Phase II Investigation of Adjuvant Combined Cisplatin and Radiation With Pembrolizumab in Resected Head and Neck Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Head and Neck Cancer
Sponsor: Trisha Wise-Draper

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SPONSOR: Trisha Wise-Draper M.D., Ph.D., University of Cincinnati
TITLE: Phase II Investigation of Adjuvant Combined Cisplatin and 
Radiation with Pembrolizumab in Resected HNSCC
IND NUMBER: 127807
EudraCT NUMBER (Studies in Europe only): N/A
Sponsor-Investigator Signature
Date

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Protocol #: UCCI-HN-15-01
Title: Phase II Investigation of Adjuvant Combined Cisplatin and Radiation with 
Pembrolizumab in Resected HNSCC.
Coordinating Center: University of Cincinnati Cancer Center
Principal Investigator & Medical Oncologist Chair:
Trisha Wise-Draper, MD, PhD 
3125 Eden Ave
Cincinnati, OH 45267-0562
Telephone: 513-558-2826
Fax: 513-558-6703
wiseth@ucmail.uc.edu
Head and Neck Surgeon Chair
Medical Oncologist Co-Chair
Keith Casper MD, (UMich)
Maura Gillison, MD, PhD (MDA)
Radiation Oncology Chair
Michelle Mierzwa, MD (UMich)
Collaborating Centers:
The Ohio State University (OSU), Medical University of
South Carolina (MUSC), University of Louisville (UofL), 
University of Michigan (UMich), MD Anderson (MDA)
Principal Investigator (OSU):
Matthew Old, MD
Principal Investigator (MUSC):
Paul O’Brien, MD 
Principal Investigator (MD Anderson):
Maura Gillison, MD, PhD 
Principal Investigator (UofL):
Neal Dunlap, MD
Principal Investigator (UMich):
Frank Worden, MD
Laboratory Studies:
Laura Conforti, PhD 
University of Cincinnati
Edith Janssen, PhD 
CCHMC
Statistician:
J. Jack Lee 
MD Anderson
Roman Jandarov 
University of Cincinnati

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Pathologist:
Ben Hinrichs
University of Cincinnati
Protocol Version/ Version Date: Amendment 17, 18 March 2021
TABLE OF CONTENTS
Page
1. TRIAL SUMMARY........................................................................................................11
2. TRIAL DESIGN .............................................................................................................11
2.1
Trial Design .....................................................................................................11
2.2
Trial Diagram ..................................................................................................12

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3. OBJECTIVES AND HYPOTHESES ...................................................................................12
3.1
Primary Objectives and Hypotheses................................................................12
3.2
Secondary Objectives and Hypotheses............................................................13
3.3
Exploratory Objectives....................................................................................13
4. BACKGROUND AND RATIONALE .................................................................................14
4.1
Background…..................................................................................................14
4.1.1
Pharmaceutical and Therapeutic Background… .............................................14
4.1.2
Preclinical and Clinical Trial Data… .................................................................15
4.1.3
Adjuvant Treatment in Head and Neck Cancer…............................................15
4.2
Rationale ........................................................................................................16
4.2.1
Rationale for the Trial and Selected Patient Population.................................16
4.2.2
Rationale for Dose Selection/Regimen/Modification .....................................17
4.2.2.1 Pembrolizumab… ......................................................................................17
4.2.2.2 Cisplatin ....................................................................................................17
4.2.3
Rationale for Endpoints…................................................................................18
4.2.3.1 Safety Endpoints….....................................................................................18
4.2.3.2 Efficacy Endpoints.....................................................................................18
4.2.3.3 Biomarker Research..................................................................................19
5. METHODOLOGY .........................................................................................................20
5.1
Entry Criteria...................................................................................................20
5.1.1
Diagnosis/Condition for Entry into the Trial ...................................................20
5.1.2
Subject Inclusion Criteria ................................................................................20
5.1.3
Subject Exclusion Criteria................................................................................22
5.2
Trial Treatments..............................................................................................23

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5.2.1 Pretreatment Evaluations/Management...........................................................24
5.2.1.1 Required Evaluations/Management.........................................................24
5.2.1.2 Highly Recommended Evaluations/Management ....................................24
5.2.2 Dose Selection/Modifications............................................................................24
5.2.2.1 Dose Selection...........................................................................................24
5.2.2.2 Dose Administration .................................................................................25
5.2.2.2.1 Cisplatin Guidelines..........................................................................25
5.2.2.2.2 Pembrolizumab Guidelines ..............................................................25
5.2.2.2.3 Radiation Guidelines........................................................................25
5.2.2.2.3.1 Dose Specifications...................................................................25
5.2.2.2.3.2 Technical Factors......................................................................26
5.2.2.2.3.3 Localization, Simulation, and Immobilization...........................26
5.2.2.2.3.4 Target and Normal Tissue Volume Restrictions ........................26
5.2.2.2.3.5 Treatment Planning and Delivery Dose Prescription to PTVs....27
5.2.2.2.3.6 Dose Constraints to Normal Structures.....................................28
5.2.2.2.3.7 Compliance Criteria...................................................................29
5.2.2.2.3.8 Radiation Therapy Adverse Effects............................................29
5.2.2.3 Lead-in Population for Safety Analysis...........................................................29
5.2.2.3.1 Dose Limiting Toxicity ..................................................................29
5.2.2.4 Dose Modifications ...................................................................................30
5.2.2.4.1 Pembrolizumab................................................................................30
5.2.2.4.2 Cisplatin ...........................................................................................34
5.2.3 Timing of Dose Administration...........................................................................36
5.2.4 Surgery ...............................................................................................................37

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5.2.4.1 Surgery Quality Assurance Reviews..........................................................37
5.3
Stratification...................................................................................................37
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited) .....................37
5.4.1
Acceptable Concomitant Medications.............................................................38
5.4.2
Prohibited Concomitant Medications .............................................................38
5.5
Rescue Medication and Supportive Care .........................................................39
5.5.1 Supportive Care Guidelines..............................................................................39
5.5.1.1 Pembrolizumab.........................................................................................39
5.5.1.2 Cisplatin ....................................................................................................43
5.6
Diet/Activity/Other Considerations.................................................................43
5.6.1 Diet...................................................................................................................43
5.6.2 Contraception...................................................................................................43
5.6.3 Use in Pregnancy..............................................................................................43
5.6.4 Use in Nursing Women.....................................................................................43
5.7
Subject Withdrawal/Discontinuation Criteria..................................................43
5.8
Subject Replacement Strategy.........................................................................45
5.9
Clinical Criteria for Early Trial Termination ......................................................45
6. Trial Flow Chart ..........................................................................................................45
6.1
Study Flow Chart.............................................................................................45
7. Trial Procedures .........................................................................................................52
7.1
Trial Procedures ..............................................................................................52
7.1.1 Informed Consent...............................................................................................52
7.1.1.1 General Informed Consent........................................................................52

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7.1.1.2 Inclusion/Exclusion Criteria.......................................................................53
7.1.1.3 Medical History.........................................................................................53
7.1.1.4 Prior and Concomitant Medications Review.............................................53
7.1.1.4.1 Prior Medications ............................................................................53
7.1.1.4.2 Concomitant Medications ...............................................................53
7.1.1.5 Disease Details and Treatments................................................................53
7.1.1.5.1 Disease Details.................................................................................53
7.1.1.5.2 Prior Treatment Details ...................................................................53
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status .........................................53
7.1.1.6 Assignment of Screening Study Number...................................................54
7.1.1.7 Trial Compliance........................................................................................54
7.1.2 Clinical Procedures/Assessments ........................................................................54
7.1.2.1 Adverse Event (AE) Monitoring.................................................................54
7.1.2.2 Full Physical Exam .....................................................................................55
7.1.2.3 Directed Physical Exam .............................................................................55
7.1.2.4 Vital Signs..................................................................................................55
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale ...........55
7.1.2.6 Tumor Imaging and Assessment of Disease..............................................55
7.1.2.6.1 Initial Tumor Imaging.........................................................................55
7.1.2.6.2 Post-Treatment Assessment..............................................................55
7.1.2.6.3 Assessment of Disease ......................................................................55
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling............56
7.1.3 Laboratory Procedures/Assessments...................................................................57
7.1.3.1 Laboratory Safety Evaluations ..................................................................57

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7.1.3.2 Pharmacodynamic Evaluations .................................................................58
7.1.3.2.1 Peripheral Blood Monocyte Cell (PMBC) Isolation ...........................58
7.1.3.2.2 Immunohistochemistry/Immunofluorescence.................................59
7.1.3.2.3 Genomic Analysis..............................................................................59
7.1.4 Other Procedures .................................................................................................59
7.1.4.1 Withdrawal/Discontinuation ....................................................................59
7.1.5 Visit Requirements ...............................................................................................59
7.1.5.1 Screening...................................................................................................59
7.1.5.2 Treatment Period......................................................................................60
7.1.5.3 Post-Treatment Visits................................................................................60
7.1.5.3.1 Safety Follow-up Visits ......................................................................60
7.1.5.4 Follow-up Visits.........................................................................................60
7.1.5.4.1 Survival Follow-up .............................................................................61
7.2 Assessing and Recording Adverse Events ..............................................................61
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose ..........62
7.2.2 Reporting of Pregnancy and Lactation ...............................................................63
7.2.3 Immediate Reporting of Adverse Events............................................................63
7.2.3.1 Serious Adverse Events.............................................................................63
7.2.3.2 Events of Clinical Interest..........................................................................64
7.2.4 Evaluating Adverse Events..................................................................................65
7.2.5 Sponsor Responsibility for Reporting Adverse Events........................................70
8. Statistical Analysis Plan ..............................................................................................70
8.1 Statistical Analysis Plan Summary.........................................................................70
8.1.1 Safety Analysis ...................................................................................................70

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8.1.2 Efficacy Analysis.................................................................................................70
8.1.3 Power and Sample Size......................................................................................71
8.1.4 Accrual Rate.......................................................................................................71
8.2 Statistical Analysis Plan.........................................................................................72
8.2.1 Safety Endpoints................................................................................................72
8.2.2 Efficacy Endpoints..............................................................................................72
8.2.3 Analysis Population............................................................................................72
8.2.3.1 Safety Population .....................................................................................73
8.2.3.2 Efficacy Population...................................................................................73
8.2.4 Statistical Methods ...........................................................................................73
8.2.4.1 Safety Analysis.........................................................................................73
8.2.4.2 Disease Free Survival...............................................................................73
8.2.4.3 Overall Survival........................................................................................74
8.2.4.4 Biomarker Assessments...........................................................................74
9. Labeling, Packaging, Storage and Return of Clinical Supplies.......................................74
9.1 Investigational Product ...............................................................................................74
9.2 Packaging and Labeling Information...........................................................................74
9.3 Clinical Supplies Disclosure .........................................................................................75
9.4 Storage and Handling Requirements ..........................................................................75
9.5 Returns and Reconciliation .........................................................................................75
10.0 Administrative and Regulatory Details .....................................................................75
10.1 Confidentiality....................................................................................................75
10.1.1 Confidentiality of Subject Records ....................................................................76
10.1.2 Confidentiality of Investigator Information.......................................................76

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10.2 Compliance with Financial Disclosure Requirements...........................................76
10.3 Compliance with Law, Audit and Debarment ......................................................77
10.4 Compliance with Trial Registration and Results Posting Requirements................77
10.5 Quality Management System..............................................................................77
10.6 Data Management..............................................................................................77
10.6.1 Data Storage ....................................................................................................77
10.6.2 Data and Safety Monitoring.............................................................................78
11.0 Appendices...............................................................................................................78
11.1 ECOG Performance Status...................................................................................78
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) .........................79
12.0 References ...............................................................................................................79
1.0
TRIAL SUMMARY
Abbreviated Title
Adjuvant HNC anti-PD1 chemoradiation phase II study
Trial Phase
Phase II
Clinical Indication
High and Intermediate risk resected HNC
Trial Type
2 arm, non-randomized
Type of control
Historical
Route of administration
IV
Trial Blinding
None

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Treatment Groups
High risk and Intermediate risk
Number of trial subjects
80
Estimated enrollment 
period
3 years
Estimated duration of trial
8 years (5 years disease free survival (DFS) + 3-year 
enrollment period)
Duration of Participation 
for subjects
5 years
2.0 TRIAL DESIGN
2.1
Trial Design
This study will be a two arm phase II trial including 80 patients with head and neck squamous cell 
carcinoma (HNSCC) eligible for resection. Patients who are identified to be clinically high risk (see 
inclusion) prior to resection will be screened and consented to receive 1 dose Pembrolizumab followed 
by resection. Post-resection, patients will be stratified and if high risk features are confirmed by 
pathology (extracapsular extension [ECE], or positive margins), patients will receive concurrent weekly 
Cisplatin, daily radiation and every three week Pembrolizumab as shown in schema. If those enrolled 
prior to resection are found to not have high risk pathological features, they will go on to receive 
radiation and Pembrolizumab. Eight patients from each group will be enrolled as part of a lead-in on a 
rolling basis to determine the safety of this combination with stopping rules if expected toxicity is 
exceeded. There will be a fair proportion of patients who are identified to be high risk prior to resection 
but do not have confirmed high risk pathologic features. Therefore, we expect that using our criteria, 
that at least 50% (or 40 patients) will have high risk features requiring chemotherapy in addition to 
radiation (CRT) and Pembrolizumab while the remaining intermediate risk patients will receive radiation 
and Pembrolizumab. For correlative studies, archived or fresh biopsy samples and resection tissue will 
be assessed by H&E and IHC for immune phenotype. Blood samples will also be collected as described 
in section 7 for correlative studies. Patients will be followed approximately weekly during treatment,
then monthly for the first 3 months following treatment and then every 3 months thereafter for the first 
two years. A repeat PET/CT or CT scan will be performed at 3 months post-treatment to assess for early 
relapse. Patients will be assessed every 3 months for the first 2 years and then every 6 months for the 
next 3 years for disease free survival (DFS) and overall survival (OS).
2.2
Trial Diagram

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3.0 OBJECTIVES & HYPOTHESES
3.1
Primary Objectives & Hypotheses
(1) Objective: Determine the frequency and severity of side effects of Pembrolizumab when 
administered in combination with radiation alone or Cisplatin and radiation therapy (CRT) in 
patients undergoing adjuvant treatment for resected HNSCC.

Hypothesis: Combining Pembrolizumab with concurrent Cisplatin and radiation will be 
safe, causing minimal interruption to standard of care therapy in patients with resected 
HNSCC.
(2) Objective: To estimate the 1 and 3 year disease free survival (DFS) combining Pembrolizumab 
with adjuvant CRT in patients with resected high risk HNSCC.

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
Hypothesis: Combining Pembrolizumab to concurrent Cisplatin and radiation will 
increase DFS in patients with resected HNSCC relative to historic data as there is not a 
current comparison in this trial.
(3) Objective: To estimate the 1 and 3 year disease free survival (DFS) combining Pembrolizumab 
with adjuvant radiation in patients with resected intermediate risk HNSCC.

Hypothesis: Combining Pembrolizumab to radiation will increase DFS in patients with 
resected HNSCC relative to historic data as there is not a current comparison in this trial.
3.2
Secondary Objectives & Hypotheses
(1) Objective: To estimate the 1 and 3 year overall survival (OS) combining Pembrolizumab with 
adjuvant CRT in patients with resected high risk HNSCC.

Hypothesis: Combining Pembrolizumab to concurrent Cisplatin and radiation will 
increase OS in patients with resected HNSCC relative to historic data as there is not a 
current comparison in this trial.
(2) Objective: To estimate the 1 and 3 year overall survival (OS) combining Pembrolizumab with 
adjuvant radiation in patients with resected intermediate risk HNSCC.

Hypothesis: Combining Pembrolizumab to radiation will increase OS in patients with 
resected HNSCC relative to historic data as there is not a current comparison in this trial.
(3) Objective: Determine the change in distribution of the tumor immune microenvironment before 
and after Pembrolizumab administration in tumor biopsy tissue using markers of T cells and T cell 
activation including but not limited to CD4, CD8, CD38, HLA-DR, PD-1 and PD-L1.

Hypothesis: Pembrolizumab administration will result in enhanced immune stimulation 
in tumors marked by T cell infiltration/activation.
(4) Objective: Determine the baseline adenosine receptor expression in HNSCC patients and the 
effect of PD-1 inhibition by Pembrolizumab in activated T cells combined with peripheral T cell 
activation by flow cytometry.

Hypothesis: Pembrolizumab administration will result in increased adenosine receptor 
expression which will confer resistance to T cell activation.
3.3
Exploratory Objectives
(1) Objective: Determine immunoregulatory activity in the serum including immune related 
cytokines including but not limited to IL-2 and IL-6.
(2) Objective: Study peripheral blood T cell and tumor infiltrating lymphocyte functionality 
(motility, calcium response to antigen presentation, ion channel function, cytotoxicity, apoptosis 
and cytokine release) to see if and what type of functionality is gained after anti-PD1 treatment.
(3) Objective: Assess the presence of myeloid derived suppressor cells, pro- and anti-inflammatory 
monocytes and dendritic cells in the blood and tissue at the different points of treatment as a 

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marker of prognosis using staining that would include, but not be limited to CD14, CD16, CD11c, 
CD1c, CD303, CD141, CD68, PDL-1, CD33, GR1, and HLA-DR.
(4) Objective: Assess disease free and overall survival at 5 years. 
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, PD1 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, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 

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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). It is now known that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and two different PD-1 inhibitors, Pembrolizumab and nivolumab, are FDA approved for 
therapeutic intervention in melanoma (as well as squamous cell carcinoma of the lung for nivolumab).
Pembrolizumab specifically is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 
and PD-L2. KeytrudaTM (Pembrolizumab) has recently been approved in the United States for the 
treatment of patients with unresectable or metastatic melanoma and disease progression following 
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.
4.1.3
Adjuvant treatment in Head and Neck Cancer
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although 
early stage tumors are often cured with surgery or radiation, up to 60% of patients present with locally 
advanced disease requiring multimodality treatment. Many patients with locally advanced disease will 
undergo upfront surgical resection, but unfortunately, the rate of relapse both locally and distantly after 
surgery alone is high, particularly in patients with high risk features (multiple lymph node involvement, 
extracapsular spread or those with positive surgical margins). Two pivotal studies by the EORTC and 
RTOG published in 2004 demonstrated increased progression free1,2 and overall survival1 in patients who 
received adjuvant concurrent Cisplatin and radiation albeit with higher toxicity over radiation alone. 
However, PFS and OS were only 47% and 53% respectively at 5 years and even lower if HPV positive 
patients were excluded. Follow-up meta-analysis by Bernier et al. in 2005 demonstrated that the only 
common characteristics between both studies who received benefit from the addition of chemotherapy 
to radiation were ECE and positive margins3. Approximately 70% of the patients in the EORTC and 59% 
of RTOG study had one or both of these high risk features which may explain why overall survival benefit 
was seen in the EORTC trial only. When the data was pooled together from both studies, the risk of 
relapse in the high risk group was reduced by 42% whereas those without these features did not seem 
to benefit from the addition of chemotherapy. Currently standard of care per NCCN guidelines consists 
of chemotherapy and radiation for this high risk group and radiation only in those with intermediate 
features (multiple lymph node involvement, perineural invasion, etc). However, despite current 
standards, patients continue to have high rates of relapse in both groups. In fact, even patients 
(combined risk factors) who received CRT in the EORTC study had a DFS of only 48% at 5 years (54% at 2
years in the RTOG study) suggesting that novel treatments are necessary in order to improve outcomes 
in these patients.
4.2
Rationale

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4.2.1
Rationale for the Trial and Selected Subject Population
Interestingly, the negative immune cell regulator, PD1 ligand-1 
(PD-L1), has been found to be up-regulated on many tumors as 
mentioned above including HNSCC. Recently, Pembrolizumab 
was shown to have activity in metastatic HNSCC with a decrease 
in tumor burden in up to 46% of patients with recurrent and 
metastatic HNSCC (ASCO 2014) leading to the initiation of a 
phase III study in this group. Besides PD-L1 expression, it was 
shown that patients with low tumor burden had increased 
response rates to Pembrolizumab. Therefore, patients who have
had the bulk of 
their disease 
resected may 
have a superior 
response.
Additionally, Dr. 
John Morris’ 
laboratory and 
others have 
demonstrated 
that MHC-1, PD-
L1, and
preliminarily PD-L2 are further increased in response 
to radiation treatment suggesting a possible 
mechanism of resistance and that anti-PD-1 rather 
than anti-PD-L1 would result in less resistance.
Importantly, 1 week pre-treatment with anti-PD-L1 
antibody prior to radiation (but not 5 days post- 
radiation treatment) resulted in increased survival of 
mice bearing HNSCC tumors (see figure 2) compared 
to radiation alone. Additionally, others have
demonstrated that PD-L1 is also increased in response to Cisplatin exposure. Therefore, we 
hypothesize that the addition of Pembrolizumab prior and concurrently to combined radiation or 
Cisplatin and radiation (CRT) after surgical resection in high risk HNSCC will result in enhanced tumor 
response.
4.2.2
Rationale for Dose Selection/Regimen/Modification
4.2.2.1 Pembrolizumab
An open-label Phase I trial (Protocol 001) was 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 
Figure 1. A. Murine HNSCC 
cell lines were irradiated with 
indicated dose and cells 
were stained with anti-MHC- 
1 or PD-L1 antibodies and 
expression was measured 
by flow cytometry. B. Meer 
murine HNSCC cells were 
injected into the flanks of 
immunocompetent 
mice. 
The tumors were irradiated 
with 10Gy and tumors were 
resected, homogenized, and 
stained 
with 
anti-PD-L1 
antibody for analysis byflow

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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 was identified.
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life. Pharmacodynamic data (IL-2 release assay) suggested that 
peripheral target engagement is durable (>21 days). This early PK and pharmacodynamic data provided 
scientific rationale for testing a Q2W and Q3W dosing schedule.
Similar efficacy and safety of Pembrolizumab was seen when dosed at either 2 mg/kg or 10 mg/kg Q3W 
in melanoma patients. In addition, there was a flat exposure-response relationship of Pembrolizumab 
for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W which did not depend 
on tumor burden.
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.
4.2.2.2 Cisplatin
Cisplatin is often given as either bolus dosing or weekly dosing when combined with radiation treatment 
in HNSCC. In locally advanced disease without surgical resection, patients are often offered bolus 
Cisplatin dosing at 100mg/m2 days 1, 22 and 43 of radiation based off a pivotal study by Adelstein et al.4 
The same dosing was used in the older adjuvant studies mentioned above but with a significant increase 
in toxicity over radiation alone especially in regards to increase in renal dysfunction, myelosuppression, 
ototoxicity and emetogenesis. In the post-operative setting, in which many patients have poor nutrition 
and decreased functional status, there is a concern that patients would not be able to tolerate this bolus 
dosing and other dosing schedules would be more ideal. Based on data from Ang et al. 2004, it was 
proposed that patients require at least a cumulative dose of 200mg/m2 of Cisplatin regardless of the 
dosing schedule (fractionated, high dose, weekly)5. Weekly Cisplatin was also shown to be effective with
concurrent radiation in nasopharyngeal cancer and was demonstrated to result in lower toxicity over the 
standard dosing, further strengthening a role for this dosing schedule in HNSCC6. NRG has established 
weekly dosing to be the current standard for adjuvant studies and is currently being used in RTOG 1216 
and 0920. Therefore, we feel weekly dosing (40mg/m2 for 6 doses) is most appropriate in this patient 
population.

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4.2.3
Rationale for Endpoints
4.2.3.1 Safety Endpoints
Clinically, the addition of Pembrolizumab to Cisplatin and radiation has yet to be explored. Pre-clinically, 
the addition did not add any unexpected toxicity in small analyses. Based on the current safety profile 
of Pembrolizumab alone, and the fact that the toxicities are unique to immunotherapy compared to 
radiation and chemotherapy, we do not expect to observe any additional adverse effects and that this 
will therefore be a safe combination. However, because this combination has not yet been explored in 
this setting (although many clinical trials are currently being designed), we will continue to monitor 
safety throughout this study using CTCAE guidelines. We will perform a lead-in of 8 patients in each arm 
in order to determine any unexpected toxicities beyond what had been documented for these therapies. 
As long as current standard of therapy is not felt to be significantly impacted (delay in >2 out of 8 patients 
in each arm), the trial will proceed.
4.2.3.2 Efficacy Endpoints
This is a phase II non-randomized study and therefore will rely on historical controls for the primary 
efficacy endpoint of disease free survival (DFS) in resected high risk HNSCC. Based on the pivotal RTOG 
9501 and EORTC 22931 adjuvant studies, disease free survival at 1 year was approximately 66% and 76% 
respectively for the CRT arms and 58% and 72% respectively for radiation only arms (See table). The 3 
year estimates are somewhat closer between the two studies.
RTOG 9501
EORTC 22931
Study Group
RT
CRT
RT
CRT
Disease Free Survival 1 year
58%
66%
72%
76%
Disease Free Survival 3 year
37%
47%
40%
57%
There were several differences in these studies including number of lymph nodes involved (94% had ≥ 2
lymph nodes in RTOG versus only 57% in EORTC) and the 
number of patients with at least 1 high risk feature (ECE 
or positive margins) was also different (approximately 
70% of the patients in the EORTC and 59% of RTOG 

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study) which may account for these differences.
Based on phase I data, Pembrolizumab resulted in response rates up to 46% at least in those patients 
positive for PD-L1. Therefore, we expect that the addition of Pembrolizumab will significantly reduce the 
chance of relapse in this population and therefore, will result in improved DFS. Most locoregional 
relapses (the most common cause of death in this group) occur within the first year. Therefore, our 
primary and secondary endpoints respectively will be DFS at 1 and 3 years, which will reflect early and 
late relapse. Our historical baseline will be based off the RTOG 9501 data due to the fact that entry 
criteria included either ECE, positive margins or ≥2 lymph nodes all of which are considered to be 
either high risk or high-intermediate risk which is the group we are most interested in for this study 
and encompasses our inclusion criteria.
4.2.3.3 Biomarker Research
It has been established that the expression of PD-L1 on tumors and PD-1 on T cells in the 
microenvironment, confers a poor prognosis in HNSCC. In addition, the frequency of peripheral blood 
myeloid derived suppressor cells also strongly correlates with a poor prognosis. However, the inhibition 
of the PD-1/PD-L1 interaction results in impressive tumor responses in a variety of tumors. It is assumed 
that this is mediated through T-cell mediated tumor cell killing. However, the contribution of the 
microenvironment remains unclear. Additionally, analysis of tissue after inhibition of this response and 
the effect on the tumor microenvironment remains relatively unexplored. In this study, we have the 
unique opportunity to analyze resected tumor tissue after exposure to 1 dose of Pembrolizumab which 
will give insight to these processes. In addition, the mechanism of resistance to PD-1/PD-L1 inhibition is 
unclear. As mentioned in the background, up-regulation of PD-L2 may be an explanation for poor 
responses to PD-L1 inhibition but would not explain the lack of effect in at least 50% of patients to anti- 
PD-1. Here we will investigate possible novel mechanisms of resistance described in detail below.
Tumor Microenvironment and Mechanism of Resistance to anti-PD-1
The tumor microenvironment exerts an immune suppressive role in cancer by limiting the capacity of T 
cells to accumulate among cancer cells resulting in immune-mediated cell death7. Various aspects of the 
tumor microenvironment have been shown to limit T cell function: hypoxia, indoleamine 2,3- 
dioxygenase (IDO), adenosine and PGE27. The suppressive effects of adenosine and hypoxia on T 
lymphocytes are mediated by ion channels (Kv1.3 and KCa3.1)8-12. Both adenosine and PGE2 signal 
through their respective receptors, cAMP/PKA and their effect in mast cells is mediated by KCa3.1 
channels12-15. Evidence exists that alterations of the tumor microenvironment improve the efficacy of 

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immune checkpoint blockade. In a recent study in mice, the combination therapy of anti-PD1 with 
blockers of the adenosine receptor (A2AR) proved to be superior to anti-PD1 monotherapy16. On the 
other hand, the anti-PD1 therapy could also make the immune cells more sensitive to the tumor 
microenvironment as it has been reported that PD1 blockade in mice increases the expression of A2AR in 
tumor infiltrating T lymphocytes (TILs). The goal of this collateral study is to determine whether (1) the 
tumor microenvironment and tumor microenvironment-related features of TILs at baseline (pre-drug) 
can be used as predictors of responders and non-responders; (2) anti-PD-1 treatment alters the 
characteristics of TILs making them more susceptible to the immune suppression of the tumor 
microenvironment with the consequent development of resistance to anti-PD-1 therapy; (3) unique
alterations of T cell phenotype and function pre-drug or after therapy can be found in peripheral blood 
T cells.
5.0 METHODOLOGY
5.1
Eligibility Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial
Histologically or cytologically confirmed locally advanced HNSCC including the oral cavity, 
larynx or pharynx (except nasopharynx).
5.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial.
2. Be  18 years of age on day of signing informed consent.
3. Patients who are eligible for resection must have one or more of the following clinical features:
a. Any T stage with ≥ N2 disease;
b. T4 disease, any N stage;
c.
T3 Oral Cavity, any N stage; or
d. Clinical evidence of extra-capsular extension on scans.
4. Pre-operative scans including chest imaging preferably PET/CT and CT neck w/contrast. (CT chest 
and CT neck w/contrast would also be acceptable). If contrast is contraindicated, MRI neck is 
acceptable.
5. Must be willing to undergo definitive resection with neck dissection.
6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion 
before study drug administration if unable to provide archived biopsy tissue. Please note sample 
does not have to be sent to UC prior to enrollment in study as long as it is documented that 

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sample exists prior to treatment. (For MDA only, patients with available archival tissue will also 
have a mandatory fresh biopsy at enrollment.)
7. Have a performance status of 0 or 1 on the ECOG Performance Scale.
8. Demonstrate adequate organ function as defined in Table 1. All screening labs should be 
performed within 10 days of treatment initiation.
Table 1 Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of the screening exam)
Renal
Serum creatinine OR 
Measured or calculateda 
creatinine clearance
(GFR can also be used in place of 
creatinine or CrCl)
within upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > institutional 
ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with 
total bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN
Albumin
>2.5 mg/dL
Coagulation
International Normalized Ratio (INR) 
or Prothrombin Time (PT)
Activated Partial Thromboplastin 
Time (aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
9. Female subjects 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.

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10. 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.
11. 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.
5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1.
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form 
of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Short bursts 
of steroids of 5-7 days (for COPD exacerbation or other similar indication) are allowed.
2.
Has nasopharyngeal or sinonasal carcinoma.
3.
Has confirmed metastatic disease. Metastatic disease to neck nodes is considered locally 
advanced disease and not metastatic and therefore is allowable.
4.
Patients who have HPV+ disease of oropharynx. HPV+ disease outside of oropharynx is 
acceptable.
5.
Has a known history of active TB (Bacillus Tuberculosis).
6.
Hypersensitivity to Pembrolizumab or any of its excipients.
7.
Has a known additional malignancy that was diagnosed within the last five years that is either 
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 active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment.
9.
Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of 
the trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator.

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12. Has known psychiatric or substance abuse disorders that, in the opinion of the investigator, 
would interfere with cooperation with the requirements of the trial.
13. 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.
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known Hepatitis B (e.g., HBsAg reactive) or known Hepatitis C (e.g., HCV RNA [qualitative] is 
detected).
16. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; 
however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
5.2
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 
(Initial infusion)
200 mg
once
IV infusion
Day -21 to -7 
(prior to 
resection)
Experimental
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of
each 3 week 
cycle starting 
7 days 
before CRT 
for 7 doses 
(including 
initial dose)
Experimental
Cisplatin
40mg/m2
Weekly
IV infusion
4-8 weeks 
after 
resection for 
6 doses to 
begin with 
radiation
Standard of 
Care for High 
Risk only

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Radiation
60 Gy
Daily M-F
IMRT
4-8 weeks 
after 
resection 
over 6 
weeks
Standard of 
care
Treatment will be administered on an outpatient basis. Protocol treatment (pre-surgical Pembro dose) 
must begin only after eligibility criteria are confirmed by the UC PI (registration), see study flow for more 
specific timeframes.
5.2.1
Pretreatment Evaluations/Management
Note: This section lists baseline evaluations needed before the initiation of protocol treatment that do 
not affect eligibility.
5.2.1.1 Required Evaluations/Management
1. Standard of care dental evaluation with management within 3 months prior to the start of 
radiation.
2. Assessment of swallowing function/dysphagia using CTCAE, v. 4 criteria prior to the start of 
radiation.
5.2.1.2 Highly Recommended Evaluations/Management
1. Assessment by dietician with recommendations on diet during and after treatment as well as 
evaluation for prophylactic gastrostomy tube placement (especially if the patient is ≥ 10% below ideal 
body weight) within 4 weeks prior to the start of adjuvant treatment.
2. Audiogram evaluation as needed.
3. EKG within 8 weeks prior to the start of treatment.
5.2.2
Dose Selection/Modification
5.2.2.1 Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background and 
Rationale.
5.2.2.2
Dose Administration
5.2.2.2.1
Cisplatin Guidelines

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Cisplatin can be given either before or after the radiation therapy fraction that is given on the same day. 
If radiation is held for more than 2 days (for any reason), Cisplatin may be held as well until radiation 
resumes. Cisplatin should only continue during radiation and doses should not be made up after the 
completion of radiation. Patients should receive no more than 6 total doses.
(Note: Cisplatin given within 24 hours of planned administration due to holidays, for example, is 
acceptable). Weekends count as days.
Patients must be vigorously hydrated before and after Cisplatin administration as per institutional 
standard regimens. Adequate diuresis is recommended per clinical discretion. A suggested, but not 
mandatory regimen, would be pre- hydration with 1 liter ½ NS with 1 g MgSO4 and KCL 20mEq over 2 
hours and to repeat same after Cisplatin (pre-and post-hydration). Other suggested, but not mandatory, 
regimens could be 1-1.5 liter NS pre-hydration followed by addition 1-1.5 liter NS post-hydration. Any 
pre-existing dehydration should be corrected, and additional days of IV fluid can be considered per 
clinical discretion.
5.2.2.2.2
Pembrolizumab Guidelines
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Infuse 
pembrolizumab (MK-3475) over approximately 30 minutes, with a window of -5 and +10 minutes, 
through a peripheral line or indwelling catheter. The first dose will be given no more than 3 weeks and 
no less than 7 days prior to resection. Ideally, the pre-surgery dose of Pembrolizumab will be given 
between 1-2 weeks before surgery. Post-surgery, Pembrolizumab will be between 4 and 11 weeks and 
will continue during radiation and 3 months after completion. The first adjuvant Pembrolizumab dose 
is to begin 1 week prior to radiation.
Pembrolizumab will be administered before Cisplatin on days they are given together. If fluids are 
administered along with Pembrolizumab, then hydration should include only NS. Radiation may be given 
before or after infusions. If a Pembrolizumab dose is missed outside the +/-1 day window up to week 7 
and +/-3 day window week 10 and beyond per the schedule of events, it should be skipped and not made 
up.
The Pharmacy Manual contains specific instructions for the preparation of the Pembrolizumab infusion 
fluid and administration of infusion solution.
5.2.2.2.3
Radiation Therapy Guidelines 
5.2.2.2.3.1 Dose Specifications:
The prescribed radiotherapy dose will be 60-66 Gy in 2-2.2 Gy once-daily fraction size (total of 30-33 
fractions). Radiotherapy should begin on a Monday, or Tuesday. The daily dose of 2-2.2Gy Gy will be
prescribed such that 95% of the PTV volume receives at least 95% of prescribed dose. The spinal cord 
dose may not exceed 45 Gy to any volume larger than 0.03 cc.
5.2.2.2.3.2 Technical Factors
Treatment Planning/Delivery: Megavoltage energy photon beam irradiation is required. 3D conformal 

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or IMRT treatment planning may be may be used, and daily IGRT will be used.
5.2.2.2.2.3 Localization, Simulation, and Immobilization
1. Patients must have an immobilization device (e.g., aquaplast mask) made prior to treatment planning 
CT scan.
2. All patients will undergo CT simulation for treatment planning. The treatment planning CT scan may 
be completed with or without IV contrast. The treatment planning CT scan must be performed with the 
immobilization device and in the treatment position. Slice thickness should be 0.3 cm or less.
5.2.2.2.2.4 Target and Normal Tissue Volume Restrictions
Definition of Target Volumes
CTV60: CTV60 will include the primary tumor bed (based on preoperative imaging, preoperative physical 
exam/endoscopy, operative findings, pathologic findings) plus the post-operative neck. This volume may 
include the skin. It is recognized that after surgery, there can be considerable distortion of normal 
anatomy. If possible, preoperative GTV(s) should be fused onto the postoperative radiation therapy 
planning CT scan, and appropriate margins added for microscopic spread (1.5-2 cm). CTV60 also will 
include the ipsilateral pathologically positive hemineck (if both sides of the neck are proven 
pathologically positive, CTV60 will include both sides). This generally means encompassing nodal levels 
2a, 3, and 4. Nodal levels 1, 2b, 5a, and 5b are included in CTV60 in selected circumstances. For questions, 
contact the Lead Radiology/Oncology Investigator, Dr. Michelle Mierzwa.
CTV56: This will include all other regions felt to be at risk for harboring microscopic cancer that do not 
meet the criteria for CTV60. For example, this would apply to the contralateral hemineck being irradiated 
electively for a midline primary cancer.
CTV66 Optional: This may be defined at the discretion of the treating radiation oncologist. This would 
include a region or regions felt to be at especially high risk for recurrence (e.g., an area of very close 
margin of resection or nodal extracapsular extension).
Planning Target Volumes (PTVs): In general, the PTV should not go outside of the skin surface; if it does 
exceed the skin surface, the application of bolus material over this portion of the PTV may be considered 
to treat skin to full dose.
PTV Expansion The minimum CTV-to- PTV expansion is 3 mm (a larger expansion may be necessary for a 
target volume subject to significant intra-fraction variability, such as the non-immobilized oral tongue). 
In general, the CTV-to-PTV expansion should not exceed 10 mm.
Definition of Normal Tissues/Organs at Risk (OARs)
Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 vertebral body). 
Superior to this is brainstem and inferior to this is cord. The inferior border of the spinal cord is at 
approximately T3-4 (i.e., just below the lowest slice level that has PTV on it). The spinal cord shall be 

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defined based on the treatment planning CT scan. In addition, however, a Planning Risk Volume (PRV) 
spinal cord shall be defined. The PRVcord = cord + 5 mm in each dimension.
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction where it meets 
the spinal cord. For the purposes of this study, the superior most portion of the brainstem is 
approximately at the level of the top of the posterior clinoid. The brainstem shall be defined based on 
the treatment planning CT scan. In addition, however, a Planning Risk Volume (PRV) brainstem shall be 
defined. The PRVbrainstem = brainstem + 3 mm in each dimension.
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is to keep the lip 
dose much lower than the oral cavity dose. The definition of lips is self-explanatory. The oral cavity will 
be defined as a composite structure consisting of the anterior 1⁄2 to 2/3 of the oral tongue/floor of 
mouth, buccal mucosa, and palate.
Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan.
OARpharynx: This will be defined as the “uninvolved” posterior pharyngeal wall plus adjacent constrictor 
muscles. This extends from the superior constrictor region (the inferior pterygoid plates level) to the 
cricopharyngeal inlet (posterior cricoid cartilage level). This should not overlap the PTVs.
Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom of OARpharynx 
and extends to the thoracic inlet.
Glottic/Supraglottic Larynx (GSL): Obviously, for patients who have had a total laryngectomy, this 
structure is not applicable. This will be defined as a “triangular prism shaped” volume that begins just 
inferior to the hyoid bone and extends to the cricoid cartilage inferiorly and extends from the anterior 
commissure to include the arytenoids. This includes the infrahyoid but not suprahyoid epiglottis.
Mandible: This includes the entire boney structure of the mandible from TMJ through the symphysis. It 
is recognized that for oral cavity cancers, this may overlap with CTVs and PTVs.
Unspecified Tissue Outside the Targets: This will be defined as tissue located between the skull base and 
thoracic inlet that is not included in either the target volumes or the normal tissues described above.
5.2.2.2.2.5 Treatment Planning and Delivery Dose Prescription to PTVs
As described in Section 5.2.2.2.2.1, prescribed radiotherapy dose will be 60-66 Gy in 2-2.2 Gy once daily 
fraction size. For inverse planning IMRT, the goal is for 95% of the PTV60 to receive 95% of 2 Gy with a 
minimum dose (cold spot) of no less than 56 Gy. It is recognized that portions of the PTV60 close
to/within the skin may receive significantly less than 56 Gy. Bolus should be considered for these 
cutaneous areas deemed to be at risk for microscopic disease.
For IMRT prioritization, PTV60 will be the highest priority target structure. PTV66 and PTV56, if 
applicable, will be ranked in the IMRT planning as lower priority than PTV60 although higher priority 
than normal structures other than spinal cord and brain stem.

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5.2.2.2.2.6 Dose Constraints to Normal Structures
Spinal Cord: The PRVcord (as defined in Section 6.4.2.1) should not exceed 45 Gy to any volume in excess 
of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV should not exceed 50 Gy to any 
volume in excess of 0.01 cc. In treatment planning, the spinal cord PRV should be given the highest 
priority.
Brainstem: The PRVbrainstem (as defined in Section 6.4.2.2) should not exceed 50 Gy to any volume in 
excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the PRVbrainstem should 
be given less priority than the PRVcord but more priority than the other critical structures listed below.
Lips: Reduce the dose as much as possible unless lips involved with primary tumor. The mean dose should 
be < 20 Gy. The maximum dose will be < 35 Gy.
Oral Cavity: (uninvolved) Reduce the dose as much as possible. The mean dose should be < 30 Gy.
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The treatment 
planning goal will be for this individual parotid gland to receive a mean dose of < 26 Gy. Additional 
planning goals may include: 1) At least 50% of one parotid will receive < 30 Gy; and/or 2) At least 20 cc 
of parotid tissue (from the combination of both glands) will receive < 20 Gy.
OARpharynx: Reduce the dose as much as possible. Some recommended (but not mandatory) treatment 
goals include: 1) No more than 33% of the OARpharynx exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No 
more than 15% of the OARpharynx exceeds 60 Gy.
Cervical Esophagus: Reduce the dose as much as possible. For oral or oropharyngeal cancer, some 
recommended (but not mandatory) treatment goals include: 1) No more than 33% of the esophagus 
exceeds 45 Gy; 2) Mean dose < 35 Gy; 3) No more than 15% of the esophagus exceeds 54 Gy. For larynx 
cancer, higher doses are expected and permitted. Some recommended doses (but not mandatory) 
treatment goals include: 1) No more than 33% of the esophagus exceeds 50 Gy; 2) Mean dose < 45 Gy;
3) No more than 15% of the esophagus exceeds 60 Gy.
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. Goal should be mean < 35Gy.
Mandible: Reduce the dose as much as possible, hot spots within the mandible should be avoided. It is 
recommended that maximum dose within the mandible be < 66 Gy. For tumors that were not clinically 
or pathologically involving the mandible, the CTV should be contoured off the mandible.
Unspecified Tissue Outside the Targets: For the typical case in which there is no CTV66, no more than 
5% of unspecified tissue can receive greater than 58 Gy and no more than 1% or 1cc of unspecified tissue 
can receive 64 Gy or more. When a boost is used to increase the dose to high risk regions to as much as 
66 Gy, these numbers can be increased. In this case, no more than 5% of the unspecified dose should 
exceed the level of the boost dose, and no more than 1% or 1 cc should exceed the boost dose value 
plus 10%.

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5.2.2.2.2.7 Compliance Criteria
Treatment breaks for radiation must be clearly indicated in the treatment record along with the 
reason(s) for the treatment break(s). Treatment breaks, if necessary, ideally should not exceed five 
treatment days at a time and ten treatment days total. Treatment breaks should be allowed only for 
resolution of severe acute toxicity and/or for intercurrent illness and not for social or logistical reasons.
5.2.2.2.2.8 Radiation Therapy Adverse Events
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.0 will be utilized for grading all adverse events. Placement of a feeding tube 
should be recorded as adverse event “use of a feeding tube during and after treatment” (e.g., greater 
than or less than 50% of nutrition by tube). Other common radiation adverse events include: fatigue, 
weight loss, regional alopecia, xerostomia, hoarseness, transient ear discomfort, and skin erythema and 
desquamation within the treatment fields. Less common long-term treatment adverse events include: 
hypothyroidism, loss of hearing, chronic swallowing dysfunction requiring permanent feeding tube, and 
skin/soft tissue fibrosis. Much less common radiation adverse events include: mandibular 
osteoradionecrosis, and cervical myelopathy (< 1% with restriction of spinal cord dose to max dose of 45 
Gy).
5.2.2.3 Lead-in Population for Safety Analysis
The first eight patients from each arm will be enrolled as the lead-in population. Safety analysis will be 
performed with this population and will be analyzed on a rolling basis. Weekly conference calls with all 
the sites will be held to determine if any of these first 8 patients have experienced a dose limiting toxicity, 
DLT, (described below) to evaluate the safety of the combination as well as the safety of administering 
Pembrolizumab before surgery. Safety analysis will be considered complete for each arm at four weeks 
after the eighth patient has finished CRT. Patients will continue to be enrolled past the initial safety 
cohort, but if at any time, safety analysis reveals >2 out of the 8 patients in the safety cohort have 
developed a DLT, then no further patient may be enrolled to that arm due to excess toxicity with this 
combination. If the safety event occurs prior to surgery only, than the pre-surgery dose of 
Pembrolizumab will be discontinued for the following patients but the trial will continue with adjuvant 
treatment only.
5.2.2.3.1 Dose Limiting Toxicity
Dose limiting toxicity will be defined as any adverse effect, that in the treating investigator’s opinion, 
was felt to be due to Pembrolizumab and significantly delayed standard of care treatment (> 7 days delay 
in surgery, >3 days for radiation, and/or >7 days for Cisplatin dose). In these patients, Pembrolizumab 
will be discontinued permanently.
5.2.2.4 Dose Modification
5.2.2.4.1 Pembrolizumab - Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab and combination therapy

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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 and the most current investigator’s 
brochure for supportive care guidelines, including use of corticosteroids.
Table 3
Dose Modification Guidelines for Drug-Related Adverse Events
General instructions:
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to 
taper over at least 4 weeks.
2. For situations where Pembrolizumab has been withheld, Pembrolizumab can be resumed after 
AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab 
should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.
3. For severe and life-threatening Immune Related AEs, IV corticosteroid should be initiated first 
followed by oral steroid. Other immunosuppressive treatment should be initiated if Immune 
Related AEs cannot be controlled by corticosteroids.
Immune-
Toxicity grade
Action taken to
Immune Related AE
Monitor and
related AEs
or conditions
Pembrolizumab
management with
follow-up
(CTCAE v 4.0)
corticosteroid and/or 
other
therapies
Pneumonitis
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper
Add prophylactic 
antibiotics for 
opportunistic 
infections

Monitor 
participants for 
signs and 
symptoms of 
pneumonitis

Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroi d 
treatment

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Grade 3 or 4, 
or recurrent 
Grade 2
Permanently 
discontinue

Diarrhea / 
Colitis
Grade 2 or 3
Withhold
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper

Monitor 
participants for 
signs and symptoms 
of enterocolitis (ie, 
diarrhea, 
abdominal pain, 
blood or mucus in 
stool with or 
without fever) and 
of bowel 
perforation (ie, 
peritonea l signs 
and ileus).
Participants with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
out colitis.

Participants with 
diarrhea/coli tis 
should be advised 

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Grade 4
Permanently 
discontinue
to drink liberal 
quantities of clear  
fluids. If sufficient 
oral fluid intake is 
not feasible, fluid 
and electrolytes 
should be 
substituted via IV 
infusion.
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 0.5- 1 
mg/kg prednisone 
or equivalent) 
followed by taper

Monitor with liver 
function tests 
(consider weekly or 
more frequently 
until liver enzyme 
value returned to 
baseline or is stable
AST / ALT
elevation or 
Increased 
bilirubin
AST / ALT
elevation or 
Increased 
bilirubin
Grade 3 or 4
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper

Monitor with liver 
function tests 
(consider weekly or 
more frequently 
until liver enzyme 
value returned to 
baseline or is stable
Type 1 
diabetes 
mellitus 
(T1DM) or
Hyperglycemi 
a
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell failure
Withhold
Initiate insulin 
replacement therapy 
for participants with 
T1DM
Administe
r 
anti- 
hyperglyc
emic 
in 

Monitor 
participants for 
hyperglycemi a or 
other signs and 
symptoms of 
diabetes.

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participan
ts 
with 
hyperglyc
emia
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue1
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.

Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitari sm 
and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidi 
sm
Grade 3 or 4
Withhold or 
permanently 
discontinue1
Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate

Monitor for signs 
and symptoms of 
thyroid disorders.
Hypothyroidis 
m
Grade 2-4
Continue
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs 
and symptoms of 
thyroid disorders.
Grade 2
Withhold
Nephritis 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper.

Monitor changes 
of renal function
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue
  Based on severity 
of AE administer 
corticosteroids

  Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes
Myocarditis
Grade 1 
Withhold
Based on severity 
of AE administer 

Ensure adequate 
evaluation to 

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Grade 2, 3 or 4
Permanently 
discontinue
corticosteroids
confirm etiology 
and/or exclude 
other causes
Intolerable/ 
persistent 
Grade 2
Withhold
Grade 3
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis
All other 
immune- 
related AEs
Grade 4 or 
recurrent 
Grade 3
Permanently 
discontinue
Based on type and severity 
of AE administer 
corticosteroids

Ensure 
adequate 
evaluation to 
confirm 
etiology 
and/or 
exclude 
other causes
1. Withhold or permanently discontinue Pembrolizumab is at the discretion of the investigator or 
treating physician.
NOTE:
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of 
Pembrolizumab is required, Pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is 
controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
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. If a pembro dosed is held, then that dose is considered missed.
5.2.2.4.2 Cisplatin
Use the actual body weight for all patients. There should be no dose modifications because of obesity.

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Cisplatin dose can be reduced up to 2 times if AEs occur (1st dose reduction of 25% to 30mg/m2 and then 
subsequently to 23mg/m2). However, if AEs as listed below continue to occur despite 2 subsequent 
dose reductions, therapy should be discontinued permanently. Chemotherapy dose should never be 
escalated.
Neutropenia: If on the day of scheduled treatment with Cisplatin the absolute neutrophil count (ANC) is
< 1000/mm3, hold chemotherapy treatment but not the radiation until ANC ≥ 1000/mm3, then treat at 
25% dose reduction. Neutropenic fever (i.e. any fever > 38.5°C with an ANC <1000/mm3) will require a 
25% dose reduction of the next Cisplatin dose.
Thrombocytopenia: If on the day of scheduled treatment with Cisplatin the platelet count is < 
75,000/mm3, hold chemotherapy treatment but not the radiation until platelets are ≥ 75,000/mm3, 
then treat at 75% dose.
Neurotoxicity: If grade 2 neurotoxicity develops, hold Cisplatin (but continue RT) until toxicity improves 
to < grade 1, then reduce the following Cisplatin dose by 25%. If any signs of grade 3 or greater 
neurotoxicity occur, discontinue Cisplatin, but continue RT.
Renal Adverse Events: Cisplatin dose should be based on the serum creatinine or creatinine clearance 
immediately prior to the second and third Cisplatin dose using the following guidelines:
Note: If creatinine is > 1.5 mg/dl, creatinine clearance must be calculated (Cockcroft-Gault) in order to 
make dose adjustment. If the calculated clearance is 50 mL/min or above, a 24-hour urine collection is 
not needed, but if the calculation is less than 50 mL/min, a 24-hour urine collection is mandated, and 
the Cisplatin dose will be determined as follows:
Serum Creatinine Creatinine Clearance Cisplatin Dose (Dose reductions should be made from current 
dose level)
≤ 1.5 mg/dl or > 50 ml/min then administer full dose
> 1.5 mg/dl and 40-50 ml/min then administer at 25% dose reduction
> 1.5 mg/dl and < 40 ml/min Hold drug*
*Cisplatin should be held (but the RT continued) and the creatinine measured weekly, until it is
< 1.5 mg/dl or the creatinine clearance is > 50 ml/min, and then the next and following doses of 
Cisplatin should be given at a dose reduction of 25%.
Nausea and Vomiting: Maximum supportive therapy will be given, and Cisplatin will be continued at full 
dose for ≤ grade 2 nausea and vomiting. For grade 3 nausea and vomiting refractory to supportive 
therapy, Cisplatin will be held until recovery to < grade 2. No dose reductions will be made.
Mucositis: Significant mucositis (grade 3-4, CTCAE, v. 4) is expected from radiation and Cisplatin and 
should not be a reason for a treatment break, unless it significantly interferes with fluid intake or 
nutrition. Aggressive supportive care is encouraged as well as consideration of a PEG tube if not already 

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done.
Ototoxicity: For clinical hearing loss not requiring a hearing aid, reduce Cisplatin by 2 dose levels 
(23mg/m2). For hearing loss requiring a hearing aid, discontinue Cisplatin. For grade 2-3 tinnitus (CTCAE,
v. 4) at the time of retreatment, hold Cisplatin until improvement to grade 1 or less and then reduce the 
following doses of Cisplatin by 2 dose levels. If tinnitus does not improve to grade 1 or less by the last 
day of radiation therapy, discontinue Cisplatin. An audiogram is recommended when there is any report 
of significant change in hearing and/or an increase in tinnitus.
Other Toxicities: For any other grade 3-4 adverse events, hold Cisplatin until toxicities have recovered to 
grade 1 or less. Dose may be reduced by 1 or 2 dose levels for next treatment if felt necessary by 
discretion of investigator.
If any doses of Cisplatin are skipped due to hematologic, neurologic, renal, or other adverse events, these 
doses will NOT be made up at end of treatment. Cisplatin will continue only during time of radiation 
treatment. If a weight change of ≥10% occurs, the following Cisplatin doses should be adjusted.
5.2.3
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). Study Drug may be administered up 
to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. Cisplatin 
should not be delayed more than 1 day of scheduled dose. Pembrolizumab should be given 30 minutes 
prior to Cisplatin dose on days in which they are administered together.
All trial treatments will be administered on an outpatient basis. 
Cisplatin
Cisplatin will be given at 40mg/m2 starting concurrently with radiation one week after first post-surgery 
Pembrolizumab dose is given. Cisplatin will be given weekly for 6 doses during the radiation treatment. 
Any skipped doses will not be made up at the completion of radiation therapy.
Formulation: Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and 
hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The pH range 
will be 3.5 to 4.5. Cisplatin injection also is available from the manufacturer in aqueous solution, each ml 
containing 1 mg Cisplatin and 9 mg NaCl and HCL or NaOH to adjust pH.
Mechanism of Action: The dominant mode of action of Cisplatin is inhibition of the incorporation of DNA 
precursors, although protein and RNA synthesis are also inhibited. Although Cisplatin is thought to act 
as an alkylating agent, there are data to indicate that its mode and sites of action are different from 
those of nitrogen mustard and other standard alkylating agents.
Administration: Cisplatin will be given as a bolus, infused over 1-2 hours along with appropriate 
hydration and anti-emetics.

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Storage and Stability: Reconstituted solution of Cisplatin is stable for 20 hours when stored at 27°C and 
should be protected from light if not used within 6 hours. The vials and injection should not be
refrigerated. Cisplatin has been shown to react with aluminum needles, producing a black precipitate 
within 30 minutes.
Adverse Events: Human toxicity includes nausea, vomiting, renal toxicity (with an elevation of BUN and 
creatinine and impairment of endogenous creatinine clearance, as well as renal tubular damage, which 
appears to be transient), ototoxicity (with hearing loss that initially is in the high-frequency range, as 
well as tinnitus), and hyperuricemia. Much more severe and prolonged toxicity has been observed in 
patients with abnormal or obstructed urinary excretory tracts. Myelosuppression, often with delayed 
erythrosuppression, is expected as well.
Supply: Cisplatin is commercially available. The use of drug(s) or combination of drugs in this protocol 
meet the criteria described under Title 21 CFR 312.2(b) for IND exemption.
5.2.4
Surgery
Patients must have undergone gross total surgical resection no earlier than 7 days and no later than 21 
days after initial Pembrolizumab administration.
5.2.4.1
Surgical Quality Assurance Reviews
The Surgical Oncology Co-Chair, Keith Casper, MD, will perform a Quality Assurance Review after 
complete data for the first 20 cases enrolled has been received at UCCC. He will review pathology and 
operative reports for compliance with eligibility based on documentation of the pathologic descriptors 
for high-risk disease: extracapsular nodal extension or invasive cancer seen on microscopic evaluation 
of resection margins. Dr. Casper will perform the next review after complete data for the next 20 cases 
enrolled has been received at UCCC. The final cases will be reviewed within 3 months after this study 
has reached the target accrual or as soon as complete data for all cases enrolled has been received at 
UCCC, whichever occurs first.
5.3
Stratification
After surgical resection, patients will be stratified into two groups: high risk patients with proven positive 
surgical margins or extracapsular extension of lymph nodes or intermediate risk including all patients 
not meeting criteria for high risk. There is a small chance that although patients are identified clinically 
to require radiation prior to surgery, that the pathology will deem the patient to be low risk and radiation 
would not be considered standard of care. In the event, the investigator feels it is not in the best interest 
of patient to administer radiation (or radiation would not be considered standard of care), then patient 
may be withdrawn from the study.
5.4
Concomitant Medications/Vaccinations (allowed & prohibited)

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Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed while on 
treatment or in end of treatment follow-up period. If there is a clinical indication for one of these or
other medications or vaccinations specifically prohibited during the trial, discontinuation from trial 
therapy or vaccination may be required. The investigator should discuss any questions regarding this 
with the Sponsor. The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician and decision must be discussed with PI to determine if patient 
remains eligible to receive treatment.
5.4.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be administered at 
the discretion of the investigator in keeping with the community standards of medical care. All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, over- 
the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 30 days 
after the last dose of trial treatment should be recorded. Concomitant medications administered after 
30 days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined in Section 
7.2.
5.4.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase 
of this trial:

Biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than Pembrolizumab

Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.

Systemic glucocorticoids should be avoided if possible. Steroids are allowed as anti-emetic 
around Cisplatin dosing, as short bursts of 5-7 days if required for clinical indication (ie COPD) or 
to modulate symptoms from an event of clinical interest of suspected immunologic etiology. The 
chronic 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 other than specified as allowed, should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically necessary.

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The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.5
Rescue Medications & Supportive Care
5.5.1
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.
5.5.1.1 Pembrolizumab
Suggested supportive care measures for the management of adverse events with potential immunologic 
etiology are outlined below and in greater detail in the investigator’s brochure. Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of corticosteroids. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the investigator determines the events to be 
related to Pembrolizumab.
Note: if after the evaluation the event is determined not to be related, the investigator is instructed to 
follow the ECI reporting guidance 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.

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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

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:

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o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Management of Infusion Reactions: Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.
Table 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 
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).

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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.
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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Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration.
5.5.1.2 Cisplatin
High dose Cisplatin is a highly emetogenic regimen with significant incidence of delayed nausea and 
vomiting. The following guidelines are suggested:
1. For acute nausea and vomiting, premedication should include a 5-HT3 antagonist, such as 
granisetron 1 mg iv; ondansetron, up to 16 mg iv; or palonosetron, 0.25 mg iv; plus a 
corticosteroid, such as dexamethasone, up to 20 mg iv. Fosaprepitant may also be included as 
premedication.
2. Breakthrough nausea and vomiting should be managed at the discretion of the medical 
oncologist or radiation oncologist.
3. Delayed nausea and vomiting (greater than 24 hours after chemotherapy administration) may be 
managed by the addition of aprepitant concurrently or with metoclopramide and 
dexamethasone.
5.6
Diet/Activity/Other Considerations
5.6.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting.
5.6.2
Contraception
Cisplatin is known to be teratogenic and embryotoxic. 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 

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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 7.2.2-Reporting of Pregnancy and Lactation to the Sponsor. 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.
5.6.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with Pembrolizumab/Cisplatin, 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 without delay and within 24 hours to the Sponsor if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling 
or life-threatening complication to the mother or newborn).
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and the 
pregnancy reported to the Sponsor and followed as described above and in Section 7.2.2.
5.6.4
Use in Nursing Women
It is unknown whether Pembrolizumab is excreted in human milk and there are mixed reports on 
Cisplatin excretion. 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.
5.7
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 7.1.4 – Other Procedures.
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws consent.

Confirmed radiographic disease progression

Unacceptable adverse experiences as described in Section 5.2.1.2

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
Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) and 
Section 7.1.5 (Visit Requirements). After the end of treatment, each subject will be followed for 30 days 
for adverse event monitoring (serious adverse events will be collected for 90 days after the end of 
treatment as described in Section 7.2.3.1). Subjects who discontinue for reasons other than progressive 
disease will have post-treatment follow-up for 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 may be followed by telephone or in person for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
5.8
Subject Replacement Strategy
Patients who are unfit or unwilling to continue study after resection will be replaced. Patients who 
choose not to undergo surgical resection after initial dose of Pembrolizumab will be replaced. In addition, 
any patient who does not complete at least 1 week of adjuvant treatment will also be replaced.
5.9
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be provided so that 
appropriate adjustments to subject treatment can be made.
6.0 TRIAL FLOW CHART
6.1
Study Flow Chart

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Trial Period:
Screening Phase
Pre- 
surgery
Dose
Surgery
Adjuvant Treatment
End of 
Treatment
Post-Treatment
Post CRT
Treatment Dose Title:
Pre- 
screenin 
g (Visit 
1)
Main 
Study 
Screening 
(Visit 2) P
Pre- 
Surgery 
Dose P
1
2
3
4
5
6
7
8
9
10
NA
Discon
Safety 
Follow- 
upn
Survival 
Follow-
Upa
Scheduling Window
(Days):
-35 to -7
-22 to -7
-21 to -7
0
28 to
77
± 1
± 1
± 1
± 1
± 1
± 1
± 3
± 3
± 3
± 14
At time of 
Disconc
30 days
and 3 
months 
post 
discon
+/- 2
weeks
Adjuvant Treatment
(Week):
1
2
3
4
5
6
7
10
13
16
19
(20d)
20d
Administrative Procedures
Informed Consent
x
Xo
Xo
Inclusion/Exclusion 
Criteria
x
Demographics and 
Medical History
x
Prior and Concomitant 
Medication Review
x
X
X
X
X
X
X
X
X
X
X
X
X
x
Pembrolizumab 
Administrationj
x
x
x
x
x
x
X
Cisplatin 40mg/m2 
weekly if indicatedb
x
x
x
x
x
x
Radiation 2-2.2 Gy Fxs 
M-F
x
x
x
x
x
x

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Trial Period:
Screening Phase
Pre- 
surgery
Dose
Surgery
Adjuvant Treatment
End of 
Treatment
Post-Treatment
Post CRT
Treatment Dose Title:
Pre- 
screenin 
g (Visit 
1)
Main 
Study 
Screening 
(Visit 2) P
Pre- 
Surgery 
Dose P
1
2
3
4
5
6
7
8
9
10
NA
Discon
Safety 
Follow- 
upn
Survival 
Follow-
Upa
Scheduling Window
(Days):
-35 to -7
-22 to -7
-21 to -7
0
28 to
77
± 1
± 1
± 1
± 1
± 1
± 1
± 3
± 3
± 3
± 14
At time of 
Disconc
30 days
and 3 
months 
post 
discon
+/- 2
weeks
Adjuvant Treatment
(Week):
1
2
3
4
5
6
7
10
13
16
19
(20d)
20d
Post-study anticancer 
therapy status
x
x
Survival Status
X
X
X
x
Clinical 
Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
x
Full Physical 
Examinatione
X
x
x
Directed Physical 
Examination
X
X
X
x
x
X
x
Dental Exam
Xh
Dysphagia/Swallowing 
Function
Xl
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
x
x

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Trial Period:
Screening Phase
Pre- 
surgery
Dose
Surgery
Adjuvant Treatment
End of 
Treatment
Post-Treatment
Post CRT
Treatment Dose Title:
Pre- 
screenin 
g (Visit 
1)
Main 
Study 
Screening 
(Visit 2) P
Pre- 
Surgery 
Dose P
1
2
3
4
5
6
7
8
9
10
NA
Discon
Safety 
Follow- 
upn
Survival 
Follow-
Upa
Scheduling Window
(Days):
-35 to -7
-22 to -7
-21 to -7
0
28 to
77
± 1
± 1
± 1
± 1
± 1
± 1
± 3
± 3
± 3
± 14
At time of 
Disconc
30 days
and 3 
months 
post 
discon
+/- 2
weeks
Adjuvant Treatment
(Week):
1
2
3
4
5
6
7
10
13
16
19
(20d)
20d
ECOG Performance 
Status
x
x
x
x
x
x
x
x
x
x
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine 
or Serum -HCG
x
CBC with Differentialm
x
xk
x
x
x
x
x
x
x
x
x
x
x
Comprehensive Serum 
Chemistry Paneli, m
x
xk
x
x
x
x
x
x
x
x
x
x
x
Urinalysis
x
x
x
x
x
x
T3, FT4 and TSH
x
xk
x
x
x
x
x
PT/INR, PTT
x
xk
x
x
x
x
x
Efficacy Measurements
Tumor Imagingf
x
x

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Trial Period:
Screening Phase
Pre- 
surgery
Dose
Surgery
Adjuvant Treatment
End of 
Treatment
Post-Treatment
Post CRT
Treatment Dose Title:
Pre- 
screenin 
g (Visit 
1)
Main 
Study 
Screening 
(Visit 2) P
Pre- 
Surgery 
Dose P
1
2
3
4
5
6
7
8
9
10
NA
Discon
Safety 
Follow- 
upn
Survival 
Follow-
Upa
Scheduling Window
(Days):
-35 to -7
-22 to -7
-21 to -7
0
28 to
77
± 1
± 1
± 1
± 1
± 1
± 1
± 3
± 3
± 3
± 14
At time of 
Disconc
30 days
and 3 
months 
post 
discon
+/- 2
weeks
Adjuvant Treatment
(Week):
1
2
3
4
5
6
7
10
13
16
19
(20d)
20d
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Archival or Newly 
Obtained Tissue 
Collectiong
x
x
Correlative Studies 
Blood Collectiong
x
xk
x
x

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Trial Period:
Screening Phase
Pre- 
surgery
Dose
Surgery
Adjuvant Treatment
End of 
Treatment
Post-Treatment
Post CRT
Treatment Dose Title:
Pre- 
screenin 
g (Visit 
1)
Main 
Study 
Screening 
(Visit 2) P
Pre- 
Surgery 
Dose P
1
2
3
4
5
6
7
8
9
10
NA
Discon
Safety 
Follow- 
upn
Survival 
Follow-
Upa
Scheduling Window
(Days):
-35 to -7
-22 to -7
-21 to -7
0
28 to
77
± 1
± 1
± 1
± 1
± 1
± 1
± 3
± 3
± 3
± 14
At time of 
Disconc
30 days
and 3 
months 
post 
discon
+/- 2
weeks
Adjuvant Treatment
(Week):
1
2
3
4
5
6
7
10
13
16
19
(20d)
20d
a.
Patients will be followed every 3 weeks for first 3 months following CRT (post CRT above) and then every 3 months (every 12 weeks) for first 2 years 
followed by every 6 months (24 weeks) for a total of 5 years. Adjuvant weeks are numbered starting with first Pembrolizumab infusion which 
should begin 4-11 weeks after resection. FU visits can be conducted by phone if the study subjects will not see a study doctor on those days.
b.
Only patients with confirmed high risk features (+ECE and/or + margins) will receive Cisplatin.
c.
Time of discontinuation is either after last Pembrolizumab dose which will correspond to safety visit at week 20 or at time that patient discontinues 
treatment due to side effects, progression or withdrawal of consent.
d.
Safety visit will be completed on week 20 unless study discontinued early at which time it should be done at 30 days post-treatment. 30 day safety 
follow up visit only needed for subjects who withdraw or discontinue the study.
e.
Full physical exam only includes full head and neck and fiberoptic exam at week 19 but can be completed between week 11 and 20 to count towards 
week 19 assessment.
f.
Pre-operative scans including chest imaging preferably PET/CT and CT neck + contrast. (CT chest and CT neck + contrast would also be acceptable). 
If contrast contraindicated, MRI of neck is also acceptable. Post CRT imaging requires a PET/CT or CT of neck and chest.
g.
See procedure manual for tissue specifications and tubes required. MDA fresh tissue to be collected per MDA standard.
h.
Dental exam to be completed anytime before initiation of radiation.

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Trial Period:
Screening Phase
Pre- 
surgery
Dose
Surgery
Adjuvant Treatment
End of 
Treatment
Post-Treatment
Post CRT
Treatment Dose Title:
Pre- 
screenin 
g (Visit 
1)
Main 
Study 
Screening 
(Visit 2) P
Pre- 
Surgery 
Dose P
1
2
3
4
5
6
7
8
9
10
NA
Discon
Safety 
Follow- 
upn
Survival 
Follow-
Upa
Scheduling Window
(Days):
-35 to -7
-22 to -7
-21 to -7
0
28 to
77
± 1
± 1
± 1
± 1
± 1
± 1
± 3
± 3
± 3
± 14
At time of 
Disconc
30 days
and 3 
months 
post 
discon
+/- 2
weeks
Adjuvant Treatment
(Week):
1
2
3
4
5
6
7
10
13
16
19
(20d)
20d
i.
See Table 5 for full list.
j.
Pembrolizumab to be given 30 minutes before Cisplatin on days administered together.
k.
To be drawn before surgery (day of surgery or up to 4 days prior acceptable).
l.
This assessment must be performed prior to the start of radiation treatment.
m. For the Radiation and Pembrolizumab arm (intermediate risk), safety labs are not required on non-pembro administration weeks.
n.
3 month post-discontinuation visit is highly recommended, but optional.
o.
Informed consent may be obtained on the same day as screening procedures or on the same day as the pre-surgical pembro dose provided the 
subject has been given a copy of the consent form in advance of this visit to review or adequate time for review on the same-day has been 
documented.
p.
Pre-surgical dose and pre-screening visits may occur on the same day as long as consent is obtained, and eligibility is confirmed prior to prembro 
dose. All screening labs should be performed within 10 days of treatment initiation (the pre-surgical dose of Pemrolizumab).

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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the 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.
7.1.1
Administrative Procedures
7.1.1.1 Informed Consent
The Investigator or clinical coordinator must obtain documented consent from each potential 
subject prior to participating in a clinical trial.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature 
or by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.

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7.1.1.2 Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3 Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.
7.1.1.4 Prior and Concomitant Medications Review
7.1.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.
7.1.1.4.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.
7.1.1.5 Disease Details and Treatments
7.1.1.5.1
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status.
7.1.1.5.2
Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
7.1.1.5.3
Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial 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 

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the subject will move into survival follow-up.
7.1.1.6 Assignment of Screening/Study Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to allocation. Each subject will be assigned only 
one screening number. Screening numbers must not be re-used for different subjects. UCCC 
will be responsible for assigning screening numbers.
Any subject who is screened multiple times will retain the original screening number assigned 
at the initial screening visit. The screening number will be their study number as well once 
they are allocated to treatment.
7.1.1.7 Trial Compliance
Interruptions from the protocol specified treatment plan for greater than 3 weeks delay of 
Pembrolizumab doses, greater than five day delay for radiation treatment or more than 2 
skipped doses for Cisplatin treatment require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff. The 
total volume of Pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of Pembrolizumab administered. The instructions for 
preparing and administering Pembrolizumab will be provided in the Pharmacy Manual. 
Treatment with standard therapies will be prepared and administered as per the approved 
product label.
7.1.2
Clinical Procedures/Assessments
7.1.2.1 Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 11.2). 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 7.2 for detailed information regarding the assessment and recording 

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of AEs.
7.1.2.2 Full Physical Exam
The investigator or qualified designee will perform a full physical exam during the screening 
period. Clinically significant abnormal findings should be recorded as medical history. Full 
physical exam only includes full head and neck and fiberoptic exam at week 19 but can be 
completed between week 11 and 20 to count towards week 19 assessment.
7.1.2.3 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration at each visit, and at any safety follow-up visits.
7.1.2.4 Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified 
in the Trial Flow Chart (Section 6.0). Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure. Height will be measured at screening only.
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial 
treatment as specified in the Trial Flow Chart.
7.1.2.6 Tumor Imaging and Assessment of Disease
Imaging will be performed at independent sites and the assessment of response will be 
determined by independent site investigators.
7.1.2.6.1
Initial Tumor Imaging
Prior to resection all patients should preferably undergo PET/CT and CT neck with contrast. 
However, chest CT with or without contrast in addition to CT neck with contrast is acceptable.
Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 42 days prior to the first 
dose of trial treatment.
7.1.2.6.2
Post-Treatment Assessment Imaging
Twelve weeks (+/- 2 weeks) after completion of last radiation treatment (week 19 on flow 
chart), a PET/CT or CT of neck and chest should be performed to assess for early relapse. 
Patients will be followed clinically for recurrence after initial post-treatment imaging. No 

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further imaging is required after initial assessment unless there is suspicion of relapsed 
disease.
7.1.2.6.3
Assessment of Disease
Patients will be assessed for response 12 weeks after completion of radiation. A full physical 
exam including head and neck and fiberoptic exam should be performed if indicated per 
standard of care but not required per protocol every 12 weeks for first 2 years following CRT 
and then at least every 24 weeks for the next 3 years. For patients felt to have a relapse at 
any time, a thorough ENT exam as well as a repeat biopsy is recommended to confirm 
relapsed disease. Follow-up imaging in 4-8 weeks is also acceptable if biopsy is not yet felt 
to be necessary or is non-diagnostic. Patients will be followed clinically every three months 
and any concern for relapsed disease or progression should trigger either imaging or biopsy 
for confirmation. Patients will be followed for relapse for a total of 5 years.
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling
Any subjects with oropharyngeal cancers must have documented HPV status (either by p16 
or in situ).
Biopsy tissue:
For UC and all Sub-sites: Either a newly obtained core or archival biopsy tissue must be 
submitted (or determined available and sent at earliest convenience) prior to neoadjuvant 
Pembrolizumab dose.
For UC only: A biopsy block will be reviewed by the study pathologist (Ben Hinrichs) and 
retained in the histopathology core. All requests for tissues will be performed per study 
manual.
For all Sub-sites: Biopsy tissue should be submitted ideally as a block (preferred), or as 25 
FFPE slides and 5 tissue scrolls.
For MDA only: Patients, including those with available archival tissue, will have a mandatory 
fresh biopsy at enrollment. Fresh tissue from biopsy will be processed by the Gillison 
laboratory using normal procedures for single cell RNA sequencing.
Resection tissue:
For UC only: A resection block will be identified by the study pathologist (Ben Hinrichs) and 
retained in the histopathology core. All requests for tissues will be performed per study 
manual. Additional fresh tissue from resection should be collected and submitted per lab 
manual instructions. Fresh tissue will be prepared and cut by UC Pathology and/or Head and 
Neck Surgical Team (at least 500mg [0.5cm3] but if feasible, 2gm [2cm3] is preferable).

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For all Sub-sites: Resection tissue should be submitted as a block (preferred), or as 25 FFPE 
slides and 5 tissue scrolls from all sub-sites.
For MDA only: Fresh tissue from resection will also be collected. Fresh tissue from resection 
collected from MDA will be processed by the Gillison laboratory using normal procedures for 
single cell RNA sequencing.
Blood samples will be collected pre-dose of pre-surgical Pembrolizumab, immediately prior 
to resection, pre-dose first adjuvant Pembrolizumab dose and on adjuvant week 3 pre-dose 
of Cisplatin.
Detailed processing, shipping and handling will be provided in the procedures manual.
7.1.3
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below.
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5. 
Table 5 Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human 
chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
(β-hCG)†
Platelet count
Alanine aminotransferase 
(ALT)
Protein
Total 
thriiodothyronine (T3)
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity
Free tyroxine (T4)
Red Blood Cell 
Count
Lactate dehydrogenase (LDH)
Microscopic 
exam (If 
abnormal)
Thyroid stimulating 
hormone (TSH)
Absolute 
Neutrophil 
Count
Carbon Dioxide ‡
results are 
noted
Absolute 
Lymphocyte 
Count
(O2 or biocarbonate)
Urine 
pregnancy test
†
Prothrombin time 
PT/INR

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Uric Acid
Partial Thromboplastin 
Time (PTT)
Calcium
Chloride
Blood for correlative 
studies
Glucose
Phosphorus
Potassium
Sodium
Creatinine
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.
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing. Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.
7.1.3.2 Pharmacodynamic Evaluations
7.1.3.2.1 Peripheral Blood Monocyte Cell (PBMC) Isolation
40 mls of whole blood will be collected in purple top EDTA tubes at 4 timepoints prior to 
Pembrolizumab administration (on day -28-6 before resection), on day of resection (day 0), 
prior to Pembrolizumab administration on adjuvant week 1, before 2nd chemotherapy 
(Cisplatin) and radiation on week 3 (see study calendar) and transferred at room temperature 
within 24 hours to UCCC.
PBMCs and plasma will be separated by Ficoll centrifugation at UCCC. Plasma will be frozen 
and stored at -80oC. PBMCs will be either cryopreserved or immediately processed for flow 
cytometry and functional analysis. Stored plasma will be used for cytokine assays. Please see 
procedure manual for full details.

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7.1.3.2.2 Immunohistochemistry/Immunofluorescence/RNA In Situ Hybridization
Archived biopsy and resected tissue and if fresh resected tissue (Cincinnati only) will be 
shipped to University of Cincinnati for analysis. FFPE and Frozen sections will be used to 
analyze the immune cell phenotype (markers include but are not limited to CD4, CD8, PD-1, 
FOXP3, A2aR, PD-L1, CD73).
7.1.3.2.3 Genomic Analysis
When sufficient tissue is available, FFPE sections may be analyzed by RNA Sequencing and/or 
next generation whole exome sequencing to understand change in molecular pathways 
and/or prognostic genetic modifications as well as potential predictors of treatment 
response. At MDA, fresh biopsy and resection tissue will be used for single cell RNA seq 
analysis.
7.1.4
Other Procedures
7.1.4.1 Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.5
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1 Screening
Potential subjects will be evaluated to determine that they fulfill the entry requirements as 
set forth in Section 5.1. Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose trial 
treatment except for the following:

Laboratory tests and ECOG PS are to be performed within 10 days prior to the 
first dose of trial treatment.

For women of reproductive potential, a serum pregnancy test will be 

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performed within 72 hours prior to the first dose of trial treatment. A urine 
test may be considered if serum test is not appropriate.

Archival or newly obtained tumor collection is required to be obtained within 
28 days prior to the first dose of trial treatment.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria and 
they have not yet started treatment, however, re-screening tests will not be covered by study. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
7.1.5.2 Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
7.1.5.3 Post-Treatment Visits
7.1.5.3.1 Safety Follow-Up Visit
If subjects do not discontinue or withdraw early:

The mandatory Safety Follow-up Visit should correspond to approximately a week 
after the post-treatment imaging (week 19) on week 20's End of 
Treatment/Discontinuation visit.
If subjects discontinue or withdraw early:

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.
For all subjects, all AEs that occur prior to the Safety Follow-Up Visit should be recorded. 
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.
7.1.5.4 Follow-up Visits
Subjects will receive the follow-up PET/CT or CTs as outlined in flowchart in section 6.0. If 
subjects have no detectable relapse, they will complete the week 20 Safety Follow-up Visit 
(End of Treatment), and then they will move into the follow-up (post-treatment) stage of the 
study. Subjects will have follow-up visits every 3 months (12 weeks) either in person at a 
doctor visit or by phone (if being seen by outside oncologist) for the first 2 years and then 
every 6 months (24 weeks) for the next 3 years to monitor for relapse, or until time of 

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withdrawal of consent, or death, whichever comes first. Phone calls are an acceptable form 
of follow up for all subjects regardless if they are in the care of a local or outside oncologist. 
If subjects develop a relapse, they will continue to be followed at the time-points described 
in the flowchart in section 6.0. Every effort should be made to confirm relapse if suspected. 
During the follow up period, the follow up and survival follow up visits can be calculated in 
months rather than weeks in order to avoid potential protocol deviations with the 
scheduling window.
If patients have relapsed disease at time of post-treatment imaging, they should have follow- 
up imaging at discretion of investigator and, in addition to mandated 30-day safety follow- 
up, move into survival follow-up.
7.1.5.4.1 Survival Follow-up
Once a subject experiences confirmed disease relapse/progression or starts a new anti- 
cancer therapy, the subject moves into the survival follow-up phase and should be contacted 
by telephone, if seen by an outside oncologist, every  3 month (12 weeks) for the first 2 
years and then every 6 months (24 weeks) for the next 3 years to assess for survival status 
until death, withdrawal of consent, or at the end of the study, whichever occurs first.
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be
any unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol- 
specified procedure, whether or not considered related to the medicinal product or protocol- 
specified procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Merck’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. 
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use.
Adverse events may occur during the course of the use of Merck product in clinical trials or 
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.

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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 on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria 
is described in section 7.2.3.1.
If any adverse events related to study drug, pembrolizumab continue after the 30 days post 
treatment, they should be followed until resolution and/or if they are ongoing at the end of 
the follow up period, they should continue to be followed per standard of care per their 
MD.
New SAE/AE’s are to be collected and documented in the study EDC during follow up (past 
30 days following cessation of treatment) only if they are found to be related to study drug, 
pembrolizumab.
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck
For purposes of this trial, an overdose of Pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of Pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically 
indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220)
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck

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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 Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)
7.2.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck
7.2.3.1 Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
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;

Is another 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, must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety.
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.
Additionally, any serious adverse event, considered by an investigator who is a qualified 

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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 Sponsor and to Merck.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number: +1-215-993-1220
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2 Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI). ECIs identified 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, 
must be recorded as such on the Adverse Event case report forms/worksheets and reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety (Attn: 
Worldwide Product Safety; FAX 215 993-1220) regardless of attribution to study treatment, 
consistent with standard SAE reporting guidelines. Events of clinical interest for this trial 
include:
1. An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
1. Additional adverse events:

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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.
7.2.4
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. 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
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
Seriousness
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.

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

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No, there is not a
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to
reasonable possibility
administration of the Merck product is not reasonable OR there is another obvious cause of the AE.
Merck product
(Also entered for a subject with overdose without an associated AE.)
relationship

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7.2.5
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
8.0 STATISTICAL ANALYSIS PLAN
8.1
Statistical Analysis Plan Summary
8.1.1
Safety Analysis
The All-Patients-as-Treated (APaT) population will be employed for safety analyses. The 
safety endpoints are all adverse events graded from 1 to 5. Fisher’s exact test will be used 
to compare the proportion of adverse events among patients treated by Pembrolizumab + 
radiotherapy in this study with historical patients treated by radiotherapy only and compare 
patients treated by Pembrolizumab + radiotherapy + Cisplatin in this study with historical 
patients treated by radiotherapy + Cisplatin. Both the adverse events by grade as well as 
severe adverse event (SAE; yes/no) will be analyzed. RTOG 9501 data will be used for 
historical controls using targeted rates of 50% for CRT and 39% for RT. We expect that the 
addition of Pembrolizumab will not add undue toxicity over standard treatment and 
therefore, will give insight to the development of future trials.
8.1.2
Efficacy Analysis
All patients who received ≥1 dose of Pembrolizumab will serve as the primary analysis 
population in this study. The primary efficacy endpoint is to estimate the disease-free-survival 
(DFS) (i.e., time from treatment allocation to documented first relapse) at 1 year and 3 years. 
Key secondary efficacy endpoints include overall survival (OS) (i.e., time from treatment 
allocation to death due to any cause) at 1 year and 3 years. After resection, patients will be 
stratified based on adverse risk features. Kaplan-Meier method will be used to estimate 
survival rates for DFS and OS at 1 and 3 years. The survival rates will be compared with 
historical censored data (RTOG 9501: 66% in CRT and 58% in RT) using the log-rank test.
We will use estimates of the 95% CI for RTOG 9501 for DFS at 1 and 3 years (see below 
obtained from RTOG), in order to compare our results.

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RTOG 9501
Study Group
RT Intermediate Risk
CRT High Risk
Disease Free Survival 1 
year
(95%Cl)
68.8%
(59.4%-78.2%)
65.4%
(57.1%-73.6%)
Disease Free Survival 3 
year
(95%CI)
44.1%
(34%-54.2%)
45.5%
(36.9%-54.2%)
We would expect that adding Pembrolizumab would increase the DFS above these rates in 
RTOG 9501 and that our results would not fall outside of the lower bound of the CI above.
8.1.3
Power and Sample Size
Based upon RTOG 9501, we expect that DFS at 1 year and 3 years will be 65.4% and 53.5% 
respectively for patients with high risk features undergoing CRT. We expect to reach similar 
DFS in this study. We expect that at least 50% of patients (~40 patients) based on defined 
inclusion criteria will have high risk disease confirmed at resection (+ECE or + margins). With 
an expected sample size of at least N=40 in the CRT arm, and adding Pembrolizumab to 
Cisplatin and radiation, we expect to reach over 80% power to detect an increase of 21% in 
DFS at year 1 (86% DFS compared to 65% at 1 year) using the one-sample exact test at 
significance level, alpha=0.025 (one-sided). In comparison, assuming that we will reach a 
similar 1 year DFS of 68.8% in the radiation alone arm, by adding Pembrolizumab, and 
assuming N=40, we expect to reach over 80% power to detect an increase of 19% in DFS at 1 
year (88% DFS compared to 69% at 1 year). Every effort will be made to ensure that we have 
40 patients either reached the DFS endpoints or were followed for at least one year without 
disease recurrence in both strata.
8.1.4
Accrual Rate
At the University of Cincinnati, we see approximately 150 new cases of surgically treatable 
(oral cavity, larynx, hypopharynx) stage III/IV HNSCC per year. Of those, approximately 100% 
oral cavity, > 50% larynx, and 50% hypopharynx receive surgical resection and about 40% 

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require adjuvant therapy. We therefore, expect to accrue approximately 1-2 patients per 
month at UC. Per discussions with our other sites (OSU, Univ of Louisville, MUSC, USCD and 
Univ of Mich, MD Anderson) we expect to add ~ 1-2 patients a month from each as well. 
Therefore, we expect enrollment for this phase II study to be completed within 1 year based 
on 80 patients.
8.2
Statistical Analysis Plan
8.2.1
Safety Endpoints
The safety endpoints are all adverse events graded from 1 to 5 described in Section 7. 
The Lead-in population will be assessed for DLTs as described in section 5.2.2.3.1.
8.2.2
Efficacy Endpoints
Primary Endpoint
Disease Free Survival (DFS): measured from the time of treatment allocation to the time of 
discovery of the first evidence after treatment of any tumor (local, regional, metastatic, or 
second primary) or death from any cause. DFS at 1 and 3 years will be the primary efficacy 
endpoints.
Secondary Endpoints
Overall Survival (OS): defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up. OS at 1 and 3 years will be used as secondary endpoints.
Locoregional Control: failure was defined as the reappearance of tumor in the original 
tumor bed or the development of cervical-node metastases after treatment.
Biomarker analysis including proportion of T cell population subsets before and after 
immunotherapy both in tumor tissue and peripheral blood.
Exploratory Endpoints
Change in serum cytokines and T cell functionality before and after immunotherapy. DFS and 
OS will also be measured at 5 years similar to above.
8.2.3
Analysis Population

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8.2.3.1 Safety Analysis Population
The All Patients as Treated (APaT) population will be used for the analysis of safety data in 
this study. The APaT population consists of all subjects who received at least 1 dose of study 
treatment. Only those patients who continue treatment after resection will be compared to 
RTOG 9501 historical controls. Those who receive only pre-resection Pembrolizumab will still 
be analyzed for safety but there will be no direct comparison. Subjects will be included in the
treatment group corresponding to the trial treatment they actually received for the analysis 
of safety data. Subjects who take incorrect trial treatment for the entire treatment period 
will be included in the treatment group corresponding to the trial treatment actually 
received. At least one laboratory or vital sign measurement obtained subsequent to at least 
one dose of trial treatment is required for inclusion in the analysis of each specific parameter. 
To assess change from baseline, a baseline measurement is also required.
8.2.3.2 Efficacy Analysis Population
The analysis of primary efficacy endpoints are based on all patients who received ≥1 dose of 
Pembrolizumab. Subjects will be included in the treatment group to which they are stratified 
after resection.
8.2.4
Statistical Methods
8.2.4.1 Safety Analysis
Descriptive statistics will be provided for safety endpoints. Exact test will be used to compare 
patients treated by Pembrolizumab + radiotherapy in this study with historical patients 
treated by radiotherapy only (targeted rate of grade 3 and 4 adverse effects is 39%) and 
compare patients treated by Pembrolizumab + radiotherapy + Cisplatin in this study with 
historical patients treated by radiotherapy + Cisplatin (targeted rate of grade 3 and 4 adverse 
effects is 50%).
8.2.4.2 Disease Free Survival
Kaplan-Meier method will be used to estimate the disease free survival rates at 1, 3 and 5 
years among patients treated with combined Pembrolizumab, radiation therapy and +/- 
Cisplatin. 95% CI of these rates will be provided. These survival rates at 1 year will be 
estimated and compared with historical data (RTOG 9501: 65.4% in CRT and 68.8% in RT) via 
the one-sample exact test, point and confidence interval estimation. We will also use the 
log-rank test and Cox model to compare the DFS between the trial data and the historical 
data if patient level data obtained from RTOG 9501. An interim analysis will be done 
throughout study at the PI and statistician discretion.

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8.2.4.3 Overall Survival
Kaplan-Meier method will be used to estimate the overall survival rates at 1, 3 and 5 years 
among patients treated with combined Pembrolizumab, radiation therapy and +/- Cisplatin. 
95% CI of these rates will be provided. These survival rates will be compared with historical 
data using the log-rank test. We will also use Cox model to compare the historical data if 
patient level data obtained from RTOG 9501.
8.2.4.4 Biomarker Assessments
All biomarker measures will be summarized with descriptive statistics, i.e., percentages for 
categorical outcomes and means/medians for continuous outcomes, with corresponding 
standard errors and 95% confidence intervals. Responses will be tabulated by determined 
response and toxicities will be tabulated by type and grade. For IHC, the percentage of 
positive cells per area will be multiplied by the staining intensity for each tumor to determine 
quantitative expression pre- and post-treatment; a 25% change in expression will be 
considered a positive response. We will use descriptive statistics and graphical displays to 
evaluate change in serum markers and flow cytometry markers between pre- and post- 
treatment.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
9.1
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7 Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
Cisplatin 10mg
Lyophilized Powder for Injection
The Cisplatin will be supplied by commercially available product.
9.2
Packaging and Labeling Information

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Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.5
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the investigational 
pharmacy (if used per site) and the amount remaining at the conclusion of the trial.
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal 
are kept.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar or 
expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.

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10.1.1 Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data. By signing the consent form, the subject 
agrees to this process. If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations.
10.1.2 Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all sub-investigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law. This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.
Additionally, the investigator’s name and business contact information may be included when 
reporting certain serious adverse events to regulatory authorities or to other investigators. 
By signing this protocol, the investigator expressly consents to these uses and disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
10.2
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the Sponsor's 
responsibility to determine, based on these regulations, whether a request for Financial 

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Disclosure information is required. It is the investigator's/sub-investigator's responsibility to 
comply with any such request.
10.3
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
Practice (e.g., International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all applicable 
federal, state and local laws, rules and regulations relating to the conduct of the clinical trial.
10.4
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.
10.5
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
10.6
Data Management
10.6.1 Data Storage
Data collection and storage will be managed by the University of Cincinnati Cancer Center, 
Clinical Trials Office (UCCC CTO). The UCCC CTO will maintain storage of all clinical data in 
accordance with federal guidelines and GCP. Data will be entered in a secure, password 
protected storage database, OnCore and/or RedCap. All hardcopies of data will be securely 
maintained (in a locked room or cabinet) and will only be accessible to members of the study 
team.

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10.6.2 Data and Safety Monitoring
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
Any new significant finding that may affect the patient’s willingness to continue in the study 
will be shared with patients. Immediately after the study is approved and before the first 
patient is enrolled, investigators will meet, develop and finalize all measurements/variables 
for the study. Each patient, once enrolled, will be provided a unique ID for the study. Personal 
information, such as name, SSN, address, phone number and DOB, will be de-identified. 
Confidentiality will be maintained during the phases of the trial including monitoring, 
preparation of interim results, review, and response to monitoring recommendations.
Exceptions may be made under circumstances where there are serious adverse events or 
when it is deemed appropriate for patient safety.
Study progress will be monitored regularly by the UCCC Data Safety Monitoring Board 
(DSMB). Membership consists of persons independent of, and without any conflicts of 
interest with, this trial. The DSMB includes experts in the fields of relevant clinical expertise 
(oncology) and biostatistics.
It is the responsibility of the sponsor-investigator to ensure that the DSMB is apprised of all 
new safety information relevant to the study IND and the study. Study progress & safety 
information will be prepared by the DSMB Coordinator with input from the PI as to the 
current status of the trial. This compiled information presented to the DSMB will include: a 
narrative summary from the PI as to trial progress and identification of any trends of 
significance or explanation of any SAEs or other safety related events; the accrual rate with 
projected completion date for the accrual phase; exclusion rates and reasons; pretreatment 
characteristics of patients accrued when relevant; and, the frequency and severity of adverse 
events.
The DSMB will function in an advisory capacity and recommendations/requests from the 
DSMB will be reviewed by the sponsor-investigator and promptly addressed.
The study data from participating sub-sites will be reviewed remotely via RedCAP and in 
person by the Study Monitor as per the Clinical Monitoring Plan (Plan kept on file with UCCC 
CTO office).
11.0 APPENDICES
11.1 ECOG Performance Status

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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.
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI common terminology 
criteria for adverse events (CTCAE) version 4.0 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html)
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16. Beavis PA, Milenkovski N, Henderson MA, et al. Adenosine receptor 2A blockade 
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