A Phase II Trial of Pembrolizumab Sequentially Following Single Fraction Non-ablative Radiation to One of the Target Lesions, in Previously Treated Patients With Stage IV NSCLC
Phase: PHASE2
Conditions: Stage IV Non-Small Cell Lung Cancer
Sponsor: Case Comprehensive Cancer Center



 
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ROSWELL PARK PRINCIPAL INVESTIGATOR: 
Chen Hongbin, MD 
Roswell Park Cancer Institute 
 
 
  
 
 
 
ALLEGHANY PRINCIPLE INVESTIGATOR: 
Gene Finley, MD 
West Penn Alleghany Oncology Network 
 
 
 
 
 
  
 
RUSH UNIVERSITY PRINCIPAL INVESTIGATOR: 
Gaurav Marwaha, MD 
Rush University Cancer Center  
Radiation Oncology 
 
 
 
 
 
 
 
 
NYU LANGONE PRINCIPAL INVESTIGATOR: 
Vamsidhar Velcheti, MD 
NYU Langone- Laura and Isaac Perlmutter Cancer Center 
 
 
 
  
 
 
 
 
STATISTICIAN:  
 
Brian Hobbs, PhD 
 
 
 
 
Cleveland Clinic Taussig Cancer Institute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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STUDY COORDINATOR: 
Sarah Devonshire 
 
 
 
 
Case Comprehensive Cancer Center 
 
 
 
 
Cleveland Clinic Taussig Cancer Institute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
STUDY NURSE:  
 
Jessica Pasko 
 
 
 
 
Case Comprehensive Cancer Center 
 
 
 
 
Cleveland Clinic Taussig Cancer Institute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
SPONSOR:  
 
 
Cleveland Clinic/Case Comprehensive Cancer Center  
 
 
 
SUPPORT/FUNDING: 
 
Merck 
 
SUPPLIED AGENT: 
 
Pembrolizumab 
 
IND #:  
 
 
 
N/A 
 
 
OTHER AGENT:  
 
Single Fraction Radiation Therapy (SFRT) (8Gy x 1) 
 

 
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SUMMARY OF CHANGES 
 
Protocol Date 
Section/P
age 
Change 
Rationale for Change 
12/13/2016 
 
Initial IRB approval 
 
03/14/2017 
 
Merged all events that were labeled on study 
calendar as Prescreen Visit one to Visit2.  All 
events will be done in one Visit.  Added 
footnotes regarding screening labs and radiology 
consult.  Local labs added to Visit 2 Screening. 
Both study calendars were updated and replaced 
page 4 and page 42. Section Number changed 
from  7.1.5.3.1 > 3.1.5.3.1. 
 
08/01/2017 
P.5 
Delete Correlative Studies  
Duplicate entry 
08/01/2017 
P.13 on 
Correct Section Header Numbering throughout 
document 
Not sequential  
08/01/2017 
P.26 
Added radiation to multiple lesions 
Clarification 
08/01/2017 
P.26 
Added exception to entry criteria 
Clarification 
08/01/2017 
P.28 
Exclusion Criterion 7,10 
clarification 
08/01/2017 
P.31 
Table 2 changed for consistency 
clarification 
08/01/2017 
P.33 
Removed 4D CT simulation 
Not relevant 
08/01/2017 
P.33 
Nonpreviously erradiated fields 
Clarification 
08/01/2017 
P.34 
SFRT 33 days to be consistent 
Clarification 
08/01/2017 
P.35 
Deleted Radiation Therapy Information 
Not relevant 
08/01/2017 
P.48 
Correletives Information added 
Clarification 
08/01/2017 
P.47 
StudyID vs. Registration Number  
Clarification 
08/01/2017 
P.70 
Deleted Reference 
Erroneous 
08/25/2017 
P5, 43 
Add blood draws 
Missed in AM2 
04/10/2018 
 
Eligibility criteria changed to reflect new 
changes in clinical practice based on updated key 
trial results. Removed the language referring to 
one prior line of therapy.  
Changed eligibility 
to 
meet 
current 
standard practice 
4/10/2018 
 
CTCAE updated to V.5 
Updated 
4/10/2018 
 
Minor administrative changes throughout 
Clarification 
4/10/2018 
 
Clarification provided as to the number of 
lesions that can be treated with SFRT 
Clarification  
8/7/2018 
 
Updated PI throughout document 
PI change 
8/7/2018 
P30 
Updated Table 1 to remove PK 
Erroneous 
1/28/2019 
 
Minor administrative changes throughout 
Clarification 
1/28/2019 
 
CTCAE change back to V.4 throughout 
Clarification 
1/28/2019 
P.3 
Personnel changes 
Updated 

 
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Protocol Date 
Section/P
age 
Change 
Rationale for Change 
1/28/2019 
P.6 
Protocol Summary treatment section clarified 
Clarification 
1/28/2019 
P.25 
Added disease monitoring window to 9 weeks 
+/- 14 days 
Updated 
1/28/2019 
 
Deleted 
Table 
1 
Laboratory 
Tests 
and 
renumbering of all subsequent tables  
Duplicate 
entry, 
Updated 
1/28/2019 
P.32, 33 
Exlusion criteria changed to reflect a recovered 
AE ≤ Grade 2 and add autoimmune disease as a 
separate exclusion criteria 
Updated 
1/28/2019 
P.37 
Clarification in following all treatment related 
AEs to resolution or new anti-neoplastic therapy  
Clarification  
1/28/2019 
P.37 
Added survival follow up window to +/- 14days 
Updated 
1/28/2019 
P.38, 39 
Table added SOC column and footnotes for 
clarification 
Updated 
1/28/2019 
P.43 
Prohibited Concomitant Medication section 
modified to allow an exception of steroid 
treatment at the discretion of the investigator 
Updated 
1/28/2019 
P.50 
6.9 revision to End of Treatment and Follow Up 
visit procedures 
Clarification 
1/28/2019 
P.50 
Deleted section 6.9.1 ‘Discontinuation of Study 
Therapy after Complete Response’ 
Erroneous 
1/28/2019 
P.53 
Changed 
SAE 
reporting 
to 
Cancersaeinbox@ccf.org and updated Merk 
reporting fax number 
Updated 
06/06/2019 
 
Minor administrative changes throughout 
Clarification 
06/06/2019 
P.1, 2, 3 
Change protocol number to version date. Update 
Personnel to reflect multisite format and add 
NYU Langone as a site and Jessica Pasko as 
research nurse to the protocol 
Updated 
06/06/2019 
P. 20 
Remove 
inconsistent 
inclusion/exclusion 
verbiage 
Clarification 
06/06/2019 
P. 26 
Figure 2 - Study Overview Flow Diagram 
Updated 
06/06/2019 
P. 28 
Treatment 
tumor 
tissue 
collection 
allows 
exception at the sponsor investigator’s discretion 
Updated 
06/06/2019 
P. 31 
Allowed safety follow up visit to be earlier than 
30 (+/- 7) days in the event of starting a new 
anti-cancer therapy 
Updated 
06/06/2019 
P. 32, 33 
Baseline archival tissue of any age now 
accepted; 
measurable 
lesion 
and 
tissue 
clarification 
Updated 
06/06/2019 
P. 36 
Pembrolizumab treatment windows clarified 
Clarification 
06/06/2019 
P. 39 
Table 3 study schema, C1 local laboratory 
procedures deleted 
Duplicate 
entry, 
Clarification 

 
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Protocol Date 
Section/P
age 
Change 
Rationale for Change 
06/06/2019 
P. 40 
Table 3 study schema: peripheral blood, serum, 
PBMC/IRC blood collection deleted at safety 
follow up, C8 treatment, and moved to C8/EOT. 
All correlative labs removed at C1. PBMC 
collection moved to screening. Duplicate tissue 
column deleted.  
Updated, 
Erroneous 
06/06/2019 
P. 40 
6.4 study schema bullet points updated: ‘a’ to 
reflect pembrolizumab clarification; ‘c’ removal 
of CT pelvis scan unless clinically indicated; ‘d’ 
baseline tissue and additional tissue updates; ‘i’ 
pregnancy test timeline added to schema 
 
Updated, 
Clarification 
06/06/2019 
P. 42 
Table 4 changed to reflect accurate CTCAE v4.0 
verbiage: ‘Infusion related reaction’ and ‘renal 
and urinary disorders- Other, specify’ 
Updated 

 
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PROTOCOL SUMMARY 
 
Abbreviated Title 
A Phase II Trial of Pembrolizumab Sequentially Following 
Focal Radiation to One or More of the Target Lesions in 
Previously Treated Patients with Stage IV NSCLC 
Trial Phase 
Phase II 
Clinical Indication 
1. Patients with metastatic NSCLC, with at least 2 
measurable lesions 
Objectives 
Primary Objective: To determine the tumor responses 
outside the radiation field (abscopal effect) after radiation 
followed by pembrolizumab in metastatic NSCLC. 
Secondary Objectives: 
1. To determine the progression-free and overall 
survival 
in 
patients 
with 
NSCLC 
receiving 
pembrolizumab, 
who 
receive 
Single 
Fraction 
Radiation Therapy (SFRT) 
2. To determine the safety and toxicity of the 
combination of SFRT and pembrolizumab 
3. To examine potential predictive biomarkers in tumor 
samples and peripheral blood in patients treated with 
pembrolizumab and SFRT 
4. To determine the local control of SFRT in the 
radiated lesion(s), when SFRT is given with 
pembrolizumab 
5. To evaluate the induction of a T-cell response in 
patients with metastatic NSCLC treated with 
radiation and the effect of radiation 
 Treatment  
1. SFRT (8GYx1) to one or more sites of metastatic 
disease 
2. Pembrolizumab, every 3 weeks for 8 cycles until 
progression or unacceptable toxicity. After cycle 8 
(End of Treatment visit) patients will continue 
pembrolizumab as standard of care if they are 
tolerating and have no disease progression. 
Number of trial subjects 
48 patients 
 
 
 
 
 
 
 

 
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ABBREVIATIONS  
 
 
 
 
CCCC 
Case Comprehensive Cancer Center 
CRF 
Case Report Form 
DCRU 
Dahm’s Clinical Research Unit 
DSTC 
Data Safety and Toxicity Committee 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRMC 
Protocol Review and Monitoring Committee 
SOC 
Standard of Care 
CCF 
Cleveland Clinic Foundation 
UH 
University Hospitals 

 
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TABLE OF CONTENTS 
1 
INTRODUCTION ...................................................................................................... 13 
1.1 
Background of Study Disease .............................................................................. 13 
1.1.1 Name and Description of Investigational Agent Pembrolizumab ...................... 13 
1.1.2 Pharmaceutical and Therapeutic Background .................................................... 13 
1.1.3 Preclinical Data ................................................................................................... 15 
1.1.4 Clinical Trial Data ............................................................................................... 16 
1.2 
Single Fraction Radiation Therapy (SFRT) ....................................................... 18 
1.2.1 Rationale ............................................................................................................. 18 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 24 
2.1 
Study Objectives ................................................................................................... 24 
2.1.1 Primary Objective ............................................................................................... 24 
2.1.2 Secondary Objective ........................................................................................... 24 
2.1.3 Exploratory Objectives ....................................................................................... 24 
2.2 
Efficacy Endpoints ................................................................................................ 24 
2.2.1 Primary Endpoint ............................................................................................. 24 
2.2.2 Secondary Endpoints: ....................................................................................... 24 
2.2.3 Safety Endpoints ................................................................................................. 25 
2.2.4 Biomarker Research ............................................................................................ 25 
3 
STUDY DESIGN........................................................................................................ 26 
3.1 
Study Design .......................................................................................................... 26 
3.1.1 Tumor Imaging and Assessment of Disease ....................................................... 26 
3.1.2 Tumor Tissue Collection and Correlative Studies Blood Sampling ................... 27 
3.1.3 Laboratory Procedures/Assessments .................................................................. 29 

 
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3.2 
Number of Subjects .............................................................................................. 29 
3.3 
Replacement of Subjects ...................................................................................... 29 
3.4 
Expected Duration of Treatment and Subject Participation ............................ 29 
3.5 
Clinical Criteria for Early Trial Termination ................................................... 29 
4 
SUBJECT SELECTION............................................................................................ 30 
4.1 
Entry Criteria ........................................................................................................ 30 
4.1.1 Informed Consent ................................................................................................ 30 
4.1.2 Inclusion/Exclusion Criteria ............................................................................... 30 
4.1.3 Medical History .................................................................................................. 31 
4.1.4 Prior and Concomitant Medications Review ...................................................... 31 
4.1.5 Disease Details and Treatments .......................................................................... 31 
4.1.6 Diagnosis/Condition for Entry into the Trial ...................................................... 31 
4.2 
Subject Inclusion Criteria .................................................................................... 32 
4.3 
Subject Exclusion Criteria ................................................................................... 33 
5 
REGISTRATION ....................................................................................................... 35 
6 
TREATMENT PLAN ................................................................................................. 35 
6.1 
Screening ................................................................................................................ 35 
6.2 
Treatment/Core Study Period ............................................................................. 36 
6.2.1 Timing of Dose Administration .......................................................................... 36 
6.2.2 Treatment Regimen Overview ............................................................................ 37 
6.3  Post-Study Follow-Up Period ................................................................................... 38 
6.3.1 Safety Follow-Up Visit ....................................................................................... 38 
6.4 Study Schema .............................................................................................................. 39 
6.5 
Definition of Dose Limiting Toxicity ................................................................... 41 
6.5.1 Pembrolizumab Dose Selection/Modification .................................................... 41 

 
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6.5.2 SFRT Dose Modification and Supportive Care .................................................. 43 
6.6 
Concomitant Medications and Supportive Care Guidelines ............................ 43 
6.6.1 Concomitant Medications ................................................................................... 43 
6.6.2 Supportive Care Guidelines ................................................................................ 44 
6.7 
Diet, Sexual Activity, and Other Considerations ............................................... 48 
6.7.1 Diet ...................................................................................................................... 48 
6.7.2 Sexual Activity .................................................................................................... 48 
6.8 
Trial Compliance (Medication/Diet/Sexual Activity/Other) ............................. 50 
6.9 
Withdrawal/Discontinuation................................................................................ 50 
6.9.1 Discontinuation of Study Therapy after Complete ResponseError! Bookmark not defined. 
7 
ADVERSE EVENTS.................................................................................................. 51 
7.1 
Evaluating Adverse Events .................................................................................. 51 
7.2 
Assessing and Recording Adverse Events .......................................................... 51 
7.3 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and Merck ............................................................................................... 52 
7.4 
Reporting Pregnancy and Lactation to the Sponsor and to Merck ................. 53 
7.5 
Immediate Reporting of Adverse Events to the Sponsor and to Merck .......... 53 
7.5.1 Serious Adverse Events ...................................................................................... 53 
7.5.2 Events of Clinical Interest ................................................................................... 55 
7.6 
Protocol-Specific Exceptions to Serious Adverse Event Reporting ................. 55 
7.7 
Sponsor Responsibility for Reporting Adverse Events ..................................... 56 
8 
STATISTICAL ANALYSIS PLAN ............................................................................ 59 
8.1 
Pre-Planned Subset Analysis ............................................................................... 59 
9 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................................................................. 60 
9.1 
Investigational Product ........................................................................................ 60 

 
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9.2 
Packaging and Labeling Information ................................................................. 60 
9.3 
Clinical Supplies Disclosure ................................................................................. 60 
9.4 
Storage and Handling Requirements .................................................................. 60 
9.5 
Returns and Reconciliation .................................................................................. 60 
10 
ADMINISTRATIVE AND REGULATORY DETAILS ........................................... 61 
10.1 
Confidentiality ....................................................................................................... 61 
10.2 
Compliance with Financial Disclosure Requirements ....................................... 61 
10.3 
Compliance with Law, Audit and Debarment ................................................... 61 
10.4 
Compliance with Trial Registration and Results Posting Requirements ........ 61 
10.5 
Quality Management System ............................................................................... 61 
10.6 
Data Management ................................................................................................. 62 
11 
APPENDICES ........................................................................................................... 63 
11.1 
Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) .............. 63 
11.2 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 63 
APPENDIX I ..................................................................................................................... 64 
REFERENCES ...................................................................................................................... 65 
 
 
  
 
 
 
 

 
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1 INTRODUCTION 
1.1 Background of Study Disease 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the 
United States with the majority of patients presenting with advanced disease. Despite 
improvements in survival with the addition of targeted agents to chemotherapy, the median 
survival for patients with advanced NSCLC remains a disappointing 12 months. (1) In patients 
who are able to tolerate treatment beyond first line, responses are even lower and median 
survival is only minimally improved with chemotherapy. Despite the development of new and 
effective therapies, the five-year survival rate for patients with advanced NSCLC remains less 
than 5%. (2) Strategies using monoclonal antibodies targeting the immune-checkpoint pathways 
have recently shown activity in several solid tumors including NSCLC. (3-6) Pembrolizumab is a 
fully human IgG4 monoclonal antibody targeting the Programmed death-1 receptor interfering 
with the binding with its ligands PD-L1 and PD-L2. Recent clinical trials with pembrolizumab 
demonstrated clinical activity in NSCLC. (4) 
1.1.1 Name and Description of Investigational Agent Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-1 
receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is being advanced for clinical 
development as an intravenous immunotherapy for advanced malignancies. See investigator 
brochure for further details. (7) 
1.1.2 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors.(3, 8, 9) 
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). (10, 11) The structure of murine PD-1 
has been resolved. 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-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 

 
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tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade.(12, 13) 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. PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural 
Killer cells. Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells. (14, 15) 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.(16, 17). 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. (8) Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. High 
expression of PD-L1 on tumor cells has been shown to correlate with poor prognosis and 
survival in various malignancies. (18-21) PD-1 has been suggested to regulate tumor-specific T-
cell expansion in subjects with melanoma (MEL). (18) 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 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. KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for 
the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
Recently approval of nivolumab (MDX-1106, BMS-936558), an IgG4 antibody against PD-1, 
based on data in NSCLC has validated the role of PD-1 as an attractive target for clinical 
therapeutic intervention in NSCLC subjects. (22) The approval was based on phase III open-
label CheckMate-017 study involved 272 previously treated patients with advanced or metastatic 
squamous cell NSCLC. Participants were randomized to the fully human IgG4 monoclonal 
antibody nivolumab at 3 mg/kg intravenously every 2 weeks (n = 135) or docetaxel at 75 mg/m2 
(n = 137) intravenously every 3 weeks. Treatment with nivolumab improved OS by 41% versus 
docetaxel (9.2 vs 6.0 months; HR = 0.59; 95% CI, 0.44-0.79; P = .00025). This approval was 
further supported by phase II data of CheckMate -063 study presented at the 2014 Chicago 
Multidisciplinary Symposium in Thoracic Oncology. The study included 117 heavily pretreated 
patients with advanced squamous cell NSCLC. All patients had failed two or more systemic 
treatments and 65% of participants (n = 76) had previously failed three or more treatments. 
Seventy-six percent of patients were within 3 months of completion of most recent therapy. 
Nivolumab was administered at 3 mg/kg intravenously every 2 weeks until disease progression 
or treatment discontinuation. At 11 months follow-up ORR, as assessed by an independent panel, 
was 14.5% (95% CI, 8.7-22.2), with a median duration of response that was not yet reached. The 

 
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estimated 1-year survival rate was 41% (95% CI, 31.6-49.7) and the median OS was 8.2 months 
(95% CI, 6.05-0.91). An additional 26% of patients had stable disease for a median duration of 6 
months (95% CI, 4.73-10.91), producing a disease control rate (ORR plus stable disease) of 
41%. Responses were observed independent of PD-L1 status for patients with quantifiable PD-
L1 expression. Adverse events (AEs) of all types and grades occurred in 74% of patients; 
however, 85% of patients were able to receive at least 90% of their planned dose intensity. Grade 
3/4 drug-related AEs were reported in 17% of patients. The most common (≥2%) grade 3/4 AEs 
were fatigue (4.3%), pneumonitis (3.4%), and diarrhea (2.6%). Discontinuations due to drug-
related AEs of any grade occurred in 12% of patients. Two drug-related deaths (pneumonia, 
ischemic stroke) occurred in patients with multiple comorbidities and progressive disease. (23) 
 
Recently phase 1 data from Keynote-001 was published on the role of pembrolizumab in 
advance NSCLC. In this phase 1 study, 495 patients received at least one dose of pembrolizumab 
(at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per 
kilogram every 2 weeks). The objective response rate was 19.4%, and the median duration of 
response was 12.5 months. The median duration of progression-free survival was 3.7 months, 
and the median duration of overall survival was 12.0 months. In a patient population with PD-L1 
expression of at least 50% of tumor cells response rate was 45.2%, median progression-free 
survival of 6.3 months and overall survival was not reached. PD-L1 expression was assessed in 
tumor samples using immunohistochemical analysis, with results reported as the percentage of 
neoplastic cells with staining for membranous PD-L1 (proportion score). Common side effects 
attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear 
difference according to dose or schedule. (24) Pembrolizumab is approved for use in patients 
with advanced chemotherapy refractory NSCLC expressing PD-L1. However, the role of PD-L1 
expression in determining treatment with PD-1 inhibitors is unclear at this time. Nivolumab, 
another agent in the same class, is currently FDA approved for all patients with advanced 
chemotherapy refractory NSCLC irrespective of the PD-L1 status. No significant differences 
were seen between docetaxel and Nivolumab in patients who were PD-L1 negative. (25) 
 
1.1.3 Preclinical Data 
Due to the lack of cross-reactivity of pembrolizumab with PD-1 from rodents (or other 
nonprimate species), a commercially available, hamster anti-mouse PD-1 analog antibody (clone 
J43) was used for in vivo efficacy studies in mice. Anti-mouse PD-1 (J43) was tested as a 
monotherapy in several syngeneic murine tumor models. The tumor growth curves in Figure 1 
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 1). 
 
 

 
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Figure 1 - The experiment described in Figure 1 was analyzed for the effects of anti-mouse PD-1 on the long-term 
survival of treated mice in each of the groups. Mice receiving 10 mg/kg of anti-mouse PD-1 demonstrated an 
increased chance of overall survival, with 50% of the mice surviving beyond 60 days with no evidence of tumor 
relapse 
1.1.4 Clinical Trial Data 
An open-label phase 1 trial (Keynote 001) was recently publishes in New England Journal of 
Medicine, in this large phase I trial side effects, safety, and antitumor activity of pembrolizumab 
was evaluated in patients with advanced NSCLC. A total of 495 patients received at least one 
dose of pembrolizumab between May 2012 and February 2014. With a primary objective of 
safety, side effect profile, and antitumor activity, patients were given intravenous pembrolizumab 
at a dose of 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram 
every 2 weeks over a 30-minute period.  
Overall treatment was well tolerated and the most common treatment related adverse events were 
fatigue, pruritus, and decreased appetite. Only 9.5% of patient experienced adverse events of 
grade 3 or higher. Pneumonitis of grade 3 or greater was observed in 9 patients and caused death 
in one patient.  
At the time of the data cutoff, the median duration of follow-up was 10.9 months (range, 5.2 to 
27.5), and 115 patients (23.2%) continued to receive treatment. Efficacy data from this study 
showed an overall response rate of 19.4% (95% confidence interval [CI], 16.0 to 23.2). The 
response rate was 18.0% (95% CI, 14.4 to 22.2) in the previously treated patients (n-394) and 
24.8% (95% CI, 16.7 to 34.3) in the previously untreated patients (n-101). The median duration 
of response was 12.5 (range, 1.0 to 23.3) months in all patients, 23.2 months (range, 1.0 to 23.3) 
in previously untreated patients and 10.4 months (range, 1.0 to 10.4) in previously treated 
patients. Median progression-free survival was 3.7 months (95% CI, 2.9 to 4.1) for all the 
patients, 3.0 months (95% CI, 2.2 to 4.0) for previously treated patients, and 6.0 months (95% 
CI, 4.1 to 8.6) for previously untreated patients. Median overall survival was 12.0 months (95% 

 
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CI, 9.3 to 14.7) for all patients, 9.3 months (95% CI, 8.4 to 12.4) for previously treated patients, 
and 16.2 months (95% CI, 16.2 to not reached) for previously untreated patients 
Subjects were required to submit a newly obtained tumor biopsy prior to initiating therapy with 
pembrolizumab to evaluate the tumors for expression of PD -L1, the presumptive predictive 
biomarker of pembrolizumab, using a preliminary immunohistochemistry assay. PD-L1 
positivity was defined as membranous staining in at least 1% of cells (neoplastic and intercalated 
mononuclear inflammatory cells) within tumor nests or a distinctive staining pattern caused by 
the infiltration of mononuclear inflammatory cells in the stroma that formed a banding pattern 
adjacent to tumor nests. A modified H-score scoring system of PD-L1 expression was 
established for NSCLC by analyzing tumor specimens from resected NSCLC specimens. Results 
were reported as the percentage of neoplastic cells showing membranous staining of PD-L1 
(proportion score). 
For the training group, 136 patients were finally included and their associated clinical outcome 
data were used to assess an optimal cut point for PD-L1 positivity. An optimal PD-L1 cut point 
was identified by receiver operator characteristic curve analyses and by considering clinical 
implications of false positive and false negative results. Cut points were identified based upon a 
proportions score (PS) method of IHC analysis with the tumors expressing at or greater than the 
highest cut point (PS >50%) referred to as PD-L1 strongly positive tumors, and tumors 
expressing >1% but less than 50% referred to as the PD -L1 weak tumors. Outcomes based on 
irRC were used as the primary outcome for the analysis. 220 patients were included in validation 
group and the response rate was 45.2% (95% CI, 33.5 to 57.3) in the 73 patients with a 
proportion score of at least 50%. Among all the patients with a proportion score of at least 50%, 
median progression-free survival was 6.3 months; median overall survival was not reached. 
Clinical data regarding combination of radiation with immunotherapy with a checkpoint inhibitor 
is limited to assess abscopal effect. Several case reports have described the role of abscopal 
effects, and several ongoing trials are further assessing it in various malignancies. (26-30) 
Several other ongoing clinical trials are assessing the activity of pembrolizumab in NSCLC with 
a combination of chemotherapy and/or radiotherapy. Currently ongoing trials of pembrolizumab 
in NSCLC includes; NCT02220894- Study of MK-3475 (Pembrolizumab) Versus Platinum-
based Chemotherapy for Participants With PD-L1-positive Advanced or Metastatic Non-small 
Cell Lung Cancer; NCT01840579- In Part B participants with advanced non-small cell lung 
cancer (NSCLC) will receive pembrolizumab in combination with either cisplatin/pemetrexed or 
carboplatin/paclitaxel by non-random assignment to assess the safety and tolerability of the 
combination therapy; NCT02422381- study will evaluate the safety of adding an investigational 
drug, pembrolizumab to standard treatment with gemcitabine; NCT02343952, assessing effect of 
Consolidation Pembrolizumab (MK-3475) following Chemoradiation in Patients With 
Inoperable/Unresectable Stage III NSCLC; NCT02085070 - to study the activity of 
pembrolizumab in untreated brain metastases from melanoma or non-small cell lung cancer; 
NCT02039674- study is to determine safety, tolerability, and efficacy of pembrolizumab 
(MK3475) in combination with chemotherapy or immunotherapy in participants with 
unresectable or metastatic non-small cell lung cancer (NSCLC); NCT02316002, Phase II Study 
of Pembrolizumab After Curative Intent Treatment for Oligometastatic Non-Small Cell Lung 
Cancer.  

 
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1.2 Single Fraction Radiation Therapy (SFRT) 
1.2.1 Rationale 
1.2.1.1 
Rationale for the Trial and Selected Subject Population 
NSCLC is the leading cause of cancer-related mortality in the United States, with the majority of 
patients presenting with advanced disease. Despite improvements in survival with the addition of 
targeted agents to chemotherapy the median survival for patients with advanced NSCLC remains 
a disappointing 12 months. (1) However, despite this aggressive therapy, the majority of patients 
will experience systemic recurrence and eventually die from their lung cancer. Tumors with high 
mutational burden present a wider array of tumor-specific antigens and prompt T-cell recognition 
and invasion. (31) Tumor evasion of immune surveillance is required for cancer progression. 
(32) The tumor milieu contains several suppressive mechanisms including the infiltration by 
specific immune inhibitory cells (e.g. Tregs and myeloid-derived suppressor cells), production of 
soluble factors/cytokines (IL-6, IL-10, and TGF-β), and activation of co-inhibitory pathways 
(e.g. PD-1/PDL-1, B7-H4, IDO-1, CTLA-4 etc). Recent evidence highlights the pivotal role of 
the 
immune 
checkpoint 
pathways 
in 
maintaining 
an 
immunosuppressive 
tumor 
microenvironment. (33) Strategies using monoclonal antibodies targeting the immune-
checkpoint pathways have recently shown activity in several solid tumors including NSCLC. (3-
6) Pembrolizumab is a fully human IgG4 monoclonal antibody targeting the Programmed death-
1 receptor interfering with the binding with its ligands PD-L1 and PD-L2. Recent clinical trials 
with pembrolizumab demonstrated clinical activity in NSCLC. (4)  
There is substantial evidence that radiotherapy (RT) is capable of converting the irradiated tumor 
into an immunogenic hub. The processes of antigen presentation and development of cellular 
immunity are complex, and subject to modulation due to the tumor microenvironment. Antigen 
presenting cells in the tumor microenvironment acquire the antigens from the tumor cells. The 
APCs mature with expression of MHC class I and II on cell surface for interaction with antigen 
specific T-cells. The antitumor effect of radiation is through DNA damage and insufficient repair 
resulting in apoptosis mediated by the BCL2, p53-dependent, and TRAIL (tumor necrosis factor 
(TNF)-related apoptosis-inducing ligand) dependent mechanisms. In addition to tumor cell 
apoptosis in the irradiated tumor, several mechanisms resulting in increased tumor specific 
immune responses have been described. Radiation depletes the suppressor T-cells in the tumor 
microenvironment (34) and produces pro-inflammatory cytokines that enhance the infiltration of 
effector (CD8+) T-cells. (35-37) Preclinical models demonstrate that radiation promotes the 
immunological recognition of the tumor and higher expression of different cancer testis family 
antigens and a higher expression of MHC-I in a dose-dependent scale. (38) In addition, 
preclinical data using B16 melanoma cells expressing the prototypic tumor stem cell marker 
CD133 revealed that hypofractional RT with anti-PD1 induced robust tumor T-cell infiltration 
and prolonged survival compared to RT or anti-PD1 alone.(39) The idea of enhanced systemic 
anti-tumor immune response following radiation is further supported by several anecdotal case 
reports of regressions of distant non-radiated tumor lesions, known as the abscopal effect. (27-
30) The abscopal effect has also been observed in patient receiving anti-CTLA4 antibody, in 
both NSCLC and melanoma. (26, 30) In an ongoing single arm trial with radiation and 
ipilumumab in chemotherapy refractory NSCLC overall response rate (ORR) of non-ablative RT 
followed by ipilumumab was 18% in the intent to treat population and 33% in patients receiving 
4 cycles of ipilimumab. (40) In addition to these responses a shift in T-cell receptor clonality 

 
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differentiated responders from non-responders to therapy in this trial. Beyond the above few case 
reports and small single arm combination trial with ipilimumab, this interaction has not been 
well studied in a prospective study and the details of the mechanism are unclear. 
In this proposal, we plan to investigate this phenomenon of ‘in-vivo immunization’ with focal 
RT to one of the target tumor lesions and the potential for augmenting the anti-tumor immune 
response with pembrolizumab. The dose of radiation will be non-ablative and focal to one or 
more of the tumor lesions, and hence would expect minimal anticipated toxicity from the 
radiation. The preliminary clinical data from the pembrolizumab clinical trials are promising, and 
strategies such as this to augment tumor specific antigen presentation may augment the responses 
and clinical benefit from pembrolizumab. 
1.2.1.2       Rationale for Dose Selection/Regimen/Modification  
a) Dose of Pembrolizumab:  
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab. The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting 
toxicities were observed. This first in-human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W). No MTD has been identified to date. The highest dose tested in PN001 
(10.0 mg/kg Q2W) will be the dose and schedule utilized in Cohorts A, B, C and D of this 
protocol to test for initial tumor activity. Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
dosing schedule.  
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of pembrolizumab were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed for 
other antibodies and would support both body weight normalized dosing or a fixed dose across 
all body weights. Pembrolizumab has been found to have a wide therapeutic range based on the 
melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 
the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden on 

 
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exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on (1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, (2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, (3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model), and (4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that (1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, (2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response, and 
(3) will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
b) Dose of Radiation and Choice of Modality: 
Most patients with metastatic NSCLC requiring palliative radiation receive 8 Gy SFRT or 20 Gy 
in 5 fractions. Several randomized controlled trials demonstrated that a single fraction of 
radiotherapy (8 Gy) is equivalent in palliation, and local control in comparison to a longer course 
of radiotherapy in patients with bone metastases. (41, 42) Similarly even in patients with lung or 
other visceral metastases no significant difference in symptom palliation and overall survival 
were noted with single fraction versus multiple fractions of radiation. (43) Moreover, SFRT is 
cost effective and prevents delays to initiation of systemic therapy. Animal studies suggest that 
low dose (2–4 Gy) SFRT can promote tumor immunity via major histocompatibility complex 
(MHC) up-regulation, antigen presentation, and vascular normalization. (44) At higher doses, 
SFRT likely retains these immunogenic effects, but also recruits T cells into the tumor and leads 
to greater direct tumor cell death due to apoptosis or necrosis. (45) Using a B16 mouse 
melanoma model, Lee et al. showed that SFRT (20 Gy) is more effective than fractionated 
radiation therapy (FRT; 45 Gy in 3 fractions) in controlling tumors though the total dose of 
radiation was far less. (45) In their model, the efficacy of SFRT was dependent on CD8 T-cells. 
Thus, we suspect that 8 Gy x 1 fx could potentially be well tolerated, effective, immunogenic, 
practical and cost effective regimen to evaluate for the immune-priming effect. 
Patients with more than a single symptomatic lesion will be treated to some or all of their lesions, 
depending on disease burden, necessity for palliation of particular lesions, proximity to other 
major organs or neurovascular regions, and other patient considerations. There are no anatomic 
locations that will be deemed inappropriate for RT other than the brain. 
  

 
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Radiation will be delivered using electrons for subcutaneous lesions or rib lesions, and photons 
using 3D conformal planning and IMRT (intensity modulated radiation treatment) for deeper 
tumors in the neck, mediastinum, and retroperitoneal regions. None of the patients will be treated 
with stereotactic radiotherapy techniques. Standard doses of prophylactic antiemetic pre-
medications including ondansetron and dexamethasone will be administered if thought to be 
clinically indicated before treatment of abdominal and retroperitoneal masses 
1.2.1.3       Rationale for Biomarker Research 
The relationship between PD-L1 and responses to PD1 inhibitors is not entirely clear at this time. 
(46, 47) In patients with NSCLC even though there appears to be an association between PD-L1 
expression and response in some trials there has been no association in some trials. (23, 25, 46-
50) The discrepancy in the predictive value of the PD-L1 assay are likely related to differences in 
the definition of positivity, variability of assays across clinical trials and the temporal and spatial 
heterogeneity of PD-L1. (51, 52) The expression of PD-L1 has also been correlated with the 
extent of tumor lymphocytic infiltrate. (51, 52) The latter has been observed to be increased after 
radiation therapy, suggesting one possible mechanism for an improved systemic response after 
SFRT. (39) We propose here to treat NSCLC patients without regard to PD-L1 expression on 
biopsies done just prior to initiation of pembrolizumab. When feasible, tissue specimens will be 
obtained before SFRT and pembrolizumab treatment, and again after SFRT, and local and 
systemic response will be correlated to expression. The majority of PD-L1 positive tumors were 
associated with CD4 and CD8 tumor infiltrating lymphocytes (TILs), while the minority of the 
PD-L1 negative tumors had associated TILs. Moreover, the staining pattern of PD-L1 on 
melanocytes differed based on proximity to TILs. Interferon-γ, a primary inducer of B7-H1 
expression, can be detected at the interface of PDL1 positive melanocytes and TILs, possibly 
reflecting activation of PD-1 on the TILs. This interaction, therefore, might be predictive of 
antitumor response to PD-1 blockade. Additional mediators of this pathway that might be 
associated with anti-tumor response, and will be studied on pre-treatment specimens from 
patients enrolled in this trial. Expression of other members of the B7 super-family of ligands, 
including PD-L2 and B7-H4 on tumor cells, might be associated with activation of PD-1 on 
tumor cells.(53, 54) Galectin-9 (the ligand to TIM3), has been proposed as a mediator of PD-1 
related T-cell exhaustion. (55) A more sophisticated and accurate predictive biomarker model 
might be built by incorporating markers on T cells, in addition to quantification of T cell tumor 
infiltrate. Specifically, co-expression of TIM-3 and PD-1 might be associated with sensitivity to 
PD-1 blockade.(55) LAG-3 (lymphocyte-activation gene 3) synergizes with PD-1 to inhibit T 
cell activation.(56, 57) Co-expression of PD-1 and CTLA-4 on T cells is thought to be co-
inhibitory, and co-inhibition of these molecules is the basis of ongoing clinical trials. While the 
T-cell stimulatory role of PD-1H (PD-1 Homologue) on T cells was recently described, its 
association with anti-tumor response in the setting of PD-1 blockade has yet to be determined. 
We propose to evaluate several biomarkers studies in collaboration with the Yale Translational 
Immunology Lab, to characterize the nature of the tumor immune cell populations and several 
immune evasive pathways including PD-L1 and PD-1. We will use novel quantitative 
immunofluorescence based assays developed by our collaborators described in earlier 
publications. (51, 58-62)  
 
Peripheral circulating immune cell phenotyping will be done by Genoptix Inc. In addition, MHC 
Dextramer® reagents will be used for detection of antigen-specific T cells pre and post 

 
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treatment. We will monitor changes of the circulating immune cell population’s pre and post 
treatment and at the time of progression. Novel immune SEQ platforms will be used to 
interrogate T and B-cell receptor repertoire over time pre-post treatment and at progression. This 
will identify and define highly expanded clones and diversity of lymphocyte populations.  
Correlations between genomic, transcriptomic and proteomic profiles of subjects tumors, and 
efficacy outcomes will be assessed to identify gene mutations, gene amplifications, RNA-
expression levels, and protein-expression levels. Genomic sequencing of tumor cells from tissue 
relative to non-tumor cells from whole blood will be profiled to identify the genomic variances 
that may contribute to response or disease progression and provide an understanding of 
molecular abnormalities. RNA sequencing will be conducted to provide expression data and give 
relevance to DNA mutations; Quantitative proteomics analysis will be conducted to determine 
the exact amounts of specific proteins and to confirm expression of genes that are correlative of 
response and disease progression. 
 
A recent study (NCT01176461) with a mass spectroscopy based serum proteomic assay BDX008 
took pre-nivolumab treated melanoma samples from 119 patients. The same assay was 
independently validated with pre-treatment serum of 30 patients from a non-protocol study using 
PD-1 blockade regimens. The evaluation showed that patients in the non-protocol study 
classified as having a high likelihood of good outcome had a 74 percent lower risk of death 
compared to those with a profile associated with low likelihood of good outcome (hazard ratio 
[HR] 0.26, p=0.002). Of the 119 patients in the nivolumab trial, those with a profile predicting 
high likelihood of good outcome had a 50 percent lower risk of disease progression (HR 0.50, 
p=0.001) and a 62 percent lower risk of death (HR 0.38, p=0.001) compared to those with a 
profile predicting low likelihood of good outcome. (63) We will evaluate the predictive value of 
this assay in our trial on all the pre-treatment samples. These studies will be done in 
collaboration with Biodesix Inc.  
An additional potential biomarker of tumor response is cell-free tumor-derived circulating DNA 
(ctDNA). We will collaborate with BioCept Inc. to develop an ultrasensitive assay for measuring 
small amounts of cell-free mutant DNA released into the blood from dying tumor cells. The 
assay covers a broad panel of mutations and uses novel error suppression techniques applied to 
next-generation sequencing data to enable identification of rare mutant DNA down to a 
fractional abundance of ~0.02%. Because such ctDNA is highly tumor-specific and is rapidly 
cleared from the bloodstream, this assay exhibits excellent promise as a quantitative cancer 
biomarker. Rapid decreases in ctDNA levels have been observed following treatment with 
surgery, radiation therapy, and systemic therapy (sometimes with an initial spike from tumor 
kill). Thus, we hypothesize that quantitative changes in ctDNA may provide information that is 
complementary to radiologic studies for tracking the efficacy of treatment with the PD-1 
inhibitor pembrolizumab in patients with non-small cell lung cancer.  
We will also evaluate novel quantitative CT imaging algorithms developed in collaboration with 
the Case Biomedical engineering group to detect tumor inflammation. These imaging based 
biomarkers could potentially predict tumors with high tumor infiltrating lymphocytes, predict 
response based on pre-treatment imaging, and also help monitoring patients treated with 
immunotherapy and potentially help identify early responders and pseudo-progression.  

 
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1.2.1.4       Statistics and Sample Size 
The primary goal of the trial is to assess the RECIST-defined tumor response rate outside the 
radiation field in previously treated NSCLC patients given radiation to an index lesion followed 
by pembrolizumab. Secondary goals include assessment of toxicity, other efficacy measures such 
as progression-free survival, response duration, overall survival, and local control of disease 
within the radiation field, immune response, and biomarkers such as PD-L1 expression.  
 
In previous studies (KEYNOTE 001 and 010) the ORR to pembrolizumab monotherapy has been 
approximately 20% in this population. Based on this, an underlying ORR of >35% would be 
considered positive in the current trial whereas a <20% ORR would be considered negative. A 
two-stage accrual design that allows for early stopping due to lack of efficacy will be employed 
to test this hypothesis. The maximum accrual goal is 48 eligible and evaluable patients. Initially 
29 eligible and evaluable patients will be entered into the trial. If <6 patients respond (observed 
ORR <21%) the trial will be stopped for (relative) lack of efficacy. If more than 6 patients 
respond an additional 19 eligible and evaluable patients will be entered. Pembrolizumab plus 
radiation will be considered effective if overall 12 or more patients respond (ORR >25%). With 
this design the likelihood of stopping the trial early for lack of efficacy is >64% if the underlying 
ORR is <20% and <7% if it is >35%. The overall type I and II errors are 20% and 10%, 
respectively. 
 
Safety is an important secondary endpoint. Toxicity will be graded using CTCAE version 4.0 
criteria, categorized by organ system, and summarized as frequency counts and percentages. 
Assuming the trial accrues all 48 patients, the risk of a particular type and/or grade of toxicity 
will be estimable using an exact 90% confidence interval that has a maximum half-width of 
13%. The likelihood of observing at least one such event is 86% even if the associated risk is 
only 5%. 
 
Secondary efficacy endpoints such as progression-free survival, response duration, and overall 
survival will be summarized using the Kaplan-Meier method. Local control will be summarized 
as a frequency count and percentage. Other endpoints, such as PD-L1 expression, will be 
summarized as medians and ranges (e.g. proportion of cells expressing PD-L1) or frequency 
counts and percentages (e.g. number and percent of patient with PD-L1 expression in >50% of 
cells) as appropriate. 
 
Methods such as Fisher’s exact test, chi-square tests, logistic regression (categorical data), the 
logrank test and proportional hazards models (time to event data) will be used to compare patient 
groups. These analyses are primarily exploratory and it is acknowledged that they will have 
relatively low statistical power. 
 
All genomic, transcriptomic, and proteomic molecular analyses will be exploratory. These 
studies would be analyzed using a prospective-retrospective statistical analysis plan (SAP). 

 
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2 STUDY OBJECTIVES AND ENDPOINTS 
Hypothesis: Focal radiation therapy to tumors can lead to improved tumor antigen presentation 
in patients with NSCLC. Such treatments could improve tumor responses to pembrolizumab in 
patients, by enhancing the host immune response. 
2.1 Study Objectives 
2.1.1 Primary Objective 
Objective: To determine the tumor responses outside the radiation 
2.1.2 Secondary Objective 
Objective:  
1. To determine the progression-free and overall survival in patients with NSCLC receiving 
pembrolizumab, who receive Single Fraction Radiation Therapy (SFRT) 
2. To determine the safety and toxicity of the combination of SFRT and pembrolizumab 
3. To examine potential predictive biomarkers in tumor samples and peripheral blood in 
patients treated with pembrolizumab and SFRT 
4. To determine the local control of SFRT in the radiated lesion(s), when SFRT is given 
with pembrolizumab 
5. To evaluate the induction of a T-cell response in patients with metastatic NSCLC treated 
with radiation and the effect of radiation 
2.1.3 Exploratory Objectives 
To examine potential predictive biomarkers in tumor samples and peripheral blood in patients 
treated with pembrolizumab and SFRT.  
2.2 Efficacy Endpoints 
2.2.1 
Primary Endpoint  
The Best Overall Response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The anti-tumor activity will be evaluated as an efficacy 
endpoints based on radiographic (CT). RECIST 1.1 will be applied for evaluation of tumor 
response. 
2.2.2 Secondary Endpoints:  

 
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1. Progression Free Survival (PFS) is defined as the time from initiation of study drug 
post-SFRT, until the first documented, confirmed progression of disease. PFS will also be 
measured and report from the initiation of study drug, pre-SFRT.  
2. Overall Survival (OS) will be measure from the initiation of study therapy 
3. Durable Overall Response at 6 months and 12 months 
4. Local Control with SFRT: The target lesion(s) selected for SFRT will be followed for 
local control. For the purpose of the study, local control will be defined as a complete 
response, partial response, or stable disease within the planning target volume. The 
duration of local control will be measured from the time of SBRT treatment fraction. 
2.2.3 Safety Endpoints 
1. Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.0), 
timing, seriousness and relationship to study treatments 
2. For patients receiving SFRT to lung lesions, the development of grade 3 or greater 
pneumonitis that is probably or definitely attributable to either SFRT or pembrolizumab 
within the follow-up period will be monitored 
2.2.4 Biomarker Research 
1. Evaluate predictive biomarkers on pre-treatment biopsies and peripheral blood samples 
Tissue based biomarkers: PD-L1 expression will be evaluated using chromogenic staining 
using the FDA approved DAKO PDL-1 IHC assay (22C3) and using novel quantitative 
immunofluorescence (QIF) based platforms. In addition to PD-L1, we will evaluate the 
predictive value of several other immune evasion and/or activation markers in the tumor 
and immune infiltrate compartments. These assays will be done in the Translational 
Immuno-oncology lab at the Yale University, New Haven, CT and in Collaboration with 
Genoptix Inc.  
Peripheral Blood based biomarkers:  
a) Proteomic assays in collaboration with Biodesix and Pandey lab at Johns Hopkins 
will be used and validated to determine predictive value 
b) Frequency and phenotypic character of PBMC subsets including DCs, MDSCs, T-
cells and Natural killer (NK) cells, these will be done in collaboration with 
Genoptix Inc.  
In addition, exploratory biomarkers using imaging-derived quantitative measurements of 
responses; these will be done in collaboration with the Center for Computational Imaging and 
Personalized Diagnostics at the Case Western Reserve University, Cleveland, OH.  

 
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Figure 2 - Study Overview Flow Diagram  
3 
STUDY DESIGN 
3.1 Study Design 
 
This is a phase II trial of pembrolizumab sequentially following focal radiation to one or more of 
the target lesions, in patients with stage IV Non-Small Cell Lung Cancer (NSCLC). The primary 
goal of this trial is to evaluate the efficacy of focal radiation (RT) to index lesion(s) as a way of 
enhancing the anti-tumor immune response to pembrolizumab. The primary efficacy endpoint is 
overall RECIST-defined response outside the radiation field. To accomplish this goal 48 patients 
will be enrolled in this study. 
3.1.1 Tumor Imaging and Assessment of Disease 
The initial tumor imaging will be performed within 30 days prior to the first dose of trial 
treatment. CT scans are the required modality for measureable disease unless a subject has a 
clinical condition e.g. severe contrast allergy, or the lesions are significantly better visualized 
through the use of an MRI. The same imaging technique must be used for a subject throughout 
the study. Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 30 days prior to the first 
dose of trial treatment. Repeat imaging would be performed after every 2 cycles of therapy for 
the remainder of the on-study treatment period or more frequently if clinically indicated. CT 
timing should follow calendar days and should not be adjusted for delays in cycle starts or 
extension of pembrolizumab cycle frequencies. This protocol recommends that patients receiving 
pembrolizumab as standard of care after EOT will have CT scans every 9 weeks +/- 14 days until 
the subject experiences confirmed disease progression or starts a new antineoplastic therapy. 
Subjects who discontinue trial treatment for reasons other than disease progression should also 
receive tumor imaging every 9 weeks +/- 14 days until the subject experiences confirmed disease 
progression or starts a new antineoplastic therapy.  
Disease progression for trial eligibility will be according to RECIST 1.1 criteria. Local reading 
(investigator assessment with site radiology reading) will be used to determine eligibility and for 
subject management. De-identified imaging will also be obtained from all participating sites for 

 
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imaging correlative studies to be done by collaborators at Case Western Reserve University 
Biomedical Engineering group. 
3.1.2 Tumor Tissue Collection and Correlative Studies Blood Sampling 
3.1.2.1 
Correlatives in Biopsy Tissue 
All the tissue based immunological correlatives PD-L1 expression and other exploratory 
correlatives will be performed by NavigateBiopharma and in the Translational Immuno-
oncology Laboratory lab at the Yale University. Both these laboratories are specialized in 
measurement of immune biomarkers and have access to CLIA-compliant facilities. 
 
i. 
Measurement of Tumor infiltrating immune cells on pre-treatment and post treatment 
biopsies: The automated quantitative spectral multiplexing platform for evaluation of 
immune biomarkers is highly novel. We have previously developed and validated ways 
to reproducibly measure and quantify TILs and immune biomarkers by QIF. (51, 59, 61) 
To understand the tumor immune landscape, we will characterize the immune infiltrates 
in the samples using a previously described and validated assay to objectively interrogate 
different lymphocyte subsets. (59) This assay comprises the simultaneous staining and 
measurement of tumor cells (cytokeratin), T cells (CD3), cytotoxic T cells (CD8) and B 
lymphocytes (CD20). The signal intensity and amount of cells will be measured using 
informatic tools as described for PD-L1. These will be done in collaboration with Tumor 
immunology lab at Yale to develop and validate several immune biomarker panels for 
potential use in the clinical setting. This collaboration will expand on our previous work. 
 
ii. 
Measurement of several immune biomarkers in the tumor and stromal compartments on 
pre-treatment and post treatment biopsies: PD-L1 expression will be determined for all 
patients on pre-treatment samples per standard of care using the DAKO PD-L1 assay in 
the Yale CLIA lab. Positivity will be determined by the presence of any (non-nuclear) 
PD-L1 signal present in intact tumor and/or stromal cells within the tumor region of the 
tissue examined, as evaluated by a pathologist in preparations stained with chromogenic 
immunohistochemistry for PD-L1 and counterstained with hematoxylin. Operationally, a 
positivity threshold of signal present in >1% of cells will be used. An additional 3-tiered 
semi-quantitative categorical result will be rendered by the pathologist based in the 
estimation of the percentage of positive cells including 1+ (<30%), 2+ (30-<60%) and 3+ 
(60-100%). PD-L1 negative cases will be those with absence of any detectable signal in 
the sample tested and with appropriate tissue and staining controls.  
 
In addition to chromogenic PD-L1 IHC using a novel platform, we can increase specific 
staining of multiple tissue biomarkers (PD-L2, B7H4, TIM-3, VISTA, LAG-3, IDO-1 
etc.), and are able to reach 6-plex and beyond in a single image retaining the morphologic 
context of the tumor. The incorporation of such novel approaches could positively impact 
the value of tissue biomarker determination for anti-cancer immunotherapies. Finally, 
additional correlative studies using novel approaches with higher sensitivity and 
throughput, such as the Luminex assay69 and CyTOF massspect based cytometry70, will 
be pursued once these platforms are appropriately standardized. 
 

 
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iii. 
Omics Testing: We will evaluate the genomic, transcriptomic, and proteomic profile of 
subjects’ tumors to identify gene mutations, gene amplifications, RNA-expression, and 
protein-expression using the Nantomics “Omics platform”. The exploratory genomics, 
transcriptomic, and proteomics molecular profiling will be performed on formalin-fixed, 
paraffin embedded (FFPE) tumor tissue and whole blood samples (subject matched 
normal comparator against the tumor tissue) by next-generation sequencing and mass 
spectrometry-based quantitative proteomics. Collection of tumor tissue and whole blood 
is mandatory for this study, unless an exception is approved by the sponsor investigator. 
See lab manual for tissue collection requirements.  
 
iv. 
Next Generation Sequencing for T-cell receptor clonality: TCR sequencing and clonality 
quantification on pre-and post-treatment samples will be performed using ImmunoSeq 
assay in a multiplexed PCR method using forward primers specific to TCR Vβ gene 
segments and reverse primers specific to TCR Jβ gene segments. In addition, using 
Immune Repertoire Capture™ (IRC™) technology we will evaluate immune response, 
enabling the identification and generation of functional human antibodies and TCRs. This 
delivers an unparalleled quantitation of the adaptive immune response. This will be done 
in collaboration with Atreca Inc. 
 
v. 
Pharmacodynamic analyses: The intended molecular pharmacodynamic effect of oral 
THU-decitabine is depletion of DNMT1 in tumor tissue. This will be measured by QIF. 
DNMT1-depletion is expected to induce p53-independent cell cycle exits, with 
downregulation of MYC and upregulation of p27/CDKN1B. This will be measured by 
QIF also. Finally, the intracellular accumulation of decitabine to deplete DNMT1 
depends on relative expression in the cancer cells of pyrimidine metabolism enzymes 
DCK, CDA and UCK2, and also the growth fraction of the malignancy, measured by 
surrogates such as KI67. These parameters will also be measured by QIF. 
3.1.2.2 
    Correlatives in Blood 
i. 
Phenotypic character of PBMC: To be performed by GenOptix. Multiplex T cell 
phenotyping flow cytometry panels. We will design a broad T-cell flow cytometry panel 
composed of multiple exhaustion markers, checkpoint receptors and activation markers. 
Non-biased automated algorithms will be used to determine T-cell signatures predictive 
of response and resistance to immunotherapies. The putative markers in the panel may 
include CD3, CD4, CD8, CD45RO, CD45RA, CCR7, CD95, CD27, CD25, CD57, CD107, 
CD69 CD11A, TIM3, HLA-DR, PD-1, LAG3, OX40, ICOS, CCR4, CXCR3, CCR6, BIM, 
EOMES, CTLA-4. In addition to T-cells, we will evaluate other immune cell subsets 
including dendritic cells (DCs), monocyte populations, and NK cells. A whole blood 
immunophenotyping assay will quantify the absolute number and proportion of NK cells 
(CD56+CD3-), NKT cells (CD56+CD3+), B cells (CD19+), and monocytes (CD16+). In 
addition, 
both 
myeloid 
(CD45+HLADR+ 
CD11c+CD123-) 
and 
plasmacytoid 
(CD45+HLA-DR+CD11c-CD123+) DC frequencies will be measured in this precision-
validated multiparameter flow cytometric assay. In addition, PBMCs will be 
cryopreserved for future potential studies using platforms such as Mass cytometry 

 
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(CyTOF), IRC™ and CIBERSORT, and will be correlated to the immunologic response, 
clinical response, and survival data.  
 
ii. 
Serum proteomic and ctDNA correlatives: Exploratory proteomic analysis using MALDI 
ToF mass-spectrometry and ProTS will be performed in collaboration with Biodesix and 
the Pandey lab at Johns Hopkins on baseline and on treatment plasma samples at time 
points defined in the protocol from patients in the study.  
 
PBMCs, Serum and plasma will be banked for other potential correlatives 
 
3.1.3      Laboratory Procedures/Assessments 
Laboratory Safety Evaluations (Hematology and Chemistry) are to be performed.  
 
Laboratory tests for screening or entry for participants who experience regression after 
confirmed CR should be performed within 10 days prior to the first dose of treatment. After 
Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. Results 
must be reviewed by the investigator or qualified designee and found to be acceptable prior to 
each dose of trial treatment.  
3.2 Number of Subjects 
The maximum accrual goal is 48 eligible and evaluable patients. Initially 29 eligible and 
evaluable patients will be entered into the trial. If <6 patients respond (observed ORR <21%) the 
trial will be stopped for (relative) lack of efficacy. If more than 6 patients respond an additional 
19 eligible and evaluable patients will be entered 
3.3 Replacement of Subjects 
Patients who do not receive treatment on study, e.g. do not receive C1D1 of study treatment, will 
not be counted towards the accrual goal of 48 participants and will be replaced.  
3.4 Expected Duration of Treatment and Subject Participation 
Subjects will complete 8 cycles (28 weeks) of on study treatment. Before they begin study 
treatment they will receive SFRT to one or more target lesions. If participants experience 
complete response while on study treatment they will stop treatment with pembrolizumab. If they 
experience recurrence after this time they have the option of re-starting treatment on trial as long 
as all eligibility requirements are still met.  
3.5 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 

 
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3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
4 
SUBJECT SELECTION 
4.1 Entry Criteria 
4.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form, and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use. The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial. The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
4.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial 

 
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4.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator. Details regarding the disease for which 
the subject has enrolled in this study will be recorded separately and not listed as medical 
history.  
4.1.4 Prior and Concomitant Medications Review 
4.1.4.1 
Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting trial. Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not be listed as a prior medication.  
4.1.4.2 
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial. All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7. 
4.1.5 Disease Details and Treatments 
4.1.5.1 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
4.1.5.2 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation, and surgeries.  
4.1.5.3 
Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatments. The safety follow-up visit should occur 30-days (+/- 7 days) after 
discontinuation of Pembrolizumab or prior to the start of a new anti-cancer therapy, whichever 
occurs first. Once new anti-cancer therapy has been initiated, the subject will move into survival 
follow-up.  
4.1.6 Diagnosis/Condition for Entry into the Trial 
1. Histologically documented, metastatic NSCLC 

 
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2. Patients with EGFR and ALK alterations should have been treated with at least 1 line of 
targeted tyrosine kinase inhibitor  
3. At least 2 distinct measurable metastatic sites; patients can have radiation to multiple 
measurable disease sites as clinically indicated, however, there must be at least 1 
measurable non-radiated target lesion for primary endpoint assessment of abscopal 
response. 
4. Agreeable and clinically feasible pre-treatment biopsy if archival tissue is not available 
and an exception is not granted by the sponsor investigator.  
4.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1.  
4. Be willing to provide archival tissue of any age or tissue from a newly obtained core or 
excisional biopsy of a tumor lesion if an exception is not granted by the sponsor 
investigator.  
5. Have a performance status of ≤1 ECOG Performance Scale. 
6. Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 10 days of treatment initiation  
Table 1 - Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 
days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
aCreatinine clearance should be calculated per institutional standard. 
 

 
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7. Have one measurable lesion outside of the planned radiation field (defined as not 
receiving direct beam from any of the treatment portals).   
8. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.  
9. Female subjects of childbearing potential (Section 6.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 6.7.2.1, for the course of the 
study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject. 
 
10. Male subjects of childbearing potential (Section 6.7.2) must agree to use an adequate 
method of contraception as outlined in Section 6.7.2.1, starting with the first dose of 
study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject. 
4.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has a known history of active TB (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy within 2 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 2 or at baseline) from adverse events 
due to a previously administered agent.  
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for 
the study. 

 
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Note: If subject received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.  
Exception: any AEs related to adequate organ function laboratory values that are within 
parameters in Table 1 adequate organ function is met per Laboratory Values 
7. Patients who have previously received radiation overlapping with the current planned 
radiation treatment fields are ineligible. Overlap is defined as any tissue falling within the 
direct path of both prior and current planned radiation fields.  
8. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are clinically stable for at least 4 weeks and, have no evidence of new or enlarging 
brain metastases and also are off steroids 3 days prior to dosing with study medication. 
Stable brain metastases by this definition should be established prior to the first dose of 
pembrolizumab. 
10. Has had prior chemotherapy, within 2 weeks prior to study treatment. Patients on targeted 
therapy (tyrosine kinase inhibitor) may go on the study after 5 days off therapy. Patients 
can be screened but cannot start study treatment until after the above washout period. 
11. Patients who have an active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.  
12. Has history of (non-infectious) pneumonitis that required steroids, evidence of interstitial 
lung disease or active, non-infectious pneumonitis. 
13. Has an active infection requiring systemic therapy. 
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 

 
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17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
20. Has received a live vaccine within 30 days of planned start of study therapy. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
5 
REGISTRATION 
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures. Each subject will be assigned only one screening number. Screening 
numbers must not be re-used for different subjects. Any subject who is screened multiple times 
will retain the original screening number assigned at the initial screening visit.  If the subject is 
found to be eligible he/she will retain screening number as the on study identification number. 
6 TREATMENT PLAN 
The Study Schema (Section 6.4) summarizes the trial procedures to be performed at each visit. 
Individual trial procedures are described in detail below. It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
6.1 Screening 
Approximately 30 days prior to study treatment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements. Screening procedures may be repeated after consultation 
with the Sponsor. Written consent must be obtained prior to performing any protocol specific 
procedure. Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified 
time frame. Screening procedures are to be completed within 28 days prior to the first dose of 
trial treatment except for the following: 
1. Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment. 

 
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However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Please see the Pharmacy Manual for specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
6.2.1.1 
SFRT Planning 
Patients will undergo CT simulation and treatment planning per standard practice. Patient 
immobilization should be sufficient to ensure minimal intra- and inter-fraction set-up error, and 
is otherwise left to the discretion of the treating radiation oncologist. The treating physician will 
define a planning target volume (PTV) to which the dose will be described, and which will be 
used to define local control or local failure. 3D conformal beam arrangement is encouraged, 
though advanced techniques are allowed at the discretion of the treating radiation oncologist. At 
least 90% of the PTV should receive 90% or more the prescription dose. All organs at risk within 
5 cm of the PTV will be contoured, and dose-volume histograms produced. For the treatment 
dose of 8 Gy x 1 in a non-previously irradiated field it is not expected that normal tissue dose-
limits would be exceeded, however, the treatment field should be evaluated at the discretion of 
the treating radiation oncologist.  
This will be followed by pembrolizumab 200mg solution intravenously every 3 weeks until 
progression of disease (PD) (RECIST) or unacceptable toxicity (protocol defined). Treatment 
cycles will be every 21 days, and formal radiographic assessment will be performed at baseline 
and then after every 2 cycles i.e. end of C2, C4, etc. Tumor measurements will be performed 
according to RECIST criteria. 
6.2.2 Treatment Regimen Overview 
Refer to the study schema in section 6.4 for a full list of tests and procedures during the 
screening, treatment, and follow-up periods. 
6.2.2.1    Clinical Procedures/Assessments 
6.2.2.1.1 
Adverse Event Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Study Schema, and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 7). Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs). Refer to the ECI guidance document regarding the identification, evaluation 
and management of potential irAEs.  

 
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Please refer to section 7 for detailed information regarding the assessment and recording of AEs. 
6.2.2.1.2 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical history.  
6.2.2.1.2 
Directed Physical Exam 
The investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration for each visit.  
6.2.2.1.2 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, and at treatment discontinuation as specified in the 
Study Schema. Vital signs should include temperature, pulse, respiratory rate, weight, and blood 
pressure. Height will be measured at screening only. 
6.2.2.1.2 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix I) at screening, 
prior to the administration of each dose of trial treatment, and at treatment discontinuation of trial 
treatment as specified in the Study Schema.  
6.3  Post-Study Follow-Up Period 
6.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted 30 days +/- 7 days after the last 
dose of core study (i.e. after 8 cycles) treatment or EOT visit, whichever comes first. All AEs 
that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with a treatment 
related AE of Grade ≥ 1 will be followed until the resolution of the AE to Grade 0 or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first.   
6.3.1.1 
Survival Follow-Up 
Subjects will be followed every 12 weeks +/- 14 days post study for survival status and record of 
anti-cancer treatments for up to 5 years in follow-up until death, withdrawal of consent, or the 
end of the study, whichever occurs first. If the subject has any anti-cancer treatments subsequent 
to study completion at any time during that five year follow-up period, their subsequent 
treatment would be recorded. This will be done by review of patients’ medical records, 
communication with patients treating physicians, review of public obituary records or contact of 
patients 
by 
telephone.

 
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6.4 Study Schema 
 
a) 
Patients will begin pembrolizumab on the same day as the SFRT but no greater than 3 days after the SFRT. Patients will receive subsequent Pembrolizumab every 3 weeks (± 7 days per protocol) until progression 
or unacceptable toxicity. A treatment break for up to 6 weeks will be allowed upon discussion with study PI. The core study period will end at 8 cycles. After cycle 8 (End of Treatment visit) patients will continue 
pembrolizumab as standard of care if they are tolerating and have no disease progression. 
b) 
Patients will be monitored post study every 12 weeks (± 14 days) for survival status; these could be done by review of patient’s medical records or contacting patient’s medical provider or the subject. Patients on 
standard of care pembrolizumab will begin survival follow up after pembrolizumab progression or start of new anti-neoplastic therapy. 
c) 
Patient’s disease will be monitored with CT scans of the chest and abdomen after every 2 cycles (i.e. prior to every odd cycle ± 7 days) or sooner, if clinically indicated, while on study treatment. CT scans of the 
pelvis will be completed only for known pelvic disease or pelvic symptoms as clinically indicated.  
 
d) 
Patients must be willing to provide archival tissue of any age or obtain a fresh biopsy at screening. If available, tissue collected <6 weeks from the start of study treatment is recommended. If a previous PDL1 
status is obtained, a patient may be eligible for a tissue exemption from the sponsor investigator. Patients must be willing to provide a repeat treatment biopsy after 2 cycles of pembrolizumab, before cycle 3 
imaging is performed. Both baseline and treatment biopsies can be evaluated on a case by case basis and an exception may be made at the discretion of the sponsor investigator. 
e) 
Consult radiation oncologist for radiation simulation consult. This can be done on the same day or a different day of patient’s oncology physical exam as long as it is within the 28 day screening window. 
f) 
Screening laboratory tests are to be performed within 10 days prior to the first dose of study drug. 
g) 
Imaging can be done within 30 days of start of treatment  
h) 
Patients on standard of care pembrolizumab beyond the 8 cycles of study treatment, will have CT scans every 9 weeks (± 14 days). 
i)  
For female subjects of reproductive potential, a urine or serum pregnancy test must be performed within 72 hours prior to first dose of trial treatment. 
Peripheral Blood/Flow 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
Serum 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
PBMC/IRC 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 

 
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6.5 Definition of Dose Limiting Toxicity  
For the purpose of determining the safety of SFRT and pembrolizumab combination, a DLT will 
be considered to be any of the following adverse events which are probably or definitely 
attributable to study treatment, and which occur between the SFRT and within 60 days of the last 
fraction of SFRT. 
1. Any non-hematologic, non-laboratory toxicity which is grade 3 or greater and does not 
resolve to grade 2 or lower with supportive care within 14 days. 
2. Any non-hematologic, non-laboratory toxicity which is grade 4 or greater 
For patients with lung targets, the development of grade 3 or greater pneumonitis that is probably 
or definitely attributable to either SFRT or pembrolizumab within the follow-up period will be 
considered a DLT, regardless of whether it resolves 
6.5.1 Pembrolizumab Dose Selection/Modification 
6.5.1.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Sections 1.1 and 1.3.  
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.  
6.5.1.2 
Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 4. See Section 6.6 for 
supportive care guidelines, including use of corticosteroids. 
 
 

 
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Table 4 - Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatm
ent For 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, 
ALT, 
or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) 
or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia 
associated 
with 
evidence of beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can be 
continued 
while 
endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted 
 
Infusion 
related 
reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite 
adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal and urinary 
disorders - 
Other, specify 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 
or 
Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% 
relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b 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. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue 
study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 
12 weeks of the last dose. 

 
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6.5.1.3 
Dosing Interruptions 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for interruption 
should be documented in the patient's study record. 
6.5.2 SFRT Dose Modification and Supportive Care 
SFRT with 8Gy is considered a palliative dose and we do not anticipate any significant 
unexpected adverse events from treatment. However, if any grade 3 or greater adverse event 
occurs during radiation treatment that are probably or definitely attributable to radiation, this will 
be counted as a DLT. These patients will be allowed to continue with trial therapy 
pembrolizumab if the toxicity resolves to grade 0 or 1 with supportive measures within 12 
weeks. If greater than 20% (2/10) SFRT related DLTs are seen in the first 10 patients; the study 
will be put on hold for safety review by the DSMB.  
6.6 Concomitant Medications and Supportive Care Guidelines 
6.6.1 Concomitant Medications 
6.6.1.1 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the Merck Clinical team. The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.  
6.6.1.2 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids. If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7. 

 
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6.6.1.3 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids, or short courses of corticosteroid treatment unrelated to study 
treatment, may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Subjects may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria (Section 4.3) describes other medications which are prohibited in this 
trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.6.2 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.  Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab.  
Note: If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 6.5.1.2 for dose 
modification.  

 
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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
 
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.  
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 

 
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o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 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 liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 

 
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o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 5 shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
Table 5 - 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 
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. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg 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 ventilator 
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. 

 
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6.7 Diet, Sexual Activity, and Other Considerations 
6.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
6.7.2 Sexual Activity 
6.7.2.1    Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either:  
1. Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
2. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
3. Has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:  
Practice abstinence† from heterosexual activity  
OR  
Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 

 
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 Intrauterine device (IUD) 
 Vasectomy of a female subject’s male partner  
 Contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
 Diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
 Cervical cap with spermicide (nulliparous women only)  
 Contraceptive sponge (nulliparous women only)  
 Male condom or female condom (cannot be used together) 
 Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy. If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
6.7.2.2    Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study. The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and within 
24 hours to the Sponsor and within 2 working days to Merck 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).  
 

 
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The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as described above and in 
Section 7.4. 
6.7.2.3    Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment. 
6.8 Trial Compliance (Medication/Diet/Sexual Activity/Other) 
Interruptions from the protocol specified treatment plan for > 3 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management. 
The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered. The instructions for preparing and 
administering pembrolizumab will be provided in the Pharmacy Manual. Standard of care 
therapy will be prepared and administered as per the approved product label 
6.9 Withdrawal/Discontinuation 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons. When a subject 
discontinues/withdraws prior to trial completion, all applicable activities scheduled for the final 
trial visit should be performed at the time of discontinuation. Any adverse events which are 
present at the time of discontinuation/withdrawal should be followed in accordance with the 
safety requirements outlined in Section 7.2 - Assessing and Recording Adverse Events. Subjects 
who a) attain a CR or b) complete 24 weeks of treatment with pembrolizumab may discontinue 
treatment with the option of restarting treatment if they meet the criteria specified in Section 
6.9.1. After discontinuing treatment following assessment of CR, these subjects should return to 
the site for a Safety Follow-up Visit (described in Section 6.3.1) and then proceed to the Follow-
Up Period of the study (described in Section 6.3.1.1). 
A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved. 

 
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 Unacceptable adverse experiences as described in Section Intercurrent illness that 
prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6.2.2 (Treatment 
Regimen Overview). After the end of study treatment, each subject will be followed for 30 days 
for adverse event monitoring. Subjects who discontinue study treatment for reasons other than 
progressive disease will have post-treatment follow-up visits for disease status every 9 weeks +/- 
14 days until disease progression, initiating a non-study cancer treatment, withdrawing consent, 
or becoming lost to follow-up. Additionally, subjects who continue to receive pembrolizumab as 
standard of care will be followed for disease status every 9 weeks +/- 14 days until disease 
progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to 
follow-up.  After documented disease progression or initiation of a non-study cancer treatment, 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
7 ADVERSE EVENTS 
7.1 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
7.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency 

 
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and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal. Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment must be 
reported by the investigator if they cause the subject to be excluded from the trial, or are the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment through 30 days following cessation of treatment, all adverse events 
must be reported by the investigator. Such events will be recorded at each examination on the 
Adverse Event case report forms/worksheets. The reporting timeframe for adverse events 
meeting any serious criteria is described in section 7.5.1. The investigator will make every 
attempt to follow all subjects with non-serious adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention. If the subject requires a blood draw, fresh tumor biopsy etc., 
the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.  
7.3 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose). No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 

 
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If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
7.4 Reporting Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment must 
be reported by the investigator if they cause the subject to be excluded from the trial, or are the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment through 120 days following 
cessation of Sponsor’s product, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, must be reported by the investigator. All 
reported pregnancies should be followed to the completion/termination of the pregnancy. Every 
effort should be made to report pregnancy outcomes of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth as serious events (Important Medical Events). If the pregnancy continues to term, the 
outcome (health of infant) should also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.5 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.5.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
 Results in death 
 Is life threatening 
 Results in persistent or significant disability/incapacity 
 Results in or prolongs an existing inpatient hospitalization 

 
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 Is a congenital anomaly/birth defect 
 Is another important medical event  
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
Merck for collection purposes. 
 Is a new cancer (that is not a condition of the study) 
 
 Is associated with an overdose. 
Refer to Table 7 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment, any serious 
adverse event, or follow up to a serious adverse event, including death due to any cause other 
than progression of the cancer under study (reference Section 7.2 for additional details) that 
occurs to any subject must be reported within 1 business day to the Sponsor and within 2 
working days to Merck Global Safety if it causes the subject to be excluded from the trial, or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment through 90 days following cessation of treatment, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause other than progression of the cancer under study whether or not related to 
the Merck product, must be reported within 1 business day to the Sponsor and within 2 working 
days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period (Section 6.3) 
must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be emailed to the Sponsor, 
Dr. Pennell, at 
 and to the Cleveland Clinic SAE inbox at 
  
 
SAE reports and any other relevant safety information are also to be forwarded to the 
Merck Global Safety facsimile number: 
 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 

 
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the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
7.5.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment, any ECI, or 
follow up to an ECI, that occurs to any subject must be reported within 24 hours to the Sponsor 
and within 2 working days to Merck Global Safety if it causes the subject to be excluded from 
the trial, or is the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment through 90 days following cessation of treatment, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck product, 
must be reported within 24 hours to the Sponsor and within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1. An overdose of Merck product, as defined in Section 7.3, that is not associated with 
clinical symptoms or abnormal laboratory results.  
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  
7.6 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.5 Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless there is 
evidence suggesting a causal relationship between the drug and the event. Any such event will be 
submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 working days 
either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 

 
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The Sponsor will monitor aggregated efficacy endpoint events and safety data to ensure the 
safety of the subjects in the trial. Any suspected endpoint which upon review is not progression 
of the cancer under study will be forwarded to Merck Global Safety as a SAE within 2 working 
days of determination that the event is not progression of the cancer under study 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
7.7 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. Please refer to the Manual of 
Operations for more details on SAE routing procedures. 

 
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Table 6 Evaluating Adverse Events 
 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred 
(Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of 
length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective 
procedure to treat a pre-existing condition that has not worsened is not a serious adverse event. A pre-existing condition is a clinical 
condition that is diagnosed prior to the use of a Merck product and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 
hours and to Merck within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse 
event for collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical 
interest and must be reported within 24 hours to the Sponsor and to Merck within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will 
be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or 
worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. 

 
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This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based 
upon the available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely Merck product caused 
the adverse event (AE): 
Relationship 
to Merck Product 
(continued)  
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)? 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
 
Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Sponsor’s product; or (3) the trial is a single-dose drug trial); 
or (4) Sponsor’s product(s) is/are only used one time. 
 
Rechallenge 
Was the subject re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
 
Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the 
trial is a single-dose drug trial); or (3) Sponsor’s product(s) is/are used only one time 
 
Note: if a rechallenge is planned for an adverse event which was serious and which may have been caused by 
Merck product, or if re-exposure to Merck product poses additional potential significant risk to the subject, 
then the rechallenge must be approved in advance by the sponsor as per dose modification guidelines in the 
protocol. 
 
Consistency with 
Trial Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck 
product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best 
clinical judgment, including consideration of the above elements. 

 
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8 
STATISTICAL ANALYSIS PLAN 
The primary goal of the trial is to assess the RECIST-defined tumor response rate outside the 
radiation field in previously treated NSC lung cancer patients given radiation to an index lesion 
followed by pembrolizumab. Secondary goals include assessment of toxicity, other efficacy 
measures such as progression-free survival, response duration, overall survival, and local control 
of disease within the radiation field, immune response, and biomarkers such as PD-L1 
expression.  
In previous studies (KEYNOTE 001 and 010) the overall response rate (ORR) to pembrolizumab 
monotherapy has been approximately 20% in this population. Based on this an underlying ORR 
in the current trial >35% would be considered positive whereas a <20% ORR would be 
considered negative. A two-stage accrual design that allows for early stopping due to lack of 
efficacy will be employed to test this hypothesis. The maximum accrual goal is 48 eligible and 
evaluable patients. Initially 29 eligible and evaluable patients will be entered into the trial. If <6 
patients respond (observed ORR <21%) the trial will be stopped for (relative) lack of efficacy. If 
more than 6 patients respond an additional 19 eligible and evaluable patients will be entered. 
Pembrolizumab plus radiation will be considered effective if overall 12 or more patients respond 
(ORR >25%). With this design the likelihood of stopping the trial early for lack of efficacy is 
>64% if the underlying ORR is <20% and <7% if it is >35%. The overall type I and II errors are 
20% and 10%, respectively. 
Safety is an important secondary endpoint. Toxicity will be graded using CTCAE version 4.0 
criteria, categorized by organ system, and summarized as frequency counts and percentages. 
Assuming the trial accrues all 48 patients the risk of a particular type and/or grade of toxicity 
will be estimable using an exact 90% confidence interval that has a maximum half-width of 13%. 
The likelihood of observing at least one such event is 86% even if the associated risk is only 5%. 
Secondary efficacy endpoints such as progression-free survival, response duration, and overall 
survival will be summarized using the Kaplan-Meier method. Local control will be summarized 
as a frequency count and percentage. Other endpoints, such as PD-L1 expression, will be 
summarized as medians and ranges (e.g. proportion of cells expressing PD-L1) or frequency 
counts and percentages (e.g. number and percent of patient with PD-L1 expression in >50% of 
cells) as appropriate. 
Methods such as Fisher’s exact test, chi-square tests, logistic regression (categorical data), the 
logrank test and proportional hazards models (time to event data) will be used to compare patient 
groups. These analyses are primarily exploratory and it is acknowledged that they will have 
relatively low statistical power. 
All genomic, transcriptomic, and proteomic molecular analyses will be exploratory. These 
studies would be analyzed using a prospective-retrospective statistical analysis plan (SAP). 
8.1 Pre-Planned Subset Analysis 

 
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Preplanned sub-set analysis will be performed based on (1) histology, (2) number of disease sites 
at the time of study treatment (≤4 versus >4), (3) PD-L1 status (TPS < 50 and TPS ≥ 50) pre-
treatment, and (4) TILs status on pre-treatment samples. 
9 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
 
Table 7 - Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.3 Clinical Supplies Disclosure 
This trial is open-label, therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text. 
Random code/disclosure envelopes or lists are not provided. 
9.4 Storage and Handling Requirements 
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. 
9.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  

 
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Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
10 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1   Confidentiality 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow the 
sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 
information that includes all hospital records relevant to the study, including subjects’ medical 
history. The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and dispensation, 
and all IRB correspondence for as long as needed to comply with local, national and 
international regulations. No records will be destroyed until the Principal Investigator confirms 
destruction is permitted.  
10.2 Compliance with Financial Disclosure Requirements 
All investigators will follow institutional policy for financial disclosure relating to the study and 
will be in compliance with federal and institutional guidelines for human research studies. 
10.3 Compliance with Law, Audit and Debarment 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.   
10.5 Quality Management System 
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 

 
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accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements. 
For multicenter studies, participating sites must inform the sponsor-investigator of pending 
audits.  
10.6 Data Management 
The Overture and OnCore™ Databases will be utilized, as required by the Case Comprehensive 
Cancer Center, to provide data collection for both accrual entry and trial data management. 
Overture and OnCore™ are Clinical Trials Management Systems housed on secure servers 
maintained at Case Western Reserve University. Access to data through Overture and OnCore™ 
is restricted by user accounts and assigned roles. Once logged into the Overture or OnCore™ 
system with a user ID and password, Overture and OnCore™ define roles for each user which 
limits access to appropriate data. User information and password can be obtained by contacting 
the OnCore™ Administrator at OnCore-registration@case.edu. 
Overture and OnCore™ are designed with the capability for study setup, activation, tracking, 
reporting, data monitoring and review, and eligibility verification. This study will utilize 
electronic Case Report Form completion in the Overture database. A calendar of events and 
required forms are available in Overture and OnCore™. 
 

 
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11 APPENDICES 
 
11.1 Common Terminology Criteria for Adverse Events V 4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
11.2 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
In addition, volumetric analysis will be explored by central review for response assessment.

 
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APPENDIX I 
 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
 
0 
 
Normal activity. Full active, able to 
carry on all pre-disease performance 
without restriction.  
 
100 
 
Normal, 
no 
complaints, 
no 
evidence of disease. 
 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
 
1 
Symptoms, but ambulatory. Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., 
light housework, office work). 
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work.  
 
2 
In bed < 50% of the time. Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities. Up and about more than 
50% if waking hours. 
 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
 
50 
Requires considerable assistance 
and frequent medical care. 
 
3 
In bed > 50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
 
40 
 
Disabled, requires special care 
and assistance. 
 
30 
 
Severely disabled, hospitalization 
indicated. Death not imminent. 
 
4 
100% 
bedridden. 
Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
 
20 
Very 
sick, 
hospitalization 
indicated. Death not imminent.  
 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead 
 
 
 
 
 
 
 
 

 
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