Clinical trial NCT03217071
Conditions: Non Small Cell Lung Cancer
Keywords: non small cell lung cancer, resectable
Sponsor: Sue Yom
Start date: 2017-10-04; Completion date: 2022-03-31
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a randomized single-institution, phase II, open-label clinical trial of neoadjuvant pembrolizumab with or without low-dose stereotactic radiation therapy (SRT) in stage I-IIIA non-small lung cancer (NSCLC) patients who are planned to undergo surgical resection of their lung cancer.

Detailed description:
Two consecutive run-in cohorts will administer pembrolizumab or pembrolizumab with SRT of 12 Gy to the lateral aspect of the primary tumor. Patients will receive pembrolizumab for 2 cycles prior to surgery or SRT and surgery. Surgical resection of all involved areas of tumor will occur within 6 weeks of the last administration of pembrolizumab. It should be noted that surgery is expected to occur within a much shorter window and 6 weeks would represent the greatest allowable amount of delay.

If during the run-in, only the pembrolizumab-alone cohort meets pre-specified safety parameters, subsequently enrolled patients will enter a larger expansion cohort, with treatment given according to that cohort only. If during the run-in both cohorts meet pre-specified safety parameters, subsequently enrolled patients will enter the expansion cohort and be randomized between preoperative pembrolizumab versus pembrolizumab with SRT of 12 Gy.

Arms: arm 1: Patients will receive 200mg pembrolizumab on Day 1 of each 3 week cycle, for 2 cycles, prior to surgery. Pembrolizumab will be administered via IV infusion for 30 minutes. Surgery will occur no later than 6 weeks following the last dose of pembrolizumab. arm 2: Patients will receive 200mg pembrolizumab on Day 1 of each 3 week cycle, for 2 cycles. Pembrolizumab will be administered via IV infusion for 30 minutes.Within the week (7 days +/- 3 days) following administration of the second cycle, a single 12 Gy dose of stereotactic radiation therapy (SRT) will be delivered to 50% of the primary tumor only. Definitive surgical resection will occur no later than 6 weeks following the last dose of pembrolizumab.
Interventions: intervention 1: Pembrolizumab intervention 2: stereotactic radiation therapy (SRT) intervention 3: Surgery (Non-interventional, standard of care)
Intervention descriptions: intervention 1: All study participants will receive pembrolizumab every 3 weeks, for 2 cycles. intervention 2: Patients in Cohort 2 of the Safety run-in and patients in the expansion cohort who are randomized to the 'pembrolizumab +radiation arm' will receive one dose of SRT within 1 week (+/- 3 days) following the second administration of pembrolizumab. intervention 3: Standard of care surgery to remove cancer

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed.  
 
 
CC# 166520: PembroX: Enhancing the Immunogenicity of 
Non-Small Cell Lung Cancer with Pembrolizumab +/- 
Stereotactic Radiotherapy Delivered in the Preoperative 
Window, A Randomized Phase II Study with Correlative 
Biomarkers 
 
Protocol Number: CC #166520  
Study Drug: Pembrolizumab 
 
Version Number: 10.0 
Version Date: 03/29/2021 
 
IND Number: Exempt 
NCT Number: NCT03217071 
 
Principal Investigator (Sponsor-Investigator)  
Sue S. Yom, MD, PhD, MAS 
Helen Diller Family Comprehensive Cancer Center  
University of California, San Francisco 
  
San Francisco, CA 94143-1708  
 
 
 
Co-Principle Investigators 
Lawrence Fong, MD, PhD  
Matthew Gubens, MD  
David Jablons, MD 
 
Statistician  
Ann Lazar, PhD 
 
 
Revision History 
Version 2.0 
10/04/2016 
Version 3.0 
11/20/2016 
Version 4.0 
03/07/2017 
Version 5.0 
03/23/2017 
Version 6.0 
06/01/2017 
Version 7.0 
11/15/2017 
Version 8.0 
01/16/2018 
Version 9.0 
08/08/2018 
Version 10.0 
03/29/2021 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol No.: 166520 
Version Date: 03/29/2021 
 
1. I agree to follow this protocol version as approved by the UCSF 
Protocol Review Committee (PRC), Institutional Review Board (IRB), 
and Data Safety Monitoring Committee (DSMC). 
 
2. I will conduct the study in accordance with applicable IRB requirements, 
Federal regulations, and state and local laws to maintain the protection of the 
rights and welfare of study participants. 
 
3. I certify that I, and the study staff, have received the requisite training to 
conduct this research protocol. 
 
4. I have read and understand the information in the Investigators’ Brochure (or 
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to 
conduct the protocol in accordance with Good Clinical Practices (ICH-GCP), 
the applicable ethical principles, the Statement of Investigator (Form FDA 
1572), and with local regulatory requirements. In accordance with the FDA 
Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website. 
 
5. I agree to maintain adequate and accurate records in accordance with 
IRB policies, Federal, state and local laws and regulations. 
UCSF Principal Investigator / Study Chair 
 
 
Printed Name 
 
 
 
 
 
Signature 
Date 
 
 


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Table of Contents 
PROTOCOL SIGNATURE PAGE ................................................................................. 2 
1.0 
TRIAL SUMMARY .............................................................................................. 8 
2.0 
TRIAL DESIGN .................................................................................................... 9 
2.1 
Trial Design ........................................................................................................ 9 
2.2 
Trial Diagram .................................................................................................... 9 
3.0 
OBJECTIVES & HYPOTHESES ..................................................................... 11 
3.1 
Primary Objectives & Hypotheses ................................................................ 11 
3.2 
Secondary Objectives & Hypotheses ............................................................. 11 
3.3 
Exploratory Objectives ................................................................................... 12 
4.0 
BACKGROUND & RATIONALE .................................................................... 13 
4.1 
Background ...................................................................................................... 13 
4.1.1 Pharmaceutical and Therapeutic Background ............................................... 13 
4.1.2 Preclinical and Clinical Trial Data ................................................................ 14 
4.2 
PD-L1 expression by immunohistochemistry ............................................... 16 
4.3 
Rationale .......................................................................................................... 17 
4.3.1 Rationale for the Trial and Selected Subject Population ............................... 17 
4.3.2 Rationale for Dose Selection/Regimen/Modification ................................... 18 
4.3.3 Rationale for SRT Dosing ............................................................................. 19 
4.3.4 Rationale for Endpoints ................................................................................. 20 
4.4 
Secondary Objectives & Hypotheses ............................................................. 20 
4.5 
Exploratory Objectives ................................................................................... 21 
4.5.1 Biomarker Research ...................................................................................... 21 
5.0 
METHODOLOGY .............................................................................................. 21 


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5.1 
Entry Criteria .................................................................................................. 21 
5.1.1 Diagnosis/Condition for Entry into the Trial ................................................ 21 
5.1.2 Subject Inclusion Criteria .............................................................................. 21 
5.1.3 Subject Exclusion Criteria ............................................................................. 23 
5.2 
Trial Treatments ............................................................................................. 24 
5.2.1 Dose Selection/Modification ......................................................................... 25 
5.2.2 Timing of Dose Administration ...................................................................... 3 
5.2.3 Trial Blinding/Masking ................................................................................... 3 
5.3 
Randomization or Treatment Allocation ........................................................ 3 
5.4 
Stratification ...................................................................................................... 3 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ................. 3 
5.5.1 Acceptable Concomitant Medications ............................................................ 4 
5.5.2 Prohibited Concomitant Medications .............................................................. 4 
5.6 
Rescue Medications & Supportive Care ......................................................... 5 
5.6.1 Supportive Care Guidelines ............................................................................ 5 
5.6.2 Pneumonitis: .................................................................................................... 5 
5.6.3 Diarrhea/Colitis: .............................................................................................. 5 
5.6.4 Type 1 diabetes mellitus* ................................................................................ 6 
5.6.5 Hypophysitis: .................................................................................................. 6 
5.6.6 Hyperthyroidism or Hypothyroidism: ............................................................. 6 
5.6.7 Hepatic: ........................................................................................................... 7 
5.6.8 Renal Failure or Nephritis: .............................................................................. 7 
5.7 
Diet/Activity/Other Considerations ................................................................. 8 
5.7.1 Diet .................................................................................................................. 8 
5.7.2 Contraception .................................................................................................. 9 


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5.7.3 Use in Pregnancy ........................................................................................... 10 
5.7.4 Use in Nursing Women ................................................................................. 10 
5.8 
Subject Withdrawal/Discontinuation Criteria ............................................. 11 
5.9 
Subject Replacement Strategy ....................................................................... 11 
5.10 
Clinical Criteria for Early Trial Termination .............................................. 11 
6.0 
TRIAL FLOW CHART ....................................................................................... 0 
6.1 
Study Flow Chart .............................................................................................. 0 
6.2 
Trial Procedures ................................................................................................ 2 
6.2.1 Administrative Procedures .............................................................................. 2 
6.2.2 Clinical Procedures/Assessments .................................................................... 4 
6.2.3 Laboratory Procedures/Assessments ............................................................... 6 
6.2.4 Blood Collections ............................................................................................ 7 
6.2.5 Other Procedures ............................................................................................. 7 
6.2.6 Withdrawal/Discontinuation ........................................................................... 8 
6.2.7 Blinding/Unblinding ........................................................................................ 8 
6.2.8 Visit Requirements .......................................................................................... 8 
6.2.9 Screening ......................................................................................................... 9 
6.2.10 Treatment Period ............................................................................................. 9 
6.2.11 Post-Treatment/Safety Follow-Up Visits ........................................................ 9 
6.3 
Assessing and Recording Adverse Events ....................................................... 9 
6.3.1 Definitions of Adverse Events ........................................................................ 9 
6.3.2 Recording of an Adverse Event .................................................................... 11 
6.3.3 Follow-up of Adverse Events ........................................................................ 12 
6.3.4 Adverse Events Monitoring .......................................................................... 12 
6.4.5 Expedited Reporting ...................................................................................... 13 


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6.4.6 Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Principal Investigator and to Merck ........................................................ 15 
6.4.7 Reporting of Pregnancy and Lactation to the Principal Investigator and to 
Merck ............................................................................................................ 16 
6.4.8 Immediate Reporting of Adverse Events to the Principal Investigator and to 
Merck ............................................................................................................ 16 
6.4.8.4 Evaluating Adverse Events ........................................................................... 19 
6.4.9 Principal Investigator Responsibility for Reporting Adverse Events ........... 23 
7.0 
STATISTICAL ANALYSIS PLAN ................................................................... 23 
7.1 
Statistical Analysis Plan Summary ................................................................ 23 
7.2 
Statistical Analysis Plan .................................................................................. 23 
8.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................ 24 
8.1 
Investigational Product ................................................................................... 24 
8.2 
Packaging and Labeling Information ............................................................ 24 
8.3 
Clinical Supplies Disclosure ........................................................................... 24 
8.4 
Storage and Handling Requirements ............................................................ 24 
8.5 
Returns and Reconciliation ............................................................................ 25 
9.0 
ADMINISTRATIVE AND REGULATORY DETAILS ................................. 25 
9.1 
Pre-study Documentation ............................................................................... 25 
9.2 
Institutional Review Board Approval ........................................................... 25 
9.3 
Informed Consent ............................................................................................ 26 
9.4 
Changes in the Protocol .................................................................................. 26 
9.5 
Handling and Documentation of Clinical Supplies ...................................... 26 
9.6 
Case Report Forms (CRFs) ............................................................................ 26 
9.7 
Oversight and Monitoring Plan ..................................................................... 27 
9.8 
Regulatory Documentation ............................................................................ 27 


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9.9 
Protection of Human Subjects ....................................................................... 28 
9.9.1 Protection from Unnecessary Harm .............................................................. 28 
9.9.2 Protection of Privacy ..................................................................................... 28 
10.0 
REFERENCES .................................................................................................... 29 
APPENDIX 1 ECOG Performance Status ................................................................. 32 
APPENDIX 2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
 
33 
APPENDIX 3 Response  Evaluation  Criteria  in  Solid  Tumors  (RECIST)  1.1  
Criteria  for Evaluating Response in Solid Tumors ......................................... 34 
APPENDIX 4 UCSF Policy/Procedure for Required Regulatory Documents for 
Single Site and Multicenter Investigator-Initiated Oncology Clinical Trials 35 
APPENDIX 5 Data and Safety Monitoring Plan for a Phase II or III Institutional 
Trial  
40 
 
 
 


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1.0 
TRIAL SUMMARY 
 
Abbreviated Title 
PembroX 
Trial Phase 
II 
Clinical Indication 
Non-small cell lung cancer, resectable 
Trial Type 
Randomized phase II 
Type of control 
Control arm of randomized schema 
Route of administration 
Intravenous 
Trial Blinding 
No 
Treatment Groups 
(1) Pembrolizumab followed by surgery (2) Stereotactic radiation 
therapy and pembrolizumab followed by surgery 
Number of trial subjects 
40 
Estimated enrollment period 
9 months: 4 patients per month 
Estimated duration of trial 
25 months 
Duration of Participation 
15 months 
Estimated  average  length  of 
treatment per patient 
3 months, 12 months follow-up 
 
 
 


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2.0 
TRIAL DESIGN 
2.1 
Trial Design 
This is a randomized single-institution, phase II, open-label clinical trial of neoadjuvant 
pembrolizumab with or without low-dose stereotactic radiation therapy (SRT) in stage I- IIIA 
non-small lung cancer (NSCLC) patients who are planned to undergo surgical resection of their 
lung cancer. 
Two consecutive run-in cohorts will administer pembrolizumab or pembrolizumab with SRT of 
12 Gy to the lateral aspect of the primary tumor. Patients will receive pembrolizumab for 2 
cycles prior to surgery or SRT and surgery. Surgical resection of all involved areas of tumor will 
occur within 6 weeks of the last administration of pembrolizumab. It should be noted that in 
almost all cases, surgery is expected to occur very expeditiously, within a much shorter window 
and 6 weeks would represent only the greatest allowable amount of delay. 
If during the run-in, only the pembrolizumab-alone cohort meets pre-specified safety parameters, 
subsequently enrolled patients will enter a larger expansion cohort, with treatment given 
according to that cohort only. If during the run-in both cohorts meet pre- specified safety 
parameters, subsequently enrolled patients will enter the expansion cohort and be randomized 
between preoperative pembrolizumab versus pembrolizumab with SRT of 12 Gy. 
Patients will be followed every 12 weeks for 1 year for disease status and survival. 
2.2 
Trial Diagram 
Two consecutive run-in cohorts will be treated establishing the safety of neoadjuvant 
pembrolizumab and pembrolizumab-SRT delivered in the preoperative window. An expansion 
cohort will include a larger number of patients who will be treated with pembrolizumab alone or 
be randomized between the two arms. 
Cohort 1: 6 patients. The patients will undergo 2 cycles of pembrolizumab prior to surgery. 
Surgery will occur no later than 6 weeks following the last dose of pembrolizumab. 
If ≤33% of patients experience grade 3 immune-related toxicity attributable to study 
interventions (as determined within 30 days of date of surgery), or £ 1 patient progresses to 
unresectability over the course of study treatment, proceed to Cohort 2. 
If >33% of patients experience grade 3 immune-related toxicity attributable to study 
interventions (as determined within 30 days of date of surgery), or > 1 patient progresses to 
unresectability over the course of study treatment, the study will terminate. 
Cohort 2: 6 patients. The patients will undergo 2 cycles of pembrolizumab then within the week 
(7 days +/- 3 days) following administration of the second cycle, a single fraction of SRT (12 
Gy) will be delivered to 50% of the primary tumor only. Definitive surgical resection will occur 


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no later than 6 weeks following the last dose of pembrolizumab. 
If ≤33% of patients experience grade 3 immune-related toxicity attributable to study 
interventions (as determined within 30 days of date of surgery), or £ 1 patient progresses to 
unresectability over the course of study treatment, proceed to Expansion Cohort (randomization 
between parameters of Cohort 1 and Cohort 2, e.g. randomization between preoperative 
pembrolizumab versus pembrolizumab and SRT). 
If >33% of patients in Cohort 2 experience grade 3 immune-related toxicity attributable to study 
interventions (as determined within 30 days of date of surgery), or > 1 patient progresses to 
unresectability over the course of study treatment, then proceed to Expansion Cohort (parameters 
only of Cohort 1, e.g. preoperative pembrolizumab alone). 
Expansion Cohort: 28 patients. The patients will be treated according to Cohort 1 if Cohort 2 
failed to meet the specified safety milestones. If both cohorts met the safety milestones, then 
patients in this cohort will be randomized to parameters of either Cohort 1 or Cohort 2. Surgery 
will occur no later than 6 weeks following the last dose of pembrolizumab. 
Stopping Rule: If at any point during the study, >15% of patients progress to unresectability 
over the course of the study treatment, then the study will terminate. This stopping rule will be 
cumulatively evaluated at all timepoints during the protocol, for all patients enrolled in any phase 
of the protocol. Each case of study-induced medical unfitness, tumor progression, or any other 
cause resulting in unresectability will trigger a re-evaluation of the 15% stopping rule. 
 
* Cycle 2 of pembrolizumab should be given except as recommended per protocol, section 
5.2.1.2. 
** SRT is delivered within 7 days +/- 3 days of second pembrolizumab cycle. If second cycle is 
not given due to discontinuation, SRT should not be given (patient should continue to surgery 


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when deemed safe by treating surgeon). 
^ Surgery will take place no later than 6 weeks following last dose of pembrolizumab, e.g. no 
later than week 7 if only one cycle of pembrolizumab was tolerated, or if two cycles of 
pembrolizumab were given, week 10. 
# Adjuvant blood collection will take place at follow-up visits (30d, 90d, 180d and 360d (+14d) 
after surgery). 
Adjuvant therapy such as systemic therapy +/- radiation therapy following surgery will be 
administered according to the standard of care per judgment of the treating physician(s). 
3.0 
OBJECTIVES & HYPOTHESES 
3.1 
Primary Objectives & Hypotheses 
(1) Objective: To determine the change in the number of infiltrating CD3+ T cells/ μm2 in the lung 
cancer tissue between the paired biopsy and thoracotomy specimens, as quantified by 
immunohistochemistry (IHC) and image analysis. 
Hypothesis: For resectable NSCLC, the administration of pembrolizumab +/- low-dose 
stereotactic SRT in the preoperative window will enhance tumor immunogenicity, resulting in 
two-fold greater infiltrating CD3+ T cells/ μm2 in the primary and/or regional environment at the 
time of surgical resection, as compared to the time of initial biopsy. 
3.2 
Secondary Objectives & Hypotheses 
(1) Objective: To assess the safety of preoperative pembrolizumab +/- SRT when combined 
with surgery; 
Hypothesis: In patients scheduled for NSCLC resection, pembrolizumab, or pembrolizumab 
+ SRT, given in the preoperative window, will meet safety criteria described by the protocol; 
(2) Objective: To record the toxicity of preoperative pembrolizumab +/- SRT when combined 
with surgery, according to CTCAE v. 4, including immune-related adverse events (AEs); 
Hypothesis: In patients scheduled for NSCLC resection, pembrolizumab, or pembrolizumab 
+ SRT, given in the preoperative window, will result in acceptable short-term and 
perioperative toxicity; 
(3) Objective:  To  determine  the  1-year  overall  survival  rate  resulting  from  
preoperative pembrolizumab +/- SRT when combined with surgery; 
Hypothesis: In patients scheduled for NSCLC resection, pembrolizumab + SRT given in the 
preoperative window will result in a higher 1-year survival rate than pembrolizumab alone; 


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(4) Objective: To determine the 1-year relapse free survival rate resulting from preoperative 
pembrolizumab +/- SRT when combined with surgery; 
Hypothesis: In patients scheduled for NSCLC resection, pembrolizumab + SRT given in the 
preoperative window will result in a higher 1-year relapse free survival rate than 
pembrolizumab alone; 
(5) Objective: To determine the 1-year rate of distant metastases resulting from preoperative 
pembrolizumab +/- SRT when combined with surgery; 
Hypothesis: In patients scheduled for NSCLC resection, pembrolizumab + SRT given in the 
preoperative window will result in a lower 1-year distant metastasis rate than pembrolizumab 
alone; 
(6) Objective: To assess quality of life associated with preoperative pembrolizumab +/- SRT when 
combined with surgery; 
Hypothesis: In patients scheduled for NSCLC resection, pembrolizumab, or pembrolizumab 
+ SRT, given in the preoperative window, will result in acceptable short-term and 
perioperative quality of life; 
(7) Objective: To determine the rate of unresectability that results from a program of preoperative 
pembrolizumab +/- SRT to be followed by a planned surgery; 
Hypothesis: In patients scheduled for NSCLC resection, either pembrolizumab or 
pembrolizumab + SRT given in the preoperative window will both result in <15% overall 
rate of unresectability following the preoperative program; 
3.3 
Exploratory Objectives 
(1) Objective: To determine the difference in the number of infiltrating T cell subsets (cytotoxic 
CD8+, helper CD4+ FOXP3-, and regulatory CD4+ FOXP3+ T cells) between the biopsy and 
the surgery specimens, as quantified by IHC and image analysis; 
Hypothesis: Preoperative pembrolizumab +/- SRT will produce quantitatively detectable 
changes in the infiltrating T cell subsets as compared to pre-treatment biopsy; 
(2) Objective: To determine the change in the intratumoral T-cell repertoire by TCR sequencing and 
single-cell T-cell profiling; 
Hypothesis: Preoperative pembrolizumab +/- SRT will produce quantitatively detectable 
changes in the intratumoral T-cell repertoire as compared to pre-treatment specimens; 
(3) Objective: To quantify treatment-induced changes in the circulating T cell immune response 
using TCR sequencing and enzyme-linked immunospot (ELISPOT) assays; 


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Hypothesis: Preoperative pembrolizumab +/- SRT will produce quantitatively detectable 
changes in the circulating T cell immune response as compared to pre-treatment specimens; 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-3475. 
4.1.1 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 CD3, 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 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 


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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 
(MEL). 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 States for 
the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
The first-in-human phase I study showed that pembrolizumab was well tolerated at doses of up to 
10 mg/kg every 2 weeks and demonstrated evidence of antitumor activity in multiple tumor types 
including melanoma, Merkel cell carcinoma, and NSCLC (Patnaik 2015). Based on these data, 
pembrolizumab was first approved in September 2014 by the FDA for the treatment of 
unresectable or metastatic melanoma and disease progression following ipilimumab and a BRAF 
inhibitor, in patients who were BRAF V600 mutation—positive (Robert 2014). In October 2015, 
the FDA granted accelerated approval for pembrolizumab to treat patients with advanced or 
metastatic NSCLC whose disease progressed after other treatments and with tumors that express 
PD-L1 based on the results of the KEYNOTE-001 trial (Garon 2015). 
KEYNOTE-001 
A total of 495 patients with locally advanced or metastatic NSCLC were assigned to 3 dose 
expansion cohorts and received at least 1 dose of pembrolizumab. Overall, 50% of patients were 
male with a median age of 64 (range, 28–93) and most had good Eastern Cooperative Oncology 
Group (ECOG) performance statuses of 0 or 1. Among 495 patients, about 80% had non-squamous 
histology and had previously received more than two lines of chemotherapy. Patients were treated 
with pembrolizumab alone at a dose of either 2 mg/kg every 3 weeks (Q3 W) (n = 6), or 10 mg/kg 
Q3 W (n = 287), or 10 mg every 2 weeks (Q2 W) (n = 202) (Garon 2015). Across patients 
regardless of dose, schedule, histology, and history of smoking, the overall response rate (ORR) 
was 19.4% [95% confidence interval (CI), 16.0–23.2] by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1. ORR was 18.0% [95% CI, 14.4–22.2] for 394 patients previously treated 
and 24.8% [95% CI, 16.7–34.3] for 101 treatment-naïve patients. Stable disease was observed as 
the best overall response for 108 (21.8%) patients. Pembrolizumab demonstrated a response rate 
of 33.3% [95% CI, 4.3–77.7] at 2 mg/kg Q3 W, 19.2% [95% CI, 14.8–24.2] at 10 mg/kg Q3 W, 
and 19.3% [95% CI, 14.1–25.4] at 10 mg/kg Q2 W. Patients with squamous histology (n = 85) 
showed an ORR of 23.5% [95% CI, 15.0–34.0] and the ORR for patients with non-squamous 
histology was 18.7% [95% CI, 15.0–22.9]. Smoking status influenced ORR (10.3% for never 
smokers vs. 22.5% for former/current smokers). Notably, the median duration of response was 
12.5 months (range, 1.0–23.3) for all patients, 10.4 months (range, 1.0–10.4) for previously treated 


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patients, and 23.3 months (range, 1.0–23.3) in treatment-naïve patients. At the data collection 
cutoff (August 2014), the median duration of PFS was 3.7 months [95% CI, 2.9–4.1] in all patients 
(3.0 months [95% CI, 2.2–4.0] in previously treated patients, and 6.0 months [95% CI, 4.1–8.6] in 
treatment-naïve patients), and the median duration of OS was 12.0 months [95% CI, 9.3–14.7] in 
all patients (9.3 months [95% CI, 8.4–12.4] for previously treated patients and 16.2 months [95% 
CI, 16.2—not reached] for previously untreated patients) (Garon 2015). For adverse events (AEs) 
considered to be treatment related, fatigue, pruritus, and decreased appetite were the most common 
AEs and occurred in 10–20% of all patients. There was no clear difference between the incidence 
of AEs and the dose/schedule of pembrolizumab. AEs of grade 3 or higher were reported in 47 of 
495 patients (9.5%). Immune-related AEs occurred in ≥2% of patients including hypothyroidism 
(n = 34, 6.9%), hyperthyroidism (n = 9, 1.8%), infusion-related reaction (n = 10, 2%), and 
pneumonitis (n = 18, 3.6%). There was a single case of grade 5 interstitial lung disease that resulted 
in death (Garon 2015). 
KEYNOTE-010 
The pivotal phase II/III randomized KEYNOTE-010 trial compared the effects of pembrolizumab 
and docetaxel in patients with previously treated NSCLC (NCT01905657). From August 2013 to 
April 2015, this international, open-label study randomized 1034 patients with PD-L1 positive 
NSCLC to the FDA-approved dose of 2 mg/kg of pembrolizumab, an elevated dose of 10 mg/kg 
of PD-1 inhibitor, or 75 mg/m2 of docetaxel. All three regimens were administered at 3-week 
intervals. All patients had progressed following platinum-based chemotherapy and eligible 
patients expressed PD-L1 on >1% of their tumor cells, and predefined subgroup analysis will be 
performed for those of strongly PD-L1-positive patients, defined as those expressing PD-L1 on 
≥50% of their tumor cells. The primary endpoint was OS and secondary endpoint was PFS. Tumor 
response was measured by RECIST 1.1 at week 12, and then every 6 weeks thereafter. Promising 
results were recently published (Herbst 2016). Pembrolizumab improved overall survival versus 
docetaxel in both standard and higher-dose arms (median 14.9 and 17.3 months with 2 mg/kg and 
10 mg/kg of pembrolizumab, respectively and 8.2 months with docetaxel), as well as in the overall 
study population and in the strongly PD-L1-positive subgroup. Hazard ratio (HR) for OS of 0.54 
[95% CI, 0.38–0.77] and 0.50 [95% CI, 0.36–0.70] for the two dosing schedules of pembrolizumab 
(at 2 mg/kg and 10 mg/kg, respectively) was noted for the patients with the highest biomarker 
expression  (tumor  proportion  score,  TPS  ≥  50%)  as  compared  to  docetaxel.  Interestingly, 
pembrolizumab also demonstrated a benefit in OS for patients in the total study population (>1% 
PD-L1 positivity in the tumor was required at study entry), with hazard ratios of 0.71 [95% CI, 
0.58–0. 88] and 0.61 [95% CI, 0.49–0.75] in the pembrolizumab arms at 2 mg/kg and 10 mg/kg, 
respectively. PFS also significantly improved with both dosing schedules of pembrolizumab 
versus chemotherapy in high PD-L1 expressers (median 5.0 and 5.2 vs. 4.1 months). Based on the 
promising efficacy of pembrolizumab in previously treated NSCLC, several clinical trials of 
pembrolizumab as first-line therapy or adjuvant therapy for NSCLC after curative resection are 
currently underway. 
KEYNOTE-042 
Based on the promising results especially chemo-naïve NSCLC patients from early clinical trial, 


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pembrolizumab is being evaluated as first-line therapy. KEYNOTE-042 trial (ClinicalTrial.gov, 
NCT02220894), a randomized, open-label phase I trial will evaluate the efficacy and safety of 
pembrolizumab vs. platinum doublet chemotherapy as first-line therapy for PDL-1 positive 
advanced NSCLC. Eligible patients with advanced PDL-1 positive NSCLC without EGFR 
mutations or ALK translocation and ≥1 measurable lesion will be randomized 1:1 to 
pembrolizumab 200 mg every 3 weeks or investigator’s choice of carboplatin plus paclitaxel or 
carboplatin plus pemetrexed (Mok 2015). Patients will be stratified by ECOG PS (0 vs. 1), 
histology (squamous vs. non-squamous),  region (East Asia vs. non-East Asia), and  PDL-1 
expression (strong vs. weak [staining in ≥50% vs. 1–49% of tumor cells assessed by 
immunohistochemistry with the 22C3 antibody]). Primary end point is overall survival in patients 
with PDL-1 strongly positive tumors and secondary endpoints include progression-free survival in 
strongly positive patients and PFS and OS in all patients. 
4.2 
PD-L1 expression by immunohistochemistry 
Pembrolizumab has been approved for use with a companion diagnostic, the PD-L1 
immunohistochemistry (IHC) 22C3 pharmDx test, the first test designed to detect PD-L1 
expression in NSCLC. The clinical trial assay was developed by Dako, an in vitro diagnostic 
manufacturer. In the KEYNOTE-001 trial, the overall prevalence of PD-L1 expression ≥1% was 
60.8% among 824 patients including 58.6% of the 643 previously treated patients and 68.5% of 
the 181 previously untreated patients. The prevalence of a proportion score (PS) of at least 50% 
was 24.9% among previously untreated patients and 22.7% among previously treated patients 
(Garon 2015). Notably, the ORR (45.2% vs. 16.5% vs. 10.7%), PFS (6.4 vs. 4.1 vs. 4.0 months), 
and OS (not reached vs. 10.6 vs. 10.4 months) were significantly higher for patients whose tumors 
expressed PD-L1 membranous staining ≥50% compared to patients with a PS of 1–49% or those 
with a score less than 1%. A cutoff of ≥50% PD-L1 positivity in tumor cell membranes was 
determined as optimal by receiver operating characteristic (ROC) analysis. In contrast, PD-L1 
expression was not associated with predictive markers of any efficacy endpoints in the Checkmate 
017 study with nivolumab, in which patients with pretreated squamous NSCLC were compared 
with those treated with docetaxel (Brahmer 2015). There was a favorable trend of unstratified 
hazard ratios toward nivolumab in patients with higher PD-L1 expression (≥10%, ≥5%, and ≥1%) 
and similar rates of objective response were observed among patients with PD-L1 positive tumors 
and those with PD-L1 negative tumors. On the other hand, another trial of nivolumab in pretreated 
advanced non-squamous NSCLC (Checkmate 057) compared with docetaxel demonstrated a 
meaningful separation of the overall survival curves across all pre-specified PD-L1 expression 
levels (at ≥1%, ≥5%, and ≥10%) (Borghaei 2015). However, PD-L1 expression in both studies 
was evaluated retrospectively in pretreatment (archival or recent) tumor biopsy specimens using 
rabbit monoclonal antihuman PD-L1 antibody (clone 28-8, Epitomics). In a phase I study of anti- 
PD-L1 antibody MPDL3280A, PD-L1 was stained with an antihuman PD-L1 rabbit monoclonal 
antibody (clone SP142, Ventana) and PD-L1 expression was evaluated on both tumor cells and 
tumor-infiltrating immune cells. While the association of response to MPDL3280A treatment and 
tumor-infiltrating immune (TIL) cell PD-L1 expression was significant, the association with tumor 
cell PD-L1 expression was not (Herbst 2014). 
Recent pooled sensitive analyses of phase I–III clinical trials of PD-1/PD-L1 inhibitors 
(nivolumab, pembrolizumab, or MPDL3280A) including 511 NSCLC patients showed that 


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patients with PD-L1 positive tumor achieved significantly more responses than PD-L1-negative 
patients (23.2% vs. 14.5%), with an absolute difference of 8.7% (95% CI 1.1–15.5) (Carbognin 
2015). However, the use of PD-L1 IHC positivity as a predictive marker remains controversial in 
the context of different anti-PD-L1 antibodies, staining techniques, definitions of positive tumor 
cells or immune cells, tumor site (primary vs. metastasis), tumor type (archival vs. recent), and 
various cutoffs. 
4.3 
Rationale 
4.3.1 Rationale for the Trial and Selected Subject Population 
We hypothesize that neoadjuvant treatment with pembrolizumab and targeted stereotactic 
radiation therapy (SRT) will improve patients’ immunogenic responses during and after surgical 
treatment of their non-small cell lung cancer. The timing of the interventions during the 
neoadjuvant phase will allow us to perform comprehensive analyses on tumor specimens before 
any treatment and after initial response to pembrolizumab alone or pembrolizumab with SRT. 
In this study, patients are offered immunotherapy +/- SRT before surgery but are free to pursue 
chemotherapy +/- external beam radiation therapy after surgery. It is important to call attention  
to this deliberate aspect of the study design, which ends protocol-mandated treatment at the time 
of surgery, such that patients are allowed to pursue postoperative treatment appropriate to their 
surgical/pathologic stage. While chemotherapy is considered part of the perioperative standard of 
care for NSCLC patients undergoing resection, the only available randomized evidence showed 
no statistical difference in long-term disease-free survival, whether chemotherapy was 
administered preoperatively or postoperatively (Felip 2010). Thus, neoadjuvant chemotherapy 
given prior to surgery is not considered a standard of care, and in fact the extremely well 
established standard of care is to offer postoperative chemotherapy +/- radiotherapy depending 
on the pathologic outcome at surgery, as advocated by the guidelines issued by the European 
Society of Medical Oncologists on this subject (McElnay 2014). Likewise, there is no clear 
benefit to external beam radiotherapy whether given preoperatively or postoperatively. In 
addition, emerging recent evidence indicates that in several different tumor types, cisplatin may 
stimulate upregulation of PD-L1 and that this could be associated with subsequent cisplatin 
resistance (Zhang 2016, Mesnage 2016, Yan 2016). Therefore, the rationale for administration of 
immunotherapy prior to administration of cisplatin, with the possibility of inducing a durable 
immune response prior to surgery and expected postoperative therapy, may offer a more 
therapeutically effective strategy. 
Furthermore, our thoracic surgery service has extensive experience performing operations on 
patients who are currently receiving immunotherapy for a variety of malignancies, and thus far 
there have been no issues with delays due to therapy. It is expected that the amount of delay of 
surgery will be relatively minimal, even accounting for administration of 1-2 cycles of 
pembrolizumab. Given the relatively poor outcomes for NSCLC, even among patients who are 
eligible for definitive surgical resection, novel approaches to treating this population are greatly 
needed. 
The strategy offered in this study will allow us to define a rationale for therapies that, when 


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combined with standard surgical resection in the first-line setting, could result in more complete 
and durable responses for patients. The study design will allow us to investigate intratumoral and 
circulating immunologic changes as a result of preoperative therapy, as well as potential 
mechanisms of synergy between pembrolizumab and stereotactic radiation therapy in addressing 
local-regional and distant disease recurrence. 
4.3.2 Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475. 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 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. 10.0 mg/kg Q2W, the highest dose tested in 
PN001, was utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity. 
Recent data from other clinical studies within the MK-3475 program has shown that a lower 
dose of MK-3475 and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days). This early PK 
and pharmacodynamic data provide scientific rationale for testing a Q2W and Q3W dosing 
schedule. 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of MK-3475 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 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 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, 


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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. 
4.3.3 Rationale for SRT Dosing 
The dose of radiation therapy prescribed in this study is based on a number of preclinical and 
clinical studies that have investigated the immunologic effects of radiation doses in this range in 
combination with PD-1 antibodies. 
For example, Verbrugge et al. irradiated triple-negative AT3 breast tumors in mice with a single 
fraction of 12 Gy with or without anti-CD137 antibody, a co-stimulatory molecule designed to 
boost immune-mediated antitumor effects of radiotherapy (Verbrugge 2012). Anti-CD137 
therapy significantly enhanced radiotherapy-induced tumor control, but the response was short- 
lived. The addition of anti-PD-1 antibody to anti-CD137 antibody and radiation led to cures at 
the primary irradiated tumor site, while anti-PD1 monotherapy was not very effective. After 
testing of various radiation regimens, they found that 12 Gy x 1 fraction led to 100% cure, 
whereas the cure rates with 5 Gy x 4 fractions and 4 Gy x 5 fractions were 80% and 40%, 
respectively. 
Zeng et al. found that a radiation regimen of 12 Gy x 1 fraction, when combined with anti-PD-1 
antibody, led to long-term survival in a mouse glioma model whereas neither therapy by itself did 
(Zeng 2013). The combination therapy was associated with increased infiltration by cytotoxic T 
cells and decreased regulatory T cells within the tumor microenvironment. Deng et al. also used 
this radiation regimen (12 Gy x 1 fraction) and anti-PD- L1 therapy to show synergistic inhibition 
of TUBO mammary carcinoma and MC38 colon adenocarcinoma growth in mice (Deng 2014). 
Furthermore, they showed that PD-L1 expression was upregulated in tumor cells after radiotherapy 
and that radiation and anti-PD-L1 led to a synergistic reduction in the local accumulation of tumor-
infiltrating myeloid-derived suppressor cells that normally suppress T cell function within the 
tumor microenvironment. 
Twyman-Saint Victor et al. conducted preclinical studies using both anti-CTLA4 and anti-PD-1 
(or PD-L1) therapy and radiation (Twyman-Saint Victor 2015). B16- F10 melanoma tumors 
were grown in the bilateral flanks of mice. Tumor in one flank was irradiated (20 Gy) and 


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growth was assessed in both the irradiated and the unirradiated tumors. Mice were treated with 
anti-CTLA4 antibody, anti PD-1/PD-L1 antibody or both prior to and after irradiation. In these 
experiments, the addition of radiation to anti-CTLA4 improved responses in irradiated and 
unirradiated tumors; however, resistance was common. Integrated genomic and immune  
profiling revealed that resistance was due to upregulation of PD-L1 on melanoma cells and 
associated with T cell dysfunction, known as exhaustion. Even in the presence of dual  
checkpoint blockade, omission of radiation resulted in high rates of relapse. Investigation into 
how each treatment impacted mechanisms that influence response revealed that anti-CTLA4 
predominantly inhibits regulatory T cells (Treg) to increase the CD8+ T cell to Treg (CD8/Treg) 
ratio, radiation enhances the diversity of the T cell receptor repertoire of intratumoral T cells, and 
anti- PD-L1 reverses T cell exhaustion. Together, dual checkpoint blockade promotes expansion 
of T cells, while radiation shapes the T cell receptor repertoire of the expanded peripheral clones. 
Many ongoing studies at present are testing comparisons between various single-fraction doses 
versus more fractionated regimens in combination with immunomodulatory compounds. At least 
based on available data from in vivo studies delivering radiation in combination with CTLA-4 
antibody, it appears that 12 Gy is sufficient to enact a vaccine-like effect in the primary tumor 
when given with immunomodulatory agents. In combination with anti-PD-1 therapy, it also 
appears that 12 Gy is also likely to be effective, although prior studies have not analyzed effects 
outside the primary tumor. For the purpose of this study, 12 Gy was chosen as a dose likely to 
produce a substantive immune effect but also very likely to be safe. Partial SRT (irradiation will 
be prescribed to approximately 50% of the primary tumor) will be given to avoid CD4+ and 
CD8+ T cell depletion within the irradiated primary tumor and allow for the assessment of local 
effects resulting from reshaping of the intratumoral T cell repertoire. 
4.3.4 Rationale for Endpoints 
The primary endpoint for this study is the change in number of infiltrating CD3+ T cells/ μm2 in 
the lung cancer tissue from before and after pembrolizumab +/- SRT, based on quantification using 
immunohistochemistry (IHC) and image analysis. This endpoint was selected as a marker of T cell 
proliferation and activation. It is expected that immunologic activation would be reflected by the 
presence of this biomarker. The purpose of this study is to determine whether neoadjuvant 
pembrolizumab +/- SRT is sufficient to produce a two-fold change in the CD3+ T cell population, 
comparing pre-treatment biopsy tissue to post-treatment resection specimens. 
Despite the generally high efficacy of surgery in producing local control for most NSCLC patients, 
a large percentage will succumb to regional or distant metastatic disease manifestation. Therefore, 
this study will also include exploratory objectives aimed at the possibility of a potential 
improvement in 1-year clinical outcomes from the addition of neoadjuvant immune modulation. 
4.4 
Secondary Objectives & Hypotheses 
Secondary objectives include safety according to criteria described by the protocol (≤33% grade  
3 immune-related toxicity); toxicity according to CTCAE v. 4, including immune-related adverse 
events (AEs); and quality of life. 


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Other secondary objectives include the 1-year overall survival rate, 1-year relapse free survival, 
1 year rate of distant metastases, and rate of progression to unresectability following the 
preoperative program. These exploratory data will provide an initial basis for investigating which 
of these two programs might provide the best overall clinical benefits and merit further study. 
4.5 
Exploratory Objectives 
4.5.1 Biomarker Research 
PD-L1 expression will be tested in tumor specimens to investigate correlations to immune 
response from treatment with pembrolizumab. 
Other exploratory objectives will further describe immune changes resulting from neoadjuvant 
pembrolizumab +/- SRT. These will include: changes in the number of infiltrating T cell subsets; 
change in the intratumoral T-cell repertoire by TCR sequencing and single-cell T-cell profiling; 
and treatment-induced changes in the circulating T cell immune response using TCR sequencing 
and enzyme-linked immunospot (ELISPOT) assays. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
1. Histologically or cytologically confirmed non-small cell lung cancer, performed on a 
biopsy that occurred within the last 120 days. 
2. PET-CT within the last  75 days showing radiographic stage I to IIIa lung cancer 
(mediastinal staging biopsy is allowed but not required). 
3. Documentation that the patient is a candidate for surgical resection of their lung 
cancer by an American Board of Thoracic Surgery-certified surgeon. 
4. Measurable disease as defined by RECIST v1.1. 
5. Adequate tissue specimens for correlative biomarker analysis. The patient should be 
willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion. Newly-obtained is defined as a specimen obtained up to 120 days prior to 
initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot 
be provided (e.g. inaccessible or subject safety concern) may submit an archived 
specimen only upon agreement from the Principal Investigator. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
7. Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical 
procedures to NCI CTCAE Version 4.0 grade 1. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 


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1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ³ 18 years of age on day of signing informed consent. 
3. Demonstrate adequate organ function as defined in Table 1. All screening labs should 
be performed within 10 days of treatment initiation, unless specified below. 
Table 1 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobina 
≥9 g/dL or ≥5.6 mmol/L 
Renal 
Serum creatinine OR 
Measured or calculatedb 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 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN 
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 
aPatients cannot have received transfusion or erythropoietin (EPO) within 7 days of the hemoglobin (Hgb) lab 
test as this may artificially inflate the Hgb lab value. 
bCreatinine clearance should be calculated per institutional standard. 
4. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. 
5. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception, as outlined in Section 5.7.2 – Contraception, for the 
course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
6. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 


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5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is ineligible for an operation based on medical or oncologic contraindications to 
surgery. 
2. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. 
3. Has evidence of interstitial lung disease. 
4. Has an active second malignancy, i.e. patient known to have potentially fatal cancer 
present for which he/she may be (but not necessarily) currently receiving treatment. 
Patients with a history of malignancy that has been completely treated, with no 
evidence of that cancer currently, are permitted to enroll in the trial if curative therapy 
has been completed, such as basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ cervical 
cancer. 
5. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
6. 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. 
7. Has a known history of active TB (Bacillus Tuberculosis) 
8. Hypersensitivity to pembrolizumab or any of its excipients. 
9. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
10. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study. 
- 
Note: If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting therapy. 
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 (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 


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12. Has an active infection requiring systemic therapy. 
13. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator. 
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
15. 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. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
19. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the 
first dose of the study drug. Administration of killed vaccines is allowed. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines, and are not allowed. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2.  
Table 2 Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequenc
Route of 
Administratio
Regimen/Trea
t- ment 
P
i d
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 
3-week cycle 
Experimental 
Stereotactic radiation therapy will be given at a prescription dosage of 12 Gy at the 80% isodose 
line, to be delivered in one single treatment session in one day, to 50% +/- 10% of the primary 
tumor volume, as determined by volumetric measurement of the total tumor volume and the 
volume of that tumor within the prescribed planning target volume (PTV). The lateral half of the 
tumor should be encompassed within the PTV and the medial aspect of the tumor relative to the 
patient should not be included in the PTV. Treatment may be delivered from either a linear 
accelerator or robotic SRT delivery system. SRT, if the patient is to receive it according to the 
terms of the protocol, should be given within 7 days (+/- 3 days) following the second 
administration of pembrolizumab. If the second cycle is not given, then SRT should not be given. 


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During dose expansion, trial treatment should begin on the day of randomization or as close as 
possible to the date on which treatment is allocated/assigned. 
5.2.1 Dose Selection/Modification 
5.3.2.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background 
and Rationale. 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual. 
5.2.1.1 Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure, 
including coadministration with additional compounds, may represent an immunologic etiology. 
These adverse events may occur shortly after the first dose or several months after the last dose 
of pembrolizumab/combination and may affect more than one body system simultaneously.. 
Pembrolizumab/combination treatment must be withheld for drug-related toxicities and severe or 
life-threatening AEs as per Table 3 below. See Section 5.6 for supportive care guidelines, 
including use of corticosteroids. 
If a patient continues to experience toxicity, or if dosing with study drug is interrupted for > 14 
consecutive days due to toxicity, treatment  should be discontinued unless otherwise agreed 
between the investigators before reintroduction of study drug. 
The following dose modification rules will be used with respect to potential toxicity. Toxicity 
will be assessed according to the NCI Common Terminology Criteria for Adverse Events 
Version 4.0 (CTCAE v4.0). 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult.  Therefore, while the investigator may attribute a 
toxicity event to the combination, to stereotactic radiotherapy, or to pembrolizumab alone, for 
adverse events listed in Table 3, both interventions must be held according to the criteria in 
Table 3 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse 
Events Associated with Pembrolizumab. 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications. 
Restarting Study Interventions: 


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Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 3. 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions. 
If the toxicities do resolve and conditions are aligned with what is defined in Table 
3, the combination of stereotactic radiotherapy and pembrolizumab may be restarted 
at the discretion of the investigator. In these cases where the toxicity is attributed to 
the combination or to stereotactic radiotherapy alone, re-initiation of 
pembrolizumab as a monotherapy may be considered at the principal investigator’s 
discretion.  


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Table 3 Dose Modification and Toxicity Management Guidelines for Immune-Related AEs associated with pembrolizumab 
monotherapy and IO Combinations 
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if irAEs are not 
controlled by corticosteroids. 
2. 
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last study 
intervention treatment. 
3. 
The corticosteroid taper should begin when the irAE is < Grade 1 and continue at least 4 weeks. 
4. 
If study intervention has been withheld, study intervention may resume after the irAE decreased to < Grade 1 after corticosteroid taper.  
irAEs 
Toxicity Grade (CTCAE 
v5.0) 
Action with pembrolizumab 
Corticosteroid and/or other 
therapies 
Monitor and Follow-up 
Pneumonitis 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
• Add prophylactic antibiotics 
for opportunistic infections 
• 
Monitor participants for signs 
and symptoms of pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
Recurrent Grade 2, Grade 3 
or 4 
Permanently discontinue 
Diarrhea/Colitis 
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor participants for signs 
and symptoms of enterocolitis 
(i.e., diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (i.e., peritoneal signs 
and ileus) 
• 
Participants with ≥Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis 
• 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion 
Recurrent Grade 3 or Grade 
4 
Permanently discontinue 
AST or ALT 
Elevation or 
Increased Bilirubin 
Grade 2 a 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5 to 1 
mg/kg prednisone or 
• 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 


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equivalent) followed by 
taper 
value returned to baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently discontinue 
• Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
T1DM or 
Hyperglycemia 
New onset T1DM or Grade 
3 or 4 hyperglycemia 
associated with evidence of 
b-cell failure 
Withhold d 
• Initiate insulin replacement 
therapy for participants with 
T1DM 
• Administer 
antihyperglycemic in 
participants with 
hyperglycemia 
• 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated 
• 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with nonselective 
beta- blockers (e.g., 
propranolol) or thionamides 
as appropriate 
• 
Monitor for signs and symptoms 
of thyroid disorders. 
Grade 3 or 4 
Withhold or permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid replacement 
hormones (e.g., 
levothyroxine or 
liothyroinine) per standard 
of care 
• 
Monitor for signs and symptoms 
of thyroid disorders. 
Nephritis: grading 
according to 
increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
• Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) 
followed 
by 
taper. 
• 
Monitor changes of renal function 
Grade 3 or 4 
Permanently discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently discontinue 
Exfoliative 
Suspected SJS, TEN, or 
Withhold 


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Dermatologic 
Conditions 
DRESS 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed SJS, TEN, or 
DRESS 
Permanently discontinue 
All other irAEs 
persistent Grade 2 
Withhold 
• Based on severity of AE, 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 
Withhold or discontinue 
based on the evente. 
Events that require 
discontinuation include 
and not limited to: 
Gullain-Barre Syndrome, 
encephalitis 
recurrent Grade 3 or Grade 
4 
Permanently discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-
Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a  AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x 
baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 
2, pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs. 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may 
be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of 
T1DM). 
 


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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Principal Investigator. The reason for interruption 
should be documented in the patient's study record. 
5.2.2 Timing of Dose Administration 
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 (Section 6.0). 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, for 2 
cycles. 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. 
5.2.3 Trial Blinding/Masking 
This trial is open label; therefore, the subject, the trial site personnel, the Principal Investigator 
and/or designee are not blinded to treatment. 
5.3 
Randomization or Treatment Allocation 
For the run-in cohorts, consecutive patients will be enrolled. 
In the expansion cohort, consecutive patients will be enrolled if only Cohort 1 conditions are 
fulfilled. If Cohort 1 and Cohort 2 both meet safety criteria, then patients will be enrolled in the 
Expansion Cohort using permuted-block randomization with block size of 4. 
5.4 
Stratification 
No stratification is to be performed. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for one of these or other medications or 


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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 
Principal Investigator. The final decision on any supportive therapy or vaccination rests with the 
treating investigator and/or the subject's primary physician. 
5.5.1 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 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2. 
5.5.2 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 
• Investigational agents other than pembrolizumab 
• Radiation therapy outside of that prescribed per protocol 
• 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 
Principal Investigator. 
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 


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no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 Rescue Medications & Supportive Care 
5.6.1 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 does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
5.6.2 Pneumonitis: 
5.6.2.1 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. 
5.6.2.2 For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed. 
5.6.2.3 Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
5.6.3 Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus). 
5.6.3.1 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 


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GI consultation and endoscopy to confirm or rule out colitis. 
5.6.3.2 For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
5.6.3.3 For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids. 
5.6.3.4 When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
5.6.4 Type 1 diabetes mellitus*  
*(if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if 
associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
5.6.4.1 For T1DM or Grade 3-4 Hyperglycemia 
5.6.4.1.1 Insulin replacement therapy is recommended for  Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
5.6.4.1.2 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
5.6.5 Hypophysitis: 
5.6.5.1 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. 
5.6.5.2 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. 
5.6.6 Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
5.6.6.1 Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
5.6.6.1.1 In  hyperthyroidism,  non-selective  beta-blockers  (e.g.  propranolol)  are 
suggested as initial therapy. 
5.6.6.1.2 In  hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care. 
5.6.6.2 Grade 3-4 hyperthyroidism 
5.6.6.2.1 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 


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steroid dose is tapered. 
5.6.7 Hepatic: 
5.6.7.1 For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
5.6.7.1.1 Treat with IV or oral corticosteroids 
5.6.7.2 For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
5.6.7.3 When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
5.6.8 Renal Failure or Nephritis: 
5.6.8.1 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. 
5.6.9 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 3 below shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab (MK-
3475). 
 


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Table 3 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
cation at subsequent dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. Additional appropriate 
medical therapy may include but is not limited to: 
IV fluids Antihistamines NSAIDS 
Acetaminophen Narcotics 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion 
rate (e.g., from 100 mL/hr to 50 mL/hr). Otherwise dosing will 
be held until symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
Subject 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab (MK-3475) 
with: 
Diphenhydramine 50  mg po  
(or 
equivalent 
dose 
of 
antihistamine). 
Acetaminophen 
500-1000 
mg po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Stop Infusion. 
No subsequent dosing 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids Antihistamines NSAIDS 
Acetaminophen Narcotics Oxygen 
 
infiltrates)  
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
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. 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 


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5.7.2 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. 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the absence 
of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after 
the last dose of study drug by complying with one of the following: 
(1) practice abstinence† from heterosexual activity; OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner 
• 
contraceptive rod implanted into the skin  
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only) 


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• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. 
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the study 
subjects of childbearing potential must adhere to the contraception requirement (described above) 
from the day of study medication initiation (or 14 days prior to the initiation of study medication 
for oral contraception) throughout the study period up to 120 days after the last dose of trial 
therapy. If there is any question that a subject of childbearing potential will not reliably comply 
with the requirements for contraception, that subject should not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study. The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated. The outcome 
of the pregnancy will be reported to the Principal Investigator and to Merck without delay and 
within 24 hours to the Principal Investigator 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 Principal Investigator. If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Principal Investigator and to Merck and followed 
as described above and in Section 7.2.2. 
5.7.4 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. 


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5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Principal Investigator if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons. Specific 
details regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
5.9.5 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
5.9.6 Confirmed radiographic disease progression 
5.9.7 Intercurrent illness that prevents further administration of treatment per protocol 
5.9.8 Investigator’s decision to withdraw the subject 
5.9.9 The subject has a confirmed positive serum pregnancy test 
5.9.10 Noncompliance with trial treatment or procedure requirements 
5.9.11 The subject is lost to follow-up 
5.9.12 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6. 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). 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. After documented disease progression each subject will be followed by telephone 
for overall survival until death, withdrawal of consent, or the end of the study, whichever occurs 
first. 
5.9 
Subject Replacement Strategy 
Patients who drop out before starting pembrolizumab will be replaced. In addition, patients who 
come off study before completing surgery without grade ≥3 toxicity will be replaced. The 
frequency of each of these events will be reported and reasons for replacement reviewed. 
5.10 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be provided 


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so that appropriate adjustments to subject treatment can be made. 
 


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6.0 
TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screeninga 
 
Treatment Cyclesb 
Surgical Treatment 
Follow-Up 
Treatment Cycle: 
Screening 
1 
2 
End- Induction/ 
Safety Visit 
SRTc 
Surgical Treatment 
Post-Treatment/ 
Safety Visitse 
Scheduling Window: 
-28d to -1d 
± 3d 
± 3d 
No later than 
7d (± 3d) 
No later than 7d 
(± 3d) 
no later than 6wksd 
At 30d, 90d, 
180d,360d after 
surgery (+14d) 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X 
X 
X 
 
X 
X 
Trial Treatment Administration 
 
X 
X 
 
 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
 
X 
X 
Full Physical Examination 
X 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
 
X 
 
 
X 
Vital Signs and Weight 
X 
X 
 
X 
 
 
X 
ECOG Performance Status 
X 
X 
 
X 
 
 
X 
Laboratory Procedures/Assessmentsf 
Pregnancy Test – Urine or Serum β-
HCGg 
X 
Coagulation 
X 
 
 
 
 
 
 


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Trial Period: 
Screeninga 
 
Treatment Cyclesb 
Surgical Treatment 
Follow-Up 
Treatment Cycle: 
Screening 
1 
2 
End- Induction/ 
Safety Visit 
SRTc 
Surgical Treatment 
Post-Treatment/ 
Safety Visitse 
Scheduling Window: 
-28d to -1d 
± 3d 
± 3d 
No later than 
7d (± 3d) 
No later than 7d 
(± 3d) 
no later than 6wksd 
At 30d, 90d, 
180d,360d after 
surgery (+14d) 
Hematology 
X 
X 
X 
X 
 
X 
X 
Comprehensive Serum Chemistry 
Panel 
X 
X 
X 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
 
 
X 
Thyroid function 
X 
X 
X 
Efficacy Measurementsh 
Tumor Imaging (F-18 FDG PET/CT 
in screening with MRI/CT brain in 
stage II/III patients, and CT chest at 
360d or as otherwise clinically 
indicated) 
X 
X 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Bloodi 
Archival or Newly Obtained 
Tissue Collection 
X 
 
 
 
 
 
X 
Correlative Studies Blood 
Collection 
X 
 
X 
X 
 
X 
X 
aScreening procedures to be completed within 28 days of C1D1 with the exception of fresh tumor specimens and tumor imaging, please see information in footnotes, 
respectively. 
bPatients receive 2 cycles of pembrolizumab. 1 cycle is defined as 3 week intervals. 
cIf patient is scheduled to receive SRT, the day of radiation therapy will be no later than 7d (+/- 3d) following the second cycle of pembrolizumab. 
dNo later than 6 weeks after the last dose of pembrolizumab. 
eAfter surgery, patients to return for clinical and laboratory assessments at 30 days (first follow-up visit to occur), 90 days, 180 days, and 360 days (+ 21 days) after date of surgery. 
fScreening labs performed within 10d of treatment initiation can be applied to Cycle 1 lab tests. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. Results 
must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose of trial treatment.  
gFemales of childbearing potential: negative urine or serum pregnancy test within 3d prior to receiving trial treatment. If urine test is positive or non-confirmatory, a serum pregnancy test will be 
required. 
hAll patients to have a full-body F-18 FDG PET/CT scan ≤75d prior to study treatment; patients with stage II and stage III disease should also have brain CT or MRI ≤75d prior to study treatment. 
Additional imaging during treatment will be under investigator discretion. During Follow-up phase, imaging studies are to be completed at the discretion of investigator or qualified designee. 
iNewly obtained specimen is preferred, however archived tissue will be acceptable due to inaccessibility or subject safety concern. Specimens that are newly obtained are defined as collection up to 120d 
prior to initiation of study treatment. 
For correlative studies and blood collection: research-donated blood will be collected pre-pembrolizumab infusion for cycle 1 and cycle 2, at the safety visit during cycle 2 (blood should be collected 
prior to SRT administration if patient will receive SRT), prior to surgical treatment, and at each post-treatment/safety follow-up visit (30d, 90d, 180d and 360d (+14d) after surgery). 


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6.2 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit. 
Individual trial procedures are described in detail below. It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Principal Investigator 
and/or Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require 
that additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
6.2.1 Administrative Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating 
in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation in 
the trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use. The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial. The communication of this information 
will be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Principal Investigator requirements. 
6.2.1.1 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 


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ensure that the subject qualifies for the trial. 
6.2.1.2 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. 
6.2.1.3 Prior and Concomitant Medications Review 
6.2.1.3.1 
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. 
6.2.1.3.2 
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial. All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2. 
6.2.1.4 Disease Details and Treatments 
6.2.1.4.1 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status. 
6.2.1.4.2 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
6.2.1.4.3 
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 new therapy. Once new anti-cancer therapy has been initiated the subject will move into 
survival follow-up. 
6.2.1.5 Assignment of Screening Number 
At the time of screening, the patient will be assigned a screening number. 


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6.2.1.6 Assignment of Randomization Number 
At the time of randomization during dose expansion, the patient will be assigned a randomization 
number. 
6.2.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
6.2.2 Clinical Procedures/Assessments 
6.2.2.1 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 Trial Flow Chart 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 11.2). Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. 
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs. 
6.2.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period. Clinically significant abnormal findings should be recorded as medical history. A full 
physical exam should be performed during screening, 
6.2.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration. 
6.2.2.4 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 Trial Flow Chart 
(Section 6.0). Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure. Height will be measured at screening only. 
6.2.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart. 


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6.2.2.6 Tumor Imaging and Assessment of Disease 
All patients will undergo a full-body F-18 FDG PET/CT scan within  75 days prior to start of 
treatment or randomization (only during dose expansion). Patients with stage II and III disease 
should have a brain CT or MRI within  75 days prior to start of treatment. 
Following the time of surgery, the investigator or qualified designee will assess disease with 
imaging studies according to the investigator’s determination of the standard of care. 
6.2.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Prior to treatment or randomization (only during dose expansion), tissue collections include fresh 
sampling (preferred) of the primary tumor (core or excisional biopsy) or archival tissue, due to 
safety and inaccessibility, and blood samples (please see Table 6, Trial Flow for details). 
If the patient has clinically involved lymph nodes and investigation of the nodes is clinically 
warranted, every effort should be made to collect tissue via core needle biopsy from the involved 
lymph nodes. If bronchoscopy is performed, it is highly encouraged to collect lavage specimens 
as well, although this is not mandatory. 
Research-donated blood will be collected prior to pembrolizumab infusion during cycle 1 and 
cycle 2; prior to surgical treatment, and at each post-treatment/safety follow-up visit (30d, 90d, 
180d and 360d (+14d) after surgery). 
Overall Schema: 
 
* Cycle 2 of pembrolizumab should be given except as recommended per protocol, section 5.2.1.2. 
** SRT is delivered within 7 days +/- 3 days of second pembrolizumab cycle. If second cycle is not given 
due to discontinuation, SRT should not be given (patient should continue to surgery when deemed safe by 
treating surgeon). 


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^ Surgery will take place no later than 6 weeks following last dose of pembrolizumab, e.g. no later than 
week 7, or if two cycles of pembrolizumab were given, week 10. 
# Adjuvant blood collection will take place at follow-up visits (30d, 90d, 180d and 360d (+14d) after 
surgery). 
6.2.3 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) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5. 
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) 
Free thyroxine (T4) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Thyroid stimulating hormone 
(TSH) 
Absolute Lymphocyte Count 
(CO2 or biocarbonate) 
Urine pregnancy test † 
PK 
Uric Acid 
Blood for correlative studies 
Calcium 
Chloride 
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 
Creatinine 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required. 
‡ If considered standard of care in your region. 
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment. 


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6.2.4 Blood Collections 
All patients will have 4 (four) 10mL green top tubes of blood specimens collected prior to 
pembrolizumab infusion during cycle 1 and cycle 2, prior to surgical treatment, and at each post-
treatment/safety follow-up visit (30d, 90d, 180d and 360d (+14d) after surgery). 
Sample collection, storage and shipment instructions for blood samples are provided in the 
Laboratory Manual. 
6.2.5 Other Procedures 
Fresh sampling (preferred) of the primary tumor (core or excisional biopsy) is required, or archival 
tissue may be substituted for reasons due to safety and inaccessibility. 
If the patient has clinically involved lymph nodes and investigation of the nodes is clinically 
warranted, every effort should be made to collect tissue via core needle biopsy from the involved 
lymph nodes. 
6.2.5.1  Pretreatment samples 
Core biopsies of primary tumor +/- involved lymph nodes will be performed by a qualified 
radiologist, pathologist, surgeon, or pulmonologist. One to four core biopsies will be performed 
(number determined by safe accessibility and size of lesion at the discretion of the physician 
performing the biopsy). Core biopsies are required, however if it is deemed technically infeasible, 
or if a core biopsy is deemed very high risk by the physician performing the biopsy, then fine-
needle aspiration (FNA) may be acceptable in 1-2 extremely select cases based on pre-approval 
by the study Principal Investigators. 
For intraparenchymal lung biopsies, an 18G core needle biopsy is preferred. If this is not 
considered to be safe by the physician performing the procedure, then an FNA with a higher gauge 
needle will be acceptable. 
Biopsy sites other than intraparenchymal lung should use a 16 G if possible, but 18 G or FNA will 
be acceptable if the physician performing the biopsy feels that it is safer. One to three needle passes 
at minimum will be obtained, but if the physician determines it is safe, up to 6 passes may be 
obtained. 
Sample collection, storage and shipment instructions for pre-treatment tissue samples are provided 
in the Laboratory Manual. 
6.2.5.2 Post-treatment samples: 
Patients will undergo surgical resection of their primary tumor and associated lymph nodes. 
Patients in cohort 1 will have received pembrolizumab alone prior to resection, whereas patients 
in cohort 2 will have received pembrolizumab and radiation to half of the primary tumor. 


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In all cases, post-treatment excisional samples should be first taken from the primary tumor tissue 
that was treated with pembrolizumab only (medially oriented half of tumor). The portion of tumor 
which received radiation is the lateral aspect of the tumor relative to the patient. 
Therefore, mandated post-treatment tissue samples should always be removed from the medial 
aspect of the tumor. 
If it is feasible and specimen collection will not interfere with the patient’s clinical care, tissue 
samples should also be collected from the radiated portion of the tumor (lateral aspect). These 
tumor samples should be labeled so that their orientation (medial vs lateral) is clear. 
Samples from clinically involved lymph nodes are requested if feasible and if collection will not 
interfere with the patient’s clinical care. These samples should be labeled by the designated nodal 
station. 
Sample collection, storage and shipment instructions for post-treatment tissue samples are 
provided in the Laboratory Manual. 
6.2.5.3 Lavage (fluid) specimens 
If bronchoscopy is performed, it is highly encouraged to collect lavage specimens as well, although 
this is not mandatory. If a patient has clinical indication for bronchoscopy, lavage fluid may be 
obtained. Any excess leftover fluid, up to 1000mL, should be submitted. 
Sample collection, storage and shipment instructions for fluid samples are provided in the 
Laboratory Manual. 
6.2.6 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled 
for the final trial visit should be performed at the time of discontinuation. Any adverse events 
which are present at the time of discontinuation/withdrawal should be followed in accordance with 
the safety requirements outlined in Section 7.2 - Assessing and Recording Adverse Events. 
6.2.7 Blinding/Unblinding 
This trial is open label; therefore, the subject, the trial site personnel, the Principal Investigator 
and/or designee are not blinded to treatment. 
6.2.8 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related details 
are provided above in Section 7.1 - Trial Procedures. 


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6.2.9 Screening 
Screening period will be conducted days -28 to -1. 
6.2.10 Treatment Period 
Treatment will initiate with the first dose of pembrolizumab. A second dose of pembrolizumab 
will be delivered 3 weeks later, +/- 3 days. 
If the patient is scheduled to receive SRT on the protocol, the day of radiation delivery will be no 
later than 7 days following the date anticipated for administration of the second cycle of 
pembrolizumab, +/- 3 days. If the second cycle is not given, then SRT should not be given. 
Surgical resection, if the patient is medically and physically able to undergo the procedure, should 
be delivered no later than 6 weeks (42 days +/- 3 days) after the last dose of pembrolizumab. 
6.2.11 Post-Treatment/Safety Follow-Up Visits 
After the date of surgery, patients will return for clinical and laboratory assessments at 30 days 
(first follow-up visit), 90 days, 180 days, and 360 days (+/- 14 days) after the date of surgery. 
These assessments are required but imaging studies are to be ordered at the discretion of the 
investigator or a qualified designee. 
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. 
Every effort should be made to collect information regarding disease status until the start of new 
anti-neoplastic therapy, disease progression, death, end of the study. Information regarding post-
study anti-neoplastic treatment will be collected if new treatment is initiated. 
Correlative blood samples will be collected at each follow-up visit. Details are provided in 
Section 6.0 – Trial Flow Chart 
6.3 
Assessing and Recording Adverse Events 
6.3.1 Definitions of Adverse Events 
6.3.1.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related. 
More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., an abnormal 


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laboratory finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality. An adverse event can arise from any use of the drug (e.g., off-label use, 
use in combination with another drug) and from any route of administration, formulation, or dose, 
including an overdose. 
6.3.1.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse reactions 
are a subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event. 
6.3.1.3 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 
the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction. 
6.3.1.4 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has been 
observed, or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure. For example, a certain number of non-acute deaths in a cancer trial would be anticipated 
as an outcome of the underlying disease, but such deaths would generally not be listed as a 
suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation. Such events would be considered unexpected 
until they have been observed with the drug under investigation. For example, although 
angioedema is anticipated to occur in some patients exposed to drugs in the ACE inhibitor class 
and angioedema would be described in the investigator brochure as a class effect, the first case of 
angioedema observed with the drug under investigation should be considered unexpected for 
reporting purposes. 


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6.3.1.5 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either the 
investigator or Principal Investigator, it results in any of the following outcomes: 
6.4.1.5.1 Death 
6.4.1.5.2 Life-threatening adverse event 
6.4.1.5.3 Inpatient hospitalization or prolongation of existing hospitalization 
6.4.1.5.4 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life function 
6.4.1.5.5 Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
6.3.1.6 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or Principal Investigator, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death. 
6.3.2 Recording of an Adverse Event 
All Grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug. Data about these events and their severity will 
be recorded using the NCI CTCAE v4.0. 
If there are specific data plans to this study, such as Grade 1 & 2 AEs are also being entered into 
OnCore, describe that process here. 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 
Attribution categories are: 
• 
Definite – The adverse event is clearly related to the investigational agent(s) or study 
procedure. 
• 
Probable – The adverse event is likely related to the investigational agent(s) or study 


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procedure. 
• 
Possible – The adverse event may be related to the investigational agent(s) or study 
procedure. 
• 
Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
study procedure. 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE. When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, 
cautery) indicated; limiting age-appropriate instrumental activities of daily 
living (ADL) 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL 
Grade 4: 
Life-threatening consequences; urgent intervention indicated  
Grade 5: 
Death related to AE 
6.3.3 Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved. Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 
6.3.4 Adverse Events Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 


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the Institutional Review Board (IRB); and, when the study is conducted under an Investigational 
New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA 
reporting criteria. 
[The manufacturer and/or grant sponsor may also need to be notified, as applicable.] 
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis. The Site Committee will review 
and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the attribution of 
relationship of the adverse event to the administration of the study drug(s). 
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
Site Committee meetings. The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and the attribution of relationship of the adverse event to the administration of the 
study drug(s). 
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every six weeks. 
For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2 or 3 
Institutional Study at the Helen Diller Comprehensive Cancer Center please refer Appendix 4 
Multicenter Institutional Studies. 
6.4.5 Expedited Reporting 
6.4.5.1 Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event. The contact may be by phone or e-
mail. 
6.4.5.2 Reporting to UCSF Institutional Review Board (IRB) 
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event. 
6.4.5.3 Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 


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serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all three 
definitions: 
6.4.1.10.1 Suspected adverse reaction - A suspected adverse reaction is defined as any 
adverse  event for which there is a reasonable possibility that the treatment or 
procedure caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal 
relationship between  the treatment or procedure and the adverse event. A 
suspected adverse reaction  implies a lesser degree of certainty about causality 
than an adverse reaction. 
6.4.1.10.2 Unexpected - An adverse event or suspected adverse reaction is considered 
unexpected if it is not listed in the investigator brochure or package insert(s), or is 
not  listed at the specificity or severity that has been observed, or, if an 
investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the 
current application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of treatment or procedure or as anticipated from the pharmacological 
properties of the treatment or procedure, but are not specifically mentioned as 
occurring with the particular treatment or procedure under investigation. 
Adverse events that would be anticipated to occur as part of the disease process 
are considered unexpected for the purposes of reporting because they would not 
be listed in the investigator brochure. For example, a certain number of non-acute 
deaths in a cancer trial would be anticipated as an outcome of the underlying 
disease, but such deaths would generally not be listed as a suspected adverse 
reaction in the investigator brochure. 
Some adverse events are listed in the Investigator’s Brochure as occurring with 
the same class of treatment, or as anticipated from the pharmacological properties 
of the drug, even though they have not been observed with the drug under 
investigation. 
Such events would be considered unexpected until they have been observed with 
the drug under investigation. For example, although angioedema is anticipated to 
occur in some patients exposed to drugs in the ACE inhibitor class and 
angioedema would be described in the investigator brochure as a class effect, the 
first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes. 
6.4.1.10.3 Serious - An adverse event or suspected adverse reaction is considered serious if, 
in  the view of either the investigator or Principal Investigator, it results in any of 
the following outcomes: 
6.4.1.10.3.1 
Death 


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6.4.1.10.3.2 
Life-threatening adverse event 
6.4.1.10.3.3 
Inpatient hospitalization or prolongation of existing hospitalization 
6.4.1.10.3.4 
A persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life function 
6.4.1.10.3.5 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
If the adverse event does not meet all three of the definitions, it should not be 
submitted as an expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 
calendar days after the Investigator determines that the suspected adverse reaction 
qualifies for reporting (21 CFR 312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported 
to FDA no later than 7 calendar days after the Investigator’s initial receipt of the 
information (21 CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND 
safety report will be submitted to FDA as a Follow-up IND Safety Report without 
delay, as soon as the information is available (21 CFR 312.32(d)(2)). 
6.4.5.4 Expedited Reporting to Merck. 
Investigators must report all SAEs to Merck within 24 hours of becoming aware of the event. 
6.4.6 Definition of an Overdose for This Protocol and Reporting of Overdose to the Principal 
Investigator 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 


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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 
Principal Investigator and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 
) 
6.4.7 Reporting of Pregnancy and Lactation to the Principal Investigator 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 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 Principal Investigator and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
) 
6.4.8 Immediate Reporting of Adverse Events to the Principal Investigator and to Merck 
6.4.8.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
6.4.8.1.1 Results in death; 
6.4.8.1.2 Is life threatening; 
6.4.8.1.3 Results in persistent or significant disability/incapacity; 
6.4.8.1.4 Results in or prolongs an existing inpatient hospitalization; 


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6.4.8.1.5 Is a congenital anomaly/birth defect; 
6.4.8.1.6 Is another important medical event 
6.4.8.1.7 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. 
6.4.8.1.7.1 is a new cancer (that is not a condition of the study); 
6.4.8.1.7.2 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 Principal Investigator 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 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 Principal 
Investigator and within 2 working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified physician 
to be related to Merck product that is brought to the attention of the investigator at any time 
following consent through the end of the specified safety follow-up period 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 Principal Investigator 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 Merck 
Global Safety facsimile number: 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 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 
) at the time of submission to FDA. 


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6.4.8.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be reported within 24 hours to the Principal Investigator and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
). 
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 Principal Investigator 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 Principal Investigator 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 Principal Investigator, 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. 
6.4.8.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck, unless there is evidence 
suggesting a causal relationship between the drug and the event. Any such event will be submitted 
to the Principal Investigator 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 Principal Investigator will monitor unblinded aggregated efficacy endpoint events and safety 
data to ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 


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not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under study 
Hospitalization related to convenience (e.g., transportation issues etc.) will not be considered a 
SAE. 
6.4.8.4 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. 


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


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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 


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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 product; or (3) the trial is a single-dose drug trial); or (4) product(s) is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
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 PRINCIPAL INVESTIGATOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
Consistency 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or with 
Trial 
toxicology? 
Treatmen
t Profile 
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 
There is evidence of exposure to Merck product. The temporal sequence
of possibility of Merck product 
The AE is more likely explained by Merck product than by another cause.
relationship. 
the AE onset relative to the administration of Merck product is 
reasonable. 
No, there is not a reasonable 
Subject did not receive the Merck product OR temporal sequence of the 
possibility of Merck product 
the AE is more likely explained by another cause than the Merck 
product. relationship 
AE onset relative to administration of Merck product is not reasonable 
OR 
(Also entered for a subject with overdose without an associated AE.) 
 


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6.4.9 Principal Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
7.0 STATISTICAL ANALYSIS PLAN 
7.1 
Statistical Analysis Plan Summary 
Forty evaluable subjects will be enrolled in the study. Two sequential run-in cohorts will be 
conducted to confirm safety, after which the remaining patients will be randomized between 
preoperative pembrolizumab versus preoperative pembrolizumab and SRT. The primary study 
endpoint is based on the anticipated degree of improvement in tumor immunogenicity as measured 
by the number of infiltrating CD3+ T cells/ μm2 in the lung cancer tissue. 
7.2 
Statistical Analysis Plan 
Sample size justification: 
The sample size is based upon the anticipated number of patients who will have samples that will 
be useful for study of immunologic changes in the number of infiltrating CD3+ T cells/μm2 in the 
lung cancer tissue between the pre-treatment (baseline) biopsy and post-treatment thoracotomy 
specimens. 
The sample size is fixed at 40 patients. It assumes successful accrual of 6 patients from each of the 
two run-in cohorts and an additional 28 patients from the randomized expansion cohort, for a total 
of 40 patients. However, past clinical experience indicates that as many as one-third of patients 
may not be able to complete a new successful core needle biopsy procedure and only prior archived 
tissues will be available for any analysis (which may eventually turn out to be insufficient to 
evaluate for primary endpoint). These patients who enrolled but whose core biopsy is later found 
to be inadequate after initiation of therapy will be allowed to continue on the protocol but will not 
be included in the primary endpoint. 
The null hypothesis is that a two-fold increase will be seen in 15% of the evaluable 26 patients 
(assuming up to one third of samples may be inevaluable for primary endpoint). The alternative 
hypothesis is that a two-fold increase will be seen in 40% of the evaluable 26 patients. This yields 
90% statistical power, with one sided 5% alpha level based on an exact binomial test. 
The goal of achieving a two-fold increase in 40% of the evaluable population is a reasonable one, 
as estimated from a previous study showing greater-than-three-fold increase in 57% of patients 
when CD3+ T cells/um2 were measured in prostate cancer tissue treated with a cell- based cancer 
immunotherapy, with a null hypothesis having been set at a two-fold increase in 15% of the 
population (Fong 2014). The current study includes immunotherapy +/- stereotactic radiation 
therapy, both of which are anticipated to create increased immunogenicity against NSCLC. 


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It is anticipated that accrual will be completed in 10 months (4 patients per month), with each 
patient treated for approximately 2.5-3 months and then followed for 12 months after completing 
protocol therapy. Total study duration is 25 months. 
A binomial exact test will be performed to compare the proportion of patients achieving a two-
fold increase from baseline using a 1-sided test under the null hypothesis of 15%. Exact 95% 
confidence intervals will be presented with associated estimate. P <0.05 will be considered 
statistically significant. 
8.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
8.1 
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7.  
Table 7 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
8.2 
Packaging and Labeling Information 
Clinical  supplies  will  be  affixed  with  a  clinical  label  in  accordance  with  
regulatory requirements. 
8.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Principal 
Investigator 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. 
8.4 
Storage and Handling Requirements 
Clinical  supplies  must  be  stored  in  a  secure,  limited-access  location  under  the  
storage conditions specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at 


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the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
8.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the subjects 
and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
9.0 ADMINISTRATIVE AND REGULATORY DETAILS 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP 
and all applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject 
recruitment materials, and any other written information to be provided to subjects before 
any protocol related procedures are performed on any subjects. 
The clinical investigation will not begin until either FDA has determined that the study 
under the Investigational Drug Application (IND) is allowed to proceed or the Investigator 
has received a letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of 
Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable 
regulatory requirements. The IRB must comply with the regulations in 21 CFR §56 and 
applicable regulatory requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF Institutional Review Board (IRB). Prior to obtaining IRB approval, 
the protocol must be approved by the Helen Diller Family Comprehensive Cancer Center 
Site Committee and by the Protocol Review Committee (PRC). The initial protocol and all 


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protocol amendments must be approved by the IRB prior to implementation. 
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their participation. 
Participants must sign the IRB -approved informed consent form prior to participation in 
any study specific procedure. The participant must receive a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in 
the medical record or research file. 
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must 
be documented in the form of an amendment. The amendment must be signed by the 
Investigator and approved by PRC and the IRB prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, 
an amendment may be implemented prior to IRB approval. In this circumstance, however, 
the Investigator must then notify the IRB in writing within five (5) working days after 
implementation. The Study Chair and the UCSF study team will be responsible for 
updating any participating sites. 
9.5 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs. 
The date, quantity and batch or code number of the drug, and the identification of patients 
to whom study drug has been dispensed by patient number and initials will be included. 
The sponsor- investigator will maintain written records of any disposition of the study 
drug. 
The Principal Investigator shall not make the investigational drug available to any 
individuals other than to qualified study patients. Furthermore, the Principal Investigator 
will not allow the investigational drug to be used in any manner other than that specified 
in this protocol. 
9.6 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for 
safety monitoring and data analysis. All study data will be entered into OnCore®  via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry 
with a secure access account. The Clinical Research Coordinator (CRC) will complete the 
CRFs as soon as possible upon completion of the study visit; the Investigator will review 


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and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained 
by UCSF personnel. All source documentation should be kept in separate research folders 
for each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the 
UCSF DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study 
data. At study completion, when the CRFs have been declared to be complete and accurate, 
the database will be locked. Any changes to the data entered into the CRFs after that time 
can only be made by joint written agreement among the Study Chair, the Trial Statistician, 
and the Protocol Project Manager. 
9.7 
Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the 
monitoring entity for this study. The UCSF DSMC will monitor the study in accordance 
with the NCI- approved Data and Safety Monitoring Plan (DSMP). The DSMC will 
routinely review all adverse events and suspected adverse reactions considered “serious”. 
The DSMC will audit study-related activities to ensure that the study is conducted in 
accordance with the protocol, local standard operating procedures, FDA regulations, and 
Good Clinical Practice (GCP). Significant results of the DSMC audit will be 
communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable. See Appendix 12.4 Data and 
Safety Monitoring Plan for a Phase 2 Institutional Study, for additional information. 
9.8 
Regulatory Documentation 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent 
form, HIPAA authorization and any other information pertaining to participants must be 
approved by the UCSF Institutional Review Board (IRB). Prior to implementing this 
protocol at the participating sites, approval for the UCSF IRB approved protocol must be 
obtained from the participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating 
site can be initiated and begin enrolling participants: 
• Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authorization 


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• Participating Site IRB approved consent form 
• Participating Site IRB membership list 
• Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 
• Curriculum vitae and medical license for each investigator and consenting 
professional 
• Documentation of Human Subject Research Certification training for 
investigators and key staff members at the Participating Site 
• Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment. 
9.9 
Protection of Human Subjects 
9.9.1 Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The IRB 
reviews all proposed studies involving human experimentation and ensures that the subject’s rights 
and welfare are protected and that the potential benefits and/or the importance of the knowledge 
to be gained outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document accurately and 
clearly communicates the nature of the research to be done and its associated risks and benefits. 
9.9.2 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the individuals 
described in the informed consent document. 
 
 


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10.0 
REFERENCES 
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, 
Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, 
Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange 
C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced 
nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627- 39. 
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski 
A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, 
Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, 
Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small- cell lung cancer. 
N Engl J Med. N Engl J Med. 2015 Jul 9;373(2):123-35. 
Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Caliò A, Cuppone F, Sperduti I, 
Giannarelli D, Chilosi M, Bronte V, Scarpa A, Bria E, Tortora G. Differential activity of 
nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed 
death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. 
PLoS One. 2015 Jun 18;10(6):e0130142. 
Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and 
anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 
Feb;124(2):687-95. 
Felip E, Rosell R, Maestre JA, Rodríguez-Paniagua JM, Morán T, Astudillo J, Alonso G, Borro 
JM, González-Larriba JL, Torres A, Camps C, Guijarro R, Isla D, Aguiló R, Alberola V, Padilla 
J, Sánchez-Palencia A, Sánchez JJ, Hermosilla E, Massuti B; Spanish Lung Cancer Group. 
Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus 
surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol. 2010 Jul 1;28(19):3138-45. 
Fong L, Carroll P, Weinberg V, Chan S, Lewis J, Corman J, Amling CL, Stephenson RA, Simko 
J, Sheikh NA, Sims RB, Frohlich MW, Small EJ. Activated lymphocyte recruitment into the tumor 
microenvironment following preoperative sipuleucel-T for localized prostate cancer. J Natl Cancer 
Inst. 2014 Sep 24;106(11). 
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, 
Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman 
JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki 
GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators.Pembrolizumab for the 
treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. 
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, 
Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, 
Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of 
response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014 Nov 
27;515(7528):563-7. 


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Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, 
Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-
Filhart M, Garon EB.Pembrolizumab versus docetaxel for previously treated, PD-L1- positive, 
advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 
2016 Apr 9;387(10027):1540-1550. 
McElnay P, Lim E. Adjuvant or neoadjuvant chemotherapy for NSCLC. J Thorac Dis. 2014 May;6 
Suppl 2:S224-7. 
Mesnage SJ, Auguste A, Genestie C, Dunant A, Pain E, Drusch F, Gouy S, Morice P, Bentivegna 
E, Lhomme C, Pautier P, Michels J, Le Formal A, Cheaib B, Adam J, Leary AF. Neoadjuvant 
chemotherapy (NACT) increases immune infiltration and programmed death- ligand 1 (PD-L1) 
expression in epithelial ovarian cancer (EOC). Ann Oncol. 2016 Nov 17. pii: mdw625. [Epub 
ahead of print] 
Mok T, Wu Y-L, Watson PA, Zhang J, Rangwala RA, Lopes G. Phase 3 KEYNOTE-042 trial of 
pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients 
(pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 
2015;33(suppl): abstr TPS8105. 
Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, 
Chen C, Smith L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, Yearley 
JH, Wu D, Laterza O, Lehnert M, Iannone R, Tolcher AW. Phase I Study of Pembrolizumab (MK-
3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors. Clin Cancer 
Res. 2015 Oct 1;21(19):4286-93. 
Robert C, Ribas A, Wolchok JD, Hodi FS,Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, 
Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus 
C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, 
Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-
refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 
2014 Sep 20;384(9948):1109-17. 
Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, 
Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, 
Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, 
Vonderheide RH, Minn AJ. Radiation and dual checkpoint blockade activate non-redundant 
immune mechanisms in cancer. Nature. 2015 Apr 16;520(7547):373-7. 
Verbrugge I, Hagekyriakou J, Sharp LL, Galli M, West A, McLaughlin NM, Duret H, Yagita H, 
Johnstone RW, Smyth MJ, Haynes NM. Radiotherapy increases the permissiveness of established 
mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012 Jul 
1;72(13):3163-74. 
Yan F, Pang J, Peng Y, Molina JR, Yang P, Liu S. Elevated Cellular PD1/PD-L1 Expression 
Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells. PLoS One. 2016 Sep 


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9;11(9):e0162925. 
Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, Durham N, Meyer C, Harris TJ, 
Albesiano E, Pradilla G, Ford E, Wong J, Hammers HJ, Mathios D, Tyler B, Brem H, Tran PT, 
Pardoll D, Drake CG, Lim M. Anti-PD-1 blockade and stereotactic radiation produce long- term 
survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013 Jun 1;86(2):343-9. 
Zhang P, Ma Y, Lv C, Huang M, Li M, Dong B, Liu X, An G, Zhang W, Zhang J, Zhang L, Zhang 
S, Yang Y. The up-regulation of PD-L1 promotes the resistant response in non-small cell lung 
cancer patients with neo-adjuvant chemotherapy. Cancer Sci. 2016 Sep 1. doi: 10.1111/cas.13072. 
[Epub ahead of print] 
 
 


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APPENDIX 1 ECOG Performance Status 
Grade 
Description 
0 
Normal  activity.  Fully  active,  able  to  carry  on  all  pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol. Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 


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APPENDIX 2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html). 
 
 


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APPENDIX 3 Response  Evaluation  Criteria  in  Solid  Tumors  (RECIST)  1.1  
Criteria  for Evaluating Response in Solid Tumors 
 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging 
technique in this study. 
 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan; 45(2):228-47. 
 
In addition, volumetric analysis will be explored by central review for response 
assessment. 
 
 


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APPENDIX 4 UCSF Policy/Procedure for Required Regulatory Documents for 
Single Site and Multicenter Investigator-Initiated Oncology Clinical Trials 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) for both IND and IND-exempt trials. 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents serve 
to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. 
Filing essential documents in a timely manner can greatly assist in the successful management of 
a clinical trial. 
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as 
paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) 
in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
Procedures 
Single Site (HDFCCC) Therapeutic Essential Regulatory Documents:  
Documents Filed in iRIS: 
• Current and prior versions of the Informed Consent Form(s) (ICFs). 
• IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals. 
• Current and prior approved protocol versions. 
• Current IRB roster 
• Current and prior versions of the Investigator Brochure (IB). 
• Serious Adverse Event (SAE) Reports. 
• Subject diary and handouts (if applicable). 
• Single Patient Exception (SPE) Report(s) to IRB with Approval Letter(s) from IRB. 
• Protocol Violation (PV) Reports with acknowledgement from the IRB. 
Documents Filed in OnCore®: 
• Package Insert (if the study drug is commercial). 
• Protocol signature page(s) with Pl signature(s) for all protocol versions. 
• Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC) document. 


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• Screening/enrollment log. 
• Data and Safety Monitoring Committee (DSMC) monitoring reports. 
• DSMC dose escalation approvals with study status summary forms. 
• Case Report Form (CRF) completion manual. 
• Drug Destruction Standard Operating Procedure (SOP). 
• Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator's signature. 
• For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will 
need Financial Disclosure Forms, CVs, MD Licenses, and Staff Training Documents 
(i.e., Collaborative Institute Training Initiative (CITI), etc.). 
• As applicable, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center. 
• Serious Adverse Event (SAE) reports to IRB and Principal Investigator. 
• MedWatch reporting to FDA and Principal Investigator. 
• Drug Destruction Standard Operating Procedure (SOP). 
• For all laboratories listed on the FDA 1572, will need CUA certifications, CAP 
certifications, lab licenses, CV(s) and Medical License(s) of Lab Director(s), and 
laboratory reference ranges. 
Documents Filed in Regulatory Binder: 
• Delegation of Authority Log with signatures (to be scanned in OnCore once the trial 
is complete). 
Additional Essential Documents for Therapeutic Multicenter Trials for the Coordinating Center 
(filed in OnCore or Zip Drive): 
• 
Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent 
Form (ICF), and Health Insurance Portability and Accountability Act {HIPAA) 
Consent Form for the Participating Site(s). 
• 
For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s), will need Financial Disclosure Forms, CVs, MD Licenses, and 
Staff Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) 
(for investigational New Drug Application). 
• 
Site Initiation Visit (SIV) minutes and correspondence with the Participating Site(s). 
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center for the Participating Site(s). 
• 
Protocol Violations (PV) Reports to IRB with acknowledgement from IRB for 
Participating Site(s). 
• 
Single Patient Exception (SPE) Reports to IRB with IRB Approval Letters for 
Participating Site(s). 
• 
Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s). 
• 
Data and Safety Monitoring Committee (DSMC) monitoring reports for the 
Participating Site(s). 


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• 
For all laboratories listed on FDA 1572, will need CUA certifications, CAP 
certifications, lab licenses, CVs and Medical License(s) of Lab Director(s), and 
laboratory reference ranges for the Participating Site(s). 
• 
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all 
participating site(s) in Multicenter studies or Contract Research Organization (CRO) 
Monitoring Plan (if an outside CRO is used for the study). 
• 
Serious Adverse Event (SAE) forms submitted to the IRB for the Participating 
Site(s). 
Required Multicenter Essential Regulatory Document Checklist for Therapeutic  and Non-
Therapeutic Trials (For Start-Up Only): 
• 
See attached checklist(s). 
Required Essential Regulatory Documents for Single Site and Multicenter Therapeutic IND-
Exempt Studies (filed in OnCore): 
• 
For IND Exempt studies, the Essential Regulatory Documents for UCSF would 
include all documents in Section #1 of this policy. The Essential Regulatory 
Documents from the participating site(s) for Multicenter Trials when UCSF is the 
Coordinating Center would only include the signed protocol signature page, CV of 
the Pl, and the IRB approval letters. All other documents in Section #2 of this policy 
would be the responsibility of the Participating Site(s). 
Required Essential Regulatory Documents for Single Site Non-Therapeutic Studies (filed in 
OnCore): 
• 
For Single Site non-therapeutic trials, all Regulatory Documents in Section #1 of this 
policy are required except for: current and prior versions of the Investigator Brochure 
(IB), package insert (if the study drug is commercial), DSMC dose escalation 
approvals with study status summary forms, approvals for Biosafety Committee, 
Radiation Committee, and Infusion Center, and drug destruction SOPs. 
Required Essential Regulatory Documents for Multicenter Non-Therapeutic Studies (filed in 
OnCore): 
• 
For Multicenter non-therapeutic trials with UCSF as the Coordinating Site, all 
required Regulatory Documents listed above in Section #5 for Single Site non- 
therapeutic trials are required for the Coordinating Site. The only required Regulatory 
Documents from the Participating Site(s) will be: IRB approval letters, IRB roster, 
and ICF and HIPAA consent forms, the Delegation of Authority Log (with NIH or 
CITI human subject protection training certificates or GCP training certification), 
Protocol Violations and Single Patient Exception (SPE) reports to the IRB with 
supporting fax documentation (if applicable), Serious Adverse Event (SAE) forms 
submitted to both the IRB and the Principal Investigator, and the Data and Safety 
Monitoring Committee (DSMC) monitoring reports for the Participating Site(s). If 


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applicable, a copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan 
for all participating site(s) in Multicenter studies or Contract Research Organization 
(CRO) Monitoring Plan (if an outside CRO is used for the study) will be required. 
Alternate Procedures 
There are no alternate procedures to the HDFCCC policy for requirements for Essential 
Regulatory Documents for Multicenter Investigator-Initiated Oncology Clinical Trials. 
References 
• 
ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance (current 
version). 
• 
International Conference on Harmonization: Good Clinical Practice: Consolidated 
Guideline (current version). 
• 
International Conference on Harmonization: Essential Documents for the Conduct of a 
Clinical Trial (current version). 
• 
21CFR50 
• 
21 CFR56.11 
• 
45CFR46 
• 
21 CFR312 
Required Regulatory Documents for Sub-Sites Participating in Therapeutic UCSF Investigator 
Initiated Multicenter trial 
Directions: Scan the documents in a zip drive and upload to OnCore. 
1572 
PI and Sub investigators: 
• CV and Medical license 
• Financial disclosure form 
• NIH or CITI human subject protection training certification  
Laboratories: 
• CLIA &CAP and Lab Licenses 
• CV and Medical License of Lab Director 
• Laboratory reference ranges 
Local Institutional Review Board 
IRB Approval letter 
Reviewed/Approved documents 
• Protocol version date: 
  
 
• Informed consent version date:    
 
• Investigator Brochure version date:    
 


UCSF Helen Diller Family Comprehensive Cancer Center 
Version date: 03/29/2021 
Protocol CC#: 166520 
Phase II – Pembrolizumab +/- Stereotactic Radiotherapy 
 Page 39 of 82 
•
HIPAA
Current IRB Roster
Other 
Delegation of Authority Log 
•
Include NIH or CITI human subject protection training certificates or GCP
training certification
Pharmacy
•
Drug destruction SOP and
Policy Protocol signature
page  Executed subcontract


UCSF Helen Diller Family Comprehensive Cancer Center 
Version date: 03/29/2021 
Protocol CC#: 166520 
Phase II – Pembrolizumab +/- Stereotactic Radiotherapy 
 Page 40 of 82 
APPENDIX 5 Data and Safety Monitoring Plan for a Phase II or III Institutional 
Trial 
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes:  
•
Semiannual auditing (depending on trial accrual)
•
Review of serious adverse events
•
Minimum of biennial regulatory auditing
2.
Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.   
All institutional Phase II and III therapeutic trials are audited on a semiannual basis, with all data 
from twenty percent of the enrolled participants audited by the DSMC Monitor/Auditor.  The 
assigned DSMC Monitor/Auditor will review no more than a total of 10 participant charts during 
the course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report to the 
study team within 20 business days after the auditing visit is complete for the PI and the study 
team to resolve all action items from this report within 20 business days.  An abbreviated 
regulatory review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA logs, 1572 
forms, etc.) will occur at each participant monitoring review; however, a full regulatory review 
will occur on a biennially basis by the DSMC for regulatory compliance. 
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.   
3.
Review and Oversight Requirements
3.1 
Adverse Event Monitoring
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or unexpected and 
whether or not considered to be associated with the use of the investigational agent(s) or study 
procedure, will be entered into OnCore®, UCSF’s Clinical Trial Management System.   


UCSF Helen Diller Family Comprehensive Cancer Center 
Version date: 03/29/2021 
Protocol CC#: 166520 
Phase II – Pembrolizumab +/- Stereotactic Radiotherapy 
 Page 41 of 82 
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program 
(CTEP) of the National Cancer Institute.  Adverse events are further given an assignment 
of attribution or relationship to investigational agent or study procedure.  Attribution 
categories are: 
•
Definite – The adverse event is clearly related to the investigational agent(s) or
study procedure.
•
Probable – The adverse event is likely related to the investigational agent(s) or
study procedure.
•
Possible – The adverse event may be related to the investigational agent(s) or
study procedure.
•
Unrelated – the adverse event is clearly not related to the investigational agent(s)
or study procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings.  The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and attribution assignment. 
3.2 
Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria: 
•
Death.
•
Life-threatening (i.e., results in an immediate risk of death).
•
Requires inpatient hospitalization or prolongation of existing hospitalization,
•
Permanent or significant disability/incapacity
•
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that
suggests a significant hazard, contraindication, side effect, or precaution that may
require medical or surgical intervention to prevent one of the outcomes listed
above.
•
Event occurring in a gene therapy study.
•
Event that changes the risk/benefit ratio of a study.
•
Any other event the Principal Investigator judges to be serious or which would
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.   
UCSF IRB website for guidance in reporting serious adverse events: 


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ICF_001.pdf: 
CC# 166520
ICF 03-29/2021
PAGE 1 OF 19SUE YOM, MD, PHD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
CC# 166520: PembroX: Enhancing the Immunogenicity of Non-Small Cell Lung 
Cancer with Pembrolizumab +/- Stereotactic Radiotherapy Delivered in the 
Preoperative Window, A Randomized Phase II Study with Correlative Biomarkers
This is a clinical trial, a type of research study.  Your study doctors, Drs. Sue Yom, 
David Jablons, Matthew Gubens, Collin Blakely, or other participating doctors from the 
University of California, San Francisco (UCSF) Thoracic Oncology Program, will explain 
the clinical trial to you.
Clinical trials include only people who choose to take part.  Please take your time to 
make your decision about participating.  You may discuss your decision with your family 
and friends and with your health care team.  If you have any questions, you may ask 
your study doctor.
You are being asked to take part in this study because you have stage I-III non-small 
cell lung cancer (NSCLC) and are eligible for surgery.
If you choose to participate in this study, all study procedures will take place at the 
UCSF Helen Diller Family Comprehensive Cancer Center Mt Zion campus, although 
surgery will be done at the UCSF Parnassus campus.
Why is this study being done?
The purpose of this study is to find out if giving pembrolizumab, with or without a low 
dose of radiation therapy, improves the immune response in patients with NSCLC who 
are having surgery. The immune response is when the immune system attacks causes 
of disease.
Pembrolizumab is an immunotherapy drug that works by helping your immune system 
attack cancer cells.  Pembrolizumab is approved by the United States Food and Drug 
Administration (FDA) for use in certain patients with skin cancer and non-small cell lung 
cancer. Pembrolizumab is being used in this study as an investigational drug, meaning 
it is not approved for use in patients with NSCLC who are eligible for surgery. 
In this study, low-dose radiation therapy is combined with pembrolizumab to find out if 
radiation can boost the immune response of pembrolizumab. Radiation therapy is not 
used in this study to directly treat the tumor.
Who pays for this study?
Merck, the manufacturer of pembrolizumab, is supplying the study drug at no cost to 
study participants and covering the costs of radiation therapy, for patients who receive 
IRB NUMBER: 17-21952
IRB APPROVAL DATE: 05/12/2021
IRB EXPIRATION DATE: 04/12/2022
NCT03217071


CC# 166520
ICF 03-29/2021
PAGE 2 OF 19SUE YOM, MD, PHD
radiation therapy, and is providing funding to the UCSF Helen Diller Family 
Comprehensive Cancer Center for this study.  
How many people will take part in this study?
Forty people will take part in this study at UCSF.
What will happen if I take part in this research study?
Before you begin the main part of the study...
If you choose to participate in this study, you will need to have the following tests and 
procedures done to make sure it is okay for you to be in the study. Some of these tests 
and procedures are part of regular cancer care and may be done even if you do not join 
the study. If you have had some of them recently, they may not need to be repeated. 
This will be up to your study doctor. You will also have some tests and procedures done 
for research purposes because you are participating in the study.
To be done within 4 weeks of starting pembrolizumab (unless otherwise indicated):

You will be asked about your medical history including any past treatments or 
surgeries for your disease. 

You will have a physical exam and will be asked how you are feeling.

Your vital signs, including height, weight, temperature, breathing rate, blood 
pressure, pulse, and oxygen in your blood levels will be recorded. 

You will be asked about any medicines you are taking including over-the-counter 
medicines, vitamins, or herbal treatments.

You will be asked how easy or hard it is for you to carry out your daily activities.

A total of 3 tablespoons of blood will be taken by inserting a needle into a vein in 
your arm. The blood sample will be used for routine safety tests.

If you are a woman of childbearing potential, you will have a urine or blood 
pregnancy test within 3 days of starting pembrolizumab.

You will provide a urine sample for routine safety tests. 

You will have a PET-CT (Positron Emission Tomography - computed 
tomography) scan of your whole body within 75 days of starting pembrolizumab. 
If you have stage 2 or 3 NSCLC you will also have a CT (computed tomography) 
or MRI (magnetic resonance imaging) of your brain.
o
A PET-CT scan shows how the organs and cells work in your body and is 
done to show activity of the cells in your tumor. You will be asked to not 
eat for six hours before the scan and to drink at least two large glasses of 
water within one hour of the study. Your PET scan will begin with an 
IRB NUMBER: 17-21952
IRB APPROVAL DATE: 05/12/2021
IRB EXPIRATION DATE: 04/12/2022


CC# 166520
ICF 03-29/2021
PAGE 3 OF 19SUE YOM, MD, PHD
injection of a radioactive substance into a vein in your arm.  You will be 
asked to rest quietly for a period of time (usually about 20 to 40 minutes) 
as the radioactive substance circulates throughout your body.  After this 
time, you will be positioned within a large ring (similar to a big donut hole) 
on a scanning bed.  Once positioned properly, the bed will move you into 
the scanner.  As pictures are being taken, you will be asked to remain very 
still so clear images will be taken.  The imaging time takes about one hour.
o
A CT scan uses special x-ray equipment to make detailed pictures of body 
tissues and organs.  For this exam, you will need to lie still on a table 
inside a large doughnut-shaped machine.  The table will move, and the 
machine will make clicking and whirring noises as the pictures are taken.  
If necessary, an iodine dye (contrast material) will first be given.  The 
iodine dye makes tissue and organs more visible in the pictures.  The 
iodine dye may be given orally (by mouth), intravenously (into a vein), or 
rectally (fill up the loops of your bowels).  The CT scan is done in the 
radiology department and takes about 30 minutes.
o
An MRI uses special equipment to make detailed pictures of body tissues 
and organs.  For this exam, you will lie down on a narrow bed which will 
then be placed in a tunnel that is 6 feet long by 2 feet wide and open at 
each end.  You will need to lie there quietly for about one hour, during 
which there will be a loud banging noise.  You may feel warm during this 
procedure.  If necessary, gadolinium (contrast material) will first be 
injected into a vein.  The gadolinium makes tissue and organs more visible 
in the MRI.  The MRI scan is done in the radiology department and takes 
about 90 minutes.

You will be asked to undergo a tumor biopsy procedure, so that markers in your 
tumor tissue before and after receiving pembrolizumab, or pembrolizumab and 
radiation, can be compared. A biopsy involves removing a piece of the tumor 
tissue, usually with a needle. A CT scan or ultrasound may be used to help guide 
the needle. This procedure will be done at the site where we can most easily get 
a piece of the tumor. The biopsy needle will be inserted into tumor tissue and a 
small piece of the tumor will be removed. This will be done 1-3 times. This 
procedure takes about 30 minutes. If the study doctor determines that you should 
not have a biopsy done, because it is not safe or your tumor is not accessible, 
you may not need to have a biopsy done if you already had a previous biopsy 
done and we can obtain your prior biopsy sample.
During the main part of the study...
If the tests and procedures show that you can be in the main part of the study, and you 
choose to take part, you will receive pembrolizumab alone, or pembrolizumab in 
combination with a small amount of radiation therapy, before having surgery.
There are two parts to this study, Part 1 and Part 2. If you choose to participate in this 
study, you will either be in the first part or second part, but not both. 
IRB NUMBER: 17-21952
IRB APPROVAL DATE: 05/12/2021
IRB EXPIRATION DATE: 04/12/2022


CC# 166520
ICF 03-29/2021
PAGE 4 OF 19SUE YOM, MD, PHD
During Part 1:

Pembrolizumab will be given to 6 study participants before surgery.  

If pembrolizumab does not cause bad side effects in these participants, the next 
6 study participants will be given pembrolizumab, in combination with radiation 
therapy, before surgery. 
During Part 2: 

If the combination of pembrolizumab and radiation therapy does not cause bad 
side effects in participants during Part 1, then study participants in Part 2 will be 
randomized (randomly assigned) to either receive pembrolizumab alone, or in 
combination with radiation therapy. Randomization means that you are put into a 
group by chance, like the flip of a coin. 

If the combination of pembrolizumab and radiation therapy in participants during 
part 1 does cause bad side effects, then all additional study participants will 
receive pembrolizumab alone. 
Pembrolizumab
Pembrolizumab will be given in ‘cycles.’ Each cycle is 3 weeks (21 days). You will 
receive pembrolizumab once every 3 weeks for 2 cycles. Pembrolizumab will be given 
by intravenous (IV) infusion, meaning it will be given directly into your vein using a 
pump. This will take about 30 minutes.
Radiation Therapy (Only if you are receiving radiation therapy in addition to 
pembrolizumab)
If you are receiving radiation therapy in addition to pembrolizumab, you will be given a 
single low dose of stereotactic radiation therapy within 1 week of your second dose of 
pembrolizumab. The radiation will be given to part of the tumor. The radiation is not 
intended to treat the tumor. Its purpose is to increase the response of your immune 
system against the tumor.
Your radiation doctor (radiation oncologist) will schedule a special CT scan (CT 
simulation scan) to design radiation treatment that is appropriate for you. During this 
scan, you will lie flat on a table and will not be able to move. This procedure simulates 
the position that you will be in during radiation treatments. The simulation scan will take 
approximately 1 hour. 
During radiation therapy, you will lie flat on a table and will not be able to move. You will 
receive a low dose of radiation aimed at a part of the tumor. The radiation treatment will 
take about 15 minutes.
IRB NUMBER: 17-21952
IRB APPROVAL DATE: 05/12/2021
IRB EXPIRATION DATE: 04/12/2022


CC# 166520
ICF 03-29/2021
PAGE 5 OF 19SUE YOM, MD, PHD
The following tests and procedures will also be done during the main part of the 
study:
Day 1 Cycle 1 Pembrolizumab

You will have a physical exam and will be asked how you are feeling.

Your vital signs, including height, weight, temperature, breathing rate, blood 
pressure, pulse, and oxygen in your blood levels will be recorded. 

You will be asked about any medicines you are taking including over-the-counter 
medicines, vitamins, or herbal treatments.

You will be asked how easy or hard it is for you to carry out your daily activities.

About 3 tablespoons of blood will be taken by inserting a needle into a vein in 
your arm. The blood sample will be used for routine safety tests and to look for 
markers that might signal a response to the study drug.
Day 1 Cycle 2 Pembrolizumab

You will be asked about any medicines you are taking including over-the-counter 
medicines, vitamins, or herbal treatments.

You will be asked about any side effects that you may be experiencing. A side 
effect is an unwanted response to a medicine.

About 3 tablespoons of blood will be taken by inserting a needle into a vein in 
your arm. The blood samples will be used for routine safety tests and to look for 
markers that might signal a response to the study drug.
End of treatment/safety visit

You will have a physical exam and will be asked how you are feeling.

Your vital signs, including height, weight, temperature, breathing rate, blood 
pressure, pulse, and oxygen in your blood levels will be recorded. 

You will be asked about any medicines you are taking including over-the-counter 
medicines, vitamins, or herbal treatments.

You will be asked how easy or hard it is for you to carry out your daily activities.

You will be asked about any side effects that you may be experiencing. 

A total of 3 tablespoons of blood will be taken by inserting a needle into a vein in 
your arm. The blood sample will be used for routine safety tests and to look for 
markers that might signal a response to the study drug.
Before your surgery (6 weeks within your last dose of pembrolizumab), the following will 
be performed: 
IRB NUMBER: 17-21952
IRB APPROVAL DATE: 05/12/2021
IRB EXPIRATION DATE: 04/12/2022


CC# 166520
ICF 03-29/2021
PAGE 6 OF 19SUE YOM, MD, PHD

You will be asked about any medicines you are taking including over-the-counter 
medicines, vitamins, or herbal treatments.

You will be asked about any side effects that you may be experiencing. 

A total of 3 tablespoons of blood will be taken by inserting a needle into a vein in 
your arm. The blood sample will be used for routine safety tests and to look for 
markers that might signal a response to the study drug.
Surgery – A biopsy will be taken at the time of your surgery. This sample will be tested 
for markers that that might signal or predict a response to the study drug.
Follow-up Visits: 30 days, 90 days, 180 days, 360 days after surgery:

You will have a physical exam and will be asked how you are feeling.

Your vital signs, including height, weight, temperature, breathing rate, blood 
pressure, pulse, and oxygen in your blood levels will be recorded. 

You will be asked about any medicines you are taking including over-the-counter 
medicines, vitamins, or herbal treatments.

You will be asked about any side effects that you may be experiencing. 

You will be asked how easy or hard it is for you to carry out your daily activities.

You will be asked about your health status and any anti-cancer therapy you are 
receiving.

A total of 3 tablespoons of blood will be taken by inserting a needle into a vein in 
your arm. The blood sample will be used for routine safety tests and to look for 
markers that might signal a response to the study drug.

You will provide a urine sample for routine safety tests. 

You will have a CT of your chest 1 year after your surgery.
How long will I be in the study?
You will receive pembrolizumab, the study drug, for 2 cycles (6 weeks) as long as your 
disease is not getting worse and you do not have any bad side effects. If the study drug 
is stopped or you withdraw from the study, you will be followed until any side effects 
from the study drugs have resolved. You will be asked to come into the office for follow-
up visits one month, 3 months, 6 months, and 1 year after your surgery.
We would like to keep track of your medical condition for the rest of your life. We would 
like to do this by calling you on the telephone once a year to see how you are doing. 
Keeping in touch with you and checking on your condition every year helps us look at 
the long-term effects of the study.
IRB NUMBER: 17-21952
IRB APPROVAL DATE: 05/12/2021
IRB EXPIRATION DATE: 04/12/2022


CC# 166520
ICF 03-29/2021
PAGE 7 OF 19SUE YOM, MD, PHD
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about 
stopping or decide to stop. He or she will tell you how to stop your participation safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the pembrolizumab and radiation can be evaluated by your doctor. Another reason to 
tell your doctor that you are thinking about stopping is to discuss what follow-up care 
and testing could be most helpful for you.
The study doctor may stop you from taking part in this study at any time if he/she 
believes it is in your best interest, if you do not follow the study rules, or if the study is 
stopped.
What side effects or risks can I expect from being in the study?
You may have side effects while on the study. Everyone taking part in the study will be 
watched carefully for any side effects. However, doctors don't know all the side effects 
that may happen.  Side effects may be mild or very serious. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after 
you stop taking the pembrolizumab. In some cases, side effects can be serious, long 
lasting, or may never go away. 
You should talk to your study doctor about any side effects you experience while taking 
part in the study.
Pembrolizumab works by helping your immune system to fight your cancer. However, 
pembrolizumab can also cause your immune system to attack normal organs and tissue 
in your body and can affect the way they work, which can result in side effects. These 
side effects may be serious (i.e. causing hospitalization or be life-threatening), may 
result in death, and/or may occur after you stop taking pembrolizumab.  These side 
effects can affect more than one of your normal organs and tissues at the same time.
Risks Related to Pembrolizumab
Very common (seen in 20% or more of patients who receive pembrolizumab)

Itching of the skin

Loose or watery stool

Cough
Common (seen in at least 5% but less than 20% of patients who receive 
pembrolizumab)

Joint pain
IRB NUMBER: 17-21952
IRB APPROVAL DATE: 05/12/2021
IRB EXPIRATION DATE: 04/12/2022


CC# 166520
ICF 03-29/2021
PAGE 8 OF 19SUE YOM, MD, PHD

Rash

Fever

Back pain

Pain in your belly

Loss of skin color

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, or have 
infrequent or hard stools (hypothyroidism)

Low levels of salt in the blood that may cause you to feel tired, confused, have a 
headache, have muscle cramps and/or feel sick to your stomach (hyponatremia)
Less common (seen in at least 1% but less than 5% of patients who receive 
pembrolizumab):

Inflammation of the lungs so you may feel short of breath and cough 
(pneumonitis).  

Too much thyroid hormone so you may feel anxious, feel angry, have trouble 
sleeping, feel weak, tremble, sweat, feel tired, have loose and watery stools 
(hyperthyroidism

Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have 
a fever, feel short of breath, experience a decrease in your blood pressure at the 
time of receiving your infusion (IV) or just after, or have pain at the site of infusion

Inflammation of the bowels/gut, which may cause severe  pain in your belly with 
loose or watery stools,  and black, tarry, sticky stools or stools with  blood or 
mucus (colitis)

Inflammation of the skin so you may have peeling of the skin, itchiness, and/or 
skin redness. The skin inflammation (i.e. peeling, itching and redness) could also 
be widespread throughout your body. More severe skin reactions may involve the 
inside of your mouth, the surface of your eye and genital areas, and/or may 
cause the top layer of your skin to peel from all over your body, which can cause 
severe infection (Severe skin reactions, including Stevens-Johnson syndrome/or 
toxic epidermal necrolysis). 
Rare (seen in less than 1% of patients who receive pembrolizumab):

Inflammation of the nerves that may cause pain, weakness or tingling in your  
hands and feet, and may spread to your legs, arms and upper body leading to 
severe muscle weakness and possible temporary paralysis (Guillain-Barré 
syndrome)

Inflammation of the muscles so you may feel weak or have pain in your  muscles 
(myositis)
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
Inflammation of the pancreas (a gland in your abdomen that controls sugar 
levels), so you may have severe pain in the top part of your belly  that may move 
to your back, feel sick to your stomach, and  vomiting that gets worse when you 
eat (pancreatitis)

Inflammation of the eye so you may have eye redness, blurred vision, sensitivity 
to light, eye pain, see floaters or have headaches

Inflammation of the liver that may make you feel sick to your stomach and vomit, 
feel like not eating, feel tired, have a mild fever, a pain in the right side of your 
belly, yellow eyes and skin, and dark urine (hepatitis)

Inflammation of the pituitary gland (a gland in the head), which may cause you to 
feel sick to your stomach or have headaches, changes in your behavior, double 
vision, few to no menstrual cycles, weakness, vomiting and dizziness or fainting 
(hypophysitis)

Adrenal glands (glands on top of the kidneys) that may not make enough 
hormone, which could cause tiredness, weight loss, muscle weakness, feeling 
faint, having joint, muscle and belly aches, nausea, vomiting, loose or watery 
stools, fever, salt craving, and sometimes darkening of the skin like a suntan 
(adrenal insufficiency) 

Type 1 Diabetes, a condition that can cause too much sugar in your blood, 
feeling thirstier than usual, frequent urination and weight loss. You are likely to 
need regular insulin shots.

Inflammation of the kidney so you may pass less urine or have cloudy or bloody 
urine, swelling and low back pain (nephritis)

Inflammation of the middle layer of your heart wall that may cause your heart to 
have difficulty pumping blood throughout your body, which can cause chest pain, 
shortness of breath and swelling of the legs.  You may experience a fast or 
irregular heartbeat that may cause dizziness or fainting (myocarditis).  

Inflammation of the thyroid gland, an organ that makes and stores thyroid 
hormones. This condition may lead to change in your heart rate, blood pressure, 
body temperature, and the rate at which food is converted into energy 
(thyroiditis).  

A condition that may make you feel weak and tired and may cause drooping of 
the eyelids, blurred or double vision, difficulty swallowing, slurred speech, 
weakness in your arms and legs, or difficulty breathing (myasthenic 
syndrome/myasthenia gravis including exacerbation) 

The formation of small clusters of immune cells (called granulomas) in parts of 
your body, such as your lymph nodes, eyes, skin, or lungs (sarcoidosis)

Inflammation of the brain with confusion and fever. This may also include: 
disorientation, memory problems, seizures (fits), changes in personality and 
behavior, difficulty speaking, weakness or loss of movement in some parts of 
your body, and loss of consciousness (encephalitis).
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
Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the 
arms or legs, bladder or bowel problems including needing to urinate more 
frequently, urinary incontinence, difficulty urinating, and constipation (myelitis) 

Inflammation of the blood vessels (vasculitis) - symptoms include fever, fatigue, 
weight loss, and muscle and joint pain
In addition to what is specifically listed above, drugs that help stimulate the 
body’s immune response against tumor cells (immunotherapy drugs), such as 
pembrolizumab, can cause severe inflammation to every organ.
Furthermore, it is possible that taking pembrolizumab may result in delay of your 
surgery or inability to have your surgery promptly. The study investigators do not 
believe that this is likely, but it is possible. The study investigators will be 
checking for this throughout the study and the study will be stopped if the drug is 
having this effect on patients.
Additionally, since pembrolizumab was approved (for melanoma) in September 
2014, the following side effects have been reported by people receiving 
pembrolizumab. These side effects were voluntarily reported from a group of 
people of unknown size. It is not possible to estimate the frequency of this side 
effect:

Inflammation of the joints which may include joint pain, stiffness, and/or 
swelling (arthritis)

Severe responses of the immune system that cause the body to attack its 
own blood cells, spleen, liver, lymph nodes, skin and brain.  This may 
include fever, rash, inflammation of the liver, yellowing of the skin, an 
enlarged liver and spleen, low blood counts, and enlarged lymph nodes.  
The nervous system may also be affected and cause confusion, seizures, 
and even coma (hemophagocytic lymphohistiocytosis).

Changes in eyesight, eye pain, whitish patches on the skin and hearing 
loss (Vogt-Koyanagi-Harada syndrome).

Inflammation and scarring of the bile ducts (tubes that carry digestive fluid 
that is made in the liver). This can cause symptoms similar to those seen 
with inflammation of the liver (hepatitis) such as pain in right side of your 
belly, yellow eyes and skin, feeling tired, and itching (sclerosing 
cholangitis).
If you have had a solid organ transplant (for example, if you have received a 
kidney or heart transplant), you may experience rejection of the transplanted 
organ. Your doctor will monitor you and should tell you what signs and 
symptoms you should report depending on the type of organ transplant that you 
have had.
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Risks Related to Radiation Therapy
Radiation therapy aimed at the chest may cause these side effects:

Difficulty swallowing

Shortness of breath

Breast or nipple soreness

Shoulder stiffness

Cough, fever, and fullness of the chest. This is known as radiation pneumonitis 
and happens between 2 weeks and 6 months after radiation therapy

Radiation fibrosis, which is permanent scarring of the lungs from untreated 
radiation pneumonitis. The radiation oncologist knows how to lower the risk of 
fibrosis in the planning process.
Risks Related to Study Procedures:

Blood drawing (venipuncture) risks:  Drawing blood may cause temporary 
discomfort from the needle stick, bruising, infection, and fainting.

Infusion risks: As with most intravenous products, you may experience pain, 
irritation, swelling or bruising, or a slight chance of infection at the site where the 
intravenous catheter (small tube) is inserted into your vein. These side effects may 
also be observed at the site where blood is drawn for laboratory tests.  

Radiation risks: This research study involves exposure to a significant amount of 
radiation. The radiation therapy will be delivered at a prescription dosage of 12 Gy 
targeted at only part of the tumor. While this amount of radiation is not intended to 
treat your condition, it does involve a risk of a secondary cancer. However, the 
UCSF Radiation Safety Committee has reviewed the use of radiation in this research 
study and has designated this use as acceptable to obtain the benefits provided by 
the results of the study. If you are pregnant or breast feeding, you SHOULD NOT 
participate in this study. If you have any questions regarding the use of radiation or 
the risks involved, please consult the physician conducting the study.

CT scan risks:  CT scans involve the risks of radiation.  In addition, if contrast 
material (iodine dye) is used, there is a slight risk of developing an allergic reaction, 
from mild (itching, rash) to severe (difficulty breathing, shock, or rarely, death).  The 
contrast material may also cause kidney problems, especially if you are dehydrated 
or have poor kidney function.  You will be asked about any allergies or related 
conditions before the procedure.  If you have any of these problems, you may not be 
allowed to have a CT scan with contrast.
Having a CT scan may mean some added discomfort for you.  In particular, you may 
be bothered by feelings of claustrophobia when placed inside the CT scanner, or by 
lying in one position for a long time.  If contrast material is used, you may feel 
discomfort when it is injected by vein.  You may feel warm and flushed and get a 
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metallic taste in your mouth. Rarely, the contrast material may cause nausea, 
vomiting or a headache.

PET-CT scan risks:  PET-CT scans involve the risks of radiation (see above).  In 
addition, if a contrast material is injected, there is a slight risk of developing an 
allergic reaction, from mild (itching, rash) to severe (difficulty breathing, shock, or 
rarely, death). The study doctors will ask you about any allergies or related 
conditions before the procedure.  If you have any of these problems, you may not be 
allowed to have a PET-CT scan.
Having a PET-CT scan may mean some added discomfort for you.  In particular, you 
may be bothered by feelings of claustrophobia when placed inside the CT scanner, 
or by lying in one position for a long time.  If contrast material is used, you may feel 
discomfort when it is injected in your veins.  You may feel warm and flushed and get 
a metallic taste in your mouth. Rarely, the contrast material may cause nausea, 
vomiting or a headache.

MRI risks:  Because the MRI machine acts like a large magnet, it could move iron-
containing objects in the MRI room during your examination, which in the process 
could possibly harm you.  Precautions have been taken to prevent such an event 
from happening; loose metal objects, like pocketknives or key chains, are not 
allowed in the MRI room.  If you have a piece of metal in your body, such as a 
fragment in your eye, aneurysm clips, ear implants, spinal nerve stimulators, or a 
pacemaker, you will not be allowed into the MRI room and cannot have an MRI.
Having an MRI may mean some added discomfort for you.  In particular, you may be 
bothered by feelings of claustrophobia and by the loud banging noise during the 
study.  Temporary hearing loss has been reported from this loud noise.  This is why 
you will be asked to wear earplugs.  At times during the test, you may be asked to 
not swallow for a while, which can be uncomfortable.
Because the risks to a fetus from MRI are unknown, pregnant women must not 
participate in this study. 
Contrast agent (gadolinium) risks: A few side effects of gadolinium injection such 
as mild headache, nausea, and local pain may occur. Rarely (less than 1% of the 
time) low blood pressure and lightheadedness occurs. This can be treated 
immediately with intravenous fluids. Very rarely (less than on in one thousand), 
patients are allergic to gadolinium. These effects are most commonly hives and itchy 
eyes, but more severe reactions have been seen which result in shortness of breath.
Patients with severe kidney disease sometimes have a bad reaction to gadolinium 
contrast. The condition is called nephrogenic systemic fibrosis (NSF). It can cause 
skin to tighten or scar and can damage internal organs. Sometimes it can be life-
threatening. There are no reports of NSF in patients with normal kidney function. 
Before you have an MRI scan requiring an injection of gadolinium contrast, you will 
have a blood test in order to check the function of your kidneys. Based on your 
medical history and the results of the test, a doctor will decide whether it is safe for 
you to undergo the MRI scans.
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
Tumor Biopsy risks: While we make every effort to minimize the pain related to the 
procedure, the procedure is usually uncomfortable and sometimes painful. Patients 
may develop bruising, soreness or scarring at the biopsy site. Wherever the biopsy 
is done in your body, it can lead to bleeding in that area, damage of organs near 
where the biopsy is done, or infection.  While it is uncommon, sometimes bleeding or 
pain from the biopsy will require you to stay overnight in the hospital or require you 
to go to the operating room to control any bleeding.  Additionally, if the biopsy 
involves the lungs, it can cause the lungs to deflate and if this occurs, you might 
require treatment to correct this.  
For biopsy procedures, patients usually receive local anesthesia (for example 
lidocaine), meaning the biopsy site is numbed. Side effects from local anesthesia are 
rare but may include convulsions or seizures, breathing problems, chest pain, rapid 
heart rate, irregular heartbeat, dizziness, bluish lips and fingernails, drowsiness, 
headache, itching, nausea and/or vomiting, raised red swellings on the skin, lips, 
tongue, or in the throat, restlessness, unusual tiredness or weakness, back pain, 
difficulty opening the mouth, inability to hold bowel movement and/or urine, loss of 
sexual function, temporary paralysis (loss of function) of legs, persistent or 
prolonged numbness or tingling (“pins and needles” sensations) of lips and mouth, 
and shivering.
Imaging equipment may be used to guide the needle to the desired site.  This may 
involve ultrasound or x-ray, see Radiation risks above.  In addition, a patient may be 
injected with a contrast dye (for example iodine).  Side effects of iodine can include 
hives, itching, light headedness, nausea and a metallic taste in the mouth.  Rarely, 
iodine can cause a severe allergic reaction, including shock, very low blood pressure 
and cardiac arrest.

Reproductive risks:  You should not become pregnant or father a baby while on 
this study because the drugs in this study can affect an unborn baby.  Women 
should not breastfeed a baby while on this study.  It is important to understand that 
you need to use birth control while on this study.  Check with your study doctor 
about what kind of birth control methods to use and how long to use them.  Some 
methods might not be approved for use in this study.  

Study Drug and Radiation Interaction Risks:  Pembrolizumab, alongside radiation 
therapy, taken in combination with other medicines may be associated with other 
risks that are unknown at this time. Although there is limited information on how 
pembrolizumab, alongside radiation therapy, might interact with other medications, it 
is important to share with your study doctor any medications (prescription, over-the-
counter, and herbal supplements) that you are taking.

Randomization risks:  You may be assigned to a treatment program by chance, 
and the treatment you receive may prove to be less effective or to have more side 
effects than the other study treatment(s) or other available treatments.

Unknown Risks: The experimental treatments may have side effects that no one 
knows about yet.  The researchers will let you know if they learn anything that might 
make you change your mind about participating in the study.
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
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
If you receive pembrolizumab with or without radiation and it proves to treat your 
condition more effectively, you may benefit from participating in the study, but this 
cannot be guaranteed.
What other choices do I have if I do not take part in this study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study. 

Taking part in another study.

Getting no treatment.
Please talk to your doctor about your choices before deciding if you will take part in this 
study.
How will information about me be kept confidential?
Participation in research involves some loss of privacy.  We will do our best to make 
sure that information about you is kept confidential, but we cannot guarantee total 
privacy.  Some information from your medical records will be collected and used for this 
study.  If you do not have a UCSF medical record, one will be created for you.  Your 
signed consent form and some of your research tests will be added to your UCSF 
medical record.  Therefore, people involved with your future care and insurance may 
become aware of your participation and of any information added to your medical record 
as a result of your participation.  Study tests that are performed by research labs, and 
information gathered directly from you by the researchers will be part of your research 
records and may be added to your medical record.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at 
scientific meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include:

The University of California

Merck & Co., Inc., the supplier of pembrolizumab, including companies it hires to 
provide study-related services. 

The National Cancer Institute (NCI) and other government agencies, e.g., the Food 
and Drug Administration (FDA), involved in keeping research safe for people. 
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What are the costs of taking part in this study?
Merck is supplying the study drug pembrolizumab at no cost to you.  Merck is also 
covering the costs of radiation therapy for patients assigned to receive radiation therapy 
during this study.
Two types of procedures will be done during this study.  Some are part of your standard 
medical care and others are only for research.  You or your insurer will be billed for the 
standard medical care.  You will be responsible for your co-pays, deductibles, and any 
other charges that your insurer will not pay.  Any procedures done only for research will 
not be charged to you or your insurer.  There is a possibility that your insurer may not 
cover standard medical care costs because you are in a research study or because you 
are receiving medical services out of network.
Before you agree to be in this study, you may want to contact your healthcare 
payer/insurer to see if your plan will cover the costs required as part of your 
participation. You may request more information about the costs of participating in this 
study and discuss this with the study team.
If you have any questions, your doctor and the study team will be able to provide you 
with answers.
For more information on clinical trials and insurance coverage, you can visit the National 
Cancer Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-
coverage. You can print a copy of the "Clinical Trials and Insurance Coverage" 
information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and 
ask them to send you a free copy.
Will I be paid for taking part in this study?
You will not be paid for taking part in this study.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, if you feel that you have been injured 
because of taking part in this study. You can tell the study doctor in person or call Dr. 
Yom at 
. 
Treatment and Compensation for Injury:  If you are injured as a result of being 
in this study, the University of California will provide necessary medical 
treatment.  The costs of the treatment may be billed to you or your insurer just 
like any other medical costs or covered by the University of California or the 
study sponsor Merck, depending on a number of factors.  The University and the 
study sponsor do not normally provide any other form of compensation for injury.  
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For further information about this, you may call the office of the Institutional 
Review Board at 415- 476-1814.  
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to 
take part in the study. If you decide to take part in this study, you may leave the study at 
any time. No matter what decision you make, there will be no penalty to you and you will 
not lose any of your regular benefits. Leaving the study will not affect your medical care. 
You can still get your medical care from our institution. 
We will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions, concerns, or complaints you 
have about this study.  Contact your study doctor Sue Yom, MD 
If you wish to ask questions about the study or your rights as a research participant to 
someone other than the researchers or if you wish to voice any problems or concerns 
you may have about the study, please call the office of the Institutional Review Board at 
415-476-1814.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify 
you.  At most, the Web site will include a summary of the results.  You can search this 
Web site at any time. 
************************************************************
ADDITIONAL OPTIONAL RESEARCH SECTION:
Please note: This section of the informed consent form is about additional, optional 
research studies that are being done with people who are taking part in the main study. 
You may take part in these optional studies if you want to. You can still be a part of the 
main study even if you say "no" to taking part in any of these optional studies.
You can say "yes" or "no" to each of the following studies. Please mark your choice for 
each option.
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Blood and Tissue Samples for Future Research
Blood and tissue samples are collected and used in the main study. We would like to 
keep some of the blood and tissue that is left over for future research. If you agree, the 
blood and tissue samples will be kept at UCSF and may be used in future research to 
learn more about cancer and other diseases. 
The future research that may be done with your samples is not designed specifically to 
help you. It might help people who have cancer and other diseases in the future.
Reports about future research done with your samples will not be given to you or your 
doctor. These reports will not be put in your health record and will not have an effect on 
your care.
Things to Think About
The choice to let us keep the leftover blood and tissue for future research is up to you. 
No matter what you decide to do, it will not affect your care. 
If you decide now that your samples can be kept for research, you can change your 
mind at any time. Just contact your study doctor:
Sue Yom, MD
UCSF Helen Diller Family Comprehensive Cancer Center
and let us know that you do not want us to use your blood and tissue samples. Then 
any samples that remain will no longer be used for research, but any data already 
collected will continue to be used.
In the future, people who do research may need to know more about your health. While 
UCSF may give them reports about your health, it will not give them your name, 
address, phone number, or any other information that will let the researchers know who 
you are.
Sometimes blood and tissue samples are used for genetic research (about diseases 
that are passed on in families). Even if your samples are used for this kind of research, 
the results will not be put in your health records.
Your blood and tissue samples will be used only for research and will not be sold. The 
future research done with your samples may help to develop new products in the future.
You will not be paid for donating your blood and tissue samples for future research.
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Benefits
The benefits of research using blood and tissue samples include learning more about 
what causes cancer and other diseases, how to prevent them, and how to treat them.
Risks
The greatest risk to you is the release of information from your health records. We will 
do our best to make sure that your personal information will be kept private. The chance 
that this information will be given to someone else is very small.
Risks specifically related to Genetic Testing
There is a risk someone could get access to the personal information in your medical 
records or other information researchers have kept about you. Someone might be able 
to trace this information back to you. The researchers believe the chance that someone 
will identify you is very small, but the risk may change in the future as people come up 
with new ways of tracing information. In some cases, this information could be used to 
make it harder for you to get or keep a job. There are laws against misuse of genetic 
information, but they may not give full protection. The researchers believe the chance 
these things will happen is very small but cannot promise that they will not occur.
Making Your Choice
Please read the sentence below and think about your choice. After reading each 
sentence, put your initials in the "Yes" or "No" box.  If you have any questions, please 
talk to your doctor or nurse, or call the Institutional Review Board at 415-476-1814.
No matter what you decide to do, it will not affect your care.
1. I allow my samples (blood and tissue) from the main study to be stored and used for 
future medical research. 
YES 
NO
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CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of 
Rights to keep.
You will be asked to sign a separate form authorizing access, use, creation, or 
disclosure of health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to 
which you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Participant's Name (print)
Date
Participant's Signature for Consent
Date
Person Obtaining Consent
Date
Witness (only required if the participant is a
Date
non-English speaker
IRB NUMBER: 17-21952
IRB APPROVAL DATE: 05/12/2021
IRB EXPIRATION DATE: 04/12/2022