Conditions: Squamous Cell Carcinoma of the Head and Neck
Keywords: radiation resected
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
A small group of skin cancers of the head and neck, called resected cutaneous squamous carcinomas, are more aggressive than most cancers of this type, even after being treated with standard therapy. This trial will use stronger treatment to look at the safety and effectiveness (efficacy) of combining a drug called Pembrolizumab with radiation after a cancer has already been treated to suppress secondary tumor formation in high risk cutaneous squamous cell cancer of the head and neck.

Primary Objective To assess safety by looking at the people with dose limiting responses

Detailed description:
Primary Objective:

To assess safety and estimate 1-year progression-free survival (PFS) of postoperative radiation therapy (RT) + concurrent and adjuvant Pembrolizumab in high risk resected cutaneous squamous cell cancer of the head and neck (cSCC-HN).

Secondary Objectives

1. To evaluate the relationship of baseline programmed death-ligand 1 (PD-L1) expression by tumor and tumor-infiltrating lymphocytes (TILs) to preliminary efficacy .
2. To phenotype tumor infiltrating lymphocytes and peripheral blood lymphocytes (PBLs), and investigate tumor suppressor populations including Tregs, myeloid-derived suppressor cells (MDSCs) and cluster of differentiation 8 (CD8) suppressor cells and assess ex vivo for effector function by cytokine production and cytotoxicity assays as well as suppressor function in assays with autologous PBLs.
3. To evaluate the tumor microenvironment (TME), and immune markers at the invasive margin of the tumor, including CD8, PD-1, PD-L1, TIM-3, galectin-9 or HMGB-1, BTLA and HVEM, as well as Lag-3, CTLA-4 and others.
4. To evaluate the genomic and/or transcriptomic profile of these tumors using RNA-seq /Whole Transcriptome Shotgun Sequencing

Trial Design:

This is a phase II trial evaluating the addition of concurrent and adjuvant fixed-dose pembrolizumab in combination with standard intensity-modulated radiation therapy (IMRT), in order to establish safety and estimate efficacy of this regimen to be tested in a subsequent randomized registration trial.

Thirty seven patients will be enrolled.

Arms:
arm 1: IMRT 60-66Gy for 6 weeks in combination with Pembrolizumab every 3 weeks for 16 weeks

Interventions: intervention 1: Pembrolizumab intervention 2: IMRT 60-66Gy
Intervention descriptions: intervention 1: 200mg every 3 weeks for 16 weeks given by IV infusion intervention 2: 60-66Gy for 6 weeks

Protocol document:
ICF_001.pdf: 
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%$!$($#$ !$%$)4!*--++-!*%%$
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Prot_SAP_002.pdf: 
Protocol v 12/04/2019 
  1 
STUDY NUMBER:  CASE 6316 
ClinicalTrials.gov #:   NCT03057613 
Protocol   Date: 
 December 4, 2019  
STUDY TITLE:  A Phase II Study of the Addition of Pembrolizumab to Postoperative 
Radiotherapy in Resected High Risk Cutaneous Squamous Cell Cancer of the Head and Neck 
PRINCIPAL INVESTIGATOR: Shlomo Koyfman, MD 
Case Comprehensive Cancer Center 
Radiation Oncology 
Cleveland Clinic  
Taussig Cancer Center 
9500 Euclid Avenue  
Cleveland, OH 44195 
 
    
CO-PI: 
Min Yao, MD 
Case Comprehensive Cancer Center 
University Hospitals Cleveland Medical Center 
Seidman Cancer Center 
11100 Euclid Avenue  
Cleveland, OH 44106 
 
 
Brian Gastman, MD 
Department of Plastic Surgery 
Cleveland Clinic 
9500 Euclid Ave  
Cleveland OH 44195 
 
  


 
Protocol v 12/04/2019                                                                                                                                                     2 
 
Jessica Geiger, MD 
 
 Case Comprehensive Cancer Center 
 
 Solid Tumor Oncology 
 
 Cleveland Clinic  
 
 Taussig Cancer Institute  
 
 9500 Euclid Avenue 
 
 
 
 
 
 Cleveland, OH 44195 
 
  
 
 
David Adelstein, MD 
 
Case Comprehensive Cancer Center 
 
Solid Tumor Oncology 
 
Cleveland Clinic  
 
Taussig Cancer Institute 
 
 
9500 Euclid Avenue 
 
 
 
 
 
Cleveland, OH 44195 
 
 
 
 
 
 
Nikhil Joshi, MD 
 
Case Comprehensive Cancer Center 
 
Radiation Oncology 
 
Cleveland Clinic 
 
Taussig Cancer Center 
 
9500 Euclid Avenue 
 
Cleveland, OH  44195 
 
 
 
  
 
 
STATISTICIAN:  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
STUDY COORDINATOR: 
  
 
 
 
 
 
 
 
 
 
  


 
Protocol v 12/04/2019                                                                                                                                                     3 
 
  
 
 
 
 
  
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center 
 
 
 
SUPPORT/FUNDING: 
 
Merck  
 
SUPPLIED AGENT(S):  
Pembrolizumab (Supplied by Merck) 
 
IND #:  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol v 12/04/2019                                                                                                                                                     4 
 
TABLE OF CONTENTS: 
 
1.0      Trial Summary 
 
2.0       Trial Design 
2.1       Trial Design 
2.2       Trial Diagram 
 
3.0         Objectives and Hypotheses 
3.1         Primary Objectives and Hypotheses 
3.2         Secondary Objectives and Hypotheses 
 
4.0           Background and Rationale 
4.1 
 Background 
4.1.1 
 Pharmaceutical and Therapeutic background 
4.1.2  
 Preclinical and Clinical Data 
4.2  
 Rationale 
4.2.1  
 Rationale for the Trial and Selected Subject population 
4.2.2 
 Rationale for Dose Selection/Modification 
4.2.3 
 Rationale for Endpoints 
4.2.3.1  Rationale for Efficacy Endpoints 
4.2.3.2   Rationale for Safety Endpoints 
4.2.3.3  Rationale for Correlative Endpoints/Biomarker Research 
 
5.0         Methodology 
5.1          Entry Criteria 
5.1.1       Subject Inclusion Criteria 
5.1.2       Subject Exclusion Criteria 
5.2  
Trial Treatments 


 
Protocol v 12/04/2019                                                                                                                                                     5 
 
5.2.1    Dose Selection/Modification 
5.2.1.1    Dose Selection 
5.2.1.2    Dose Modification  
5.2.2      Timing of Dose Administration 
5.2.3     Trial Blinding/Masking 
5.3          Randomization or Treatment Allocation 
5.4          Stratification 
5.5          Concomitant Medications/Vaccinations (allowed & prohibited) 
5.5.1       Acceptable Concomitant Medications 
5.5.2       Prohibited Concomitant Medications 
5.6          Rescue Medications & Supportive Care 
5.6.1       Supportive Care Guidelines 
5.7          Diet/Activity/Other Considerations 
5.7.1       Diet 
5.7.2      Contraception 
5.7.3      Use in Pregnancy 
5.7.4      Use in Nursing Women 
 
5.8         IMRT 
5.8.1   Immobilization and Simulation 
5.8.2   Target Delineation 
5.8.3   Critical Normal Structures  
5.8.4   Treatment Planning and Delivery 
5.8.5   Image Guidance for IGRT  
5.8.6   Definition of Normal Tissues/Organs at Risk (OARs) 
5.8.7   Dose Prescription 
5.8.8   Radiation Therapy Treatment Interruptions 
5.9  
  Subject Withdrawal/Discontinuation Criteria 
5.10 
  Clinical Criteria for Early Trial Termination 
 
6.0        Trial Flow Chart 
6.1 
 Study Flow Chart 
 
7.0 
           Trial Procedures 
7.1 
  
Trial Procedures 
7.1.1   
Administrative Procedures 
7.1.1.1          Informed Consent 
7.1.1.1.1         General Informed Consent  


 
Protocol v 12/04/2019                                                                                                                                                     6 
 
7.1.1.2         Inclusion/Exclusion Criteria 
7.1.1.3         Medical History 
7.1.1.4         Prior and Concomitant Medications Review 
7.1.1.5         Disease Details and Treatments 
7.1.2            Clinical Procedures/Assessments 
7.1.2.1         Adverse Event (AE) Monitoring 
7.1.2.2         Physical Exam 
7.1.2.3         Vital Signs 
7.1.2.4         Eastern Cooperative Oncology Group (ECOG) Performance Scale 
7.1.2.5         Tumor Imaging and Assessment of Disease 
7.1.2.6         Tumor Tissue Collection and Correlative Studies Blood Sampling 
7.1.3             Laboratory Procedures/Assessments 
7.1.3.1         Withdrawal/Discontinuation 
7.1.4            Visit Requirements 
7.1.4.1         Screening 
7.1.4.2         Treatment Period 
7.1.5.3            Follow-Up Visits 
 
7.2 
          Assessing and Recording Adverse Events 
7.2.1            Definition of an Overdose for This Protocol and Reporting of Overdose to the    
                       Sponsor and to Merck                   
7.2.2            Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
7.2.3            Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1         Serious Adverse Events 
7.2.3.2         Events of Clinical Interest 
7.2.4            Evaluating Adverse Events 
7.2.5            Sponsor Responsibility for Reporting Adverse Events 
7.2.6            Investigator Responsibility for Reporting Adverse Events 
 
8.0 
           Statistical Analysis Plan 
8.1  
 
Study Design  
8.2               Justification of Design and Sample Size:    
8.3  
            Statistical Analysis Plan 
 
9.0 
            Labeling, Packaging, Storage and Return of Clinical Supplies  
9.1 
            Investigational Product  
9.2 
            Packaging and Labeling Information 
9.3 
            Clinical Supplies Disclosure 
9.4 
            Storage and Handling Requirements 
9.5 
            Returns and Reconciliation 
 
10.0 
           Administrative and Regulatory Detail  
10.1.1   
Confidentiality of Data 
10.1.2   
Confidentiality of Subject Records 
10.1.3   
Confidentiality of Investigator Information 
10.1.4   
Confidentiality of IRB/IEC Information 


 
Protocol v 12/04/2019                                                                                                                                                     7 
 
10.2   
Compliance with Financial Disclosure Requirements 
10.3   
Compliance with Law, Audit and Debarment 
10.4   
Compliance with Trial Registration and Results Posting Requirements 
10.5 
            Quality Management System 
 
10.6                 Data Management 
 
10.7                Appendices 
10.8              ECOG Performance Status 
10.9 
            Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
10.10  
Tissue and Blood processing for correlative science 
                        
 
11.0  References 
 
12.0 
Protocol Amendments 
 
           Summary of Changes v08/03/2017 
                       Summary of Changes v08/29/2017 
                       Summary of Changes v09/27/2017 
 
           Summary of Changes v10/30/2018 
 
           Summary of Changes v12/04/2019 


 
Protocol v 12/04/2019                                                                                                                                                     8 
 
1.0 TRIAL SUMMARY 
Protocol Number/Title 
CASE 6316 A Phase II Study of the Addition of 
Pembrolizumab to Postoperative Radiotherapy in Resected 
High Risk Cutaneous Squamous Cell Cancer of the Head and 
Neck 
Study Phase 
II  
Brief Background/Rationale
 
 
 
While outcomes in resected cutaneous squamous carcinomas 
are typically very favorable, a subset of high risk resected 
cancers in the head and neck have a more aggressive disease 
course despite the routine use of adjuvant radiotherapy.  This 
trial is a treatment intensification protocol which seeks to 
establish the safety and efficacy of concurrent and adjuvant 
Pembrolizumab in combination with radiation in the 
adjuvant treatment of high risk cutaneous squamous cell 
cancer of the head and neck.   
Primary Objective  
To assess safety (% of DLTs) and estimate 1-year PFS of 
postoperative RT + concurrent and adjuvant Pembrolizumab 
in high risk resected cSCC-HN. 
Secondary Objective(s) 
Patterns of Failure  
Correlative Objective(s) 
 
1) To evaluate the relationship of baseline PD-L1 
expression by tumor and tumor-infiltrating 
lymphocytes (TILs) to preliminary efficacy. 
2) To phenotype tumor infiltrating lymphocytes and 
peripheral blood lymphocytes (PBLs), and 
investigate tumor suppressor populations including 
Tregs, MDSCs and CD8 suppressor cells and assess 
ex vivo for effector function by cytokine production 
and cytotoxicity assays as well as suppressor 
function in assays with autologous PBLs.   
3) To evaluate the tumor microenvironment (TME), 
and immune markers at the invasive margin of the 
tumor, including CD8, PD-1, PD-L1, TIM-3, 
galectin-9 or HMGB-1, BTLA and HVEM, as well 
as Lag-3, CTLA-4 and others. 
4) To evaluate the genomic and/or transcriptomic 
profile of these tumors using RNA-seq /Whole 
Transcriptome Shotgun Sequencing    
Sample Size 
37 participants 
Age >18, Male and females eligible 
Disease sites/Conditions 
Skin cancer of the head and neck (squamous) 
Interventions 
IMRT 60-66Gy over 6 weeks 
 
Pembrolizumab every 3 weeks for 16 weeks (6 doses) 
 
 


 
Protocol v 12/04/2019                                                                                                                                                     9 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
•  This is a phase II trial evaluating the addition of concurrent and adjuvant fixed-dose 
pembrolizumab in combination with standard IMRT, in order to establish safety and 
estimate efficacy of this regimen to be tested in a subsequent randomized registration trial. 
Thirty seven patients will be enrolled.  
• The primary safety endpoint will be proportion of DLTs. The primary efficacy endpoint will 
be 1-year PFS. The primary signal to move forward with a subsequent confirmatory 
randomized study will be a 24% overall DLT rate and a favorable 1yr PFS estimate 
compared to historical controls.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol v 12/04/2019                                                                                                                                                     10 
 
2.2 Trial Diagram 
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
 
3.1 
Primary Objective(s) & Hypothesis(es) 
 
(1) Objective: To assess safety and estimate 1-year PFS of postoperative RT + concurrent and 
adjuvant Pembrolizumab in high risk resected cSCC-HN. 
Hypothesis:  The addition of concurrent and adjuvant Pembrolizumab to postoperative RT in 
high risk cutaneous SCC will be safe and yield favorable 1yr PFS results.   
 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) 
Objective:   
5) To evaluate the relationship of baseline PD-L1 expression by tumor and tumor-infiltrating 
lymphocytes (TILs) to preliminary efficacy . 
6) To phenotype tumor infiltrating lymphocytes and peripheral blood lymphocytes (PBLs), 
and investigate tumor suppressor populations including Tregs, MDSCs and CD8 suppressor 


 
Protocol v 12/04/2019                                                                                                                                                     11 
 
cells and assess ex vivo for effector function by cytokine production and cytotoxicity assays 
as well as suppressor function in assays with autologous PBLs.   
7) For those participants for whom tumor tissue is available, we will evaluate the tumor 
microenvironment (TME), and immune markers at the invasive margin of the tumor, 
including CD8, PD-1, PD-L1, TIM-3, galectin-9 or HMGB-1, BTLA and HVEM, as well 
as Lag-3, CTLA-4 and others.   
8) If sufficient tumor is available, we will also evaluate the genomic and/or transcriptomic 
profile of a subset of tumors using RNA-seq /Whole Transcriptome Shotgun Sequencing    
 
Hypotheses:   
1) Baseline PD-L1 expression will not be associated with 1yr PFS. 
2) Peripheral immune profiles on PBMC will dynamically change from baseline through 
treatment and after completion of therapy and correlate with 1yr PFS.  
3) Changes in the TME at the marginal edge of the tumor will correlate with 1yr PFS and be 
marker dependent. 
4) Baseline genomic/proteomic tumor profiles will correlate with 1yr PFS 
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.  


 
Protocol v 12/04/2019                                                                                                                                                     12 
 
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type 
(V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases 
SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3, PKC and ZAP70 which are involved in the CD3 T-cell signaling 
cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct 
from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-
cells, T regs and Natural Killer cells.  Expression has also been shown during thymic development 
on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of 
cell types, including non-hematopoietic tissues as well as in various tumors .  Both ligands are type 
I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and 
contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.  
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific 
T-cell expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 
and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the 
treatment of patients with unresectable or metastatic melanoma and disease progression following 
ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 


 
Protocol v 12/04/2019                                                                                                                                                     13 
 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Disease Background: 
Cutaneous squamous cell cancer (cSCC) is the second most common cancer in the U.S. with an 
estimated incidence of over 700,000 people annually.1 While most are highly curable with surgery 
alone, there is a well-recognized subset of patients who demonstrate an aggressive clinical phenotype 
marked by locoregional recurrence and/or distant metastatic spread.  These patients are 
overwhelmingly comprised of cSCC of the head and neck (cSCC-HN), and frequently demonstrate 
high risk features including large T3/4 tumors, nodal involvement, lymphovascular space invasion, 
perineural invasion, and multiply recurrent disease.2  In a recent population based study, as many as 
5,600 patients were estimated to develop nodal metastases and up to 8,700 deaths were attributable 
to cSCC.1  Postoperative radiotherapy has been shown in a number of studies to reduce locoregional 
recurrence and in some studies improve overall survival in this disease.3-6  However, there are 
currently no randomized data supporting the use of systemic therapy concurrently and/or adjuvantly 
to RT, and significant failure rates, both locoregionally and distantly, underscore the limited 
treatment options for these patients and the need for intensification strategies in addition to RT.   
While radiation is typically a highly effective treatment for both cutaneous and mucosal SCC of the 
head and neck, a mechanism of radioresistance that is becoming increasingly clarified is the tumor 
microenvironment altering and inhibiting the innate immune response of the host.  As a result of 
recruitment of inhibitory immune cells (e.g. Tregs; activated macrophages), T-cell activation is 
suppressed and treatment resistance emerges.  PD-1 is expressed by multiple immune cells (e.g. 
cytotoxic T cells, NK cells, dendritic cells) and when coupled with its ligands PD-L1 and PD-L2, the 
complex promotes “immune escape” in a number of cancers. 7 7, 13, 14    In mucosal head and neck 
cancer specifically, PD-L1 expression is common, and has been demonstrably linked to the immune-
privileged, invasive front of HPV + SCC.8,9 A recently completed Phase Ib/II study in mucosal head 
and neck cancer supported this hypothesis as Pembrolizumab, a high-affinity IgG4 mAb which 
blocks the interaction of PD-1 with both PD-L1 and PD-L2, produced impressive response rates 
(20% by RECIST criteria) in heavily pretreated recurrent/metastatic patients.10  
Cutaneous SCC of the head and neck shares many parallels with mucosal SCC as they are both 
considered to be more prevalent in “immune-weakened” states. While mucosal disease demonstrates 


 
Protocol v 12/04/2019                                                                                                                                                     14 
 
defective antigen presenting cells (APC), and quantitative and qualitative T lymphocyte deficiencies, 
skin cancer is a disease of aging as older, less robust immune systems become less effective at 
preventing sun damaged mutated skin cells from cancerization.11,12 There is early emerging work 
implicating PD-1 in particular in cutaneous SCC pathways. A recent study demonstrated that immune 
neutralization of PD-1+ cells resulted in decreased papilloma incidence in mice which was associated 
with CD4+ and CD8+ T cell infiltrates, as well as increased interferon- and decreased transforming 
growth factor- production within tumors, supporting the role of PD-1 blockade in SCCS.13   Another 
study associates a higher incidence of seropositivity to particular strains of papillomavirus in organ 
transplant patients as a potential mechanism for the increased incidence in cSCC in these patients, 
highlighting an important potential overlap between cSCC-HN and mucosal head and neck cancer, 
known to be frequently HPV induced.14  
Radiotherapy induces immune responses by releasing tumor antigen, recruiting chemokines and 
making cells more vulnerable to T-cell killing.15  PD-L1 upregulation following RT in the tumor 
microenvironment has been recently demonstrated, and inhibiting its activity using anti-PD-L1 
treatment enhanced the effectiveness of RT via a cytotoxic T-cell dependent mechanism.16   A recent 
landmark study in melanoma analyzed samples from 46 patients treated with Pembrolizumab and 
found that tumor regression after therapeutic PD-1 blockade required pre-existing CD8(+) T cells 
that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.17 This emerging 
picture of the importance of the immune response in general, and the PD-1 pathway in particular, 
being highly associated with carcinogenesis and response to RT provides a sound basis to pursue 
PD-1 blockade in high risk cSCC-HN.  
   
4.2.2 Rationale for Dose Selection/Regimen/Modification  
 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical activity 
of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose levels, 1 
mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid 
tumors.  All three dose levels were well tolerated and no dose-limiting toxicities were observed.  
This first in human study of MK-3475 showed evidence of target engagement and objective 
evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No 
MTD has been identified to date.  Recent data from other clinical studies within the MK-3475 
program has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient 
for target engagement and clinical activity. 


 
Protocol v 12/04/2019                                                                                                                                                     15 
 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  A population 
pharmacokinetic analysis has been performed using serum concentration time data from 476 
patients. Within the resulting population PK model, clearance and volume parameters of MK-3475 
were found to be dependent on body weight. The relationship between clearance and body weight, 
with an allometric exponent of 0.59, is within the range observed for other antibodies and would 
support both body weight normalized dosing or a fixed dose across all body weights.  MK-3475 
has been found to have a wide therapeutic range based on the melanoma indication.  The 
differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 
for MK-3475 in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W 
(i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between the 
NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure 
between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 
3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as 
assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose 
of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained 
with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure 
range established in melanoma as associated with maximal efficacy response and 3) will maintain 
individual patients exposure in the exposure range established in melanoma that are well tolerated 
and safe.  


 
Protocol v 12/04/2019                                                                                                                                                     16 
 
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. 
Recent in vitro studies have demonstrated enhanced radiosensitization with the administration of 
Pembrolizumab prior to the initiation of radiotherapy (Personal communication: Robert Ferris MD, 
PhD).  As such, the initial dose of Pembrolizumab will be given in this study the week prior to the 
beginning of IMRT.  This is consistent with other trials investigating the combination of PD-1 
inhibitors and RT being done in the cooperative group setting.  A pilot study that investigated the 
safety of adding Pembrolizumab to head and neck IMRT in addition to weekly cisplatin was recently 
presented at ASCO 2017.  Powell, et al reported excellent safety profile of 27 patients with locally 
advanced head and neck cancer treated with chemoradiation with weekly cisplatin, and 70Gy in 35 
fractions of IMRT along ith Pembrolizumab 200mg fixed dose IV every 3 weeks beginning 4-7 days 
prior to the initiation of radiation 2 doses concomitant with IMRT and 5 additional doses post IMRT.  
21 patients (78%) completed all planned doses of Pembrolizumab. 3 discontinued due to irAEs (G2 
peripheral motor neuropathy, G3 AST elevation, G1 Lhermitte-like syndrome). 3 discontinued due 
to protocol reasons (early neck dissection -2 pts, prolonged hospitalization-1 pt). All pts completed 
the full radiation dose (70 Gy) without significant delay (defined as > 5 days). 23 (85%) received the 
goal target dose of cisplatin (200 mg/m2). There was one patient death due to concurrent illness, 
unrelated to treatment.18  Based on these results, the NRG Oncology HN-003 study which was 
designed as a phase I safety study of the addition of Pembrolizumab to postoperative head and neck 
IMRT and weekly cisplatin discontinued their planned phase I safety study and converted to an open 
label efficacy signal study.  We therefore feel quite confident in the safety of our proposed regimen 
as our study involves less extensive IMRT fields and does not include any concurrent chemotherapy.  
We will however monitor DLTs very carefully and include that as a co-primary endpoint of the study. 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
1yr PFS in this patient cohort is suboptimal, and an important measure of disease control.   
 
4.2.3.2 Safety Endpoints 
The primary safety endpoints for this study will be dose limiting toxicity (DLT).  DLT for this study 
is defined as the occurrence of a severe adverse event (AE) listed below that is at least possibly 


 
Protocol v 12/04/2019                                                                                                                                                     17 
 
related to pembrolizumab, and occurs from the initiation of treatment thru 30 days after the final 
administration of the study treatment.  AEs will be graded according to NCI CTCAE version 4.0.  
At the completion of the study, a total DLT rate will be assessed.  A DLT rate of <24% will be 
deemed acceptable and if met, the regimen will be deemed appropriate for future study in randomized 
studies.   
The following events will be considered a DLT:  
• Any  Grade 3  immune-related toxicity (including graft rejection), except: 
o Grade 3 dermatologic toxicity resolving to Grade 1 or lower with < 2 weeks of 
systemic immunosuppression 
• Any  Grade 3 non hematologic toxicity except: 
o Grade 3 in-field radiation dermatitis for which IMRT is not held or held  1 week (5 
fractions) 
o Grade 3 mucositis for which IMRT is not held or is held  1 week (5 fractions) 
o Asymptomatic Grade 3-4 hypomagnesemia or hypokalemia 
o Grade 3 fatigue 
o Grade 3 dysphagia or feeding tube use 
o Grade 3 weight loss 
o Grade 3 pain 
• Grade 3 neutropenia with fever (oral temperature > 39°C) 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 neutropenia with/without fever, requiring antibiotics 
• Grade 4 thrombocytopenia 
• Toxicity of any grade that results in inability to complete IMRT within 8 weeks 
 
4.2.3.3 Rationale for Correlative Endpoints/Biomarker Research 
 
Central hypothesis:  Cutaneous squamous cell carcinoma (CSCC) is responsive to combination of 
PD-1 inhibition and radiation therapy. 
To test our hypothesis correlatively we propose the following aims: 
 
Aim 1. To correlate baseline PD-1 expression in the tumor with disease related outcomes. 


 
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Rationale: It is unknown whether patients with tumors that express higher levels of PD-1 
preferentially respond compared to those that do not.  As such, this will be systematically evaluated 
on all patients. 
Research Plan:   FFPE tissue blocks will be collected from patients and slides will be cut for 
subsequent biomarker staining. Analysis of PD-L1 expression will be performed by 
immunohistochemical staining using the Merck assay.  Either complete circumferential or partial 
linear plasma membrane staining will constitute positive PD-L1 staining.  A cut-off of  5% tumor 
cell membrane staining will be reported as positive. 
 
Aim 2. To define response to radiation/PD-1 inhibition based on tumor microenvironment 
and peripheral blood alterations in patients with CSCC. 
Rationale:  Many solid tumors do respond to checkpoint inhibitors.  Little is known in regards to 
CSCC patients who will or will not respond to the proposed treatment regimen of post-operative 
radiation and anti-PD-1 therapy.   
Research Plan:  Prospectively we will stratify study patients into two groups: those that do, or do 
not respond to the proposed therapy based on historical published data from our institution.  The 
following are the proposed assays for evaluation. 
 
A. Peripheral Blood Lymphocytes  
Flow cytometry:  Peripheral blood samples drawn from patients pretreatment and at specified times 
post treatment will be isolated by centrifugation.  Surface biomarker expression will be assessed by 
FACS similar to the analysis of tumor-resident lymphocytes.  Staining will evaluate  CD3, CD4, 
CD8 expression as well as cytotoxic markers (perforin, FasL, Granzyme A&B,  markers of 
dysfunction/exhaustion  (PD-1, TIM-3, Lag-3), and  markers characteristic of regulatory cells 
(Foxp3, CD25, GITR, CD27, CD28) and markers for myeloid derived suppressor cells.  Finally, 
we will assess TCR clonal diversity using PCR methods. 
 
 
B. Tissue 
Patients for whom fresh tissue is available (e.g. if they consented to other tissue banking IRB 
approved protocols such as IRB 3164 or 15-1580) or for whom FFPE is available, may have some 
or all of the following additional correlative studies performed, depending on tissue availability.  
These include: 


 
Protocol v 12/04/2019                                                                                                                                                     19 
 
Immunohistochemistry:  Tumor tissues will be stained and evaluated for indicators of inflammation 
including the relative degree of lymphocyte infiltration and characterization of immune populations 
via expression of CD3, CD4, and CD8, as well as the expression of various regulatory-associated 
markers including PD-1, PDL-1, and galectin-9. 
Flow cytometry:  tumor tissue will be disassociated by digestion with collagenase/hyaluronidase, 
prior to FACS analysis of immune population phenotype including CD3, CD4, CD8, and the 
following cytotoxic markers:  perforin, FasL, Granzyme.  Studies will also evaluate markers of 
dysfunction/exhaustion including PD-1, TIM-3, Lag-3, TIGIT and markers associated with 
regulatory cells/suppression including Foxp3, GITR, CD25, CD27, and CD28 and markers for 
myeloid derived suppressor cells.  Finally, we will assess TCR clonal diversity using PCR 
methods. 
Cytoxicity assays: Tumor resident CD3+CD8+ T cells will be purified by FACS sorting and 
functionally evaluated for recognition of autologous SCCA and/or general functional ability.  
Readouts will include proliferation (CFSE dilution, 3-H thymidine incorporation), cytotoxicity (51-
Cr release, CD107a staining), and production of interferon gamma and IL-2. 
Gene expression analysis: Tumor tissue specimens will be checked by a pathologist to ensure that 
each contains at least 60% tumor content.  Total RNA will then be isolated from 30 to 60 mg of 
snap-frozen tissue followed by purification of mRNA.  Isolated mRNA will then be used to 
construct a library using the non-stranded TruSeqs protocol, which will then be subjected to high-
throughput shotgun sequencing using the Illumina HiSeq 2500 platform by the Case Western 
Reserve University Genomics Core.  Data analysis of transcription profiles will be done in 
association with the CWRU Genomics Core and correlated with treatment outcome and overall 
survival data. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1) Histologic diagnosis of cutaneous squamous cell carcinoma of the head and neck that 
has been resected with no evidence of gross residual disease (margin positivity is 
acceptable).  
2) Patients must have undergone resection of the disease and demonstrate high risk 
pathologic features including: 


 
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 Invasion of the axial skeleton or skull base or skull base foramina 
 Node positive disease 
 Tumor greater than 2cm with any 1 additional feature, including: 
 Recurrent Disease 
 Perineural invasion 
 Lymphovascular space invasion 
 Poorly differentiated histology 
 Positive Margins 
 Satellitosis or in-transit metastases 
• Note: Not all patients with tumors >2cm with one additional risk factor may be ideal 
candidates for this study, such as patients with only focal perineural invasion without other 
adverse features.  Clinical judgment should be used by the investigator in carefully selecting 
patients believed to be at significant risk of recurrence with radiation alone.  
3) Patients are required to have CT neck and chest or PET/CT and have no documented 
evidence of distant metastases 
4) Patients must not have a history of the following immunosuppressive conditions: bone 
marrow transplantation and/or organ transplants and/or chronic rheumatic conditions 
that require active immunosuppressive therapy.  Patients with a history of chronic 
lymphoid or leukemic malignancies which are not under active therapy (no active 
therapy within the last 3 months) will be eligible. Patients with chronic lymphoid or 
leukemic malignancies are eligible with or without active disease as long as they have 
not had treatment within the past three months. 
5) Patients may not have had prior therapy with a checkpoint inhibitor (e.g. anti-CTLA-4, 
anti-PD-1 or anti-PD-L1 therapy);  
6) Patients may not have had prior radiotherapy (>30Gy) to the area requiring treatment 
that would result in any overlap of tissue in both fields 
7) Patients may have received chemotherapy or radiation for a previous, curatively treated 
malignancy provided at least 2 years have elapsed and there is no current evidence of 
disease (patients with previous or concurrent additional skin cancers will be eligible).  
Patients with chronic lymphoid or leukemic malignancies are eligible with or without 
active disease as long as they have not had treatment within the past three months. 
8) Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 


 
Protocol v 12/04/2019                                                                                                                                                     21 
 
9) Age  18 
10) Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
11) 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.  
12) 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. 
13) Patients must have adequate laboratory values as per Table 1. 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute 
neutrophil 
count 
(ANC) 
1,500 /mcL 
Platelets 
100,000 / mcL 
Hemoglobin 
9 g/dL or 5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
1.5 X upper limit of normal (ULN) OR
 
60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
 1.5 X ULN OR 
 
Direct bilirubin  ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT)
 2.5 X ULN  OR
 5 X ULN for subjects with liver metastases 


 
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Albumin 
>2.5 mg/dL 
 
 
 
aCreatinine clearance should be calculated per institutional standard. 
 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment. 
2. Has a known history of active TB   (Bacillus Tuberculosis) 
 
3. Hypersensitivity to pembrolizumab. 
4. Has a history of the following immunosuppressive conditions: bone marrow transplantation, 
and/or organ transplants and/or chronic rheumatic conditions that require active 
immunosuppressive therapy.  Patients with chronic lymphoid/leukemic malignancies that 
have undergone treatment in the last 3 months will be ineligible.  
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 
or who has not recovered (i.e.,  Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiotherapy within 2 weeks 
prior to study Day 1 or who has not recovered (i.e.,  Grade 1 or at baseline) from adverse 
events due to a previously administered agent. 
- 
Note:  Subjects with  Grade 2 neuropathy are an exception to this criterion and 
qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or a separate primary squamous cell 
carcinoma of the skin. Patients with chronic lymphoid or leukemic malignancies are eligible 
with or without active disease as long as they have not had treatment within the past three 
months.  
8. Has metastatic disease.  


 
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9. Has known history of, or any evidence of active, non-infectious 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.   
12. Has known psychiatric or substance abuse disorders that 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 received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
15. Has known active Hepatitis B (e.g., HBsAg reactive) or 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 
200 mg flat 
dose 
Q3W 
IV infusion 
Week 1, 4, 7, 10, 13, 
16 
Experimental
IMRT 
60-66Gy 
5 days/wk 
NA 
Wks 2-7 for 30 
treatments 
Standard of 
Care 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
 


 
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The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background 
and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modification  
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 3 below. See Section 5.6.1 and Events of 
Clinical Interest Guidance Document for supportive care guidelines, including use of corticosteroids. 
There are no dose reductions for pembrolizumab. If the subject meets retreatment criteria, the full dose of 200 
mg will be administered. If subjects do not meet retreatment criteria, then the dose of pembrolizumab will be 
SKIPPED. 
 
Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose. 
3-4 
Permanently discontinue 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for 
new 
onset 
Type 
1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia 
associated with evidence 
of beta cell failure.  
 
Resume pembrolizumab when patients are 
clinically and metabolically stable. 
Hypophysitis 
2-3
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism 
3 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 


 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
or less of prednisone or equivalent per day within 
12 weeks. 
4
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with 
pembrolizumab can be 
continued while 
treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued 
while treatment for the thyroid disorder is 
instituted. 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity1 
3 or Severe 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
1 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug 
has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.  Note: Pembrolizumab does not 
need to be held for grade 3 dysphagia, grade 3 pain, grade 3 weight loss, or grade 3 fatigue, which are expected 
toxicities for head and neck radiation and will be managed aggressively by treating investigators per standards of 
care. 
 
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. 
5.2.2 Timing of Dose Administration 
 
The first dose of Pemrbolizumab should be administered week 1, the week prior to the beginning of 
radiotherapy (5-10 days preRT is acceptable).  RT will begin the week after the initial infusion of 
Pembrolizumab, typically on a Monday or Tuesday.  Trial treatment should be administered as per 
the Trial Flow Chart (Section 6.0).  Trial treatment may be administered up to 3 days before or after 


 
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the scheduled Day 1 of each cycle due to administrative reasons. All trial treatments will be 
administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given 
the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the treatment 
administered. 
5.3 
Randomization or Treatment Allocation 
All patients will receive IMRT and Pembrolizumab as described above. 
 
5.4 
Stratification 
This is a phase II trial evaluating the addition of concurrent and adjuvant fixed-dose pembrolizumab 
in combination with standard IMRT, in order to establish safety and estimate efficacy of this regimen 
to be tested in a subsequent randomized registration trial. Thirty seven patients will accrued.  The 
primary safety endpoint will be proportion of DLTs. The primary efficacy endpoint will be 1-year 
PFS. The primary signal to move forward with a subsequent confirmatory randomized study will be 
a 20% overall DLT rate and a favorable 1yr PFS compared to historical controls.  
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The investigator should discuss any questions regarding this with the Merck Clinical team.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur during 


 
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the trial period, documentation of drug dosage, frequency, route, and date may also be included on 
the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded.  Concomitant medications administered 
after 30 days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined 
in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or 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 for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below and in greater detail in the ECI guidance 
document. 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 


 
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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 (as outlined in 
the ECI guidance document). 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. Suggested conditional procedures, as appropriate, can 
be found in the ECI guidance document. 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   


 
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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. 


 
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 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  
 
 
Table 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 


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


 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
Hospitalization may be 
indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration.
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
 
 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is 45 years of age and has not had menses for greater 
than 1 year will be considered postmenopausal), or 3) not heterosexually active for the duration of 
the study.  The two birth control methods can be either two barrier methods or a barrier method plus 
a hormonal method to prevent pregnancy. Subjects should start using birth control from study Visit 
1 throughout the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives 
will include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 


 
Protocol v 12/04/2019                                                                                                                                                     33 
 
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 and to Merck.  If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The outcome 
of the pregnancy will be reported to the Sponsor and to Merck without delay and within 24 hours to 
the Sponsor and within 2 working days to Merck if the outcome is a serious adverse experience (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother 
or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and the 
pregnancy reported to the Sponsor and to Merck and followed as described above and in Section 
7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects 
who are breast-feeding are not eligible for enrollment. 
5.8 
IMRT 
IMRT will be delivered in 30 fractions over 6 weeks (five fractions per non-holiday week) in one 
plan (SIB) to a total dose of 60-66Gy. Missed treatments due to holidays or logistic reasons can be 
compensated for by delivering an additional BID treatment during the week, OR treating on the 
Saturday or Sunday of that week, OR adding to the end of treatment. 
 
5.8.1 Immobilization and Simulation 
Patients must have an immobilization device (e.g. Aquaplast mask) made prior to 
treatment planning CT scan.  Use of a an immobilizing mouthpiece is optional as clinically 
indicated.  


 
Protocol v 12/04/2019                                                                                                                                                     34 
 
 
It is preferable to perform treatment planning CT scan with IV contrast if nodal regions or skull 
base will be targeted and there are no medical contraindications to the use of 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 thinner. 
5.8.2 Target Delineation 
There should be no Gross Tumor Volume (GTV).  The Clinical Target Volume (CTV_60) is 
defined as the tumor and/or lymph node bed that was dissected.  All patients must have a CTV_60.  
There are two optional CTVs that can be used. Elective areas deemed at risk of subclinical disease 
that have not been dissected (e.g. elective nodes) can be treated to a lower dose of 54Gy (CTV_54).  
For areas of highest risk, such as positive margins, or extranodal extension, a high risk CTV 
(CTV_66) can be used to focally boost these areas in a simultaneous fashion.  This treatment 
volumes should be kept as small as possible.  
The Planning Target Volume (PTV_60) should be a 3mm expansion around CTV_60.  If additional 
CTV’s are used, they should have their own PTV (e.g. CTV_54 PTV_54) with a 3mm margin.  
In general, as the skin is the origin of disease, it will often be targeted.  In these cases, the PTV 
should be allowed to extend outside of the external skin surface and 5mm of custom bolus must be 
used.  When the skin is not part of the target, then the PTV can be shaved out of skin by 3-5mm to 
enhance planning capabilities.   
 
All plans must be normalized such that 95% of the volume of the PTV_60 is covered with 
prescription dose of 60 Gy. Additionally: At 1 cc PTV1 volume on the DVH curve, the dose 
should not be > 110% of the prescribed dose.  At a volume of 0.03 cc within the PTV_60 
volume on the DVH curve, the dose should not be < 95% of the prescribed dose. For any volume 
of tissue outside the PTVs that has a size of 1 cc, the dose should not be > 70 Gy. 
Elective treatment of lymph nodes is at the discretion of the treating radiation oncologist, and will 
be determined on a case by case basis.  In general, for tumors of the scalp, if lymphatics are 
targeted, they should include: occipital, parotid, anterior cervical (levels 2-4), and posterior cervical 
(level 5) nodes. When targeting lymph nodes for tumors of the face (e.g. nose, cheek, temple, 
eyelid, lip): parotid, anterior cervical (levels 2-4), and submandibular (level 1B) should be 
included.  For ear tumors, pre and post-auricular nodes should be included in addition to parotid, 
anterior cervical (levels 2-4), and posterior cervical  nodes.   
For patients with perineural invasion of named nerves, these nerves should be included in the 
elective CTV_54 to their origin of the skull base.   For those with extensive involvement or 


 
Protocol v 12/04/2019                                                                                                                                                     35 
 
proximal involvement adjacent to the skull base, the involved nerves should be targeted bach to the 
respective nerve ganglion (e.g. Meckel cave for the Gasserion ganglion of the trigeminal nerve). 
5.8.3   Critical Normal Structures  
The normal tissue volume to be contoured will depend on the site of origin of the cancer.  In 
general, they will include the brainstem, spinal cord, cochlea mandible, glottic larynx, supraglottis, 
constrictors, esophagus, trachea, oral cavity, lips and parotid and submandibular salivary glands 
that are not at risk.  For tumors of the scalp and other requiring treatment of the skull base, the 
following should also be included: eyes, lenses, optic nerves, optic chiasm, pituitary, 
hypothalamus.  The PRV (planning risk volume) spinal cord contours will be defined at least 0.5 
cm larger in the radial dimension than the spinal cord (i.e. the cord diameter on any given slice will 
be 1.0 cm larger than the cord itself).  
5.8.4 Treatment Planning and Delivery 
Megavoltage energy photon beam irradiation is required. Static beam intensity modulation or 
volumetric arc based planning are acceptable for planning. 
5.8.5 Image Guidance for IGRT  
IGRT with daily conebeam CT is required recommended. If a cone beam CT is not available, 
portal images should be used. Region-of-Interest (ROI) or “clip box” for fusion should be set to 
encompass the high dose PTV and adjacent spinal cord.   When the skull base is targeted, the 
globes and optic nerves should routinely be included, if possible, for alignment purposes.  
Following the registration, the translational and (if the appropriate technology is available) 
rotational corrections should be applied to the treatment couch. If all the variances are less than 
10 mm (this typically corresponds to one half of the usual PRV margin), the treatment can proceed 
with appropriate corrections; however, re-imaging is not mandatory. If one or more of the 
corrections are larger than 10 mm, the imaging must be repeated in addition to performing 
table/positioning adjustments. However, the use of numerous repeat IGRT studies should be 
avoided (see next section). 
 
5.8.6 Definition of Normal Tissues/Organs at Risk (OARs) 
NOTE: Only the parts of the normal tissues/organs at risk outside the PTVs will be 
considered for dose optimization purposes. Only those OAR that are in proximity to the 


 
Protocol v 12/04/2019                                                                                                                                                     36 
 
treatment volume must be contoured.  Contouring OAR that are far from the treated area and 
will receive negligible doses is unnecessary. 
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 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. This is irrespective of whether or not IGRT is used. 
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 ½ to 2/3 of 
the oral tongue/floor of mouth, buccal mucosa, and palate. 
OARpharynx/constrictors:  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). 
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): 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. 
Other structures (self explanatory): Optic Nerves, optic chiasm, orbits, lenses, cochlea, lacrimal 
glands, parotid glands, submandibular glands 
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. 


 
Protocol v 12/04/2019                                                                                                                                                     37 
 
 
5.8.7 Dose Prescription 
Doses to PTVs 
See Section 5.8.2 above for definitions of CTVs and PTVs and their prescribed doses. The goal 
is for 95% of the PTV60 to receive  2 Gy with a minimum dose (cold spot) of no less than 54 Gy. 
It is recognized that portions of the PTV60 close to the skin may receive significantly less than 
54 Gy if it is not deliberately targeted with custom bolus applied.  This is acceptable as long as 
cold spots within PTV60 do not exist at a depth deeper than 8 mm beneath the skin.  For PTV_66, 
when used, 95% of the volume should get the prescription dose, and <0.03cc should receive 
>110% of the dose.  This criteria does not apply for PTV_54 when used.    
Doses to Normal Structures  
Spinal Cord: The PRVcord 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 spinal cord PRV 
should be given the highest priority. 
Brainstem: The brainstem  should not exceed 56 Gy to any volume in excess of 0.03 cc 
(approximately 3 mm x 3 mm x 3 mm).  The PRVbrainstem (brainstem +3mm) should be 
limited to 60Gy.  These can be exceeded in cases where the tumor abutted the brainstem and 
was resected.  Max point dose to the brainstem can never exceed 62Gy.   
Optic Nerves and Chiasm: These should be limited to a max dose of 54Gy. 
Orbits: Should be limited to a max dose of 50Gy with 95% <45Gy.  These doses may be 
exceeded when the tumor is abutting the globe preoperatively and is adjacent to the 
postoperative bed.  The max dose to 0.03cc of the globe can never exceed 52Gy.   
Lacrimal Gland: This should be limited to a mean <30Gy whenever possible.  This may be 
exceeded when the tumor location approximated this structure preoperatively and is 
subsequently at risk or adjacent to the tumor bed.   
Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy 
when possible. 
Oral Cavity:  Reduce the dose as much as possible. The mean dose should be < 30 Gy 
when possible.   
Parotid Glands (not targeted): 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.   


 
Protocol v 12/04/2019                                                                                                                                                     38 
 
Submandibular gland (not targeted): If level Ib is not a target, aim to reduce mean 
contralateral submandibular gland to < 39 Gy. 
OARpharynx/constrictors: Reduce the dose as much as possible. Some recommended (but 
not mandatory) treatment goals include: 1) No more than 33% of the OARpharynx exceeds 
50Gy; 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.  Some recommended (but 
treatment goals include: Mean dose < 30 Gy. 
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. The glottic 
larynx mean dose is recommended to be <25 Gy.  
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, except in 
areas overlapping PTV. 
Unspecified Tissue Outside the Targets: No more than 1cc of unspecified tissue outside the 
targets can receive 70 Gy or more


 
Protocol v 12/04/2019                                                                                                                                                     39 
 
 
5.8.8 Radiation Therapy Treatment Interruptions 
Treatment interruptions are strongly discouraged. Treatment breaks must be clearly indicated 
in the treatment record when they occur. Patients who have treatment interruptions in 
radiation for >3 weeks will be taken off study. The interruption of radiation therapy for grade 
4 mucositis / dermatitis / dysphagia is at the discretion of the treating radiation oncologist. 
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.  
Pembrolizumab will not be administered during radiotherapy treatment breaks. 
 
5.9 
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 7.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• 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).   


 
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5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 


 
Protocol v 12/04/2019                                                                                                                                                     41 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
 
 
Study Treatment (weeks) 
Post- 
tx 
Long 
term f/u 
 
Pre-
studya 
1 
2
3 
4 
5 
6 
7 
10 
13 
16 
20f 
32f , 52f 
Medical 
History, 
PE, 
Vital Signs 
X 
 
x 
x
X 
x 
x 
x 
x 
x 
 
X 
 
x 
 
x 
x 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
x 
x
X 
x 
x 
x 
x 
x 
X 
x 
X 
x 
ECOG PS 
X 
x 
x
X 
x 
x 
x 
X 
x 
X 
x 
X 
x 
CBC 
with 
Differential  
X 
x 
 
 
x 
 
 
x 
x 
 
X 
 
x 
 
x 
x 
Complete 
metabolic panel
X 
x 
 
 
x 
 
 
X 
x 
 
X 
 
x 
 
x 
x 
Concomitant 
meds 
X 
x 
 
 
x 
 
 
x 
x 
x 
x 
X 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testb
X 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
X 
 
 
X 
 
 
X 
x 
x 
x 
X 
x 
Immune Status 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol v 12/04/2019                                                                                                                                                     42 
 
CT neck and 
chest 
(with 
contrast 
if 
possible)c 
(CT 
Chest preferred, CXR 
acceptable) 
X 
 
 
 
 
 
 
 
 
 
 
X 
x 
PET/CT and/or  
MRIc (optional)
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dental 
evaluationd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab
 
X 
 
 
X 
 
 
X 
x 
x 
x 
 
 
IMRT 
 
 
x
X 
x 
x 
x 
X 
 
 
 
 
 
Adverse event 
evaluation 
 
X 
 
 
x 
 
 
x 
x 
 
x 
 
x 
 
x 
 
Correlatives:  
submission of 
tumor tissuee 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Correlatives:  
bloode 
x 
 
 
 
 
 
 
X 
 
 
 
X 
X (52 
wks) 
 
a. 
Pre-treatment evaluations will be performed within 4 weeks prior to registration, unless 
otherwise specified.  This excludes imaging which will be eligible within 12 weeks of 
registration on study. 
b. 
 For women of childbearing potential, pregnancy test must be completed within 2 
weeks of beginning treatment. 
• c.   
CT neck and chest CT will be acceptable if done within 12 weeks of trial 
registration. PET/CT is optional and only recommended if there is concern for gross 


 
Protocol v 12/04/2019                                                                                                                                                     43 
 
residual disease. MRI brain and/or orbits may be important for tumors near the skull 
base, especially those with perineural invasion. In these cases, MRI is recommended 
to be obtained at baseline, at wk 20 follow up, and at later follow up visits as 
clinically indicated. While the routine surveillance images are scheduled for weeks 
20, 32 and 52, changes in patient symptoms or persistent symptoms may prompt the 
clinician to order a CT at any time, as per standard practice. 
d.    
Dental evaluation is recommended for those who will receive significant (>45Gy) dose 
of radiation to the mandible.  However, it is not required. 
e. 
Baseline tumor tissue will be sent to Merck for PD-1 testing.  Blood will be collected 
at designated times (+/- 4 weeks to accommodate patient preference, transportation needs and 
scheduling needs around coordination of appointments) and sent to the Gastman lab.  
Additional study of tumor tissue (fresh and/or FFPE) may be done if the patient has consented 
to other tissue banking protocols.   
f.   
These weeks are suggestions, but are flexible and can be before or after these 
designated times by 4 weeks to accommodate patient preference, transportation needs and 
scheduling needs around coordination of appointments. 
 
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 must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 


 
Protocol v 12/04/2019                                                                                                                                                     44 
 
 
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 a 
dhere to IRB/ERC requirements, applicable laws and regulations and Sponsor requirements. 
 
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.   
 


 
Protocol v 12/04/2019                                                                                                                                                     45 
 
7.1.1.4 Prior and Concomitant Medications Review 
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 
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 Treatment 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
     7.1.1.6       Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
     7.1.1.7        Subsequent Anti-Cancer Therapy Status 
 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
 
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 


 
Protocol v 12/04/2019                                                                                                                                                     46 
 
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); see the separate ECI guidance document in Appendix 4 regarding the 
identification, evaluation and management of potential irAEs.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Physical Exam 
 
The investigators or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening.  For all other study visits, 
including those performed immediately prior to treatment administration, focused physical 
exams are acceptable. 
7.1.2.3 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. 
7.1.2.4 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, discontinuation of trial treatment and 
at protocol specified follow up assessments, as specified in the Trial Flow Chart.   
7.1.2.5 Tumor Imaging and Assessment of Disease 
As this is an adjuvant trial, there will be no anticipated measureable disease to record.  RECIST 
and other such response criteria do not apply.  However, there will be baseline imaging and 
surveillance imaging to evaluate for locoregional and distant recurrence as specified in the 


 
Protocol v 12/04/2019                                                                                                                                                     47 
 
Trial Flow Chart (section 6.0).  In the event of clinical or radiographic recurrence of disease, 
biopsy to confirm recurrent disease is strongly recommended.   
 
7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
Tumor tissue will be sent to Qualtek for PD-1 testing.  Blood will be collected on all patients 
at the times specified in the study flow chart (section 6.1) and sent to the Gastman lab for 
analysis.  Sufficient FFPE may be available from tumor samples to allow for additional 
correlative study.  Also, patients may have fresh tissue available for correlative study if they 
consented to a separate tissue banking protocol (e.g. IRB 3164 or 15-1580).  In these cases, 
additional experiments may be performed as outlined in section 4.2.3.3.  The consent form 
clearly states that blood will be collected for research purposes and that tumor tissue that is 
stored in pathology can be used for correlative science.    
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.  


 
Protocol v 12/04/2019                                                                                                                                                     48 
 
Table 5  Laboratory Tests 
Hematology 
Chemistry 
Other 
Hematocrit 
Albumin 
Serum -human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Thyroid stimulating hormone (TSH)
Platelet count 
Alanine aminotransferase 
(ALT) 
Blood for correlative studies 
(recommended) 
WBC (total and differential) Aspartate aminotransferase 
(AST) 
 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
 
Absolute Lymphocyte Count   (CO2 or biocarbonate) 
 
Red Blood Cell Count 
Calcium 
 
 
Chloride 
 
 
Glucose 
  
 
Potassium   
  
 
Sodium 
  
 
Total Bilirubin 
  
 
Blood Urea Nitrogen 
 
 


 
Protocol v 12/04/2019                                                                                                                                                     49 
 
Laboratory tests for screening or entry into the study should be performed within4 weeks  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.  
 
7.1.3.1 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.   
 
7.1.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.    
 
7.1.4.1 Screening 
Potentially eligible patients will be screened according to the eligibility checklist.  Patients 
deemed ineligible, as well as those that are offered trial participation and decline enrollment 
will be recorded as “screen failures.” 
 
7.1.4.2 Treatment Period 
During the treatment period patients will be seen as follows: 
Weeks 1-6: patients will be seen in radiation oncology weekly for their SOC weekly on 
treatment visit. They will often be assessed in radiation oncology 2-6 weeks post completion 
of radiotherapy for a routine toxicity check, but this is not mandated.  
Weeks 1-16: Patients will be seen by medical oncology every three weeks preceding the 
administration of Pembroluzimab for toxicity check and lab review.  Additional visits may be 
required during intervening weeks as clinically indicated, but are not mandatory. 
 
7.1.5.3  Follow-Up Visits 


 
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A mandatory Safety Follow-Up Visit should be conducted approximately 4 weeks after the last 
dose of trial treatment.  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.   
Following the initial post treatment follow up visit (week 20), patients will be seen around 
weeks 32 and 52.  These target visit dates are preferred but there will be flexibility in these 
visits based on provider and patient scheduling and travel needs.  Visits performed within 4 
weeks before or after these target dates will be acceptable to allow for flexibility in patient 
transport needs, coordination of appointments and cancellations.  At each follow up visit, 
patients will have vital signs, weight, medical history, focused physical exam, lab evaluation, 
imaging,  ECOG performance status, and correlative blood samples (if applicable), as specified 
in the Trial Flow Chart (Section 6.0).  For patients who experience disease recurrence, they 
should still be followed for overall survival.   
Any patient who fails to make follow up appointments can be contacted by telephone at 
routinely scheduled follow up times to assess for toxicity, disease and survival status until 
death, withdrawal of consent, or 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 


 
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of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
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. 
 
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-


 
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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 215-661-6229) 
 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
 
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); 


 
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• Is associated with an overdose; 
• Is another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
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 
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:  +1-215-661-6229 
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 215-661-6229) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 


 
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reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215-661-6229) 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.   
 
 
 
 
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 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event 
as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have 
caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct 
normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 


 
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observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition 
which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a 
serious adverse event. An overdose that is not associated with an adverse event is considered a non-serious event of 
clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, the event may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and 
units 
Action 
taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused 
the adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing 


 
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the likelihood of a relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; 
the greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 
 
 
 
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: 
(continued) 
to Merck 
product 
(continued)  
Dechallenge
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 


 
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(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose 
drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 
or (2) the trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS 
SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF 
REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED 
IN ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the 
Merck product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician 
according to his/her best clinical judgment, including consideration of the above elements. 


 
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Record one of the 
following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative 
to the administration of the Merck product is reasonable.  The AE is more likely explained by the 
Merck product than by another cause. 
No, there is not a 
reasonable possibility 
Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR there is another obvious cause of the AE.  
(Also entered for a subject with overdose without an associated AE.) 


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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.  
7.2.6 Investigator Responsibility for Reporting Adverse Events 
It is the Case Comprehensive Cancer Center’s Principal Investigator’s responsibility to ensure that  
ALL serious adverse events are reported to the Case Comprehensive Cancer Center’s Data Safety  
Toxicity Committee. This submission is simultaneous with their submission to the Sponsor or other  
Regulatory body.  
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 Study Design  
This is a phase II trial evaluating the addition of concurrent and adjuvant fixed-dose 
pembrolizumab in combination with standard IMRT, in order to establish safety and estimate 
efficacy of this regimen to be tested in a subsequent randomized registration trial. At the 
conclusion of the study, the primary safety endpoint will be proportion of DLT.  The primary 
efficacy endpoint will be 1-year PFS. Progression-free survival (PFS) will be calculated from 
treatment initiation to disease progression or death from any cause or last follow up.   
8.2 Justification of Design and Sample Size:    
The target sample size will be 34 patients.  Assuming a <10% drop out or ineligibility rate, 37 patients 
will be enrolled to ensure 34 evaluable patients (all evaluable patients will be analyzed). The sample 
size was generated based on the primary safety endpoint.  DLT <20% is acceptable and >40% is 
unacceptable.  If 11 or more of 34 patients experience DLT, this regimen will be considered too 
toxic.  The significance level and power of this design are 6% and 86%, respectively.  If 8 or fewer 
patients experience DLTs, the regimen will be deemed safe to proceed for further study.  If 9 or 10 
patients experience DLTs, the PI will examine the type, reversibility and duration of DLTs and a 
careful decision will be made whether to pursue this regimen further in this adjuvant population.  
8.3  Statistical Analysis Plan 
DLT will be estimated using an exact 95% confidence interval.  If 11 or more patients experience 
DLT the regimen will be considered too toxic.  One-year PFS will be estimated using the Kaplan-
Meier method and a 95% confidence interval constructed using Greenwood’s method.  One year 
PFS outcomes will be assessed overall and also separately for immunocompetent patients vs. 
immunosuppressed patients (e.g. CLL).  These outcomes will be compared to our historical dataset 
for both subsets respectively.  Adverse events will be tabulated by category and grade.  The rates of 


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adverse events will be estimated using an exact 95% confidence.  The relationship between 1yr 
PFS and baseline PD-L1 expression will be assessed using logistic regression.  Immunoprofiles in 
peripheral blood in serial samples will be tested using random effects ANOVA.  Bioinformatic 
analysis will be applied to all genomic and transcriptomic data. 
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 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to 


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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 
10.1.1 Confidentiality of Data 
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. 
10.1.2 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. 
 
10.1.3 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. 


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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. 
 
10.1.4 Confidentiality of IRB/IEC Information 
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial. The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies. 
 
10.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug A dministration 
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 Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure f orm, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 


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transmission of information to countries that do not have laws protecting personal data. 
 
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. The Code of Conduct, a collection of goals and considerations that govern the ethical 
and scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 - 
Merck Code of Conduct for Clinical Trials. The investigator also agrees to allow monitoring, audits, 
IRB/ERC review and regulatory authority inspection of trial-related documents and procedures and 
provide for direct access to all trial-related source data and documents. The investigator agrees not 
to seek reimbursement from subjects, their insurance providers or from government programs for 
procedures included as part of the trial reimbursed to the investigator by the Sponsor. 
 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor. Trial documentation will be promptly and fully disclosed to the Sponsor by the 
investigator upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any regulatory 
authorities. The investigator agrees to promptly take any reasonable steps that are requested by the 
Sponsor as a result of an audit to cure deficiencies in the trial documentation and worksheets/case 
report forms.  
 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 


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correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae. By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed. The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained. The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files. 
 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial. 
 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened. In the event the Sponsor prematurely terminates a 
particular trial site, the Sponsor will promptly notify that trial site’s IRB/IEC. 
 
For a single-center trial, the Protocol CI is the principal investigator. In addition, the Sponsor must 
designate a principal or coordinating investigator to review the trial report that summarizes the trial 
results and confirm that, to the best of his/her knowledge, the report accurately describes the conduct 


Protocol v 12/04/2019                                                                                                                                                     66 
 
and results of the trial [Clinical Study Report (CSR) CI]. The Sponsor may consider one or more 
factors in the selection of the individual to serve as the Protocol CI and or CSR CI (e.g., availability 
of the CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones). The Protocol CI 
must be a participating trial investigator. 
 
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 
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature. By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.  The investigator will have access to all study related events and outcomes and 
will have license to analyze and publish this data as he deems fit without any limitations.  
The OnCore Database will be utilized, as required by the Case Comprehensive Cancer Center, to 
provide data collection for both accrual entry and trial data management.  OnCore is a Clinical Trials 
Management System housed on secure servers maintained at Case Western Reserve 
University.  OnCore properly used is compliant with Title 21 CFR Part 11.  Access to data through 
OnCore is restricted by user accounts and assigned roles.  Once logged into the OnCore system with 


Protocol v 12/04/2019                                                                                                                                                     67 
 
a user ID and password, OnCore defines roles for each user which limits access to appropriate data. 
User information and password can be obtained by contacting the OnCore Administrator at oncore-
registration@case.edu. 
OnCore is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification. This study will utilize electronic Case Report 
Form completion in the OnCore database.  A calendar of events and required forms are available in 
OnCore. 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and Safety 
Monitoring Plan in accordance with NCI regulations.  
 Registry Integration  
         CASE 4311 registry (IRB CC 00192), will share data with IRB 17-069.  Data shared will only pertain 
to mutual patients consented to IRB 17-069 and patients eligible for inclusion in CASE 4311. The 
clinical data collected by CASE 4311/IRB CC 00192, particularly data regarding cancer recurrence, 
will be used in conjunction with data collected under IRB 17-069. 
 
 


Protocol v 12/04/2019                                                                                                                                                     68 
 
10.7  APPENDICES 
10.8  ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
10.9   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) 
 
 
 
 
 
 
 
 


Protocol v 12/04/2019                                                                                                                                                     69 
 
Appendix 10.10 – Tissue and Blood processing for correlative science 
 
 
Study #1: Specimen Collection for PD-L1 Expression 
• All patients will have slides cut from FFPE tissue blocks for analysis of PD-L1 
expression by IHC staining 
• FFPE tissue will be obtained from the Tissue Procurement and/or pathology department 
(CCF) or Biorepository and/or pathology department (UH) and assigned a unique 
identification number.  All other PHI will be redacted from the pathology report. 
• Five slides will be cut from each FFPE block for PD-L1 and H&E staining. 
o One slide each for H&E, PD-L1, and Isotype and two for repeat staining if needed 
• Results: QualTek Molecular Laboratories Clinical Laboratories will report to Merck and 
study investigators.  
• Residual Material:   FFPE specimens will be retained by Cleveland Clinic and University 
Hospitals in anatomic pathology per their routine, and made available for future use as 
indicated.    
 
Study #1 Specimens shipped to: 
QualTekMolecularLaboratories 
MISP Receiving 
300 Pheasant Run 
Newtown, PA  USA  18940 
Phone: 215-504-7402 
Fax: 805-830-6379 
MISPsamples@qmlabs.com 
 
 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Five slides from 
primary 
tumor 
FFPE blocks 
 
Baseline 
Tumor 
specimen 
Sections 
will 
be 
4 
micron thickness onto 
Fisher ProbeOn Plus 
Slides, Cat Number 22-
230-900. 
Tissue sections must be 
placed on the painted/ 
textured side of the 
slide. 
Slides shipped cold (2-8oC) 
and in the dark using 
QualTek-supplied 
packing 
materials.   


Protocol v 12/04/2019                                                                                                                                                     70 
 
Study #2: Blood Collection for Immune Biomarker Analysis 
• All patients will have blood collected at specific time points (pre-treatment and weeks 7, 
20, and 52).  +/- 4 weeks is allowed on follow up visits.   
• At each time point, up to 50cc of blood will be collected and processed by research 
laboratory personnel (Dr. Gastman, PI) to isolate lymphocytes and freeze for further 
analysis. 
• Specimens will be assigned the same unique identification number used for Study #1 and 
any other personal health information (PHI) will be redacted from the pathology report. 
• Results: Research laboratory personnel will report to Merck and study investigators.  
• Residual Material:  cryopreserved specimens will be retained by the research laboratory 
until the study conclusion. 
 
For CC:  Samples will typically be collected by CRA.  Gastman lab will then be contacted 
as follows: 
 
Please call Ye Tian (Field)  (Gastman Lab) at 773-226-2782 for pickup. If there is no 
response, please page Dr. Brian Gastman at 216-401-4776.  The samples will be picked up 
by Gastman lab personnel and transported to: 
 
9500 Euclid Avenue 
Gastman Laboratory 
Lerner Research institute, NE4-217 
Cleveland, Ohio 44195 
Phone:  (216) 444-0202 
 
For UH:  Samples will be collected by research nurse.  These samples should be collected 
by the research nurse before 12PM, to allow sufficient time for the TRPC (translational 
research and pharmacology core) to courier the samples to CC before 5pm.  Generally, 
samples cannot be received at CC after 5PM.  In the event that samples are late, they should 
still be sent to CC. 
 
The research nurse will then contact the Translational Research and Pharmacology Core 
of UH (Attn: Erin Hohler) at 216-286-3889 or 216-286-3890, pager 33471, 
emh14@case.edu.  The tissue will then be picked up by the TRPC staff and they will 
arrange for courier of the tissue to Cleveland Clinic.  
 
The TRPC should then courier the blood same day to: 
 
Cleveland Clinic Central Biorepository 
Pathology and Lab Medicine Institute- L15 
Surgical Pathology- Tissue Procurement 
2119 East 93rd St 
Cleveland, Ohio 44106 
Phone (216)444-0047 
 
When specimens arrive at L15, please call Ye Tian (Fields)  (Gastman Lab) at 773-226-
2782 for pickup. If there is no response, please page Dr. Brian Gastman at 216-401-4776.  
Also, please email the following personnel notifying them that a sample was collected:  
samsaj@ccf.org; 
robinss@ccf.org; 
koyfmas@ccf.org;tisscenterap@ccf.org;THOMPSS9@ccf.org; 
tainy2@ccf.org 
gastmab@ccf.org  
   
 


Protocol v 12/04/2019                                                                                                                                                     71 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Up 
to 
50cc 
of 
peripheral 
whole 
blood in heparin 
(green 
top) 
or 
EDTA 
(lavender/purple 
top) tubes 
 
Pre-treatment, 
weeks 7, 20, and 
52 
Lymphocytes 
isolated 
by centrifugation over 
Ficoll 
gradient 
and 
stored 
frozen 
in 
FBS/10% DMSO in 1.8 
mL cryovials. 
Samples 
should 
be 
stored at -80oC 
CCF: After collection, blood 
tubes will be delivered to 
Gastman Lab. 
UH: After collection, blood 
tubes 
will 
be 
sent 
to 
anatomic 
pathology 
via 
courier (L-15). 


Protocol v 12/04/2019                                                                                                                                                     72 
 
Study #3 and #4: Fresh or FFPE Tissue for Immune Biomarker Analysis and Tumor Gene 
Expression Analysis (Optional) 
• For patients who consent to other IRB-approved tissue banking protocols: 
o Fresh tumor tissue will have been received, de-identified, processed and stored 
(frozen).  RNA isolation may have also taken place for gene expression analysis 
o This tissue may be sent to the Gastman lab for experimentation.   
• FFPE tissue may be obtained in patients for whom fresh tissue is not available: 
o FFPE tissue will be obtained from the Tissue Procurement (CC) or Biorepository 
(UH) tissue bank and assigned a unique identification number.  All other PHI will 
be redacted from the pathology report. 
o Up to 10 slides will be cut from each tissue block for immune biomarker staining  
o A small punch will be taken for RNA isolation for subsequent gene expression 
analysis 
• Results: Research laboratory personnel will report to Merck and study investigators.  
• Residual Material:  cryopreserved specimens, tissue slides, and genetic material will be 
retained by the research laboratory until the study conclusion. 
 
Specimens shipped to: 
 
For Cleveland Clinic: 
Gastman Laboratory 
Lerner Research Institute 
NE4-217 
Phone: 216-444-0202 
 
For University Hospitals: 
 
Cleveland Clinic Central Biorepository 
Pathology and Lab Medicine Institute- L15 
Surgical Pathology- Tissue Procurement 
2119 East 93rd St 
Cleveland, Ohio 44106 
Phone (216)444-0047 
 
When specimens arrive at L15, please call Ye Tian (Field) (Gastman Lab) at 773-226-2782 
for pickup. If there is no response, please page Dr. Brian Gastman at 216-401-4776.   
Also, please email the following personnel notifying them that a sample was collected:  
samsaj@ccf.org; 
robinss@ccf.org; 
koyfmas@ccf.org; 
tisscenterap@ccf.org; 
THOMPSS9@ccf.org; tiany2@ccf.org gastmab@ccf.org  
 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Fresh primary tumor 
tissue or up to 10 
slides cut from FFPE 
tissue 
blocks 
and 
3mm punches taken 
from FFPE tumor 
blocks. 
 
Time of primary 
surgical resection 
or from baseline 
tumor specimen 
Tumors dissociated by 
enzymatic 
digestion 
followed by freezing in 
FBS/10% 
DMSO 
for 
subsequent 
analysis.  
Samples should be stored 
at -80oC. 
RNA isolation from fresh 
tissue or FFPE punches by 
organic extraction/ silica 
column purification. 
Tumor tissue will be delivered 
to Gastman lab. 


Protocol v 12/04/2019                                                                                                                                                     73 
 
11.0  REFERENCES 
1. 
Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of 
disease, nodal metastasis, and deaths from disease in the United States, 2012. Journal of the American 
Academy of Dermatology 2013;68:957-66. 
2. 
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Squamous Cell Skin 
Cancer. 
2015. 
(Accessed 
3/8, 
2015, 
at 
http://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf.) 
3. 
Kwan W, Wilson D, Moravan V. Radiotherapy for locally advanced basal cell and squamous 
cell carcinomas of the skin. Int J Radiat Oncol Biol Phys 2004;60:406-11. 
4. 
Lin C, Tripcony L, Keller J, et al. Perineural infiltration of cutaneous squamous cell 
carcinoma and basal cell carcinoma without clinical features. International journal of radiation 
oncology, biology, physics 2012;82:334-40. 
5. 
Mendenhall WM, Amdur RJ, Hinerman RW, Cognetta AB, Mendenhall NP. Radiotherapy 
for cutaneous squamous and basal cell carcinomas of the head and neck. The Laryngoscope 
2009;119:1994-9. 
6. 
Wang JT, Palme CE, Morgan GJ, Gebski V, Wang AY, Veness MJ. Predictors of outcome 
in patients with metastatic cutaneous head and neck squamous cell carcinoma involving cervical 
lymph nodes: Improved survival with the addition of adjuvant radiotherapy. Head & neck 
2012;34:1524-8. 
7. 
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nature 
reviews Immunology 2008;8:467-77. 
8. 
Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD. Relationship between the expressions of PD-
L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral oncology 
2011;47:1148-53. 
9. 
Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in 
immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer research 
2013;73:1733-41. 
10. 
Seiwert TY ea. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-
associated and non-HPV–associated head and neck (H/N) cancer. . Journal Clinical Oncology;(suppl; 
abstr 6011). :32:5s. 
11. 
Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in 
antigen-processing machinery in head and neck cancer. Clinical cancer research : an official journal 
of the American Association for Cancer Research 2006;12:3890-5. 
12. 
Whiteside TL. Immunobiology of head and neck cancer. Cancer metastasis reviews 
2005;24:95-105. 
13. 
Belai EB, de Oliveira CE, Gasparoto TH, et al. PD-1 blockage delays murine squamous cell 
carcinoma development. Carcinogenesis 2014;35:424-31. 
14. 
Madeleine MM, Carter JJ, Johnson LG, et al. Risk of squamous cell skin cancer after organ 
transplant associated with antibodies to cutaneous papillomaviruses, polyomaviruses, and TMC6/8 
(EVER1/2) variants. Cancer medicine 2014;3:1440-7. 
15. 
Hodge JW, Guha C, Neefjes J, Gulley JL. Synergizing radiation therapy and immunotherapy 
for curing incurable cancers. Opportunities and challenges. Oncology 2008;22:1064-70; discussion 
75, 80-1, 84. 
16. 
Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically 
promote antitumor immunity in mice. The Journal of clinical investigation 2014;124:687-95. 
17. 
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting 
adaptive immune resistance. Nature 2014;515:568-71. 


Protocol v 12/04/2019                                                                                                                                                     74 
 
18. 
Powell SF GM, Sumey CJ, et al. Safety of pembrolizumab with chemoradiation (CRT) in 
locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). J Clin Oncol 35, 
2017 (suppl; abstr 6011). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol v 12/04/2019                                                                                                                                                     75 
 
 
 
12.0 
SUMMARY OF CHANGES  v08/03/2017 
 
 
Protocol 
Date 
Section 
Change 
08/03/17 
2.1 
 Safety run in period and Phase II portion was deleted from this section 
08/03/17 
4.2.2 
The following was added to this section: 
 A pilot study that investigated the safety of adding Pembrolizumab to 
head and neck IMRT in addition to weekly cisplatin was recently 
presented at ASCO 2017.  Powell, et al reported excellent safety profile 
of 27 patients with locally advanced head and neck cancer treated with 
chemoradiation with weekly cisplatin, and 70Gy in 35 fractions of 
IMRT along ith Pembrolizumab 200mg fixed dose IV every 3 weeks 
beginning 4-7 days prior to the initiation of radiation 2 doses 
concomitant with IMRT and 5 additional doses post IMRT.  21 patients 
(78%) completed all planned doses of Pembrolizumab. 3 discontinued 
due to irAEs (G2 peripheral motor neuropathy, G3 AST elevation, G1 
Lhermitte-like syndrome). 3 discontinued due to protocol reasons (early 
neck dissection -2 pts, prolonged hospitalization-1 pt). All pts 
completed the full radiation dose (70 Gy) without significant delay 
(defined as > 5 days). 23 (85%) received the goal target dose of cisplatin 
(200 mg/m2). There was one patient death due to concurrent illness, 
unrelated to treatment.18  Based on these results, the NRG Oncology 
HN-003 study which was designed as a phase I safety study of the 
addition of Pembrolizumab to postoperative head and neck IMRT and 
weekly cisplatin discontinued their planned phase I safety study and 
converted to an open label efficacy signal study.  We therefore feel quite 
confident in the safety of our proposed regimen as our study involves 
less extensive IMRT fields and does not include any concurrent 
chemotherapy.  We will however monitor DLTs very carefully and 
include that as a co-primary endpoint of the study. 
 
 
08/03/17 
4.2.3.2 
Initial safety run in information deleted from this section 
08/03/17 
5.1.1 
4) Lymphoid malignancies deleted.   Patients with a history of chronic 
lymphoid or leukemic malignancies which are not under active 
therapy (no active therapy within the last 3 months) will be eligible. 
 
08/03/17 
5.1.2 
4) Lymphoid malignancies deleted 
Patients with chronic lymphoid/leukemic malignancies that have 
undergone treatment in the last 3 months will be ineligible.  
 
08/03/17 
5.4 
Safety run in period and Phase II portion was deleted from this section 
08/03/17 
8.0 
Initial safety run in period deleted from this section 


Protocol v 12/04/2019                                                                                                                                                     76 
 
Protocol 
Date 
Section 
Change 
08/03/17 
8.3 
One year PFS outcomes will be assessed overall and also separately for 
immunocompetent patients vs. immunosuppressed patients (e.g. CLL).  
These outcomes will be compared to our historical dataset for both 
subsets respectively.  Added to this section 
08/03/17 
Table 1 
Removed coagulation section 
08/03/17 
7.1.5.3 
Changed 2nd paragraph “visits performed within 3 weeks…” to within 
4 weeks… 
08/03/17 
Appendix 
10.10 
Study #2, 3 and 4 lab address change for Cleveland Clinic from NE6-
251 to NE4-217 
 
 
Protocol date change to 08/03/2017 on page 1 and the footer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol v 12/04/2019                                                                                                                                                     77 
 
SUMMARY OF CHANGES v08/29/2017 
 
Protocol 
Date 
Section 
Change 
08/29/17 
5.0 #7 
Patients with chronic lymphoid or leukemic malignancies are eligible 
with or without active disease as long as they have not had treatment 
within the past three months  Added to this section 
08/29/17 
 
Protocol date change to 08/29/2017 on page 1 and the footer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol v 12/04/2019                                                                                                                                                     78 
 
SUMMARY OF CHANGES v09/27/2017 
 
Protocol 
Date 
Section 
Change 
09/27/17 
5.1.1#4 
Patients with chronic lymphoid or leukemic malignancies are eligible 
with or without active disease as long as they have not had treatment 
within the past three months  Added to this section 
09/27/17 
5.1.2 #7 
Patients with chronic lymphoid or leukemic malignancies are eligible 
with or without active disease as long as they have not had treatment 
within the past three months  Added to this section 
09/27/17 
 
Protocol date change to 09/27/2017 on page 1 and the footer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol v 12/04/2019                                                                                                                                                     79 
 
 
SUMMARY OF CHANGES v08/30/2018 
 
Protocol 
Date 
Section 
Change 
08/30/18 
7.1.2.6 
page 49 
Removed Laboratory tests for screening or entry into the study should 
be performed within 10 days prior to the first dose of treatment.   
Added Laboratory tests for screening or entry into the study should be 
performed within 4 weeks prior to the first dose of treatment.   
08/30/18 
Study #2 
page 71 
Removed lab contact information for Lukas Pfannenstiel 443-622-
9736.  Added contact information for Ye Tian (Field) 773-226-2782. 
konczov@ccf.org was removed and tiany2@ccf.org was added. 
08/30/18 
Study #3 
& 4 page 
73 
Removed lab contact information for Lukas Pfannenstiel 443-622-
9736.  Added contact information for Ye Tian (Field) 773-226-2782. 
konczov@ccf.org was removed and tiany2@ccf.org was added. 
08/30/18 
7.2.1 
Changed fax # to 215-661-6229 
08/30/18 
7.2.2 
Changed fax # to 215-661-6229 
08/30/18 
7.2.3.1 
Added a note further clarifying serious adverse events, Changed fax # 
to 215-661-6229 
08/30/18 
7.2.3.2 
Changed fax # to 215-661-6229, Removed, “this trial site guidance for 
assessment and follow-up of these criteria can be found in the 
investigator trial file binder (or equivalent) 
Removed additional adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol v 12/04/2019                                                                                                                                                     80 
 
 
SUMMARY OF CHANGES v10/30/2018 
 
Protocol 
Date 
Section 
Change 
10/30/2018 
5.1.1 
Added: Invasion of the axial skeleton or skull base or skull base 
foramina and Tumor greater that 2cm with any 1 additional feature  
Removed:  Note: Not all patients with T2N0 cancer with one 
additional risk factor may be ideal candidates for this study, such as 
patients with only focal perineural invasion without other adverse 
features.  Clinical judgment should be used by recurrence with 
radiation alone. 
10/30/2018 
6.0 
Added: (CT chest preferred, CXR acceptable) and superscript c: CT 
neck and chest CT will be acceptable if done within 12 weeks of trial 
registration. PET/CT is optional and only recommended if there is 
concern for gross residual disease. MRI brain and/or orbits may be 
important for tumors near the skull base, especially those with 
perineural invasion. In these cases, MRI is recommended to be 
obtained at baseline, at wk 20 follow up, and at later follow up visits 
as clinically indicated. While the routine surveillance images are 
scheduled for weeks 20, 32 and 52, changes in patient symptoms or 
persistent symptoms may prompt the clinician to order a CT at any 
time, as per standard practice. 
Removed:  CT neck and chest will be acceptable if done within 12 
weeks of trial registration.  PET/CT is optional and only recommended 
if there is concern for gross residual disease.  MRI brain and/or orbits 
may be important for tumors near the skull base, especially those with 
perineural invasion.  In these cases, MRI is recommended to be 
obtained at baseline, at wk 20 follow up, and at later follow up visits as 
clinically indicated.  While the routine surveillance CT are scheduled 
for weeks 20, 32 and 52, changes in patient symptoms or persistent 
symptoms may prompt the clinician to order a CT at any time, as per 
standard practice guidelines. 
 
10/30/2018 
 
Protocol date change to 10/30/2018 on page 1 and the footer 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol v 12/04/2019                                                                                                                                                     81 
 
 
SUMMARY OF CHANGES v12/04/2019 
 
Protocol 
Date 
Section 
Change 
12/04/19 
Page 1  
Updated protocol date to 12/04/2019 and footer protocol date to 
12/04/2019. 
12/04/19 
Page 67 
Added registry integration information.