Conditions: Soft Tissue Sarcoma Bone Sarcoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 144
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the efficacy of pembrolizumab in patients with advanced sarcomas.

Detailed description:
This is a multi-institutional phase II study of pembrolizumab in patients with advanced sarcomas. This study will have two treatment groups, one group for patients with soft tissue sarcoma and one group for patients with bone sarcoma.

Initial enrollment for this study included a total of 86 patients with soft tissue sarcoma and bone sarcomas.

In the expansion portion, there will be an additional 30 patients with undifferentiated pleomorphic sarcoma (UPS) and 30 patients with dedifferentiated or other high grade liposarcoma (LPS) enrolled into the study.

Arms:
arm 1: Patients with the following types of soft tissue sarcoma: leiomyosarcoma, poorly differentiated/de-differentiated liposarcoma, high grade pleomorphic undifferentiated sarcoma/MFH, MPNST and synovial sarcoma). Pembrolizumab will be administered at 200 mg intravenously every 3 weeks arm 2: Patients with the following types of bone sarcoma: Ewing sarcoma, osteosarcoma, and chondrosarcoma \[de-differentiated or mesenchymal\]. Pembrolizumab will be administered at 200 mg intravenously every 3 weeks arm 3: Patients with the following types of soft tissue sarcoma: poorly differentiated/de-differentiated liposarcoma, high grade pleomorphic undifferentiated sarcoma. Pembrolizumab was administered at 200 mg intravenously every 3 weeks

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
Confidential 
Protocol SARC028 
v 5.0: 09JAN2020 
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1 
 
SARC Protocol #: 028 
 
TITLE: SARC028: A Phase II Study of the Anti-PD1 Antibody Pembrolizumab (MK-3475) in 
Patients with Advanced Sarcomas 
 
Sponsor:  SARC (Sarcoma Alliance for Research through Collaboration) 
 
Supporter: Merck Inc. 
 
 
 
 
 
 
 
 
 
 
 
IND # 
[125067] 
 
Version # / Version Date 
5.0 / 09JAN2020 
 
 
NCT #:  
02301039 
Confidentiality Statement 
The information contained in this document, especially the unpublished data, has 
been generated by SARC and therefore provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff and 
applicable Institutional Review Board. It is understood that this information will 
not be disclosed to others without written authorization from SARC except to the 
extent necessary to obtain informed consent from those persons to whom the drug 
may be administered. 


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Principal Investigator: 
Hussein Tawbi, MD, PhD 
Associate Professor 
Department of Melanoma Medical Oncology 
Division of Cancer Medicine 
The University of Texas MD Anderson Cancer Center 
1400 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-792-6111 
Fax: 713-745-1046 
Email: HTawbi@mdanderson.org 
 
 
 
Statistician: 
John Crowley, PhD 
Cancer Research and Biostatistics (CRAB) 
1730 Minor Ave, Suite 1900 
Seattle, WA 98101-1468 
Phone: (206) 652-9711 
Fax: (206) 652-4612 
Email: johnc@crab.org 
 
 
SARC Operations Office: 24 Frank Lloyd Wright Drive 
Lobby A, Suite 3100; PO Box 406 
Ann Arbor, MI 48105 
Telephone: (734) 930-7600 
Fax: (734) 930-7557 
Email: sarc@sarctrials.org 


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GLOSSARY OF ABBREVIATIONS 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate aminotransferase 
Ca 
Calcium 
CBC 
Complete Blood Count 
CI 
Confidence interval 
CR 
Complete Response 
Cr 
Creatinine 
DLT 
Dose Limiting Toxicity 
ECOG 
Eastern Cooperative Oncology Group 
FISH 
Fluorescence in situ hybridization 
G-CSF 
Granulocyte colony-stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
Hgb 
Hemoglobin 
IHC 
irAE 
irECL 
irRC 
Immunohistochemistry 
Immune Related Adverse Events 
Immune Related Events of Clinical Interests 
Immune Related Response Criteria 
K 
Potassium 
INR 
International Normalized Ratio 
LLN 
Lower limit of normal 
ITP 
Idiopathic thrombocytopenic purpura 
LVEF 
Left Ventricular Ejection Fraction 
MDSCs 
Myeloid-derived suppressor cells 
MUGA 
Multiple Gated Acquisition scan 
NCI 
National Cancer Institute 


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NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NSCLC 
Non-small-cell lung carcinoma 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death-ligand 1 
PFS 
Progression free survival 
PLT 
Platelets 
PS 
Performance Status 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable Disease 
SF 
Shortening Fraction 
STS 
Soft Tissue Sarcoma 
T3 
Tri-iodothyronine 
T4 
Thyroxine 
TILs 
Tumor-infiltrating lymphocytes 
TNM 
TNM Classification of Malignant Tumors (tumor/nodes/metastasis) 
TSH 
Thyroid-Stimulating Hormone 
TTP 
Time to Tumor Progression 
Tregs 
Regulatory T cells 
ULN 
Upper Limit of Normal 
VEGF 
Vascular endothelial growth factor 
WBC 
White Blood Cells 


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Roles and Responsibilities of Study Personnel: 
 
Hussein Tawbi, MD, PhD: Principal Investigator of the study 
Denise Reinke, MS, NP, MBA: President and CEO, SARC 
Erin Peregrine Antalis, MPH, PhD, Research Manager 
John Crowley, PhD: Study Statistician 


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ARM A 
High Grade Soft Tissue 
Sarcomas 
 
 
 
ARM B 
 
 
Bone Sarcomas 
S 
C 
R 
E 
E 
N 
I 
N 
G 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre- 
treatment 
(Week 0) 
Post- 
treatment 
(Week 8) 
Post- 
treatment 
(Week 34, 
Cycle 12 
Optional) 
At    
Progression 
(Optional) 
Pembrolizumab 200 mg IV 
every 3 weeks 
T 
U 
M 
O 
R 
A 
S 
S 
E 
S 
S 
M 
E 
N 
T 
T 
I 
S 
S 
U 
E 
B 
I 
O 
P 
S 
Y 
Pembrolizumab 200 mg IV 
every 3 weeks 
T 
I 
S 
S 
U 
E 
B 
I 
O 
P 
S 
Y 
T 
U 
M 
O 
R 
A 
S 
S 
E 
S 
S 
M 
E 
N 
T 
P 
R 
O 
G 
R 
E 
S 
S 
I 
O 
N 
T 
I 
S 
S 
U 
E 
T 
I 
S 
S 
U 
E 
B 
I 
O 
P 
S 
Y 
B 
I 
O 
P 
S 
Y 


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STUDY SYNOPSIS 
 
Primary Objective 
 
1. To determine the efficacy of pembrolizumab (MK-3475, SCH 900475) in patients with 
advanced sarcomas as measured by Objective Response Rate (ORR) using RECIST 1.1 
 
Secondary Objectives 
 
1. To determine the safety and tolerability of pembrolizumab in this patient population 
2. To determine the Progression-Free Survival (PFS) by RECIST 1.1 and Overall Survival 
(OS) in this patient population 
3. To determine the response rate as measured by the immune-related Response Criteria (ir- 
RC) 
 
Exploratory Objectives 
 
1. To determine the effect of pre-treatment PD-L1 expression levels on response rates and 
the role of PD-L1 expression as a predictive biomarker for clinical benefit 
2. To determine the association of circulating regulatory T cells (Tregs) and Myeloid- 
Derived Suppressor Cells (MDSCs) at baseline and their changes while on therapy with 
clinical benefit 
3. To perform immune monitoring in the circulation and in the tumor microenvironment 
while on therapy with pembrolizumab – specifically, the frequency of circulating T cell 
populations, including NY-ESO-1 specific cytotoxic T cells, as well as T cell infiltration 
in available pre- and post- therapy tumor tissues will be assessed. 
 
Trial Design 
 
This is an open-label phase II study of pembrolizumab given at 200 mg IV every 3 weeks in 
patients with locally advanced or metastatic bone and soft tissue sarcomas. 
 
Maximum Total Number of Patients 
 
Initial enrollment was 86 patients: patients with soft tissue sarcomas and patients with bone 
sarcomas 
 
In an expansion study, there will be an additional 60 patients enrolled to the soft tissue cohort: 30 
patients with undifferentiated pleomorphic sarcoma and 30 patients with dedifferentiated or other 
high grade liposarcoma 
 
Target Population 
 
Patients with advanced refractory soft tissue or bone sarcomas 


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Efficacy Evaluations 
 
Tumor measurements by CT/MRI imaging will be performed initially at 8 weeks and every 12 
weeks subsequently - RECIST 1.1 will be the primary outcome measure and immune-related 
Response Criteria (ir-RC) will be a secondary outcome. 
 
Duration of Participation 
 
Each patient will participate in the trial from the time of Informed Consent Form (ICF) is 
signed through final protocol-specified contact. After a screening phase for eligibility, patients 
will receive pembrolizumab every 3 weeks. Treatment for patients that achieve stable disease 
(SD), a partial response (PR), or a complete response (CR) can continue for a maximum of 2 
years total duration of treatment. At the discretion of the investigator, patients who have 
progressive disease (PD) but continue to achieve clinical benefit, may also continue on 
therapy for a maximum of 35 cyclestotal duration of treatment.  
 
Safety Evaluations/ Concerns 
 
Safety evaluations will be done according to CTCAE version 4.0 with special emphasis 
on immune-related adverse events (ir-AEs). 
 
Correlative Studies 
 
Blood for research studies will be collected prior to first study drug administration, at week 8, 
week 20 and week 32 and flow cytometry analyses will be performed to determine the presence 
of PD-1 expressing T cells, as well as the proportion of circulating Treg cells and MDSCs. 
 
In the initial enrollment and in the first 20 patients of the expansion cohorts (UPS and LPS), pre- 
and post-treatment biopsies at week 0 and week 8 are mandatory. Biopsies at cycle 12 (week 34) 
and at progression are optional. PD-L1 expression, T cell infiltration, as well as suppressor sub- 
populations will be compared between pre and post-treatment biopsies. 
 
Brief Statistical Design 
 
In the initial enrollment of the study we tested the hypothesis that pembrolizumab has clinical 
activity in patients with advanced sarcoma. A patient will be classified as a treatment success if 
he/she achieves a Partial Response (PR) or better by RECIST 1.1. For each arm, an ORR of 25% 
will be considered clinically meaningful and a response rate less than 10% will be considered 
ineffective. In this study with a single stage design, we will accrue 40 patients in each arm. The 
treatment will be considered a success if 8 or more of 40 enrolled patients have a PR or better by 
RECIST 1.1. This design has a one-sided type I error of 4.2% and a power of 82% to detect a 
difference between 10 and 25% response rates. This design will also have 87% power to detect 
an improvement in the 4-months PFS rate from 20% to 40% with a one-sided type I error of 4%. 
 
In the original 86 patient group, 80 patients were evaluable for objective response rate by 


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RECIST 1.1. Among 40 evaluable patients in the STS cohort, there were 7 partial responses with 
an ORR of 18%. Four partial responses were seen among 10 patients with undifferentiated 
pleomorphic sarcoma for an ORR of 40%. Two additional PRs were observed in the 
dedifferentiated/high grade liposarcoma cohort (2 out of 10) for an ORR of 20%. There was an 
additional PR seen in the synovial sarcoma cohort. Among 40 evaluable patients in the bone 
sarcoma cohort, there were 2 partial responses with an ORR of 5%. 1 PR was seen each in the 
dedifferentiated/high grade chondrosarcoma and osteosarcoma cohorts. Given the observed PRs 
in the UPS and dedifferentiated/high grade liposarcoma cohorts, we will enroll patients to 
expansion cohorts to include an additional 30 patients each (UPS and LPS) to further explore and 
confirm the activity of pembrolizumab. 
In the study expansion, the response rates for undifferentiated pleomorphic sarcoma cohort and 
the poorly differentiated/dedifferentiated liposarcoma cohort will be analyzed separately. In each 
subtype cohort, we will analyze a total of 40 patients (10 from part 1 of the study and 30 from 
the expansion cohort). An objective response rate of 25% will be considered clinically 
meaningful and a response rate less than 10% will be considered lack of efficacy. The treatment 
will be considered a success if 8 or more of 40 enrolled patients have a PR or better by RECIST 
1.1. This design has a one-sided type I error of 4.2% and a power of 82% to detect a difference 
between 10 and 25%. 
 
At least 20 patients in each of the undifferentiated pleomorphic sarcoma and poorly 
differentiated/dedifferentiated expansion cohorts will have mandated biopsies for correlative 
analysis. The remaining 10 patients in each of the cohorts will not be required to obtain baseline 
and 8-week tumor biopsies, although archival tissue will be required for PD-L1 testing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
SARC Protocol #: 028 ..................................................................................................................... 1 
Roles and Responsibilities of Study Personnel:............................................................................ 5 
STUDY SCHEMA .......................................................................................................................... 6 
STUDY SYNOPSIS ........................................................................................................................ 7 
Secondary Objectives...................................................................................................................... 7 
Exploratory Objectives ................................................................................................................... 7 
Trial Design ..................................................................................................................................... 7 
Maximum Total Number of Patients ............................................................................................ 7 
Target Population ........................................................................................................................... 7 
Efficacy Evaluations ....................................................................................................................... 8 
Safety Evaluations/ Concerns ........................................................................................................ 8 
Correlative Studies.......................................................................................................................... 8 
Brief Statistical Design ................................................................................................................... 8 
1. 
OBJECTIVES ............................................................................................................. 16 
1.1 
Primary Objective ...................................................................................................... 16 
1.2. 
Secondary Objectives ................................................................................................. 16 
1.3. 
Exploratory Objectives .............................................................................................. 16 
2. 
BACKGROUND ......................................................................................................... 16 
2.1 
Study Disease ............................................................................................................... 16 
2.2 
Study Agent - Pembrolizumab ................................................................................... 18 


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2.3 
Background ................................................................................................................. 18 
2.4 
Clinical Rationale ....................................................................................................... 19 
2.5 
General Investigational Approach ............................................................................ 20 
2.6 
Chemical Properties ................................................................................................... 20 
2.7 
Structure ...................................................................................................................... 21 
2.8 
Physico-Chemical Properties ..................................................................................... 21 
2.9 
Pharmaceutical Formulation ..................................................................................... 21 
2.10 
Nonclinical Pharmacology ......................................................................................... 21 
2.11 
Affinity and Ligand Blockade of Pembrolizumab ................................................... 22 
2.12 
In Vivo Efficacy of Analog Anti-Mouse PD-1 Antibody (as a Monotherapy) in 
Syngeneic Tumor Models ............................................................................................................. 22 
2.13 
Non-Clinical Toxicology Summary of Results ......................................................... 23 
2.14 
Clinical Summary of Results ..................................................................................... 23 
2.15 
Preclinical and Clinical Trial Data ........................................................................... 24 
2.16 
Rationale for the Trial and Selected Patient Population ......................................... 24 
2.17 
Study Design ................................................................................................................ 27 
2.18 
Correlative Studies ..................................................................................................... 28 
3. 
PATIENT SELECTION ............................................................................................ 28 
3.1 
Eligibility Criteria ....................................................................................................... 28 
3.2 
Inclusion Criteria ........................................................................................................ 28 
3.3 
Exclusion Criteria ....................................................................................................... 30 
3.4 
Inclusion of Women and Minorities .......................................................................... 32 
4. 
REGISTRATION PROCEDURES ........................................................................... 32 
4.1 
General Guidelines ..................................................................................................... 32 
4.2 
Registration Process ................................................................................................... 32 


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5. 
TREATMENT PLAN ................................................................................................. 32 
5.1 
Agent Administration ................................................................................................. 32 
Table 1: Treatment Dosing Schedule .......................................................................................... 33 
5.2 
Time of Drug Administration .................................................................................... 33 
5.3 
Trial Blinding/Masking .............................................................................................. 33 
5.4 
General Concomitant Medication and Supportive Care Guidelines ..................... 33 
5.4.1 
Concomitant Medications/Vaccinations ................................................................... 33 
5.4.1.1 
Prohibited Concomitant Medications ....................................................................... 33 
5.4.2 
Rescue Medications & Supportive Care ................................................................... 34 
5.4.2.1 
Supportive Care Guidelines ....................................................................................... 34 
Table 2: Infusion Reaction Treatment Guidelines ..................................................................... 37 
5.5 
Diet/Activity/Other Considerations .......................................................................... 38 
5.5.1 
Diet ............................................................................................................................... 38 
5.5.2 
Contraception.............................................................................................................. 38 
5.5.3 
Use in Pregnancy ......................................................................................................... 39 
5.5.4 
Use in Nursing Women ............................................................................................... 39 
5.6 
Duration of Therapy ................................................................................................... 40 
5.7 
Duration of Follow Up ................................................................................................ 40 
5.8 
Criteria for Removal from Study .............................................................................. 41 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ....................................................... 41 
6.1 
Discontinuation of Therapy: ...................................................................................... 41 
6.2 
Withholding/Resuming Therapy ............................................................................... 42 
Table 4: Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab ................................................................................................. 43 
Table 5: Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines . 47 


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7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .................. 48 
7.1 
Adverse Events and Laboratory Abnormalities ...................................................... 48 
7.1.1 
Adverse Events (AEs) ................................................................................................. 48 
7.1.1.1 
Definition of Adverse Events ..................................................................................... 48 
7.1.1.2 
CTCAE term (AE description) .................................................................................. 48 
7.1.1.3 
Intensity ....................................................................................................................... 48 
7.1.1.4 
Drug-Adverse Event relationship .............................................................................. 49 
7.1.1.5 
Progression of Underlying Malignancy .................................................................... 50 
7.1.1.6 
Treatment and Follow-up AEs .................................................................................. 50 
7.1.2 
Laboratory Test Abnormalities ................................................................................. 51 
7.1.2.2 
Follow-up of Abnormal Laboratory Test ................................................................. 51 
7.1.3 
Serious Adverse Events .............................................................................................. 51 
7.1.4 
Pembrolizumab Overdose .......................................................................................... 52 
7.1.5 
Events of Clinical Interest .......................................................................................... 52 
7.2 
Handling of Safety Parameters .................................................................................. 52 
7.2.1 
Reporting of Adverse Events ..................................................................................... 52 
7.2.2 
Reporting of Serious Adverse Events (immediately reportable) ............................ 53 
7.2.3 
Reporting of Overdose to the Sponsor and to Merck .............................................. 53 
7.2.4 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................... 53 
7.2.5 
Reporting of Serious Adverse Events ....................................................................... 54 
8. 
PHARMACEUTICAL INFORMATION................................................................. 55 
8.1 
Study Agent ................................................................................................................. 55 
8.2 
Preparation and Administration ............................................................................... 55 
8.3 
Formulation, Packaging and Labelling .................................................................... 55 
Table 7. Product Descriptions ...................................................................................................... 55 


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8.4 
Storage and Handling Requirement ......................................................................... 55 
8.5 
Agent Ordering ........................................................................................................... 55 
8.6 
Agent Accountability .................................................................................................. 55 
8.7 
Destruction of Pembrolizumab .................................................................................. 56 
9. 
CORRELATIVE/SPECIAL STUDIES .................................................................... 56 
9.1 
Laboratory Correlative Studies ................................................................................. 56 
9.1.1 
Collection, Handling and Shipping of Specimens .................................................... 56 
9.1.2 
Correlative Studies ..................................................................................................... 56 
9.1.3 
Biopsy ........................................................................................................................... 58 
10. 
STUDY EVALUATIONS AND STUDY CALENDAR .......................................... 59 
10.1 
SCREENING STUDIES............................................................................................. 59 
10.2 
ON STUDY EVALUATIONS ................................................................................... 59 
10.3 
OFF TREATMENT EVALUATIONS ..................................................................... 60 
STUDY CALENDAR ................................................................................................................... 61 
11. 
MEASUREMENT OF EFFECT ............................................................................... 62 
11.1 
Antitumor Effect – Solid Tumors .............................................................................. 62 
11.1.1 
Definitions.................................................................................................................... 62 
11.1.2 
Disease Parameters ..................................................................................................... 62 
11.1.3 
Methods for Evaluation of Measurable Disease....................................................... 63 
11.1.4 
Response Criteria ........................................................................................................ 64 
11.1.4.1 
Evaluation of Target Lesions ..................................................................................... 64 
11.1.4.2 
Evaluation of Non-Target Lesions............................................................................. 65 
11.1.4.3 
Evaluation of Tumor Response ................................................................................. 66 
11.1.4.4 
Best Overall Response when confirmation of CR and PR required ...................... 66 
11.1.5 
Duration of Response ................................................................................................. 67 


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11.1.6 
Progression-Free Survival .......................................................................................... 68 
11.1.7 
Response Review ......................................................................................................... 68 
11.1.8 
Definition of Tumor Response Using irRC............................................................... 68 
11.1.8.1. 
Definition of Index Lesions Response Using irRC ................................................... 68 
11.1.8.2 
Definition of Non-Index Lesions Response Using irRC .......................................... 69 
11.1.8.3 
Impact of New Lesions on irRC ................................................................................ 69 
11.1.8.4 
Definition of Overall Response Using irRC .............................................................. 69 
Table 8: Immune-Related Response Criteria Definitions ......................................................... 70 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS ............................. 70 
12.1 
Data Reporting ............................................................................................................ 70 
12.1.1 
Method ......................................................................................................................... 71 
12.1.2 
Data Safety and Monitoring ...................................................................................... 71 
12.1.3 
Patient Accrual and Participating Centers .............................................................. 71 
12.2 
Multi-institutional Guidelines .................................................................................... 71 
12.3 
Data and Participating Site Monitoring ................................................................... 72 
12.4 
Handling of Patient Data ............................................................................................ 72 
13. 
STATISTICAL CONSIDERATIONS ...................................................................... 73 
13.1 
Study Design/Endpoints ............................................................................................. 73 
13.2 
Sample Size/Accrual Rate .......................................................................................... 73 
13.3 
Analysis of Secondary Endpoints .............................................................................. 74 
13.4 
Reporting and Exclusions .......................................................................................... 74 
14. 
REFERENCES ............................................................... Error! Bookmark not defined. 
APPENDIX A .................................................................................... Error! Bookmark not defined. 
APPENDIX B .................................................................................... Error! Bookmark not defined. 
 


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1. 
OBJECTIVES 
 
1.1 
Primary Objective 
 
1. To determine the efficacy of pembrolizumab (MK-3475, SCH 900475) in patients with 
advanced sarcomas as measured by Objective Response Rate (ORR) using RECIST 1.1 
 
1.2. 
Secondary Objectives 
 
1. To determine the safety and tolerability of pembrolizumab in this patient population 
2. To determine the Progression-Free Survival (PFS) by RECIST 1.1 and Overall Survival 
(OS) in this patient population 
3. To determine the response rate as measured by the immune-related Response Criteria (ir- 
RC) 
 
1.3. 
Exploratory Objectives 
 
• To determine the effect of pre-treatment PD-L1 expression levels on response rates and 
the role of PD-L1 expression as a predictive biomarker for clinical benefit 
• To determine the association of circulating regulatory T cells (Tregs) and Myeloid- 
Derived Suppressor Cells (MDSCs) at baseline and their changes while on therapy with 
clinical benefit 
• To perform immune monitoring in the circulation and in the tumor microenvironment 
while on therapy with pembrolizumab – specifically, the frequency of circulating T cell 
populations, including NY-ESO-1 specific cytotoxic T cells, as well as T cell infiltration 
in available pre- and post- therapy tumor tissues will be assessed. 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
In 2014, there will be an estimated 15,040 new cases of soft tissue and bone/joint 
cancers associated with 8,230 deaths in the USA. Sarcomas account for nearly 21% 
of all pediatric solid cancers and less than 1% of all adult solid cancers [1]. 
Bone/joint and soft tissue cancers are respectively the third and fourth leading causes 
of cancer related deaths in patients under the age of 20 [2]. Trend analysis from 2001 
to 2010 indicates that soft tissue sarcoma-associated death rates are increasing in men 
[3]. 
 
Sarcomas represent a heterogeneous group of malignancies with more than 50 distinct 
histologic subtypes with varying age and location at presentation. The rarity and 
diversity of sarcomas contribute to the slow progress made in the systemic treatment 
of sarcoma.  Treatment outcomes reflect the extent of disease at presentation with 
early localized disease being treated with curative surgery and potentially adjuvant 


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systemic therapy, and advanced disease with metastasectomy, aggressive tumor 
debulking, or palliative chemotherapy. 
 
Despite recent advances in our understanding of the biology of this group of diseases, 
prognosis of metastatic sarcoma remains poor and reflects subtype and age at disease 
onset. In patients with metastatic or recurrent disease, the overall median survival is 
approximately one year and about 10% of these patients are still alive at 5 years. 
Response to conventional chemotherapy and radiation therapy varies with some 
subtypes being remarkably sensitive, although the majority are still fairly resistant. 
The first order kinetics demonstrated by cytotoxic agents cannot be relied upon to 
eliminate residual tumor cells, and therefore, to achieve long term control/cure. This 
limitation is reflected by relapses despite aggressive systemic therapy. The last 
decade has seen newer agents being explored in treatment of sarcoma. These new 
therapies have ranged from novel cytotoxic agents, such as trabectedin, 
palifosfamide, and TH-302 alone or in combination with novel targeted agents, such 
as pazopanib, mTOR inhibitors, or VEGF inhibitors. Some of these treatments have 
demonstrated benefit, but it remains limited at best. 
 
Sarcomas, and other malignancies, including melanoma and NSCLC, have been 
shown to evolve and escape the immune system by co-opting the naturally occurring 
immune checkpoints. These checkpoints function as feedback loops to dampen the 
immune response leading to tumor tolerance. Immune checkpoint blockade has 
emerged as a novel and promising therapeutic strategy to reverse the immune 
system’s tolerance to tumors and lead to long term durable control of metastatic 
tumors, and perhaps even cures. The FDA approved ipilimumab, an antibody that 
blocks the immune checkpoint CTLA-4 expressed receptor on the surface of activated 
T cells, in 2011 on the basis of durable benefit and improvement in overall survival in 
patients with advanced metastatic melanoma. Given its mechanism of action it has 
been evaluated in other malignancies including sarcoma. A Phase II pilot study using 
the anti-CTL4 monoclonal antibody, ipilumumab, in synovial sarcomas expressing 
the NY-ESO1 antigen was conducted. In this study, 6 patients were treated with one 
course of ipilimumab given at 3 mg/kg every 3 weeks for 3 doses only.  Although 
there were no RECIST responses observed and only one patient demonstrated an 
immune response, patients tolerated the treatment well with manageable side effects. 
This study was terminated early for slow accrual, lack of activity, and lack of immune 
responses [4]. 
 
Antibodies that target the immune checkpoint represented by the PD-1/PD-L1 and 
PD-L2 axis, such as pembrolizumab, utilized in the current study, have been 
developed with greater clinical success than ipilimumab and have demonstrated 
activity beyond melanoma. The role of the PD-1/PD-L1 axis in STS is presently 
being elucidated. In one retrospective study of tumor specimens from 105 cases, it 
was determined that the degree of PD-1 positivity in tumor infiltrating lymphocytes 
and PD-L1 overexpression in tumor specimens correlated with a poorer prognosis and 
more aggressive disease [5].  These studies suggest that PD-1 and PD-L1 staining 


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may be viable biomarkers for prognosis, and possibly, treatment using anti-PD-1 
treatment strategies. Pre-clinical trials using implanted fibrosarcoma mouse models 
have demonstrated activity of anti-PD-1 therapy and that this activity may be 
independent of PD-L1 staining [6]. Other studies in fibrosarcoma rodent xenografts 
have shown modest activity using anti-PD-1 therapy alone but significantly enhanced 
activity when combined with a dual checkpoint antibody directed at LAG-3 [7]. 
Therefore, although anti-PD1 therapy has not been tested in clinical trials in sarcoma 
patients, there is ample rationale for using anti-PD1 treatment alone and in 
combination with other checkpoint inhibitors in patients with advanced STS. 
 
2.2 
Study Agent - Pembrolizumab 
 
Pembrolizumab formerly known as MK-3475 and SCH 900475 is a potent humanized 
IgG4 mAb with high specificity for binding to the PD-1 receptor, and thus inhibiting 
its interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Overall, as of 03-Mar-2018, approximately 25,519 patients have been treated with 
pembrolizumab in clinical studies. Pembrolizumab has an acceptable preclinical 
safety profile and is FDA approved for the treatment of advanced melanoma, non-
small cell lung cancer, squamous cell head and neck cancer, urothelial cancer, 
classical Hodgkin lymphoma, MSI-H or mismatch repair deficient colon cancer or 
solid tumors, and gastric/gastroesophageal junction adenocarcinoma. 
 
2.3 
Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [8]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies [9; 10; 11; 12; 13]. In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells to FoxP3+ regulatory 
T-cells seem to correlate with improved prognosis and long-term survival in many 
solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control. The normal function of PD-1, expressed on the cell surface 
of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions. PD-1 (encoded by the 
gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has 
been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands (PD-L1 and/or PD-L2) [14; 15]. 
 
The structure of murine PD-1 has been resolved [16]. PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine- 


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based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) 
and an immunoreceptor tyrosine-based switch motif (ITSM). 
 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation 
of effector molecules, such as CD3ζ, PKCθ and ZAP70 which are involved in the 
CD3+ T-cell signaling cascade [14; 17; 18; 19]. The mechanism by which PD-1 
down-modulates T-cell responses is similar to, but distinct from that of CTLA-4, as 
both molecules regulate an overlapping set of signaling proteins [20; 21]. PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and  
CD8+ T-cells, B-cells, Tregs and natural killer cells [22; 23]. Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as 
subsets of macrophages and dendritic cells [24]. 
 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues, as well as, in 
various tumors [25; 26; 27; 20]. Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 
is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments. PD-L2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues [20]. 
 
Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in patients with melanoma [28]. 
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab (previously known as MK-3475 and SCH 900475) is a potent and 
highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype 
designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2. 
 
2.4 
Clinical Rationale 
 
Therapeutic studies in mouse models show that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells 
ultimately lead to tumor rejection, either as a monotherapy or in combination with 
other treatment modalities. Anti-mouse PD-1 and anti-mouse PD-L1 have 
demonstrated anti-tumor responses as a monotherapy in models of squamous cell 


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carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma. Blockade of 
the PD-1 pathway effectively promoted CD8+ T cell infiltration into the tumor and 
the presence of IFN-γ, granzyme B, and perforin, indicating that the mechanism of 
action involved local infiltration and activation of effector T cell function in vivo 
[29, 30, 31,35, 36, 37]. In addition, the combination of gemcitabine and anti-PD-L1 
mAb demonstrated synergy in the rejection of pancreatic mouse tumors [29]. 
 
Immuno-modulatory agents recently showed promising efficacy in multiple cancer 
types. Two recent Phase III studies of Ipilimumab (IPI), an anti-CTL4 mAb, showed 
significant prolongation of overall survival in patients with melanoma [38-39]. 
Recent data with anti-PD-1 antibodies, including pembrolizumab and nivolumab 
(BMS-936558), have validated PD-1 as an attractive target for clinical intervention 
and have provided proof of concept for anti-PD-1 mAbs in melanoma and RCC [40- 
42]. Nivolumab showed an overall response rate of approximately 28% in patients 
with advanced melanoma and 27% in patients with RCC who had failed prior therapy 
[41]. In addition, an objective response rate of near 20% was observed in NSCLC 
patients [41, 43]. Pembrolizumab has shown an overall response rate of over 40% in 
patients with melanoma and over 20% in patients with NSCLC. Importantly, 
responses have been of long duration and both pembrolizumab and nivolumab are 
generally well-tolerated. Based on these data and considerations, the anti-PD-1 
antibody, pembrolizumab, appears to be an attractive candidate for continued clinical 
development in cancer. The positive findings of PD-1 targeted interventions in 
traditionally “non-immunogenic cancers” provide compelling rationale to expand the 
therapeutic benefits of anti-PD-1 antibodies to other malignancies, including sarcoma. 
 
2.5 
General Investigational Approach 
 
Refer to current Investigator’s Brochure for information on General 
Investigational Approach. 
 
2.6 
Chemical Properties 
 
Pembrolizumab is a humanized anti-PD-1 mAb of the IgG4/kappa isotype with a 
stabilizing S228P sequence alteration in the fragment crystallizable (Fc) region. 
Pembrolizumab binds to human PD-1 and blocks the interaction between PD-1 and its 
ligands. The theoretical molecular weight of the polypeptide is 146,288 Da and its 
theoretical pI is 7.5. The parental murine anti-human PD-1 antibody (hPD-1.09A) 
was produced by immunizing mice with hPD-1 DNA. The pembrolizumab antibody 
was generated by humanization of the parental antibody by the Medical Research 
Council (Cambridge, UK) using complementarily-determining region (CDR) grafting 
technology (U.S. Patent No. 5,225,539). The gene segments encoding the variable 
heavy and light chains of pembrolizumab, as well as, human IgG4, were codon- 
optimized, synthesized, and ligated into a vector. A single expression plasmid, 
pAPD11V1-GA was constructed for the expression of both the heavy and light 
antibody chains of pembrolizumab. The nucleotide sequences encoding the heavy and 


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light chains, along with their respective promoters and poly A signal sequences have 
been confirmed by DNA sequence analysis. The pAPD11V1-GA expression vector 
was subsequently used to transfect CHO-DXB-11 cells for the development of the 
pembrolizumab-producing cell line. 
 
2.7 
Structure 
 
Pembrolizumab is a highly selective humanized mAb designed to block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an 
IgG4/kappa isotype with a stabilizing sequence alteration in the Fc region. 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. 
 
2.8 
Physico-Chemical Properties 
 
Refer to current Investigator’s Brochure for Physico-Chemical Properties 
 
2.9 
Pharmaceutical Formulation 
 
Refer to current Investigator’s Brochure for information on Pharmaceutical 
Formulation 
 
2.10 
Nonclinical Pharmacology 
 
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 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- 


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FU and this combination therapy results in increased efficacy, as well as complete 
regression rates in vivo. 
 
2.11 
Affinity and Ligand Blockade of Pembrolizumab 
 
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. 
 
2.12 
In Vivo Efficacy of Analog Anti-Mouse PD-1 Antibody (as a Monotherapy) in 
Syngeneic Tumor Models 
 
Due to the lack of cross-reactivity of pembrolizumab with PD-1 from rodents (or 
other non-primate species), a commercially available, hamster anti-mouse PD-1 
analog antibody (clone J43) was used for in vivo efficacy studies in mice. The affinity 
of J43 for recombinant mouse PD-1 is 0.64 nM. J43 is a relatively weak PD-1 binder 
(~22 fold) compared to pembrolizumab. The antibody is capable of blocking 
recombinant murine PD-1 ligands PD-L1 and PD-L2 with IC50 values of 8.2 nM and 
2.9 nM, respectively. Thus, the ligand blocking capacity of J43 is less potent than that 
of pembrolizumab (~14 fold for PDL1, ~1.5 fold for PD-L2). Anti-mouse PD-1 (J43) 
was tested as a monotherapy in several syngeneic murine tumor models. In all 
monotherapy experiments, tumor cells were implanted subcutaneously in syngeneic 
hosts and were staged at 50-80 mm3 before dosing was initiated. Anti-murine PD-1 or 
isotype control antibody was administered intraperitoneally (IP) every 3 to 4 days for 
a total of five treatments (the doses and schedule were determined based on 
experiments published in literature). Efficacy was determined by monitoring tumor 
volumes and long term survival for each experimental group. An example of anti- 
murine PD-1 monotherapy efficacy is shown in Figure 1 (arrows indicate days of 
treatment). 


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Figure 1: Effect of Anti-PD-1 Monoclonal Antibody Monotherapy on Growth of 
MC38 Tumor 
 
[Redacted] 
The tumor growth curves in Figure 2 show that anti-mouse PD-1, administered at 
10 mg/kg, potently inhibited the subcutaneous growth of MC38 colon 
adenocarcinoma tumors in most animals. In addition to inhibiting tumor growth, anti- 
mouse PD-1 administered at 10 mg/kg induced complete tumor regression in 50% of 
the animals resulting in long-term tumor free survival (Figure 2 below). At the 2 
mg/kg dose, two of 10 mice in this experiment experienced complete rejection of 
their tumor. None of the mice treated with either dose of the control antibody 
demonstrated complete rejection of their tumor. 
 
Figure 2: Effects of Anti-PD-1 Monoclonal Antibody Monotherapy on Survival in 
MC38 Tumor Model 
 
[redacted] 
 
 
 
2.13 
Non-Clinical Toxicology Summary of Results 
 
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, i.e. tissue processing for IHC, that are well recognized 
limitations of tissue cross-reactivity studies and, thus not considered toxicologically 
relevant. 
 
No reproductive or developmental toxicity studies are planned with pembrolizumab 
and therefore, inclusion of women of childbearing potential in clinical trials should be 
in accordance with the study protocol and applicable regulatory guidance (e.g., ICH 
M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals). 
 
2.14 
Clinical Summary of Results 
 


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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 have 
been reported in [45], however, since the potential exists in anti-PD-1 monoclonal 
antibodies, investigators should be vigilant to this possibility. Less than 1% of 
patients assayed thus far had confirmed positive ADA samples and among these, no, 
or no clear impact on exposure has been observed. 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 irRC, 
respectively. Pembrolizumab monotherapy induces an ORR of 39%/43% in patients 
with ipilimumab-naive melanoma by central independent RECIST and oncology 
review/investigator assessed irRC, 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 monotherapy induces an ORR of 21%/24% in patients with 
previously-treated NSCLC by central independent RECIST/investigator assessed 
irRC, 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 irRC/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 drug reactions 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%). Primarily on 
post-marketing experience, arthritis was also added as an adverse drug reaction. 
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. Immune-mediated adverse drug reactions may be fatal and may occur 
after discontinuation of pembrolizumab therapy. 
 
2.15 
Preclinical and Clinical Trial Data 
 
Refer to current Investigator’s Brochure for Preclinical and Clinical Trial data. 
 
2.16 
Rationale for the Trial and Selected Patient Population 
 
PD-1 is a receptor expressed by activated T and B cells, which binds to two known 


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ligands: PD-L1 (B7-H1) [1;2] and PD-L2 [B7-DC] [3;4]. PD-1 negatively regulates T 
cell functions through the engagement of PD-L1, which is expressed by a wide 
variety of tissues [1;2;5]. PD-L1 is also expressed by human tumors, including 
melanoma, either constitutively or after treatment with IFN-α [6]. In chronically 
infected mice, Lymphocytic Choriomeningitis Virus-specific CD8+ T cells exhibit a 
diminished capability to produce cytokines, lyse infected cells and proliferate in a 
progressive and hierarchical fashion [7]. These “exhausted” T cells have been shown 
to up-regulate PD-1, and blockade of the PD-1/PD-L1 pathway led to increased 
cytokine production and proliferation, resulting in a significant reduction of the viral 
load [8]. 
 
Anti-PD-1 therapy has been recently tested in clinical trials with great promise. A 
mAb with the same target, nivolumab, has shown evidence of clinical efficacy in 
larger clinical trials including a total of 296 patients with advanced cancers, including 
melanoma, non-small cell lung cancer and renal cancer [9;10]. Cumulative response 
rates (all doses) were 28% among patients with melanoma (26 of 94 patients) with 
response rate ranging from 19 to 41% per dose level. Interestingly, 
immunohistochemical analysis on pre-treatment tumor specimen indicated that all 
responding patients had PD-L1-positive tumors, although recent updates at [44] 
indicate this to be a less consistent finding. 
 
Pembrolizumab is a potent and highly selective humanized mAb of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD- 
L1 and PD-L2. An open label Phase I study continues to evaluate the safety and 
clinical activity of single agent pembrolizumab. Updated results were presented at 
ASCO 2014 [45].The dose escalation portion of this study evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks, in patients with 
advanced solid tumors. All three dose levels were well tolerated and no DLTs were 
observed. An expansion cohort is currently being treated at 10 mg/kg q 3 weeks. 
Preliminary evidence of antitumor activity was observed in melanoma and NSCLC 
with confirmed overall response rate (per RECIST 1.1) of more than 30% in 
melanoma, and has typically been durable. 
 
Of 133 patients who were dosed with pembrolizumab and evaluable for AEs fatigue 
(22%), rash (18%), and pruritus (14%) were the most common drug-related AEs 
(mostly grade 1-2). The incidence of drug-related grade 3-4 AEs was 10%. There 
were 4 drug-related cases of pneumonitis, all grade 1-2. Grade 3-4 drug-related 
hypothyroidism (n = 1) and hyperthyroidism (n = 1) were noted [11]. 
 
Targeting the PD-1 pathway is proving to be an impressive strategy in cancer therapy 
and clinical efficacy has already been demonstrated in several tumor types that are 
not traditionally considered “immunogenic”, including NSCLC. Phase III studies are 
being conducted in non-melanoma advanced malignancies. Advanced sarcoma 
continues to be a refractory disease and little progress has occurred in its management 
beyond the recent approval of pazopanib on the basis of modest but meaningful 


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benefit. Novel therapeutics are clearly needed for patients with advanced sarcomas. 
 
Based on evidence that immunogenic Cancer-Germ line or Cancer Testis Antigens 
(CTA) are widely expressed on many STS; including synovial sarcoma, uterine 
leiomyosarcoma and myxoid-round cell liposarcoma, immunotherapeutic approaches 
present an attractive treatment option in STS [12;13]. 
 
Clinical data using adoptive transfer of T cells engineered against the CTA, NY-ESO-
1, demonstrated impressive tumor responses in 4 of 6 patients in a study lead by 
Rosenberg at the NCI [14]. Other vaccine studies using peptides from the t(x;18) 
SS18-SSX fusion genes found in most synovial sarcomas, demonstrated induction of 
peptide specific cytotoxic T cells in 4 patients with clinical benefit in one patient [15]. 
 
The anti-CTL4 monoclonal antibody, ipilimumab, has been tested in synovial 
sarcomas expressing the NY-ESO1 antigen in a separate study. In this study 6 
patients were treated with one course of ipilimumab given at 3 mg/kg every 3 weeks 
for 3 doses only. There were no RECIST responses observed and only one patient 
demonstrated an immune response, although patients tolerated the treatment well 
with manageable side effects. This study was terminated early for slow accrual, lack 
of activity, and lack of immune responses. There were several limitations to this 
study: 
a) it was based on objective RECIST responses, which are now thought to be less 
reflective of the immune-based clinical activity of ipilimumab; b) the dose 
chosen was relatively low and the course perhaps too short to document any 
potential underlying benefit; and c) it is not known whether additional patients 
would have changed the outcome of this trial [16]. Nonetheless, there is no 
otherwise reported clinical evidence of benefit using anti-CTL4 therapy alone in 
STS. 
 
The role of the PD-1/PD-L1 axis in STS is presently being elucidated. In one 
retrospective study of tumor specimens from 105 cases, it was determined that the 
degree of PD-1 positivity in tumor infiltrating lymphocytes and PD-L1 
overexpression in tumor specimens correlated with a poorer prognosis and more 
aggressive disease [17]. These studies suggest that PD-1 and PD-L1 staining may be 
viable biomarkers for prognosis and, possibly, treatment using anti-PD-1 treatment 
strategies. Preclinical trials using implanted fibrosarcoma mouse models have 
demonstrated activity of anti-PD-1 therapy and that this activity may be independent 
of PD-L1 staining [18]. Other studies in fibrosarcoma rodent xenografts have shown 
modest activity using anti-PD-1 therapy alone but significantly enhanced activity 
when combined with a dual checkpoint antibody directed at LAG-3 [19]. Therefore, 
although Anti-PD1 therapy has not been tested in clinical trials, there is ample 
rationale for using anti-PD1 treatment alone and in combination with other 
checkpoint inhibitors in patients with advanced STS. 
 
This study is therefore a Phase II clinical trial to determine the preliminary clinical 


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efficacy of the anti-PD1 antibody pembrolizumab in patients with advanced 
sarcomas. Given the heterogeneity of advanced sarcomas, the study will have two 
separate arms that each encompasses sarcoma subtypes with similar anatomic 
primary sites and patterns of progression. 
 
In the original 86 patient group, 80 patients were evaluable for objective response rate 
by RECIST 1.1. Among 40 evaluable patients in the STS cohort, there were 7 partial 
responses with an ORR of 18%. Four partial responses were seen among 10 patients 
with undifferentiated pleomorphic sarcoma for an ORR of 40%. Two additional PRs 
were observed in the dedifferentiated/high grade liposarcoma cohort (2 out of 10) for 
an ORR of 20%. There was an additional PR seen in the synovial sarcoma cohort.  
Among 40 evaluable patients in the bone sarcoma cohort, there were 2 partial 
responses with an ORR of 5%. 1 PR was seen each in the dedifferentiated/high grade 
chondrosarcoma and osteosarcoma cohorts. 
 
Given the observed PRs in the UPS and dedifferentiated/high grade liposarcoma 
cohorts, we will enroll patients to expansion of both cohorts to include an additional 
30 patients each (UPS and LPS) to further explore and confirm the activity of 
pembrolizumab. 
 
2.17 
Study Design 
 
This is an open-label, Phase II study of pembrolizumab for patients ≥18 years of age 
with locally advanced, unresectable, recurrent, and/or metastatic soft tissue sarcomas, 
or ≥12 years of age for bone sarcomas. Patients will be assigned to one of 2 arms 
based on the sarcoma histologic subtypes: high grade aggressive soft tissue sarcomas 
(specifically leiomyosarcoma, poorly differentiated/de-differentiated liposarcoma, 
high grade pleomorphic undifferentiated sarcoma/MFH, MPNST and synovial 
sarcoma), and bone sarcomas (Ewing Sarcoma, osteosarcoma, and chondrosarcoma 
[de-differentiated or mesenchymal]). The patient population must meet all eligibility 
criteria specified in Section 3. A total of up to 80 patients will be included in the 
study. Patients will undergo screening evaluations to determine eligibility within 30 
days of the first dose. Each 21 day dosing period will constitute a cycle. 
 
Pembrolizumab is a potent humanized IgG4 anti-PD-1 mAb with high specificity of 
binding to the PD-1 receptor, thus perpetuates inhibition of PD-L1 and PD-L2 
interaction. Based on preclinical in vitro data, pembrolizumab has higher affinity and 
receptor-blocking activity compared to other anti-PD-1 products in development. 
Pembrolizumab has an acceptable preclinical safety profile and is being advanced for 
clinical development as an IV immunotherapy for advanced malignancies. 
Pembrolizumab has been evaluated at 2 and 10 mg/kg every 3 weeks but a flat dose 
of 200 mg IV every 3 weeks will be utilized for further development. 
 
Patients will be assessed for response (RECIST 1.1) by CT or MRI beginning 8 
weeks (± 1 week) after treatment initiation and then every 12 weeks (± 1 week) until 
progression or treatment discontinuation, whichever occurs first. Treated patients will 


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be allowed to continue study therapy after initial RECIST 1.1 defined progression if 
they are assessed by treating physician to be deriving clinical benefit and tolerating 
study drug. Treating physician may consult with overall study PI as needed for help 
with assessing patient. Such patients should discontinue study therapy upon further 
evidence of progression. 
 
In the initial enrollment and in the first 20 patients enrolled in each of the UPS and 
LPS cohorts, mandatory biopsies will be obtained during screening prior to initiation 
of therapy (week 0) and at 8 weeks (± 1 week) to coincide with radiologic disease 
assessment Additional tumor biopsies (optional) at cycle 12 (week 34) and at time of 
progression may be collected for easily accessible tumors. Surgical excisional biopsies 
or core biopsies are acceptable. 
 
2.18 
Correlative Studies 
 
In part 1 of the study and in up to 20 patients enrolled in each of the UPS and LPS 
cohorts, pre- and post-treatment biopsies (week 0, 8) will be required and biopsies at 
cycle 12 (week 34) and at progression are optional. T cell infiltration as well as 
suppressor subpopulations will be compared between pre- and post-treatment 
biopsies. 
 
Blood for research studies will be collected prior to first study drug administration, at 
week 8, week 20 and week 32 and flow cytometry analyses will be performed to 
determine the presence of PD-1 expressing T cells, as well as, the proportion of 
circulating regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug 
and must meet all inclusion / exclusion criteria. Results of all baseline evaluations, 
which assure that all inclusion and exclusion criteria have been satisfied must be 
reviewed by the Principal Investigator or his/her designee prior to enrollment of the 
patient. In addition, the patient must be thoroughly informed about all aspects of the 
study, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. The following criteria apply to all patients 
enrolled onto the study unless otherwise specified. 
 
3.2 
Inclusion Criteria 
 
3.2.1 
Age ≥ 18 years (Age ≥ 12 years for patients with bone sarcomas). 
 
3.2.2 
Histologically confirmed diagnosis of unresectable, recurrent, and/or metastatic 
high grade soft-tissue or bone sarcoma of one of the following subtypes: soft 


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tissue sarcomas (leiomyosarcoma, poorly differentiated/de-differentiated 
liposarcoma, high grade pleomorphic undifferentiated sarcoma/MFH and 
synovial sarcoma), and bone sarcomas (Ewing sarcoma, osteosarcoma, and 
chondrosarcoma [de-differentiated or mesenchymal]). 
 
3.2.3 
ECOG Performance Status of 0 or 1. 
 
3.2.4 
At least one site of measurable disease on CT/MRI scans as defined by RECIST 
1.1. Baseline imaging must be performed within 30 days of dosing. 
 
3.2.5 
At least one site of accessible disease for pre- and post-treatment core biopsies for 
at least 20 patients per arm on the expansion cohorts. 
 
3.2.6 
Patients may have received 1-3 prior systemic therapies in the metastatic setting. 
 
3.2.7 
Adequate organ function within 14 days of dosing defined as: 
 
3.2.7.1 Absolute Neutrophil Count (ANC) ≥ 1000/µL 
 
3.2.7.2 Platelets ≥ 100,000/µL (transfusion independent) 
 
3.2.7.3 Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
 
3.2.7.4 ALT and AST ≤ 2.5 x institutional upper limit of normal (ULN) or ≤ 5.0 x 
institutional ULN if considered due to tumor 
 
3.2.7.5 Alkaline phosphatase ≤ 2.5 x institutional ULN unless considered due to 
tumor 
 
3.2.7.6 Serum bilirubin ≤ 1.5 x institutional ULN. NOTE: Patients with elevated 
bilirubin secondary to Gilbert’s disease are eligible to participate in the study 
 
3.2.7.7 Serum creatinine ≤ 1.5 x institutional ULN or 24-hour creatinine clearance ≥ 
50 ml/min (calculated creatinine clearance using Cockroft-Gault formula is 
acceptable) 
 
3.2.8 
Must be willing to provide and have available archival tissue for PD-L1 testing. 
 
3.2.9 
Written, voluntary informed consent. 
 
3.2.10 Fertile men and women of childbearing potential must agree to use an effective 
method of birth control from providing signed consent and for 120 days after last 
study drug administration. Women of childbearing potential include pre- 
menopausal women and women within the first 2 years of the onset of 
menopause. Women of childbearing potential must have a negative pregnancy 


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test ≤ 72 hours prior to Day 1 of study. 
 
Effective methods of birth control include: surgically sterile, barrier device 
(condom, diaphragm), contraceptive coil, intrauterine device (IUD), and 
abstinence. 
 
3.2.11 Life expectancy of >12 weeks. 
 
3.2.12 Patients with central nervous system disease are eligible for enrollment if they 
have received prior radiotherapy or surgery to sites of CNS metastatic disease and 
are without evidence of clinical progression for at least 4 weeks prior to 
screening, have no evidence of new or enlarging brain metastases, and are off 
steroids for at least 7 days before first dose of pembrolizumab. 
 
3.3 
Exclusion Criteria 
 
3.3.1 
Prior systemic therapy targeting PD-1: PD-L1 axis. 
 
3.3.2 
Patients who are curable by conventional multidisciplinary management. 
 
3.3.3 
Patients with severe and/or uncontrolled concurrent medical disease that in the 
opinion of the investigator could cause unacceptable safety risks or compromise 
compliance with the protocol. 
 
3.3.4 
Patients who have received wide field radiotherapy ≤ 4 weeks or limited field 
radiation for palliation < 2 weeks prior to screening or who have not recovered 
adequately from side effects of such therapy. 
 
3.3.5 
Patients who have active infections requiring therapy. 
 
3.3.6 
Patients that are known to be positive for Human Immunodeficiency Virus (HIV) 
(HIV 1/2 antibodies), active Hepatitis B (HBsAg reactive), or Hepatitis C (HCV 
RNA [qualitative] is detected); patients with negative Hepatitis C antibody testing 
may not need RNA testing. 
 
3.3.7 
Patients that have a known psychiatric or substance abuse disorder that would 
interfere with cooperation with the requirements of the trial. 
 
3.3.8 
Patients who received systemic anti-cancer treatment prior to the first dose of 
study drug within the following time frames: 
• Patients who have received cyclical chemotherapy within a period of time that 
is shorter than the cycle length used for that treatment (e.g., 6 weeks for 
nitrosourea, mitomycin-C) prior to starting study drug. 
• Patients who have received biologic therapy (e.g., antibodies) within a period 
of time that is ≤ 5 t1/2 or ≤ 4 weeks (whichever is shorter) prior to starting 


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study drug. 
• Patients who have been treated with a continuous or intermittent small molecule 
therapeutics within a period of time that is ≤ 5 t1/2 or ≤ 4 weeks (whichever is shorter) 
prior to starting study drug. 
• Patients who have received any other investigational agents within a period of 
time that is ≤ 5 t1/2 or less than the cycle length used for that treatment or ≤ 4 
weeks (whichever is shorter) prior to starting study drug. 
• Patients who have received wide field radiotherapy (including therapeutic 
radioisotopes such as strontium 89) ≤ 4 weeks or limited field radiation for 
palliation ≤ 2 weeks prior to starting study drug. 
• Patients who have undergone surgery ≤ 2 weeks prior to starting study drug 
(minor surgical procedures may be allowed). 
 
3.3.9 
Patients with active autoimmune disease or a documented history of autoimmune 
disease or syndrome that requires systemic steroids or immunosuppressive agents. 
Patients with vitiligo or resolved childhood asthma/atopy would be exception to 
this rule.  Patients that require inhaled steroids or local steroid injections would 
not be excluded from the study. Patients with hypothyroidism not from 
autoimmune disease that is stable on hormone replacement will not be excluded 
from the study. 
 
3.3.10 Women who are pregnant or nursing/breastfeeding. 
 
3.3.11 Known hypersensitivity to pembrolizumab or another mAb (another PD-1 
monoclonal antibody). This is only in the case of pembrolizumab or related mABs 
hypersensitivity 
 
3.3.12 Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
 
3.3.13 Patients with untreated central nervous system disease. Patients with controlled 
treated CNS lesions who have undergone surgery or stereotactic radiosurgery and 
stable for 4 weeks are eligible. 
 
3.3.14 Inability to comply with protocol required procedures. 
 
3.3.15 Patients with medical conditions that require chronic systemic corticosteroid 
therapy or require any other form of immunosuppressive medication. However, 
patients using physiologic replacement doses of hydrocortisone, or its equivalent, 
will be considered eligible for this study: up to 20 mg hydrocortisone (or 5 mg of 
prednisone) in the morning and 10 mg hydrocortisone (or 2.5 mg prednisone) in 
the evening. 
 
3.3.16 Patients with the risk factors for bowel obstruction or bowel perforation 
(examples include but not limited to a history of acute diverticulitis, intra- 


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abdominal abscess, abdominal carcinomatosis). 
3.3.17 Patients who have received a live vaccine within 30 days prior to the first dose of 
trial treatment. 
3.3.18 Patients who have had allogeneic SCT/solid organ transplant 
 
3.4 
Inclusion of Women and Minorities 
 
Men, women, children (age ≥12 for bone sarcomas only), and members of all ethnic 
and racial groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
After obtaining informed consent, only eligible patients will be enrolled in this trial. 
Eligible patients will be registered by local sites through an electronic database, and 
will be issued a subject unique identifying number. An investigator is required to 
prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the investigation on each patient treated with 
the study drug in the study or registered to the study. SARC may request faxed copies 
of selected source documents with PHI redacted for verification of records, accuracy 
of electronic submissions and review of data. 
 
While all study evaluations must be performed by the Investigator, as described in 
Section 10 (Study Evaluations and Study Calendar), only data related to the primary 
and secondary endpoints, as well as safety data, will be captured in the eCRFs. 
 
4.2 
Registration Process 
 
This study uses a web based data capture system. All patient registration and Case 
Report Forms (CRFs) will be submitted electronically via a web-based electronic 
database. All patients must be registered on the study website prior to start of 
treatment. Data Managers and other authorized users will be provided with a unique 
user identification number and password to access the site. All study case report 
forms may be accessed online through the study website. In case there are problems 
accessing the website, please contact the SARC office directly by phone: 734-930- 
7600 or by fax: 734-930-7557. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Pembrolizumab will be administered at 200 mg intravenously every 3 weeks. The 
pharmacist will prepare pembrolizumab for administration. The Pharmacy Manual 
that contains specific instructions for pembrolizumab dose calculation, reconstitution, 


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preparation and administration of the infusion fluid will be provided by Merck. The   
treatment dosing schedule for this trial is outlined below in Table 1. 
 
Table 1: Treatment Dosing Schedule 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
every 3 
weeks 
IV infusion 
30 minutes (-5/+10) 
Experimental 
 
The pembrolizumab dosing interval may be increased due to toxicity as described in 
Section 6.2. Pre medications will not be administered prior to study drug. 
 
5.2 
Time of Drug Administration 
 
Study drug should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Study Calendar 
(Section 10). After the first cycle, trial treatment may be administered ± 3 days to the 
scheduled Day 1 of each cycle. 
 
All trial treatments will be administered on an outpatient basis. 
 
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle 
intervals may be increased due to toxicity as described in Section 6.2). Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., allowed infusion time is between 25 and 
40 minutes). 
 
5.3 
Trial Blinding/Masking 
 
This is an open-label trial; therefore, the Sponsor, site Investigator and patient will 
know the treatment to be administered. All enrolled patients will receive 
pembrolizumab. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 
Concomitant Medications/Vaccinations 
 
Any concomitant medications that the patient is taking that leads to an Adverse 
Event (AE) grade 1 or greater based on CTCAE v 4.0 will be recorded. This data 
will be captured on the Adverse Events eCRF. 
Also, any concomitant medication abnormality fulfilling the criteria for a Serious 
Adverse Event (SAE) should be reported as such, in addition to being recorded as 
an adverse event in the eCRF. 
 
5.4.1.1 Prohibited Concomitant Medications 


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Patients are prohibited from receiving the following therapies during the 
Screening and Treatment Phase (including retreatment for post-complete 
response relapse) of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy 
o Note: Radiation therapy to a symptomatic solitary lesion or to 
the brain may be allowed after consultation with Sponsor. 
• Live vaccines within 30 days prior to the first dose of study drug and 
while on study. Examples of live vaccines include, but are not limited 
to the following: measles, mumps, rubella, chicken pox, yellow fever, 
rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; 
however intranasal influenza vaccines (e.g. Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
• Glucocorticoids for any purpose other than to treat or prevent any AE, 
or to modulate symptoms from an event of clinical interest of suspected 
immunologic etiology. The use of physiologic dose of corticosteroids 
is allowed. 
 
Patients who require the use of any of the aforementioned treatments for clinical 
management, per the site Investigator’s assessment should be removed from the 
trial. Patients may receive other medications that the investigator deems to be 
medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this 
trial. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.4.2 
Rescue Medications & Supportive Care 
 
5.4.2.1 Supportive Care Guidelines 
 
Patients should receive appropriate supportive care measures as deemed 
necessary by the treating site Investigator including but not limited to the 
items outlined below: 
 
Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids (1-2 mg/kg/day 
of prednisone or equivalent). 


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o For Grade 3-4 events, bronchoscopy should be performed to 
exclude infectious etiologies before starting immunosuppression. 
Once infectious etiologies are excluded, immediately treat with 
intravenous steroids (1-2 mg/kg/day of prednisone or equivalent). If 
symptoms persist for more than 3-5 days, then begin infliximab 5 
mg/kg. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
Permanently discontinue pembrolizumab. 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Permanently 
discontinue pembrolizumab. 
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 (1-2 
mg/kg/day prednisone or equivalent). 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids (1-2 
mg/kg/day prednisone or equivalent) followed by high dose oral 
steroids. If grade 3-4 diarrhea persists for more than 3-5 days, then begin 
infliximab 5 mg/kg. 
 For 
grade 
4 
diarrhea/colitis, 
permanently discontinue 
pembrolizumab. 
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 


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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 (1-2 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. 
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. 
 
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 (1-2 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. Replacement of 
appropriate hormones may be required as the steroid dose is 
tapered. 
 Permanently discontinue pembrolizumab for Grade 4 
hyperthyroidism. 
 
Hepatic Adverse Events: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids (0.5-1 mg/kg/day 
prednisone or equivalent) 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 


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48 hours (1-2 mg/kg/day prednisone or equivalent. If grade 3-4 hepatitis 
persists for more than 3-5 days, then begin mycophenolate 1 g twice 
daily. Permanently discontinue pembrolizumab for AST or ALT > 5x 
ULN or total bilirubin >3x ULN. 
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
o Renal Failure or Nephritis:For Grade 2 events, treat with 
corticosteroids (1-2 mg/kg/day prednisone or equivalent). 
o For Grade 3-4 events, treat with systemic corticosteroids (1-2 
mg/kg/day prednisone or equivalent). Permanently discontinue 
pembrolizumab. 
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. For Grade 3-4 events, stop infusion and 
permanently discontinue pembrolizumab. 
 
Table 2 below shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 2: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK- 
3475) with: 
Diphenhydramine 50 mg 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 


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Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae (e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
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. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration. 
 
• Steven Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): 
 For signs or symptoms of SJS or TEN, withhold pembrolizumab and 
refer the patient for specialized care for assessment and treatment. 
 If SJS or TEN is confirmed, permanently discontinue pembrolizumab. 
o Immune-mediated myocarditis management 
 
 For suspected immune-mediated myocarditis, ensure adequate 
evaluation to exclude other etiologies, and administer 
corticosteroids as appropriate. 
 
5.5 
Diet/Activity/Other Considerations 
 
5.5.1 
Diet 
 
Patients should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
 
5.5.2 
Contraception 


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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. 
Men and non-pregnant, non-breast-feeding women may be enrolled if they are 
willing to use 2 methods of birth control or are considered highly unlikely to 
conceive. Highly unlikely to conceive women are defined as: 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥ 45 years of age and has not had 
menses for more than 1 year), or 3) not heterosexually active for the duration of the 
study. The two birth control methods can either be two barrier methods or a barrier 
method plus a hormonal method to prevent pregnancy. Patients should start using 
birth control from study visit 1 throughout the study period up to 120 days after the 
last dose of study therapy. 
 
The following are considered adequate barrier methods of contraception: 
diaphragm, condom, copper intrauterine device, sponge, or spermicide. 
Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent 
(including subcutaneous, intrauterine, or intramuscular agents). 
 
Patients 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 they must adhere to the contraception requirement 
(described above) for the duration of the study and during the follow-up period 
defined in section 7.2.4. If there is any question that a patient will not reliably 
comply with the requirements for contraception, that patient should not be entered 
into the study. 
 
5.5.3 
Use in Pregnancy 
 
If a patient inadvertently becomes pregnant while on treatment with 
pembrolizumab, the patient will immediately be removed from the study. The site 
will contact the patient at least monthly and document the patient’s status until the 
pregnancy has been completed or terminated. The site will report the outcome of 
the pregnancy to SARC without delay and within 24 hours 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 site   
investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to SARC. If a male 
patient impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to SARC and followed as 
described above and in Section 7.2.4. 
 
5.5.4 
Use in Nursing Women 
 
It is unknown whether pembrolizumab is excreted in human milk. Since many 


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drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, patients who are breast-feeding are not eligible for 
enrollment. 
 
5.6 
Duration of Therapy 
 
Treatment may continue until one of the following criteria applies: 
 
o Patient achieves SD, PR, or CR and completes 35 cycles of treatment 
without unacceptable adverse event(s) (Section 6.1). 
 
o Clinical or radiographic disease progression as defined by RECIST 1.1. 
Patient may be allowed to continue treatment after progression for a 
maximum of 35 cycles of treatment if they are deriving clinical benefit 
(refer to section 2.17). 
 
o Patient decides to withdraw from the study 
 
o General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the site 
investigator 
 
o Unacceptable adverse event(s) (Section 6.1) 
 
o Need for > 2 dose delays due to toxicity 
 
o Pregnancy in patient 
 
o Patient is lost to follow-up. 
 
5.6.1 Duration of Participation 
 
Each patient will participate in the trial from the time of Informed Consent Form (ICF) 
is signed through final protocol-specified contact. After a screening phase for 
eligibility, patients will receive pembrolizumab every 3 weeks. Treatment for patients 
that achieve SD, a PR, or a CR can continue for a maximum of 2 years. At the 
discretion of the investigator, patients who have progressive disease (PD) but continue 
to achieve clinical benefit, may also continue on therapy for a maximum total duration 
of treatment of 35cycles. 
 
5.7 
Duration of Follow Up 
 
Patients will be followed for 30 days +/- 14 days after termination of study treatment 
or until death, whichever occurs first. Patients removed from study for adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 


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5.8 
Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 5.6 
applies. The reason for study removal and the date the patient was removed must be 
documented in the eCRF including death or lost to follow up. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose reduction of pembrolizumab will not be permitted in individual patients. 
 
6.1 Discontinuation of Therapy: 
 
Therapy with pembrolizumab will be permanently discontinued for any of the following: 
 
a. Severe or life-threatening adverse reactions, including, but not limited to, any of the 
following (SARC must be notified in the event of these AEs and final decision regarding 
treatment will be made after a discussion): 
 
• Drug related grade 4 toxicity (non-hematologic or hematologic) 
 
• Diarrhea with abdominal pain, fever, ileus, or peritoneal signs; increase in stool 
frequency (7 or more bowel movements over baseline), stool incontinence, need 
for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, 
and gastrointestinal perforation 
 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times 
upper limit of normal. For patients with liver metastasis who entered the study 
with grade 2 elevation of AST/ALT, pembrolizumab will be permanently 
discontinued if AST/ALT increase ≥ 50% relative to baseline and lasting ≥ 1 
week) 
 
• Total serum bilirubin >3 times upper limit of normal 
 
• Severe (i.e., CTCAE grade 3 or 4) motor or sensory neuropathy, Guillain-Barré 
syndrome, or myasthenia gravis or other neurologic symptoms that impact 
activity of daily living 
 
• Severe immune-mediated reactions involving any other organs (e.g., nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis) 
 
• Immune-mediated ocular disease that is unresponsive to topical 
immunosuppressive therapy 
 
• Grade 4 infusion reaction 


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• Confirmed diagnosis of Stevens-Johnson Syndrome (SJS) or Toxic Epidermal 
Necrolysis (TEN) 
 
b. Inability to reduce corticosteroid dose for immune-related adverse reactions to ≤ 10 mg 
prednisone or equivalent per day 
 
c. New or worsening ophthalmologic disorders, including loss of visual acuity or visual 
field and evidence of retinopathy. 
 
6.2 Withholding/Resuming Therapy 
 
Study therapy will be withheld for the following adverse reactions: 
 
a. A drug-related clinically significant toxicity ≥ Grade 2, with the exception of the 
adverse reactions listed under requirement of permanent discontinuation of study therapy. 
 
b. Grade 2 fatigue does not require the withholding of pembrolizumab. 
 
c. When toxicity resolves or improves to ≤ grade 1, therapy with pembrolizumab will 
resume. 
 
d. In case toxicity does not resolve or improve to ≤ grade 1 within 12 weeks after last 
administration of pembrolizumab, study drug discontinuation should be considered after 
discussion with SARC and overall study PI. If SARC, study PI and Merck are in 
agreement, patients who still have grade 2 toxicity at 12 weeks may continue on study 
only if asymptomatic and controlled. 
 
e. Two dosing delays due to toxicity will be permitted. In the event of a third occurrence 
of a toxicity, which would require dosing delay, study therapy will be discontinued 
permanently. 
 
f. For signs or symptoms of SJS or TEN, withhold KEYTRUDA® and refer the patient 
for specialized care for assessment and treatment. 
 
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab 
 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than on body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical 
to reduce complications. Based on existing clinical trial data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care. 


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For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 4. 
 
Table 4: Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab 
 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow- 
up 
Pneumonitis 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor 
participants for 
signs and 
symptoms of 
pneumonitis 
• 
Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
• 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor 
participants for 
signs and 
symptoms of 
enterocolitis (ie, 
diarrhea, 
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 pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks. 
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. 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow- 
up 
Grade 4 
Permanently 
discontinue 
abdominal pain, 
blood or mucus 
in stool with or 
without fever) 
and of bowel 
perforation 
(ie, peritoneal 
signs and ileus). 
• 
Participants with 
≥ Grade 2 
diarrhea 
suspecting colitis 
should consider 
GI consultation 
and performing 
endoscopy to rule 
out colitis. 
• 
Participants with 
diarrhea/colitis 
should  be 
advised to drink 
liberal quantities 
of clear fluids. If 
sufficient oral 
fluid intake is not 
feasible,  fluid 
and electrolytes 
should be 
substituted via IV 
infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with 
liver function 
tests (consider 
weekly or more 
frequently until 
liver enzyme 
value returned to 
baseline or is 
stable 
Grade 3 or 4 
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM 
• Administer anti-hyperglycemic in 
participants with hyperglycemia 
• 
Monitor 
participants for 
hyperglycemia or 
other signs and 
symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• 
Monitor for signs 
and symptoms of 


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Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow- 
up 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated. 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non-selective beta- 
blockers (eg, propranolol) or 
thionamides as appropriate 
• 
Monitor for signs 
and symptoms of 
thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs 
and symptoms of 
thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold 
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes 
of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids 
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM). 


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Guidelines for Infusion Reactions 
 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table 5. 


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Table 5: Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (e.g. from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such 
as medical / surgical events or logistical reasons not related to study therapy. Subjects 
should be placed back on study therapy within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 
7.2) will determine whether the event requires expedited reporting in addition to routine 
reporting. 
 
7.1 
Adverse Events and Laboratory Abnormalities 
 
7.1.1 Adverse Events (AEs) 
 
7.1.1.1 Definition of Adverse Events 
 
Per the International Conference of Harmonization (ICH), an AE is any untoward 
medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product. Pre-existing 
conditions which worsen during a study are to be reported as AEs. 
 
7.1.1.2 CTCAE term (AE description) 
 
The descriptions found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site (http://ctep.cancer.gov). All adverse events regardless of CTCAE grade must 
also be evaluated for seriousness. 
 
7.1.1.3 
Intensity 
 
Intensity of all adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a five-point scale 
(grades 1 to 5) and reported in detail on the CRF. Adverse events not listed on the 
CTCAE should be graded as follows: 


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CTC 
Grade 
Equivalent To: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily 
activity 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated although this 
could improve the overall well-being or symptoms of the 
patient 
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment 
or medical intervention is indicated in order to improve the 
overall well-being or symptoms; delaying the onset of 
treatment is not putting the survival of the patient at direct 
risk. 
Grade 4 
Life threatening/ 
disabling 
An immediate threat to life or leading to a permanent mental 
or physical conditions that prevents work or performing 
normal daily activities; treatment or medical intervention is 
required in order to maintain survival. 
Grade 5 
Death 
AE resulting in death 
 
7.1.1.4 
Drug-Adverse Event relationship 
 
The causality relationship of study drug to the adverse event will be assessed by 
the investigator as either: Yes or No. 
 
If there is a reasonable suspected causal relationship to the study medication, i.e. 
there are facts (evidence) or arguments to suggest a causal relationship, drug- 
event relationship should be assessed as Yes. 
 
The following criteria should be considered in order to assess the relationship as 
  Yes: 
• 
Reasonable temporal association with drug administration 
• 
Known response pattern to suspected drug 
• 
Disappears or decreases on cessation or reduction in dose 
• 
Reappears on re-challenge 
 
The following criteria should be considered in order to assess the relationship as 
No: 
• 
It does not follow a reasonable temporal sequence from administration of 
the drug 
• 
It may readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to 
the patient 
• 
It does not follow a known pattern of response to the suspected drug 


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• 
It does not reappear or worsen when the drug is re-administered. 
 
7.1.1.5 Progression of Underlying Malignancy 
 
Progression of underlying malignancy is not reported as an adverse event if it is 
clearly consistent with the suspected progression of the underlying cancer as 
defined by RECIST criteria, or other criteria as determined by protocol. 
 
Hospitalization due solely to the progression of underlying malignancy should 
NOT be reported as a serious adverse event. Clinical symptoms of progression 
may be reported as adverse events if the symptom cannot be determined as 
exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study. 
 
Symptomatic deterioration may occur in some patients. In this situation, 
progression is evident in the patient’s clinical symptoms, but is not supported by 
the tumor measurements or, the disease progression is so evident that the 
investigator may elect not to perform further disease assessments. In such cases, 
the determination of clinical progression is based on symptomatic deterioration. 
These determinations should be a rare exception as every effort should be made to 
document the objective progression of underlying malignancy. 
 
If there is any uncertainty about an adverse event being due only to the disease 
under study, it should be reported as an AE or SAE. 
 
7.1.1.6      Treatment and Follow-up AEs 
 
After the discontinuation of therapy with pembrolizumab continue to follow up 
AEs as follows: 
 
Related AEs:  Follow until one of the following occurs: 
 Resolved or improved to baseline 
 Relationship is reassessed as unrelated 
 Death 
 Start of new anti-cancer regimen 
 Investigator confirms that no further improvement can be expected 
 Clinical or safety data will no longer be collected or final database closure 
 
Unrelated severe or life threatening AEs: Follow until one of the following 
occurs: 
 Resolved or improved to baseline 
 Severity improved to grade 2 
 Death 
 Start of new anti-cancer regimen 
 Investigator confirms that no further improvement can be expected 


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 Clinical or safety data will no longer be collected or final database closure 
 
Unrelated Grade 1 or Grade 2 AEs: Follow as clinically indicated. 
The final outcome of each adverse event must be recorded on the eCRF. 
7.1.2 Laboratory Test Abnormalities 
 
7.1.2.1 
Abnormal Laboratory Tests 
 
Laboratory test results will be recorded as adverse events only if they meet 
criteria for CTCAE v 4.0 grade 1 or greater. These data will be captured on the 
adverse events eCRF. 
 
Any laboratory result abnormality fulfilling the criteria for a SAE should be 
reported as such, in addition to being recorded as an adverse event on the eCRF. 
 
7.1.2.2 
Follow-up of Abnormal Laboratory Test 
In the event of medically significant unexplained abnormal laboratory test values, 
the test should be repeated and followed until it has returned to the normal range, 
baseline value and/or an adequate explanation of the abnormality is found. If a 
clear explanation is established it should be recorded on the eCRF. 
 
7.1.3 Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any 
use of pembrolizumab that: 
 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event 
 
Progression of the disease under study is not considered an adverse event unless it 
results in hospitalization or death. 
 
Any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause other than progression of the cancer that occurs to any 
patient from the time treatment is started (Day 1) through 30 days following 
cessation of treatment, or the initiation of new anti-cancer therapy, whichever is 
earlier, whether or not related to pembrolizumab, must be reported within 24 


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hours to the SARC. SARC will notify Merck within 1 working day as outlined in 
the section 7.2.2. 
 
Non-serious Events of Clinical Interest will be handled in the same manner as 
SAEs. 
 
Additionally, any serious adverse event assessed by a site Investigator as related 
to pembrolizumab, regardless of the time elapsed, even if the study has been 
closed, should be reported to SARC and Merck (as outlined in the section 7.2.2). 
 
A copy of all reports submitted to FDA will be sent to Merck at: 
Merck Global Safety, 
Attn: Worldwide Product Safety; 
Fax: 215-993-1220 
 
7.1.4 Pembrolizumab Overdose 
For purposes of this trial, an overdose will be defined as any dose exceeding the 
prescribed dose for pembrolizumab by 20% (> 240 mg). No specific information 
is available on the treatment of overdose of pembrolizumab. In the event of 
overdose, pembrolizumab should be discontinued and the subject should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated. 
 
7.1.5 Events of Clinical Interest 
 
Events of clinical interest (ECI) are selected adverse events for this trial 
including: 
 
1. An overdose of pembrolizumab, as defined in Section 7.1.4, 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 2 x the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2 x 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. 
 
7.2 
Handling of Safety Parameters 
 
7.2.1 Reporting of Adverse Events 


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All adverse events (related and unrelated) grade 1-5 occurring during the study 
and up to 30 days after the last dose of study medication must be reported and 
recorded in the study database. Reporting the specific time of onset of a given AE 
is only necessary when it occurs in relation to study drug administration. 
 
7.2.2 Reporting of Serious Adverse Events (immediately reportable) 
 
Any clinical adverse event or abnormal laboratory test value that is serious and 
which occurs during the course of the study (as defined in section 7.1.3below), 
must be reported to SARC within 24 hours of the site investigator becoming 
aware of the event. If only limited information is initially available, follow-up 
reports are required. The original SAE form must be kept on file at the study site. 
 
SAEs must be reported on the MedWatch Form 3500A along with the completed 
Fax/Email Coversheet and faxed or emailed to SARC office (See Appendix B). 
SARC will notify Merck within 1 working day by faxing the complete report to: 
 
 
Merck Global Safety 
Attn: Worldwide Product Safety 
Fax: 215-993-1220 
 
Related Serious Adverse Events MUST be collected and reported regardless of 
the time elapsed from the last study drug administration, even if the study has 
been closed. 
 
Unrelated Serious Adverse Events must be collected and reported during the 
study and for up to 30 days after the last dose of study medication 
 
7.2.3 Reporting of Overdose to the Sponsor and to Merck 
 
If an adverse event(s) is associated with (“results from”) the overdose of 
pembrolizumab, the adverse event(s) is reported as a serious adverse event, even 
if no other seriousness criteria are met. 
 
If a dose of pembrolizumab 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 
within 24 hours to SARC. SARC will notify Merck within 1 working day as 
outlined in the section 7.2.2. 
 
7.2.4 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 


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Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of the site investigators or their designees to report any pregnancy 
or lactation in a patient (spontaneously reported to them), including the pregnancy 
of a male patient's female partner that occurs during the trial or within 120 days of 
completing the trial completing the trial, or 30 days following cessation of 
treatment if the patient initiates new anticancer therapy, whichever is earlier. All 
patients and female partners of male patients who become pregnant must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events ((Important Medical Events). If the pregnancy continues to term, 
the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to SARC. SARC will notify Merck 
within 1 working day as outlined in the section 7.2.2. 
 
7.2.5 Reporting of Serious Adverse Events 
 
Any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause other than progression of the cancer that occurs to any 
patient from the start of study treatment (Day 1) through 30 days following 
cessation of treatment, or the initiation of new anti-cancer therapy, whichever is 
earlier, whether or not related to pembrolizumab, must be reported within 24 
hours to SARC. SARC will notify Merck within 1 working day as outlined in the 
section 7.2.2. 
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety 
and will be handled in the same manner as SAEs. 
 
Additionally, any serious adverse event assessed by a site Investigator, who is a 
qualified physician as related to pembrolizumab, regardless of the time elapsed, 
even if the study has been closed, should be reported to SARC and Merck (as 
outlined in the section 7.2.2). 
 
A copy of all 15 Day Reports and Annual Progress Reports will be submitted as 
required by FDA and will be cross referenced according to local regulations to 
Merck’s  Pembrolizumab IND Number at the time of submission 
 
A copy of all reports submitted to FDA will be sent to Merck at: 
Merck Global Safety, 
Attn: Worldwide Product Safety; 
Fax: 215-993-1220 
 
All subjects with serious adverse events must be followed up for outcome. 
 


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8. PHARMACEUTICAL INFORMATION 
 
8.1 
Study Agent 
 
Pembrolizumab is a potent and highly selective humanized mAb of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 
and PD-L2. 
 
8.2 
Preparation and Administration 
 
Pembrolizumab will be given at 200 mg intravenously every 3 weeks. 
 
 
8.3 
Formulation, Packaging and Labelling 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Pharmacist will receive open label packages of the drug. Clinical 
Supplies will be provided by Merck as summarized in Table 7. 
 
Table 7. Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/4ml 
Solution for Injection 
 
8.4 
Storage and Handling Requirement 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. Receipt and dispensing of trial medication must be 
recorded by an authorized person at the trial site. Clinical supplies may not be used 
for any purpose other than that stated in the protocol. 
 
8.5 
Agent Ordering 
 
Pembrolizumab will be provided by Merck. Details will be provided in the 
Operations Manual. 
 
8.6 
Agent Accountability 
 
Accountability and patient compliance will be assessed by maintaining adequate drug 
dispensing and return records. Compliance with individual patient dosing is assured as 
the drug is administered intravenously and recorded at the clinical site. 
Accurate records must be kept for each study drug provided by Merck. The drug 
dispensing log must be kept current and contain the following information: 
- 
documentation of drug shipments received from Merck (date received and quantity) 
- 
disposition of unused study drug not dispensed to patient 
- 
the identification of the patient to whom the study medication was dispensed 
- 
the date(s) and quantity of the study medication dispensed to the patient 


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This inventory must be available for monitoring. All supplies, including unused, 
partially used or empty containers will be destroyed according to sites drug destruction 
policy. Copies of the dispensing & inventory logs will be sent to SARC for remote 
monitoring. 
 
8.7 
Destruction of Pembrolizumab 
Local or institutional regulations may require immediate destruction of used 
pembrolizumab for safety reasons e.g., cytotoxicity. In these cases, it may be 
acceptable for investigational site staff to destroy dispensed pembrolizumab before 
monitoring is done provided that source document verification is performed on the 
remaining inventory and reconciled against the documentation of quantity shipped, 
dispensed, returned and destroyed. 
 
Written documentation of destruction must contain the following: 
- 
Identity (batch numbers or patient numbers) of pembrolizumab destroyed 
- 
Quantity of pembrolizumab destroyed 
- 
Date of destruction (date discarded in designated hazardous container for 
destruction) 
- 
Method of destruction (the site must provide the sponsor with documentation of 
their institutional policy and procedures for handling and disposing of hazardous 
drugs) 
- 
Name and signature of responsible person (or company) who destroyed 
pembrolizumab. 
 
A list of the adverse events and potential risks associated with pembrolizumab can be 
found in Section 7.1. 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
All biospecimens collected from patients enrolled in SARC028 study will be kept at a 
SARC designated specimen bank 
 
9.1.1 
Collection, Handling and Shipping of Specimens 
 
Details for collection, handling and shipment of specimens will be provided in the 
Operations Manual. 
 
9.1.2 
Correlative Studies 
 
The following correlative studies will be performed using blood for research studies 
and tumor tissues collected from the patients included in the study. In the expansion 
cohort, correlative tumor samples will be collected from 20 patients in each of the 
expansion cohorts of UPS and LPS. Ten (10) patients in each expansion cohort 


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whose disease is not amenable to biopsy can be enrolled and for these patients, tissue 
correlative samples will not be collected. 
 
All subjects enrolled will have correlative blood samples collected. 
• 
Evidence of immune up-regulation at tumor sites: 
o 
Increased tumor-infiltrating CD8+ T cells using immunohistochemistry 
(IHC). 
o 
Evaluation of PD-1and PD-L1 expression by T cells and malignant cells, 
respectively, using IHC. 
Sections of formalin-fixed, paraffin-embedded tumor samples will be obtained 
from tumor biopsies of the patients as previously indicated. Standard 
immunohistochemistry (IHC) will be performed using antibodies against human 
B7-H1/PD-L1, human PD-1, CD3, CD8, CD4 and may include additional 
markers:  CCR7, CD45RO, CD68 and CSPG4. Slides will be evaluated and 
scored independently by two experienced pathologists. PD-L1 expression will be 
expressed as % of positive cells among malignant cells. PD-1 expression will be 
expressed as % of PD-1 positive cells relative to the total number of CD3 cells. 
We expect to observe a significant increase of CD8+ TILs after treatment with 
pembrolizumab as compared to pre-treatment. We also expect that PD-L1 
expression by malignant cells will increase after treatment with pembrolizumab as 
compared to pre-treatment. 
• 
Inhibition of malignant cell proliferation, increased pro-apoptotic activity, up- 
regulation of HLA antigen and MA expression, and inhibition of STAT signaling 
pathways associated with sarcoma cell proliferation and survival: 
o 
The expression of β2m-associated HLA-A and HLA-B/C loci gene 
products and of HLA class II antigens will be assessed by immunostaining of 
frozen tissue sections. The HLA-A-specific mAb LGIII-147.4.1[46], the HLA- 
B/C-specific mAb B1.23.2 [47] and the HLA class II antigen-specific mAb LGII- 
612.14 [48] will be used as molecular probes. 
o 
The expression of APM components LMP2, LMP7, LMP10, TAP1, 
TAP2, calnexin, calreticulin, ERP57 and tapasin will be assessed by staining 
formalin fixed, paraffin embedded tissue sections with the mAb SY-1, HB2, TO- 
7, NOB1, NOB2, TO-5, TO-11, TO-2 and TO-3 [49, 50]. 
o 
To investigate the effect of therapy on sarcoma cell proliferation and 
apoptosis, sections of formalin fixed, paraffin embedded sarcoma metastases will 
be analyzed for p-Histone H3 and Cleaved Caspase-3 expression by IHC staining. 
The results will be expressed as the positive cell numbers from 10 randomly 
selected high-power (magnification ×200) fields per section by quantitative 
analysis. 
o 
Other immunological endpoints will include studies of STAT 1/3/5a/5b 
and IFNAR, MHC class I and pERK expression. 
• 
Reversal of PD1+ TA-specific CD8+ and CD4+ T cell dysfunction and rescue of 
memory TA-specific CD8+ and CD4+ T cells from terminal exhaustion: 
Tumor biopsy samples will be processed to obtain single cell suspensions to 
isolate TILs and tumor cells. Multiparameter flow cytometry will be used to 


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investigate the phenotype and functions of TILs and the expression of PD-L1 by 
sarcoma cells and tumor-infiltrating cells ex vivo. CD3+ T cells will be isolated 
with magnetic beads (Miltenyi, Biotec) and CD3+ and non-CD3+ cells will be 
used for flow cytometry studies. We expect that therapy with pembrolizumab 
will result in increased number and function of CD8+ and CD4+ TILs at tumor 
sites. 
 
Evaluation of NY-ESO-1-specific CD8+ and CD4+ T cells in patients with NY- 
ESO-1 expressing sarcoma at periphery (leukapheresis) and at tumor sites using 
flow cytometry including tetramer and intracellular cytokine staining. CD8+ 
and CD4+ T cell responses against NY-ESO-1 and other sarcoma antigens will 
be evaluated from PBLs of the sarcoma patients using peptide libraries and flow 
cytometry assay. 
 
9.1.3 
Biopsy 
 
Pre- and post-treatment biopsies will be required for 20 patients in each of the 
expansion cohorts of UPS and LPS. Mandatory biopsies will be obtained during 
screening prior to first study drug administration (week 0), and at week 8 (± 1 week). 
Additional optional biopsies of easily accessible tumors may also be performed at 
cycle 12 (week 34) and at time of progression. Surgical excisional or core biopsies 
are acceptable. Ten patients whose disease is not amenable to biopsy can be enrolled 
in each of the expansion cohorts of UPS and LPS and no biopsy will be required. 
 
Archival tissue will be mandatory for PD-L1 testing on all patients. 
 
Schedule for Tumor Biopsy Samples Collection 
Time points for Tumor biopsy samples 
collection 
20 Patient 
Cohorts (UPS 
and LPS) 
10 Patient Cohorts (UPS 
and LPS) without 
disease amenable to 
Archival Tumor 
Samples 
After eligibility is 
confirmed 
Mandatory 
Mandatory 
Mandatory , pre- 
treatment 
After eligibility is 
confirmed, prior to first 
study drug administration 
Mandatory 
Mandatory, on- 
treatment 
At week 8 (+/- 1week) 
Mandatory 
Optional, cycle 
12 
At week 34 (+/- 1week) 
Optional 
Optional, end of 
study treatment 
At disease progression 
Optional 
 
Biopsies will be processed for IHC: 
 
1. Evaluation of PD-L1 expression 


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2. Evaluation of CD8+ and CD4+ T cell infiltrates. 
 
Biopsies will be processed for single cell suspensions for intracellular cytokine 
assays: 
1. Expression of inhibitory receptors including Tim-3 and BTLA by CD8+ 
and CD4+ TILs. 
 
2. Expression of a number of inhibitory ligands including PD-L1, HVEM, 
and galectin-9 by tumor cells and tumor-infiltrating antigen presenting 
cells. 
 
10. STUDY EVALUATIONS AND STUDY CALENDAR 
 
10.1 
SCREENING STUDIES 
 
The following procedures will be performed during the screening period: 
• Informed consent 
• History/demographics updated within 2 weeks prior to patient enrollment 
• Documentation of sarcoma histology and grade, and prior sarcoma therapies 
• Physical exam, including height, weight, vital signs, ECOG performance 
status 
• CBC with differential 
• Comprehensive Serum Chemistry Panel 
• T3, FT4, and TSH 
• PT (or INR) and aPTT 
• Urinalysis 
• Serum β–HCG or urine pregnancy test for women of childbearing potential 
• Archival Formalin Fixed Paraffin Embedded (FFPE) Tumor Samples (on 
patients enrolled in the expansion cohorts) 
• Blood for research studies will be collected (pre-treatment) after eligibility for 
study is confirmed 
• Tumor Biopsy (pre-treatment) after eligibility for study is confirmed. 
• Baseline radiologic imaging that is appropriate for the specific histologic 
subtype per National Comprehensive Cancer Network guidelines for sarcoma 
(see http://www.nccn.org/professionals/physican_glas/PDF/sarcoma.pdf and 
http://www.nccn.org/professionals/physician_gls/PDF/bone.pdf) 
• EKG within 30 days prior to first study drug administration. 
 
The screening period will be up to 30 days prior to first study drug administration 
(Day1 Cycle1). Laboratory baseline evaluations are to be conducted within 14 days 
prior to first administration of study drug. Radiologic imaging must be done 30 days 
prior to first study drug administration 
 
10.2 
ON STUDY EVALUATIONS 


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Patients who have previously met laboratory inclusion criteria at screening may 
potentially receive Cycle 1 dose of medication even if laboratory studies drawn on 
Cycle 1 day one do not meet the eligibility criteria. Study drug may be given as long 
as labs do not meet threshold for dose delay/schedule modification. Cycle visits will 
occur at each treatment visit (i.e. every 3 weeks) from study initiation. The following 
procedures will be performed during the treatment period: 
• Physical exam, including weight, vital signs, ECOG performance status 
• Administration of study drug 
• Recording of adverse events 
• Relevant laboratory evaluations, WBC, Hgb, Plt, ANC, Cr, K, Ca, ALT, AST, 
Total Bilirubin, alkaline phosphatase, PT (or INR), PTT, TSH, Free T4, T3 
• Blood for research studies will be collected at week 8 (± 1 week) and then 
every 12 weeks (± 1 week) subsequently until patient completes 12 cycles 
• Disease assessments will be performed at week 8 (± 1 week) and then every 
12 weeks (± 1 week) subsequently 
• Biopsy at week 8 (± 1 week) and optional biopsy may be collected at cycle 12. 
 
NOTE: All studies can be obtained ± 3 days of stated time point unless otherwise 
noted. 
 
10.3 
OFF TREATMENT EVALUATIONS 
 
Final visit is to be performed at the time (or within 30 days +/- 14 days of removal 
from the treatment).  Off treatment evaluations will include: 
• Physical exam: height, weight vital signs, ECOG performance status 
• Serum β–HCG or urine pregnancy test for women of childbearing potential 
• Relevant laboratory evaluations, including CBC with differential and 
comprehensive serum chemistry panel 
• Urinalysis 
• PT (or INR) and PTT 
• EKG 
• Recording of adverse events (for unresolved adverse events, patients should 
be monitored for 30 days following the last dose of study drug) 
• Extent of disease evaluation with appropriate radiographic procedures if not 
performed within 30 days of the final visit 
• Off treatment Biopsy collected due to progression (optional). 
 
Follow-Up: 
Patients who complete study treatment should be followed for survival every 6 
months. Patient will be contacted by phone at a minimum and survival status will be 
collected and documented. Survival status can also be assessed via patient’s medical 
records or via certified letter. 


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STUDY CALENDAR 
 
Pre- 
Study 
Wk 
1 
Wk 
4 
Wk 
7 
Wk 
10 
Wk 
13 
Wk 
16 
Wk 
19 
Wk 
22 
Wk 
25 
Wk 
28 
Wk 
31 
WkK 
34+ 
Off 
Treatmentl 
Study Drug Admin a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
History/Demographics 
X 
Physical exam b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with Differential c 
X f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum 
Chemistry Paneld 
X f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, FT4, T3 
X f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT (or INR) and PTT 
X f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X f 
X 
Serum or urine pregnancy test e 
X f 
X 
EKG 
X g 
X 
Archival Tumor Samples 
(FFPE) (only patients from 
expansion) 
X 
Adverse event evaluation 
X -------------------------------------------------------------------------------------------- X 
X 
Biopsies 
X 
XJ  --------------------------------------------------------------------------------------------X  J 
XJ 
Radiologic evaluation 
X h 
First radiologic measurements will be performed at 8 weeks (± 1 week) initially, then 
every 12 weeks subsequently. 
X i 
Blood Sample Collection 
X m 
Blood samples will be collected at 8 weeks (± 1 week), week 20 (± 1 week), week 32 
(± 1 week). Collection will end after patient completes cycle 12 
Follow up 
X n 
a: Pembrolizumab 
b: Including height, weight ,vital signs, ECOG performance status 
c: WBC, Hgb, Plt, ANC, PT (or INR), PTT 
d:Cr, K, Ca, ALT, AST, Alkaline phosphatase, Total bilirubin 
e: Women of childbearing potential 
f: Laboratory baseline evaluations are to be conducted within 14 days prior to first study drug dose 
g:EKG within 30 days prior to first study drug administration 
h: Scans and x-rays must be performed within 30 days prior to first study drug dose 
i: Extent of disease evaluation with appropriate radiographic procedures if not performed within 30 days of the final visit. 
j: Mandatory biopsies will be collected pre and post treatment at week 0 and 8 and optional biopsies may be collected at cycle 12 (week 34) 
and at time of progression for 20 patients enrolled in the expansion cohorts of UPS and LPS. 
k: Patients may continue on study drug beyond 12 cycles at discretion of study doctor. Use monthly visits as a template for every monthly 
evaluations as long as patient remains on study drug. 
l: Off-study evaluation should be performed at the time (or within 30 days) of removal from study. 
m: Blood samples will be collected pre-treatment (after eligibility is confirmed) 
n: Patient will be followed for survival every 6 months via phone call at a minimum. Survival status will be documented after each call. 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be evaluated for response initially after 
first 8 weeks on study and then every 12 weeks. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. 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. 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with pembrolizumab. 
 
Evaluable for objective response. 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. These 
patients will have their response classified according to the definitions stated 
below. (Note: Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
11.1.2 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) as 
> 20 mm by chest x-ray or as > 10 mm with CT scan, MRI, or calipers by clinical 
exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area are not 
considered measurable unless there is evidence of progression after radiation 
therapy. 
 
Malignant lymph nodes. 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. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 


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mm 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. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non- 
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
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. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. 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. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
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. 
 
11.1.3 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. 


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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. 
 
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. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
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 


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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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions. 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) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): 
Unequivocal progression (see comments 
below of existing non-target lesions. (Note: 
the appearance of one or more new lesions is 
also considered progression). 
 
Note: When the patient also has measurable 
disease. In this setting, to achieve 
‘unequivocal progression’ on the basis of 
the non-target disease, there must be an 
overall level of substantial worsening in 
non-target disease such that, even in 
presence of SD or PR in target disease, the 
overall tumor burden has increased 
sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of 
one or more non-target lesions is usually not 
sufficient to quality for unequivocal 
progression status. The designation of 
overall progression solely on the basis of 
change in non-target disease in the face of 


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SD or PR of target disease will therefore be 
extremely rare. 
 
11.1.4.3 
Evaluation of Tumor Response 
 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ 
Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, 
PD = Progressive Disease, and NE = inevaluable 
* In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
11.1.4.4 
Best Overall Response when confirmation of CR and PR 
required 
 
The best overall response is the best response recorded from the start of the 
study treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient's best overall response assignment will depend on the 
achievement of both measurement and confirmation criteria. 


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Overall 
response 
First time point 
Overall 
Response 
Subsequent 
time point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, 
PD = Progressive Disease, and NE = Inevaluable 
a If a CR is truly met at first time point, then any disease seen at a 
subsequent time point, even disease meeting PR criteria relative to baseline, 
makes the disease PD at that point (since disease must have reappeared 
after CR). Best response would depend on whether minimum duration for 
SD was met. However, sometimes ‘CR’ may be claimed when subsequent 
scans suggest small lesions were likely still present and in fact the patient 
had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
 
11.1.5 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 


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The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the baseline 
measurements. 
 
11.1.6 Progression-Free Survival 
 
Progression-Free Survival is defined as the duration of time from start of 
treatment to time of progression or death, whichever occurs first. 
 
11.1.7 Response Review 
 
All responses will be investigator assessed. Responses may also be reviewed by 
an expert(s) independent of the study at the study’s completion. 
 
11.1.8 Definition of Tumor Response Using irRC 
 
The sum of the products of diameters (SPD) at tumor assessment using the 
immune-related response criteria (irRC) for progressive disease 
incorporates the contribution of new measurable lesions. Each net 
percentage change in tumor burden per assessment using irRC criteria 
accounts for the size and growth kinetics of both old and new lesions as 
they appear. 
 
11.1.8.1. 
Definition of Index Lesions Response Using irRC 
 
• 
irComplete Response (irCR): Complete disappearance of all index 
lesions. This category encompasses exactly the same patients as 
“CR” by the modified WHO (mWHO) criteria. 
 
• 
irPartial Response (irPR): Decrease, relative to baseline, of 50% or 
greater in the sum of the products of the two largest perpendicular 
diameters of all index and all new measurable lesions (i.e., 
Percentage Change in Tumor Burden). Note: the appearance of 
new measurable lesions is factored into the overall tumor burden, 
but does not automatically qualify as progressive disease until the 
SPD increases by ≥25% when compared to SPD at nadir. 


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• 
irStable Disease (irSD): Does not meet criteria for irCR or irPR, in 
the absence of progressive disease. 
 
• 
irProgressive Disease (irPD): At least 25% increase Percentage 
Change in Tumor Burden (i.e., taking sum of the products of all 
index lesions and any new lesions) when compared to SPD at 
nadir. 
 
11.1.8.2 
Definition of Non-Index Lesions Response Using irRC 
 
• 
irComplete Response (irCR): Complete disappearance of all non- 
index lesions. This category encompasses exactly the same patients 
as “CR” by the mWHO criteria. 
 
• 
irPartial Response (irPR) or irStable Disease (irSD): non-index 
lesion(s) are not considered in the definition of PR, these terms do 
not apply. 
 
• 
irProgressive Disease (irPD): Increases in number or size of non- 
index lesion(s) does not constitute progressive disease unless/until 
the Percentage Change in Tumor Burden increases by 25% (i.e., 
the SPD at nadir of the index lesions increases by the required 
amount). 
 
11.1.8.3 
Impact of New Lesions on irRC 
 
New lesions in and by themselves do not qualify as progressive 
disease. However, the contribution of new measurable lesions to 
total tumor burden is included in the SPD which in turn feeds into 
the irRC criteria for tumor response. Therefore, new non- 
measurable lesions will not discontinue any patient from the study. 
 
11.1.8.4 
Definition of Overall Response Using irRC 
 
Overall response using irRC will be based on these criteria: 
 
• 
Immune-Related Complete Response (irCR): Complete 
disappearance of all tumor lesions (index and nonindex together 
with no new measurable/unmeasurable lesions) for at least 4 weeks 
from the date of documentation of complete response. 
 
• 
Immune-Related Partial Response (irPR): The sum of the 
products of the two largest perpendicular diameters of all index 
lesions is measured and captured as the SPD baseline. At each 


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subsequent tumor assessment, the sum of the products of the two 
largest perpendicular diameters of all index lesions and of new 
measurable lesions are added together to provide the Immune 
Response Sum of Product Diameters (irSPD). A decrease, relative 
to baseline of the irSPD compared to the previous SPD baseline, of 
50% or greater is considered an immune Partial Response (irPR). 
 
• 
Immune-Related Stable Disease (irSD): irSD is defined as the 
failure to meet criteria for immune complete response or immune 
partial response, in the absence of progressive disease. 
 
• 
Immune-Related Progressive Disease (irPD): It is recommended 
in difficult cases to confirm PD by serial imaging. Any of the 
following will constitute progressive disease: 
 
• At least 25% increase in the sum of the products of all 
index lesions over baseline SPD calculated for the index 
lesions. 
 
• At least a 25% increase in the sum of the products of all 
index lesions and new measurable lesions (irSPD) over the 
baseline SPD calculated for the index lesions. 
 
Table 8: Immune-Related Response Criteria Definitions 
Index 
Lesion 
Definition 
Non-Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New  
Unmeasurable 
Lesions 
Percent change 
in tumor burden 
(including 
measurable new 
lesions when 
present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
≥ -50% 
irPR 
Stable 
Disease 
Any 
Any 
Any 
<-50% to <+25% 
irSD 
Progressive 
Disease 
Any 
Any 
Any 
≥ +25% 
irPD 
 
 
12. DATA REPORTING / REGULATORY CONSIDERATIONS 
 
12.1 
Data Reporting 
 


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12.1.1 
Method 
 
A final study report describing the outcome of the trial will be created at 
the end of the study. 
 
12.1.2 Data Safety and Monitoring 
 
SARC is responsible for the Data Safety Monitoring for this trial. SARC Clinical Trials 
Review Committee convenes monthly and will provide safety oversight for this trial. The 
purpose of the Clinical Trials Review Committee is to review the status of the on-going 
SARC studies, which includes, but is not limited to: 
o 
Review of all safety data (Serious Adverse Events reported). 
o 
Review of protocol deviations/violations. 
o 
Review of study progress/accrual. 
o 
Discussion of statistical aspects of all protocols. 
 
The committee is chaired by the SARC Medical Officer, who is responsible for leading 
the meeting and providing medical oversight. Attendance includes all overall study 
Principal Investigators on active SARC studies, SARC Research Project Managers, 
SARC President, and a biostatistician. 
 
Safety oversight for this trial is also supported by the SARC Clinical Research Committee 
which is made up of senior sarcoma investigators and the SARC President. This 
committee also convenes monthly. The Medical Officer updates the committee on the 
ongoing clinical trial status as well as any areas of concern particularly related to safety. 
This committee provides an additional level of medical oversight for this trial. 
 
12.1.3 Patient Accrual and Participating Centers 
 
There will be approximately 10 sites collaborating to accrue patients to this study. It 
is anticipated that accrual will take approximately 2 years. 
 
This trial will be posted at ClinicalTrials.gov website. 
 
12.2 Multi-institutional Guidelines 
 
The trial coordinating center (Operations Center) will be SARC. Patients will be 
registered electronically via the study website, and adverse events (as defined in 
Section 
7) will be reported to the SARC. 
 
IRB Approvals: 
The protocol must be approved at each participating site prior to enrolling patients. 
Documentation of individual institutional IRB approval, for the current protocol must be 
provided to SARC prior to enrolling patients in the trial. In addition, documentation 


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of approval of all protocol amendments and of yearly continuing review must be 
provided to the SARC Research Project Manager to allow patient entry. The 
mailing address is: 
 
SARC 
24 Frank Lloyd Wright Drive, PO Box 
406 Ann Arbor, MI 48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email: sarc@sarctrials.org 
 
Patient Registration: 
Patient Registration will be centrally managed by SARC electronically via the 
study website (see Section 4.2). 
 
Data Collection and Toxicity Reporting: 
Registration reports will be generated by SARC RPM to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies by the Research Project Manager. Any potential 
problems will be brought to the attention of the site Principal Investigator for discussion 
and action. 
 
Access to the password protected study website will be limited to individuals involved in 
the clinical trial: SARC, overall Study PI, participating site PIs, research nurses, and data 
managers responsible for this trial. 
 
A phone conference will be held between the Study Principal Investigator, the 
Operations Center, site investigators, and participating sites staff biweekly to address 
issues, accrual, observed toxicities, and compliance with submission of required 
studies. 
 
Adverse Events reporting will be performed as outlined in Section 7. 
 
12.3 Data and Participating Site Monitoring 
 
Data from participating sites should be available when the protocol is monitored. The site 
Principal Investigator is responsible for having all records and data for all patients 
enrolled at his/her site available at that site for monitoring. Queries as appropriate will be 
submitted to sites to clarify data. Submission of biologic specimens will be tracked on the 
study website. 
 
12.4 Handling of Patient Data 
 
All patient data will be captured and maintained in a study specific database with 
password protected access. Data is entered using an assigned patient identification 


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number. 
 
The data provided to those reviewing the results, for example the study statistician will 
include the patient identification numbers, but will not include patient identifiable data. 
 
The research samples obtained in this study will only be sent using the patient 
identification number which can only be linked to the patient at a given institution by the 
treating physician. 
 
All documentation that contains personal health information that may include patient 
identifiable information will be maintained at the site to preserve patient confidentiality. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
A patient will be classified as a treatment success if he/she achieves a response of PR or 
better. On each arm of the study, we will test the hypothesis that pembrolizumab has 
clinical activity in patients with advanced sarcoma. An objective response rate of 25% 
will be considered clinically meaningful and a response rate less than 10% will be 
considered lack of efficacy. In a single stage design, we will accrue 40 patients in each 
arm. The treatment will be considered a success if 8 or more of 40 enrolled patients 
have a PR or better by RECIST 1.1. This design has a one-sided type I error of 4.2% 
and a power of 82% to detect a difference between 10 and 25%. 
 
In the study expansion, the response rates for undifferentiated pleomorphic sarcoma 
cohort and the poorly differentiated/dedifferentiated liposarcoma cohort will be analyzed 
separately. In each subtype cohort, we will analyze a total of 40 evaluable patients (10 
from part 1 of the study and 30 from the expansion cohort). An objective response rate of 
25% will be considered clinically meaningful and a response rate less than 10% will be 
considered lack of efficacy. The treatment will be considered a success if 8 or more of 40 
enrolled patients have a PR or better by RECIST 1.1. This design has a one-sided type I 
error of 4.2% and a power of 82% to detect a difference between 10 and 25%. 
 
13.2 
Sample Size/Accrual Rate 
 
Initial enrollment was 86 patients: with soft tissue sarcomas and with bone sarcomas 
 
In the expansion study, there will be an additional 60 patients with soft tissue sarcoma 
enrolled: 30 patients with undifferentiated pleomorphic sarcoma and 30 patients with 
poorly differentiated/dedifferentiated liposarcoma. 
 
At least 20 patients in each of the undifferentiated pleomorphic sarcoma and poorly 
differentiated/dedifferentiated cohorts will have mandated biopsies for correlative 
analysis. The remaining 10 patients in each of the cohorts will not be required to obtain 


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baseline and 8-week tumor biopsies, although archival tissue will be required for PD-L1 
testing. 
 
13.3 
Analysis of Secondary Endpoints 
 
This design will also allow 87% power to detect an improvement in the 3-months PFS 
rate from 20% to 40% with a one-sided type I error of 4%. 
 
Progression-free survival will be estimated by the product-limit method. PDL1 
expression levels and baseline circulating T cell counts will be related to response via 
logistic regression, and to PFS via Cox regression. Changes in T cell counts will be 
related to outcome using appropriate landmarks. Several secondary objectives are clinical 
and include PFS, OS, ir-RC, and safety all of which will be analyzed taking into account 
the primary endpoint. All other correlative secondary objectives are exploratory as those 
data have not been previously reported in sarcoma and therefore will serve as hypothesis 
generating. 
 
Mandatory pre/post biopsies will be performed for at least 20 patients enrolled in each of 
the expansion subtype cohorts. Because clear biomarkers for response to pembrolizumab 
remain to be determined and may not be histology specific, all samples will be evaluated 
as a single cohort for correlative assessments. PD1 expression on fresh biopsy tissue at 
both time points will be assessed. Cases will dichotomized into low/high expressers at 
baseline, and low/high expression changers from pre to post-treatment. Assuming an 
objective response rate of 10% in tumors with low expression at baseline, this will allow 
90% power to detect a difference in objective response of 10% vs 40% using a two-sided 
5% level test of proportions. Assuming up to 20% dropout between pre and post biopsies, 
if 64 patients have both pre and post biopsies, there will be 80% power to detect a 
difference in objective response of 10% vs 40% between low and high changers, using a 
two-sided 5% level test of proportions. 
 
Any analyses by individual histologic subtypes will be exploratory only. 
 
13.4 
Reporting and Exclusions 
 
13.4.1 Evaluation of toxicity: Safety evaluations will be done according to CTCAE 
v 4.0 with special emphasis on immune-related adverse events (ir-AEs). 
 
13.4.2 Evaluation of response: Tumor measurements by CT/MRI imaging will be 
performed initially at 8 weeks and then every 12 weeks. (RECIST 1.1) will be 
the primary outcome measure and immune-related Response Criteria (ir-RC) 
will be a secondary outcome.


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