A Phase I/II Study of MK-3475 With Gemcitabine in Patients With Previously-Treated Advanced Non-small Cell Lung Cancer (NSCLC)
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Providence Health & Services

Product:  MK-3475  
1 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
 
 
 
Support Provided By:  Merck   
 
TITLE:  A Phase I/II Study of Pembrolizumab With Gemcitabine in Patients with 
Previously-Treated Advanced Non-small Cell Lung Cancer (NSCLC). 
 
 
 
 
 
 
 
Coordinating Center: 
Earle A. Chiles Research Institute 
Providence Portland Medical Center 
Clinical Trials Office 
4805 NE Glisan St, 2N35 
Portland OR 97213 
503-215-6805 
Fax: 503-215-6725 
 
Primary Investigator: 
Rachel E. Sanborn, M.D. 
Earle A. Chiles Research Institute 
Providence Portland Medical Center 
4805 NE Glisan St, 2N35 
Portland OR 97213 
503-215-6259 
Fax: 503-215-6841 
 
 

Product:  MK-3475  
2 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
 
Molecular Correlatives: 
Bernard A. Fox, Ph D. 
Endowed Chair and Chief,  
Molecular and Tumor Immunology 
Earle A. Chiles Research Institute  
Providence Portland Medical Center 
4805 NE Glisan St, 2N35 
Portland OR 97213 
503-215-6841 
 
 
 

Product:  MK-3475  
3 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase I/II Study of Pembrolizumab With Gemcitabine in 
Patients with Previously-Treated Advanced Non-small 
Cell Lung Cancer (NSCLC) 
Trial Phase 
I-II 
Clinical Indication 
Previously-treated advanced NSCLC 
Trial Type 
Open-label, non-randomized phase I study, followed by open-label non-
randomized phase II 
Type of control 
Historical control 
Route of administration 
IV 
Trial Blinding 
N/A 
Treatment Groups  
Single arm, non-randomized, Pembrolizumab in combination with 
gemcitabine. 
Number of trial subjects 
16-46 
Estimated duration of trial 
1 Year 
Duration of Participation 
2 Years 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
Phase I dose de-escalation component, followed by phase II nonrandomized study, 
compared with historical controls 
 
 

Product:  MK-3475  
4 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
 
2.2 
Trial Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS 
3.1 
Primary Objective(s) & Hypothesis 
(1) Objective: Safety 
Hypothesis:  The combination of pembrolizumab with gemcitabine will be safe and 
feasible in patients with previously-treated advanced NSCLC. 
3.2 
Secondary Objective(s) & Hypothesis 
(1) Objective:  Progression-free survival 
Hypothesis:  The combination of pembrolizumab with gemcitabine will improve 
progression-free survival over that seen with either gemcitabine or pembrolizumab 
administered as single-agent therapy for patients with previously-treated advanced 
NSCLC, in comparison with historical controls. 
Phase I (6-36 patients), dose de-
escalation 
Pembrolizumab 200 mg iv every 
3 weeks, for 2 years, or until 
disease progression 
Gemcitabine 1250 mg/m2 iv Days 
1, 8 every 3 weeks, for maximum 
6 cycles 
Phase II (10 patients) 
Pembrolizumab MTD iv every 3 
weeks, for 2 years, or until 
disease progression 
Gemcitabine 1250 mg/m2 iv Days 
1, 8 every 3 weeks, for maximum 
6 cycles 

Product:  MK-3475  
5 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
(2) Objective:  Overall survival 
(3) Objective:  Response rate 
3.3 
Exploratory Objective 
(1) 
Objective: Correlative analysis of outcomes retrospectively compared with tumor PD-
L1 expression, tumor immune score, and immune response as assessed by serial protein 
arrays. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Non-small cell lung cancer (NSCLC) is the most common cancer killer worldwide, and in the 
United States alone in 2014, an estimated 159,000 people will die from lung cancer (1).  The 
majority of patients with NSCLC are diagnosed at an advanced stage, when goals of therapy 
are palliative, but not curative.  Palliative chemotherapy has been shown to help prolong life 
and improve quality of life for patients with good performance status with advanced disease, 
but duration of disease control with chemotherapy is still short, and average survival with 
palliative chemotherapy is still only approximately 12 months (2, 3). 
Gemcitabine is an active agent for patients with NSCLC, commonly used in the first-line 
setting for advanced squamous cell lung cancer in combination with platinum drugs, or as 
single agent therapy in the salvage setting for patients with any histology of NSCLC.  
Gemcitabine is used frequently for elderly patients with NSCLC due to its relatively lower 
toxicity profile.  As it does not cause neuropathy, it is an attractive agent for patients with either 
preexisting neuropathy from other medical conditions, or chemotherapy-induced neuropathy.  
Single agent gemcitabine has been shown to have progression-free survival (PFS) ranging 
between 2.5-4.25 months, and median survival of 4.4-7 months in the first-line setting for 
patients over the age of 70 (4-6).  Phase III trials of gemcitabine in the second-line setting for 
NSCLC have not been performed, but in phase II studies median time to progression is 2.5 
months, with median overall survival 9.5 months, and overall response rate 18.5% (7).  
Chemotherapy agents alone have reached a plateau of therapeutic efficacy.  Targeted therapy 
agents have made a significant impact in survival and quality of life for patients with advanced 
NSCLC, particularly for those patients with sensitizing mutations (8, 9), however, resistance 
ultimately develops and patients inevitably experience disease progression on targeted 
therapies.  There is a significant need for agents able to induce long-term responses and 
survival, with manageable side effects. 
 

Product:  MK-3475  
6 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
4.1.1 Pharmaceutical and Therapeutic Background 
Refer to the Investigator’s Brochure (IB) for detailed background information on 
pembrolizumab. 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [10].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [11-15].  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) [16; 17].  The 
structure of murine PD-1 has been resolved [18].  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved 
in the CD3 T-cell signaling cascade [16, 19-21].  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 [22; 23].  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 [24; 25].  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells 
[26].  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 [22, 
27-29].  Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic 
tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments.  PD-L2 is thought to control immune T-cell activation in lymphoid organs, 
whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues [22].  
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) [30].  This suggests that the PD-

Product:  MK-3475  
7 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as 
an attractive target for therapeutic intervention. 
Pembrolizumab (previously known as MK-3475; SCH 900475) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block 
the interaction between PD-1 and its ligands, PD-L1 and PD-L2 without ADCC or CDC 
activity.   
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
In a large phase I study involving 296 patients, anti-PD1 (Nivolumab) demonstrated 
responses in patients with melanoma, renal cell carcinoma, and NSCLC.  Patients received a 
dose range of anti-PD1 of 1.0-10.0 mg/kg intravenously every two weeks (of 8-week treatment 
cycles) for up to two years (12 cycles).  For the 76 patients with heavily-pretreated advanced 
NSCLC (55% having received at least 3 lines of prior therapy), the response rate was 18%.  
Progression-free survival in this population was an impressive 26 weeks, with 7% of patients 
experiencing prolonged stable disease (31).  In long-term follow up, the estimated duration of 
response was 74 weeks, with ongoing response in 55% of the responding patients.  1-year 
overall survival was 42%, with 2-year overall survival 14% (32). 
A maximum tolerated dose of Nivolumab was not reached, with 5% of patients 
discontinuing therapy due to treatment-related adverse events.  Toxicity did not appear to be 
dose-related.  For the overall population, the incidence of grade 3 or 4 treatment-related adverse 
events was 14%.  Serious adverse events attributed to drug occurred in 11% of patients.  
Adverse events which were potentially immune related included vitiligo, colitis, hepatitis, 
hypophysitis, thyroiditis, and pneumonitis, with grade 3 or 4 toxicity occurring in 6% of 
patients (18 patients total).  Of the grade 3 or 4 adverse events, three patients (1%) developed 
pneumonitis, three developed colitis (1%), two patients each developed ALT or AST 
elevations (1% each).  Pruritis, macular rash, elevated thyroid-stimulating hormone, hypo- and 
hyperthyroidism were recorded in 1 patient each.  One patient developed a grade 3 or 4 
infusion-related reaction.  For patients developing pneumonitis, there was no relationship seen 
between dose level or number of doses administered, or to tumor type. Ultimately, three drug-
related pneumonitis deaths were reported, with two of these occurring in patients with NSCLC.  
Patients with mild or moderate pneumonitis were treated with glucocorticoids, although 
patients with more severe pneumonitis required more aggressive immune suppression, with 
infliximab or mycophenolate (31).   The investigators concluded that although pneumonitis 
was observed, overall the toxicities with the study drug were acceptable, and the drug was safe 
to be administered in the outpatient setting.  The unprecedented results of an immunotherapy 
approach in NSCLC, along with other tumors, has prompted widespread investigation and 

Product:  MK-3475  
8 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
development of immunotherapy agents, including anti-PDL1 and anti-PD1 agents 
(www.clinicaltrials.gov).   
Pembrolizumab is being investigated in a number of different therapeutic settings currently 
(www.clinicaltrials.gov).  The KEYNOTE-001 phase I study in previously-treated advanced 
NSCLC evaluated pembrolizumab at 10 mg/kg iv every 2 or every 3 weeks, and evaluated 
patients for response based upon tumor PD-L1 expression.  PFS was not significantly different 
between patients with PD-L1 positive or negative tumors, with median PFS 10 weeks for PD-
L1 negative tumors and 11 weeks for PD-L1 positive tumors based upon independent central 
review using RECIST v1.1 (16 weeks for both based upon investigator review using irRC; 3).  
Overall response rate was 21% for patients with PD-L1 positive tumors treated with every 3 
week dosing, with duration of response of 31 weeks based upon independent central review 
(33). 
Although gemcitabine as a chemotherapy drug has been generally considered to be purely 
immunosuppressive, preclinical studies have indicated that gemcitabine increases antigen 
cross-presentation, as well as increases the percentage of intratumoral primed tumor-specific 
CD8 T cells, without increasing functional tolerance (34).  Gemcitabine combined with 
nonspecific immunotherapy (anti-CD40 antibody) in subsequent preclinical experiments using 
a mesothelioma murine model demonstrated synergism between the two agents.  It was 
postulated that gemcitabine induced immunological priming via increasing tumor antigen 
cross-presentation as well as upregulating antigen-presenting cells through induction of 
apoptosis, thereby improving subsequent antitumor immune response induced by 
immunotherapy (35). 
We thus propose a feasibility study of pembrolizumab in combination with gemcitabine for 
patients with previously-treated advanced NSCLC.  Should pembrolizumab demonstrate safety 
and tolerability in this patient population, as well as efficacy signal, this would support further 
investigation with a randomized trial with the potential for establishing a new standard of care 
for a very large patient population with significant need. 
4.2.2 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 pembrolizumab.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  Recent data 
from other clinical studies within the pembrolizumab program has shown that a lower dose of 
pembrolizumab and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic 

Product:  MK-3475  
9 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  
This early PK and pharmacodynamic data provides scientific rationale for testing a Q3W 
dosing schedule.   
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given 
dose among tumor types.  Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to pembrolizumab to a clinically 
meaningful extent.  Taken together, these data support the use of lower doses (with similar 
exposure to 2 mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being evaluated in 
NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and 
neck cancer in PN012, which are expected to provide additional data supporting the dose 
selection. 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within 
the exposure range established in melanoma as associated with maximal clinical response.  A 
population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 subjects from 
PN001.   The distribution of exposures from the 200 mg fixed dose are predicted to 
considerably overlap those obtained with the 2 mg/kg dose, with some tendency for individual 
values to range slightly higher with the 200 mg fixed dose.   The slight increase in PK 
variability predicted for the fixed dose relative to weight-based dosing is not expected to be 
clinically important given that the range of individual exposures is well contained within the 
range of exposures shown in the melanoma studies of 2 and 10 mg/kg to provide similar 
efficacy and safety.  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 tumor types and indication settings.  
Table 1.  Dose Schema for Pembrolizumab and Gemcitabine 
21-day Cycles 
Cycle 1/Day 
1 
C1/D8 
C2/D1 
C2/D8 
Study Drug 
 
 
 
 
Pembrolizumaba 
200 mg 
intravenously 
X 
 
X 
 
Gemcitabineb 
1250 mg/m2 
intravenously 
X 
X 
X 
X 
a. Pembrolizumab will be administered on Day 1 every 21 days (3 weeks) for 2 years, or until 
confirmed disease progression or prohibitive toxicity, whichever comes first. 

Product:  MK-3475  
10 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
b. Gemcitabine will be administered on Days 1 and 8 of each 21 day (3 week) cycle for a 
maximum of 6 cycles, or until disease progression or prohibitive toxicity, whichever comes 
first. 
Table 2.  Dose modifications due to toxicity. 
Pembrolizumab  
 
Initial dose 
200 mg Day 1 every 21 days 
-1 Dose level 
100 mg Day 1 every 21 days 
Gemcitabine  
 
Initial dose 
1250 mg/m2 Days 1, 8 every 21 days 
-1 Dose level 
1000 mg/m2 Days 1, 8 every 21 days 
-2 Dose level 
800 mg/m2 Days 1, 8 every 21 days 
 
4.2.3 Rationale for Endpoints 
Pembrolizumab has not yet been evaluated in combination with gemcitabine in patients with 
previously-treated advanced NSCLC.  We propose that the combination will be safe and 
feasible.  The primary objective of this study will be to establish safety of the combination in 
this patient population. 
4.2.3.1 Efficacy Endpoints 
We propose that pembrolizumab in combination with gemcitabine will improve PFS over 
gemcitabine alone for patients with advanced NSCLC.  We propose that the combination of 
pembrolizumab and gemcitabine will be synergistic, with potential based upon the phase II 
portion of this study for further evaluation with a larger randomized trial in this population 
with significant unmet need. 
We further propose that the combination of pembrolizumab and gemcitabine will improve 
overall survival for patients with previously-treated advanced NSCLC compared with 
gemcitabine alone, with potential based upon the phase II portion of this study for further 
evaluation with a larger randomized trial in this population with significant unmet need. 
We propose that the overall response rate with the combination of pembrolizumab and 
gemcitabine will be improved compared with gemcitabine alone for patients with previously-
treated advanced NSCLC. 

Product:  MK-3475  
11 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
4.2.3.2 Biomarker Research 
Immunoscore and immunoprofiling evaluation: 
We hypothesize that checkpoint blockade with anti-PD-1 will only be effective in patients with 
a pre-existing anti-cancer immune response. We also hypothesize that the objective assessment 
of immune infiltrate present in the cancer of patients enrolled on this study will inform 
subsequent trial design, by identifying a predictive biomarker of response. In studies of patients 
with resected colorectal cancer, tumor infiltration by CD3+ and CD8+ cytotoxic T cells as 
quantified by immunohistochemical (IHC) staining, digital imaging and an objective 
assessment of the tumor center and invasive margins (the immunoscore) was shown to 
correlate with survival and tumor recurrence (36).  High densities of CD8+ T cells at the center 
and invasive margins (high immunoscore) correlated with earlier T-stage tumors, while low 
density infiltration (low immunoscore) correlated with larger tumors and disease relapse.  In a 
recent study, a positive immunoscore independently correlated with significantly lower risk of 
disease recurrence and improved survival and provided a significantly better prognostic 
correlation than TNM staging (37). An international consortium has begun a retrospective 
analysis of 5000 patients to validate the CD3+ CD8+ immune score as a prognostic biomarker 
in patients with colon cancer and Drs. Fox and Bifulco at our Institute serve on the Society for 
Immunotherapy of Cancer (SITC) Taskforce that is coordinating and standardizing staining 
for the 23 participating centers in 17 countries (38). Thus, our group is experienced in this 
assessment and well suited to perform the proposed studies (39). 
In NSCLC, resected stage I adenocarcinomas were evaluated for infiltrating immune cells 
(helper, cytotoxic, and memory T cells, regulatory T cells, B cell, NK cell, and macrophage 
infiltration) in the tumor and surrounding microenvironment.  A high density of regulatory T 
cells in the stroma (but not the tumor) was associated with higher risk of tumor recurrence, and 
an inverse correlation of regulatory T cells to CD3+ T cells in stroma correlated strongly with 
risk of recurrence (40).   
Currently, there is not a definitive biomarker that predicts with absolute reliability benefit (or 
lack thereof) with immunotherapy agents, including pembrolizumab.  Although tumor PD-L1 
expression is under investigation as a likely biomarker, tumor responses have been 
demonstrated in patients treated with anti-PD-1 and anti-PD-L1 agents whose tumors are 
considered negative for PD-1 and PD-L1 expression.  Thus, further investigation to develop 
an understanding of those patients potentially more (or less) likely to experience a benefit from 
immunotherapy, including pembrolizumab, is critical.  Assessment of a pre-treatment 
predictive assessment of prognosis or potential benefit from immunotherapy, such as the 
immunoscore, carries a significant potential that could be translated into further investigations 
in other disease stages with pembrolizumab or other immunotherapy agents. 
Humoral Immune response assessment – 9000 Protein spotted Arrays: 
What does the immune system of a patient recognize if they experience a PR or CR following 
treatment with pembrolizumab? A major question in the field is whether these responses are 
targeting mutated or non-mutated proteins. Monitoring for immune response with serial protein 

Product:  MK-3475  
12 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
arrays will allow for assessment of patients with and without a pre-existing humoral immune 
response (as demonstrated by changes in immune studies), and exploratory analyses comparing 
outcomes between those patients generating immune responses and those who do not.  This 
may allow for development of further predictors of benefit with immunotherapy agents.  
Additionally, these studies may help determine the targets of immune destruction, aiding in 
assessing pembrolizumab’s mechanism of action. Our group recently used these arrays to 
assess potential cancer antigens in a patient with advanced prostate cancer who experienced a 
durable CR (6 years+) following treatment with ipilimumab (41).  
Immunophenotyping of whole blood: 
Our Institute has invested substantial resources to develop an outstanding immunological 
monitoring laboratory under the direction of Dr. Keith Bahjat. The proposed studies will 
evaluate whole blood samples for changes in T cell subsets. The four panels evaluate: 1) T cell 
cocktail - CD4 and CD8 T cells for absolute numbers of naïve. memory, central memory and 
effector memory subsets, 2) T Help cocktail, 3) T reg cocktail and 4) a DCNK Cocktail. 
Together, these 4 panels detailed in the budget justification section, provide a solid overview 
of changes in these immune cell subsets. Additionally, blood from the pre and week 12 interval 
will be cryopreserved for possible functional studies. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Women or men with advanced, histologically proven NSCLC.  Mixed histologies are allowed 
as long as no small cell elements are seen. Advanced disease is defined as disease not treatable 
with curative intent, such as stage IV disease, or recurrent stage III disease. 
5.1.2 Subject Inclusion Criteria 
1. Women or men with advanced, histologically proven NSCLC.  Mixed histologies are 
allowed as long as no small cell elements are seen. Advanced disease is defined as 
disease not treatable with curative intent, such as stage IV disease, or recurrent stage 
III disease. 
2. Patients must have received at least one but no more than three prior systemic therapies 
for advanced disease.  Prior neoadjuvant or adjuvant chemotherapy will not be included 
in the assessment as a prior chemotherapeutic regimen, unless disease recurrence was 
less than 12 months after completing therapy. 
3. Per Good Clinical Practice, any toxicity related to prior therapies that, in the opinion 
of the investigator, would potentially be worsened with anti-PD1 therapy or 
gemcitabine should be resolved to less than Grade 1.   

Product:  MK-3475  
13 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
5. Age > 18 years. 
6. Women of childbearing potential must have a negative pregnancy test and must avoid 
becoming pregnant while on treatment. Men must avoid fathering a child while on 
treatment. 
7. Ability to give informed consent and comply with the protocol.  
8. Anticipated survival minimum 3 months. 
9. Prior therapy with investigational agents must have been completed at least 3 weeks 
prior to study enrollment.   
10. Patients must have normal organ and marrow function as defined by:  
a. Leukocytes 
 
 
 
≥ 3,000/µL 
b. Platelets 
 
 
 
≥ 100,000/µL 
c. Total bilirubin  
 
 
Within normal institutional limits 
d. AST (SGOT)/ALT (SGPT)  
≤ 2 x institutional upper limit of normal 
 
11. Measurable disease by RECIST 1.1 criteria. 
12. Treated brain metastases will be allowed, provided they are asymptomatic.  Radiation 
treatment for brain metastases must have been completed at least 2 weeks prior to 
enrollment.  Patients must demonstrate stable symptoms and seizure control on a 
consistent dose of anticonvulsants (if deemed necessary) for at least 2 weeks prior to 
enrollment. Patients must have been either off corticosteroids, or on a stable or 
decreasing dose of </= 10mg Prednisone or Prednisone equivalent daily for at least 2 
weeks. Treatment for brain metastases may include whole brain radiotherapy (WBRT), 
radiosurgery (RS; Gamma Knife, KINAC, or equivalent), neurosurgical resection with 
radiation, or a combination as deemed appropriate by the treating physician. 
13. Radiation for symptomatic lesions outside the CNS must have been completed at least 
2 weeks prior to study enrollment.  If measurable disease is within the radiation field, 
there must be evidence of clear progression (using RECIST criteria) at the time of study 
enrollment. 
5.1.3 Subject Exclusion Criteria 
1. Prior therapy with any anti-PD-1, anti-PD-L1, or anti-CTLA4 antibody. 

Product:  MK-3475  
14 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
2. Prior therapy with gemcitabine. 
3. Prior complications from radiation, such as history of radiation pneumonitis or 
pulmonary edema, that, in the opinion of the investigator, may have risk of increasing 
toxicity with anti-PD1 therapy. 
4. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis. 
5. Evidence of interstitial lung disease. 
6. Previous allergic reaction to gemcitabine. 
7. Active autoimmune disease except vitiligo or stable hypothyroidism.  
8. Active and ongoing steroid use greater than 10mg Prednisone or Prednisone equivalent 
daily. Non-systemically absorbed treatments (such as inhaled or topical steroid therapy 
for asthma, COPD, allergic rhinitis) are allowed. 
9. Active other malignancy, except for controlled basal cell skin carcinoma.  
10. HIV positive and/or Hepatitis B or C positive. 
11. Other medical or psychiatric conditions that in the opinion of the Principal Investigator 
would preclude safe participation in this protocol. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 3. 
 
 
 
 
Table 3  Trial Treatment—Phase I portion, initial dose cohort. 
Drug 
Dose/Potenc
y 
Dose 
Frequenc
y 
Route of 
Administratio
n 
Regimen/Treatmen
t Period 
Use 
Pembrolizu-
mab 
200 mg 
Q21 days IV infusion 
24 Months 
Experimenta
l 
Gemcitabin
e 
1250 mg/m2 Days 1, 8 
of 21-
IV infusion 
6 cycles 
Standard of 
Care 

Product:  MK-3475  
15 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
Drug 
Dose/Potenc
y 
Dose 
Frequenc
y 
Route of 
Administratio
n 
Regimen/Treatmen
t Period 
Use 
day 
schedule 
The pembrolizumab dosing interval may be increased due to toxicity as described in Section 
5.2.1.2. 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 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 the dose preparation and administration are provided in the Procedures Manual. 
Dose Limiting Toxicity (DLT) will be defined as grade 4 hematologic, or grade 3 or 4 non-
hematologic toxicity using NCI Common Terminology Criteria for Adverse Events v4.0 that 
in the opinion of the investigator is considered at least possibly related to treatment.  Any grade 
3 or 4 hematologic or non-hematologic toxicity will result in stopping of therapy until the 
toxicity has resolved to grade 1 or less.  If treatment needs to be held for longer than 3 weeks 
from the scheduled dose due to toxicity, this is also considered DLT.  If resolution of the 
toxicity to grade 2 or less has not occurred within four weeks, the patient will be withdrawn 
from study. 
The initial phase I cohort will enroll a maximum of 6 patients. 
If DLT felt to be attributed to pembrolizumab is observed in two or more patients, then a dose 
de-escalation will occur, with six further patients enrolled receiving pembrolizumab 100 mg 
iv every 3 weeks.  If DLT felt to be attributed to gemcitabine is observed in two or more 
patients, then a dose de-escalation of gemcitabine will occur, with six further patients enrolled 
receiving the next lower dose of gemcitabine (See Dose Modifications, Table 2, Section 4.2.2).  
Dose de-escalation of either drug may occur separately from the other depending upon 
attribution of toxicity. 
If DLT felt to be attributed to pembrolizumab is observed in two or more patients in the dose 
de-escalated cohort, the combination will be considered not feasible, and accrual will be halted. 
After the first 2 patients are enrolled and start therapy, further enrollment will be held until 
both patients complete 6 weeks of therapy.  If DLT is seen in one or fewer patients, then accrual 
will reopen.  Enrollment will then be held again after enrollment of 2 more patients until both 
patients complete 6 weeks of therapy.  If dose-de-escalation criteria are not met, then 
enrollment will open to complete the phase I cohort with the same dose of pembrolizumab to 
a maximum of 6 patients total.   

Product:  MK-3475  
16 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
If no DLTs are seen, then the phase II portion will commence enrollment. 
The MTD in the phase I portion of the study will be used in the phase II portion of the trial. 
5.2.1.2 Dose Modification  
Dose adjustments of gemcitabine should be made according to the greatest degree of toxicity 
as recorded according to the CTCAE Version 4.0, and are listed in Table 4.  Dose re-escalation 
after dose reduction for toxicity of either drug will not be allowed.  There will be no more than 
two dose reductions allowed for gemcitabine and no more than one dose reduction of 
pembrolizumab. 
A maximum of a six-week treatment delay will be permitted to allow recovery from 
gemcitabine-induced toxicities.  If a subject experiences recurring toxicities despite 2 dose 
reductions of gemcitabine, treatment should be discontinued.  The subject will continue to be 
followed for resolution of toxicity as well as for disease progression and survival. 
Subjects who require dose delays of gemcitabine for chemotherapy-related toxicity may 
continue to receive pembrolizumab on schedule, provided the toxicity is not thought to be due 
to pembrolizumab (See Table 5 for management of pembrolizumab-related toxicities). 
Table 4.  Gemcitabine dose modification guidelines for drug-related toxicities. 
Hematologic Toxicities 
Neutropenia:  Day 1 
1)  Grade 1 
2)  Grade 2 
3)  Grade ≥3 
 
1)  No dose modification 
2)  Hold dose until ≤ Grade 1* 
3)  Hold dose until ≤ Grade 1*   
Reduce dose -1 level* 
Neutropenia:  Days 8 
1)  Grade 1 
2)  Grade 2 
3)  Grade ≥ 3 
1)  No dose modification 
2)  Hold dose until ≤ Grade 1* 
3)  Hold dose until ≤ Grade 1* 
Reduce dose -1 level*  
Febrile Neutropenia 
(one reading of oral temp. >38.5°C, or 
three readings of oral temperature 
>38.0° C in a 24-hour period) 
1)  First event 
2)  Second 
event 
3)  Third 
event 
1)  Administer G-CSF and delay 
treatment cycle a minimum of 1 week.  
Hospitalization and antibiotic therapy as 
clinically indicated. 
Discontinue treatment if ANC does not 
recover within 28 days. 
 
Reduce dose -1 level* 

Product:  MK-3475  
17 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
 
2)  Reduce dose –2 level* 
3)  Discontinue treatment 
 
Grade 3 or 4 Infection without 
Neutropenia 
1)  First event 
2)  Second 
event 
3)  Third 
event 
1)  Consider prophylactic antibiotics 
with subsequent cycles 
2)  Reduce to –1 dose level* 
3)  Reduce to –2 dose level* 
Anemia 
1)  Grade 1 
2)  Grade ≥2 
1)  No dose reduction 
2)  Transfuse red blood cell products and 
administer erythropoietin products at 
investigator discretion 
Thrombocytopenia 
1)  
≥100,000/µL 
2)  ≤ 
100,000/µL 
1)  No dose reduction 
2)  Hold gemcitabine until platelet count 
recovers to ≥100,000/µL (maximum 28 
days);*Reduce dose –1 level* 
 
Non-Hematologic Toxicities 
Grade 1 
N/A 
No change in therapy 
Grade 2 
N/A 
Hold gemcitabine until ≤ Grade 1 
Grade 3-4 
1. First event 
2. Second 
event 
Supportive care as necessary 
Hold gemcitabine until ≤ Grade 1 
1. Reduce dose -1 level* 
2. Reduce dose -2 level* 
* Doses held during a course of therapy will be deleted and will not be administered at a later time.  If a dose 
reduction is required day 8, the dose reduction will be permanent.  If treatment is held for over 4 weeks due to 
hematologic toxicity, the patient will be removed from the study. 
 
Pembrolizumab will be withheld for drug-related Grade 3 or 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 5 below. 
 
 

Product:  MK-3475  
18 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
Table 5: Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening immune-related AEs (irAEs), IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 

Product:  MK-3475  
19 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• 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 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 

Product:  MK-3475  
20 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
In case toxicity does not resolve to Grade 0-1 within 6 weeks after last infusion, trial treatment should be discontinued after consultation 
with the Sponsor and Primary Investigator.  With investigator and Sponsor agreement, subjects with a laboratory adverse event still at 
Grade 2 after 6 weeks may continue treatment in the trial only if asymptomatic and controlled.  For information on the management of 
adverse events, see Section 5.6.1.   
Subjects who experience a recurrence of the same severe or life-threatening event at the same grade or greater with re-challenge of 
pembrolizumab should be discontinued from trial treatment. 
 
 

Product:  MK-3475  
21 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Days 1 and 8 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. 
Gemcitabine should be infused prior to pembrolizumab infusion, according to institutional 
standard protocol.  Antiemetics should be administered according to institutional standard of 
care protocol, with the exception of the prohibition of prophylactic corticosteroids as 
antiemetic (See Section 5.6.1 regarding supportive care medications). 
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals may 
be increased due to toxicity as described in Section 5.2.1.2).  Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible.  However, given the variability 
of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
The Procedures Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.  
5.2.3 Trial Blinding/Masking 
This is an open-label non-randomized trial; therefore, the Sponsor, investigator and subject 
will know the treatments administered. 
5.3 
Randomization or Treatment Allocation 
N/A 
5.4 
Stratification 
No stratification will be used for this study. 
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 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 Sponsor.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the Primary 
Investigator, the Sponsor, and the subject.  

Product:  MK-3475  
22 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
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 (including retreatment for post-complete response relapse) of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab and gemcitabine 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed after consultation with Sponsor and Primary Investigator.   
• 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, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) 
are live attenuated vaccines, and are not allowed.  
• Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor and Primary 
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. 

Product:  MK-3475  
23 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
There are 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 (including institutional standard 
of care supportive measures such as antiemetic prophylaxis prior to chemotherapy 
administration) as deemed necessary by the treating investigator including but not limited to 
the items outlined below: 
• Diarrhea: 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).  In symptomatic 
subjects, infectious etiologies should be ruled out, and if symptoms are persistent 
and/or severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (Grade 3), pembrolizumab will be 
permanently discontinued and treatment with systemic corticosteroids should 
be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started and 
continued over at least 1 month. 
o In subjects with moderate enterocolitis (Grade 2), pembrolizumab should be 
withheld and anti-diarrheal treatment should be started.  If symptoms are 
persistent for more than one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent).  When symptoms improve to 
Grade 1 or less, corticosteroid taper should be started and continued over at 
least 1 month.  Regarding guidelines for continuing treatment with 
pembrolizumab, see Section 5.2. 
o All subjects who experience diarrhea 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. 
• Nausea/vomiting: Nausea and vomiting should be treated aggressively, including 
administration of prophylactic antiemetic therapy according to standard institutional 
practice.  The use of corticosteroids as antiemetic prophylaxis is prohibited.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
• Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard institutional 
practice. 

Product:  MK-3475  
24 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
• Immune-related adverse events: Please see Section 5.6.1.1 below and the separate 
guidance document in the administrative binder regarding diagnosis and management 
of adverse experiences of a potential immunologic etiology.   
• Management of Infusion Reactions:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness 
of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; 
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation 
of tumor pain due to treatment); Urticaria (hives, welts, wheals); Vomiting. 
Table 6 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
Table 6  Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 

Product:  MK-3475  
25 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.  irAEs may be predicted based on the nature of the pembrolizumab 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action.  Special attention should be paid to AEs that may be suggestive 
of potential irAEs.  An irAE can occur shortly after the first dose or several months after the 
last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of Clinical 
Interest and Immune-Related Adverse Event Guidance Document located in the 
Administrative Binder.  Subjects who develop a Grade 2 or higher irAE should be discussed 
immediately with the Sponsor and Primary Investigator.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 7. 

Product:  MK-3475  
26 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
Table 7  General Approach to Handling irAEs 
irAE 
Withhold/Discontinue 
pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold pembrolizumab 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold pembrolizumab 
Discontinue if unable to reduce 
corticosteroid dose to < 10 mg 
per day prednisone equivalent 
within 12 weeks of toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 4 
weeks. 
 
5.6.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab 
and have an evaluation.  The evaluation may include chest radiography, bronchoscopy, and 
pulmonary function tests to rule out other causes such as infection.  If the subject is determined 
to have study drug associated pneumonitis, the suggested treatment plan is detailed in Table 8. 
Table 8.  Recommended Approach to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue 
pembrolizumab? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold pembrolizumab, 
may return to treatment if 
improves to Grade 1 or 
resolves within 12 weeks 
Report immediately as ECI 
Consider pulmonary consultation with 
bronchoscopy and biopsy/BAL and Infectious 
Disease consultation as appropriate. 
Systemic corticosteroids are indicated (1-2 mg/kg 
daily prednisone or equivalent).  Patients with 
suspected or diagnosed pneumonitis should be 
started on steroid treatment immediately, and steroid 
treatment should not be delayed for a therapeutic 
trial of antibiotics.  Treatment of both a potential 
infectious etiology and pneumonitis in parallel may 
be warranted. 
When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less 
than 4 weeks.  Permanently discontinue for inability 
to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.   
Conduct an in person evaluation approximately 
twice weekly until the patient is improving.   
Consider frequent chest x-ray as part of monitoring. 
Discontinue pembrolizumab if upon re-challenge the 
patient develops a second episode of Grade 2 or 
higher pneumonitis. 
 

Product:  MK-3475  
27 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
Grade 3 and Grade 4 
Permanently discontinue 
pembrolizumab 
Report immediately as ECI. 
Hospitalize patient and consider bronchoscopy with 
biopsy and/or BAL. 
Systemic corticosteroids are indicated 
(methylprednisolone 125 mg IV).  When symptoms 
improve to Grade 1 or less, a high dose oral steroid 
(prednisone 1-2 mg/kg daily or dexamethasone 4 mg 
every 4 hours) taper should be started and continued 
over no less than 4 weeks.  If IV steroids followed 
by high dose oral steroids does not reduce initial 
symptoms within 48 to 72 hours, treat with 
additional anti-inflammatory measures. 
Discontinue anti-inflammatory measures upon 
symptom relief and initiate a prolonged steroid taper 
over 45 to 60 days.  If symptoms worsen during 
steroid reduction, initiate a re-tapering of steroids 
starting at a higher dose of 80 or 100 mg followed 
by a more prolonged taper and administer additional 
anti-inflammatory measures, as needed.  In addition, 
prophylactic antibiotics for opportunistic infections 
should be considered. 
The use of infliximab may be indicated as 
appropriate.   
Refer to the Event of Clinical Interest and Immune-
related Adverse Event Guidance Document for 
additional recommendations. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
• First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
• Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis ≥ Grade 2 
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. 
5.7.2 Contraception 
Pembrolizumab and gemcitabine may have adverse effects on a fetus in utero.  Furthermore, it 
is not known if pembrolizumab has transient adverse effects on the composition of sperm.  
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods 
of birth control or are considered highly unlikely to conceive.  Highly unlikely to conceive is 
defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and 

Product:  MK-3475  
28 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
has not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be either 
two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Subjects should start using birth control from study Visit 1 throughout the study period up to 
120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medications may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to the Primary Investigator, and to Merck.  If there is any question that a subject 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment, 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 Primary Investigator and to Merck without delay and within 
24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  The 
study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to the Primary 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.  Significant risk to the infant 
via human milk exposure to gemcitabine or pembrolizumab cannot be ruled out.  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. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be discontinued from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject may 
be withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, 

Product:  MK-3475  
29 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
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: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: Subjects who are clinically stable or who are clinically benefitting from 
therapy may continue treatment with pembrolizumab past first progression on 
imaging, until confirmation of disease progression on second imaging.  
Gemcitabine will not be continued beyond first radiographic progression (RECIST 
v1.1, see Section 12.3).  
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of treatment with pembrolizumab 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment based upon 
approval of the Primary Investigator and Merck, including review of clinical and 
laboratory status. 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 

Product:  MK-3475  
30 
Protocol/Amendment No.: 15-011A Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
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 
Subjects in the initial phase I safety portion of the study who are not able to complete the 
evaluation period for safety will be replaced. 
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 so that appropriate adjustments to subject treatment can be made. 

Product:  MK-3475  
31 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
 
 
Confidential  Limited Access 
 
6.0 TRIAL FLOW CHART

Product:  MK-3475  
32 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
 
 
Confidential  Limited Access 
 
 
6.1 
Study Flow Chart 
Baseline evaluations are to be conducted within 4 weeks prior to enrollment except for EKG which may be performed within 8 weeks 
prior to enrollment.  Scans must be done within 4 weeks prior to the start of therapy. 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment 
Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
C1/ 
D1 
 
C2 
/D1  
 
C3/ 
D1 
 
C4/ 
D1 
 
C4/ 
D8 
To be repeated beyond 
8 cycles 
Discon 
Safety 
Follow
-up 
Follo
w Up 
Visits 
Surviva
l 
Follow-
Up  
C1/ 
D8 
C2/ 
D8 
C3/ 
D8 
 
5 
6 7 8 
Scheduling 
Window (Days): 
 
-28 to -1 
 
 
± 3 
 
± 3 
 
± 3 
 
± 3 
± 
3 
± 
3 
± 
3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8 
weeks 
post 
discon 
Every 
12 
weeks   
 
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusio
n Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medication 
Review 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X X X 
X 
X 
X 
X 
Pembrolizumab 
Administrationa 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X X X 
 
 
 
 
Gemcitabine 
Administrationb 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X (Days 1, 
8 for a 
maximum 
of 6 cycles) 
 
 
 
 
 
 
 

Product:  MK-3475  
33 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
 
 
Confidential  Limited Access 
 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment 
Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
C1/ 
D1 
 
C2 
/D1  
 
C3/ 
D1 
 
C4/ 
D1 
 
C4/ 
D8 
To be repeated beyond 
8 cycles 
Discon 
Safety 
Follow
-up 
Follo
w Up 
Visits 
Surviva
l 
Follow-
Up  
C1/ 
D8 
C2/ 
D8 
C3/ 
D8 
 
5 
6 7 8 
Scheduling 
Window (Days): 
 
-28 to -1 
 
 
± 3 
 
± 3 
 
± 3 
 
± 3 
± 
3 
± 
3 
± 
3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8 
weeks 
post 
discon 
Every 
12 
weeks   
Post-study 
anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Clinical Procedures/Assessments 
Review Adverse 
Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
 
Full Physical 
Examination 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X X X 
X 
X 
 
 
Vital Signs and 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
 
ECOG 
Performance Status 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X X X 
X 
X 
X 
 
EKG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
HIV, Hepatitis 
serologies 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test – 
Urine or Serum β-
HCG 
 
Xd 
 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
X
d 
X
d 
X
d 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
Differential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Days 1 and 
8 through 
X X X 
X 
X 
 
 

Product:  MK-3475  
34 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
 
 
Confidential  Limited Access 
 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment 
Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
C1/ 
D1 
 
C2 
/D1  
 
C3/ 
D1 
 
C4/ 
D1 
 
C4/ 
D8 
To be repeated beyond 
8 cycles 
Discon 
Safety 
Follow
-up 
Follo
w Up 
Visits 
Surviva
l 
Follow-
Up  
C1/ 
D8 
C2/ 
D8 
C3/ 
D8 
 
5 
6 7 8 
Scheduling 
Window (Days): 
 
-28 to -1 
 
 
± 3 
 
± 3 
 
± 3 
 
± 3 
± 
3 
± 
3 
± 
3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8 
weeks 
post 
discon 
Every 
12 
weeks   
cycle 6 
gemcitabine
) 
Comprehensive 
Serum Chemistry 
Panele 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X X X 
X 
X 
 
 
Urinalysis 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X X X 
 
 
 
 
T3, FT4 and TSHf 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging 
(CT Thorax 
including entire 
liver and adrenal 
glands)  
X 
 
 
 
 
 
Xg 
 
 
 
Xg 
 
 
 
 
 
 
X 
 
 
Archival Tissue Collection/Correlative Studies Blood 
Blood for immune 
parameters 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Xh 
ProtoArray® 
Immune Response 
Biomarker 
Profiling 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Submit archived 
slides (if available) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Product:  MK-3475  
35 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
 
 
Confidential  Limited Access 
 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment 
Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
C1/ 
D1 
 
C2 
/D1  
 
C3/ 
D1 
 
C4/ 
D1 
 
C4/ 
D8 
To be repeated beyond 
8 cycles 
Discon 
Safety 
Follow
-up 
Follo
w Up 
Visits 
Surviva
l 
Follow-
Up  
C1/ 
D8 
C2/ 
D8 
C3/ 
D8 
 
5 
6 7 8 
Scheduling 
Window (Days): 
 
-28 to -1 
 
 
± 3 
 
± 3 
 
± 3 
 
± 3 
± 
3 
± 
3 
± 
3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8 
weeks 
post 
discon 
Every 
12 
weeks   
for immunoscore 
and PD-L1 testing 
 
 
 
a. 
Pembrolizumab administration will be every 21 days for 2 years, or until disease progression or prohibitive toxicity, whichever 
comes first. 
b. 
Gemcitabine will be administered on Days 1 and 8 of each 21 day cycle for a maximum of 6 cycles, or until disease progression or 
prohibitive toxicity, whichever comes first. 
c. 
Within 6 months of enrollment 
d. 
All females with childbearing potential starting at baseline, and then with Day 1 of each cycle throughout pembrolizumab 
administration. 
e. 
Albumin, Alkaline Phosphatase, Total bilirubin, Bicarbonate, BUN, Calcium, Chloride, Creatinine, Glucose, LDH, Phosphorus, 
Potassium, Total Protein, SGOT [AST], SGPT [ALT], Sodium 
f. 
TSH, free T3, free T4 should continue every 6 weeks beginning at Cycle 6 of study treatment and continue throughout study 
treatment. 
g. 
CT scan must be done prior to Week 7 treatment.  Disease assessment (CT scans) should be performed every 6 weeks for 2 
years, then every 2 months while in follow up.  Imaging to include pelvis or other locations as clinically appropriate. 
h. 
Every 12 weeks for 2 years or until progressive disease. 
 
 

Product:  MK-3475 
36 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
7.0 TRIAL PROCEDURES 
7.1 
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 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. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 

Product:  MK-3475 
37 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Subject Identification Card 
Not applicable. 
7.1.1.4 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.   
7.1.1.5 Prior and Concomitant Medications Review 
7.1.1.5.1 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.  
7.1.1.5.2 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. 
7.1.1.6 Disease Details and Treatments 
7.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.6.3 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 

Product:  MK-3475 
38 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
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.  
7.1.1.7 Assignment of Study Number 
Study Numbers will be assigned at enrollment based on order of enrollment and study 
ID, as follows:  MK-01, MK-02, MK-03, etc. 
All case report forms, study reports, and laboratory samples for research tests will be 
labeled with the full patient Study Number.   
7.1.1.8 Assignment of Randomization Number 
Not applicable 
7.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) 
Not applicable 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 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 12.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.6.1.1 and the separate guidance document in the administrative 
binder regarding the identification, evaluation and management of AEs of a potential 
immunological etiology.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 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,  

Product:  MK-3475 
39 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
7.1.2.3 Directed Physical Exam 
Additional directed physical examinations will be performed as deemed appropriate by the 
investigator or qualified designee in assessment of symptoms or side effects. 
7.1.2.4 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, pulse oximetry recording, weight and blood pressure.  Height will be measured at 
screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Tumor response will be measured using RECIST v1.1 (See Section 12.3).  CT scans will be 
performed every 6 weeks for 2 years, then every 2 months while in follow up. 
Subjects with first disease progression may continue to receive pembrolizumab until 
confirmation of disease progression on next imaging, provided they remain clinically stable 
and appear to be receiving benefit from therapy.  Gemcitabine will not be continued beyond 
first radiographic progression. 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 Tumor specimens will be evaluated for expression of PD-L1 by immunohistochemistry and 
for tumor immune score.  Immune monitoring will be conducted with collection of peripheral 
blood and assessment of protein arrays, and compared pre-treatment and at 12 weeks after 
initiation of pembrolizumab.  Additional samples may be archived at 3 month intervals 
thereafter while receiving pembrolizumab therapy. 
Blood for immune parameters: This includes sera for protoArray, and heparinized blood for 
immunophenotyping and WBC banking. Five x 10cc sodium heparin (green top) tubes and 1 
x 10cc serum separator tube (SST) are drawn at the pre-treatment time point and at week 12. 
Tubes are transported at room temperature to the Immunological Monitoring Laboratory for 
processing. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  The total amount of blood/tissue to be drawn/collected over the course of the 

Product:  MK-3475 
40 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures Manual.  
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.  
The total amount of blood/tissue to be drawn/collected over the course of the trial (from pre-
trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by visit 
and by sample type per subject can be found in the Procedures Manual.  
 

Product:  MK-3475 
41 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
Table 9  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and 
differential) 
Aspartate 
aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase 
(LDH) 
Microscopic exam (If 
abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil 
Count 
Carbon Dioxide  
results are noted 
Free tyroxine (T4) 
 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone 
(TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total 
bilirubin is elevated 
above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required.   
 
 
 
 

Product:  MK-3475 
42 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.  
7.1.3.2 Pharmacokinetic/Pharmacodynamic Evaluations 
Not applicable. 
 
 
7.1.4 Other Procedures 
7.1.4.1 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.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 5.6.  After discontinuing treatment following assessment of 
CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4). 
7.1.4.2 Blinding/Unblinding 
Not applicable for this study. 
7.1.5 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. 
7.1.5.1 Screening 
Baseline evaluations are to be conducted within 4 weeks prior to enrollment except 
for EKG, which may be performed within 8 weeks prior to enrollment.  Scans must 
be done within 4 weeks prior to the start of therapy. 
7.1.5.1.1 Screening Period 
During the screening period, subjects will complete procedures as outlined in the Study Flow 
Chart in Section 6.1.  Screening procedures include documentation of informed consent, 
review and confirmation of eligibility via inclusion and exclusion criteria, review of 
demographics and medical history, prior and concomitant medication review and 
documentation, recording of vital signs and weight, ECOG performance status.   

Product:  MK-3475 
43 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
Laboratory investigations will include documentation of HIV and hepatitis serologies, 
pregnancy test (for women of childbearing potential), PT/INR and aPTT, CBC with 
differential, comprehensive serum chemistry panel, urinalysis, and thyroid studies including 
T3, free T4, and TSH.   
7.1.5.2 Treatment Period 
Studies, procedures, and treatments will be performed as outlined in Section 6.1 Study Flow 
Chart. 
7.1.5.3 Post-Treatment Visits 
Post-treatment visits will include End of Treatment visit at the time of study discontinuation, 
Safety follow up visit (as outlined in Section 7.1.5.3.1 below), follow up visits every 8 weeks 
after study discontinuation. 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  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.   
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 8 weeks (56 ± 7 days) by radiologic 
imaging to monitor disease status.  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 or if the subject begins retreatment with pembrolizumab as detailed in 
Section 5.6.  Information regarding post-study anti-neoplastic treatment will be collected if 
new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 5.6 will continued to be followed per protocol until disease progression.  Details are 
provided in Section 6.1 – Trial Flow Chart.    
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  

Product:  MK-3475 
44 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the pembrolizumab or gemcitabine, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, or any other study 
procedure, the subject is first required to provide consent to the main study and AEs will be 
captured according to guidelines for standard AE reporting. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for gemcitabine or pembrolizumab by 20% over the prescribed dose. No specific 
information is available on the treatment of overdose of pembrolizumab. In the event of 

Product:  MK-3475 
45 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
overdose, gemcitabine and pembrolizumab should be discontinued and 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 either gemcitabine or 
a Merck product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
If a dose of gemcitabine or 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 Primary Investigator and Sponsor and within 2 working days hours to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Primary Investigator and Sponsor and 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 
993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
gemcitabine or pembrolizumab that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 

Product:  MK-3475 
46 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
Refer to Table 10 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to gemcitabine or 
pembrolizumab, must be reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to gemcitabine or pembrolizumab that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor and to Merck. 
An unanticipated event that is serious and definitely or probably caused by the study treatment (drugs 
or device) will be reported to the IRB in accordance with their guidelines and within their timelines. 
Collaborating sites must comply with all local IRB requirements and copies of all IRB approvals from 
these sites must be provided by the site’s clinical research staff to the PH&S Regional Research Office. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
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 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 

Product:  MK-3475 
47 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to the Sponsor within 24 hours and to Merck Global Safety within 
2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
A separate guidance document has been provided entitled “event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.”  This document provides guidance 
regarding identification, evaluation and management of ECIs and irAEs.  Additional ECIs are 
identified in this guidance document and also need to be reported to the Sponsor within 24 
hours and to Merck Global Safety within 2 working days of the event.   
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not 
related to the Merck’s product, must be reported within 24 hours to the Sponsor and to Merck 
Global Safety within 2 working days. 

Product:  MK-3475 
48 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
7.2.4 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 (See Section 12.2). 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. 

Product:  MK-3475 
49 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
Table 10  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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); 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) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. 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. 
 
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 the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the 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 the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the 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 the 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 
 

Product:  MK-3475 
50 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018 
 
 
 
 
Confidential  Limited Access 
 
 
 
 
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 the 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 Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the 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) Merck 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 THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

Product:  MK-3475 
51 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Sample Size 
The phase I de-escalation portion of the study described in section 5 involves a design with 
dose cohort size of 6, toxicity evaluated after each 2 enrollments, and only allowing de-
escalation.  At completion of phase I, data will be collected for at least 6 weeks of follow-up 
on 6 patients at the MTD or maximum doses studied (200 mg pembrolizumab plus 1250 mg/m2 
gemcitabine) if MTD was not reached.  In phase II, an additional 10 patients will be enrolled 
at the final dose from phase I for a total of N=16 subjects.  With 24 mo of follow-up, N=16 
provides 80% power to detect a difference between median survival times of 3 mo in a 
historical control compared to 9 mo in the current study, assuming exponential survival 
distributions and using a 2-sided test at alpha=.05 level of significance.  The historical control 
is based on estimates of median survival times seen in the literature ranging from 2.5-4.25 mo.  
Total number of patients enrolled will range from 16 to 46 ( (3 gemcitabine doses x 2 
pembrolizumab doses x 6/cohort) + 10 in phase II).  Sample size was calculated using SAS 9.3 
(SAS Institute Inc., Cary, NC). 
8.2 
Statistical Analysis Plan Summary 
Primary outcome      
• Frequencies of toxicities 
Secondary outcomes    
• Progression-free survival (PFS)  
• Overall survival (OS)  
• Response rate (CR, PR, SD, PD) 
Exploratory analyses   
• Association between immune response (serial protein array measures from 
peripheral blood samples) and response rate and survival (progression-free and 
overall survival) over time, assessed as retrospective analysis. 
• Association between immune response time(s) of interest and PFS and OS, 
assessed as retrospective analysis. 

Product:  MK-3475 
52 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
• Association between baseline PD-L1 expression in tumor tissue and PFS, OS, 
and Best overall response (CR+PR+SD vs PD), assessed as retrospective 
analysis. 
• Association between baseline tumor tissue immune score and PFS, OS, and 
Best overall response, assessed as retrospective analysis. 
8.3 
Statistical Analysis Plan 
Safety and feasibility 
If phase I is completed with 0-1 DLTs at the final dose tested, the combination therapy will be 
considered feasible.  Safety will be summarized by listing frequencies of all toxicities at all 
doses after phase I.  Additional safety and other analyses will be performed as needed over 
follow-up.  Analyses will be done for each dose cohort separately.  
Survival analysis 
PFS will be analyzed by modeling time to the first of death or progression.  OS will be analyzed 
by modeling time to death.  Patients alive at last date of follow-up will be censored.  Both PFS 
and OS will be described with Kaplan-Meier survival curves.  Confidence intervals of median 
survival times of patients in this study, from both phases I and II, treated with the phase II dose 
of pembrolizumab and gemcitabine combination therapy will be calculated to see whether they 
are greater than 3 months, the median survival times from historical controls of patients with 
previously-treated advanced NSCLC that received gemcitabine single agent therapy. 
Response 
Frequencies of tumor response levels (CR, PR, SD, PD) will be listed for each time point. 
Exploratory analyses 
All exploratory analyses will be performed as retrospective analysis. 
Immune response as measured by serial protein array measures from peripheral blood samples 
at baseline and across follow-up times will be described with means and standard deviations.  
If within subject changes from baseline to particular follow-up time are observed using paired 
t-tests, association with outcome Best overall response will be modeled using logistic 
regression with baseline and change since baseline as independent variables.   
Cox proportional hazards regression of PFS and OS will be used to assess univariate effects of 
baseline tumor PD-L1 expression and tumor immune score measures.  Multivariate survival 
Cox proportional hazards models will be used to test association of PD-L1 and immune score 
measures while controlling for each other on PFS and OS.   

Product:  MK-3475 
53 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
 T-tests, or wilcoxon rank-sum tests if nonparametrics are needed, will be used to test the 
effects of the same baseline PD-L1 expression and immune score measures on best overall 
response.   Log transformations will be used as needed to meet model assumptions.   
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Gemcitabine will be obtained as commercially-available product.  Refer to the Gemcitabine 
label for full information regarding product warnings. 
How Supplied 
Gemzar (gemcitabine for injection, USP), is available in sterile single-use vials individually 
packaged in a carton containing: 200 mg white to off-white, lyophilized powder in a 10-mL 
size sterile single-use vial – NDC 0002-7501-01 (No. 7501) 
1 g white to off-white, lyophilized powder in a 50-mL size sterile single-use vial – NDC 0002-
7502-01 (No. 7502) 
Storage and Handling 
Unopened vials of Gemzar are stable until the expiration date indicated on the package when 
stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions 
between 15° and 30°C (59° and 86°F) 
Pembrolizumab will be supplied by Merck. 
How Supplied 
Pembrolizumab is provided as a white to off white lyophilized powder (50 mg/vial) or as a 
liquid solution (100 mg/vial) in Type I glass vials intended for single use only. Pembrolizumab 
Powder for Solution for Infusion, 50 mg/vial, is reconstituted with sterile water for injection 
prior to use. Pembrolizumab is formulated with L-histidine as buffering agent, polysorbate 80 
as surfactant, sucrose as stabilizer/tonicity modifier, and hydrochloric acid (HCl) and/or 
sodium hydroxide (NaOH) for pH adjustment (if necessary).  
Storage and Handling 
The drug product is stored as a stable lyophilized powder or liquid solution under refrigerated 
conditions (2°C - 8°C). 

Product:  MK-3475 
54 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
The product after reconstitution with sterile water for injection and the liquid drug product is 
a clear to opalescent solution which may contain extraneous and proteinaceous particulates. 
The reconstituted product and liquid product is intended for IV administration. The 
reconstituted drug product solution and liquid drug product can be further diluted with normal 
saline in IV containers made of polyvinyl chloride (PVC) or non-PVC material. Reconstituted 
vials should be immediately used to prepare the infusion solution in the IV bag and the infusion 
solution should be immediately administered. If not used immediately, vials and/or IV bags 
may be stored at 2-8 °C for up to a cumulative time of 20 hours. If refrigerated, the vials and/or 
IV bags should be allowed to equilibrate to room temperature prior to subsequent use. 
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 
hours. This includes room temperature storage of reconstituted drug product solution and liquid 
drug product in vials, room temperature storage of infusion solution in the IV bag and the 
duration of infusion. 
Please refer to the pembrolizumab Investigator’s Brochure for additional product information. 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
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 

Product:  MK-3475 
55 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Protocol Modifications and Amendments 
All modifications or amendments to the protocol or informed consent document must be 
approved by the Principal Investigator and submitted to the PH&S IRB for review and 
approval. All modifications and amendments will be documented with a new version number 
and date. All changes to the informed consent document will include the date of the revision 
on the form. 
 
No changes will be implemented until IRB approval is obtained except when a potential threat 
to patient safety exists. 
The IRB will be notified of any significant deviations from the approved protocol. 
Documentation of all IRB correspondence will be maintained in the central regulatory file. 
10.2 Continuing Review and Final Reports 
An annual progress report (continuing review) will be submitted to the PH&S IRB for the 
duration of the study. A final report to the PH&S IRB will be submitted at the summation of 
the study. 
10.3 Record Retention 
According to 21 CFR 312.62(c), the investigator shall retain required records for a period of 2 
years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated. If no application is to be filed or if the application is not approved 
for such indication, the investigator shall retain these records until 2 years after the 
investigation is discontinued or the IND is withdrawn and the FDA is notified. 
 
The investigator must retain protocols, amendments, IRB/IBC approvals, completed, signed, 
dated consent forms, patient source documents, case report forms, quality monitoring reports, 
drug accountability records and all documents of any nature regarding the study or patients 
enrolled. All records will be maintained under restricted access by the Clinical Trials 
Department at Providence Portland Medical Center while the study remains active. Records 
may be placed in long-term storage after the study is completed. The location of long-term 
storage will be secure and easily accessed for regulatory purposes. 
10.4 Confidentiality 
Study patients will be identified by their assigned study number on all forms and biospecimen 
sample labels.  Patient study data will be collected on eCRFs that are maintained in the Velos 
eResearch CTMS.  eResearch is a web-based application that is accessed using a unique 

Product:  MK-3475 
56 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
username and password (one login per user).  Patient study charts are maintained in a keycode 
access file room within the Clinical Trials Department.  
 
10.5 Compliance with Financial Disclosure Requirements 
Any investigator conducting Research at Providence must comply with the Providence COIR 
Policy and complete a Providence COIR disclosure form. The COIR disclosure form must be 
completed prior to submitting Research studies through a Providence IRB or non-Providence 
IRB of record, prior to submitting a grant; regardless of the source of funding. 
10.6 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
10.7 Quality Management System 
Quality Assurance (QA) personnel review study monitoring reports and if necessary, determine follow-
up actions to resolve significant findings. QA has the authority to request immediate corrective action 
if significant patient safety issues are identified.   
 
QA will track and trend results from study monitoring reports as well as associated corrective and 
preventive actions.  A QA summary report will be provided to the IRB at the time of continuing review. 
 
QA personnel do not have a direct reporting relationship to the Principal Investigator and are not 
responsible for enrollment or coordination of care for study participants. 
 
10.8 Data Management 
Study Monitoring 
Study monitoring activities (Quality Control Reviews) are performed by a Contract Research 
Organization (CRO) or clinical research staff members who have completed specialized training in 
study monitoring procedures and human subjects’ protections.  Individuals who perform study 
monitoring activities do not report to Principal Investigators or research scientists and may not monitor 
studies for which they have direct responsibility. 
Study monitoring activities are conducted regularly and include (but are not limited to) review and 
verification of the following:  
• 
Eligibility 
• 
Informed Consent process 
• 
Adherence to protocol treatment plan 
• 
Case Report Forms (CRFs) 

Product:  MK-3475 
57 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
• 
Source Documentation 
• 
Adverse Events 
• 
Regulatory Reporting 
 
Results of study monitoring activities will be reported to applicable study personnel, the Clinical Trials 
Manager and Quality Assurance. 
Data Reporting 
eCRFs will be completed in Velos eResearch Clinical Trials Management System, a part 11 compliant 
application. 
 
 

Product:  MK-3475 
58 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
11.0 LIST OF REFERENCES 
1. Siegel R, Ma J, Zou Z, et al.  Cancer Statistics, 2014.  Ca Cancer J Clin 2014; 64: 9-
29. 
2. Scagliotti GV, Parikh P, von Pawel J, et al.  Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with 
advanced-stage non-small-cell lung cancer.  J Clin Oncol 2008; 26: 3543-3551. 
3. Sandler A, Gray R, Perry MC, et al.  Paclitaxel-carboplatin alone or with bevacizumab 
for non-small cell lung cancer.  New Engl J Med 2006; 355: 2542-2550. 
4. Gridelli C, Perrone F, Gallo C, et al.  Chemotherapy for elderly patients with advanced 
non-small-cell lung cancer:  The Multicenter Italian Lung Cancer in the Elderly Study 
(MILES) Phase III randomized trial.  J Nat Cancer Institute.  2003; 95: 362-372. 
5. Stinchcombe TE, Peterman AH, Lee CB, et al.  A randomized phase II trial of first-line 
treatment with gemcitabine, erlotinib, or gemcitabine and erlotinib in elderly patients 
(Age ≥ 70 years) with stage IIIB/IV non-small cell lung cancer.  J Thoracic Oncol 2011; 
6: 1569-1577. 
6. LeCaer H, Greillier L, Corre R, et al.  A multicenter phase II randomized trial of 
gemcitabine followed by erlotinib at progression, versus the reverse sequence, in 
vulnerable elderly patients with advanced non small-cell lung cancer selected with a 
comprehensive geriatric assessment (the GFPC 0505 study).  Lung Cancer 2012; 77: 
97-103. 
7. Cho K-H, Song Y-B, Choi I-S, et al.  A phase II study of single-agent gemcitabine as 
a second-line treatment in advanced non-small cell lung cancer.  Jpn J Clin Oncol 2006; 
36: 50-54. 
8. Rosell R, Carcereny E, Gervais R, et al.  Erlotinib versus standard chemotherapy as 
first-line treatment for European patients with advanced EGFR mutation-positive non-
small-cell lung cancer (EURTAC):  A multicentre, open-label, randomised phase 3 
trial.  Lancet Oncol  2012; 13: 239-246. 
9. Shaw AT, Yeap BY, Solomon BJ, et al.  Effect of crizotinib on overall survival in 
patients with advanced non-small-cell lung cancer harbouring ALK gene 
rearrangement:  A retrospective analysis.  Lancet Oncol 2011; 12:  1004-1012. 
10. Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8. 
11. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.   
12. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
13. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade 
of programmed death-1 ligands on dendritic cells enhances T cell activation and 
cytokine production. J Immunol 2003;170:1257-66.   
14. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42. 
15. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-
1 expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.   

Product:  MK-3475 
59 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
16. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400. 
17. Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal 
cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.   
18. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7. 
19. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19. 
20. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94.   
21. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4.   
22. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.   
23. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.   
24. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.   
25. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10(840):841.   
26. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57:97-106.   
27. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications 
of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.   
28. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59.   
29. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-
7.   
30. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6.   
31. Topalian SL, Hodi FS, Brahmer JR, et al.  Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer.  New Engl J Med 2012; 366: 2443-2454. 

Product:  MK-3475 
60 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
32. Brahmer JR, Horn L, Antonia SJ, et al.  Nivolumab in patients with non-small cell lung 
cancer:  Overall survival and long-term safety in a phase 1 trial.  J Thoracic Oncol 
2013; 8: S365 (abstr). 
33. Garon EB, Leighl NB, Rizvi NA, et al.  Safety and clinical activity of MK-3475 in 
previously treated patients with non-small cell lung cancer (NSCLC).  Proc Am Soc 
Clin Oncol 2014; 32: 8020 (abstr). 
34. Nowak AK, Lake RA, Marzo AL, et al.  Induction of tumor cell apoptosis in vivo 
increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing 
host tumor-specific CD8 T cells.  J Immunol 2003; 170: 4905-4913. 
35. Nowak AK, Robinson BWS, Lake RA.  Synergy between chemotherapy and 
immunotherapy in the treatment of established murine solid tumors.  Cancer Research 
2003; 63: 4490-4496. 
36. Pages F, Kirilovsky A, Mlecnik B, et al.  In situ cytotoxic and memory T cells predict 
outcome in patients with early-stage colorectal cancer.  J Clin Oncol 2009; 27: 5944-
5951. 
37. Mlecnik B, Tosolini M, Kirilovsky A, et al.  Histopathologic-based prognostic factors 
in colorectal cancers are associated with the state of the local immune reaction.  J Clin 
Oncol 2011; 29: 610-618. 
38. Ascierto, PA, Capone M, Urba WJ, Bifilco CB, Botti G, Lugli A, Marincola FM, 
Ciliberto G, Galon J, Fox BA,  The additional facet of immunoscore: immunoprofiling 
as a possible predictive tool for cancer treatment. J Transl Med, 2013 Mar 11(1):54. 
PMCID: PMID:23452415  
39. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Galon J, Mlecnik B, 
Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco 
C, Nagtegaal ID, Palmqvist R, Masucci GV, Botti G, Tatangelo F, Delrio P, Maio M, 
Laghi L, Grizzi F, Asslaber M, D'Arrigo C, Vidal-Vanaclocha F, Zavadova E, 
Chouchane L, Ohashi PS, Hafezi-Bakhtiari S, Wouters BG, Roehrl M, Nguyen L, 
Kawakami Y, Hazama S, Okuno K, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, 
Itoh K, Patel PS, Shukla SN, Wang Y, Kopetz S, Sinicrope FA, Scripcariu V, Ascierto 
PA, Marincola FM, Fox BA, Pagès F: Towards the introduction of the Immunoscore 
in the classification of malignant tumors. J Pathol. 2014 Jan;232(2):199-209. PMCID: 
PMC3681569  
40. Suzuki K, Kadota K, Sima CS, et al.  Clinical impact of immune microenvironment in 
stage I lung adenocarcinoma:  Tumor interleukin-12 receptor β2, IL-7R, and stromal 
FoxP3/CD3 ratio are independent predictors of recurrence.  J Clin Oncol 2013; 31: 409-
498. 
41. Graff JN, Puri S, Bifulco C, Fox BA, Beer TM. Sustained Complete Response to 
CTLA-4 Blockade in a Patient with Metastatic, Castration-Resistant Prostate Cancer. 
Cancer 
Immunology 
Research 
Published 
OnlineFirst 
February 
3, 
2014; doi:10.1158/2326-6066.CIR-13-0193 
 

Product:  MK-3475 
61 
Protocol/Amendment No.:  15-011A, Amendment 4, 28FEB2018  
 
  
 
Confidential  Limited Access 
 
12.0 APPENDICES 
12.1 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. 
 
12.2 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) 
12.3 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.