic 
corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by 
a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 
mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1- 
34) followed by a corticosteroid taper. Pneumonitis led to discontinuation of pembrolizumab 
in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the nine patients with Grade 
2-3 pneumonitis. 
 
Risk: Immune-Mediated Colitis 
Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 
3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving pembrolizumab. The median 
time to onset of colitis was 6.5 months (range 2.3-9.8). The median duration was 2.6 months 
(range 0.6 weeks-3.6 months). All three patients with Grade 2 or 3 colitis were treated with 
high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) 
with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of 
initial treatment was 7 days (range 4-41), followed by a corticosteroid taper. One patient 
(0.2%) required permanent discontinuation of pembrolizumab due to colitis. All four patients 
with colitis experienced complete resolution of the event. 
 
Risk: Immune-Mediated Hepatitis 
Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a 
Grade 4 case in 1 (0.2%) patient, receiving pembrolizumab. The time to onset was 22 days 
for the case of Grade 4 hepatitis which lasted 1.1 months. The patient with Grade 4 hepatitis 
permanently discontinued pembrolizumab and was treated with high-dose (greater than or 
equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a 
corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event. 
 
Risk: Immune-Mediated Hypophysitis 
Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 
4 case (0.2% each), in patients receiving pembrolizumab. The time to onset was 1.7 months 
for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 
hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg 
prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and 
remained on a physiologic replacement dose. 
 
Risk: Renal Failure and Immune-Mediated Nephritis 
Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune 
nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 
and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months after the first 
dose of pembrolizumab (5 months after the last dose) and lasted 3.2 months; this patient did 
not have a biopsy. Acute interstitial nephritis was confirmed by renal biopsy in two patients 
with Grades 3-4 renal failure. All three patients fully recovered renal function with treatment 
with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per 
day) followed by a corticosteroid taper. 

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Risk: Immune-Mediated Hyperthyroidism and Hypothyroidism 
Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) 
and 1 (0.2%) patients, respectively, receiving pembrolizumab. The median time to onset was 
1.5 months (range 0.5-2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of 
two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial 
treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or 
equivalent per day) followed by a corticosteroid taper. One patient (0.2%) required permanent 
discontinuation of pembrolizumab due to hyperthyroidism. All five patients with 
hyperthyroidism experienced complete resolution of the event. Hypothyroidism occurred in 
34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving 
pembrolizumab. The median time to onset of hypothyroidism was 3.5 months (range 0.7 
weeks-19 months). All but two of the patients with hypothyroidism were treated with long-term 
thyroid hormone replacement therapy. The other two patients only required short-term thyroid 
hormone replacement therapy. No patient received corticosteroids or discontinued 
pembrolizumab for management of hypothyroidism. 
 
Risk: Infusion reactions 
 
Pembrolizumab infusion reactions may consist of fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticarial, rash, vomiting, myalgia, 
dizziness, or hypertension. Severe reactions may include acute respiratory distress 
syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. Patients 
should be closely monitored for such reactions. Guidelines for patients who experience an 
infusion related or allergic reaction during or after infusion with pembrolizumab are detailed 
in Appendix B. 
 
Risk: Other Immune-Mediated Adverse Reactions 
Other clinically important immune-mediated adverse reactions can occur. The following 
clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients 
treated with pembrolizumab: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, 
hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain 
parenchyma, and adrenal insufficiency. 
 
Across clinical studies with pembrolizumab in approximately 2000 patients, the following 
additional clinically significant, immune-mediated adverse reactions were reported in less 
than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis. 
 
11.3.2 - Adverse Drug Reactions – Pembrolizumab 
Adverse drug reactions observed in an uncontrolled, open-label, multiple cohort trial in which 
411 patients with unresectable or metastatic melanoma received pembrolizumab at either 2 
mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks (Trial 1). The median duration of 
exposure to pembrolizumab was 6.2 months (range 1 day to 24.6 months) with a median of 
10 doses (range 1 to 51). 
 
Pembrolizumab was discontinued for adverse reactions in 9% of the 411 patients. Adverse 
reactions, reported in at least two patients that led to discontinuation of pembrolizumab were: 

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pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients 
receiving pembrolizumab. The most frequent serious adverse drug reactions reported in 2% 
or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis. Table 8 
presents adverse reactions identified from analyses of the 89 patients with unresectable or 
metastatic melanoma who received pembrolizumab 2 mg/kg every three weeks in one cohort 
of Trial 1. This cohort of Trial 1 excluded patients with severe immune-related toxicity related 
to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or 
Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or 
equivalent dose) for greater than 12 weeks; a medical condition that required systemic 
corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial 
lung disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of 
the 89 patients in this cohort, the median age was 59 years (range 18-88), 33% were age 65 
years or older, 53% were male, 98% were white, 44% had an elevated LDH, 84% had Stage 
M1c disease, 8% had brain metastases, and 70% received two or more prior therapies for 
advanced or metastatic disease. The median duration of exposure to pembrolizumab was 6.2 
months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23). Fifty-one 
percent of patients were exposed to pembrolizumab for greater than 6 months and 21% for 
greater than 1 year. Pembrolizumab was discontinued for adverse reactions in 6% of the 89 
patients. The most common adverse reactions (reported in at least 20% of patients) were 
fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and 
diarrhea. 
 
Table 8: Adverse Reactions in ≥10% of patients with unresectable or metastatic 
melanoma treated with pembrolizumab 2mg/kg every 3 weeks. 
 
Adverse Reaction 
All Grades 
(%) 
Grade 3* 
(%) 
General Disorders and Administration Site Conditions 
Fatigue 
47 
7 
Peripheral Edema 
17 
1 
Chills 
14 
0 
Pyrexia 
11 
0 
Gastrointestinal Disorders 
Nausea 
30 
0 
Constipation 
21 
0 
Diarrhea 
20 
0 
Vomiting 
16 
0 
Abdominal pain 
12 
0 
Respiratory, Thoracic And Mediastinal Disorders 
Cough 
30 
1 
Dyspnea 
18 
2 
Skin And Subcutaneous Tissue Disorders 
Pruritus 
30 
0 
Rash 
29 
0 
Vitiligo 
11 
0 
Metabolism and Nutrition Disorders 
Decreased appetite 
26 
0 
Musculoskeletal and Connective Tissue Disorders 
Arthralgia 
20 
0 
Pain in extremity 
18 
1 
Myalgia 
14 
1 
Back pain 
12 
1 
Nervous System Disorders 
Headache 
16 
0 
Dizziness 
11 
0 
Blood and Lymphatic System Disorders 
Anemia 
14 
5 
Psychiatric Disorders 

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Insomnia 
14 
0 
Infections and Infestations 
Upper respiratory tract infection 
11 
1 
There were no Grade 5 adverse reactions reported. Of the ≥10% adverse reactions, 
none was reported as Grade 4. 
 
Other clinically important adverse reactions observed in up to 10% of patients treated with 
pembrolizumab were: Infections and infestations: sepsis 
 
 
Table 9: Laboratory Abnormalities Increased from baseline in ≥20% of patients with 
unresectable or metastatic melanoma treated with pembrolizumab 2mg/kg every 3 
weeks. 
 
Laboratory Test 
All Grades 
% 
Grades 3-4 
% 
Chemistry 
Hyperglycemia 
40 
2* 
Hyponatremia 
35 
9 
Hypoalbuminemia 
34 
0 
Hypertriglyceridemia 
25 
0 
Increased Aspartate 
Aminotransferase 
24 
2* 
Hypocalcemia 
24 
1 
Hematology 
Anemia 
55 
8* 
* 
Grade 4 abnormalities in this table limited to hyperglycemia, increased 
aspartate aminotransferase, and anemia (one patient each) 
 
11.4 Dose adjustments, delays, rules for withholding and restarting treatment and 
permanent discontinuation. 
11.4.1 Talimogene laherparepvec 
Dose reductions – talimogene laherparepvec 
Dose reductions with regards to changes in the concentrations of talimogene laherparepvec 
are not permitted. However, patients may require a reduction in the volume injected due to a 
disease response (defined in dosing section) or due to local toxicity at the injection site. 
 
Dose delays and rules for withholding/restarting treatment – talimogene laherparepvec 
 
If a subject experiences any of the following treatment-related toxicities, talimogene 
laherparepvec administration should be delayed until the toxicity has resolved to at least 
CTCAE 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 

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Upon restarting study therapy, the patient’s treatment schedule should be reset from the date 
that therapy is reinitiated as to maintain appropriate treatment windows between therapy 
administrations. 
 
If the subject requires corticosteroid dosing of >10 mg prednisone daily (or equivalent) and/or 
other immunosuppressive medication for related toxicities talimogene laherparepvec dosing 
must be held until the corticosteroid dose has decreased to ≤10 mg prednisone daily (or 
equivalent) and the administration of the other immunosuppressive medication has 
discontinued. 
 
Subjects who are receiving talimogene laherparepvec may not receive systemic intravenous 
or oral antiherpetic drugs (e.g., acyclovir, valacyclovir, famciclovir), but may receive a topically 
administered antiherpetic drug more than 20 cm from a talimogene laherparepvec 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). 
 
Dosing of talimogene laherparepvec could also be delayed for active herpetic cutaneous or 
mucosal lesions, herpes labialis, antiviral therapy, or active dermatoses in the region of the 
injected tumors. 
Permanent discontinuation – talimogene laherparepvec 
If talimogene laherparepvec dosing is delayed by more than 9 weeks from the last dose 
(approximately 12 weeks from the previous dose) due to the occurrence of adverse events 
that are related to talimogene laherparepvec, then treatment should be discontinued. If 
talimogene laherparepvec dosing is delayed by more than 9 weeks approximately 12 weeks 
from the previous dose) for reasons other than treatment-related toxicity, the case must be 
reviewed by the principal investigator to determine if the subject can resume talimogene 
laherparepvec therapy. 
Treatment with talimogene laherparepvec should be suspended if systemic intravenous or 
oral acyclovir or other anti-viral therapy is required; if ongoing treatment is required then 
treatment should be permanently discontinued. 
In addition to criteria outlined in section 9.2, talimogene laherparepvec is to be permanently 
discontinued for subjects meeting any of the following criteria: 
- 
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 9 weeks from the date of the planned dose (i.e., approximately 
12 weeks from the previous dose) 
 
NOTE: immune-mediated glomerulonephritis, vasculitis, and pneumonitis and 
exacerbation of psoriasis have been observed in subjects receiving talimogene 
laherparepvec in clinical trials. Most of these subjects had a history of other 
autoimmune disease and/or prior treatment with agents that offered plausible 

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alternative etiologies; however, immune-mediated adverse events can potentially 
involve any organ system. 
- 
Plasmacytoma has been observed with the administration of talimogene 
laherparepvec. Permanently discontinue talimogene laherparepvec if development of 
a plasmacytoma is observed. 
- 
Any talimogene laherparepvec-related non-hematologic or hematologic toxicities 
Grade 3 or greater that, in the opinion of the investigator, would require a dose delay 
of greater than 9 weeks (approximately 12 weeks from the previous dose) or 
discontinuation of therapy. 
- 
A female subject becomes pregnant or fails to use 2 highly effective methods of 
contraception (for those subjects who are able to conceive). 
- 
A female subject breast feeds while on study treatment. 
- 
The subject develops clinical evidence of any systemic herpes infection (such as 
encephalitis or disseminated infection). 
- 
In the event talimogene laherparepvec is delayed or permanently discontinued for 
talimogene laherparepvec-related toxicity, pembrolizumab may continue to be 
administered, as long as the toxicity is clearly not related to pembrolizumab. Likewise 
in the event pembrolizumab is delayed or permanently discontinued for 
pembrolizumab-related toxicity, talimogene laherparepvec may continue to be 
administered, as long as the toxicity is clearly not related to talimogene 
laherparepvec. 
11.4.2 Pembrolizumab 
Dose reductions – Pembrolizumab 
Dose reductions of pembrolizumab are not permitted. 
 
 
Dose Modification and Toxicity Management 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure, 
including coadministration with additional compounds, may represent an immunologic 
etiology. These adverse events may occur shortly after the first dose or several months 
after the last dose of pembrolizumab/combination treatment and may affect more than one 
body system simultaneously. Pembrolizumab must be withheld for drug-related toxicities 
and severe or life-threatening AEs as per table 10 below. See Section 5.6 for supportive 
care guidelines, including use of corticosteroids. 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event 
to a single component is likely to be difficult. Therefore, while the investigator may attribute 

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a toxicity event to the combination, to talimogene laherparepvec alone or to pembrolizumab 
alone], for adverse events listed in Table 10, both interventions must be held according to 
the criteria in Table 10 Dose Modification and Toxicity Management Guidelines for Immune- 
Related Adverse Events Associated with Pembrolizumab. 
 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune- 
related, both interventions should be held according to recommended dose modifications. 
 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 10. 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions. 
• 
If the toxicities do resolve and conditions are aligned with what is defined in Table 10, the 
combination of talimogene laherparepvec and pembrolizumab may be restarted at the 
discretion of the investigator.[In these cases where the toxicity is attributed to the 
combination or to talimogene laherparepvec alone, re-initiation of pembrolizumab as a 
monotherapy may be considered at the principal investigator’s discretion 
 
Table 10. Dose modification and toxicity management guidelines for immune-related 
AEs associated with pembrolizumab monotherapy and IO combinations 
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. 
For situations where study intervention has been withheld, study intervention can be resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Study intervention 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. 
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune- 
related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizuma 
b 
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 1- 
2mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
• 
Monitor subjects for signs and symptoms of 
pneumonitis 
• 
Evaluate subjects with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment 
Grade 3 or 4, or 
recurrent grade 2 
Permanently 
discontinue 
Diarrhea / 
colitis 
Grade 2 or 3 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 1- 
2mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor subjects for signs and symptoms of 
enterocolitis (i.e. diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (i.e. peritoneal signs 
and ileus). 
• 
Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

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Recurrent Grade 
3 or Grade 4 
Permanently 
discontinue 
• 
Subjects with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion. 
AST / ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 0.5- 
1mg/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 b or 4 c 
Permanently 
discontinue 
• 
Administer 
corticosteroids 
(initial dose of 1- 
2mg/kg 
prednisone or 
equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglyce 
mia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold d 
• 
Initiate insulin 
replacement 
therapy for 
subjects with 
T1DM 
• 
Administer anti- 
hyperglycemic in 
subjects with 
hyperglycemia 
• 
Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes. 
Hypophysiti 
s 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated. 
• 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinued 
Hyperthyroi 
dism 
Grade 2 
Continue 
• 
Treat with non- 
selective beta- 
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
Permanently 
discontinued 
Hypothyroidi 
sm 
Grade 2-4 
Continue 
• 
Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine or 
liothyronine) per 
standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute 
kidney injury 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(prednisone 1- to 
2mg/kg or 
equivalent) 
followed by taper. 
• 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
• 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 

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Grade 2, 3, or 4 
Permanently 
discontinue 
• 
Based on severity 
of AE administer 
corticosteroids 
Exfoliative 
Dermatologi 
c Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other 
immune- 
related AEs 
Grade 3, or 
intolerable/ 
persistent Grade 
2 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
NOTES: 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b  AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 
10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or 
treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e 
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis). 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., 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 principal 
investigator. The reason for interruption should be documented in the patient's study record. 
The patient’s treatment schedule should be reset from the date that therapy is reinitiated. 
11.5 Guidelines for the management of specific and immune-related toxicities 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other 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 below). Refer to Section 5.2.1 for 
dose modification. 

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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 
• 
Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
• 
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 
o All subjects who experience 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. For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 
▪ Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
• 
Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 

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• 
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
▪ 
In 
hypothyroidism, 
thyroid hormone 
replacement 
therapy, with 
levothyroxine or liothyronine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism 
▪ 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
• 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
▪ 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• 
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. Table 11 below shows treatment guidelines for subjects who 
experience an infusion reaction associated with administration of pembrolizumab (MK- 
3475). 

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Table 11: Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Stop Infusion. 
Subject may be 
Requires therapy or 
Additional appropriate medical therapy may include but is not 
premedicated 1.5h 
infusion interruption but 
limited to: 
(± 30 minutes) prior 
responds promptly to 
IV fluids 
to infusion of 
symptomatic treatment 
Antihistamines 
pembrolizumab with: 
(e.g., antihistamines, 
NSAIDs 
Diphenhydramine 
NSAIDs, narcotics, IV 
Acetaminophen 
50 mg po (or 
fluids); prophylactic 
Narcotics 
equivalent dose of 
medications indicated for 
Increase monitoring of vital signs as medically indicated until the 
antihistamine). 
≤24 hrs 
subject is deemed medically stable in the opinion of the investigator. 
Acetaminophen 
If symptoms resolve within 1 hour of stopping drug infusion, the 
500-1000 mg po (or 
infusion may be restarted at 50% of the original infusion rate (e.g. 
equivalent dose of 
from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until 
analgesic). 
symptoms resolve and the subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Grades 3 or 4 
Stop Infusion. 
No subsequent 
Grade 3: 
Additional appropriate medical therapy may include but is not 
dosing 
Prolonged (i.e., not 
limited to: 
rapidly responsive to 
Epinephrine** 
symptomatic medication 
IV fluids 
and/or brief interruption 
Antihistamines 
of infusion); recurrence of 
NSAIDs 
symptoms following initial 
Acetaminophen 
improvement; 
Narcotics 
hospitalization indicated 
Oxygen 
for other clinical sequelae 
Pressors 
(e.g., renal impairment, 
Corticosteroids 
pulmonary infiltrates) 
Increase monitoring of vital signs as medically indicated until the 
Grade 4: 
subject is deemed medically stable in the opinion of the investigator. 
Life-threatening; pressor 
Hospitalization may be indicated. 
or ventilatory support 
**In cases of anaphylaxis, epinephrine should be used immediately. 
indicated 
Subject is permanently discontinued from further study drug 
treatment. 
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 
 
 
11.6 AE and SAE reporting 
 
11.6.1 Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE. See section below for the timeline for reporting 
SAEs. 

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AEs and SAEs will be collected from the time the first dose of study treatment is administered 
until 30 days (+7 days) following discontinuation of study treatment regardless of initiation of 
a new cancer therapy or transfer to hospice. 
 
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that are 
ongoing until resolution or stabilization of the event or until the subject is lost to follow-up. At 
any time after treatment discontinuation the investigator may report any adverse event that 
they believe possibly related to study treatment. 
 
11.6.2 Prompt Reporting of Serious Adverse Events and Other Events to MSKCC IRB 
Please see section 17.2 for SAE reporting guidelines. 
 
11.6.3 CTCAE term (AE description) and grade 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the 
CTCAE 
version 
4.03 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
11.6.4 Attribution of the AE: 
− 
Definite – The AE is clearly related to the study treatment. 
− 
Probable – The AE is likely related to the study treatment. 
− 
Possible – The AE may be related to the study treatment. 
− 
Unlikely – The AE is doubtfully related to the study treatment. 
− 
Unrelated – The AE is clearly NOT related to the study treatment. 
11.7 Pregnancy Testing, Prevention and Lactation Reporting 
 
11.7.1 Pregnancy Testing and Prevention 
Talimogene laherparepvec is not considered to be teratogenic. 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. 
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). 
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential. 
Female subjects will be considered of non-reproductive potential if they are either: 
(1) 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 
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) Has a congenital or acquired condition that prevents childbearing. 

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A female of child-bearing potential is defined as any female who does not meet the criteria of 
non-childbearing potential as described in the previous paragraph. 
If a female subject is of childbearing potential, she must have a serum β-HCG pregnancy test 
at screening and performed within 72 hours of the first dose of study treatment. Subjects with 
positive pregnancy test result must be excluded from the study. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 90 days after the 
last dose of talimogene laherparepvec and 120 days after the last dose of pembrolizumab 
by complying with one of the following: 
(1) Practice abstinence† from sexual activity; 
OR 
(2) Use (or have their partner use) acceptable contraception during sexual activity. 
Acceptable methods of contraception during study treatment and up to 30 days following the 
final dose of talimogene laherparepvec include: 
Male and female latex condoms 
Acceptable methods of contraception during study treatment from 30 days after the final 
dose of talimogene laherparepvec include: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner 
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only) 
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin- 
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
• 
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. 
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
• 
If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 

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days after the last dose of trial therapy. If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
If a female subject is suspected to be pregnant during the study, a serum pregnancy test 
must be performed. If pregnancy is confirmed, subject must stop study treatment 
immediately and the pregnancy must be reported. A report confirming a female subject to be 
pregnant or lactating has to be reported to Amgen and Merck within 24 hours of site 
awareness and submitted within 10 days of sponsor awareness. The site will contact the 
pregnant subject at least monthly and document the subject’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to Merck 
and Amgen without delay and within 2 working days to Merck and Amgen if the outcome is 
a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling 
or life-threatening complication to the mother or newborn). 
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn per MSKCC guidelines. If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Merck and Amgen and followed in the same 
manner as a pregnant female subject outlined in the previous paragraph. 
11.8 Additional Information Related to Pembrolizumab and Reporting 
11.8.1 Definition of a Pembrolizumab Overdose for This Protocol and Reporting of 
Pembrolizumab Overdose to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose). No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. 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) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported per MSKCC 
guidelines and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
11.8.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported per MSKCC guidelines and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
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 per MSKCC guidelines and within 2 working days to Merck Global Safety if it 
causes the subject to be excluded from the trial, or is the result of a protocol-specified 

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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 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 24 hours to Merck Global 
Safety. 
Events of clinical interest for this trial include: 
1. an overdose of Merck product, as defined in Section 11.8.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. 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. 
11.9 Additional Information Related to Accidental Exposure to Talimogene 
Laherparepvec 
In order to better assess and understand the potential risks to treated patients and/or third 
parties following the treatment of clinical trial subjects with talimogene laherparepvec, 
special reporting procedures apply for accidental exposures to talimogene laherparepvec 
and for suspected herpetic events. See Table 12 for a summary of reporting requirements. 
11.9.1 Accidental Occupational Exposure of HCPs to Talimogene Laherparepvec 
HCPs involved in your clinical trial who were directly exposed to talimogene laherparepvec 
(e.g., needle stick, splash back) but who are without signs or symptoms of herpetic illness 
should be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442). 
 
 
1.9.2 Suspected Herpetic Events 
Suspected herpetic events must be reported to Amgen within 24 hours of awareness. 
Reporting is required for: (1) suspected herpetic events in treated patients; (2) suspected 
herpetic events in at risk HCPs with direct or indirect exposure and 3) suspected herpetic 
events in treated patient’s close contacts, as outlined in Table 12. An example of the 
Suspected IMLYGICTM (Talimogene laherparepvec) or Herpes Virus Associated Adverse 
Event can be found in Appendix C. 
In addition to reporting these events, suspected herpetic lesions should be swabbed and 
submitted for qPCR testing for the detection of talimogene laherparepvec. Samples should 
be collected using appropriate technique and a flocked swab from site supplies. This test is 
likely to be more reliable if performed within the first three days of symptom appearance, 
however, all lesions should be swabbed, regardless of the timing of presentation. Amgen 
does not require qPCR or other testing for wild type HSV-1. 

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Reporting Process for ISS Treated Patients: 
Any suspected herpetic lesion should be reported to Amgen at 1-855- IMLYGIC (1-855- 
465-9442), evaluated by the Sponsor/Investigator and swabbed for qPCR testing. 
Once an initial report has been made, additional materials will be provided, including 
reporting forms and supplies needed for shipment of swab samples. Amgen will require 
patient consent for qPCR testing, which must be obtained prior to swabbing. 
Reporting Process for HCPs and Close Contacts: 
Sponsor/Investigator should advise any HCPs and/or Close Contacts with suspected 
herpetic lesions to contact their personal physician to facilitate reporting to Amgen. 
Suspected herpetic lesions can be reported by the Sponsor / Investigator, personal 
physician or exposed individual to Amgen at 1-855-IMLYGIC (1-855-465-9442). Once an 
initial report has been made, additional materials will be provided, including reporting forms 
and supplies needed for the shipment of swab samples. Amgen will require patient consent 
for qPCR testing, which must be obtained prior to swabbing 
 
Table 12. Accidental Exposure & Herpetic Event Reporting Requirement Summary 
 
 
Exposed 
person 
Reporter 
Timeframe 
for 
reporting 
to Amgen 
Report 
mechanism 
Timing of 
Swab 
Collection 
qPCR 
testing 
Required? 
Responsible 
person for 
Lesion 
swabbing 
qPCR Test 
Result 
Distribution 
Treated Patients 
with suspected 
herpetic lesions 
Investigator 
Within 24 
hours of 
Investigator 
awareness 
Contact 
Amgen at 
1-855- 
IMLYGIC 
(1-855-465- 
9442) 
to report 
event 
Collect 
swabs 
from 
suspected 
lesions 
(ideally 
within 3 
days of 
appearanc 
e of 
symptoms 
) 
Yes, if 
consent 
obtained 
Investigator 
Investigator 
and Amgen 
HCP directly 
exposed to 
product (e.g., 
needle stick, 
splash back) 
without signs of 
symptoms of 
herpetic illness 
HCP’s 
personal 
physician 
or impacted 
person 
Within 24 
hours of 
reporters 
awareness 
Contact 
Amgen at 
1-855- 
IMLYGIC 
(1-855-465- 
9442) 
to report 
event 
N/A 
N/A 
N/A 
N/A 
HCP directly or 
indirectly 
exposed to 
product with 
suspected 
herpetic lesions 
HCP’s 
personal 
physician 
or impacted 
person 
Within 24 
hours of 
reporters 
awareness 
Contact 
Amgen at 
1-855- 
IMLYGIC 
(1-855-465- 
9442) 
to report 
event 
Collect 
swabs 
from 
suspected 
lesions 
(ideally 
within 
3 days of 
appearanc 
e 
Yes, if 
consent 
obtained 
HCP or 
HCP’s 
personal 
physician 
HCP’s 
personal 
physician 
and Amgen 

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of 
symptoms 
) 
Close Contact 
(eg caregiver, 
spouse, child) 
with suspected 
herpetic lesions 
Investigator 
, Close 
Contact’s 
Personal 
Physician 
or Close 
Contact 
Within 24 
hours of 
reporters 
awareness 
Contact 
Amgen at 
1-855- 
IMLYGIC 
(1-855-465- 
9442) 
to report 
event 
Collect 
swabs 
from 
suspected 
lesions 
(ideally 
within 3 
days of 
appearanc 
e of 
symptoms 
) 
Yes, if 
consent 
obtained 
Investigator, 
Close 
Contact’s 
Personal 
Physician 
Close 
Contact’s 
personal 
physician 
and Amgen 
 
 
11.9.3 Accidental Spills 
Accidental spills of talimogene laherparepvec should be managed as per local institutional 
guidelines. All disposable materials contaminated with talimogene laherparepvec must be 
destroyed and disposed of in compliance with local institutional guidelines. 
11.9.4 Infections 
Tumor necrosis may be seen with the use of talimogene laherparepvec. The presence of 
necrotic or ulcerating lesions may pre-dispose the subject to local and/or systemic infections 
such as cellulitis, bacteremia, etc. Careful wound care and infection precautions are 
recommended if tumor necrosis results in open wounds. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 Antitumor effect 
All patients will undergo a baseline staging CT scan of the chest (with or without contrast), 
abdomen and pelvis (with contrast if renal function permits), and MRI abdomen/pelvis (with 
and without contrast) if deemed necessary by the treating physician. Response evaluations 
will occur at week 8 and every 8 weeks subsequently (± 1 week window) until 12 months, and 
then less frequently at the discretion of the treating investigator. 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline, 
version 1.1 (Primary response criteria).88 Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
In addition, patients will also be evaluated using the Immune-related revised Response 
Evaluation Criteria in Solid Tumors (irRECIST), 89 which will not be used for treatment 
decisions (Secondary Response Criteria) and are discussed separately in section 12.12. 
In subjects who have initial evidence of progressive disease (PD) as per RECIST criteria or 
irRECIST criteria, it is at the discretion of the investigator to continue a subject on study 
treatment until confirmation of PD ≥ 4 weeks. 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 if they are clinically stable as defined by the following criteria: 

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• 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 (e.g., cord compression) 
requiring urgent alternative medical intervention 
12.2 Definitions 
Evaluable for toxicity – All patients will be evaluable for toxicity from the time of their first 
treatment with talimogene laherparepvec and/or pembrolizumab. 
Evaluable for efficacy – Only those patients who have a measurable disease based on 
RECIST 1.1 criteria will be eligible for this study, as highlighted in Section 6.0. These patients 
will have their response classified according to the definitions stated below. 
Only those patients who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for response. (Note: Patients who exhibit objective disease progression prior to the end of 
cycle 1 will also be considered evaluable. Note: one cycle of therapy consists of 21 days 
where the study therapy (TVEC and pembrolizumab) is administered at the start of the cycle 
on day 1) 
 
12.2.1 Disease Parameters 
Measurable disease – Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal lesions 
and short axis for nodal lesions) as >20mm by chest x-ray, as >10mm with CT scan or MRI, 
or >10mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm 
in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
Note: Tumor lesions that are situated in a previously irradiated area are not considered 
measurable unless there is evidence of progression after radiation therapy. 
 
Non-measurable disease – All other lesions (or sites of disease), including small lesions 
(longest diameter <10mm or pathological lymph nodes with ≥10 to <15mm short axis) are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
Target lesions – All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. 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 
diameters will be used as a reference to further characterize any objective regression in the 
measurable dimension of the disease. 

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Non-target lesions – All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence or in rare cases unequivocal progression of each should be noted throughout follow- 
up. 
 
 
12.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
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 portion of study. Imaging- 
based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions - Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using 
calipers (e.g., skin nodules). 
 
Chest x-ray - Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI - This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 

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12.3.1 Primary Response Criteria (RECIST 1.1) 
 
12.3.1.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.3.1.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or MSKCC Principal Investigator). 
 
12.3.1.3 
Evaluation of Best Response 
The best response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 

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Table 13. Evaluation of Best Response – RECIST criteria 
 
Target 
Lesions 
Non- 
Target 
Lesions 
New 
Lesions 
Best 
Response 
Best Response for This 
Category also Requires: 
CR 
CR 
No 
CR 
≥ 4 wks. Confirmation 
CR 
Non-CR/ 
Non-PD 
No 
PR 
≥ 4 wks. Confirmation 
PR 
Non-CR/ 
Non-PD 
No 
PR 
SD 
Non-CR/ 
Non-PD 
No 
SD 
documented at least once ≥ 
4 wks. from baseline 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
12.4 Confirmation of response 
 
Complete or partial response may only be claimed if the criteria for each are met at a 
subsequent time point (≥4 weeks later) in studies with a primary endpoint that include 
response rate. 
 
12.4.1 Special note on target lesions that become “too small to measure” 
 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2mm). 
However, sometimes, lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being “too small to measure”. When this occurs, it is 
important that a value be recorded on the D2M form. If it is the opinion of the radiologist that 
the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion 
is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. 

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12.5 Not evaluable (NE) 
 
When no imaging/measurement is done at all at a particular time point, the patient is 
considered not evaluable (NE) at that time point. 
 
12.6 Early death 
 
If the patient has no repeat tumor assessments following initiation of study therapy resulting 
from the death of the patient due to disease or treatment, it is considered early death. 
 
12.7 Symptomatic Deterioration 
 
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time be recorded as “symptomatic 
deterioration”. Every effort should be made to document objective progression even after 
discontinuation of treatment. 
 
12.8 Duration of response 
 
Defined as the time measurement criteria are first met for CR/PR until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurement recorded on study). 
 
12.9 Duration of stable disease 
 
Measured from the start of the treatment until the criteria for progression are met, taking as 
reference the smallest sum on study (if the baseline sum is the smallest, this is the reference 
for calculation of PD). 
 
12.10 Progression-Free Survival (PFS) 
 
PFS is defined as the period from start of study treatment until recurrent or progressive of 
disease (POD) is objectively documented (taking as reference for progressive disease the 
smallest measurement recorded on study), death, or date of last evaluable tumor assessment 
 
12.11 Overall Survival (OS) 
 
OS is defined as the observed length of life from start of study treatment to death or the date 
of last contact. 
 
12.12 Secondary Response Criteria – Modified immune-related response evaluation 
Criteria in Solid (irRECIST) 
 
Immune related RECIST (irRECIST) 
In 2013, Nishino et al. demonstrated that immune-related response criteria using 
unidimensional measurements were highly concordant with the bidimensional results of 
irRC, but with less measurement variability. Based on these findings and in order to utilize 

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both the established criteria of irRC and RECIST 1.1, the two systems have been adapted, 
modified, and combined into the Immune-related Response Evaluation Criteria in Solid 
Tumors (irRECIST). The adapted irRECIST criteria are modifications to the irRC, 
incorporating the findings of Nishino et al. and the advantages of RECIST 1.1 while 
overcoming the shortcomings of each of the other guidelines. 
 
irRECIST 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al. are presented 
below. 
 
I. Baseline Assessments in irRECIST 
 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1. 
 
One new definition is added: If a subject has no measurable and no non-measurable 
disease at baseline the radiologist will assign ‘No Disease’ (irND) as the overall tumor 
assessment for any available follow-up time points unless new measurable lesions are 
identified and contribute to the total measured tumor burden (TMTB). irND is a valid 
assessment in studies with adjuvant setting where the protocol and study design allow the 
inclusion of subjects with no visible disease 
 
Follow-up Assessments in irRECIST 
 
A. Follow-up recording of target and new measurable lesions 
 
The key difference in irRECIST is that the appearance of new lesions does not 
automatically indicate progression. Instead, all measured lesions (baseline-selected 
target lesions and new measurable lesions) are combined into the total measured tumor 
burden (TMTB) at follow up. Baseline-selected target lesions and new measurable 
lesions are NOT assessed separately. Measurements of those lesions are combined into 
the TMTB, and one combined assessment provided. 
 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, 
per time point), new lesions must meet criteria as defined for baseline target lesion selection 
and meet the same minimum size requirements of 10 mm in long diameter and minimum 15 
mm in short axis for new measurable lymph nodes. New measurable lesions should be 
prioritized according to size, and the largest lesions elected as new measured lesions. 
 
B. Follow-up non-target assessment 
 
RECIST 1.1 definitions for assessment of non-target lesions apply. The response of non- 
target lesions primarily contributes to the overall response assessments of irCR and irNon- 
CR/Non-PD (irNN). Non-target lesions do not affect irPR and irSD assessments. Only a 
massive and unequivocal worsening of non-target lesions alone, even without progress in 
the TMTB is indicative of irPD. In alignment with RECIST 1.1, baseline selected non-target 
lesions can never convert to measurable lesions, not even if they increase in size at 

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subsequent time points and become measurable. Only true new lesions can be measured 
and contribute to the TMTB. 
 
C. Follow-up for New Non-Measurable Lesions 
All new lesions not selected as new measurable lesions are considered new non- 
measurable lesions and are followed qualitatively. Only a massive and unequivocal 
progression of new non-measurable lesions leads to an overall assessment of irPD for the 
time point. Persisting new non-measurable lesions prevent irCR. 
 
Overall Assessments for irRECIST 
 
The irRECIST overall tumor assessment is based on TMTB of measured target and new 
lesions, non-target lesion assessment and new non-measurable lesions. 
 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions 
per organ, up to total 5 lesions) is measured. At each subsequent tumor assessment (TA), 
the SumD At each subsequent tumor assessment (TA), the SumD of the target lesions and 
of new, measurable lesions (up to 2 new lesions per organ, total 5 new lesions) are added 
together to provide the total measurable tumor burden (TMTB). 
 
 
Table 14. Evaluation of Overall Assessment – irRECIST criteria 
 
Overall Assessments by irRECIST 
Complete Response (irCR) 
Complete disappearance of all measurable 
and non-measurable lesions. Lymph nodes 
must decrease to < 10 mm in short axis. 
Partial Response (irPR) 
Decrease of ≥ 30% in TMTB relative to 
baseline, non-target lesions are irNN, and no 
unequivocal progression of new non- 
measurable lesions 
• 
If new measurable lesions appear in 
subjects with no target lesions at 
baseline, irPD will be assessed. That 
irPD time point will be considered a 
new baseline, and all subsequent time 
points will be compared to it for 
response assessment. irPR is possible 
if the TMTB of new measurable lesions 
decreases by ≥ 30% compared to the 
first irPD documentation 
• 
irRECIST can be used in the adjuvant 
setting, in subjects with no visible 
disease on CT/MRI scans. The 
appearance of new measurable 
lesion(s) automatically leads to an 
increase in TMTB by 100% and leads 
to irPD. These subjects can achieve a 
response if the TMTB decreases at 

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follow-up, as a sign of delayed 
response. 
• 
Based on the above, sponsors may 
consider enrolling subjects with no 
measurable disease and/or no visible 
disease in studies with response 
related endpoints. 
Stable Disease (irSD) 
Failure to meet criteria for irCR or irPR in the 
absence of irPD 
Progressive Disease (irPD) 
Minimum 20% increase and minimum 5 mm 
absolute increase in TMTB compared to nadir, 
or irPD for non-target or new non-measurable 
lesions. Confirmation of progression is 
recommended minimum 4 weeks after the first 
irPD assessment. An irPD confirmation scan 
may be recommended for subjects with a 
minimal TMTB %-increase over 20% and 
especially during the flare time-window of the 
first 12 weeks of treatment, depending on the 
compound efficacy expectations, to account 
for expected delayed response. 
• 
In irRECIST a substantial and 
unequivocal increase of non-target 
lesions is indicative of progression. 
• 
IrPD may be assigned for a subject 
with multiple new non-measurable 
lesions if they are considered to be a 
sign of unequivocal massive worsening 
Other 
irNE: used in exceptional cases where 
insufficient data exist. 
irND: in adjuvant setting when no disease is 
detected 
irNN:, no target disease was identified at 
baseline, and at follow-up the subject fails 
to meet criteria for irCR or irPD 
12.13.17 
Verification of Response 
irRECIST response must be confirmed no less than 4 weeks from the initial irRECIST 
documented response. 
13.0 CRITERIA FOR REMOVAL FROM STUDY 
Patients will be removed from the study when any of the criteria listed below applies. The 
reason for removal from the study and the date the patient was removed must be documented 
in the EDC system. 
Patients may be replaced if they come off study for reasons other than progressive disease 
prior to receiving their second dose of talimogene laherparepvec and/or pembrolizumab. 
Unless otherwise stated, patients will be included in the safety and/or efficacy analyses. 
Patients evaluable for efficacy analysis will include all patients treated with talimogene 

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laherparepvec or pembrolizumab and assessable for response. Patients who are missing an 
assessment of response post baseline will not be considered evaluable for response unless 
they missed the assessment due to progression of disease in which case they will be 
considered non-responders for that time point. Patients who miss an assessment of response 
post baseline for any reason other than progression of disease will be replaced. 
 
In the absence of treatment delays due to adverse events, treatment with intralesional 
talimogene laherparepvec may continue until one of the following criteria applies: 
 
- 
Disappearance of injectable lesions, 
- 
Complete response, 
- 
Confirmed progression of disease or clinical progression, 
- 
Intercurrent illness that prevents further administration of treatment, 
- 
Intolerance of study treatment, 
- 
35 cycles from the date of the first dose of talimogene laherparepvec and Pembrolizumab 
in the setting of patients with locally advanced/metastatic sarcoma. Study therapy may 
continue beyond 35 cycles in patients who are agreeable, deemed to be clinically 
benefiting from study therapy and at the discretion of the investigator. Patients who 
discontinue study therapy after a maximum of 35 cycles of study therapy will be allowed 
to resume study therapy in the setting of progression of disease off study therapy. 
- 
After completion of up to 8 cycles of study therapy in the setting of patients with operable, 
recurrent sarcoma who will then proceed to surgical resection of their disease 
 
- 
Patient decides to withdraw from the study 
- 
End of study, whichever occurs first. 
- 
Physician’s decision to withdraw a patient from the study for a reason not listed 
- 
Subject is lost to follow-up 
 
In the absence of treatment delays due to adverse events, treatment with pembrolizumab 
may continue until one of the following criteria applies: 
 
- 
Confirmed progression of disease or clinical progression 
- 
Intercurrent illness that prevents further administration of treatment 
- 
Intolerance of study treatmentCompletion of 35 treatments (approximately 2 years) with 
pembrolizumab 
o Note: The number of treatments is calculated starting with the first 
dose. Participants who stop the combination or pembrolizumab after receiving 35 
doses may be eligible for retreatment if they progress after stopping study treatment 
provided they meet the requirements detailed in Section 9.2.1. Participants may be 
retreated in the Second Course Phase (Retreatment) for up to an additional 17 
cycles (approximately 1 year). 
 
- 
After completion of up to eight (8) cycles of study therapy in the setting of patients with 
recurrent, operablesarcoma who will then proceed to surgical resection of their disease. 

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o On completion of surgery, these patients will be expected to complete up to 17 
treatments (approximately 1 year) total (neoadjuvant and adjuvant) with 
pembrolizumab as tolerated - 
- 
Patient decides to withdraw from the study, 
- 
End of study, whichever occurs first, 
- 
Physician’s decision to withdraw a patient from the study for a reason not listed 
- 
Subject is lost to follow-up 
Subjects with a CR may stop injections of talimogene laherparepvec upon complete 
disappearance of injectable lesions, but treatment with pembrolizumab will be continued 
unless one of the criteria for treatment discontinuation is met. Study therapy may continue 
for a total of 35 cycles in the absence of confirmed progression of disease or clinical 
progression, disappearance of injectable lesions (talimogene laherparepvec only), 
intercurrent illness that prevents further administration of treatment, or intolerance of study 
treatment. Patients who discontinue study therapy after a maximum of 35 cycles of study 
therapy will be allowed to resume study therapy for an additional 17 cycles in the setting of 
progression of disease off study therapy. In the neoadjuvant setting, TVEC and 
pembrolizumab will continue for up to 8 cycles prior to surgical resection. On 
completion of surgery pembrolizumab alone will continue as tolerated for a total of 17 
cycles (neoadjuvant and adjuvant therapy). 
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 and 
pembrolizumab. The patient may be allowed to continue study treatment after initial RECIST 
1.1 defined progression if they are assessed by the treating physician to be deriving clinical 
benefit and tolerating study treatment. The treating physician may consult with the overall 
study PI for help with assessing the patient. Such patients should discontinue study therapy 
upon further evidence of progression. 
Safety follows up and End of Study 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 in patients with metastatic 
or locally advanced sarcoma. 
- 
Full medical history, physical exam, assessment of performance status by KPS or 
ECOG status 
- 
Review of concomitant medications 
- 
Complete vital signs (pulse, blood pressure, temperature, respiratory rate) as well as 
weight and height. Height may be documented at any time prior to registration. 
- 
12-lead electrocardiogram (EKG) 
- 
Serum β-HCG pregnancy test for women with child-bearing potential. 
Complete 
blood count with differential, including lymphocyte and eosinophil count. 

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- 
Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, sodium, 
potassium, chloride, bicarbonate, calcium, total protein, albumin, serum bilirubin, 
alkaline phosphatase, ASL, AST, phosphorus, magnesium, TSH, T4 free). 
- 
Amylase and lipase 
- 
An optional biopsy will be offered at progression of disease. 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value must be followed until resolution or stabilization of the 
event. 
Reporting of adverse events will occur for up to 30 days for serious adverse events (within 30 
[+7] days after the last administration of talimogene laherparepvec or pembrolizumab, 
whichever is later), Events of Clinical Interest (within 30 [+7] days after the last administration 
of talimogene laherparepvec or pembrolizumab, whichever is later), and documentation of 
concomitant medications. In the neoadjuvant cohort, reporting of serious adverse events will 
occur for up to 30 days from the date of surgical resection. 
 
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 and initiation of 
additional sarcoma therapy. Contact for all subjects will be attempted every 12 weeks (± 14 
days) following the safety follow-up visit until death, subject withdraws full consent, or up to 
12 months after the end of treatment for patients with metastatic or locally advanced 
sarcoma and for up to 36 months after the completion of surgery for recurrent, operable 
sarcoma. If patients do not proceed to surgical resection upon conclusion of study therapy, 
patients will be followed with interval scanning and clinical surveillance every 6-8 weeks for 
one year or until completion of participation on study. 
 
14.0 BIOSTATISTICS 
14.1 Primary and Secondary Endpoints Statistical Considerations 
The primary objective is to evaluate the efficacy, as assessed by the best objective response 
rate (complete response + partial response) at 24 weeks by RECIST 1.1 (primary endpoint; 
Phase II).The study will use a one stage design based on the exact binomial test. A 5% 
response rate will be considered not promising;94,95 a 30% response rate will be considered 
promising.There will be a maximum accrual of 20 patients to this study, with early stopping 
rules for predefined treatment-related toxicities. . It will be concluded that the true response 
rate is > 5% if there are 3 or more patients with an objective response among 20 patients. The 
design has a type I error rate of 0.08 and a type II error rate of 0.04. This design provides 
96% probability of a positive result if the true response rate is at least 30%, and a 92% 
probability of a negative result if the true response rate is 5% or lower. 
The patient population in this study represents patients with locally advanced/metastatic 
sarcoma that have received at least one line of previous therapy. The references 
supporting the 5% null rate include the PALETTE, double-blind, randomized placebo- 
controlled trial94 and a study looking at the efficacy of eribulin in patients with advanced 

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sarcoma.95 The PALETTE study compared pazopanib with placebo in patients with least 
one regimen containing an anthracycline and a maximum of four previous lines of systemic 
therapy for metastatic disease (no more than two lines of combination regimens). The 
response rate for pazopanib was 6% in this study.  Pazopanib was granted FDA approval 
for advanced sarcoma patients that have previously received chemotherapy on the basis of 
this study which showed an improvement in PFS favoring pazopanib. The second reference 
refers to a randomized phase 3 study that compared eribulin with dacarbazine in patients 
with advanced leiomyosarcoma and liposarcoma that have progressed on two previous 
lines of therapy including an anthracycline. In this study the proportion of patients who had 
an objective response did not differ between treatment groups (nine [4%] in the eribulin 
group vs 11 [5%] in the dacarbazine group;p=0・62). Dacarbazine is FDA approved for 
advanced sarcoma and eribulin obtained FDA approval for use in advanced liposarcoma on 
the basis of this study. Hence, a 5% response rate has been seen with standard 
chemotherapy agents approved in this patient population. Therefore, in assessing the 
efficacy of a new therapy in this study population a response rate of > 5% would be 
preferred to determine the therapy as having a signal of efficacy. 
 
 
Secondary endpoints include: 
 
1. Feasibility of the combination of talimogene laherparepvec and pembrolizumab in patients 
with locally advanced or metastatic sarcoma and early-stopping rules 
 
In order to account for unexpected toxicity of the treatment, we will implement an early 
stopping rule for sequential toxicity monitoring. The results of the previous phase I trial that 
examined the safety of this combination of drugs reported that all 21 patients in the study 
experienced a treatment-related adverse event. The treatment related adverse event rate 
was 19%; G3 treatment related adverse event rate was 29%, there were no G4 treatment 
related adverse events. However, the rate discontinuation of study therapy due to treatment 
related adverse events in the phase I study was 0%.91 This phase II study will be deemed 
feasible if the primary objective of efficacy of the combination therapy is determined without 
crossing a boundary that requires early stopping. 
The number of patients who experience pre-specified treatment-related toxicity events 
detailed as per section 11.1.1, that result in the discontinuation of the study drug(s) or delay of 
their administration ≥ 9 weeks from the planned date of study drug(s) administration , will be 
recorded. Early stopping rules will be defined such that a 10% rate of occurrence of the 
above drug-related toxicities is acceptable, whereas a 30% rate would be unacceptable. The 
study will be continuously monitored for drug-related toxicity events that result in the 
discontinuation of the study drug(s) or delay of their administration ≥ 9 weeks from the planned 
date of study drug(s) administration. Early stopping rules are defined as observing such 
events in 2/4, 3/8, 4/14 or 5/20 patients. The probability of stopping under this rule is 
approximately 10% if the true treatment related toxicity event rate (that results in treatment 
discontinuation or delay in treatment administration≥ 9 weeks) is 10%, and is approximately 
79% if the true treatment related toxicity event rate (that results in treatment discontinuation 
or delay in treatment administration≥ 9 weeks) is 30%. Enrollment will not pause, treatment 

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related toxicity events will be continuously monitored and the study terminated immediately if 
the pre- defined early-stopping rule boundary is crossed. 
2. Toxicity 
Adverse events will be graded according to the NCI CTCAE v4.03, presented on an 
individual basis and summarized using descriptive statistics. 
3. Survival 
Progression free survival (PFS) rate at 24 weeks, median PFS, overall survival (OS) 
Overall and progression-free survival intervals will be estimated using Kaplan-Meier 
methodology 
4. Best Objective Response by irRECIST 
 
Best objective response rate (complete response + partial response) at 24 weeks by 
immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), of talimogene 
laherparepvec in combination with pembrolizumab in patients with metastatic and/or locally 
advanced sarcoma. 
Descriptive statistics will be provided for demographics, safety, efficacy, and biomarkers as 
appropriate. Patients who have not experienced the event of interest by the end of the study 
will be censored at the time of the last follow-up. 
Due to the small sample size, the correlative studies using tumor biopsies will be exploratory 
and hypothesis generating in nature. 
Patients evaluable for efficacy analysis will include all patients treated with talimogene 
laherparepvec or pembrolizumab and assessable for response. Patients who are missing an 
assessment of response post baseline will not be considered evaluable for response unless 
they missed the assessment due to progression fo disease in which case they will be 
considered non-responders for that time point. Patients who miss an assessment of response 
post baseline for any reason other than progression of disease will be replaced. 
Patients evaluable for safety analysis will include all patients who have received at least one 
dose of talimogene laherparepvec and pembrolizumab. 
 
We expect to accrue approximately 1-2 patients each month and hence expect to finish 
enrollment in 10-20 months. 
 
Additional cohorts: 
 
Locally advanced/metastatic cohorts: 
 
Primary End Point 
The primary objective is to evaluate the efficacy of the combination therapy in each subtype- 
specific cohort, as assessed by the best objective response rate (complete response + 
partial response). The primary endpoint is best objective response rate (RECIST 1.1). It will 
be estimated for each subtype-specific cohort, as the proportion of evaluable patients who 
have complete response and partial response as defined by RECIST 1.1 criteria, with a two 

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sided 95% CI provided. The lower limit of the CI allowed by a sample size of 10 is provided 
for a range of possible ORR in the below table. 
 
Table 15. 95% CI for estimating ORR for a Sample Size of 10 Patients 
 
Estimated 
ORR 
0.20 
0.30 
0.40 
0.50 
CI 95% 
0.03~0.56 
0.07~0.65 
0.12~0.74 
0.19~0.81 
 
Patients evaluable for efficacy analysis will include all patients who have received at least 
one cycle of treatment with T-VEC and pembrolizumab and are assessable for response. 
Patients who are missing an assessment of response post baseline will not be considered 
evaluable for response unless they missed the assessment due to progression of disease or 
treatment related toxicities in which case they will be considered non-responders for that 
time point. Patients who miss an assessment of response post baseline for any reason 
other than progression of disease and treatment related toxicity will be replaced. 
In relation to the design of the additional locally advanced/metastatic cohorts, there will be 3 
histology specific groups: i) cutaneous angiosarcoma, ii) epithelioid sarcoma, and iii) 
undifferentiated pleomorphic sarcoma/myxofibrosarcoma. These sarcoma subtypes reflect 
the subtypes where clinical activity was demonstrated in the phase II study to date. 
We expect to accrue approximately 1-2 patients each month and hence expect to finish 
enrollment in 15-30 months. 
 
Secondary endpoints 
1. Safety 
Patients evaluable for safety analysis will include all patients who have received at least one 
dose of T-VEC and pembrolizumab. Adverse events will be graded according to the NCI 
CTCAE v4.03, presented on an individual basis and summarized using descriptive 
statistics. 
 
2. Survival  
Progression free survival (PFS) rate at 24 weeks, median PFS, overall survival (OS) 
and progression-free survival intervals will be estimated using Kaplan-Meier methodology 
 
3. Best Objective Response Rate by irRECIST  
Best objective response rate (complete response + partial response) by 24 weeks by 
immune-related response criteria (irRECIST), of T-VEC in combination with pembrolizumab 
in patients with metastatic and/or locally advanced, sarcoma. 
 
14.2 Correlative Endpoints Statistical Considerations 
The study is not powered to detect specific hypotheses; rather this data and analysis will help 
better identify patients having the potential to benefit from this therapy and aid in designing 
larger Phase III studies. 
I. 
To investigate the rate of seroconversion in patients HSV seronegative at baseline 
after initial intralesional infusion of talimogene laherparepvec.  The rate of 

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seroconversion, after initial intralesional infusion of talimogene laherparepvec, in 
patients HSV seronegative at baseline will be reported using descriptive statistics. 
II. 
To evaluate associations between selected biomarkers measured in serial peripheral 
blood over time with clinical efficacy, including immunophenotyping and functional 
analyses, evaluation of serum levels of chemokines, cytokines and other immune 
mediators, and characterization of T-cell receptor clonality in peripheral blood. 
Summary statistics will be used to for describing changes across time. In addition the 
time course of biomarker measurements will be investigated graphically, by summary 
plots or individual patient plots; their trends over time will be categorized either by 
visual inspection (if there are clear trend groups such as monotonically increasing or 
monotonically decreasing) or by pattern recognition methods such as K-means 
clustering. The associations with the observed trend in selected biomarkers analyzed 
will be evaluated using categorical data analysis (including Fisher’s exact test 
and logistic regression) for clinical outcome such as response and clinical benefit, and 
using survival data analysis (including Kaplan-Meier curve and Cox Proportional 
Hazards models) for survival outcomes such as progression-free survival and 
survival. 
III. 
To assess the potential effect of talimogene laherparepvec cell lysis and 
pembrolizumab on selected biomarker expression measured in pre- and post- 
treatment tumor tissue and the association between these biomarkers and with clinical 
outcome, including characterization of PD-1/PD-L1 expression, tumor infiltrating 
lymphocytes 
(TILs) 
and 
tumor 
antigens, 
gene 
expression 
profiling, 
and 
characterization of T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL). The 
pre- and post-treatment measurements will be compared using the paired t-test for 
each of these biomarkers. The associations with the selected biomarkers, in terms of 
both the pre-treatment measurement and the difference between pre- and post- 
treatment measurements, will be evaluated using the two-sample t-test for clinical 
outcome such as response and clinical benefit, and using survival data analysis 
(including Kaplan-Meier curve and Cox Proportional Hazards models) for survival 
outcomes such as progression-free survival and survival. More specifically, Kaplan- 
Meier curve and Cox Proportional Hazards models will be used for analyzing pre- 
treatment measurement; Kaplan-Meier curve at a landmark time point and Cox 
Proportional Hazards models allowing for time varying coefficients will be used for 
analyzing the difference between pre-and post treatment measurements. 
IV. 
To evaluate the association between baseline tumor mutational burden and 
neoantigen production with clinical efficacy of the study therapy. 
 
The associations with baseline tumor mutational burden and neoantigen production will be 
evaluated using categorical data analysis (including Fisher’s exact test and logistic 
regression) for clinical outcome such as response and clinical benefit, and using survival 
data analysis (including Kaplan-Meier curve and Cox Proportional Hazards models) for 
survival outcomes such as progression-free survival and survival. 

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V. 
To evaluate pre and posttreatment magnetic resonance Images of the recurrent, 
resectable, sarcoma in patients in enrolled in the additional neoadjuvant cohort, to 
assess for definable radiological changes that can be correlated with treatment 
response 
 
Summary statistics will be used to for describing changes across time. The 
associations between radiological changes and treatment response (clinical and 
pathological) will be evaluated using categorical data analysis (including Fisher’s exact 
test and logistic regression). 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. Study 
staff are responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
 
15.2 
Randomization 
The study is a single-arm, non-randomized, phase II clinical trial. 
 
16.0 DATA MANAGEMENT ISSUES 
A Clinical Research Coordinator (CRC), Clinical Research Associate (CRA), and a Research 
Regulatory Associate (RRA) will be assigned to the study. The responsibilities of the Clinical 
Research Coordinator (CRC), Clinical Research Associate (CRA), and Research Regulatory 
Associate (RRA) include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate the 
activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 
 
 
16.0.1 Data 
 
Data: Standardized Case Report Forms (CRFs), directions for use and sign off requirements 
have been generated for this study. Blank case report forms will be sent to the study staff at 
each participating site for use. The participating Site PI is responsible for ensuring these forms 
are completed accurately, legibly and in a timely manner. 

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Source Documentation: Source documentation refers to original records of observations, 
clinical findings and evaluations that are subsequently recorded as data. Source 
documentation should be consistent with data entered into CRFs. Relevant source 
documentation to be submitted throughout the study includes: 
o Baseline measures to assess pre–protocol disease status (ex. CT, MRI) 
o Treatment records 
o Grade 3-5 toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 
 
 
16.1 Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to   the   attention   of   the   study   team   for   discussion   and   action 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
16.2 Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in August 2018. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute 
for Data and Safety Monitoring of Clinical Trials”. 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. At a departmental/PI level, there exist procedures for quality control by the 
research team(s). Institutional processes in place for quality assurance include protocol 
monitoring, compliance and data verification audits, staff education on clinical research QA, 
and two institutional committees that are responsible for monitoring the activities of our clinical 
trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase 
I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Deputy Physician-in-Chief of Clinical Research. 
 
The degree of monitoring required will be determined based on level of risk and documented. 
 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials. The 
DSMB/C have oversight over the following trials: 
· MSK Investigator-Initiated Trials (IITs; MSK as sponsor) 
· External studies where MSK is the data coordinating center 
· Low risk studies identified as requiring DSMB/C review 
The DSMC will initiate review following the enrollment of the first participant, or by the end of 
the year one if no accruals, and will continue for the study lifecycle until there are no 
participants under active therapy and the protocol has closed to accrual. The DSMB will 
initiate review once the protocol is open to accrual. 

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Final data sets for publication are required to be locked and stored centrally for potential future 
access requests from outside entities. 
 
16.3 Regulatory Documentation 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol document 
and each participating site will utilize that document. 
 
Participating sites that are conducting data analysis should submit this protocol to their IRB 
according to local guidelines. Copies of any site IRB correspondence should be forwarded to 
MSK. 
 
Participating sites that are conducting data analysis must submit the following documents to 
MSK before specimens can be shipped to the site: 
• Participating Site 1572 
• Conflict of Interest forms for Participating Site Investigators on the 1572 
 
Role of Stanford University as the participating site is as follows: 
• Data analysis being performed by the site: Diagnosis, Age, Gender, ECOG, Prior 
therapies, All efficacy response parameters (ORR, DOR, PFS, OS) will be shared with 
Stanford 
• The data will be shared via secure file transfer system 
• The data will be shared at the end of the study 
• Participant identifiers will not be shared 
 
 
Role of MD Anderson Cancer Center as the participating site is as follows: 
• Data analysis being performed by the site: Computational analysis of any tumor 
sequencing available and combining it with sequencing data available through MD 
Anderson cohorts. Also, genomic correlates of response to immunotherapy, 
histology-specific determinants of response to ICB 
• Data will be shared via Secure File Transfer System 
• Data will be shared as soon as possible since the study has been completed. 
• Participant identifiers will not be shared. Only clinical data and demographics will 
be shared. 
 
16.3.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSKCC and 
first approved by the MSKCC IRB/PB. Amgen has to review the protocol amendment before 
submission to the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC will 

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immediately distribute all non-expedited amendments to the participating sites, for submission 
to their local IRBs. 
16.3.2 Additional IRB Correspondence 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days 
of expiration. Failure to submit the re-approval in the stated timeline will result in suspension 
of study activities. 
 
Deviations 
A prospective protocol deviation on this study is defined as a request to treat a research 
participant who does not meet all the eligibility criteria, pretreatment evaluation, or who 
requires alteration in their study plan. If a deviation from this protocol is proposed for a 
potential or existing participant at MSKCC or a participating site, approval from the MSKCC 
IRB/PB is required prior to the action. Participating sites should contact the MSKCC PI who 
will in turn seek approval from the MSKCC IRB/PB. 
A retrospective protocol deviation is anything that occurs with a participant, which deviated 
from the protocol without prior approval from the MSKCC IRB/PB. For protocol deviations that 
are identified after they occur, the participating site should report to MSKCC as soon as 
possible. The MSKCC PI will in turn report the violation to the MSKCC IRB/PB. 
 
 
 
 
16.3.3 Document maintenance 
 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB approval 
letters referencing protocol version date and amendment number, IRB approved protocol, 
appendices, informed consent forms, deviations, violations, and approval of continuing 
reviews) is maintained in the regulatory binder on site and sent to MSKCC. 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper 
or electronic. After study closure, the participating site will maintain all source documents, 
study related documents and CRFs for 3 years. 
 
 
16.4 Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended and/or contract payments maybe withheld (if applicable), until the outstanding 
issues have been resolved. 
 
17.0 PROTECTION OF HUMAN SUBJECTS 

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Participation in this trial is voluntary. The patients will be explained e extent of the risks, 
benefits, toxicities/side effects, alternatives/options for treatment, financial costs/burdens, and 
the voluntary nature of the study. All patients will be required to sign a statement of informed 
consent, which must conform to Institutional Review Board guidelines. 
Inclusion of Women and Minorities: Memorial Sloan Kettering Cancer Center has filed forms: 
HHS 441 (civil rights), HHS (handicapped individual), 639-A (sex discrimination), and 680 
(age discrimination); we also take due notice of the NIH policy concerning inclusion of women 
and minorities in clinical research populations. Patients of all races, both male and female, 
will be accepted into the protocol. The proposed study population is as described in section 
6.0. 
Exclusion of Lactating or Pregnant Women: Lactating and pregnant women are also excluded 
because of unknown effects of talimogene laherparepvec and/or pembrolizumab that may be 
harmful to the developing fetus or nursing infant. 
Inclusion of Children in Research: The protocol/project does not include patients younger than 
the age of 18. Although sarcomas are the most common solid tumor in children, pediatric 
sarcomas are treated with specific protocols. 
Benefits: It is possible that this treatment will result in shrinkage of the tumor or in a 
stabilization of an otherwise progressing disease. It is not known, of course, whether these or 
any other favorable events will occur. It is not known whether this treatment will affect the 
overall survival of the patients. 
Costs: The patient will be responsible for the costs of standard medical care, including all drug 
administration fees and all hospitalizations, even for complications of treatment. talimogene 
laherparepvec and/or pembrolizumab will be provided to the patient without charge. 
Research-only biopsies and laboratory tests will not be charged to the patient. Research 
testing on tissue will not be charged to the patient. 
Incentives: No incentives will be offered to the patients/subjects for participation in the study. 
Alternatives: For patients with locally advanced and/or metastatic sarcomas alternative 
treatments may include conventional cytotoxic chemotherapies including, but not limited to: 
doxorubicin, ifosfamide, gemcitabine in combination with docetaxel, liposomal doxorubicin, 
dacarbazine, temozolomide, vinorelbine; and also tyrosine kinase inhibitors depending on the 
histology, including, but not limited to: imatinib, sorafenib, sunitinib, pazopanib. Talimogene 
laherparepvec and pembrolizumab are not yet approved by the Food and Drug 
Administration, but may be part of the treatment in a different clinical trial. 
Confidentiality: Every effort will be made to maintain the patient confidentiality. Research and 
hospital records are confidential. Patient’s name or any other personally identifying 
information will not be used in reports or publications resulting from this study. The Food and 
Drug Administration or other authorized agencies (e.g., qualified monitors from MSKCC or 
collaborating institutions) may review patients’ records and pathology slides, as required. 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
The consent indicates that individualized de-identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers, and members 

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of the research teams at participating sites who have received approval from MSK will be 
allowed to access this information which will not include protected health information, such as 
the participant’s name, except for dates. It is also stated in the Research Authorization that 
their research data may be shared with other qualified researchers. 
 
The consent indicates that samples and genetic information collected may be shared with 
other qualified researchers and placed in online databases. An example of an online 
database is the NIH dbGAP database, which is monitored by the National Institutes of 
Health, and may be made accessible to investigators approved by the U.S. government. 
Such information will not include identifying information such as name. It is also stated in the 
Research Authorization that research data (e.g. genomic sequence) may be shared with 
regulators. 
 
The requirements for submission of genotype/phenotype data into the NIH dbGAP or any 
other public database will be followed as per the IRB SOP for Genomic Data Sharing. 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered 
an SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 

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within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
 
The report should contain the following information: 
 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment(s) 
• If the AE was expected 
• Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
 
 
The SAE report should be completed as per above instructions. If appropriate, the report will 
be forwarded to the FDA by the IND Office The SAE report should be completed as per 
above instructions. If appropriate, the report will be forwarded to the FDA by the IND Office 
 
 
 
 
 
 
 
17.2.1 Safety Reporting to Amgen by MSKCC 
The sponsor is responsible for compliance with expedited reporting requirements for serious 
and unexpected and related adverse events (SUSARs), for generation of SAE reports 
including narratives, and for periodic reporting to Amgen of SAEs as outlined in Table 17 and 
18. In addition, Amgen requests additional product specific reporting as outlined in Table 18 
below. Sponsor/Investigators are required to report direct exposures to talimogene 
laherparepvec (e.g., needle stick, splash back) of herpetic illness and all suspected herpetic 
events, as described in Section 2. 
Table 17. Reporting Requirements for Interventional Studies 
Safety Data 
Timeframe for Submission to Amgen 
Suspected Unexpected Serious Adverse 
Reaction (SUSARs) 
Individual reports sent to Amgen at 
time of expedited reporting to IRB 
and/or FDA. 
Serious Adverse Events (SAEs) (related) 
Individual reports sent to Amgen at 
time of expedited reporting to IRB 

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and/or FDA 
Pregnancy/Lactation 
Individual reports sent within 10 days of 
investigator awareness 
(Refer to Appendix D for sample of Amgen’s 
intake forms) 
Amgen Inc. FAX 888-814-8653. If FAX is unavailable: Alternative method for report submission via 
email svc-ags-in-us@amgen.com 
Please refer to the ICH Guidelines E2A for safety related definitions and terminology: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_G 
uideline.pdf. 
Table 18. Aggregate Reports 
Safety Data 
Timeframe for submission to Amgen 
Adverse events (all serious and non-serious 
adverse events, regardless of relatedness) 
Line listing and summary tabulation 
of all adverse events sent annually AND at 
end of study 
Annual Safety Report 
(US IND Annual Report) 
Annually 
Other Aggregate Analyses 
(any report containing safety data generated 
during the course of a study) 
At time of ISS sponsor submission to any 
body governing research conduct (e.g., RA, 
IRB, etc.) 
Final (End of Study Report, including: 
• 
Unblinding data for blinded studies 
• 
Reports of unauthorized use of a 
marketed product 
At time of ISS sponsor submission to any 
body governing research conduct (e.g., RA, 
IRB, etc.) but not later than 1 calendar year 
after study completion 
Amgen Inc. FAX 888-814-8653. If FAX is unavailable: Alternative method for report submission via 
email: svc-ags-in-us@amgen.com 
 
 
18.0 INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved 
to participants prior to their inclusion in the study. Participants will also be informed 
that they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent 
form meets the requirements of the Code of Federal Regulations and the Institutional 
Review Board/Privacy Board of this Center. The consent form will include the 
following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 

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5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting 
professional will fully explain the aspects of patient privacy concerning research 
specific information. In addition to signing the IRB Informed Consent, all patients 
must agree to the Research Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The 
participant must receive a copy of the signed informed consent form. 

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20.0 APPENDICES: 
Appendix A: Supportive care guidelines 
A2.1 Pneumonitis 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
viral infection. It is important that patients with a suspected diagnosis of pneumonitis be 
managed as per the guidance below until treatment-related pneumonitis is excluded. 
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted. Management of the treatment of suspected pneumonitis with steroid treatment 
should not be delayed for a therapeutic trial of antibiotics. 
 
If an alternative diagnosis is established, the patient does not require management as below. 
Course of Action 
Grade 2 events: 
• Hold pembrolizumab. 
• Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
• Consider ID consult 
• Conduct an in person evaluation approximately twice per week 
• Consider frequent Chest X-ray as part of monitoring 
• Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
• Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the 
patient develops a second episode of Grade 2 or higher pneumonitis. 
Grade 3 and 4 events: 
• Discontinue pembrolizumab. 
• Hospitalize patient 
• Bronchoscopy with biopsy and/or BAL is recommended. 
• Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When 
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 
mg/kg once per day or dexamethasone 4 mg every 4 hours) taper should be started 
and continued over no less than 4 weeks. 
• If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue 
additional anti-inflammatory measures upon symptom relief and initiate a prolonged 
steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate 
a re-tapering of steroids starting at a higher dose of 80 or 100 mg followed by a more 
prolonged taper and administer additional anti-inflammatory measures, as needed 
• Add prophylactic antibiotics for opportunistic infections. 
A2.2 Colitis 

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All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 
disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy. 
 
Course of Action 
 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 
hours, abdominal pain, mucus or blood in stool): 
• Hold pembrolizumab. 
• Symptomatic Treatment 
• For Grade 2 diarrhea that persists >1 week, and for diarrhea with blood and/or mucus, 
o Consider GI consultation and endoscopy to confirm or rule out colitis 
o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
• If symptoms worsen or persist > 3 days treat as Grade 3 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persist for greater than 3 days): 
• Hold pembrolizumab. 
• Rule out bowel perforation. Imaging with plain films or CT can be useful. 
• Recommend consultation with Gastroenterologist and confirmation biopsy with 
endoscopy. 
• Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose 
oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 
hours) When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Taper over 6 to 8 weeks in patients with 
diffuse and severe ulceration and/or bleeding. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
• If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, consider treatment with additional anti-inflammatory measures 
as described in the literature. Discontinue additional anti-inflammatory measures upon 
symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms 
worsen during steroid reduction, initiate a re-tapering of steroids starting at a higher 
dose of 80 or 100 mg followed by a more prolonged taper and administer additional 
anti-inflammatory measures as needed. 
Grade 4 events: 
• Permanently discontinue pembrolizumab. 
• Manage as per Grade 3. 
 
A2.3 Endocrine 

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All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection. 
 
Hypophysitis 
or 
other 
symptomatic 
endocrinopathy 
other 
than 
hypo- 
or 
hyperthyroidism 
 
Grade 2 events: 
• Hold pembrolizumab 
• Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
• Pituitary gland imaging should be considered (MRIs with gadolinium and selective cuts 
of the pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
• Treat with prednisone 40 mg p.o. or equivalent per day. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
• Consultation with an endocrinologist may be considered. 
Grade 3 events: 
• Hold pembrolizumab. 
• Endocrine consultation is recommended. 
• Rule out infection and sepsis with appropriate cultures and imaging. 
• Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by 
oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
• Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis. 
• Hospitalization and endocrine consultation should be considered. 
Grade 4 events: 
• Discontinue pembrolizumab. 
• Manage as per Grade 3 
 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
Grade 2 events (and Grade 3-4 hypothyroidism): 
• Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 

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• Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
• Therapy with pembrolizumab can be continued while treatment for the thyroid disorder 
is instituted. 
• In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
• In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyronine, is indicated per standard of care. 
• Consultation with an endocrinologist may be considered. 
Grade 3 hyperthyroidism events: 
• Hold pembrolizumab. 
• Rule out infection and sepsis with appropriate cultures and imaging. 
• Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by 
oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
• Discontinue pembrolizumab. 
• Manage as per Grade 3 
 
A2.4 Hematologic 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or 
infection. Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, 
LDH, haptoglobin, bone marrow biopsy or Coomb’s test, etc., should be considered to confirm 
the diagnosis. 
 
Course of Action 
Grade 2 events: 
• Hold pembrolizumab 
• Prednisone 1-2 mg/kg daily may be indicated 
• Consider Hematology consultation. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 3 events: 
• Hematology consultation. 
• Hold pembrolizumab Discontinuation should be considered as per specific protocol 
guidance. 
• Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) 
as 
• appropriate 

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• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 4 events: 
• Hematology consultation 
• Discontinue pembrolizumab for all solid tumor indications; refer to protocol for 
hematologic 
• malignancies. 
• Treat with methylprednisolone 
 
3.5 Hepatic 
Course of Action 
Grade 2 events: 
• Hold pembrolizumab 
• Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
• Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT 
returns 
• to grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic 
• antibiotics for opportunistic infections, and resume pembrolizumab per protocol 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
• Permanently discontinue pembrolizumab for patients with liver metastasis who begin 
treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% 
relative to baseline and lasts ≥1 week. 
Grade 3 events: 
• Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin 
>3.0 times ULN. 
• Consider appropriate consultation and liver biopsy to establish etiology of hepatic 
injury, if necessary 
• Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. 
o When symptoms improve to Grade 1 or less, a steroid taper with 
dexamethasone 4 mg every 4 hours or prednisone at 1 to 2 mg/kg should be 
started and continued over no less than 4 weeks. 
•  If serum transaminase levels do not decrease 48 hours after initiation of systemic 
steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab 
is not recommended due to its potential for hepatotoxicity. 
• Several courses of steroid tapering may be necessary as symptoms may worsen when 
the steroid dose is decreased. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 4 events: 

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• Permanently discontinue pembrolizumab 
• Manage patient as per Grade 3 above 
 
A2.6 Neurologic 
 
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. 
Course of Action 
Grade 2 events: 
• Moderate (Grade 2) – consider withholding pembrolizumab. 
• Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
• Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 3 and 4 events: 
• Discontinue pembrolizumab 
• Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
• Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. If condition worsens consider IVIG or other immunosuppressive 
therapies as per local guidelines 
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
A2.7 Ocular 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other ocular disease (e.g. glaucoma or cataracts). However, the AE should be reported 
regardless of etiology. 
Course of Action 
Grade 2 events: 
• Evaluation by an ophthalmologist is strongly recommended. 
• Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitis. 
• If symptoms persist despite treatment with topical immunosuppressive therapy, 
consider oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 3 events: 
• Evaluation by an ophthalmologist is strongly recommended 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
Page 110 of 118 
 
 
• Hold pembrolizumab and consider permanent discontinuation as per specific protocol 
guidance. 
• Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per 
day. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 4 events: 
• Evaluation by an ophthalmologist is strongly recommended 
• Permanently discontinue pembrolizumab. 
• Treat with corticosteroids as per Grade 3 above 
A2.8 Renal 
 
All attempts should be made to rule out other causes such as obstructive uropathy, 
progression of disease, or injury due to other chemotherapy agents. A renal consultation is 
recommended. However, the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
• Hold pembrolizumab 
• Treatment with prednisone 1-2 mg/kg p.o. daily. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 3-4 events: 
• Discontinue pembrolizumab 
• Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
• Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or 
equivalent once per day. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
A2.9 Skin - Rash and Pruritus 
Course of Action 
Grade 2 events: 
• Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in 
combination with oral antipruritics (e.g., diphenhydramine HCl or hydroxyzine HCl). 
• Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
Grade 3 events: 
• Hold pembrolizumab. 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
Page 111 of 118 
 
 
• Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
• Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg four times orally daily. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 4 events: 
• Permanently discontinue pembrolizumab. 
• Dermatology consultation and consideration of biopsy and clinical dermatology 
photograph. 
• Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
A2.10 Other 
All attempts should be made to rule out other causes. Therapeutic specialists should be 
consulted as appropriate. 
 
Course of Action 
 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
• Withhold pembrolizumab. 
• Systemic corticosteroids may be indicated. 
• Consider biopsy for confirmation of diagnosis. 
• If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
Grade 3 events: 
• Hold pembrolizumab 
• Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab 
treatment may be restarted and the dose modified as specified in the protocol 
Grade 4 events: 
• Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• Discontinue pembrolizumab 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
Page 112 of 118 
 
 
Appendix B. Guidelines for the management of pembrolizumab infusion and 
hypersensitivity reactions. 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
• 
Diphenhydramine 50mg 
p.o. (or equivalent dose 
of antihistamine). 
• 
Acetaminophen 500- 
1000mg p.o. (or 
equivalent dose of 
antipyretic). 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop recurrent Grade 2 
infusion 
reaction 
despite 
adequate 
premedication should be permanently 
discontinued from further trial treatment 
administration. 
Grades 3 or 4 
Grade 3: 
Prolonged 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic 
medication and/or brief interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Epinephrine 
No subsequent dosing 
Grade 4: 
Life-threatening; 
pressor 
or 
ventilatory support indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
 
APPENDIX C: Sample of Report of Suspected IMLYGICTM (Talimogene 
laherparepvec) or Herpes Virus Associated Adverse Event 

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Approval date: 22-Jul-2024 
Page 113 of 118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX D: Reporting to Amgen of Pregnancy or Lactation – Notification 
Worksheets 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
Page 114 of 118 
 
 
Sample of Pregnancy Notification 
 
 
 
 
 
Sample of Lactation Notification Worksheet 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
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Appendix E: Sample of Serious Adverse Event form 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
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Appendix F: Procedure for Research Blood and Biopsy Collection 
Research Biopsy Collection 
Given the requirement for fresh and frozen tissue, FFPE archival samples cannot be 
substituted for the baseline or subsequent biopsies. 

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Approval date: 22-Jul-2024 
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The same metastatic tumor site should be biopsied at each time point if feasible. Cores will 
be representative of tumor and obtained with 18-gauge needles where appropriate and be 
of at least 1cm in length. Cores will be representative of tumor, and targeted to the de- 
differentiated component in the case of de-differentiated liposarcoma. 
The quality, viability and tumor content of biopsies will be confirmed by the on-call clinical 
pathologist at the time of retrieval. 
A goal of 6 cores should be obtained with a minimum of one formalin-fixed, one fresh and 
one flash frozen in liquid nitrogen. 
 
1 FFPE 
2 Fresh 
3 Flash frozen 
4 Fresh 
5 Flash frozen 
6 Flash frozen 
 
FFPE cores should be placed in formaldehyde solution and sent to the central pathology 
lab. 
Fresh core should be placed in RPMI media in a falcon tube and transported on ice (RPMI 
media should be kept in a fridge and should not be kept longer than two weeks) 
Flash frozen cores should be placed in a clean cryovial (nunc tube) then placed in liquid 
nitrogen for at least 2 minutes, transported in preferably a dewar flask of liquid nitrogen or in 
dry ice. 
If any extra cores are obtained, they should be flash frozen with liquid nitrogen as above. 
Samples will be labeled using an adherent, liquid nitrogen proof label with the following 
information 
1) Procurement date 
2) Study IRB number 
3) Study patient number 
4) Time point (baseline or on-treatment) 
5) Anatomical biopsy site 
 
Research blood collection 
 
At each research blood collection time point the following samples will be collected: 
4x8ml of peripheral venous blood will be collected in green/red speckled top CPT vacutainer 
tubes. The tubes will be inverted 8-10 times to mix the sodium heparin solution. Specimens 
will be placed in a biohazard bag and kept at room temperature. 
Samples will be labeled with the following information: 
1) Procurement date 
2) Study IRB number 
3) Study patient number 
4) Time point (baseline or week-X) 
 
Laboratory Contact Details 
Research blood samples and tumor biopsy samples, along with completed requisition 
forms, are to be transported to the Immune Monitoring Facility in the Zuckerman Research 
Bldg, Room Z-1513. At least 24 hr advanced notification prior to biopsy or blood collection 
must be provided by email to the IMF contacts below or entered in the IMF shared calendar 

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IRB Number: 16-1534 A(20) 
Approval date: 22-Jul-2024 
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(zzCAL_LAB_Clinical_Trials/Shared Calendar), with clinical site location and contact 
information from which samples are arriving indicated. Samples must be delivered between 
the hours of 9 am-4 pm to a member of the lab. 
Rosemarie Ramsawak <ramsawar@mskcc.org> 646-888-3106 
Zhenyu Mu <muz@mskcc.org> 646-888-2114 
Kevin Crawford <crawfork@mskcc.org> 646-888-3106 
Luisa Caro <carol@mskcc.org> 646-888-3106