Pembrolizumab Prior to Surgery for Stage 1B, 2 or 3A Non-small Cell Lung Cancer (NSCLC): A Phase II Study
Phase: PHASE2
Conditions: Non-small Cell Lung Carcinoma
Sponsor: Neal Ready MD PhD

1 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Pembrolizumab Prior to Surgery for Stage 1B, 2 or 3A Non-small Cell Lung Cancer 
(NSCLC): A Phase II Study 
Merck Protocol Number: 52567 
Thoracic Oncology Program (TOP) Protocol Number: TOP 1501 
NCT02818920 
 
 
 
 
 
 
 
Sponsor: 
PI – Duke Cancer Institute 
 
 
Funding Source: 
Merck 
 
 
Protocol Source: 
PI - Duke Cancer Institute 
 
 
Duke IRB#: 
Pro00071629 
 
 
IND#: 
 
130379 
 
 
Principal Investigator 
Neal Ready, MD, PhD 
Duke Cancer Institute 
Thoracic Oncology 
Durham, NC 27710 
919.681.6962 
Fax 919.684.5163 
ready001@duke.edu 
 
Correlative Science 
Study Chair 
Kent Weinhold, PhD 
Director, Immunology 
Core Lab 
Duke Translational 
Research Institute 
(DTRI) 
Durham, NC 27710 
kent.weinhold@duke.edu 
 
Surgical Sub-
Investigator 
Jacob Klapper, MD 
Surgical-Thoracic 
Program-DCI 
Durham, NC 27710 
jacob.klapper@duke.edu 
 
Sub-Investigator(s) 
Dennis Wigle, MD, PhD 
Mayo Clinic 
Rochester, MN 
wigle.dennis@mayo.edu 
 
Konstantin Dragnev, MD 
Dartmouth-Hitchcock   
Lebanon, NH 
Konstantin.H.Dragnev@hitchcock.org 
 
Radiology Sub-Investigator 
Jared Christensen, MD 
Department Of Radiology 
Duke University Medical Center 
Durham, NC  27710 
jared.christensen@duke.edu 
 
 
 
Statistician 
Xiaofei, Wang, PhD 
Department of Biostatistics 
Duke Cancer Institute 
Durham, NC 27710 
xiaofei.wang@duke.edu 
 
Lead Study Coordinator 
Lauren Beth Leith, RN, BSN 
Clinical Research Associate 
Beth.Leith@duke.edu 
 
Regulatory Coordinator 
Candice Singletary, MA 
Thoracic Oncology 
candice.singletary@duke.edu 
 
Data Management 
Thoracic Oncology Clinical 
Trials 
Room 00541, Duke South 
Duke Cancer Institute 
Durham, NC 
 
 
 
 
 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
V1.0-June 1, 2015       V2.0 Nov 22, 2016 
V3.0 Mar 15, 2017 
V4.0-Nov 30, 2017  
V5.0 Aug 6, 2018 
V5.1 Nov 1, 2018 
   
 
 
Statement of Compliance and Signature Page 
 
STUDY TITLE:  Pembrolizumab prior to surgery for stage 1B, 2 or 3A Non-Small Cell Lung 
Cancer (NSCLC):  A Phase II Study. 
 
 
This study will be conducted in compliance with the protocol approved by the Institutional Review 
Boards of Duke University Health System, Mayo Clinic Medical Center, Dartmouth-Hitchcock 
Medical Center, and the University of Chicago Medical Center, according to Good Clinical Practice 
standards. No deviation from the protocol will be implemented without the prior review and 
approval of the IRB except where it may be necessary to eliminate an immediate hazard to a 
research subject. In such case, the deviation will be reported to the IRB as soon as possible. The 
signature below constitutes the approval (by the PI) of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local and state legal 
and regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
Duke Sponsor Investigator:  Neal Ready, MD 
Duke University Thoracic Oncology Program 
 
 
 
__________________________________________    _____________ 
Neal Ready, MD, Duke Sponsor Investigator            Date 
 
  
__________________________________________    _____________ 
Site Principal Investigator                                           Date  
 
 
 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
TABLE OF CONTENTS 
1.0 INTRODUCTION ...............................................................................................................12 
1.1 
Lung Cancer Surgery .....................................................................................................12 
1.2 
PD1 Checkpoint, Pembrolizumab and Lung Cancer ........................................................12 
1.3 
Longitudinal Analyses of T Cell and MDSC Phenotypes ................................................13 
1.4 
Tumor Infiltrating Lymphocytes (TILs) with Specificities Against Tumor Associated 
Antigens..................................................................................................................................13 
1.5 
Biomarkers Based on Blood Profiling ............................................................................14 
1.6 
Rationale for Using Immune-Related Tumor Assessment................................................14 
2.0 BACKGROUND & RATIONALE.......................................................................................15 
2.1 
Background ...................................................................................................................15 
2.2 
Pharmaceutical and Therapeutic Background..................................................................15 
2.3 
Preclinical and Clinical Trial Data..................................................................................16 
2.4 
Rationale for Dose Selection/Regimen/Modification.......................................................16 
3.0 STUDY RATIONALE ........................................................................................................17 
3.1 
Trial Summary ..............................................................................................................18 
3.2 
Trial Design ..................................................................................................................19 
3.2.1 
Overall Risk/Benefit Assessment ............................................................................19 
4.0 OBJECTIVES......................................................................................................................20 
4.1 
Primary objective...........................................................................................................20 
4.2 
Secondary Objectives.....................................................................................................21 
5.0 STUDY PLAN /DESIGN.....................................................................................................22 
5.1 
Correlative Science Measures ........................................................................................23 
5.1.1 
Longitudinal Analyses of T Cell and MDSC Phenotypes: ........................................23 
5.1.2 
TILS ......................................................................................................................23 
5.1.3 
Biomarkers based on blood profiling .......................................................................24 
6.0 PATIENT RECRUITMENT ................................................................................................24 
6.1 
Study Population/Selection of Patients...........................................................................25 
6.2 
Inclusion Criteria...........................................................................................................25 
6.3 
Exclusion Criteria..........................................................................................................26 
6.4 
Protocol Eligibility Waivers ..........................................................................................28 
7.0 INCLUSION of WOMEN and MINORITIES ......................................................................28 
8.0 REGISTRATION PROCEDURE ........................................................................................28 
8.1 
Registration Procedure for Outside Sites ........................................................................28 
9.0 STUDY PERIODS (Visit Requirements) .............................................................................29 
9.1 
Screening ......................................................................................................................29 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
9.2 
Neoadjuvant Pembrolizumab Treatment (Cycle 1, Day 1) ...............................................30 
9.3 
Neoadjuvant Pembrolizumab Treatment (Cycle 2, Day 22) ............................................30 
9.4 
Evaluation at Completion of Neoadjuvant Pembrolizumab and Prior to Surgery. .............30 
9.5 
Surgery .........................................................................................................................31 
9.6 
Post-surgery Follow-Up Visit  (2-6 weeks following surgery) ........................................31 
9.7 
Post-Surgery Therapy (Adjuvant Standard Chemotherapy +/- Radiation Therapy) ..........32 
9.8 
Adjuvant Pembrolizumab ..............................................................................................32 
9.8.1 
Cycle 1 (Day 1) ......................................................................................................32 
9.8.2 
Cycle 2 (Day 22) ....................................................................................................33 
9.8.3 
Cycle 3 (Day 43) ....................................................................................................33 
9.8.4 
Cycle 4 (Day 64) ....................................................................................................33 
9.8.5 
End of Study Visit (*Safety Follow-up)...................................................................34 
9.8.6 
Follow-up ..............................................................................................................34 
10.0 Sample Procurement and Handling .......................................................................................34 
10.1 Blood Specimens ...........................................................................................................34 
10.2 Surgical Specimens .......................................................................................................35 
10.2.1 
Genomic  Analysis (Slides/Blocks) .........................................................................36 
10.2.2 
Other Biomarkers (blocks) ......................................................................................36 
11.0 TREATMENT.....................................................................................................................36 
11.1 Treatments Administered ...............................................................................................36 
11.2 Materials and Supplies ..................................................................................................37 
11.2.1 
Pembrolizumab ......................................................................................................37 
11.3 Dose Selection/Modification ..........................................................................................37 
11.3.1 
Dose Selection........................................................................................................37 
11.3.2 
Selection and Timing of Doses ...............................................................................38 
11.4 Pembrolizumab Dose Modifications ...............................................................................38 
11.5 Rescue Medications & Supportive Care..........................................................................41 
11.5.1 
Supportive Care Guidelines ....................................................................................41 
11.6 Dose Modifications for Obese Patients...........................................................................45 
12.0 BLINDING .........................................................................................................................45 
13.0 CONCOMITANT THERAPY/VACCINATIONS ................................................................46 
13.1 Acceptable Concomitant Medications ............................................................................46 
13.2 Prohibited Concomitant Medications..............................................................................46 
14.0 DIET/ACTIVITY/OTHER CONSIDERATIONS .................................................................47 
14.1 Diet...............................................................................................................................47 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
14.2 Contraception ................................................................................................................47 
14.3 Use in Pregnancy...........................................................................................................47 
14.4 Use in Nursing Women..................................................................................................48 
15.0 TREATMENT COMPLIANCE ...........................................................................................48 
15.1 Subject Withdrawal/Discontinuation Criteria ..................................................................48 
15.2 Clinical Criteria for Early Trial Termination ...................................................................49 
15.3 Subject Replacement Strategy ........................................................................................50 
15.4 Discontinuation of Study ...............................................................................................50 
16.0 LABELING, PACKAGING, STORAGE, AND RETURN OF CLINICAL SUPPLIES..........50 
16.1 Investigational Product ..................................................................................................50 
16.2 Packaging and Labeling Information .............................................................................51 
16.3 Clinical Supplies Disclosure ..........................................................................................51 
16.4 Storage, Handling and Disposal .....................................................................................51 
16.5 Dispensing ....................................................................................................................51 
16.6 Drug Ordering and Accountability .................................................................................51 
16.6.1 
Initial and Re-Supply Orders...................................................................................51 
16.6.2 
Pembrolizumab Accountability ...............................................................................51 
16.6.3 
Pembrolizumab Returns and Reconciliation.............................................................52 
16.6.4 
Preparation and Administration ...............................................................................52 
17.0 OUTCOME MEASUREMENTS .........................................................................................53 
17.1 Criteria for Response, Progression, and Relapse (Solid Tumors).....................................53 
17.1.1 
Measurable Disease................................................................................................53 
17.1.2 
Non-Measurable Disease ........................................................................................54 
17.1.3 
Target Lesions........................................................................................................54 
17.1.4 
Non-Target Lesions ................................................................................................54 
17.2 Guidelines for Evaluation of Measureable/Evaluable Disease..........................................54 
17.3 Response Criteria ..........................................................................................................55 
17.3.1 
Immune-Related Tumor Assessment ......................................................................56 
17.4 Cytology and Histology .................................................................................................57 
17.5 Pathologic Response Criteria .........................................................................................57 
17.6 Disease-Free Survival ...................................................................................................57 
17.7 Survival ........................................................................................................................57 
18.0 COSTS TO THE SUBJECT .................................................................................................57 
19.0 STUDY ASSESSMENTS....................................................................................................58 
19.1 Medical History.............................................................................................................58 

6 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
19.2 Prior and Concomitant Medications Review ...................................................................58 
19.2.1 
Prior Medications ...................................................................................................58 
19.2.2 
Concomitant Medications .......................................................................................58 
19.3 Disease Details and Treatments......................................................................................58 
19.3.1 
Disease Details .......................................................................................................58 
19.3.2 
Prior Treatment Details...........................................................................................58 
19.3.3 
Subsequent Anti-Cancer Therapy Status ..................................................................58 
19.4 Adverse Event (AE) Monitoring ....................................................................................59 
19.5 Full Physical Exam ........................................................................................................59 
19.5.1 
Directed Physical Exam ..........................................................................................59 
19.6 Vital Signs ....................................................................................................................59 
19.7 Laboratory Procedures/Assessments...............................................................................59 
20.0 SAFETY .............................................................................................................................61 
20.1 Safety Monitoring and Reporting ...................................................................................61 
20.2 Assessing and Recording Adverse Events.......................................................................61 
20.3 Definition of an Overdose for This Protocol & Reporting to Sponsor and to Merck .........62 
20.4 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................................63 
20.5 Immediate Reporting of Serious Adverse Events ............................................................63 
20.5.1 
Serious Adverse Events ..........................................................................................63 
20.6 Events of Clinical Interest ..............................................................................................64 
20.7 Protocol-Specific Exceptions to Serious Adverse Event Reporting ..................................65 
20.8 Evaluating Adverse Events ............................................................................................66 
21.0 QUALITY CONTROL AND QUALITY ASSURANCE ......................................................69 
21.1 Audits ...........................................................................................................................69 
22.0 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ................................................70 
22.1 Investigator Responsibilities ..........................................................................................70 
22.2 Institutional Review.......................................................................................................70 
22.3 Protocol Amendments ...................................................................................................71 
22.4 Departures from the Protocol and Reporting of Protocol Deviations ................................71 
22.5 Compliance with Trial Registration and Posting Requirements........................................71 
22.6 Conflict of Interest.........................................................................................................72 
22.7 Informed Consent/Informed Consent Process ................................................................72 
23.0 PRIVACY, DATA STORAGE, AND CONFIDENTIALITY ...............................................73 
24.0 DATA COLLECTION AND MAINTENANCE ...................................................................74 
24.1 Study Documentation ....................................................................................................74 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
24.2 Case Report Forms ........................................................................................................75 
24.3 Data Management Procedures and Data Verification.......................................................76 
25.0 STUDY CLOSURE.............................................................................................................76 
25.1 Records Retention .........................................................................................................76 
26.0 APPROPRIATENESS OF MEASUREMENTS ...................................................................77 
27.0 STATISTICAL METHODS AND ANALYTICAL PLANS..................................................77 
27.1 Statistical Considerations ...............................................................................................77 
28.0 References...........................................................................................................................79 
29.0 LIST OF APPENDICES ......................................................................................................81 
29.1 Appendix A:  STUDY SCHEDULE ..............................................................................82 
29.2 Appendix B- Correlative Science Measures ...................................................................86 
29.3 Appendix C: Performance Status Criteria .......................................................................90 
29.4 Appendix D  Standard Cockcroft and Gault Formula for Calculated Creatinine 
Clearance ................................................................................................................................91 
29.5 Appendix E -SITE BIOSPECIMEN PROCESSING FLOW CHART - TOP 1501 ...........92 
29.6 Appendix F-Blood Specimens-Duke ..............................................................................93 
29.7 Appendix G-Blood Specimens-Outside Sites ..................................................................94 
29.8 Appendix H-Tissue Specimens-Duke .............................................................................96 
29.9 Appendix I-Tissue Specimens-Outside Sites ...................................................................97 
 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
List of Abbreviations 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Transaminase 
ANC/AGC 
Absolute Neutrophil Count/Absolute Granulocyte Count 
APC 
Antigen Presenting Cell 
AST 
Aspartate Transaminase 
AUC 
Area Under the Curve 
BMS 
Bristol-Myers Squibb Company 
BORR 
Best Objective Response Rate 
BSA 
Body Surface Area 
BSC 
Best Supportive Care 
BW 
Body Weight 
CDCC 
Complement-Dependent Cellular Cytotoxicity 
CL 
Systemic Clearance 
CMax 
Peak Concentration 
CMin 
Trough Concentration 
CR  
Complete Response 
CRF 
Case Report Form (sometimes referred to as Clinical Report Form). A printed or electronic 
form for recording study participants’ data during a clinical study, as required by the 
protocol. 
CRT 
Chemotherapy-Radiation Therapy 
CRU 
Clinical Research Unit 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events; National Cancer Institute, Version 4.0 
CTLA4 
Cytotoxic T-lymphocyte Antigen 
DCI 
Duke Cancer Institute 
DCR 
Disease Control Rate 
DOCR 
Duke Office of Clinical Research 
DUHS/DUMC 
Duke University Health System/Duke University Medical Center 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
ECL 
Electrochemiluminescent 
ECRF 
Electronic Case Report Form (sometimes referred to as an electronic clinical report form). 
An electronic form for recording study participants’ data during a clinical study, as required 
by the protocol. 
Enroll/Randomize 
The act of assigning a patient to a treatment. Patients who are enrolled in the trial are those 
who have been assigned to a treatment or randomized. 
Enter/Consent 
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial.  Patients entered into 
a trial are those who sign the informed consent document directly or through their legally 
authorized representative 
GI 
Gastrointestinal 
HepB 
Hepatitis B 

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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
ICD/ICF 
A person responsible for the conduct of the clinical trial at a trial site.  If a team of 
individuals at a trial site conducts a trial, the investigator is the responsible leader of the team 
and may be called the principal investigator. 
irAE 
Immune-Related Adverse Event 
IRB/ERB 
Institutional Review Board/Ethical Review Board: a board or committee (institutional, 
regional, or national) composed of medical, professional and non-medical members whose 
responsibility it is to verify that the safety, welfare, and human rights of the subjects 
participating in a clinical trial are protected. 
irRC 
Immune-Related Response Criteria 
ITT 
Intention to Treat 
IV 
Intravenous, usually referring to a medication or substance given into a vein. 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
mAB, mAb 
Monoclonal Antibody 
MDSC 
Myeloid-Derived Suppressor Cells 
mg 
milligram: 1/100 of a gram 
m2 
meters squared 
NCA 
Non-Compartmental Analysis 
NCCN 
National Comprehensive Cancer Network 
NSCLC 
Non-Small Cell Lung Cancer 
OS 
Overall Survival 
Patient 
A subject with a defined disease 
PBMC 
Peripheral Blood Mononuclear Cells 
PFS 
Progression Free Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PK  
Pharmacokinetic 
PPK 
Population Pharmacokinetics 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumor 
RT 
Radiation Therapy/Radiotherapy  
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TAA 
Tumor Associated Antigens 
TIL 
Tumor Infiltrating Lymphocytes 
TNM Staging 
Tumor, Node and Metastasis Staging 
Treg 
Regulatory T Cells 
Wt 
Weight 
 
 
 
 

10 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
STUDY SCHEMA 
STUDY DESIGN 
This is a 30 patient single arm, open label, phase 2 trial adding neoadjuvant and adjuvant 
pembrolizumab to surgery and standard post-operative therapy in early stage non-small cell lung 
cancer. Patients with clinical stage IB (> 3cm), II, or IIIA (N0-2) NSCLC and no prior therapy 
for their current diagnosis o f l u n g c a n c e r will be eligible for the study. Patients will receive 
two cycles of neoadjuvant pembrolizumab.  Patients will undergo standard surgical resection of their 
lung cancer as deemed appropriate by their surgeon, followed by standard adjuvant chemotherapy 
(+/- radiation therapy) for their lung cancer as deemed appropriate by their medical oncologist. 
Patients will receive 4 cycles of adjuvant pembrolizumab after the completion of all standard therapy. 
Follow-up after completion of therapy will be per institutional standard practice.  
 
PATIENT ELIGIBILITY 
• All patients must have histologically documented clinical stage IB (> 3cm), IIA/IIB, or IIIA 
(N0-2) NSCLC. 
• NO prior chemotherapy, radiation therapy or biologic/targeted therapy for current 
diagnosis NSCLC.  
• ECOG Performance Status of 0-1 
• No active invasive malignancy in the past 2 years other than non-melanoma skin cancer. 
Cancers that are in-situ are not considered invasive. 
• Patient has provided informed consent and has signed Informed Consent Form. 
• No autoimmune disease that would constitute contraindication to receive pembrolizumab. 
 
REQUIRED LABORATORY DATA 
• Hemoglobin > 9 g/dL or >5.6 
mmol/L without transfusion  
ANC/AGC > 1500/µL 
• Platelets > 100,000/µL 
• Creatinine < 1.5 X ULN or creatinine clearance > 60 ml/min 
• AST/ALT 2.5x ULN  
• Bilirubin  2.0 x institutional ULN  
• INR or PT <1.5 x ULN unless on anticoagulants  
aPTT < 1.5 x ULN unless on anticoagulants 
 
Neoadjuvant Treatment: 
Pembrolizumab:  200 mg IV over 30 minutes on days 1 & 22 (every 21 days x 2 cycles) 
Surgery:  Standard surgical evaluation to occur day 29 to day 56 (at least 2 days after 
second dose of Pembrolizumab) 
 
Adjuvant Treatment: 
Chemotherapy:  Standard adjuvant chemotherapy as per treating medical oncologist. 
 

11 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Radiation: Standard adjuvant post-operative radiation therapy in selected patients for 
standard clinical indications such as N2 node metastases and /or close/positive tumor 
surgical margin. 
 
Pembrolizumab:  200 mg IV over 30 minutes every 21 days times 4 cycles 
 Patients who receive both adj CT plus Adj RT should start Pembrolizumab 
within 8 months of surgery. 
 Patients who receive only one modality of adj therapy (e.g. CT alone or RT 
alone) should start Pembrolizumab within 6 months of surgery 
 Patients who do not receive any additional therapy should start 
Pembrolizumab within 4 months of surgery. 
 
Correlative Science Measures: (refer to Appendix B for further details on the correlative science 
outcomes.) 
 
1) Tumor samples will be analyzed for tumor infiltrating T cells with specificities against 
tumor associated antigens. Tumor samples will also be evaluated to monitor populations 
of infiltrating regulatory T cells, myeloid-derived suppressor cells (MDSC), as well as 
activated and exhausted T cells. 
 
2) Blood samples will be analyzed for circulating T cells with specificities against tumor 
associated antigens: prior to treatment, before surgery, after surgery, and after completion 
of adjuvant pembrolizumab. Blood samples will also be analyzed to monitor circulating 
populations of regulatory T cells, myeloid-derived suppressor cells (MDSC), as well as 
activated and exhausted T cells.  
 
 

12 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
1.0 INTRODUCTION 
 
1.1  
Lung Cancer Surgery 
 
Surgery can be curative in early stage non-small cell lung cancer (NSCLC); however, there is still a 
significant chance of relapse. Five year survival in surgical pathologic stage IIA (T1N1M0) and IIB 
(T2N1M0) disease is 40-63% and 38-45%, respectively. (1) The clinical implications are that 
pathologically staged patients with early stage tumors (17-32% stage IA, 35-47% stage IB, 37-60% 
stage IIA, and 55-62% stage IIB) recur because they harbor regional or distant micro-metastasis 
outside their surgical resection. 
 
1.2  
PD1 Checkpoint, Pembrolizumab and Lung Cancer 
 
Programmed death receptor 1 (PD-1) is an important negative immune checkpoint that helps prevent 
autoimmunity (8, 9). In the setting of inflammation, PD-1 can be activated through interaction with a 
ligand such as program death receptor ligand 1 or 2 (PDL-1, PDL-2). Activation of PD-1 leads to T 
cell energy, exhaustion, and/or death.  Tumor cells themselves, tumor infiltrating lymphocytes, and/or 
other cells in the inflamed tumor microenvironment can express PDL, activate PD-1, and inhibit the 
T cell immune response against the tumor. Masking antibodies to PD-1 or PDL have been developed 
for cancer therapy that prevents PD1 checkpoint immune inhibition. 
 
Pembrolizumab is a programmed death receptor 1 (PD-1) masking antibody that has been approved 
for treatment of metastatic malignant melanoma, previously treated advanced stage squamous cell 
carcinoma of the head and neck, and for previously treated, advanced stage PDL- positive non-small 
cell lung cancer.  Pembrolizumab has shown single agent activity in previously treated and untreated 
advanced stage non-small cell lung cancer (10, 11,12,13). In a phase 1 trial treating different tumor 
types, some patients with heavily pretreated lung cancer had deep and durable responses to single 
agent pembrolizumab therapy (12). Durable responses were seen in both PD-L1-negative and positive 
tumors (12). Based on the single agent activity of pembrolizumab in previously treated NSCLC, 
pembrolizumab was given breakthrough therapy designation by the FDA for the treatment of patients 
with non-small cell lung cancer whose disease has progressed on or following platinum-based 
chemotherapy. A randomized phase 3 trial comparing docetaxel to pembrolizumab in previously 
treated non-small cell lung cancer has shown superior survival for pembrolizumab at different levels 
of tumor PD-L1 positivity (13). A large, randomized, phase 3 trial has been completed comparing 
pembrolizumab to platinum based chemotherapy in untreated advanced stage, PD-L1-positive non-
small cell lung cancer and the results have not yet been presented (14). Additional trials are planned 
or ongoing to study pembrolizumab in early stage non-small cell lung cancer in the adjuvant or 
neoadjuvant setting. The presence of program death receptor ligand (PDL) on tumor cells is a 
candidate predictive biomarker for pembrolizumab that may enrich therapeutic benefit. However, all 
the data thus far suggest that PDL negative lung cancer tumors can respond to PD-1 checkpoint 
therapy. Thus, it is not appropriate to exclude PDL negative tumors from clinical trials studying PD-

13 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
1 checkpoint therapy. Pembrolizumab (KeytrudaTM) has recently been approved in the US for the 
treatment of patients with previously treated, metastatic non-small cell lung cancer in which the 
cancer is PD-L1 biomarker positive.  
 
 
 
1.3          Longitudinal Analyses of T Cell and MDSC Phenotypes 
 
Immunomodulatory cells are present in the peripheral blood. Pembrolizumab has activity in NSCLC 
through the masking of PD-1 and removal of T cell inhibition through the PD-1 checkpoint. It is our 
hypothesis that characteristics of the immunomodulatory cells in the blood may be associated with 
clinical response of NSCLC to pembrolizumab and/or autoimmune adverse events to pembrolizumab.  
 
Phenotypic and functional characterization of T cell populations will be performed on peripheral 
blood mononuclear cells (PBMC), as well as TILs. It will be of critical importance to better 
understand the impact of pembrolizumab therapy on: 1) regulatory T cells (Tregs), 2) myeloid-derived 
suppressor cells (MDSC), 3) T cell activation, and 4) T cell exhaustion.  
 
We will determine if the immunomodulatory effects of the protocol treatment impact the suppressive 
mechanisms, restoring functional reactivity to important anti-tumor effector cell populations.  Functional 
TAA-specific T cell reactivities will be measured in the blood at multiple time points. A Wilcoxon rank 
sum test will be used to test for differences from baseline, as well as for any association between each 
reactivity measure and pathologic response to neoadjuvant therapy.  
 
We will explore an alternative definition for detectability suitable for expression values generated using 
Boolean gating, and determine the percentage of patients with circulating T cells meeting this definition.  
The percentage of patients with circulating T cells meeting the new definition of detectable and its exact 
confidence interval will be estimated.   
 
1.4          Tumor Infiltrating Lymphocytes (TILs) with Specificities Against Tumor 
Associated Antigens 
 
The presumed mechanism of action for pembrolizumab is the removal of T lymphocyte inhibition by 
masking the PD-1 receptor. Our hypothesis is that the masking of the PD-1 receptor by pembrolizumab 
results in the activation and proliferation of T lymphocytes with specificities against tumor associated 
antigens. In untreated lung cancer tumors, we would expect few tumors to have TIL cells with 
specificities against tumor associated antigens. Based on the response rate to pembrolizumab in 
advanced lung cancer, we hypothesize that at least 20% of lung cancers would have TIL cells with 
specificities against tumor associated antigens after pembrolizumab therapy.  
 
Fresh tumor samples will be collected at the time of surgical resection for functional TILs and processed 
per appendices H or I. For each arm, we will determine the percentage of patients with “detectable” 

14 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
(percentage of ≥ 0.05% with each value also being at least twice that of the background unstimulated 
control value) tumor infiltrating lymphocytes (TILs) after protocol treatment. The percentage of patients 
with TILs for patients who have surgical resection and its exact confidence interval will be estimated.  
 
Tumor tissue will be evaluated to determine what antigens commonly expressed in NSCLC are present. 
The TILs for that tumor will then be analyzed to determine what tumor antigens the TILs are activated 
against.  
 
We will evaluate whether presence, quantity or quality of detectable TILs is associated with pathologic 
response to neoadjuvant therapy. A Fisher exact test will be used to evaluate the association of both the 
presence and the quality of TILs with pathologic tumor response to neoadjuvant therapy. A Wilcoxon 
rank sum test will be used to test the association of the quantity of TILs and pathologic response to 
neoadjuvant therapy. 
 
1.5          Biomarkers Based on Blood Profiling 
 
Pembrolizumab has activity in NSCLC through the masking of PD-1 and removal of T cell inhibition 
through the PD-1 checkpoint. It is our hypothesis that characteristics of blood based biomarkers 
associated with inflammation and/or immune function may be associated with clinical response of 
NSCLC to pembrolizumab and/or autoimmune adverse events to pembrolizumab. 
 
The objective of the blood profiling study is to measure circulating levels of cytokines from blood 
specimens drawn as part of the study before neoadjuvant therapy, after neoadjuvant therapy, after 
surgery, and after adjuvant pembrolizumab. We will investigate the characteristics of blood analytes 
over time using exploratory plots and descriptive statistics to assess the prognostic value of the 
biomarkers on response rate, PFS, OS, and adverse events. 
 
1.6         Rationale for Using Immune-Related Tumor Assessment 
 
Pembrolizumab is an immune-stimulating antibody with evidence of anti-cancer activity (durable 
objective response and stable disease) in subjects with advanced melanoma, including subjects 
with established brain disease. Observations of clinical activity defined by tumor response endpoints 
defined by conventional criteria (e.g., mWHO) may be inadequate to realize the kinetics and 
magnitude of clinical benefit achieved with pembrolizumab. 
 
Histopathologic evidence has demonstrated pembrolizumab can produce an influx or expansion of 
tumor infiltrating lymphocytes. Therefore, early increases in lesion size detected radiologically 
or upon gross examination could be misinterpreted as progressive tumor growth and precede 
objective tumor shrinkage. In addition, the appearance of new lesions may have categorized a subject 
to have progressive disease using conventional tumor assessment criteria despite the concurrent 
observation of objective tumor responses in pre-existing lesions and a net reduction in global tumor 
burden that includes the new lesions. 

15 
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11 Nov 2018 
 
 
Therefore, patients with evidence of possible target lesion growth or new lesion appearance will 
not be presumed to have progressed and will proceed to surgery as long as all possible sites of 
disease are deemed resectable by the surgeon. 
 
2.0 BACKGROUND & RATIONALE 
 
2.1         Background 
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
pembrolizumab (MK-3475). 
 
2.2        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. 
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).  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 tail, leading to the dephosphorylation of effector 
molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  
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.  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.  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 

16 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
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.  Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma.  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. Keytruda (pembolizumab) has 
also been approved in the United States for patients with previously treated, metastatic non-small cell 
lung cancer in which the cancer is PD-L biomarker positive.  
 
2.3         Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
2.4         Rationale for Dose Selection/Regimen/Modification  
 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical activity 
of single agent pembrolizumab (MK-3475) (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 MK-3475 (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.  Recent data from other clinical 
studies within the MK-3475 (pembrolizumab) program has shown that a lower dose of MK-3475 
(pembrolizumab) and a less frequent schedule may be sufficient for target engagement and clinical 
activity. 
 
PK data analysis of MK-3475 (pembrolizumab) administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamics data 
(IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  This early 
PK and pharmacodynamics data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
 

17 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
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 MK-
3475 (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.  MK-3475 (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 MK-3475 (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 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. 
 
3.0 STUDY RATIONALE 
 
Studying neoadjuvant pembrolizumab therapy is an attractive strategy for studying the immunologic 
changes caused by PD-1 checkpoint masking. Most of the immunologic activity associated with 
pembrolizumab occurs in the tumor and surrounding microenvironment. Evaluation of post-
pembrolizumab tumor will be important to understanding factors associated with pembrolizumab 
activity, immune tolerance, and discovery of other targets for immune therapy. Pembrolizumab has 

18 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
known benefit in non-small cell lung cancer. The addition of pembrolizumab for two doses prior to 
surgery and four doses after surgery has the potential to confer clinical benefit. Large randomized 
phase 3 trials are now testing whether PD-1 checkpoint antibodies improve survival as adjuvant 
therapy after resection of early stage lung cancer.  
 
At Duke Medical Center, we are conducting an investigator-initiated, neoadjuvant trial of carboplatin, 
paclitaxel, and ipilimumab in early stage lung cancer. In cases in which there was excess tumor 
available at surgery, the laboratory of Kent Weinhold PhD has been able to disaggregate ample 
quantities of functional tumor infiltrating lymphocytes (TILs) to fully characterize the TIL population 
and ultimately determine what antigens the TILs are activated against. In other studies, in which Duke 
Cancer Institute has been a coordinating center, tumor specimens have been shipped on wet ice to 
arrive within 24 hours of surgery and functional TILs have been successfully collected as part of a 
multi-center trial in glioblastoma mulitforme. One of the most important exploratory, secondary 
objectives of this trial will be to investigate the methods that would allow assessment of immunologic 
response to pembrolizumab in the tumor, discover markers of immune therapy resistance, and 
discover new targets for immune therapy.  
 
3.1    Trial Summary 
Abbreviated Title 
TOP 1501 
Trial Phase 
 II 
Clinical Indication 
Stage IB, II or IIIA NSCLC (tumor>3 cm) 
Trial Type 
Therapeutic treatment 
Type of control 
Open Label- no treatment control 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded, open-label 
Treatment Groups  
Single Arm   
Neoadjuvant: Pembrolizumab 200mg every 21 days’ x 2 
cycles  
Surgery 
Standard adjuvant chemotherapy up to 4 cycles 
Post-operative radiation as needed as per institutional 
standard 
Adjuvant: Pembrolizumab 200 mg every 21 days for 4 
cycles 
Number of trial subjects 
32 
Estimated enrollment 
period 
Approximately 3 years; first patient in third quarter 2016   
Estimated duration of trial Estimated at 5 years from the first patient in to last subject’s 
final 2 year follow-up 
Duration of Participation 
Active treatment for approximately 10-17 months followed 
by 5 years follow-up  

19 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
 
3.2        Trial Design 
 
This a multi-institution phase 2 trial studying 2 doses of pembrolizumab prior to surgery and 4 doses 
after surgery for stage IB, II or IIIA non-small cell lung cancer. Patients will undergo standard 
diagnostic workup and pre-surgical staging for early stage lung cancer. Patients with stage IB ( > 3 
cm), II or IIIA lung cancer will be eligible. We will require that the primary tumor be> 3 cm in order 
to improve the chances that there will be adequate excess tumor after surgery for planned correlative 
science studies.  
 
Studying the tumor microenvironment after pembrolizumab is an important secondary endpoint of 
this trial. Therefore an additional eligibility requirement regardless of the lung cancer stage will be 
that the primary tumor will need to be > 3 cm by pre-treatment radiographic measurement. For 
instance, a T1, N1, Mx stage lung cancer would not be eligible for this trial. The requirement that the 
tumor is > 3 cm will increase the chances that there will be enough excess tumor at surgery to collect 
for correlative science studies. It will not be possible to know if N1 nodes are pathologic by clinical 
staging so requiring tumors to be > 3 cm by clinical staging also creates a study population that has 
been shown to benefit from preoperative or postoperative systemic therapy.  
 
Eligible patients will have ECOG PS of 0-1, good organ function, and no history of active 
autoimmune disease. Patients will receive 2 doses pembrolizumab on days 1 and 22. Patients will 
undergo standard surgical resection approximately 29 – 56 days after initiation of pembrolizumab and 
at least 2 days after the second dose of pembrolizumab. After recovery from surgery, patients will be 
evaluated to receive standard chemotherapy. 
 
Patients may receive post-operative radiation according to standard clinical indications such as close 
or positive tumor margin, or presence of N2 metastases. After completion of all standard therapy 
patients may receive 4 cycles of adjuvant pembrolizumab. Patients will have follow-up as per 
institutional standard.   
 
3.2.1 Overall Risk/Benefit Assessment 
 
The unique immune-based mechanism of action is reflected in the clinical patterns of anti-cancer 
activity in some patients. Pembrolizumab impacts tumor cells indirectly, and measurable clinical 
effects emerge after the immunological effects. Tumor infiltration with lymphocytes and the 
associated inflammation (documented by biopsy in some subjects) is likely the cornerstone of the 
effect of pembrolizumab and can manifest in various patterns of clinical activity leading to tumor 
control.  In some  c a se s, inflammation may not be noted by radiological examination and objective 
response is observed with the first tumor assessment in a manner seen in patients receiving other 
types of anti-cancer treatments. In other cases, response may be preceded by an apparent increase 
in initial tumor volume and/or the appearance of new lesions, which may be mistaken for tumor 

20 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
progression on radiological evaluations. Therefore, in subjects who are not experiencing rapid 
clinical 
deterioration, 
confirmation 
of progression 
is recommended, at the investigator’s 
discretion, to better understand the prognosis as well as to avoid unnecessarily initiating potentially 
toxic alternative therapies in subjects who might be benefitting from treatment. Immune-related (ir) 
response criteria were developed based on these observations to systematically categorize novel 
patterns of clinical activity and are currently being prospectively evaluated in clinical studies. 
 
In metastatic diseases, stabilization is more common than response, and in some instances is 
associated with slow, steady decline in tumor burden over many months, sometimes improving 
to partial 
and/or complete responses. Thus, the immune-based mechanism of action of 
pembrolizumab results in durable disease control, sometimes with novel patterns of response, which 
contribute to its improvement of OS. 
 
The immune-based mechanism of action is also reflected in the safety profile. The most common 
drug-related AEs are immune-mediated, consistent with the mechanism of action of the drug and 
generally   medically   manageable   with   topical   and/or   systemic   immunosuppressants. The 
immune-mediated adverse reactions primarily involve the GI tract, skin, liver, endocrine glands, 
and nervous system. 
 
The early diagnosis of immune-mediated adverse reactions is important in order to initiate 
ste roid therapy promptly and minimize complications. Immune-mediated adverse reactions are 
generally manageable using symptomatic or immunosuppressive therapy as recommended through 
detailed diagnosis and management guidelines, as described fully in the current IB. The management 
guidelines for general immune-mediated adverse reactions and pembrolizumab-related GI toxicities, 
hepatotoxicity, endocrinopathy, and neuropathy are provided in the appendices of the current IB. 
 
In summary, pembrolizumab offers clinically meaningful and statistically significant survival 
benefit to patients with pre-treated advanced melanoma. Pembrolizumab has shown benefit in 
NSCLC and has been approved by the FDA for previously treated metastatic non-small cell lung 
cancer. These findings, together with evidence of a safety profile that is manageable with careful 
monitoring and appropriate intervention for treatment of immune- mediated toxicities, suggest an 
acceptable benefit to risk ratio. In this trial, pembrolizumab has the potential to have additive 
therapeutic benefit when added to standard surgery and adjuvant chemotherapy by enhancing anti-
tumor immune activity. The overall risk-benefit ratio for patients entering this protocol is therefore 
at least comparable to and possibly better than alternative options. 
 
4.0 OBJECTIVES 
4.1         Primary objective 
 
The primary objective of the single arm phase II trial is to determine whether the surgery feasibility 
rate of neoadjuvant pembrolizumab is not significantly worse than the historical surgical feasibility 
rate of neoadjuvant chemotherapy. Surgery feasibility rate of a neoadjuvant therapy is the percent of 

21 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
patients who are able to undertake surgery after the neoadjuvant therapy. A total of 30 eligible 
patients will be registered to the single arm trial. Taking 5% rate of cancellation and ineligibility into 
account, the trial will enroll a total of 32 patients and eligible subjects (not screen failures) will be 
followed for 2 years for both disease recurrence and death. 
 
Primary Objective Sample Size Justification 
According to Pisters et al (JCO 2010), approximately 80% of subjects undergo surgical exploration 
within 42 days of day 1 of the last cycle of standard neoadjuvant chemotherapy.  We would like to test 
the following hypotheses:  
H0: p >= 0.80 vs. Ha: p <= 0.65 
where p is the true surgery feasibility rates after neoadjuvant pembrolizumab. With 30 evaluable 
patients receiving protocol treatment, the study has approximately 84.6% power rejecting H0:  
p>=0.80 when p=0.65 at one-sided significance level of 15%. 
 
4.2         Secondary Objectives 
 
All secondary objectives are considered exploratory in nature, and type I error will not be controlled for 
multiplicity. P-values for these statistical tests will be provided for descriptive purposes.  However, if a 
statistical test on a secondary outcome is significant at the 2-sided significance level of 0.01, the finding 
will be considered worthy of future investigation. 
 
1) We will estimate the rate of objective response rate for the protocol treatment. The definition of 
objective response will be measured by RECIST 1.1. The objective response rate (ORR=CR+PR) along 
with its 95% exact confidence interval will be estimated. 
 
2) We will evaluate disease-free survival and patterns of metastases after protocol treatment. Disease-
free survival (DFS) is defined as the time from surgical resection to disease recurrence (first disease 
recurrence or death, whichever comes first) after surgery. The Kaplan-Meier estimator will be used to 
estimate median DFS and its confidence interval. The frequencies of metastases by site will be tabulated. 
 
3) Blood-based biomarkers will be evaluated for changes before and after protocol treatment. The 
association of the baseline value and the changes of these biomarkers with clinical outcomes, such as 
objective response, overall survival and disease free survival, will be evaluated using logistics regression 
and Cox models.  
 
4) We will determine the percentage of patients with “detectable” (percentage of ≥ 0.05% with each 
value also being at least twice that of the background unstimulated control value) tumor infiltrating 
lymphocytes (TILs) after protocol treatment. The percentage of patients with TILs for patients who have 
surgical resection and its exact confidence interval will also be estimated.  
 
5) We will evaluate whether presence, quantity or quality of detectable TILs is associated with pathologic 
response to neoadjuvant therapy. A Fisher exact test will be used to evaluate the association of both the 

22 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
presence and the quality of TILs with pathologic tumor response to neoadjuvant therapy. A Wilcoxon 
rank sum test will be used to test the association of the quantity of TILs and pathologic response to 
neoadjuvant therapy. 
 
6)  Treatment-related adverse evaluate will be summarized by type and grade.  
 
7) The proportion of patients with detectable circulating T cells specific against TAA after the protocol 
treatment will be estimated and its confidence interval will be provided.  An exact binominal test will be 
used to test the increase in the proportion of patients with detectable circulating T cells specific against 
TAA after the protocol treatment relative to baseline.    
 
8) Estimate the rate of pathologic response rate for neoadjuvant pembrolizumab in early stage NSCLC. 
The pathologic response rate along with its 95% exact confidence interval will be estimated.  
 
9) Determine if the immunomodulatory effects of neoadjuvant chemotherapy plus pembrolizumab 
impact the suppressive mechanisms, restoring functional reactivity to important anti-tumor effector cell 
populations.  Functional TAA-specific T cell reactivities will be measured in the blood at 4 time points: 
baseline, after second dose pembrolizumab, after surgery, and after completion adjuvant pembrolizumab. 
A Wilcoxon rank sum test will be used to test for differences from baseline, as well as for any association 
between each reactivity measure and pathologic response to neoadjuvant therapy.  
 
10) Explore an alternative definition for detectability suitable for expression values generated using 
Boolean gating, and determine the percentage of patients with circulating T cells meeting this definition.  
The percentage of patients with circulating T cells meeting the new definition of detectable and its 95% 
exact confidence interval. 
 
11) Perform gene expression analysis on tumor to elucidate genes associated with function and 
modulation of the PD-1/PD-L1 axis. 
 
5.0 STUDY PLAN /DESIGN 
 
Standard diagnostic and staging work up will be performed prior to or during surgery according to 
institutional standard practice including:  pathologic/histologic diagnosis of non-small cell lung 
cancer, PET/CT scan, brain imaging, and if clinically indicated, mediastinoscopy.  Two doses of 
neoadjuvant pembrolizumab will be given. Standard surgical evaluation and surgery will be 
performed following completion of 2 cycles of neoadjuvant pembrolizumab therapy.  
 
After surgery, patients who are appropriate candidates will receive adjuvant chemotherapy, 
adjuvant radiation, and follow-up as per standard of care and institutional best practice. After 
all standard therapy, patients will receive 4 additional cycles of pembrolizumab every 21 days 
for 4 cycles. Patients who are not candidates for adjuvant therapy or who refuse may receive 
four cycles of adjuvant pembrolizumab.              

23 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
All post-surgical therapy is as per institutional standard of care and is not study specific. Post-
surgery chemotherapy, radiation may be given through the patient’s primary oncology team as 
per the wishes of the patient. This allows a patient to have neoadjuvant pembrolizumab and 
surgery at an institution participating in this study, receive standard chemotherapy and 
radiation therapy near home, and return to the institution participating in the study to receive 
adjuvant pembrolizumab. Patients will be seen for a visit approximately 30 days after the last 
dose of pembrolizumab and follow-up will continue until pembrolizumab related side effects 
are grade 1, or Investigator deems stable. Patients will be followed for outcome for up to 7 
years. Long term outcome data may be collected by phone.  
 
5.1         Correlative Science Measures  
(refer to Appendix B for further details on the correlative science outcomes) 
 
5.1.1 Longitudinal Analyses of T Cell and MDSC Phenotypes: 
 
Immunomodulatory cells are present in the peripheral blood. Pembrolizumab has activity in NSCLC 
through the masking of PD-1 and removal of T cell inhibition through the PD1 checkpoint. It is our 
hypothesis that characteristics of the immunomodulatory cells in the blood may be associated with 
clinical response of NSCLC to pembrolizumab 
and/or immune-related adverse events to 
pembrolizumab. 
 
Phenotypic and functional characterization of T cell populations will be performed on peripheral 
blood mononuclear cells (PBMC), as well as TILs. It will be of critical importance to better 
understand the impact of pembrolizumab therapy on: 1) regulatory T cells (Tregs), 2) myeloid-derived 
suppressor cells (MDSC), 3) T cell activation, and 4) T cell exhaustion.  
 
We will determine if the immunomodulatory effects of the protocol treatment impact the suppressive 
mechanisms, restoring functional reactivity to important anti-tumor effector cell populations.  Functional 
TAA-specific T cell reactivities will be measured in the blood at multiple time points. A Wilcoxon rank 
sum test will be used to test for differences from baseline, as well as for any association between each 
reactivity measure and pathologic response to neoadjuvant therapy.  
 
We will explore an alternative definition for detectability suitable for expression values generated using 
Boolean gating, and determine the percentage of patients with circulating T cells meeting this definition.  
The percentage of patients with circulating T cells meeting the new definition of detectable and its exact 
confidence interval will be estimated.   
 
5.1.2 TILS 
 
Tumor infiltrating lymphocytes (TILs) with specificities against tumor associated antigens: 
 

24 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
The presumed mechanism of action for pembrolizumab is the removal of T lymphocyte inhibition by 
masking the PD-1 receptor. Our hypothesis is that the masking of the PD-1 receptor by pembrolizumab 
results in the activation and proliferation of T lymphocytes with specificities against tumor associated  
antigens. In untreated lung cancer tumors, we would expect few tumors to have TIL cells with 
specificities against tumor associated antigens. Based on the response rate to pembrolizumab in 
advanced lung cancer, we hypothesize that at least 20% of lung cancers would have TIL cells with 
specificities against tumor associated antigens after pembrolizumab therapy.  
 
Fresh tumor samples will be shipped on wet ice for collection of functional TILs within 24 hours of 
surgery. We will determine the percentage of patients with “detectable” (percentage of ≥ 0.05% with 
each value also being at least twice that of the background unstimulated control value) tumor infiltrating 
lymphocytes (TILs) after protocol treatment. The percentage of patients with TILs for patients who have 
surgical resection and its exact confidence interval will be estimated.  
 
Tumor tissue will be evaluated to determine what antigens commonly expressed in NSCLC are present. 
The TILs for that tumor will then be analyzed to determine what tumor antigens the TILs are activated 
against.  
 
We will evaluate whether presence, quantity or quality of detectable TILs is associated with pathologic 
response to neoadjuvant therapy. A Fisher exact test will be used to evaluate the association of both the 
presence and the quality of TILs with pathologic tumor response to neoadjuvant therapy. A Wilcoxon 
rank sum test will be used to test the association of the quantity of TILs and pathologic response to 
neoadjuvant therapy. 
 
5.1.3 Biomarkers based on blood profiling 
 
Pembrolizumab has activity in NSCLC through the masking of PD-1 and removal of T cell inhibition 
through the PD1 checkpoint. It is our hypothesis that characteristics of blood based biomarkers 
associated with inflammation and/or immune function may be associated with clinical response of 
NSCLC to pembrolizumab and/or autoimmune adverse events to pembrolizumab. 
The objective of the blood profiling study is to measure circulating levels of cytokines from blood 
specimens drawn as part of study design before neoadjuvant therapy, after neoadjuvant therapy, after 
surgery, and following adjuvant pembrolizumab. We will investigate the characteristics of blood 
analytes over time using exploratory plots and descriptive statistics to assess the prognostic value of 
the biomarkers on response rate, PFS, OS, and adverse events. 
 
6.0 PATIENT RECRUITMENT 
 
Patients will be recruited for this study as follows: Upon determination that a patient’s tumor 
histology and/or radiographic findings are compatible with the eligibility criteria of this protocol, 
the clinical study will be briefly explained to the patient by the principal investigator (PI) or 
colleague. If the patient indicates interest in study participation, patient education sheets (if 

25 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
available) and the approved protocol consent  form  will  be  provided  to  the  patient  as  these  
provide  the  most  comprehensive explanation of the study in lay terms. If the patient shows 
continued interest, the PI or designee will thoroughly explain the required elements of informed 
consent and all aspects of the study to the patient including inclusion/exclusion criteria, risks, 
possible benefits and alternatives to study participation. 
 
6.1         Study Population/Selection of Patients 
 
The following guidelines are to assist physicians in selecting patients for whom protocol therapy 
is safe and appropriate.   Physicians should consider the risks and benefits of any therapy, and 
therefore only enroll patients for whom this treatment is appropriate.  For entry into the study, the 
following criteria MUST be met. 
 
6.2         Inclusion Criteria 
 
Patients are eligible to be included in the study only if they meet all of the following criteria. For 
time limits on imaging and blood tests see study calendar: 
 
1. 
Histologically cytologically confirmed NSCLC. 
2. 
Clinical stage IB (>3cm per CT), Stage IIA/IIB, or Stage IIIA (N0-2) amenable to surgical 
resection.  
3. 
Primary tumor > 3 cm (for all stages entered) to increase the likelihood that excess tumor 
will be available after resection. 
4. 
Patient must be deemed a surgical candidate as documented by surgeon 
within their respective institutional standards. 
5. 
ECOG performance status of 0 or 1 (Appendix C). 
6. 
NO prior chemotherapy, radiation therapy or biologic/targeted therapy for current diagnosis 
of lung cancer. 
7. 
Age ≥18 years. 
8. 
No active invasive malignancy in the past 2 years other than non-melanoma skin 
cancer. Cancers that are in-situ are not considered invasive. 
9. 
Signed written informed consent including HIPAA according to institutional guidelines. 
10. 
Adequate Organ Function: 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
(ANC) or AGC 
≥1500 per uL 
Platelets 
≥100,000  per uL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment) 
Renal 
 

26 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Serum creatinine OR 
Measured or calculated 
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 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. (Appendix 
D) 
 
11. 
Females of child-bearing potential (not surgically sterilized or postmenopausal [a woman 
who is > 45 years of age and has not had menses for greater than 1 year]) must test negative 
for pregnancy within 48 h o u r s   prior to  any initial study procedure  based  on  a  serum  
pregnancy  test.  Both sexually active males and fe ma le s  of reproductive potential must 
agree to use a reliable method of birth control, as determined by the patient and their health 
care team, during the study and for 120 days following the last dose of study drug. If subject 
uses appropriate contraceptive methods (the use of two forms at the same time) from the 
time of the initial serum pregnancy test, then the subsequent pregnancy test can be done 
within 72 hours of receiving study drug administration.  If appropriate; contraceptive 
measures are not begun immediately with the first serum pregnancy test, then subsequent 
serum pregnancy tests must be done within 48 hours prior to the study drug administration. 
12. 
Patients must agree to research blood sampling to participate in study. 
13. 
Have measurable disease based on RECIST 1.1. 
14. 
 FEV1 and DLCO > 40% predicted (or per institutional standard). 
 
6.3         Exclusion Criteria 
 
Patients will be excluded from the study if they meet any of the following criteria: 

27 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
1.       Treatment within the last 30 days with a drug that has not received regulatory approval for                       
            any indication at the time of study entry or used an investigational device within 4 weeks  
            of the first dose of treatment. 
2. 
Has a known history of active TB (Bacillus Tuberculosis). 
3. 
Hypersensitivity to pembrolizumab or any of its excipients. 
4. 
Concurrent administration of any other anti-tumor therapy. 
5. 
Has received prior therapy with an anti-PD-1, anti-PD-L-1, or anti-PD-L2 agent. 
6. 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative]. 
7. 
Inability to comply with protocol or study procedures. 
8. 
Active infection requiring antibiotics, antifungal or antiviral agents, that in the opinion of the 
investigator would compromise the patient’s ability to tolerate therapy. 
9. 
Has known history of, or any evidence of active, non-infectious pneumonitis that required 
steroids (steroid treatment of COPD or asthma allowed). 
10. 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
11. 
Has 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 system 
treatment. Patients  with  a history of inflammatory  bowel disease,  including ulcerative 
colitis and Crohn’s Disease, are excluded from this study, as are patients with a history of 
symptomatic  disease  (e.g.,  rheumatoid  arthritis,  systemic  progressive  sclerosis  
[scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s 
Granulomatosis]); motor neuropathy  considered  of  autoimmune  origin  (e.g.  Guilla in-
Barre Syndrome a n d  Mya sthe n ia  Gravis). 
12. 
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. 
13. 
Has a known additional invasive 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. 
14. 
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. 
15. 
Has had major surgery (other than definitive lung cancer surgery) within two weeks of study 
or other serious concomitant disorders that in the opinion of the investigator would 
compromise the safety of the patient or compromise the patient’s ability to complete the study. 
16. 
Has received any non-oncology vaccine therapy used for prevention of infectious diseases 
(for up to 30 da ys  before or after any dose of pembrolizumab).  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. 

28 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
17. 
Has history of myocardial infarction having occurred less than 6 months before inclusion, any 
known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac 
failure not controlled by medications. Patients with CAD recently treated with surgery and/or 
stent, if stable without symptomatic angina pectoris, active ischemia are eligible.  
18. 
Has evidence or a history of interstitial lung disease. 
19. 
 Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.  
20. 
Prisoners or subjects who are compulsorily 
detained involuntarily incarcerated) for 
treatment of either psychiatric or physical (e.g., infectious) illness. 
 
6.4         Protocol Eligibility Waivers 
 
No waivers of inclusion or exclusion criteria will be granted.   All prospective patients must 
meet all entry criteria prior to enrollment in the study.  If there are any questions regarding the 
interpretation of a criterion for a potential patient, contact the principal investigator to discuss 
the potential patient to confirm eligibility. 
 
7.0 INCLUSION of WOMEN and MINORITIES 
 
There are no exclusions based on gender, race or ethnicity in this trial. There is no evidence to 
suggest that outcomes will differ. 
 
8.0 REGISTRATION PROCEDURE 
 
Patient registration for all patients signing informed consent will be completed through the Duke 
Cancer Institute (DCI) Clinical Research Unit (CRU) into eResearch (DOCR).  The investigator 
and/or designee will enter the patient information into the DOCR Subject Registry within 1 
business day of obtaining consent.    Patients will be  enrolled  only  after  all  pre-treatment  
evaluations  are  completed  and  all eligibility criteria are met. For patients enrolled at Duke Cancer 
Institute, patient information will also be entered into MaestroCare at the time of enrollment, linking 
the patient to the research subject record (RSH), to the study encounter and the timeline (if applicable) 
prior to the close of the study encounter. 
 
8.1         Registration Procedure for Outside Sites 
 
All patients signing informed consent at outside sites must be registered with Duke (including screen 
failures – indicate screen failure status on last page of eligibility checklist). Redacted enrollment 
packet will be completed by the investigator and/or designee and faxed to the Thoracic Oncology 
Protocol Office at 919-684-8926 at the time of registration. This includes: 
 
TOP 1501 Eligibility Checklist 
 
Signed informed consent 

29 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Patients will be enrolled only after all pre-treatment evaluations are completed and all eligibility 
criteria are met and confirmed by Duke. 
 
9.0 STUDY PERIODS (Visit Requirements) 
 
The Study Schedule (Appendix A) 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. 
 
For the purpose of scheduling evaluations and to allow for patient and investigator schedules, 
holidays and weather or other emergencies requiring clinical facilities to be closed, all patient visits 
can be performed ±3 days of scheduled visits. 
 
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 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. 
 
9.1       Screening 
 
The following procedures and tests are to be performed within 30 days (unless otherwise specified) 
of study enrollment to confirm eligibility. Baseline and Cycle 1 Day 1 procedures may be completed 
on the same day. However, screening assessments for eligibility MUST have already been 
determined. Refer to Appendix A for details. Refer to Table 5 for specific laboratory test 
information. 
 
 Informed Consent 
 Eligibility 
 Medical history including demographics/smoking history 
 Height and weight (BSA calculation)  
 Vital signs (temp, B/P, pulse) 
 ECOG Performance status 
 Physical exam  
 Routine blood work (CBC, Chemistries) 
 Calculated creatinine clearance 
 Thyroid Functions (T3, FT4 & TSH) 
 Coagulation (aPTT, PT(INR) 
 Routine Urinalysis 
 Negative Pregnancy test for WOCBP only 
 EKG 

30 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 Tumor Histology 
 Medical and Surgical Evaluation 
 Staging PET/CT of chest/abdomen, Brain MRI or CT (as per standard of care) These may 
be obtained within 42 days 
 Tumor measurement to ensure primary lesion > 3 cm 
 PFTs (FEV1 and DLCO) 
 Research blood (1st Collection): blood will be collected to assess longitudinal analyses of T 
cell and MDSC phenotypes and blood based biomarkers. 4 tubes of 8.5-ml each will be 
collected. The tubes used will be ACD anti-coagulated Vacutainer (yellow tops). Samples 
will be collected prior to pembrolizumab initiation (may be collected Day 1 cycle 1 pre-
infusion), and transported/shipped to the Substrate Services Core lab for 
processing. (Refer to Appendices F and G) 
 
9.2        Neoadjuvant Pembrolizumab Treatment (Cycle 1, Day 1)  
 
(To be performed prior to receiving treatment-refer to Appendix A) 
 
 Weight (BSA calculation) 
 Vital signs (temp, B/P, pulse) 
  ECOG Performance status 
 Physical exam 
 Adverse events assessment 
 Routine blood work  
 Pregnancy test ≤ 3 days (72 hrs.) prior to first dose of pembrolizumab (for WOCBP only)  
 Dose # 1 Pembrolizumab 200 mg IV  
 
9.3       Neoadjuvant Pembrolizumab Treatment (Cycle 2, Day 22)  
 
 Weight (BSA calculation) 
 Vital signs (temp, B/P, pulse) 
 ECOG Performance Status 
 Physical exam 
 Adverse events assessment 
 Routine blood work 
 Dose #2 Pembrolizumab 
 
9.4         Evaluation at Completion of Neoadjuvant Pembrolizumab and Prior to 
Surgery. 
 
Final visit (if <1 grade 1 toxicity) for those subjects that come off treatment early for progression of 
disease, intolerance to protocol therapy, other reasons, or patient withdraws consent. Safety 

31 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Evaluation should occur 30 days (+/- 5 days) after last dose of pembrolizumab or before initiation 
of a new anti-neoplastic cancer treatment (whichever comes first). 
 
 Medical and Surgical evaluation after completion of pembrolizumab 
 Weight 
 Vital signs (temp, B/P, pulse) 
  ECOG Performance status 
 Physical Exam 
  Routine Blood work 
 Thyroid Functions (T3, FT4, & TSH) 
 Repeat imaging to evaluate tumor (Chest CT)  
 Adverse events assessment  
 Research blood (2nd Collection): blood will be collected to assess longitudinal analyses of T 
cell and MDSC phenotypes and blood based biomarkers. 4 tubes of 8.5-ml each will be 
collected. The tubes used will be ACD anti-coagulated Vacutainer (yellow tops). Samples 
will be collected, and transported/shipped to the Substrate Services Core lab for 
processing. (Refer to Appendices F & G) 
 
9.5         Surgery 
 
Surgery to occur at 4-8 weeks ( d a y s  2 9 - 5 6 )  or subject will be removed from trial unless 
approved by PI. If pembrolizumab dose 2 is delayed, then there should be at least 2 days between 
pembrolizumab infusion and surgery.  
 
The ability to perform surgery will be assessed by the surgeon and will be based on physical exam 
and radiological evaluation. Surgical therapy will be individualized based on the surgical judgment 
and patient preference and is not dictated by study protocol. Excess tumor tissue samples will also 
be collected at time of surgical resection after determination that adequate tumor has been taken by 
surgical pathology for all standard clinical studies. Specific instructions for processing and shipping 
are provided in Appendices G & H.  
 
9.6         Post-surgery Follow-Up Visit (_2-6 weeks following surgery) 
 
Subjects with bulky residual adenopathy such that resection was not attempted will be removed from 
protocol therapy and should receive standard oncology care as deemed appropriate by the treating 
physician. 
 
Subjects with positive surgical margins or N2 disease will be removed from protocol and considered 
for standard of care post-operative radiation +/_ standard chemotherapy as deemed appropriate by 
their physician.  Subjects who are completely resected or who refuse or cannot receive adjuvant 
chemotherapy will be given the option of receiving adjuvant Pembrozulimab. 

32 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
 
Vital signs (temp, B/P, pulse) 
 
Weight 
 
ECOG performance status 
 
Physical exam 
 
Routine blood work 
 
Adverse events assessment* 
 
Research blood sample (3rd collection). Research blood: blood will be collected to 
assess longitudinal analyses of T cell and MDSC phenotypes and blood based biomarkers. 4 
tubes of 8.5-ml each will be collected. The tubes used will be ACD anti-coagulated 
Vacutainer (yellow tops). Samples will be collected and transported/shipped to the 
Substrate Services Core lab for processing. This blood sample to be collected 2-6 weeks 
after surgery and prior to adjuvant therapy (Refer to Appendices F and G). 
 
*All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with 
an AE of grade > 1 will be followed until the resolution of the AE to grade 0-1 or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs that occur within 
90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded. 
 
9.7         Post-Surgery Therapy (Adjuvant Standard Chemotherapy +/- Radiation 
Therapy) 
 
After surgery, patients should be offered all standard therapies including adjuvant chemothera py 
and radiation based on the final pathologic stage of the cancer, tumor margins, and other 
standard clinical criteria. Patients should receive all standard oncology care as deemed 
appropriate by the treating physician. Since none of the post-surgical therapy is study specific, post-
surgical therapy can be given through the primary oncology team. 
 
9.8         Adjuvant Pembrolizumab 
 
Following completion of all standard adjuvant therapy, including chemotherapy and/or radiation 
therapy, patients will receive 4 cycles of pembrolizumab 200 mg every 21 days. Patients who receive 
both adjuvant CT plus adjuvant RT should start Pembrolizumab within 8 months of surgery. 
Patients who receive only one modality of adjuvant therapy (e.g. CT alone or RT alone) should start 
Pembrolizumab within 6 months of surgery. Patients who do not receive any adjuvant therapy 
should start Pembrolizumab within 4 months of surgery 
 
9.8.1 Cycle 1 (Day 1) 
 
Weight (BSA calculation) 
 
Vital signs (temp, B/P, pulse) 

33 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
 ECOG Performance status 
 
Physical exam 
 
Adverse events assessment 
 
Routine blood work 
 
Thyroid functions (T3, FT4, & TSH)  
 
Pregnancy test ≤ 3 days (72 hrs.) prior to first dose of pembrolizumab for WOCBP 
only (per institutional guidelines)  
 
Pembrolizumab 200 mg IV  
 
9.8.2 Cycle 2 (Day 22) 
 
Weight (BSA calculation) 
 
Vital signs (temp, B/P, pulse) 
 
 ECOG Performance status 
 
Physical exam 
 
Adverse events assessment 
 
Routine blood work  
 
Pregnancy test ≤ 3 days (72 hrs.) prior to first dose of pembrolizumab for WOCBP 
only (per institutional guidelines) 
 
Pembrolizumab 200 mg IV  
 
9.8.3 Cycle 3 (Day 43) 
 
Weight (BSA calculation) 
 
Vital signs (temp, B/P, pulse) 
 
ECOG Performance status 
 
Physical exam 
 
Adverse events assessment 
 
Routine blood work  
 
Pregnancy test ≤ 3 days (72 hrs.) prior to first dose of pembrolizumab for WOCBP 
only (per institutional guidelines) 
 
Thyroid functions (T3, FT4, & TSH)  
 
Pembrolizumab 200 mg IV  
 
9.8.4 Cycle 4 (Day 64) 
 
Weight (BSA calculation) 
 
Vital signs (temp, B/P, pulse) 
 
ECOG Performance status 
 
Physical exam 
 
Adverse events assessment 
 
Routine blood work   

34 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
Pregnancy test ≤ 3 days (72 hrs.) prior to first dose of pembrolizumab for WOCBP 
only (per institutional guidelines) 
 
Pembrolizumab 200 mg IV  
 
 
9.8.5 End of Study Visit (*Safety Follow-up) 
End of study evaluation is to occur approximately 30 days or more after last adjuvant 
Pembrolizumab treatment.   
 
Vital signs (temp, B/P, pulse) 
 
Weight 
 
Performance status 
 
Physical exam 
 
Routine blood work 
 
Thyroid functions (T3, FT4, & TSH)  
 
Adverse events assessment 
 
Chest CT if applicable (per radiologic evaluation appendix A) 
 
Research blood (4th Collection): blood will be collected to assess longitudinal analyses 
of T cell and MDSC phenotypes and blood based biomarkers. 4 tubes of 8.5-ml each will be 
collected. The tubes used will be ACD anti-coagulated Vacutainer (yellow tops). Samples 
will be collected, and transported/shipped to the Substrate Services Core lab for 
processing (Refer to Appendices F & G). 
 
*All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of 
Grade > 1 related to Pembrolizumab will be followed until the resolutionof the AE to Grade 0-1, or 
investigator deems stable, or until the beginning of a new anti-neoplastic therapy, whichever occurs 
first.  SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded. 
 
9.8.6 Follow-up 
 
Patients should have follow-up as per standard care of the treating institution. Outcome data 
(recurrence and survival) will be collected every 3-4 months for 2 years after surgery. Following 
that, collect follow-up every 6 months for up to five years.  Follow-up can occur by primary 
oncology provider and data can be collected by phone.  
 
Every effort should be made to collect information regarding disease status during this follow-up 
which may include the start of new anti-neoplastic therapy, disease progression, death, end of the 
study.   
 
10.0 Sample Procurement and Handling  
10.1 
Blood Specimens 
 

35 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Blood will be collected 4 times to assess longitudinal analyses of T cell and MDSC phenotypes and 
other blood based biomarkers. 
 
Samples will be collected to detect activated CD8+ T cells with specificity against tumor antigens 
and CD4 and CD8 functional memory. At each blood collection, 4 tubes of 8.5-ml each will be 
collected. The tubes used will be ACD anti-coagulated Vacutainer (yellow tops).   The following 
time points will have blood collections  
 
(Outside Sites see appendix G for processing/shipping): 
 
Collection 1:  Baseline prior to treatment initiation 
Collection 2:  After dose # 2 pembrolizumab and prior to surgery 
Collection 3:  Two to six weeks after surgery prior to initiation of adjuvant chemotherapy. 
Collection 4:  Three to six weeks after last dose of adjuvant pembrolizumab   
**** Note: it is imperative tube is filled to the fill line for proper additive to blood ratio. Specimen 
is not evaluable if not filled to the fill line.  If unable to obtain the 4 required tubes, fill as many tubes 
as possible to the fill line. 
 
******If EOS (End of Study) occurs and no adjuvant treatment with Pembrolizumab has occurred, 
draw Collection #4 at End of Study visit. 
  
 
10.2 
Surgical Specimens  
 
Patients at Duke will be approached to participate in the “DUHS Biospecimen Repository and 
Processing Core (BRPC)” eIRB 35974 protocol prior to surgery to help coordinate and facilitate 
tissue acquisition.  Tissue will be collected and released as described in this protocol to ensure 
proper involvement of pathology to minimize the chance that a tissue collection event interferes 
with appropriate clinical tissue processing and diagnosis. For those subjects that decline 
participation in this biorepository protocol, tissue will be processed as outlined below. 
 
Tumor specimen samples will be collected at time of definitive surgical resection of tumor. Lung 
tissue is harvested in the frozen section or gross dissection area of the surgical pathology suite.  
The tissue is first examined by a certified anatomic pathologist or surrogate (resident, pathology 
assistant). Relevant margins are inked, removed and examined by frozen section analysis, if 
necessary. It is imperative that harvesting tissue for use in research trials does not impede accurate 
initial assessment of critical features of the tumor resection, most notably margin status.  After the 
specimen has been processed for margin status, the frozen section assessment of the specimen is 
complete (appendix H), a specimen of excess tumor will be released and a c quire d  by  the  Tumor  
Immunology  correlative  science  staff  for  isolation  of  tumor  infiltrating lymphocytes for 
purposes of this protocol. 
 

36 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
OUTSIDE SITES: Please refer to Appendix I for processing/shipping surgical specimen to Duke 
to the Tumor Immunology Laboratory for TILs analysis. Note that the ability to obtain high quality 
TILs from fresh tissue is highly dependent on the tissue procurement. Delays in tissue processing 
usually 
lead 
to 
cell 
death 
and 
RNA 
degradation. 
Please 
carefully 
observe 
the 
precautions/instructions pertaining to shipping. 
 
10.2.1 Genomic  Analysis (Slides/Blocks) 
 
Response of tumors to immune therapy is in part related to the expression of novel antigens 
(neoantigens), abnormal patterns of wild type proteins, and/or viral antigens on the tumors cell 
surface. Genomic studies of the tumor (optional for the subject) will be of interest for comparison to 
tumor response, immune related side effects, and functional immune biomarkers. Future studies will 
utilize FFPE from the tumor resected as part of standard of care to perform relevant genomic analysis 
on the tumor cells. Future scientific studies would be submitted for scientific and IRB review. 
 
   
10.2.2  
Other Biomarkers (blocks) 
 
To ascertain the impact of PD-L1 status on response and endpoints, PD-L1 analysis will be performed 
by QUALTEK Molecular Laboratories. Duke and sites will ship formalin-fixed paraffin embedded 
blocks directly to QUALTEK Molecular Laboratories (Newtown, PA) for analysis of PD-L1. Details 
about shipment are contained in the QualtekMISP Sample Handling Manual.  
 
11.0 TREATMENT 
 
Merck will provide pembrolizumab at no cost for this study. The investigational product is 
defined as a pharmaceutical form of an active ingredient being tested as a reference in the 
study, whether blinded 
or un-blinded. 
In this study, the investigational 
product is 
pembrolizumab. Other medications use d  in  the  study  as  support  or  escape  medication  
for  preventative,  diagnostic,  or therapeutic reasons, as components of the standard of care 
for a given diagnosis, are considered non- investigational products.  
 
11.1 
Treatments Administered 
 
Patients will receive pembrolizumab** as follows: 
 
Neoadjuvant Pembrolizumab: Cycle 1 day 1: pembrolizumab 200 
mg IV 
 
Cycle 2 day 1 (21 days after cycle 1 day 1): pembrolizumab 200 mg IV 
 

37 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Pembrolizumab will be administered as a 30-minute IV infusion (treatment cycle may be delayed up 
to 3 weeks due to toxicity). Sites should make every effort to target infusion timing to be as        close 
to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window 
of -5minutes and +10 minutes is permitted (i.e., allowed infusion time is between 25 and 
40 minutes). 
 
Surgery: Standard surgical evaluation to occur after the last dose of pembrolizuma b 
followed by surgical therapy. 
 
Adjuvant chemotherapy: Is a standard consideration as per NCCN guidelines. Patients will be 
evaluated and offered adjuvant chemotherapy based on standard criteria such as T > 3 cm and/or 
metastases in N1 and/or N2 lymph nodes. Adjuvant chemotherapy is not study specific and 
should be given by commercial supply and standard of care.  
 
Adjuvant radiation: Is sometimes a standard consideration as per NCCN guidelines. Patients 
will be evaluated and offered radiation based on standard criteria such as positive post-operative 
tumor margin and/or presence of metastases in N2 lymph nodes. Adjuvant radiation is not specific 
to this study and should be given as per standard of care.  
 
Adjuvant Pembrolizumab: Three to 6 weeks after completion of all standard therapy including 
adjuvant chemotherapy and/or radiation therapy, patients will receive pembrolizumab 200 mg IV 
every 21 days for 4 doses.  
 
11.2 
Materials and Supplies 
 
Qualified personnel who are familiar with procedures that minimize undue exposure to themselves 
and to the environment 
will undertake the preparation, 
handling 
and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment.  Unused portions of 
injectable chemotherapeutic agents that do not contain a bacteriostatic agent or are prepared with 
unpreserved diluents (i.e., Sterile Water of Injection USP or 0.9% Sodium Chloride for Injection) 
should be discarded within eight hours of vial entry to minimize the risk of bacterial contamination. 
 
11.2.1 Pembrolizumab 
 
Pembrolizumab will be intravenously administered only at the investigational site. As a result, 
patient compliance is ensured. 
 
11.3 
Dose Selection/Modification 
 
11.3.1 Dose Selection 
 

38 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
The rationale for selection of doses to be used in this trial is provided in Section 2 – Background and 
Rationale.   
 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
 
11.3.2 Selection and Timing of Doses 
 
Patients in this study will receive neoadjuvant pembrolizumab on Days 1 and 22, and adjuvant 
pembrolizumab every 21 days for 4 cycles after completion of all standard therapy.  
  
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments have 
been completed as detailed on the Trial Flow Chart (Appendix A).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
 
All trial treatments will be administered on an outpatient basis. Pembrolizumab 200 mg will be 
administered as a 30-minute IV infusion every 3 weeks.  Sites should make every effort to target 
infusion timing to be as close to 30 minutes as possible.  However, given the variability of infusion 
pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 
30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
11.4 
Pembrolizumab Dose Modifications  
 
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 1 below. 
 
If pembrolizumab is delayed more than two weeks due to a related AE, then pembrolizumab will be 
discontinued and patients should proceed to surgical resection when clinically appropriate. 
 
 

39 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
Table 1 
Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold 
Treatment 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) 
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. 
4 
 
 
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 
2-4 
Therapy with pembrolizumab 
can be continued while thyroid  
Therapy with pembrolizumab 
can be continued while thyroid 

40 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Toxicity 
Hold 
Treatment For 
Grade 
Timing for Restarting 
Treatment 
 
Treatment Discontinuation 
replacement therapy is 
instituted 
replacement therapy is 
instituted. 
Infusion 
Reaction 
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 Failure or 
Nephritis 
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 
Myocarditis 
1-2 
Withhold  
Give corticosteroids based on 
AE severity (pred 1-2mg/kg 
then taper) 
3-4 
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. 
aFor 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; Refer to – 
Infusion Treatment Guidelines for further management details. 
cPatients 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 

41 
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the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Toxicity 
Hold 
Treatment For 
Grade 
Timing for Restarting 
Treatment 
 
Treatment Discontinuation 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose.   
 
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 resume 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. 
 
11.5 
Rescue Medications & Supportive Care 
 
11.5.1 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 is instructed to 
follow the ECI reporting guidance (Section 20.7).  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, can 
be found in the ECI guidance document. 
 
 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:  

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the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis treat with intravenous steroids followed by high 
dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
 Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Patients will be monitored 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 3-4 hypothyroidism): 
 In hyperthyroidism, 
non-selective beta-blockers (e.g. propranolol) 
are 
suggested as initial therapy. 

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11 Nov 2018 
 
 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. 
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 2 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
 

44 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Table 2    Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs. 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
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 pre-
medicated 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 pre-
medicated 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: 
Stop Infusion. 
No subsequent dosing 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
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11 Nov 2018 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
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. 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
 
 
11.6 
Dose Modifications for Obese Patients 
 
There is no clearly documented adverse impact of treatment of obese patients. Pembrolizumab is 
being given at a set dose of 200 mg so body weight and/or obesity is not relevant to this study.  
 
12.0 BLINDING 
 
This is an open-label study; therefore, each patient will be aware of his or her own assigned 
treatment. All staff involved in treating and caring for study patients will have full knowledge of 
treatment assignments for those patients under their care.  
 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
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11 Nov 2018 
 
13.0 CONCOMITANT THERAPY/VACCINATIONS  
 
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. Any disease progression requiring other forms of specific anti-tumor 
therapy will be cause for early discontinuation of study therapy. Acceptable and prohibite d 
concomitant therapies are reviewed below.  
 
13.1 
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 30 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 20.5. 
 
13.2 
Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase 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 
 
Radiation therapy other than post-operative radiation for lung cancer 
 
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 may be approved after consultation with the Sponsor. 

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11 Nov 2018 
 
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 describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
14.0 DIET/ACTIVITY/OTHER CONSIDERATIONS 
 
14.1 
Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
 
14.2 
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.  Non-pregnant, non-breast-
feeding women may be enrolled if they are willing to use 2 methods of birth control or are considered 
highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year 
will be considered postmenopausal).  The two birth control methods can be either two barrier methods 
or a barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives 
will include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
 
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, they 
must adhere to the contraception requirement (described above) for the duration of the study and 
during the follow-up period defined in section 20.4 -Reporting of Pregnancy and Lactation to the 
Sponsor and to Merck.  If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
 
14.3 
Use in Pregnancy 
 

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11 Nov 2018 
 
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).   
 
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 20.4.  
14.4 
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. 
 
15.0 TREATMENT COMPLIANCE 
 
Deviation(s) from the  prescribed dosage regimen are to be recorded in the comments section of the 
CRF. 
 
15.1 
Subject Withdrawal/Discontinuation Criteria 
 
The End of Treatment and Follow-up visit procedures are listed in Appendix A (Study Schedule) and 
Section 9.0 (Study Periods-Visit Requirements).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 90 
days after the end of treatment (Section 20.5.1).  Subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up for disease status until disease progression, 
initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up.  For all 
other subject’s outcome data will be collected for 2 years, then every 6 months for up to five years. 
Every effort should be made to collect information regarding disease during this follow-up which 
may include the start of new anti-neoplastic therapy, disease progression, death, or end of study. 
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 9.8.5& 20. .  
 
A subject must be discontinued from the trial for any of the following reasons: 
 

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11 Nov 2018 
 
 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 
Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 17.3.1. A subject 
with evidence of possible target lesion growth or new lesion appearance will not be presumed 
to have progressed and will proceed to surgery as long as all possible site(s) of disease are 
deemed resectable by the surgeon. 
 
 
There is toxicity deemed by the investigator or subject to be unacceptable 
 
Concurrent 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 investigator, for any reason, stops the study  
 
Termination of the study by Merck 
 
The patient, for any reason, requires treatment with another systemic agent 
potentially effective for treatment of the study indication. In this case, discontinuation from 
the study occurs immediately upon introduction of the new agent. 
 
A patient who cannot be administered the study drug after a 21-day delay must be 
discontinued from the study treatment. 
 
A patient with bulky residual adenopathy such that resection is not attempted will 
be removed from protocol therapy and  should  receive  standard  oncology  care  as  deemed  
appropriate  by  the  treating physician. 
 
The compulsory detention for the treatment of either a psychiatric or physical (e.g. 
infections disease) illness. 
 
There is clear evidence of progressive disease. 
In previous studies with pembrolizumab in solid tumors there has been transient increase 
in lesion size due to inflammatory immune response followed by clear evidence of lesion 
regression. Therefore, CAT scan evidence of progression in the global tumor burden will 
not be criteria for discontinuation or by itself deemed evidence of progression on therapy. 
It is possible index tumor may enlarge > 25% or new lesions appear after 2 doses 
pembrolizumab before repeat CAT scan. Surgical staging at time of resection will verify 
progression or whether robust inflammatory response was misinterpreted as progression 
on repeat CAT scans. 
 
15.2 
Clinical Criteria for Early Trial Termination 
 
 Quality or quantity of data recording is inaccurate or incomplete 
 Poor adherence to protocol and regulatory requirements 

50 
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11 Nov 2018 
 
 Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
 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. 
 
15.3 
Subject Replacement Strategy 
 
Subjects may be replaced during this study if they did not receive pembrolizumab for any reason. 
Otherwise replacement decisions will be made between the sponsor and investigator on a case-by-
case basis. 
 
15.4 
Discontinuation of Study 
 
This study can be terminated at any time for any reason by the PI-sponsor or the IRB.  If this occurs, 
all subjects on study should be notified as soon as possible.  Additional procedures and/or follow up 
should occur in  accordance  with  Section  15.1  which  describes  procedures  and  process  for  
prematurely withdrawn patients. 
 
16.0 LABELING, PACKAGING, STORAGE, AND RETURN OF 
CLINICAL SUPPLIES 
 
Merck Pharmaceuticals will provide pembrolizumab at no cost for this study. 
 
16.1 
Investigational Product 
 
Pembrolizumab is a potent and highly selective humanized me of the IgG4/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, PDL1and PD-L2. 
 
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 3. 
 
Table 3   Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 

51 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
16.2 
Packaging and Labeling Information  
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
Pharmacist will receive open label packages of the drug.  
 
16.3 
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. 
 
16.4 
Storage, Handling and Disposal 
 
Clinical supplies must be stored in a secure, limited access location under the storage conditions 
specified on the label.   
 
As with all injectable drugs, care should be taken when handling and preparing pembrolizuma b. 
Whenever possible, pembrolizumab should be prepared in a laminar flow hood or safety cabinet 
using standard precautions for the safe handling of intravenous agents applying aseptic technique. 
Latex gloves are required. If pembrolizumab concentrate or solution comes in contact with skin or 
mucosa, immediately and thoroughly wash with soap and water.  After final drug reconciliation, 
unused pembrolizumab solution should be disposed at the site following procedures for the disposal 
of anticancer drugs. 
 
16.5 
Dispensing 
 
It is the responsibility of the investigator to ensure that pembrolizumab is only dispensed to study 
subjects. The pembrolizumab must be dispensed only from official study sites by authorized 
personnel according to local regulations. Clinical supplies may not be used for any purpose other 
than that stated in the protocol. 
 
16.6 
Drug Ordering and Accountability 
 
16.6.1 Initial and Re-Supply Orders 
 
Following 
submission 
and approval of the required regulatory documents, a supply of 
pembrolizumab may be ordered from Merck.  Refer to the pharmacy manual for product ordering. 
 
16.6.2 Pembrolizumab Accountability 
 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
It is the responsibility of the investigator to ensure that a current record of pembrolizumab disposition 
is maintained at each study site where pembrolizumab is inventoried and disposed. This inventory 
must be available for monitoring. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
 
 Amount received and placed in storage area.  
 Amount currently in storage area. 
 Label ID number or batch number and use date or expiry date. 
 Dates and initials 
of person responsible for each pembrolizumab 
inventory 
entry/movement. 
 Amount dispensed to and returned by each subject, including unique subject 
identifiers.  
 Amount transferred to another area/site for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 Amount destroyed at study site. 
 
All supplies, including unused, partially used or empty containers will be destroyed according to sites 
drug destruction policy. 
 
16.6.3 Pembrolizumab 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.  
 
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 
a rra nge  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. 
 
16.6.4 Preparation and Administration 
 
Refer to the pharmacy manual for product preparation instructions. 
 
Pembrolizumab will be administered as a 30-minute IV infusion using an infusion pump (treatment 
cycles may be delayed for 3 weeks due to toxicity as described in Section 11). Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible.  However, given the 
variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). Attach the infusion line to the pump and prime the 
line, either with normal saline (at least 25 mL) or with infusion solution as per local SOP, before 

53 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
starting the infusion. Maximum infusion rate should not exceed 6.7 ml/min through a peripheral or 
indwelling catheter. Use 30 mL normal saline to flush the infusion line at the end of the infusion if 
institutional guidelines allow. 
 
Unused infusion solution should not be used for another infusion of the same participant or a different 
participant. 
 
DO NOT administer the product as an intravenous push or bolus. 
 
DO NOT combine, dilute or administer it as an infusion with other medicinal products. 
A central line is not required for Pembrolizumab administration, but may be used if available. 
The following infusion set materials are compatible with Pembrolizumab 
 PVC infusion set that is plasticized using Di-2-ethylhexyl Terephthalate DEHP 
 PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
 Polyehtylene lined PVC infusion set 
 Polyrethane 
 Plybutadiene 
 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 μm in-line filter made of polyethersulfone 
(PES) or polysulfone must be used during administration to remove any adventitious particles. If the 
infusion set does not contain a 0.2 to 5 μm in-line filter, it is recommended to use a 0.2 to 5m add-on 
filter which may contain an extension line (the materials of the extension line and filter should be as 
mentioned above). 
 
17.0 OUTCOME MEASUREMENTS 
 
17.1 
Criteria for Response, Progression, and Relapse (Solid Tumors) 
 
Patients should be reevaluated by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) after 
completion of neoadjuvant pembrolizumab. Unidimensional measurements in the largest diameter 
will be used. 
 
17.1.1 Measurable Disease 
 
Measurable le s io n s  a re  defined as those that can be accurately measured (select largest, most 
reproducible lesions) in at least one dimension (largest diameter in the plane of measurement is 
to be recorded) as ≥20 mm with x-ray or ≥10 mm with CT scan (CT scan slice thickness ≤5 mm) 
or MRI. If scan has slice thickness >5mm, the minimum size for a measurable lesion should be twice 
the slice thickness. Measurable lesions will also include those that can be directly measured on 
physical exam with calipers and are at least 10 mm. Lesions which cannot be accurately measured 

54 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
with calipers should be recorded as non-measurable. All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
17.1.2 Non-Measurable Disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with x-
ray or <10 mm using CT or MRI scan), are considered non-measurable disease. Lesions considered 
non- measurable include: bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitic 
involvement 
of skin 
or lungs, 
inflammatory 
breast disease, 
abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques. 
 
17.1.3 Target Lesions 
 
All measurable lesions up to a maximum of two lesions per organ (total 5 maximum target lesions) 
are considered target lesions. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. 
The baseline sum LD will be used as reference by which to characterize the objective tumor 
response. 
 
17.1.4 Non-Target Lesions 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Non-target lesions include measurable lesions that exceed the 
maximum numbers per organ or total of all involved organs as well as non-measurable lesions. 
Measurements of these lesions are not required but the presence or absence of each should be noted 
throughout follow-up. 
 
17.2 
Guidelines for Evaluation of Measureable/Evaluable Disease 
 
If subject has measurable disease, all measurements should be taken and recorded in metric notation. 
For subjects with evaluable disease only, the sites of disease will be noted at baseline and 
followed for increase or decrease in size and/or new disease. All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and never more than 30 days before 
the beginning of the treatment, unless otherwise specified. The same method of assessment and the 
same technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used to assess the antitumor effect of a treatment. 
 

55 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
≥10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
CT and MRI: These techniques should be performed with cuts of 5 mm or less in slice thickness 
contiguously. If scan has slice thickness >5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. CT is currently the best available and reproducible method to measure 
lesions for response assessment. 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
17.3 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR): At least a 30% decrease in the sum of the largest diameter (LD) of target 
lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD): At least a 20% increase and a 5 mm absolute increase in the sum of 
the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions. If scan showing new lesion is of anatomical 
region which was not included in baseline scans, it is PD. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level 
 
Incomplete Response/Stable Disease ( SD):  Persistence o f  one  or more  non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
(not attributable to different scanning technique or non-tumor) of existing non-target lesions. 
(‘Unequivocal progression’ must be an overall level of substantial worsening in non-target disease 
that is of a magnitude that, even in the presence of SD or PR in target disease, the overall tumor 

56 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
burden has increased sufficiently to merit discontinuation of therapy.) If scan showing new lesion 
is of anatomical region which was not included in baseline scans, it is PD. 
 
 
 
Table 4: Evaluation of Best Overall Response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17.3.1 Immune-Related Tumor Assessment 
 
Pembrolizumab is an immuno-stimulating antibody with evidence of anti-cancer activity (durable 
objective response and stable disease) in subjects with advanced melanoma, including subjects with 
established brain disease. Observations of clinical activity defined by tumor response endpoints 
defined by conventional criteria (e.g., mWHO) may be inadequate to realize the kinetics and 
magnitude of clinical benefit achieved with pembrolizumab. 
 
Histopathologic evidence has demonstrated pembrolizumab can produce an influx or expansion of 
tumor infiltrating lymphocytes. Therefore, early increases in lesion size detected radiologically or 
upon gross examination could be misinterpreted as progressive tumor growth and precede objective 
tumor shrinkage. In addition, the appearance of new lesions may have categorized a subject to have 
progressive disease using conventional tumor assessment criteria despite the concurrent observation 
of objective tumor responses in pre-existing lesions and a net reduction in global tumor burden that 
includes the new lesions. 
 
Therefore, patients with evidence of possible target lesion growth or new lesion appearance will not 
be presumed to have progressed and will proceed to surgery as long as all possible site of disease are 
deemed resectable by the surgeon. 
 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 

57 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
17.4 
Cytology and Histology 
 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed 
by cytology/histology. These techniques can be used to differentiate between PR and CR in rare 
cases (for example, residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain).  The cytological confirmation  of the neoplastic  origin  of any 
effusion  that  appears  or worsens during treatment when the measurable tumor has met criteria 
for response or stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
17.5 
Pathologic Response Criteria 
 
After receiving preoperative pembrolizumab, criteria for examining resected tumor will be as 
follows: 
 
 No Response: no evidence of cell death or tumor necrosis. 
 Partial Response: ≥30% tumor necrosis or cell death. 
 Complete Response: no evidence of viable tumor in surgical specimen (includes lung 
tissue and dissected lymph nodes) 
 
17.6 
Disease-Free Survival 
 
Disease-free survival (DFS) is defined as the time from surgical resection to disease recurrence 
(first disease recurrence or death, whichever comes first) after surgery. 
 
17.7 
Survival 
 
Survival will be measured from the date of enrollment. 
 
18.0 COSTS TO THE SUBJECT 
 
There will be no additional costs to subjects as a result of being in this study.  Merck will provide the 
study drug pembrolizumab free of charge. The research specific blood and tissue testing will also be 
done at no charge to the subject. 
 
Routine medical care given for the disease under study (which is care a subject would receive whether 
or not they were in this study), such as the standard chemotherapy drugs and surgery, will be charged 
to subject’s insurance company.  
 
 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
19.0 STUDY ASSESSMENTS  
 
19.1 
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.   
 
19.2 
Prior and Concomitant Medications Review 
 
19.2.1 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 the trial.  Treatment for the disease for which the subject has enrolled in this study will be 
recorded separately and not listed as a prior medication.  
 
19.2.2 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 
20.51. 
 
19.3 
Disease Details and Treatments 
 
19.3.1 Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
 
19.3.2 Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
19.3.3 Subsequent Anti-Cancer Therapy Status 
 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the 
last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after the 
last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the first dose of the 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
new therapy.  Once new anti-cancer therapy has been initiated the subject will move into survival 
follow-up.  
 
19.4 
Adverse Event (AE) Monitoring 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Study Schedule (Appendix A) 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 20.0).  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).  
Please refer to section 20 for detailed information regarding the assessment and recording of AEs.  
 
19.5 
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.  A full 
physical exam should be performed during screening.  
 
19.5.1 Directed Physical Exam 
 
For cycles that do not require a full physical exam per Study Schedule- Appendix A, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration. 
 
19.6 
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 Calendar 
(Appendix A).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
 
19.7 
Laboratory Procedures/Assessments 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis and others) are 
specified in Table 5 (below).  

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11 Nov 2018 
 
 
Table 5- Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human 
chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and 
differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity  
aPTT 
Red Blood Cell 
Count 
Lactate dehydrogenase (LDH) Microscopic exam (If 
abnormal)  
Total triiodothyronine 
(T3) 
Absolute Neutrophil 
Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute 
Lymphocyte Count 
  (CO2 or bicarbonate) 
 
Thyroid stimulating 
hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative 
studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total 
bilirubin is elevated above the 
upper limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. ‡ If considered standard of care in your region. 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
20.0 SAFETY 
 
All patients who receive at least one dose of pembrolizumab will be considered evaluable for safety 
parameters. Additionally, any occurrence of a non-SAE or SAE from time of consent forward, up to 
and including follow-up visits, will be reported as per Adverse Event Reporting sections below. 
Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (http://ctep.cancer.gov). Safety 
assessments will be based on medical review of adverse event reports and the results of vital sign 
measurements, physical examinations, and clinical laboratory tests. 
 
20.1 
Safety Monitoring and Reporting 
 
The PI at each institution is responsible for the identification and documentation of adverse events 
and serious adverse   events, as defined below.  At each study visit, the PI or designee must assess, 
through non-suggestive inquiries of the subject or evaluation of study assessments, whether an AE or 
SAE has occurred.  Adverse events that are judged to be Serious Adverse Events by the institutiona l 
PI should be reported to the Duke Cancer Institute Safety Desk as outlined in Appendix K- Reporting 
Procedures for Adverse Events and Serious Adverse Events by Participating Sites. 
 
20.2 
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 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. 
 

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11 Nov 2018 
 
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 
allocation/randomization 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 allocation/randomization 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 20.5.1 & 20.6. 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.  
 
20.3 
Definition of an Overdose for This Protocol & Reporting to Sponsor and 
to Merck 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or 
greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the adverse 
event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious 
Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose without 
adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Duke Sponsor (DCI Safety Desk) who will report within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 

63 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
20.4 
Reporting of 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 
allocation/randomization 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 allocation/randomization 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 must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important 
Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be 
reported. 
 
Such events must be reported within 24 hours to the Duke Sponsor (DCI Safety Desk) who will report 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-
1220) 
 
20.5 
Immediate Reporting of Serious Adverse Events 
 
20.5.1 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; 
 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. 

64 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 6 for additional details regarding each of the above criteria. 
 
For 
the time 
period 
beginning 
when 
the consent 
form 
is 
signed 
until 
treatment 
allocation/randomization, 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  that occurs to any subject 
must be reported within 24 hours to the Duke Sponsor (DCI Safety Desk) who will report 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 allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any 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 24 hours to the Duke Sponsor (DCI Safety 
Desk) who will report 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 specified in the paragraph above, or 
at any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Duke 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 forwarded to the DCI Safety Desk 
for forwarding to Merck Global Safety facsimile number:  +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports are 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 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. 
 
20.6 
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 Duke Sponsor (DCI Safety Desk) who will report within 
2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 

65 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
For 
the time 
period 
beginning 
when 
the consent 
form 
is 
signed 
until 
treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 24 hours to 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 allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to 
Merck product, must be reported within 24 hours to 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 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 
2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing. * 
 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of the 
criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation 
for an underlying etiology. 
 
20.7 
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 
20.5- 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. 
 
The Sponsor will monitor un-blinded 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 

66 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
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. 
 
20.8 
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. 
 
 

67 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
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 
obersvations 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 †). 

68 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
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. 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): 
 
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 
 
 
 
Relationship The following components are to be used to assess the relationship between the 
test drug and the AE: (continued) 
to Merck  
Product 
(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 Sponser’s product; or (3) the trial is a single-dose drug trial); or 
(4) Sponser’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? 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
21.0 QUALITY CONTROL AND QUALITY ASSURANCE 
 
Please refer to the External Site Monitoring Plan developed for the protocol.  
 
21.1 
Audits 
 
The Duke School of Medicine Clinical Trials Quality OARC (Office of Audit and Research Compliance) 
office may conduct audits to evaluate compliance with the protocol and the principles of GCP.   The 
PI agrees to allow the OARC auditor(s) direct access to all relevant documents and to allocate his/her 
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) Sponser’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 REEXPOSURE TO 
MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE 
SPONSER 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. 
Record one of the 
following 
Use the following scale of criteria as guidance (not all criteria must 
be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to Merck product.  The temporal 
sequence of the AE onset relative to the administration of Merck 
product is reasonable.  The AE is more likely explained by Merck 
product than by another cause. 
No, there is not a 
reasonable possibility of 
Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the 
AE onset relative to administration of Merck product is not reasonable 
OR  the AEis more likely explained by another cause than the Merck 
product.  (Also entered for a subject with overdose without an 
associated AE.) 

70 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
time and the time of the study team to the OARC auditor(s) in order to discuss findings and any relevant 
issues. 
 
OARC audits are designed to protect the rights and well-being of human research subjects. OARC audits 
may be routine or directed (for cause). Routine audits are selected based upon risk metrics generally 
geared towards  high  subject  enrollment,  studies  with  limited  oversight  or  monitoring,  Investigator 
initiated Investigational Drugs or Devices, federally-funded studies, high degree of risk (based upon 
adverse  events,  type  of  study,  or  vulnerable  populations),  Phase  I  studies,  or  studies  that  involve 
Medicare populations. Directed audits occur at the directive of the IRB or an authorized Institutiona l 
Official. 
 
OARC audits examine research studies/clinical trials methodology, processes and systems to assess 
whether the research is conducted according to the protocol approved by the DUHS IRB. The primary 
purpose of the audit/review is to verify that the standards for safety of human subjects in clinical trials 
and the quality of data produced by the clinical trial research are met. The audit/review will serve as 
a quality assurance measure, internal to the institution. Additional goals of such audits are to detect 
both random and systemic errors occurring during the conduct of clinical research and to emphasize “best 
practices” in the research/clinical trials environment. 
 
22.0 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
 
22.1 
Investigator Responsibilities 
 
Each participating institution is responsible for appropriately recording adverse events and for reporting 
serious adverse events to the DCI Safety Desk (per Appendix K) and to their local Institutional IRBs in 
accordance with the reporting requirements.  
 
22.2 
Institutional Review 
 
The protocol, informed consent form, advertising material, and additional protocol-related documents will 
be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) 
for review.  The study may be initiated only after the Duke Principal Investigator has received written and 
dated approval from the CPC and IRB. PIs at participating sites must obtain appropriate institutiona l 
approvals, including, but not limited to, local IRB approval.  
 
Principal Investigators must submit and obtain approval from their IRBs for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC at Duke will be informed about any 

71 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
protocol amendments that potentially affect research design or data analysis (i.e. amendments affecting 
subject population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.). 
 
Principal Investigators must obtain protocol re-approval from their IRBs within 1 year of the most recent 
IRB approval.  The Duke Principal Investigator will also obtain protocol re-approval from the CPC within 
1 year of the most recent IRB approval, for as long as the protocol remains open to subject enrollment. 
 
22.3 
Protocol Amendments 
 
All protocol amendments must be initiated by the Duke Principal Investigator and approved by the Duke 
IRB prior to implementation. Protocol amendments will be disseminated to participating sites for local 
IRB approval. IRB approval is not required for protocol changes that occur to protect the safety of a 
subject from an immediate hazard.  However, the Principal Investigators must report these to Duke and 
inform their IRBs and all other applicable regulatory agencies of such action immediately. 
 
Though not yet required, the CPC will be informed about any protocol amendments that potentially affect 
research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion 
criteria, agent administration, etc.). 
 
22.4 
Departures from the Protocol and Reporting of Protocol Deviations 
 
There should be no departure from the protocol if at all possible. If an emergency occurs that requires 
departure from this protocol, the principal investigator or other physician in attendance in such an 
emergency will, if circumstances and time permit, contact the Duke PI immediately by phone. Such 
contacts with the PI will be made to permit a decision as to whether or not the subject will be continued 
on study.  
 
Departures from the protocol and protocol deviations or violations need to be clearly documented on a 
Notification of Protocol Deviation/Violation form. These are events that are likely to adversely affect: 
(i) the rights and welfare of the research subject; (ii) the safety of the research subject; (iii) the 
integrity of the research data; and/or (iv) the subject’s willingness to continue study participation. 
Participating sites must report protocol deviations or violations to Duke within 7 business days. 
These events will be reviewed by Duke and reported to the Duke PI as deemed necessary. 
However, any unanticipated study-related death must be reported to Duke within 24 hours of the 
occurrence of the event. 
 
22.5 
Compliance with Trial Registration and Posting Requirements  
 
This clinical trial will be posted 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.  

72 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
22.6 
Conflict of Interest 
 
The Principal Investigators and Sub-Investigators must comply with applicable federal, state, and local 
regulations regarding reporting and disclosure of conflict of interest.  Conflicts of interest may arise from 
situations in which financial or other personal considerations have the potential to compromise or bias 
professional judgment and objectivity.  Conflicts of interest include but are not limited to royalty or 
consulting fees, speaking honoraria, advisory board appointments, publicly-traded or privately-held 
equities, stock options, intellectual property, and gifts. 
 
The Duke University School of Medicine’s Research Integrity Office (RIO) reviews and manages 
research-related conflicts of interest.  The Duke Principal Investigator and Sub-Investigators must report 
conflicts of interest annually and within 10 days of a change in status, and when applicable, must have a 
documented management plan that is developed in conjunction with the Duke RIO and approved by the 
IRB/IEC. PIs at participating sites must comply with local institutional requirements regarding conflict to 
interest reporting.  
 
22.7 
Informed Consent/Informed Consent Process 
 
Principal Investigators or the ir designee will fully explain the purpose and potential risks and benefits 
of the study to the patient prior to enrollment, and address any questions posed by the patient. In 
accordance with federal guidelines, all patients will sign a statement of informed consent, which has 
been approved by the IRB. The patient will receive a copy of the executed consent document. The signed 
consent will be retained at the investigative site for each patient. The informed consent document serves 
as authorization as deemed under HIPAA and contains the appropriate statements regarding privacy and 
confidentiality of protected health information (PHI) as well as information on withdrawal from the 
study. The investigator or designee will explain to each patient (or legally authorized representative) the 
nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits, and any discomfort the  study  may  entail.  Each patient will  be  informed  that  participation  
in  the  study  is voluntary and that he/she may withdraw from the study at any time and that withdrawal 
of consent will not affect his/her subsequent medical treatment or relationship with the treating 
physician. The patient will have as much time as he/she may need to make an informed decision 
about the study and all treatment related questions will be answered. The consent discussion should 
occur in an exam room or a private area where it is just the research staff, the patient and his/her 
family/significant other(s) if desired. 
 
The informed consent will be given by means of a standard written statement, written in non-technical 
language. For those that cannot read, or are blind, the consenter will read the consent form verbatim 
in the presence of a witness. The patient will read and consider the statement before signing and dating 
the document, and should be given a copy of the signed document. If the patient is unable to sign, 
make another kind of mark (like an X) to indicate consent. The person obtaining consent will document 
at the bottom of the consent form that the consent  was read out loud to the patient by (name of 

73 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
person obtaining consent).  If an X or mark is used instead of a signature, the person obtaining consent 
will note on the consent form that the subject wrote a mark or X instead of a signature.   The witness will 
sign the consent form.  Subjects who do not read/understand English  may be potentially  enrolled  
following DUHS HRPP policy, including obtaining IRB approval of either a short form or long form 
consent translation. No patient will enter the study before his/her informed consent document has been 
obtained. Before, during, and after the consent is signed, the research team and investigators will be 
available in person and by phone to answer any questions the participants may have.   Any and all 
other available treatment options are offered to the patient in order to avoid undue influence.   
Participants 
are not offered compensation for this study in order to avoid any monetary 
coercion/influence. The PI is responsible for ensuring that appropriate signatures have been obtained 
prior to the performance of any protocol procedures and prior to the administration of study drug. Consent 
must be documented by the subject’s (or legal representative) dated/timed signature along with the 
dated/timed signature of the person conducting the consent discussion.  The Principal Investigator or 
designee is responsible for asking the subject whether the subject wishes to notify his/her primary care 
physician about participation in the study.  If the subject agrees to such notification, the Principal 
Investigator will inform the subject’s primary care physician about the subject’s participation in the 
clinical study. 
 
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 authorized 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 authorized representative’s dated signature. 
 
23.0 PRIVACY, DATA STORAGE, AND CONFIDENTIALITY 
 
All subject data will be identified by a subject identification number and subject initials only to protect 
the subjects’ privacy.  The data will be blinded accordingly in all data analysis. Subject name or 
identifiers will not be used in reports, presentations at scientific meetings, or publications in scientific 
journals. 
 
However, in compliance with federal guidelines, investigators will permit representatives from the 
Duke School of Medicine Office of Audit and Research Compliance and/or Duke Cancer Institute 
Monitoring team to review that portion of the subject’s medical record that is directly related to the study. 
This will include all relevant study documentation including medical histories to verify eligibility, 
laboratory test results to verify transcription accuracy, X-ray reports, admission/discharge summaries 
for hospital/outpatient admissions while the subject is on-study, and autopsy reports for deaths occurring 
during the study. As part of the required content of the informed consent, the subject will be informed 
that his medical record may be reviewed. Should access to the medical record require a separate waiver 

74 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
or authorization, it is the PI’s or the PI’s designee’s responsibility to obtain such permission from the 
patient in writing before the subject is entered into the study. 
 
Principal Investigators will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.   
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the 
course of the study.  Prospective participants will be consented in an exam room where it is just the 
research staff, the patient and his family, if desired. For all future visits, interactions with research staff 
(study doctor and study coordinators) regarding research activities will take place in a private exam room. 
All research related interactions with the participant will be conducted by qualified research staff who are 
directly involved in the conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and 
key accessible only by the research staff. Subjects will be identified only by a unique study number and 
subject initials.  Electronic records of subject data will be maintained using a dedicated database 
(MediData RAVE) which is housed in an encrypted and password-protected, DCI file server.  Access to 
electronic databases will be limited to authorized key personnel only.  Subject data may be stored 
temporarily on encrypted and password-protected portable memory devices such as flash drives and 
external hard drives, but only when absolutely necessary.  Data stored on portable memory devices will 
be de-identified.  Subject data will be deleted from the portable memory device at the earliest opportunity.  
The security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.    
 
24.0 DATA COLLECTION AND MAINTENANCE 
 
24.1 
Study Documentation 
 
Study documentation includes but is not limited to source documents, case report forms, monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, 
and regulatory documents that can be found in the DCI-mandated “Regulatory Binder”, which includes 
but is not limited to signed protocol and amendments, approved and signed informed consent forms, 
FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution 
records. 
 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records,  clinical  and  office  charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, 

75 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories 
and at medico-technical departments involved in the clinical trial.  When possible, the original record 
should be retained as the source document.   However, a photocopy is acceptable provided that it is 
a clear, legible, and an exact duplication of the original document. 
 
The research nurse, re se a rch c oordina tor, data manager and PI are responsible for ensuring that 
data extraction (information required by the protocol) is completed in a timely manner for every patient 
enrolled on study. The following forms are an integral part of the study data and will be maintained 
in the patient’s clinical or research chart in accord with the institution’s practice. Any errors on the 
form should be lined through, but not obliterated with the correction inserted, initialed and dated by 
the person making the correction: 
 
Eligibility Checklist 
Serious and Non-Serious Adverse Event Forms (if applicable)  
Protocol Deviation Form (if applicable) 
 
24.2 
Case Report Forms 
 
An electronic CRF (eCRF) will be the primary data collection document for the study. The CRF will 
be updated within two weeks of acquisition of new source data.  The electronic records of subject data 
will be maintained using a dedicated database (Medidata Rave or Redcap) which is housed in an 
encrypted and password-protected DCI file server).  Access to electronic databases will be limited to 
the PI and designated study staff listed on key personnel.  Subject data may be stored temporarily on 
encrypted and password-protected portable memory devices such as flash drives and external hard drives, 
but only when absolutely necessary.  Data stored on portable memory devices will be de-identified.  
Subject data will  be  deleted  from  the  portable  memory  device  at  the  earliest opportunity.  The 
security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine. 
 
The CRFs will be updated in a timely manner following acquisition of new source data.  Only the PI and 
designated staff (as listed on key personnel), will be permitted to make entries, changes, or corrections 
in the eCRF. 
 
An audit trail will be maintained automatically by the eCRF management system. (Me dida ta  Ra ve  
or RedCap).  All users of this system will complete user training as required or appropriate per 
regulations. 
 
Users of the electronic CRF will have access based on their specific roles in the protocol. 
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be 
alerted to the presence of data inconsistencies.  Additionally, the data manager and/or designees (per key 
personnel) will cross-reference the data to verify accuracy.  Missing or implausible data will be 

76 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of data, 
completion or confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
 
All me dic a l te rms will be coded with MedDRA(Medical Dictionary for Regulatory Activities). 
Medication will be coded according to the World Health Organization Drug Dictionary. 
 
24.3 
Data Management Procedures and Data Verification 
 
Users of the electronic CRF will have access based on their specific roles in the protocol.    Completeness 
of entered data will be checked automatically by the eCRF system, and users will be alerted to the presence 
of data inconsistencies.   Additionally, the data manager and/or research nurse coordinator will cross-
reference the data to verify accuracy.  Missing or implausible data will be highlighted for the PI requiring 
appropriate responses (i.e. confirmation of data, correction of data, completion or confirmation that data 
is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
 
25.0 STUDY CLOSURE 
 
Following completion of the studies, the PI will be responsible for ensuring the following activities have 
been completed if applicable for the study: 
 
Date Clarification and/or resolution 
 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
 
Review of site study records for completeness 
 
Shipment of all remaining laboratory samples to designated laboratories (if applicable). 
Upon completion of the study, research records will be archived and handled per DUHS (or participating 
Institution’s) HRPP policy. 
 
25.1 
Records Retention  
 
The Principal Investigator will maintain study-related records for the longer of a period of: 
-at least two years after the date on which a New Drug Application is approved by the FDA (if an 
IND is involved) 
-at least two years after formal withdrawal of the IND associated with this protocol (if an IND is 
involved) 
-at least six years after study completion (Duke policy) 
 

77 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
26.0 APPROPRIATENESS OF MEASUREMENTS 
 
There are no surrogate endpoints used in this study. All efficacy and safety assessments used in this 
study are standard and appropriate for an oncology study. 
 
27.0 STATISTICAL METHODS AND ANALYTICAL PLANS 
27.1 
Statistical Considerations 
 
 
Sample size justification 
 
Futility Analysis 
 
Futility analysis is often used for assessing clinical efficacy before the trial reaches target accrual and stops 
the trial early if the therapy clearly performs worse than control. The primary objective of this one-arm 
phase II trial is not to evaluate the efficacy of pembrolizumab in this population. Since it is unlikely that 
the therapy will harm the patients, a futility analysis on the percentage of patients with adequate TIL 
collection is unnecessary. 
 
Evaluation of Investigational Therapy Safety and Feasibility 
 
Analytic methods 
Overview 
The primary objective of the single arm phase II trial is to determine whether the surgery feasibility rate 
of neoadjuvant pembrolizumab is not significantly worse than the historical surgical feasibility rate of 
neoadjuvant chemotherapy. Surgery feasibility rate of a neoadjuvant therapy is the percent of patients who 
are able to undertake surgery after the neoadjuvant therapy. A total of 30 evaluable patients will be entered 
to the single arm trial. Taking 15% rate of cancellation and ineligibility into account, the trial will enroll 
a total of 35 patients and eligible subjects (not screen failures) will be followed for 2 years for both disease 
recurrence and death. Following that, patients will be followed every 6 months for up to five years. 
 
Primary Objective Sample Size Justification 
According to Pisters et al (JCO 2010), approximately 80% of subjects undergo surgical exploration within 
42 days of day 1 of the last cycle of standard neoadjuvant chemotherapy.  We would like to test the following 
hypotheses:  
H0: p >= 0.80 vs. Ha: p <= 0.65 
wherep is the true surgery feasibility rates after combined neoadjuvant chemotherapy and pembrolizumab. 
With 30 evaluable patients receiving protocol treatment, the study has approximately 84.6% power 
rejecting H0:  p>=0.80 when p=0.65 at one-sided significance level of 15%. 
 

78 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Adverse event monitoring:  In this trial design it is difficult to accurately attribute adverse events to 
pembrolizumab, surgery, or other causes.  Further, the analysis of treatment toxicities as isolated events 
will not best represent whether or not the combination of pembrolizumab followed by surgery is safe and 
feasible. Therefore, this safety and feasibility trial will be evaluated by the following criteria: 
 
1) Whether the cumulative percentage of deaths among all treated patients related to any of the study 
treatments from the first pembrolizumab treatment until 30 days after surgery exceeds 17%. 
2) If the cumulative percentage of all treated patients deemed unable to go to surgery due to adverse events 
attributed to neoadjuvant therapy exceeds 20%.  The percentage of patients unable to go to surgery after 
pembrolizumab is a conservative estimate based on data reported for a SWOG trial that studied 
neoadjuvant chemotherapy in early stage lung cancer (22).  
 
The first 10 treated patients will be evaluated for safety and feasibility. If in the first ten patients  the 
criteria for overall therapy being not safe or feasible is met, accrual to the study will be suspended to 
allow for investigation. After consideration by the study team and the IRB, a decision will be made as 
to whether accrual can be resumed, potentially with modifications to entry criteria and/or study conduct.  
In addition, all toxicity patterns will be monitored by the DCI Safety Oversight Committee.  
 
The trial will be stopped for accrual whenever a total of 35 patients are registered or at least one of the 
thresholds of the safety and feasibility criteria is exceeded. In the event either of these two thresholds is 
exceeded, the investigational therapy will be considered “infeasible” in this setting. 
 
Accrual and follow-up 
With an expected rate of 2 patients being enrolled each month, the trial will take about 16 months to reach 
the target accrual.  All registered patients will be followed for tumor response, disease free survival and 
overall survival. 
 
Statistical Analysis Plan 
Surgery feasibility rate, the primary endpoint of the trial, will be analyzed using the data from all evaluable 
patients, who are defined as the patients who meet eligibility criteria and has received at least 1 dose of 
pembrolizumab. The surgery feasibility rate of neoadjuvant pembrolizumab as well as its confidence interval 
will be estimated.  
 
Secondary Objectives 
All secondary objectives are considered exploratory in nature, and type I error will not be controlled for 
multiplicity. P-values for these statistical tests will be provided for descriptive purposes.  However, if a 
statistical test on a secondary outcome is significant at the 2-sided significance level of 0.01, the finding will 
be considered worthy of future investigation.  
1) We will estimate the rate of objective response rate for the protocol treatment. The definition of objective 
response will be measured by RECIST 1.1. The objective response rate (ORR=CR+PR) along with its 95% 
exact confidence interval will be estimated. 

79 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
2)  We will evaluate disease-free survival and patterns of metastases after protocol treatment. Disease-free 
survival (DFS) is defined as the time from surgical resection to disease recurrence (first disease recurrence or 
death, whichever comes first) after surgery. The Kaplan-Meier estimator will be used to estimate median DFS 
and its confidence interval. The frequencies of metastases by site will be tabulated.  
3) Blood based biomarkers will be evaluated for the changes before and after the protocol treatment. The 
association of the baseline value and the changes of these biomarkers with clinical outcomes, such as 
objective response, overall survival and disease free survival, will be evaluated using logistics regression and 
Cox models. 
4) We will determine the percentage of patients with “detectable” (percentage of ≥ 0.05% with each value 
also being at least twice that of the background unstimulated control value) tumor infiltrating lymphocytes 
(TILs) after protocol treatment. The percentage of patients with TILs for patients who have surgical resection 
and its exact confidence interval will also be estimated.  
5) We will evaluate whether presence, quantity or quality of detectable TILs is associated with pathologic 
response to neoadjuvant therapy. A Fisher exact test will be used to evaluate the association of both the 
presence and the quality of TILs with pathologic tumor response to neoadjuvant therapy. A Wilcoxon rank 
sum test will be used to test the association of the quantity of TILs and pathologic response to neoadjuvant 
therapy. 
6) Treatment-related adverse events will be summarized by type and grade.  
7) The proportion of patients with detectable circulating T cells specific against TAA after the protocol 
treatment will be estimated and its confidence interval will be provided.  An exact binominal test will be used 
to test the increase in the proportion of patients with detectable circulating T cells specific against TAA after 
the protocol treatment relative to baseline.     
8) Estimate the rate of pathologic response for neoadjuvant pembrolizumab in early stage NSCLC. The 
pathologic response rate along with its 95% exact confidence interval will be estimated. 
9) Determine if the immunomodulatory effects of neoadjuvant chemotherapy plus pembrolizumab impact the 
suppressive mechanisms, restoring functional reactivity to important anti-tumor effector cell populations.  
Functional TAA-specific T cell reactivity’s will be measured in the blood at 4 time points: Collection 1, 2, 3 
and 4.  A Wilcoxon rank sum test will be used to test for differences from baseline, as well as for any 
association between each reactivity measure and pathologic response to neoadjuvant therapy.  
10)  Explore an alternative definition for detectability suitable for expression values generated using Boolean 
gating, and determine the percentage of patients with circulating T cells meeting this definition. The 
percentage of patients with circulating T cells meeting the new definition of detectable and its 95% exact 
confidence interval. 
11) Perform gene expression analysis on tumor to elucidate genes associated with function and modulation 
of the PD-1/PD-L1 axis. 
 
28.0 References 
 
1. 
Nesbitt JC,et al..  Ann Thorac Surg 1995; 60:466-472. 
2. 
Winton et al. NEJM 2005;352:2589 
3. 
Strauss et al, J Clin Oncol 2008;26:5043). 
4. 
Arriagada R, et al. N Engl J Med 2004,350:351-360. 

80 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
5. 
Winton TL, et al. J Clin Oncol 2004, 22;621s (suppl 14;abst 7018) 
6. 
Strauss GM, et al. J Clin Oncol 2004 22; 621s (suppl 14; abst 7018). 
7. 
Auperin et al. Ann Oncol 17:473-483, 2006). 
8. 
Keir ME et al. PD-1 and its ligands in tolerance and immunity.Ann Rev Immunol 26 (2008), 
pp. 677-704 
9. 
Okazaki, T et al. PD-1 and PD-1 ligands: from discovery to clinical application. Int 
Immunol, 19 (2007), pp. 813-824 
10. 
Edward Garon et al. J Clin Oncol 32 (15 suppl): 8020 2013. 
11. 
Naiyer A Rizvi et al. J Clin Oncol 32 (15 suppl): 8007 2014. 
12. 
Hodi FS, et al, N Engl J Med 2010;363:711-23. 
13. 
Herbst RS, et all. Lancet, 2016 Apr9;387(10027):1540-50. 
14. 
Mok, T, et al. J Thorac Oncol. 2016 Apr;11(4Suppl):S142 
   
 
 
 

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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required 
to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
29.0 LIST OF APPENDICES 
Appendix A 
Study Schedule 
Appendix B 
Correlative Science Measures 
Appendix C 
Performance Status Criteria 
Appendix D 
Standard Cockcroft and Gault Formula for Calculated Creatinine Clearance 
Appendix E 
Site Biospecimen Processing Flow Chart 
Appendix F 
Biomarker Blood Specimens for Correlative Sciences-Duke processing  
Appendix G 
Biomarker Blood Specimens for Correlative Sciences- Processing and Shipping for 
Outside Sites 
Appendix H 
Surgical Tissue Specimen for Correlative Sciences-Duke Processing 
Appendix I 
Surgical Specimen Tissue Handling & Processing for Shipping-  
Outside Sites 
 
 
 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
29.1 
Appendix A:  STUDY SCHEDULE 
Examination 
Baseline 
(screen)a 
 
Neoadjuvant RX 
Evaluation 
post pembrok 
SurgeryP 
Post Surgery 
FU R 
Cycle1 
Cycle 2 
Day 
 
30 to 0 
 
1  
(+/- 3 days) 
 
22 
 (+/- 3 days) 
 
pre-surgery 
 
29 – 56  
(from C1D1) 
2-6 wks. post 
Surgery 
 
Informed Consent 
X 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
Medical Hx/Demo/ 
Smoking Hx
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Vital Signs 
(temp, RR,B/P, pulse) 
X 
X 
X 
X 
 
X 
Weight/BSA 
X 
X 
X 
X 
 
X 
Physical Exam 
X 
X 
X 
X 
 
X 
Performance Status 
X 
X 
X 
X 
 
X 
Hematology b,c,e 
X 
X 
X 
X 
 
X 
Chemistriesb,d,e 
X 
X 
X 
X 
 
X 
Serum Beta HCGh 
X 
Xh 
 
 
 
 
Calculated 
CreatinineefClearance 
X 
 
 
 
 
 
Thyroid Functions  
(T3, FT4,TSH) e 
X 
 
 
 
X 
 
 
PT(INR), aPTTe 
 
X
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
PFTs (FEV1/DLCO) e 
X 
 
 
 
 
 
Radiologic Evalg 
X 
 
 
Xg 
 
Xg 
Medical & Surgical 
Evaluation 
X 
 
 
X 
 
 
EKG 
X 
 
 
 
 
 
Tumor Histology 
X 
 
 
 
 
 
Adverse Events 
 
 
X 
 
X 
 
X 
 
 
X 
Concomitant Meds 
X 
X 
X 
X 
 
X 

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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Pembrolizumab 
 
X 
X 
 
 
 
Blood Sampling j 
Xj 
 
 
Xj 
 
Xj 
Surgical Specimenp 
 
 
 
 
X 
 
Tumor Biopsy Slidesn 
 
 
 
 
X 
Examination 
STD ADJ 
CT/RT L 
 
Adjuvant Pembrolizumabm 
EOSS 
Follow-Up 
Cycle 1m 
Cycle 2 
Cycle 3Cycle 4 
Day 
 
1 
 
22 
 
43 
 
64 
>30 d post 
Pembroj 
Informed Consent 
 
 
 
 
Eligibility 
 
 
 
 
Medical History/Demo- 
Graphics/Smoking Hx 
 
 
 
 
 
Height
 
 
 
 
 
Vital Signs 
(temp, RR,B/P, pulse) 
 
X 
 
X 
 
X 
 
X 
 
X 
Weight/BSA 
 
X 
 
X 
 
X 
 
X 
 
X 
Physical Exam 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance Status 
 
X 
 
X 
 
X 
 
X 
 
X 
Hematology b,c,e 
 
X 
 
X 
 
X 
 
X 
 
X 
Chemistriesb,d,e 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum Beta HCGh 
X 
 
X 
 
X 
 
X 
 
Thyroid Functions  
(T3, FT4,TSH) e 
 
X 
 
 
X 
 
 
X 
PT(INR), aPTTe 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
PFTs (FEV1/DLCO) e 
 
 
 
 
 
Radiologic Evaluationg 
 
 
 
 
 
 
Med/surg Evaluation 
 
 
 
 
 
 
EKG 
 
 
 
 
 

84 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Tumor Histology 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
Concomitant Meds 
 
X 
X 
X 
X 
X 
Pembrolizumab 
 
X 
X 
X 
X 
 
Blood Sampling j 
 
 
 
 
Xj 
Surgical Specimenp 
 
 
 
 
 
Tumor Biopsy Slidesn 
 
 
 
 
 
 
To  allow for patient and investigator schedules, holidays, weather or other emergencies 
requiring facilities to be closed, visits can be performed ±3 days of scheduled visit 
a Pre-enrollment baseline (screen) assessments are to be performed within -30 to 0 days unless 
otherwise specified. 
b May be obtained within 3 days of pembrolizumab dosing 
c   Hematology values to include Hgb/Hct, WBC with auto or manual differential, platelets 
d Chemistries to include Na+, K+, Cl-, total protein, albumin, calcium, glucose, BUN, creatinine, 
total bilirubin (direct bilirubin if total is elevated above upper limit of normal), alkaline phosphatase, 
SGOT, SGPT, LDH, uric acid, magnesium, phosphorus.  e   Baseline required labs to be performed 
within 30 days of enrollment Pre-study tests may be used for day 1, cycle 1 tests if obtained 
within 14 days of day 1 cycle 1 treatment.  PFT’s per institutional standards. 
f Calculated creatinine clearance (see appendix D) 
g Radiologic evaluation: pre-treatment clinical staging PET/CT of chest/abdomen, brain MRI or 
CT as per standard of care (these may be performed up to 42 days); after completing cycle#2  
Pembrolizumab therapy (prior to surgery) chest CT;  post- surgery recommend chest CT every 3-
4 months (or per institutional standard of care) for 2 years  
hAll WOCBP MUST test negative for pregnancy within 48 hours prior to any initial study 
procedure based on a serum pregnancy test.  If subject uses appropriate contraceptive methods 
(section 6.2) from the time of the initial serum pregnancy test, then the subsequent pregnancy test 
can be done within 72 hours before receiving pembrolizumab. If appropriate contraceptive methods 
are not begun immediately with the first serum pregnancy test, then subsequent serum pregnancy 
tests must be done within 48 hours prior to the study drug administration. If the pregnancy test is 
positive, the subject must not receive pembrolizumab and must not be enrolled in the study, or will 
be removed from treatment. 
j  Blood samples t o  assess activated CD8+ T cells with specificity against tumor antigens and 
CD4 and CD8 functional memory.  Collection 1:  Baseline:  pre-dose #1 pembrolizumab.  
Collection 2 : After second dose of Pembrolizumab (cycle 2) and prior to surgery.  Collection 3: 
2-6 weeks after surgery.  Collection #4: Three to 6 weeks after last dose of adjuvant 
pembrolizumab. 4 tubes of 8.5 ml each (ACD anti-coagulated Vacutainer yellow tops).   

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11 Nov 2018 
 
k Evaluation Post pembrolizumab prior to surgery. Final visit (if < grade 1 toxicity) for those 
subjects that come off treatment early for  progression of disease, intolerance to protocol therapy, for 
other reasons, or patient withdraws consent; safety evaluation should occur 30 days (+/- 5days) after 
last dose pembrolizumab or before initiation of a new anti-neoplastic cancer treatment (whichever 
comes first). 
L Post-op standard therapy, including adjuvant CT and RT, based on final pathologic stage of 
cancer, tumor margins, and other standard clinical criteria.  Post-op therapy is non-study 
specific and can be given through the primary oncology team.  
m  Adjuvant Pembrolizumab: Patients who receive both adj CT plus adj RT should start 
Pembrolizumab within 8 months of surgery. Patients who receive only one modality of adj therapy 
(e.g. CT alone or RT alone) should start Pembrolizumab within 6 months of surgery Patients who do 
not receive any adjuvant therapy should start Pembrolizumab within 4 months of surgery.  
n  Tumor Biopsy Slides (appendix I)  
p Surgery to occur at 4-8 weeks (29-56 days). If dose # 2 pembrolizumab delayed, there is to 
be at least 2 days between this infusion and surge ry. Tumor Specimen collection (appendices 
G & H)  
RPost-Surgery F/U visit: Two to 6 weeks following surgery. Subjects with bulky residual 
adenopathy such that resection was not attempted will be removed from protocol therapy and should 
receive standard oncology care as deemed appropriate by the treating physician. Subjects with 
positive surgical margins or N2 disease will be removed from protocol and considered for standard 
of care post-operative radiation +/- standard chemotherapy as deemed appropriate by their physician.  
Subjects who are completely resected or who refuse or cannot receive adjuvant chemotherapy will 
be given the option of receiving adjuvant Pembrozulimab. Collection #3 research blood sample 2-6 
weeks after surgery prior to initiation of adjuvant CT. 
 SEnd of Study Visit:  End of study evaluation is to occur approximately 30 days or more after 
adjuvant Pembrolizumab treatment. SAEs will be collected for 90 days after the end of treatment.  
Final research blood sample will be collected (collection #4). Chest CT if applicable (per radiologic 
evaluation, Appendix A) 
TFollow-Up: Patients should have follow-up every 3-4 months as per standard care(of the treating 
institution (recurrence and survival) for 2 years unless patients has experienced > grade 1 toxicity 
related to Pembrolizumab (in which case follow until resolution of the AE to Grade 0-1, patient 
deemed stable by investigator, or new anti-neoplastic therapy has begun.). After 2 years follow every 
6 months for up to five years.  These evaluations may be coordinated with visits for radiologic 
disease evaluation or occur via phone follow-up. Lab assessments will be at the discretion of treating 
physician. 
 
* Upon lung cancer relapse, radiologic imaging of sites of failure is at the discretion of the treating 
physician. 
 
 

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11 Nov 2018 
 
29.2 
Appendix B- Correlative Science Measures 
Correlative Science Primary Objective 
 
Circulating T Lymphocytes with Specificity Against Tumor Associated Antigens: 
Detectable circulating T cells with specificity against TAA will be identified using the following 
process: 
 
Whenever individual patient tumor tissue is available for analysis, the expression of 10 highly 
conserved TAA’s (see Table I below) will be assessed using standard Real-Time (RT) PCR 
technology. Peptide pools representing the three most highly expressed TAA’s by each tumor 
will serve as antigen-specific stimulators for PBMC isolated from the same patient at the 4 specified 
time points. If no tumor tissue is available for TAA expression analysis, peptide pools representing 
the three most commonly expressed TAA’s on NSCLC, namely Survivin, PRAME, and MAGE-
A3, will be chosen as antigen-specific stimulators. 
 
The pe rc e nta ge  of  CD4,  CD8,  and  double  positive  (DP=CD4+/CD8+)  lymphocytes  with 
specificity  against  the  three  selected  TAA’s,    will  be  calculated  for  each  of  4  individua l 
functional markers (IL-2, TNF-α, IFN-γ, and CD107 underlined below).   For each peripheral 
blood collection, the lab will generate a total of 12 lymphocyte values (4 values each for CD4, 
CD8 and DP) for each of the three TAA’s and for CD3/CD28 (used as a positive control), as 
well as generating 12 background unstimulated negative control values.  All values will be 
expressed as percentages.  A patient will be considered to have detectable circulating T cells if 
≥1 of the 36 percentage values (12 values * 3 TAA’s) satisfies the definition of “detectable” as 
described in section 26.0 (a lymphocyte percentage of ≥0.05% at the pre-surgical peripheral 
blood collection (Collection 3) with each value also being at least twice that of the background 
unstimulated negative control value). 
 
Table I                                    TAA Peptide Pools 
(15-mers, overlapping by 11 amino acids) 
 
 
Survivin (33 peptides) 
PRAME/OIP4 (125 peptides) 
MAGE-A3 (76 peptides) 
Melan A/MART-1 (27 peptides) 
Gp100 (163 peptides) 
Tyrosinase (117 peptides) 
NY-ESO-1 (43 peptides) 
MAGE-A1 (75 peptides) 
MAGE-A4 (77 peptides) 
CEA (173 peptides) 
 

87 
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11 Nov 2018 
 
Assessing detectable circulating T cells specific against three TAA’s (individually 
selected from the Table I list of TAA’s using the process outlined above) in the following 
combinations of T cells and functional markers: 
 
* %CD4+/CD69+/IL-2+ 
*%CD4+/CD69+/TNF-α+ 
*%CD4+/CD69+/ IFN-γ+ 
*%CD4+/CD69+/ CD107+ 
 
* %CD8+/CD69+/IL-2+ 
*%CD8+/CD69+/TNF-α+ 
*%CD8+/CD69+/IFN-γ+ 
*%CD8+/CD69+/CD107+ 
 
* %DP+/CD69+/IL-2+ 
*%DP+/CD69+/TNF-α+ 
*%DP+/CD69+/IFN-γ+ 
*%DP+/CD69+/CD107+ 
 
 
Exploratory Objectives 
Tumor Infiltrating Lymphocytes with Specificity Against Tumor Associated Antigens: 
 
Using the same methods noted above, 12 lymphocyte percentage values (functional markers) for the 
3 selected TAA’s will also be generated from tumor tissue collected at surgery, and in this context 
are called tumor infiltrating lymphocytes (TILs).  These values will be used to determine the 
percentage of patients with any detectable TILs (exploratory objective 1).   Expression percentage 
values for each T cell (CD4, CD8, and DP) will also be collected corresponding to each 
combination of the 4 functional markers (excluding the combination where all four markers are 
negative) using Boolean gating. These 135 values (15 values * 3 T cells * 3 TAA’s) will be used to 
determine  a definition  of detectability  suitable  for these  measures  to avoid  missing potential 
positive values, and to determine the percentage of patients with ≥1 of the 135 values satisfying  
the new  definition  of detectable  circulating  T cells  (exploratory  objective  5).   In addition, this 
definition will also be used to explore whether the presence, quantity or quality of TILs is associated 
with pathologic response (exploratory objective 6). 
 
* Boolean gating will be performed to calculate percentage values corresponding to the following 
combinations of T cells and functional markers (excluding the combination where all 4 markers 
are negative): 
 
* %CD4+/CD69+/-IL-2+ or -TNF-α+ or -IFN-γ+ or -CD107+ or - 
* %CD8+/CD69+-IL-2+ or -TNF-α+ or -IFN-γ+ or -CD107+ or - 

88 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
* %DP+/CD69+/-IL-2+ or -TNα+ or -IFN-γ+ or -CD107+ or – 
 
For exploratory outcome 4, changes in all measures of anti-TAA reactivity listed below across time 
points will be analyzed, as well as how these values relate to pathologic response.   In addition, for 
the p h e n o t y p ic  reactivity measures with background unstimulated negative control values 
(those from the ICS panel), the percentage of patients with a positive response (a percentage 
value greater than the background unstimulated negative control value) will be calculated.  The 
distribution of the changes will be estimated with a boxplot and the median (mean) change will 
be calculated by pathologic response status (yes/no). 
 
%CD3+CD4+CD8- (CD4 T cells) 
%CD3+CD4-CD8+ (CD8 T cells) 
%CD3+CD4+CD8+ (CD4/CD8 double positive (DP) T cells) 
 
%CD4+CD152- (CTLA-4 negative CD4 T cells) 
%CD4+CD152+ (CTLA-4+ CD4 T cells) 
 
%CD4+/CD69+ (Activated CD4 T cells) 
%CD4+CD154+ (Activated CD4 T cells) 
 
%CD4+/-HLA-DR+ (Activated CD4 cells) 
%CD4+CD28+ 
%CD4+CD28- 
%CD4+/CD28+/CD152+CD279+ (Activated/Exhausted CD4 T cells) 
%CD4+CD28+CD278+ (Activated CD4 T cells/Pharmacodynamic Biomarker) 
 
%CD4+/CD25+FoxP3+/CD152 
%CD4+/CD25+FoxP3+/CD152 
%CD4+/CD25+FoxP3+/CD152 
%CD4+/CD25+FoxP3+/CD152 
 
%CD4+CD45RA+CCR7+ (Naïve CD4 T cells) 
%CD4+CD45RA-CCR7+ (Central memory CD4 T cells) 
%CD4+CD45RA-CCR7- (Effector memory CD4 T cells) 
%CD4+CD45RA+CCR7- (Effector CD4 T cells) 
 
%CD8+CD152- (CTLA-4 negative CD8 T cells) 
% CD8+CD152+ (CTLA-4 positive CD8 T cells) 
 
%CD8+CD69+ (Activated CD8 T cells) 
%CD8+CD152+ (Activated CD8 T cells 
 

89 
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to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written authorization from 
the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
%CD8+/-HLA-DR+ (Activated CD8 T cells) 
%CD8+CD28+ 
%CD8+CD28- 
%CD8+/CD28+/CD152+CD279+ (Activated/Exhausted CD8 T cells) 
 
%CD8+CD45RA+CCR7+ (Naïve CD8 T cells) 
%CD8+CD45RA-CCR7+Central memory CD8 T cells) 
%CD8+CD45RA-CCR7- (Effector memory CD8 T cells) 
%CD8+CD45RA+CCR7- (Effector CD8 T cells) 
 
%DP CD69+ (Activated DP T cells) 
%DP CD154+ (Activated DP T cells) 
 
%DP CD45RA+CCR7+ (Naïve DP T cells) 
%DP CD45RA-CCR7+ (Central memory DP T cells) 
%DP CD45RA-CCR7- (Effector memory DP T cells) 
%DP CD45RA+CCR7- (Effector DP T cells) 
 
%CD3-SSChi/HLA-DRlowCD14+ 
(Myeloid-derived 
suppressor 
cells 
(MDSC)) 
FCSxSSC (Monocyte gate) %CD3-CD14- Lin(CD16, CD19, CD20, CD56)- HLA-DR- 
CD11b+/CD33+ (MDSC) 

90 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
 
29.3 
Appendix C: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
 
 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to c a rry  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% of 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. 
 
 
 
 

91 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
29.4 
Appendix D  Standard Cockcroft and Gault Formula for Calculated 
Creatinine Clearance 
 
Standard Cockcroft and Gault Formula for Calculated Creatinine Clearance 
For serum creatinine concentration in mg/dL: 
Creatinine clearance (CrCl) will be calculated using the Cockcroft-Gault equation 
as follows: CrCl (ml/min)=  (140-age) X (actual weight in kg) x 0.85 for females 
72 x serum creatinine (mg/dl) 
 
For serum creatinine concentration in Dmol/L: 
CrCl = [(140 - age) x (wt. in kg)] / [0.81 x serum 
creatinine (mol/L)] Females: Multiply the result x 0.85 
Units: age in years, weight in kilograms. 
 
Source: Cockcroft DW, Gault MH. 1976. Prediction of creatinine clearance from serum 
creatinine. 
Nephron 16:31-4. 
 
 
 

92 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
29.5 
Appendix E -SITE BIOSPECIMEN PROCESSING FLOW CHART - 
TOP 1501 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgical  
Specimen 
Duke Tumor 
Immunology Lab 
 
TILs 
 
QUALTEK 
Newtown, PA 
 
PD-L1 analysis 
 
BLOCKS-OR SLIDES 
For PD-L1 
Sites ship directly to QUALTEK for PD-L1 
testing  –See MISP Sample Handling 
Manual. Supplies provided by QUALTEK. 
. 
Genomic Analysis 
 
If blocks are available, ship to Duke for 
future genomic research (optional) 
 
FRESH TISSUE-TILs 
 
Sites ship to Duke for TILs analysis 
(overnight). See Appendix I for instructions. 
Minimum 1 gm 
BLOOD SPECIMENS FOR 
BIOMARKERS: Specimens ship at 
ambient temp, priority overnight, to Duke 
Substrate Services Core Lab. 
 
 DO NOT SHIP THURS-SUN.  
 
See Appendix G for instructions.  

93 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
29.6 
Appendix F-Blood Specimens-Duke 
 
 Biomarker Blood Specimens for Correlative Sciences 
 
Duke Processing 
 
Blood will be collected 4 times to assess CD8+ T cells with specificity against tumor antigens. 
Blood from each of the 4 collections will also be utilized to assess the presence of circulating 
populations of regulatory T cells, myeloid-derived suppressor cells (MDSC), as well as activated 
and exhausted T cells. 
 
Blood volumes and collection time points: 
 
 At each blood collection, 4 tubes of 8.5-ml each will be collected. The tubes used will be ACD 
anti-coagulated Vacutainer (yellow tops). The following time points will have blood collections: 
 
Collection 1:    Baseline prior to treatment initiation 
Collection 2:    After dose #2 pembrolizumab prior to surgery 
Collection 3:    Two to six weeks after surgery prior to initiation of adjuvant therapy  
Collection 4:    Three to six weeks after the last dose of adjuvant pembrolizumab.  
******If EOS (End of Study) occurs and no adjuvant treatment with Pembrolizumab has 
occurred, draw Collection #4 at End of Study visit 
 
Once ACD tubes collected, Substrate Services Core lab to be contacted for pick up as PBMC 
should ideally occur within 4 hours of draw @ 919-684-3754. Tubes are to remain ambient 
(refrigeration will limit ability to recover PBMC). 
 
DTRI-IM Sample Transport Record form to be completed to accompany tube to the Substrate 
Services Core lab. 
 
** Note: it is imperative tube is filled to the fill line for proper additive to blood ratio. Specimen 
is not evaluable if not filled to the fill line.  If unable to obtain the 4 required tubes, fill as many 
tubes as possible to the fill line. 
 
 
 

94 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
29.7 
Appendix G-Blood Specimens-Outside Sites 
 
Biomarker Blood Specimens for Correlative Sciences 
 
Blood samples for biomarker analysis will be collected at four time points and labeled with the 
Participant Study ID, collection date and time. The blood samples will be collected in four (4) 
ACD (yellow top) tubes. 
Collection 1:    Baseline prior to treatment initiation 
Collection 2:    After dose #2 pembrolizumab prior to surgery 
Collection 3:    Two to six weeks after surgery prior to initiation of adjuvant therapy  
Collection 4:   Three-six weeks after last dose adjuvant pembrolizumab 
Vacutainer ACD (yellow top) tube:  Immediately after drawing the blood, gently invert the tube 
5 times.  Do not store samples on ice, but hold the tubes at room temperature. 
** Note: it is imperative tube is filled to the fill line for proper additive to blood ratio. Specimen 
is not evaluable if not filled to the fill line.  If unable to obtain the 4 required tubes, fill as many 
tubes as possible to the fill line. 
 
******If EOS (End of Study) occurs and no adjuvant treatment with Pembrolizumab has 
occurred, draw Collection #4 at End of Study visit 
  
Sample Storage Prior to Shipment: 
The samples should be held at room temperature, and must be shipped the same day the samples 
are collected. 
Sample Shipping: 
 It is imperative that samples be shipped according to IATA regulations and in appropriate 
packaging. 
 Samples should be shipped ambient for next morning delivery (priority overnight). 
 Samples are to be shipped Monday-Wednesday to be received Tuesday-Thursday (to avoid 
a late Friday afternoon or weekend delivery). Do not ship samples Thursday through 
Sunday! 
 Email the designated contact prior to shipping to ensure your samples will not be arriving 
on a university holiday and to confirm that someone will be available to receive the 
shipment (contact Robyn Osborne: robyn.osborne@duke.edu). 
 Do not ship on a national holiday or a day which is followed by a national holiday. 
 
Shipping address: 
Lab Technical Manager 
Substrate Services Core Lab 

95 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
Duke University Medical Center 
203 Research Drive. 
MSRB I, Room 459 
Durham, NC 27710 
Phone - (919) 684-3754 
Fax - (919) 684-4288 
robyn.osborne@duke.edu 
 

96 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
29.8 
Appendix H-Tissue Specimens-Duke 
 
Surgical Tissue Specimen for Correlative Sciences 
Duke Processing 
 
 
SURGICAL SPECIMEN 
 
Patients will be approached to participate in the “DUHS Biospecimen Repository and Processing 
core BRPC eIRB 35974” protocol prior to surgery. Tissue will be collected and released as 
described in this protocol to ensure proper involvement of pathology to minimize the chance that 
a tissue collection event interferes with appropriate clinical tissue processing and diagnosis. 
 
PRINCIPLE:  Lung tissue is harvested in the frozen section or gross dissection area of the surgery 
pathology suite. The tissue is first examined by a certified anatomic pathologist or surrogate 
(resident, pathology assistant). Relevant margins are inked, removed and examined by frozen 
section analysis, if necessary. It is imperative that harvesting tissue for use in research trials does 
not impeded accurate initial assessment of critical features of the tumor resection, most notable 
margin status. After the specimen has been processed for margin status, the frozen section 
assessment of the specimen is complete, a specimen of excess tumor will be released and acquired 
by the tumor immunology correlative science staff for isolation of tumor infiltrating lymphocytes 
(TILs) for purposes of this protocol (as much tissue as possible, but a minimum 1 gm).  
 
SPECIMEN:  Lung resection specimen 
 
LOCATION:  Surgical Pathology Suite 
 
QUALITY CONTROL:  Lab guidelines for safe handling of all samples must be followed. All 
tubes used for specimen processing must be labeled with the unique patient identifier or sample 
number before transfer of the tissue sample.  
 
 

97 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
29.9 
Appendix I-Tissue Specimens-Outside Sites 
 
 
BACKGROUND: 
 
The ability to obtain high quality Tumor infiltrating lymphocytes (TIL) from fresh tissue is 
highly dependent on the tissue procurement (requires as much tissue as possible, minimum 1 
gm). Delays in tissue processing usually lead to cell death and RNA degradation. Inadequate 
shipping conditions can also be a major source of pre-analytic variance in downstream 
applications. The following procedure addresses these issues. 
 
PRINCIPLE: 
 
Tumor tissue is harvested after surgical resection, weighed, kept cold at 4oC in antibiotic-
antimycotic containing Holding Medium, and shipped overnight. 
 
 
EQUIPMENT AND SUPPLIES: 
Equipment: 
Scale 
 
Supplies: 
50 ml sterile conical tube 
Parafilm  
Recloseable Zip Lock Plastic Bag 
IATA Certified Cold Shipper 
 
Reagents:  
*Holding Media (50ml):  RPMI 1640 plus 10% Human serum, with antibiotic-antimycotic and 2-Mercaptoethanol  
RPMI 1640, Hepes 
Gibco 22400-089 
44.5 ml 
Antibiotic-Antimycotic 
(100X) 
Gibco 15240-096 
  0.5 ml 
Human Serum Type AB 
(Male) 
Sigma H4522 
  5 ml 
2-mercaptoethanol 
Sigma M6250 
  0.05 ml 
 
Storage Requirements:   
Tissue samples should be kept cold on ice or at 4°C until shipped. 

98 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
11 Nov 2018 
 
 
 
QUALITY CONTROL:  
Lab guidelines for safe handling of all samples must be followed. All tubes used for specimen 
processing must be labeled with the unique patient identifier or sample number before transfer of 
the tissue sample. 
 
PROCEDURE - STEPWISE: 
 
1. After procurement, weigh the tissue, note the weight on the Sample Processing Request 
Form, and place it in a sterile 50 ml tube. Fill the tube with Tumor Holding Media and 
close tightly. Label the tube with the Study Number and Patient ID. Wrap the top with 
parafilm to prevent spillage. 
 
2. Be sure to fill out the Sample Processing Request Form and include it in the package with 
the tissue 
 
3. It is imperative that samples be shipped according to IATA regulations and in appropriate 
packaging that allows shipping with wet ice..    
4. Samples are to be shipped Monday-Wednesday to be received Tuesday-Thursday (to avoid 
a late Friday afternoon or weekend delivery). Do not ship samples Thursday through 
Sunday! ** Please ship priority overnight. 
5. Do not ship on a national holiday or a day which is followed by a national holiday. 
Email the designated contact prior to shipping to ensure your samples will not be arriving on a 
university holiday and to confirm that someone will be available to receive the shipment (contact 
Kristy Long: kristy.long@duke.edu).DTRI shipping address:  
Kristy Long 
Duke University Medical Center 
915 S. LaSalle St. 
SORF Bldg. Room 121 
Durham, NC 27710 
Phone - (919) 684-6834 
Fax - (919) 684-4288 
kristy.long@duke.edu