A Phase II Study of Pembrolizumab for Patients With Head and Neck Squamous Cell Carcinoma With Residual Disease Following Definitive Chemoradiation
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: Yale University

ClinicalTrials.gov ID: NCT02892201 
Title: Pembrolizumab in HNSCC With Residual Disease AŌer RadiaƟon 
Document Type: Protocol and SAP 
Date: 5/7/2020 

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Product:   Pembrolizumab 
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Protocol/Amendment No.:Version 6.1 (10.10.2018) 
 
 
 
 
SPONSOR: Merck and Co, Inc.  
 
TITLE: A Phase II study of Pembrolizumab for patients with head and neck squamous 
cell carcinoma with residual disease following definitive chemoradiation 
 
VERSION: 6.1 (10.10.2018) 
 
IND NUMBER: 131352 
 
PRINCIPAL INVESTIGATOR: 
 
Barbara Burtness M.D.   
Section of Medical Oncology,  
Yale Cancer Center 
333 Cedar Street, FMP114 
New Haven, CT 06520 
Tel: (203) 737-7636 
Fax: (203) 785-3788 
Barbara.Burtness@yale.edu 
 
 
 
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CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 4 
2.0 
TRIAL DESIGN.......................................................................................................... 4 
2.1 
Trial Design ............................................................................................................. 4 
2.2 
Trial Diagram .......................................................................................................... 5 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 6 
3.1 
Primary Objective(s) & Hypothesis(es) ................................................................ 6 
3.2 
Secondary Objective(s) & Hypothesis(es)............................................................. 6 
3.3 
Exploratory Objective ............................................................................................ 6 
4.0 
BACKGROUND & RATIONALE ............................................................................ 7 
4.1 
Background ............................................................................................................. 7 
4.1.1 Pharmaceutical and Therapeutic Background .......................................................... 7 
4.1.2 Preclinical and Clinical Trial Data ............................................................................ 8 
4.2 
Rationale .................................................................................................................. 8 
4.2.1 Rationale for the Trial and Selected Subject Population .......................................................... 8 
4.2.2 Rationale for Dose Selection/Regimen/Modification ............................................................. 11 
4.2.3 Rationale for Endpoints .......................................................................................................... 12 
5.0 
METHODOLOGY ................................................................................................... 13 
5.1.1 Subject Inclusion Criteria ....................................................................................................... 13 
5.1.2 Subject Exclusion Criteria ...................................................................................................... 15 
5.2 
Trial Treatments ................................................................................................... 17 
5.2.1 Dose Selection/Modification .................................................................................................. 18 
5.2.2 Timing of Dose Administration .............................................................................................. 19 
5.2.3 Trial Blinding/Masking ........................................................................................................... 19 
5.3 
Treatment Allocation ............................................................................................ 20 
5.4 
Stratification .......................................................................................................... 20 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 20 
5.5.1 Acceptable Concomitant Medications .................................................................................... 20 
5.5.2 Prohibited Concomitant Medications ..................................................................................... 21 
5.6 
Rescue Medications & Supportive Care ............................................................. 21 
5.6.1 Supportive Care Guidelines .................................................................................................... 21 
5.7 
Diet/Activity/Other Considerations ..................................................................... 25 
5.7.1 Diet 
 ............................................................................................................................. 25 
5.7.2 Contraception .......................................................................................................................... 25 
5.7.3 Use in Pregnancy .................................................................................................................... 25 
5.7.4 Use in Nursing Women ........................................................................................................... 26 
5.8 
Subject Withdrawal/Discontinuation Criteria ................................................... 26 
5.8.1 Discontinuation of Study Therapy after CR ........................................................................... 27 
5.9 
Subject Replacement Strategy ............................................................................. 27 
5.10 
Clinical Criteria for Early Trial Termination ................................................... 27 
6.0 
TRIAL FLOW CHART ........................................................................................... 29 
6.1 
Study Flow Chart .................................................................................................. 29 
6.2 
Trial Procedures ................................................................................................... 31 
6.2.1 Patient Registration Process .................................................................................................... 31 
6.2.2 Administrative Procedures ...................................................................................................... 31 
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    6.2.3   Laboratory Procedures/Assessments ........................................................... 36 
    6.2.4   Other Procedures .......................................................................................... 38 
    6.2.5   Visit Requirements....................................................................................... 38 
6.3 
Assessing and Recording Adverse Events .......................................................... 41 
6.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor and to Merck ....................................................................... 41 
6.3.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ......... 42 
6.3.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck ..... 42 
6.3.4 Evaluating Adverse Events ......................................................................... 44 
6.3.5 Sponsor Responsibility for Reporting Adverse Events .............................. 47 
7.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 47 
7.1 
Statistical Analysis Plan Summary ..................................................................... 47 
8.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 48 
8.1 
Investigational Product ........................................................................................ 48 
8.2 
Packaging and Labeling Information ................................................................. 48 
8.3 
Clinical Supplies Disclosure ................................................................................. 48 
8.4 
Storage and Handling Requirements .................................................................. 48 
8.5 
Returns and Reconciliation .................................................................................. 48 
9.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 49 
9.1 
Compliance with Trial Registration and Results Posting Requirements ........ 49 
9.2 
Quality Management System ............................................................................... 49 
9.2.1 Safety Monitoring ....................................................................................... 49 
9.2.2 Data Monitoring .......................................................................................... 49 
9.2.3 Project Team Meetings ............................................................................... 50 
9.2.4 Audit Plan ................................................................................................... 51 
9.3 
Data Management ................................................................................................. 51 
10.0 
APPENDICES ........................................................................................................... 52 
10.1 
ECOG Performance Status .................................................................................. 52 
10.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 52 
10.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 52 
11.0 
References:................................................................................................................. 53 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab in HNSCC with residual disease after radiation  
Trial Phase 
Phase II 
Clinical Indication 
Patients with residual disease following definitive intent head and neck 
radiation with or without systemic therapy 
Trial Type 
This is a phase II study of pembrolizumab given at a constant dose of 200 
mg every three weeks, for four cycles.  Biopsy is repeated after four cycles. 
Patients with resectable disease can then go on to surgery, and patients 
with unresctable disease can continue on pembrolizumab until progression 
or for up to 1 year.  
Type of control 
none 
Route of administration 
IV 
Trial Blinding 
none 
Treatment Groups  
 
Number of trial subjects 
24 
Estimated enrollment period 
18 months 
Estimated duration of trial 
18 months 
Duration of Participation 
 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a phase II study for patients with squamous cell carcinoma of the head and neck who 
have residual disease following definitive therapy with radiation (with or without systemic 
therapy).  Patients must be diagnosed with biopsy-proven residual disease within 24 weeks of 
completion of radiation therapy with or without systemic therapy.  Residual disease must be 
biopsy proven and can be either from lymph nodes in the neck, or from the primary tumor site.  
Prior to beginning study therapy patients are evaluated by an ENT to determine if they have 
disease amenable to surgical resection. Both resectable and unresectable patients will be 
eligible for participation in the study.  Patients will have repeat scans after 4 cycles (12 weeks) 
of treatment or disease progression, whichever comes first. Scans after 2 cycles will performed 
as clinically indicated.  
Patients then receive four cycles of pembrolizumab at 200mg given every three weeks. Repeat 
imaging is performed after two cycles to ensure there is not progression of disease.  Patients 
who were deemed resectable prior to being enrolled on the study who show clinical 
radiographic or clinical progression after two cycles of therapy will discontinue study drug and 
proceed to surgical resection. Patients deemed to have unresectable disease who have 
radiographic progression but have signs of clinical benefit can continue on the drug.  Following 
completion of four cycles of therapy, a biopsy is performed, and patients are again evaluated 
by ENT surgery.  Patients with disease considered amenable to surgery would go on to surgical 
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resection. Patients considered unresectable or who refuse surgery can continue pembrolizumab 
until time of progression or for 1 year. 
The primary endpoint is the overall response rate.  Secondary endpoints include change in PD-
L1 expression from baseline, changes in key immune cells, and progression free survival. 
2.2 
Trial Diagram 
  
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To determine the overall response rate to pembrolizumab for patients with 
residual disease following radiation with or without systemic therapy for squamous cell 
carcinoma of the head and neck.  The response rate is defined at the time of progression or 
the completion of four cycles of therapy, whichever is earlier.   
Hypothesis:  The use of pembrolizumab in patients with residual disease following 
radiation with or without systemic therapy will lead to an enhanced overall response rate 
due to treatment-related priming of the immune response. 
3.2 
Secondary Objective(s) & Hypothesis(es) 
1. To determine changes in PD-L1 expression following irradiation 
a. Hypothesis- irradiation will increase inflammation and PD-L1 expression  
 
2. To determine the overall response rate as a function of PD-L1 expression 
a. Hypothesis- higher rates of PD-L1 expression will be associated with higher 
overall response rates 
 
3. To evaluate median progression free survival and overall survival 
a. Hypothesis- based on limited data from previous studies the expected rate of 
DFS and OS are approximately 30% and 50% respectively  
 
4. To determine the rate of immune related adverse events in patients receiving 
immunotherapy following radiation with or without systemic therapy 
a. Hypothesis- The rate of immune related events post radiation will be similar 
to that of the baseline rate receiving immunotherapy in the metastatic setting  
 
5. To determine the rate of distant metastases 
a. Hypothesis- based on limited data from previous studies the expected rate of 
distant metastases is approximately 33% 
 
3.3 
Exploratory Objective  
1. To determine the relative changes in levels of key immune cells including CD8+ T 
cells, CD4+ Tcells, Tregs, and FOXP3+ cells following radiation with or without 
systemic therapy and immunotherapy 
2. To determine the baseline values and changes in PD-L1 expression in HPV(-) and 
HPV(+) tumors 
3. To determine changes in PD-L1 expression in patients who received radiation alone, 
versus radiosensitizer based radiation  
4. Rate of distant metastases 
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5. To examine PD-1/PD-L1 expression, tumor infiltrating lymphocytes, and other 
immune markers in responders to pembrolizumab, to define an immune signature 
predictive of post radiation response to the drug. 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors .  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
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, 
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whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
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 
Background 
Head and neck squamous cell carcinoma (HNSCC) represents the 5th most common cancer 
worldwide.  In the United States there are approximately 46,000 new diagnoses of head and 
neck squamous cell carcinoma and 8600 deaths from this cancer each year.  Several 
randomized studies have established chemoradiation (CRT) as the definitive treatment 
approach for locally advanced head and neck squamous cell carcinomas (HNSCC)1-5. The CRT 
approach took hold largely because it became evident this approach could lead to organ and 
functional preservation6.  While this was a major oncologic advance, it also presented a new 
problem, namely ensuring that patients had complete resolution of their disease in patients 
being treated with non-operative therapy. Early identification of patients that are non-
responders or only partial responders to therapy is critical, as only a minority of patients who 
recur can receive curative intent salvage surgery7. 
Prolonged time to complete response to initial therapy 
Unfortunately, clinical responses to therapy may be delayed.  In the Princess Margaret Hospital 
experience of 493 patients undergoing definitive chemoradiation for head and neck SCC, 
approximately 50% had less than a complete response to chemoradiation therapy at 8-12 week 
post therapy assessment8.  An additional 33% achieved CR between weeks 12 and 24.  Of 
patients taken to neck dissection with less than a complete response (CR), the rate of positive 
residual tumor cells within the neck was 35%. This is substantially higher than the rate of 
positive residual cells at neck dissection in patients who achieve a CR to initial therapy, which 
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was 9%.  Thus, it is estimated that approximately 10% of patients that would likely have had 
pathologic residual disease at the 8-12 week assessment will achieve pathologic CR by 24 
weeks without any further intervention.  This estimate is given by  
the percentage of patients achieving a CR between weeks 12 and 24 x (the rate of pathologic  
positivity in non-CR patients – the rate of pathologic positivity in CR patients) 
= 33% x (35%- 9%) = 8.7%, or approximately 10%. 
While the possibility of delayed complete response must be kept in mind, this is dwarfed by 
the proportion of patients with pathologic evidence of residual disease after completion of 
therapy, which in unselected analyses can be as high as 35%8-12. This number is expected to 
be higher in selected subgroups of patients with HPV(-) disease, locally advanced primary 
tumors (T3-T4), or advanced nodal disease (N2c-N3) 8, 13 
Outcomes in patients with residual disease  
The presence of residual disease following definitive radiation/chemoradiation is an 
established prognostic marker for worsened disease specific survival in HNSCC patients14.  In 
a 65 patient experience from Fox Chase Cancer Center, 43% of patients undergoing planned 
neck dissection for initial N2-N3 neck disease following chemoradiation were found to have 
persistent disease. This was associated with worsened locoregional control, recurrence free and 
overall survival15.  The 3-year recurrence free survival rate in patients with positive residual 
neck disease was 37% in comparison to 85% in patients with no evidence of residual cells (p 
= 0.002). In a separate series of 35 patients with oropharyngeal carcinoma with clinical or 
radiographic evidence of residual neck disease, viable cancer cells were found in 68% of 
specimens.  Of these, despite undergoing surgical resection of all known disease, 42% 
developed local recurrences, 29% developed regional recurrences and 25% failed distantly.  
Overall the 5-year disease specific survival was nearly 100% in patients without residual 
disease, but only 55% in patients with viable tumor cells14.  A study from MSKCC looking at 
56 patients who had neck dissections following chemoradiation demonstrated that 33% had 
viable tumor in their neck dissection specimens, and the 5-year overall survival (OS), disease 
specific survival (DSS), and relapse free survival (RFS) were worse in patients with viable 
tumor in their specimens (OS 49% vs. 93%, p = 0.0005; DSS 56% vs. 93%, p = 0.003; RFS 
30% vs.75% p = 0.004)16.  In patients with residual tumor cells, 63% developed recurrence, 
with 26% recurring locally, 19% recurring regionally, and 42% recurring distantly. Taken 
together, the results suggest that even in patients successfully salvaged with surgery, patients 
with viable tumor cells following radiation still have a worsened prognosis and are at high risk 
for local, regional, and distant failure suggesting alternative strategies for escalating therapy 
are needed.  
Rationale for immunotherapy 
Curative therapy for head and neck cancer has historically depended on surgery and/or 
radiation, and for patients with persistent or recurrent disease following initial curative therapy, 
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systemic therapy with DNA damaging agents, taxanes and EGFR inhibition, has had only a 
modest impact on survival. The identification of immune checkpoints as a potential target for 
anticancer therapy, with the possibility of sustained responses once T cell exhaustion is 
reversed, is thus of enormous interest in the field of head and neck cancer. As will be detailed 
below, the immune checkpoint ligand PD-L1 is expressed in head and neck cancer, and the 
PD-1 inhibitor pembrolizumab leads to monotherapy responses in both HPV-associated and 
HPV-negative head and neck cancer. The response rate initially reported in patients whose 
tumors express any PD-L1, defined as at least 1% of cells staining with a proprietary antibody 
to PD-L1, is approximately 20%; enrichment for patients with 50% or more of cells staining 
for PD-L1 is predictive of a higher response rate17 (Jonathan Cheng, MD email 
communication, June 2014). Thus, strategies which induce inflammation with immune 
exhaustion, and which are associated with a higher degree of PD-L1 staining or greater tumor 
infiltration by lymphocytes, may be useful in increasing the proportion of patients who will be 
responsive to this promising class of agents. We propose evaluation of pembrolizumab in 
patients who have recently completed radiation with or without systemic therapy for locally 
advanced head and neck cancer as a population in whom tumor infiltration by lymphocytes 
and immune exhaustion with high expression of PD-L1 are likely to create a unique 
opportunity for enhanced response to immune checkpoint inhibition with pembrolizumab.  
One novel strategy to deal with residual disease following RT/CRT is immunotherapy.  Of 
particular interest is the PD-1/PD-L1 pathway, which is a negative regulator of immune 
response, and is the primary method of tumor immune evasion.  PD-L1 is expressed on T-cells, 
B-cells, macrophages, dendritic cells and solid tumors, and is inducible by cytokines.  PD-L1 
activates PD-1 on T-cells, which down regulates T-cell effector function allowing cancer cells 
to evade immune surveillance. 
PD1/PDL-1 in head and neck cancer 
PD-L1 expression in human HNSCC tissue samples is reported in 46.4-100% of cases, 
although the definition of staining necessary to be considered positive varies from study to 
study.  Ranges of PD-L1 expression are 49.2-70% in HPV (+) tumors and 29-40% in HPV   (-
) tumors, with a trend towards increased expression in HPV (+) tumors18.  That targeting this 
pathway is of clinical benefit was demonstrated in a phase 1B study of pembrolizumab, an 
anti-PD-1 antibody. In patients with recurrent or metastatic HNSCC, pembrolizumab 
demonstrated a 20% response rate in heavily pretreated patients17.  Depending on the level of 
PD-L1 expression chosen as a cutoff, however, the response rate could be as high as 45.5%.   
Given that the response to anti PD-1 therapy appears related to levels of PD-L1 expression, 
and the fact that PD-L1 is inducible, the potential impact of radiation therapy on PD-L1 
expression is of considerable interest.  A study of TUBO tumors treated with 12 Gy of radiation 
and examined three days later demonstrated an increase in expression of PD-L1 on dendritic 
cells and tumor cells, compared with controls19.   This is in keeping with other well-
documented effects of radiation on the immune system.  Radiation leads to enhanced T-cell 
infiltration in the tumor microenvironment, promotes T-cell cytokine production and 
cytotoxicity, and increases the expression of tumor antigens, thereby improving tumor cell 
antigenicity20.  
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Also enticing is the potential for a synergistic effect between immunotherapy and radiation.  In 
a preclinical mouse glioma cell line, the combination of radiation therapy and PD-L1 blockade 
led to a near doubling of survival in comparison to either a PD-L1 alone arm, or a radiation 
alone arm21.  In addition, the combined treatment group demonstrated an increase in CD8 
effector T-cells (CD8/IFN- γ/TNF- α) and a decreased number of regulatory T-cells (Tregs, 
CD4/FOXP3+) compared to controls.  Moreover, to test for long-term immunity, untreated, 
and “cured” mice were challenged with flank injection of GL261-luc tumor cells. All naïve 
mice developed tumors by 21 days after injection, whereas none of the “cure” mice developed 
tumors within 60 days of implantation, suggesting this approach leads to prolonged protective 
T-cell immunity.   
Given the poor outcomes of patients with residual disease following CRT, the high levels of 
PD-L1 expression in HNSCC, the evidence of clinical response to PD-1 inhibitors in metastatic 
and recurrent HNSCC, and the upregulation of PD-L1 following irradiation in mice, the use of 
CRT as a potential priming agent for immunotherapy is promising.  Thus, the purpose of this 
study is to determine whether radiation with or without systemic therapy can upregulate PD-
L1 expression, thus optimizing patients with residual disease for anti-PD-1 therapy. 
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 MK-3475.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity.  Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
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remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The proposed strategy of pembrolizumab in this poor prognosis group of patients with residual 
disease will be deemed a strategy worthy of further investigation if the overall response rate 
could be increased to 27%.   
4.2.3.2 Biomarker Research 
The phase I dose escalation study of pembrolizumab in patients with metastatic and previously 
treated HNSCC demonstrated that response was noted in 20% of patients overall, although in 
patients with higher levels of PD-L1 expression, this number could be as high as 45.5%17.  
Overall the percentage staining positive for PD-L1 for HNSCC as a group was 78%.  The 
expression of PD-L1 has also been correlated with the extent of tumor lymphocytic infiltrate.  
The latter has been observed to be increased after radiation therapy, suggesting one possible 
mechanism for an improved systemic response after radiation. We propose here to treat 
HNSCC patients without regard to PD-L1 expression on biopsies done just prior to initiation 
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of pembrolizumab. Tissue specimens will be obtained after pembrolizumab treatment and local 
response will be correlated to expression. 
Studies conducted by Dr. Lieping Chen’s group, that characterized the PD-L1/PD-1 axis a 
number of years ago, suggest that presence of CD4 and CD8 positive cells in tumor deposits 
is important for response to PD-1 targeting therapies22.  These investigators found that the 
majority of PD-L1 positive tumors were associated with CD4 and CD8 tumor infiltrating 
lymphocytes (TILs), while the minority of the PD-L1 negative tumors had associated TILs.  
Studies have demonstrated that 33-47% of HSNCC show a T-cell inflamed phenotype  (TCIP) 
similar to melanoma, and this phenotype may in turn identify a subgroup particularly sensitive 
to immunotherapy23.  Moreover, a strong correlation exists between the T-cell inflamed 
phenotype and the mesenchymal intrinsic subtype of HNSCC in both HPV(+) and HPV (-) 
disease, which has been shown to be associated with improved overall survival24. 
An additional potential biomarker of tumor response is cell-free tumor-derived circulating 
DNA (ctDNA).  The laboratory of Abhi Patel has developed an ultrasensitive assay for 
measuring small amounts of cell-free mutant DNA released into the blood from dying tumor 
cells25.  The assay covers a broad panel of mutations and uses novel error suppression 
techniques applied to next-generation sequencing data to enable identification of rare mutant 
DNA down to a fractional abundance of ~0.02%.  Because such ctDNA is highly tumor-
specific and is rapidly cleared from the bloodstream, it is showing excellent promise as a 
quantitative cancer biomarker.  Indeed, we (and others) have observed decreases in ctDNA 
levels following treatment with surgery, radiation therapy, and systemic therapy (sometimes 
with an initial spike from tumor kill).  Thus, we hypothesize that quantitative changes in 
ctDNA may provide information that is complementary to radiologic studies for tracking the 
efficacy of treatment with the PD-1 inhibitor pembrolizumab in patients with HNSCC.    
5.0 METHODOLOGY 
5.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have biopsy-proven residual disease. Measurable disease per RECIST 1.1 is not 
required.  All measurements should be recorded in order to evaluate response.. 
4. Be willing to provide tissue from a newly obtained core biopsy of a tumor lesion.  
Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to 
initiation of treatment on Day 1 and following completion of RT/CRT.  Tissue from fine 
needle aspirations (FNA) may be used if sufficient tissue is available. 
5. Have a performance status of 0 or 1 or 2 on the ECOG Performance Scale. 
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6. Demonstrate adequate organ function as defined in Table 1 Labs value need to be 
assessed within 14 days of study treatment.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  
Albumin 
>2.5 g/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
7. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
8. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
9. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
10. Patients must have a history of Stage I-IVB SCC of the head and neck arising from the 
oral cavity, oropharynx, nasopharynx, larynx, or hypopharynx and must have been 
treated with definitive intent radiation (with or without systemic therapy) 
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11. Patients must be at least 6 weeks (42 days) and no more than 24 weeks (168 days) from 
completion of radiation with or without systemic therapy at the time of the biopsy 
confirming residual disease.  Patients must receive the first dose of study medication 
no more than 28 weeks following completion of radiation. 
12. Patients must have pathological evidence of persistent lymph node disease or persistent 
disease at the primary tumor site with viable tumor cells confirmed by a biopsy within 
24 weeks of study treatment and no evidence of metastatic disease following primary 
radiation with or without systemic therapy confirmed by a CT scan within 4 weeks of 
study treatment. If a biopsy confirming residual disease has not been performed, this 
can be performed after obtaining consent, during the screening procedures.  
13. Persistent lymph node disease with viable tumor cells will be determined by the 
histological determination of tumor viability.  
14. All persistent disease must have received at least 66 Gy in 1.8-2Gy fractions of 
radiotherapy to the area of residual disease (or a biologically equivalent dose given by 
the linear quadratic equation: biologically equivalent dose (BED) = nd (1 + d/( α/β), 
where n is the number of fractions, d dose per fraction and the α/β ratio for tumor is 
10. Previous radiation records will be obtained to confirm adequate dosing. 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving supraphysiologic doses of 
systemic steroid therapy or any other form of immunosuppressive therapy within 7 days 
prior to the first dose of trial treatment.  A physiologic dose of steroids is defined as up 
to 10mg of prednisone daily (or its equivalent).  
 
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from acute, non-
hematological adverse events due to agents administered more than 4 weeks earlier 
unless otherwise approved by the Principal Investigator. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy, any grade dysphagia, ≤ Grade 2 
pain, ≤ Grade 2 weight loss, any grade hyperpigmentation of skin, any grade 
fatigue, any grade xerostomia, and any grade dysgeusia, are an exception to this 
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criterion and may qualify for the study. Also please note that the presence of a 
feeding tube to aid with nutrition does not disqualify patients from study.    
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to the first protocol treatment or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from acute, non-hematological adverse events due to a 
previously administered agent unless otherwise approved by the Principal Investigator. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy, any grade dysphagia, ≤ Grade 2 
pain, ≤ Grade 2 weight loss, any grade hyperpigmentation of skin, any grade 
fatigue, any grade xerostomia, and any grade dysgeusia, are an exception to this 
criterion and may qualify for the study. Also please note that the presence of a 
feeding tube to aid with nutrition does not disqualify patients from study.    
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
10. Has known history of non-infectious pneumonitis that required steroids, or current 
pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
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the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of the first protocol treatment. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
19. Any patient receiving adjuvant systemic therapy following the completion of radiation 
therapy is ineligible. 
20. Any patient with evidence of distant metastatic disease on a CT within 4 weeks of 
treatment is ineligible. 
21. Evidence of interstitial lung disease. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg  
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
 
 
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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 preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 5.6.1 
for supportive care guidelines, including use of corticosteroids. 
Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure.  
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons  
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. Dosing may be interrupted for 
up to 6 weeks at the end of cycle 4 as protocol required assessments to determine treatment 
continuation are performed. 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
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5.3 
Treatment Allocation  
Patients with Stage I-IVB HNSCC of the larynx, hypopharynx, oropharynx, nasopharynx, or 
oral cavity) who have been treated with curative intent radiation, chemoradiation, or cetuximab 
and radiation within 6-24 weeks and have biopsy proven residual disease will be eligible for 
enrollment.   
All patients upon biopsy confirmation of residual disease will have restaging scans (CT 
neck/chest/abdomen/pelvis).  Patients will require evaluation by an ENT to determine whether 
their disease is considered resectable or unresectable.  Patients will then receive 
pembrolizumab at a dose of 200mg Q3 weeks for 4 cycles.  A CT scan of the 
neck/chest/abdomen/pelvis will be performed at the end of cycle 2 to check for progression of 
disease (irPD), defined using immune related response criteria. Patients with progression prior 
to four cycles of pembrolizumab will discontinue study therapy.  
After four cycles patients will undergo repeat CT neck/chest/abdomen/pelvis and a biopsy.  
Patients will then be re-evaluated by otolaryngology to determine the current status of their 
local/locoregional disease and to determine whether it is technically resectable.  At this time 
patients that are deemed resectable can go on to surgical resection, and those deemed 
unresectable or who refuse resection can continue on pembrolizumab until evidence of 
progression or for up to 1 year. These patients will not be evaluable for the study endpoints, 
although their response rates and overall survival will be reported.  An early stopping rule 
exists, such that during enrollment of the first 10 patients considered resectable, at screening 
if 3 or more become unresectable during the study the trial will close.  The plan is to enroll 24 
patients.   
5.4 
Stratification 
Since this is a single arm Phase II study, enrollment will not be stratified.   
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 Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
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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 6.3. 
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: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
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measures may include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance detailed in Section 6.3.3.2, but does not need 
to follow the treatment guidance. Refer to Section 5.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
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 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with oral corticosteroids. 
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o For Grade 3-4 events, treat with systemic (intravenous) corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 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 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), 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 medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 6.3.2-Reporting of Pregnancy 
and Lactation to the Sponsor and to Merck.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
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outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 6.3.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 6– Other Procedures. 
A subject must be discontinued from the trial treatment for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
• 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 12 months of uninterrupted treatment with pembrolizumab or 17 
administrations of study medication, whichever is later. 
• Note: 12 months of study medication is calculated from the date of first dose. 
Administrative reasons 
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The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section .6.2.5 (Visit Requirements).   
From the administration of first treatment until 30 days (unless otherwise specified) subsequent 
to last treatment or withdrawal of subject, new onset adverse events will be captured. Follow-
up and reporting of these events will follow the same procedure as for AEs observed during 
the study period. Serious Adverse Events will be collected for 90 days after the end of treatment 
as described in Section 6.3. In addition, any unexpected SAE that occurs more than 90 days 
after drug administration but is possibly, probably or definitely attributed to drug 
administration will be recorded and reported.  
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.8.1 Discontinuation of Study Therapy after CR  
Among patients who are not at the conclusion of 4 cycles of pembrolizumab candidates for 
surgery, or for those who refuse surgery at that time point, pembrolizumab will be continued 
for one year.  Discontinuation of pembrolizumab in this cohort may be considered for subjects 
who subsequently attain a confirmed CR and have been treated for at least 24 weeks with 
pembrolizumab and had at least two treatments with pembrolizumab beyond the date when the 
initial CR was declared.   
5.9 
Subject Replacement Strategy 
Patients will be replaced if they do not receive at least one cycle of pembrolizumab. 
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 
5. An early stopping rule will be put into place such that if at any time during enrollment of 
the first 10 patients considered initially resectable at screening, if 3 or more of these patients 
have local progression on the study treatment and are then deemed locally unresectable the 
trial will close early.  
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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.
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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Study Treatment Cycles 
Continuation Treatment 
Cycles 
End of Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
4D21 
To be repeated beyond 8 cycles 
Discon 
Safety 
Follow-up 
Follow 
Up Visits 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
±7 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
± 3 
30 days 
post 
discon1 
± 7 
Every 8 
weeks 
post 
discon 
± 7 
Every 12 
weeks   
± 7 
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Pembrolizumab Administration 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ENT evaluation for resectability status 
X 
 
 
 
 
X14 
 
 
 
 
X14 
 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X1 
X13 
X13 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Vital Signs and Weight2 
X 
X3 
X3 
X3 
X3 
 
X3 
X3 
X3 
X3 
X 
 
X 
 
ECOG Performance Status 
X 
X4 
X4 
X4 
X4 
 
X4 
X4 
X4 
X4 
X 
 
X 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X5 
X 
X6 
X6 
X6 
 
X6 
X6 
X6 
X6 
X 
 
 
 
Comprehensive Serum Chemistry Panel, 
Magnesium, Phosphorous, LDH, LFTs 
X5 
X 
X6 
X6 
X6 
 
X6 
X6 
X6 
X6 
X 
 
 
 
Urinalysis 
X5 
 
X6 
 
X6 
 
 
X6 
 
X6 
 
 
 
 
T3, FT4 and TSH 
X5 
 
X6 
 
X6 
 
 
X6 
 
X6 
 
 
 
 

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Trial Period: 
Screening 
Phase 
Study Treatment Cycles 
Continuation Treatment 
Cycles 
End of Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
4D21 
To be repeated beyond 8 cycles 
Discon 
Safety 
Follow-up 
Follow 
Up Visits 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
±7 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
± 3 
30 days 
post 
discon1 
± 7 
Every 8 
weeks 
post 
discon 
± 7 
Every 12 
weeks   
± 7 
 
Efficacy Measurement 
CT neck/chest/abdomen/pelvis 
X7 
 
X11 
 
X11 
 
 
X11 
 
X11 
 
 
X12 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival Tissue Collection 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
Newly Obtained Tissue Collection 
X9 
 
 
 
 
X10 
 
 
 
 
X10 
 
 
 
Correlative Studies Blood Collection 
X 
 
 
 
 
X 
 
 
 
 
X15 
 
 
 
1. In the case that a patient initiates a subsequent anti-cancer therapy the 30 day follow up should occur prior to the first dose of the new therapy and patients will move to survival follow up.   
2. Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only.   
3. Vital signs will be taken prior to the administration of each dose of trial treatment and at discontinuation of each treatment.  
4. ECOG status will be evaluated prior to the administration of each dose of trial treatment and at discontinuation of each treatment.  
5. Screening lab will be assessed within 14 days of first treatment. 
6. After cycle 1, pre-treatment labs can be drawn up to 72 hours pre-dose.   
7. The baseline CT scan can be from before study enrollment as long as the scan is within 4 weeks of study treatment.  
8. Archival tissue from a biopsy prior to radiation treatment with or without systemic therapy should be requested.   
9. All patients will have a biopsy prior to the start of study treatment. This specimen may be obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1 and following completion of RT/CRT. 
This pre-treatment biopsy can be used to confirm residual disease.  
10. Patients will have a research biopsy after completion of the 4th treatment cycle or at study discontinuation if they come off treatment before cycle 4.  There will be no additional biopsy for patients who 
stay on treatment past 4 cycles.  
11. Imaging during study treatment cycles will occur at the end of cycle 2 when clinically indicated and cycle 4 or at disease progression whichever comes first (required). Less frequent imaging is acceptable 
during the continuation cycles, although a minimum of every 8 weeks is recommended. 
12. If a patient comes off trial for reasons other than disease progression imaging should be done every 9 weeks ±7 days  
13. Information on SAEs will be collected for 90 days after the end of treatment. Any unexpected SAE that occurs more than 90 days after drug administration but is possibly, probably or definitely 
attributed to drug administration will be recorded and reported. 
14. Patients will have a repeat ENT evaluation for resectability status after completion of the 4th treatment cycle or at study discontinuation if they come off treatment before cycle 4.  There will be no 
additional ENT evaluation for patients who stay on treatment past 4 cycles 
15.  Correlative blood collection will occur at end of cycle 4 as well as at discontinuation, unless discontinuation within past 21 days. 

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6.2 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
6.2.1 Patient Registration Process 
Prior to obtaining signed consent from a patient, the site principal investigator or coordinator 
must email the project manager to inquire about study space availability. If a slot is available, 
the Project Manager will provide a study ID and the potential study participant will complete 
the consent process.  The informed consent process must be completed before any study 
screening procedures may begin.  Following consent, patients will have all required screening 
procedures outlined in Section 6. The site principal investigator or other approved investigator 
must document that the patient has met all inclusion criteria and has none of the exclusion 
criteria. Following completion of eligibility testing, eligibility documents will be sent to the 
project manager. Examples of required documents are listed in the manual of operations.  
Upon review and approval of the Project Manager an email  will be sent s to the site with 
confirmation of eligibility. 
   
6.2.2 Administrative Procedures 
6.2.2.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
6.2.2.2 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 consent process must be documented and available for review in the patients 
research chart. 
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 
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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.  This can 
occur via written documentation (a formal letter), in person conversation or a phone call prior 
to an amended consent document becoming available. Regardless of the method the procedure 
must be documented and kept in the research file. As soon as possible 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 and will be provided to sites by the sponsor.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
6.2.2.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the local investigator.  All patients will 
be registered to this trial locally by the project manager.  See Patient Registration (section 
6.2.1) for more information.  
6.2.2.4 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.   
6.2.2.5 Prior and Concomitant Medications Review 
6.2.2.5.1 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.  
6.2.2.5.2 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 6.3. 
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6.2.2.6 Disease Details and Treatments 
6.2.2.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
6.2.2.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
6.2.2.6.3 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 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
6.2.2.7 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 10.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs).   
Please refer to section 6.3 for detailed information regarding the assessment and recording of 
AEs.   
6.2.2.8 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,  
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6.2.2.9 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
6.2.2.10 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
6.2.2.11 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 10.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
6.2.2.12 Tumor Imaging and Assessment of Disease 
CT neck, chest, abdomen and pelvis will be ordered at baseline and during the 3rd week of 
cycles 2, if clinically indicated,cycle 4 or at time of progression whichever comes first.  
Additional re-imaging may be obtained at the discretion of the investigator. For patients who 
are not amenable to resection following 4 cycles of therapy and who continue on 
pembrolizumab, a q8 week CT of the neck, chest, abdomen and pelvis will be obtained.   
6.2.2.12.1 Measurement of Response  
Following pembrolizumab, response will be measured in comparison to the most immediate 
pre-pembrolizumab imaging study. For complete definitions of measurable and non-
measurable disease, please refer to the RECIST v1.1 criteria.  
1. For lesions that meet the criteria for measureable disease outlined in RECIST 1.1, the 
standard RECIST response criteria will apply  
RECIST response criteria: 
Complete response: Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.   
Partial response: At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive disease:At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
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demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
2. The following 2 criteria for evaluation of clinical response will apply for lesions considered 
too small for measurement by RECIST 1.1 (for example nodes with short axis < 1.5cm or 
primary lesions or skin lesions < 1cm). 
The lesion would have to shrink to < 1cm in all three dimensions and also have at least 
a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.  
AND 
 
 One of the following two criteria are true: 
 
1) Either the biopsy performed after pembrolizumab shows no active cancer  
 
OR 
 
2) The patient has a PET scan after pembrolizumab which demonstrates that a 
previously active lesion (SUV >/= 3.0 is now PET negative (SUV < 3.0)). 
 
In the case where both PET and biopsy are both performed, and the results are disparate, the 
biopsy results will take precedence.  For example a positive biopsy in this situation would 
connote a designation of response as a PR, and a negative biopsy would connote a response as 
a CR.   
Response will be evaluated by imaging studies as described in the study calendar. If symptoms 
develop or clinical deterioration occurs, patients may be imaged prior to the pre-specified time 
points for imaging.  
6.2.2.12.2 Evaluation of Best Overall Response  
The Best Overall Response is the best response recorded from the start of the treatment until 
completion of four cycles of study drug (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). For purpose of the primary 
endpoint of the study, the overall response will be measured during the post pembrolizumab, 
in comparison to the most immediate pre-pembrolizumab imaging. 
6.2.2.12.3 Progression-Free and Overall Survival 
For the purpose of the secondary endpoints of this study, PFS is defined as the time from 
initiation of study drug until the first documented, confirmed progression of disease.  PFS will 
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also be measured and reported from the initiation of study drug.  OS will be measure from the 
initiation of study therapy. 
6.2.2.13 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Before and during trial therapy, if a lesion is biopsied or for clinical purposes, a sample will be 
retained for protocol-related correlative studies. If a patient has had a previous biopsy, the pre-
treatment sample may be taken from paraffin-embedded tissue.  
6.2.2.13.1  Study-Related Biopsies and Tissue Collection 
Tissue from fresh tissue (see below) is required at study entry.  Fresh tumor biopsy is required 
one time after pembrolizumab.  These requirements may be waived by the principal 
investigator. 
 
Tumor tissue will be obtained prior to initiation of study therapy from any primary or 
locoregional disease site and processed according to the specifications of the lab manual.  
When a biopsy is being done for standard-of-care clinical purpose, tissue will be obtained from 
this procedure if available.  Otherwise a study-related biopsy will be done.   
 
If the patient undergoes a biopsy at any point during protocol therapy for clinical purpose, extra 
tumor tissue will be collected for study purposes if available. 
 
6.2.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table  5.
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  Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (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.   
‡ If considered standard of care in your region. 
 
 
 

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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.  
6.2.3.1 Blood Collection for Serum Pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in the 
Laboratory Manual. 
6.2.3.2 Blood Collection for Anti-Pembrolizumab Antibodies  
Sample collection, storage and shipment instructions for blood samples will be provided in the 
Laboratory Manual. 
6.2.4 Other Procedures 
6.2.4.1 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 6.3 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 12 months of treatment with 
pembrolizumab may discontinue treatment After discontinuing treatment following 
assessment of CR, these subjects should return to the site for a Safety Follow-up Visit 
(described in Section 6.2.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 6.2.5.3.2). 
6.2.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 6.2 - Trial Procedures. 
6.2.5.1 Screening Period 
Prior to initiation of study therapy, the patient will require a screening visit.  Scans, and 
evaluations should be done as close to the initiation of therapy as feasible, and no more than 
28 days prior.  Laboratory studies should be completed within 14 days of initiation of therapy. 
In some cases labs will need to be repeated if screening lasts longer than 14 days.  The 
following should be addressed at the screening visit: 
1. 
Informed Consent 
2. 
Medical History 
3. 
Complete 
physical 
examination, 
vital 
signs, 
and 
measurement of height and weight 
4. 
Review of prior and concomitant medications 
5. 
CT scan of chest, abdomen and pelvis 
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6. 
ECOG Performance status evaluation 
7. 
Determination of baseline adverse event status 
8. 
Pregnancy test for women of childbearing potential, and 
counseling that sexually active women of childbearing 
potential must use an effective form of birth control during 
the entire study period 
9. 
Determination of sufficient tumor specimen for evaluation 
of PD-L1 status 
10. 
Laboratory 
studies: 
CBC 
with 
differential, 
serum 
chemistries, liver function tests, LDH, TSH, T3 and Free T4, 
PT/INR and PTT, uranalysis 
11. 
Collection of blood, fresh (within 6 weeks) tissue and 
archival tissue for correlative studies 
12. 
Evaluation by an ENT 
 
6.2.5.2 Treatment Period 
On-study visits will occur on day 1 of each cycle of MK-3475, and will include the following 
at every visit: 
 
1. 
Directed physical examination, vital signs, and measurement 
of weight 
2. 
Review of concomitant medications 
3. 
Performance status evaluation 
4. 
Determination adverse events 
5. 
Laboratory studies:  CBC with differential, serum 
chemistries, liver function tests, LDH 
6. 
TSH and Free T4 will be done every other cycle starting with  
Cycle 2 
7. 
CT scans of chest, abdomen and pelvis will be done at the 
end of cycles 2 if clinically indicated and end of cycle 4.   
8. 
Collection of blood at the end of cycle 4 for correlative 
studies. Collection of and fresh tissue at the end of cycle 4 
or at discontinuation if earlier 
9. 
Evaluation by an ENT at the end of cycle 4 or at 
discontinuation if earlier 
 
 
 
 
 
 
 
After clinically evident progression or if the patient is discontinuing treatment for any reason 
the patient will be seen for a study visit, at which the following will be addressed: 
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1. 
Directed physical examination, vital signs, and measurement 
of weight 
2. 
Review of concomitant medications 
3. 
Performance status evaluation 
4. 
Determination adverse events 
5. 
Collection of blood for correlative studies, unless end of 
cycle 4 collection within 21 days. Collection of fresh tissue 
for correlative studies if not already taken at end of cycle 4 
as described above. 
6. 
Evaluation by an ENT 
7. 
CT scans of chest, abdomen and pelvis if not already taken 
at end of cycle 4 
 
Fresh tumor specimens will be obtained if feasible during therapy if the patient undergoes 
resection or biopsy for a standard-of-care clinical purpose per the study flow chart. 
 
6.2.5.3 Post-Treatment Visits 
6.2.5.3.1 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.  Any unexpected SAE that occurs more than 90 days after drug 
administration but is possibly, probably or definitely attributed to drug administration will be 
recorded and reported. 
6.2.5.3.2 Follow-up Visits 
At each follow up visit patients will have a directed physical exam, including ECOG 
performance status, vital signs and weight.  A comment will also be made regarding the post-
study anticancer status. 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 (± 7 
days) with imaging done every 9 weeks (± 7 days). Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, or end of the study Information regarding post-study anti-neoplastic 
treatment will be collected if new treatment is initiated. 
6.2.5.3.3 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 
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every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  
6.3 
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 a clinically significant abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product or protocol-specified procedure, whether or not considered related to the medicinal 
product or protocol-specified procedure.  Any worsening (i.e., any clinically significant 
adverse change in frequency and/or intensity) of a preexisting condition that is temporally 
associated with the use of the Merck’s product, is also an adverse event. 
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. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
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. Adverse events will be recorded on 
an Adverse Event log and entered in OnCore within 72 hours of the site becoming aware of 
the event.. The reporting timeframe for adverse events meeting any serious criteria is described 
in section 6.3.3.1. 
6.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
 
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If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the project manager.  The project manager will report all overdoses within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). Sites are 
responsible for reporting to their IRB per local policy.   
6.3.2 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 project manager.  The project manager 
will report these events within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220). Sites are responsible for reporting to their IRB per local 
policy.   
6.3.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
6.3.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
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• Is an other important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
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 Merck product, and any 
unexpected Serious Adverse Event that occurs more than 90 days after drug administration but 
is possibly, probably or definitely attributed to drug administration, must be reported within 
24 hours to the Yale project manager and protocol PI.   The Yale project manager will report 
within 2 working days to Merck Global Safety.  Sites are responsible for reporting to their IRB 
per local policy.   
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 Merck product 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 Yale project manager who will then report to Merck. .All SAEs should be 
entered into OnCore within 24 hours of the site becoming aware of the event.  
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 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. 
6.3.3.2 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 project manager and protocol PI. The  project manager will 
report within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 993-1220). 
Events of clinical interest for this trial include: 
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1.  an overdose of Merck product, as defined in Section 6.3.1 - 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). 
 
ECIs (both non-serious and serious adverse events) identified above from the date of first 
dose through 90 days following cessation of treatment, or 30 days after the initiation of a 
new anticancer therapy, whichever is earlier, need to be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220), regardless of attribution to study treatment, consistent with 
standard SAE reporting guidelines.  
 
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. 
6.3.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [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 
 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was 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.) 

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6.3.5 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.  
7.0 STATISTICAL ANALYSIS PLAN 
7.1 
Statistical Analysis Plan Summary 
The primary objective of this phase II study is to determine the overall response rate in patients 
with squamous cell carcinoma of the head and neck who have residual disease following 
definitive radiation with or without systemic therapy. This will be a single arm study of 24 
patients with Stage I-IVB HNSCC who have residual disease after being treated with definitive 
radiation with or without systemic therapy.  
The expected rate of resolution of disease without any further therapy is thought to be 
approximately 10%. This is derived from the Princess Margaret Hospital experience of 493 
patients undergoing definitive chemoradiation for head and neck SCC, approximately 50% had 
less than a complete response to chemoradiation therapy at 8-12 week post therapy 
assessment26.  An additional 33% achieved CR between weeks 12 and 24.  Of patients taken 
to neck dissection with less than a complete response (CR) the rate of positive residual tumor 
cells within the neck was 35%. This is substantially higher than the rate of positive residual 
cells at neck dissection in patients who achieve a CR to initial therapy, which was 9%.  Thus 
it is estimated, that approximately 10% of patients that would likely have had pathologic 
residual disease at the 8-12 week assessment will achieve pathologic CR by 24 weeks without 
any further intervention.  This estimate is given by:  
the percentage of patients achieving a CR between weeks 12 and 24 x (the rate of pathologic 
positivity in non CR patients – the rate of pathologic positivity in CR patients) 
= 33% x (35%- 9%) = 8.7%, or approximately 10%.  
Thus, assuming a baseline response rate of 10% (based on the Princess Margaret experience 
discussed above) and an improvement in response rate to 27% after treatment of 
chemoradiation, we will have 81% power to detect this difference with 24 patients by exact 
one-sample binomial test at one-sided significance level of 0.10.  If 27% or more of patients 
in the study develop a partial or complete response to pembrolizumab, this strategy will be 
deemed worth of further investigation. 
The primary endpoint of this trial will be overall response rate and the secondary endpoint will 
be progression-free survival.  We will use descriptive statistics to calculate frequency and 
proportion for the response rate to pembrolizumab.  95% confidence interval will also be 
provided.  Exact binomial test will be used to compare the observed response rate versus 
historical control.  For the secondary endpoint, we will use Kaplan-Meier estimator to present 
the progression-free survival. 
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8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
8.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
8.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
8.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the 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. 
8.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
8.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
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Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
9.0 ADMINISTRATIVE AND REGULATORY DETAILS 
9.1 
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.     
9.2 
Quality Management System 
9.2.1 Safety Monitoring  
The Yale Cancer Center Data and Safety Monitoring Committee (DSMC) will provide the 
primary oversight of data and safety monitoring. The Yale DSMC will review and monitor 
compliance, toxicity and deviations from this study. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the 
Principal Investigator. 
The DSMC will review this protocol at a minimum of once every six months. Information to 
be provided to the committee includes: a study narrative by the PI, a summary DSMC report 
produced by OnCore (which includes participant accrual, response, trial status history, SAEs, 
Adverse Events, Deviations and survival); audit results, and monitoring reports as applicable. 
Other information (e.g. scans, laboratory values) will be provided upon request. 
9.2.2 Data Monitoring 
The study principal investigator and YCCI are responsible for monitoring the performance of 
all of the participating sites. This will be performed by conducting a study site initiation visit, 
as well as regularly scheduled monitoring visits and/or remote monitoring throughout the life 
of the protocol. At the end of the trial, the monitor will then perform a study site close-out visit 
at all participating sites.  
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YCCI will utilize their institution’s initiation, monitoring and close-out visit reports. Following 
each site visit, a visit report will be generated containing information on site activities, and a 
summary of pertinent points and action items together with a copy of the follow-up letter will 
be sent to each investigative site.  
During these monitoring visits, some of the items that will be reviewed are the following:  
• Training of the sites  
• Site personnel qualifications to participate in the trial  
• That study related documents are current  
• That regulatory compliance is accomplished  
• That each subject has signed the informed consent  
• That the current and approved protocol is complied with (including reporting and 
logging of all protocol deviations)  
• That all SAEs and AEs have been reported to the local regulatory and Ethics/IRB 
Committees, YCCI and Merck, as appropriate  
• That source documentation matches CRFs  
• That required procedures for study drug accountability, distribution, and storage are 
followed.  
YCCI will document the required study monitoring activities in a Study Monitoring Plan.  
9.2.3 Project Team Meetings 
Scheduled meetings will be held and will include the protocol investigators and research staff 
involved with the conduct of the protocol. 
 
During these meetings the investigators will discuss: 
• Safety of protocol participants (adverse events and reporting) 
• Validity and integrity of the data (data completeness on case report forms and complete 
source documentation) 
• Enrollment rate relative to expectation of target accrual, (eligible and ineligible 
participants). 
• Retention of participants, adherence to the protocol and protocol violations 
• Protocol amendments 
 
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9.2.4 Audit Plan 
The Yale Center for Clinical Investigation (YCCI) Office of Quality Assurance and Training 
will audit the trial at least annually or as determined by the YCC DSMC. The overall principal 
investigator, study coordinator and/or data manager may request access to all source 
documents and other study documentation for on-site or remote monitoring, audit or 
inspection. 
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the 
Principal Investigator or Yale. The purpose of these audits or inspections is to examine study-
related activities and documents to determine whether these activities were conducted and data 
were recorded, analyzed, and accurately reported in accordance with the protocol, institutional 
policy, and any applicable regulatory requirements. 
9.3 
Data Management 
The investigators are required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must 
be explained. OnCore will be the designated electronic data capture tool. All data should be 
entered onto OnCore within 2 weeks of each study visit.  AEs need to be entered within 72 
hours and SAEs need to the entered within 24 hours of the site becoming aware of the event.  
 
 
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10.0 APPENDICES 
10.1 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. 
 
10.2 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) 
10.3 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. 
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In addition, volumetric analysis will be explored by central review for response assessment. 
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