Phase Ib Study of Pembrolizumab in Combination With Chemo Radiotherapy (CRT) for Locally-advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Phase: PHASE1
Conditions: Head and Neck Cancer, Squamous Cell Carcinoma, Oral Cavity Cancer, Oropharynx Cancer, Hypopharynx Cancer, Larynx Cancer, Laryngeal Cancer
Sponsor: Sanford Health

 
SH MISP203 v08/22/2018                                                                                              Page 1 
 
 
 
 
SPONSOR: Sanford Research 
 
PROTOCOL: SH MISP203 
 
TITLE:  Phase IB study of Pembrolizumab in combination with chemo radiotherapy 
(CRT) for locally-advanced squamous cell carcinoma of the head and neck (SCCHN)  
 
PRINCIPAL INVESTIGATOR:  Steven F. Powell, MD 
 
IND NUMBER:   127798 
 
Version History:  
Amendment 6, 08/22/2018 
Amendment 5, 02/01/2018 
Amendment 4, 10/5/2017 
Amendment 3, 12/02/2016 
Amendment 2, 09/23/2016 
Amendment 1, 1/11/2016 
Initial 8/4/2015 
 
NCT Number:   02586207 
 
 
 

 
SH MISP203 v08/22/2018                                                                                              Page 2 
 
STUDY TEAM: 
 
Principal Investigator/Medical Oncology: 
Steven F. Powell, MD1 
Sanford Cancer Center/Sanford Research 
1309 W. 17th Street Suite 101 
Sioux Falls, SD 57104 
605-328-8000/Fax: 605-328-8001 
Steven.Powell@SanfordHealth.org 
 
 
Medical Monitor 
Maria C. Bell, MD1 
Chief Medical Officer of Development and Research 
Sanford Health 
1309 W. 17th Street Suite 102 
Sioux Falls, SD  57104 
(605)312-3250 
Maria.Bell@SanfordHealth.org 
 
 
Study Sites: 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Oncology Co-Chairs: 
 
 
        Radiation Oncology Co-Chairs: 
        Mark Gitau, MD2  
 
 
 
   
    Ryan Nowak, MD1 
       Kathryn Gold, MD4   
 
 
 
    Michele Lohr, MD1 
      John Reynolds, MD3 
 
 
 
 
    Ashley Jensen, MD2 
                 
 
Surgical Oncology Co-Chair: 
 
 
         Correlative Science Co-Chairs: 
     W. Chad Spanos, MD1        
 
 
 
       John H. Lee, MD1 
       
 
 
 
 
 
 
       Ezra Cohen, MD4 
 
 
 
 
 
 
 
      Paola Vermeer, PhD1 
 
 
         Imaging Co-Chairs: 
 
 
 
   Biostatistician: 
       Christopher Fischer,MD1 
 
 
 
   James Wacker, MS1 
Aaron Berg,MD1  
 
 
 
 
 
 
Project Manager: 
Christie Ellison, RN1 
 
1- Sanford Sioux Falls,   2- Sanford Roger Maris Fargo,   3-Sanford Bismarck Oncology Clinic,   4- UC San Diego La Jolla  
Sanford Roger Maris Cancer2 
820 4th St N. 
Fargo, ND 58122 
UC San Diego Moores 
Cancer Center4 
3855 Health Sciences Drive 
La Jolla, California 92093 
Sanford Cancer Center1 
1309 W. 17th Street Suite 101 
Sioux Falls, SD 57104 
Sanford Research Cancer Biology Core1  
(Correlative Science) 
2301 East 60th Street North 
Sioux Falls, SD 57104 
Sanford Bismarck Oncology Clinic3 
300 7th St N. 
Bismarck, ND 58501 

 
SH MISP203 v08/22/2018                                                                                              Page 3 
 
 
CONTENTS 
Study Team 
Summary of Changes 
1.0 
TRIAL SUMMARY.................................................................................................. 11 
2.0 
TRIAL DESIGN........................................................................................................ 11 
3.0 
OBJECTIVE(S) & HYPOTHESIS (ES) ................................................................. 13 
4.0 
BACKGROUND & RATIONALE .......................................................................... 14 
4.1.1 Pharmaceutical and Therapeutic Background .................................................... 14 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 15 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 15 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 16 
4.2.3 Rationale for Endpoints ...................................................................................... 20 
4.2.3.1 Safety and Efficacy Endpoints ..................................................................... 20 
4.2.3.2 Pharmacokinetic, Biomarker, and Patient Report Outcomes Research ....... 21 
4.2.3.3 Exploratory Research ................................................................................... 22 
4.2.3.4 Exploratory Molecular Profiling and Analysis and its Rationale ................ 23 
4.2.3.5 Preliminary Results and Rationale for Expansion Cohort ........................... 23 

 
SH MISP203 v08/22/2018                                                                                              Page 4 
 
5.0 
METHODOLOGY ................................................................................................... 24 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 24 
5.1.2 Subject Inclusion Criteria.................................................................................... 24 
5.1.3 Subject Exclusion Criteria .................................................................................. 25 
5.2.1 Dose Selection/Modification .............................................................................. 28 
5.2.1.1 Dose Selection ............................................................................................. 28 
5.2.1.2 Dose Modification ....................................................................................... 28 
5.2.1.2.1 Dose Modification for Pembrolizumab ................................................ 28 
5.2.1.2.2 Dose Modification for Cisplatin ........................................................... 29 
5.2.1.2.3 Dose Modification for Radiation .......................................................... 31 
5.2.1.3 Timing of Dose Administration ................................................................... 31 
5.2.1.3.1 Pembrolizumab ..................................................................................... 31 
5.2.1.3.2 Cisplatin ................................................................................................ 32 
5.2.2 Radiation ............................................................................................................. 32 
5.2.2.1 IMRT............................................................................................................ 32 
5.2.2.2 Technical Factors ......................................................................................... 32 
5.2.2.3 Immobilization, Simulation, and Localization............................................. 33 
5.2.2.4 Immobilization ............................................................................................. 33 
5.2.2.5 Planning CT scan ......................................................................................... 33 
5.2.2.6 Treatment Planning/Target Volumes ........................................................... 33 
5.2.2.7 Critical Structures ........................................................................................ 33 
5.2.2.8 Documentation Requirements ...................................................................... 34 
5.2.2.9 Compliance Criteria ..................................................................................... 34 

 
SH MISP203 v08/22/2018                                                                                              Page 5 
 
5.6.1 Acceptable Concomitant Medications ................................................................ 37 
5.6.2 Prohibited Concomitant Medications.................................................................. 37 
5.7.1 Supportive Care Guidelines for Pembrolizumab ................................................ 38 
5.7.2 Supportive Care Guidelines for Cisplatin ........................................................... 41 
5.7.3 Supportive Care Guidelines for Radiation .......................................................... 42 
5.8.1 Diet ...................................................................................................................... 42 
5.8.2 Contraception ...................................................................................................... 42 
5.8.3 Use in Pregnancy ................................................................................................ 42 
5.8.4 Use in Nursing Women ....................................................................................... 43 
5.8.4.1 Pembrolizumab ............................................................................................ 43 
5.8.4.2 Cisplatin ....................................................................................................... 43 
6.0 
TRIAL FLOW CHART ........................................................................................... 45 
7.0 
TRIAL PROCEDURES ........................................................................................... 53 

 
SH MISP203 v08/22/2018                                                                                              Page 6 
 
7.1.1 Administrative Procedures .................................................................................. 53 
7.1.1.1 Informed Consent......................................................................................... 53 
7.1.1.1.1 General Informed Consent .................................................................... 53 
7.1.1.2 Inclusion/Exclusion Criteria ........................................................................ 53 
7.1.1.3 Medical History ........................................................................................... 53 
7.1.1.4 Prior and Concomitant Medications Review ............................................... 54 
7.1.1.4.1 Prior Medications .................................................................................. 54 
7.1.1.4.2 Concomitant Medications ..................................................................... 54 
7.1.1.5 Disease Details and Treatments ................................................................... 54 
7.1.1.5.1 Disease Details ...................................................................................... 54 
7.1.1.5.2 Prior Treatment Details ......................................................................... 54 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status .............................................. 54 
7.1.1.6 Assignment of Screening Number ............................................................... 54 
7.1.1.7 Assignment of Study Subject Number ......................................................... 55 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) ................................... 55 
7.1.2 Clinical Procedures/Assessments ........................................................................ 55 
7.1.2.1 Adverse Event (AE) Monitoring .................................................................. 55 
7.1.2.2 Full Physical Exam ...................................................................................... 55 
7.1.2.3 Directed Physical Exam ............................................................................... 56 
7.1.2.4 Vital Signs .................................................................................................... 56 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 56 
7.1.2.6 Tumor Imaging and Assessment of Disease ................................................ 56 
7.1.2.6.1 Baseline Tumor Imaging ...................................................................... 56 
7.1.2.6.2 Tumor Imaging During Trial ................................................................ 56 

 
SH MISP203 v08/22/2018                                                                                              Page 7 
 
7.1.2.6.3 Assessment of Disease – RECIST 1.1, irRECIST 1.1, PET 
Response, Salvage Surgery ................................................................... 57 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling ............ 58 
7.1.2.7.1 Tumor Tissue Collection ...................................................................... 58 
7.1.2.7.2 Correlative Blood Sampling ................................................................. 59 
7.1.3 Laboratory Procedures/Assessments .................................................................. 59 
7.1.3.1 Tissue Collection and Evaluation ................................................................ 60 
7.1.4 Other Procedures ................................................................................................. 61 
7.1.4.1 Withdrawal/Discontinuation ........................................................................ 61 
7.1.4.2 Blinding/Unblinding .................................................................................... 61 
7.1.5 Visit Requirements .............................................................................................. 61 
7.1.5.1 Screening...................................................................................................... 61 
7.1.5.1.1 Screening Period ................................................................................... 61 
7.1.5.2 Treatment Period .......................................................................................... 62 
7.1.5.3 Post-Treatment Visits................................................................................... 62 
7.1.5.4 Safety Follow-Up Visit ................................................................................ 62 
7.1.5.5 Follow-up Visits........................................................................................... 62 
7.1.5.6 Survival Follow-up ...................................................................................... 63 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sanford Research and to Merck .......................................................................... 63 
7.2.2 Reporting of Pregnancy and Lactation to Sanford Research and to Merck ........ 64 
7.2.3 Immediate Reporting of Adverse Events to Sanford Research and to Merck .... 64 
7.2.3.1 Serious Adverse Events ............................................................................... 64 
7.2.3.2 Events of Clinical Interest ............................................................................ 65 
7.2.4 Evaluating Adverse Events ................................................................................. 66 

 
SH MISP203 v08/22/2018                                                                                              Page 8 
 
7.2.4.1 Table 6  Evaluating Adverse Events ............................................................ 67 
7.2.5 Sanford Research Responsibility for Reporting Adverse Events ....................... 69 
7.3.1 Study Oversight Committee ................................................................................ 69 
7.3.2 Data Safety and Monitoring Board (DSMB) ...................................................... 69 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 69 
8.4.1 Efficacy Endpoints .............................................................................................. 71 
8.4.2 Safety Endpoints ................................................................................................. 71 
8.4.2.1 Analysis Populations .................................................................................... 72 
8.4.2.2 Efficacy Analysis Populations ..................................................................... 72 
8.4.2.3 Safety Analysis Populations ........................................................................ 72 
8.4.3 Statistical Methods .............................................................................................. 73 
8.4.3.1 Statistical Methods for Efficacy Analyses ................................................... 73 
8.4.3.2 Table 7: Statistical Methods for Key Efficacy Endpoints ........................... 73 
8.4.4 Statistical Methods for Safety Analyses ............................................................. 74 
8.4.5 Summaries of Baseline Characteristics, and Demographics ............................... 74 
8.4.6 Patient Reported Outcomes (PROs) Evaluation ................................................. 74 
8.4.7 Interim Analyses ................................................................................................. 75 
8.4.7.1 Interim Efficacy Analysis ............................................................................ 75 
8.4.7.2 Multiplicity .................................................................................................. 75 
8.4.7.3 Sample Size and Power Calculations ........................................................... 75 

 
SH MISP203 v08/22/2018                                                                                              Page 9 
 
8.4.7.4 Subgroup Analyses and Effect of Baseline Factors ..................................... 76 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 77 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 78 
10.1.1 Confidentiality of Data ....................................................................................... 78 
10.1.2 Confidentiality of Subject Records ..................................................................... 78 
10.1.3 Confidentiality of Investigator Information ........................................................ 78 
10.1.4 Confidentiality of IRB/IEC Information ............................................................. 79 
11.0 
APPENDICES ........................................................................................................... 83 

 
SH MISP203 v08/22/2018                                                                                              Page 10 
 
12.0 
References ................................................................................................................ 100 
13.0 
Signatures ................................................................................................................ 104 
INVESTIGATOR’S STATEMENT .................................................................................. 104 
 
 
 
 

 
SH MISP203 v08/22/2018                                                                                              Page 11 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab in combination with CRT for LA-SCCHN 
Trial Phase 
Phase IB 
Clinical Indication 
Stage III-IVB Head and Neck Squamous cell carcinoma 
Trial Type 
Interventional 
Type of control 
Historical  
Route of administration 
Intravenous 
Trial Blinding 
Unblinded, open-label 
Treatment Groups  
(1) Pembrolizumab 200 mg days -7 (load), 15, 36, 57, 78, 99, 120, 
141,   cisplatin 40 mg/m2 on days 1, 8, 15, 22, 29, 36, and 
radiation 70 Gy fractionated over 35 days starting on day 1 
Number of trial subjects 
57 subjects will be enrolled  (34 HPV+ subjects and 23 HPV- subjects) 
Estimated enrollment period 
30 months 
Estimated duration of trial 
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through the final protocol-specified 
contact. After a screening phase of 28 days, eligible subjects will receive 
treatment on Day -7 with a loading dose of the study drug.  This will 
continue during concurrent therapy with cisplatin and radiation, which 
will begin on day 1.  Treatment will continue until completion of therapy, 
documented confirmed disease progression, unacceptable adverse 
event(s), intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the patient, noncompliance with trial 
treatment or procedure requirements; or administrative reasons. After the 
end of treatment, each patient will be followed for 30 days for adverse 
event monitoring (serious adverse events will be collected for 90 days after 
the end of treatment or 30 days after the end of treatment if the patient 
initiates new anticancer therapy, whichever is earlier). Subjects who 
discontinue for reasons other than disease progression will have post-
treatment follow-up for disease status until end of study, disease 
progression, initiating a non-study cancer treatment, withdrawing consent, 
or becoming lost to follow-up. All subjects will be followed by telephone 
for overall survival until death, withdrawal of consent, or the Investigator 
is notified by Sanford Research to discontinue follow-up. 
Duration of Participation 
60 months 
 
 
 
2.0 TRIAL DESIGN 
 
Trial Design 
This is a single-arm, multi-site, open-label trial of pembrolizumab (MK-3475) used in 
combination with standard, cisplatin-based, definitive chemoradiotherapy (CRT) in patients 
with stage III-IVB squamous cell carcinoma of the head and neck (SCCHN).  Approximately 
57 patients with Stage III-IVB SCCHN will be enrolled to evaluate both the safety and efficacy 
of this novel combination.  Of those 57 subjects 34 will be HPV+ and 23 will be HPV-.  
Subjects will not be randomized and will all receive the study treatment.  
 

 
SH MISP203 v08/22/2018                                                                                              Page 12 
 
Treatment will consist of a loading dose of pembrolizumab 200 mg IV given 7 days prior to 
initiation of CRT (day-7).  CRT with cisplatin 40 mg/m2 IV weekly and head and neck 
radiation at 70 Gy fractionated  at 2 Gy once daily over 35 days, will begin on day 1.  CRT 
will end on approximately day 46-50.  Pembrolizumab 200 mg IV will continue following 
CRT in an adjuvant fashion starting on day 57 for an additional 5 doses, as tolerated, through 
day 141.  Subjects will be evaluated for response on day 150-157 with a CT of the neck.   
 
To support the exploratory nature of this study, correlative objectives will be explored to 
generate hypotheses for future research.  These objectives will largely involve evaluation of 
the immune response during CRT, the effect of PD-1 inhibition on this response, and potential 
biomarkers for response to this combination.  Section 6 outlines specific trial procedures.  
 
This trial will utilize a Data and Safety Monitoring Board to monitor safety and efficacy of this 
novel combination.  There will be an interim efficacy analysis.  More details are given in 
section 8.7.   
 
Efficacy, as defined primarily by complete response (CR) at treatment end and secondarily by 
1- and 2-year progression-free survival (PFS), overall survival (OS), locoregional control 
(LRC), and cumulative incidence of distant metastases (DM) will be evaluated.   These 
outcomes will be correlated with exploratory objectives.    
 
Trial Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Salvage surgery is considered standard of care, see protocol section 7.1.2.6.3.4. 
 
Treatment Naïve 
Stage 
III-IVB SCCHN? 
Yes 
Concurrent Treatment 
Pembrolizumab 200 mg days 
 -7 (load), 15, 36 
Cisplatin 40 mg/m2 days 1, 8, 
15, 22, 29, 36 
Radiation 70 Gy in 35 
fractions 
Completed  
CRT?  
Yes  
Adjuvant Treatment 
Pembrolizumab 
200 
mg days 57, 78, 99, 
120, 141   
 
Treatment 
End Imaging 
CR 
Safety and Survival 
Follow-up 
PR, SD, or 
PD 
Salvage 
Surgery1 

 
SH MISP203 v08/22/2018                                                                                              Page 13 
 
3.0 OBJECTIVE(S) & HYPOTHESIS (ES) 
 
Primary Objective(s) & Hypothesis(es) 
1. Objective: To determine the safety and tolerability of pembrolizumab given in combination 
with cisplatin-based chemoradiotherapy (CRT) in subjects with treatment naive Stage III-IVB 
squamous cell carcinoma of the head and neck (SCCHN).  
 
Hypothesis: Pembrolizumab can be safely added to cisplatin-based CRT and will be well 
tolerated in patients with Stage III-IVB SCCHN.   
 
2. Objective: To evaluate the efficacy of pembrolizumab given in combination with definitive 
CRT by complete response rate at treatment end in patients with HPV+ SCCHN and HPV- 
SCCHN.  
 
Hypothesis: The addition of pembrolizumab to standard CRT will provide a 75% or greater 
CR rate in patients with Stage III-IVB HPV- SCCHN and a 90% or greater CR rate in patients 
with Stage III-IVB HPV+ SCCHN. 
 
 
Secondary Objective(s) & Hypothesis (es) 
1. Objective: To estimate progression-free survival (PFS), overall survival (OS), the 
locoregional control rate (LRC), and distant metastases (DM) rate at 1- and 2-years in subjects 
treated with pembrolizumab given in combination with CRT. 
  
Hypothesis: The addition of pembrolizumab to standard CRT will show increased efficacy in 
terms of key survival endpoints utilized in head and neck cancer.  
 
2. Objective:  To determine the best overall response rate (ORR) as defined by RECIST 1.1 
at treatment end imaging in subjects with Stage III-IVB SCCHN treated with pembrolizumab 
given in combination with CRT.   
 
Hypothesis: The addition of pembrolizumab to standard CRT will show superior ORR 
compared to historical controls.  
 
4. Objective: To estimate the quality of life (QOL) of subjects with Stage III-IVB SCCHN 
treated with pembrolizumab in combination with CRT during therapy, treatment end, and 1- 
and 2-years following treatment.  
 
Hypothesis: Acute and long-term QOL of participants treated with the combination of 
pembrolizumab and low dose weekly cisplatin and radiation will be superior to historical 
controls.  
 
5.  Objective: To correlate ORR, PFS, OS, LRC, and DM with tumor PD-L1 expression in 
subjects with Stage III-IVB SCCHN treated with pembrolizumab in combination with CRT.  
 

 
SH MISP203 v08/22/2018                                                                                              Page 14 
 
Hypothesis: High PD-L1 expression has correlated with responses in the metastatic setting 
and will correlate with key disease response and survival outcomes in the curative intent 
setting.  
 
 
3.3 Exploratory Objectives 
To determine the genomic, transcriptomic, and proteomic profile of subjects’ tumors to 
identify gene mutations, gene amplifications, RNA-expression levels, and protein-expression 
levels.  Additional analysis will evaluate peripheral blood immune response utilizing similar 
techniques.  Correlations between genomic, transcriptomic, and proteomic profiles and 
efficacy outcomes will be assessed.   
 
 
4.0 BACKGROUND & RATIONALE 
 
Background 
Merck Sharp & Dohme Corp. holds the IND 122325 for MK-3475 (pembrolizumab).  Refer 
to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
MK-3475. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 

 
SH MISP203 v08/22/2018                                                                                              Page 15 
 
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. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Squamous cell carcinomas of the head and neck (SCCHN) are the 6th most common 
malignancy diagnosed world-wide with approximately 650,000 diagnoses per year [1].  For 
patients with locally advanced disease, multimodality therapy with concurrent 
chemoradiotherapy (CRT) remains a mainstay for treatment.  Despite this aggressive 
treatment, 5-year survival still remains less than 50% [2].  Additionally, this treatment has 
significant acute and late toxicities that leave survivors with permanent deficits impacting their 
quality of life [3].  Recent understanding of the immune clearance of head and neck cancer 
may provide insight into therapeutic approaches to improve survival and reduce toxicity. 
Clearance of SCCHN during treatment with CRT is not only related to direct cytotoxicity, but 
is also dependent on the immune clearance.  In a preclinical study performed by our group this 
was demonstrated in an HPV+ SCCHN mouse model [4].  This response is strongly dependent 

 
SH MISP203 v08/22/2018                                                                                              Page 16 
 
on an intact CD4+ and CD8+ cellular response.   Furthermore, it is apparent that radiation and 
cisplatin actually induces an immune response to therapy.  One potential mechanism of this is 
by overcoming immune resistance by decreased expression of CD47 after treatment with CRT 
[5].  Additional recent data suggests that the PD-1:PD-L1 pathway may also play an important 
role in immune resistance in head and neck cancer [6].  
The PD-1:PD-L1 pathway is an emerging target for immunotherapy in a number of diseases. 
Several monoclonal antibodies targeting this pathway are becoming clinically available.  At 
the ASCO 2014 annual meeting, data from the KEYNOTE 012 trial utilizing pembrolizumab 
(MK-3475) was reported [7].  In this phase Ib study, a 60 patient cohort of recurrent and/or 
metastatic SCCHN patients who had progressed on prior therapy experienced a 19.6% overall 
response rate.  Additionally, 28.6% of patients had stable disease. Many of these patients had 
durable (>6 month) responses or stability of disease and remain on therapy.  Furthermore, the 
drug was well tolerated, with few single-agent dose limiting toxicities.   
Based on the signal seen with single-agent pembrolizumab in this population and the 
understanding of immune clearance of SCCHN with CRT, the next step is evaluating this 
combination in primary therapy.  Our lab is evaluating this combination in our immune 
competent HPV+ SCCHN mouse model.  Using the mouse analog to pembrolizumab, we have 
determined that while the agent does not have significant single-agent activity, it strongly 
synergizes with CRT.  Preliminary data from our lab displays day 100 overall survival of  58% 
in mice treated with PD-1 in combination with CRT versus 8% in mice treated with isotype 
control (IgG1) in combination with CRT (p = 0.006). (Data unpublished, data included in 
Appendix 11.6). 
This preclinical finding is supported by recent clinical literature that suggests there may be 
synergy by adding PD-1 inhibition during primary chemoradiotherapy.  Recent biomarker data 
suggest PD-L1 upregulation in the setting of both radiation [8,9] and cisplatin [10] alone.  
Additionally, a recent translational study in HPV+ SCCHN suggests that cisplatin based CRT 
suppresses circulating immune response by upregulating PD-1 expression on circulating CD4+ 
T-cells [11].  This further supports PD-1 blockade during CRT to enhance immune response 
during treatment in this population.    
4.2.2 Rationale for Dose Selection/Regimen/Modification  
Rationale for pembrolizumab (MK-3475) dosing: 
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested 
in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to 
test for initial tumor activity.  Recent data from other clinical studies within the MK-3475 

 
SH MISP203 v08/22/2018                                                                                              Page 17 
 
program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed 
for other antibodies and would support both body weight normalized dosing or a fixed dose 
across all body weights.  MK-3475 has been found to have a wide therapeutic range based on 
the melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative 
to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the 
established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 
mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and 
exposure). The population PK evaluation revealed that there was no significant impact of 
tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
Rationale for weekly cisplatin based chemoradiotherapy:  

 
SH MISP203 v08/22/2018                                                                                              Page 18 
 
Cisplatin based chemoradiotherapy (CRT) remains the mainstay for definitive treatment for 
LA-SCCHN.  Various dosing regimens exist; however high-dose bolus cisplatin given at a 
dose of 100 mg/m2 on days 1, 22, and 43 of radiation remains the standard of care based on 
phase III data [12, 13].  Other dosing regimens include weekly cisplatin, daily cisplatin, and 
various combination regimens [14].  NCCN guidelines outline several options using cisplatin 
including high-dose bolus cisplatin, cisplatin in combination with 5-fluorouracil, cisplatin in 
combination with paclitaxel, and weekly cisplatin given at a dose of 40 mg/m2 [15].  While 
high-dose bolus cisplatin is the preferred choice due to randomized clinical trial data, weekly 
cisplatin is increasingly becoming a popular choice in clinical practice [16].   
Several reasons for weekly cisplatin gaining favor exist.  First of all, toxicity with high-dose 
bolus cisplatin is very high.  Nephrotoxicity, neurotoxicity, ototoxicity, and the high emetic 
risk with this regimen have led to investigations into other regimens.  Furthermore, many 
patients are unable to tolerate all three bolus doses, leading to potentially decreased efficacy 
[17]. 
While high-dose bolus cisplatin has never formally been compared head to head with weekly 
cisplatin in a phase III randomized trial, there have been smaller, single-institution 
comparisons both retrospectively and prospectively [16, 18, 19, 20].  In these studies, weekly 
cisplatin has been clearly better tolerated and efficacy does not seem to be impaired.  Therefore, 
current NCCN guidelines indicate that weekly cisplatin given at a dose of 40 mg/m2 during 
radiation is an option, albeit with a category 2B recommendation (Category 2B: Based on a 
lower level of evidence, there is an NCCN consensus that intervention is appropriate).      
There are several reasons while this chemotherapy backbone is appealing for combination 
chemoimmunotherapy.  First of all, this combination is associated with a generally lower 
toxicity profile than bolus cisplatin.  The high AE rate with high dose bolus cisplatin limits its 
use to only very fit patients.  This lower dose, weekly preparation opens up the opportunity to 
treat a larger population of patients, who may be excluded from trials utilizing bolus cisplatin 
chemotherapy backbones. 
Second, weekly cisplatin is more amenable to combination therapy.  A number of cisplatin 
combination studies have been performed.  With the evolution of targeted therapies and 
monoclonal antibodies, the toxicity of combination therapy with weekly cisplatin has generally 
been felt to be lower.  Despite this, many trials using high dose bolus cisplatin in combination 
with these agents have been associated with very high toxicity rates.  This has led many to use 
weekly cisplatin in novel combinations.  Some studies that have been performed include the 
combination of weekly cisplatin with: bevacizumab[21], vandetanib[22], everolimus[23], 
bortezimib [24], nimotuzumab [25], among others.  In general, these combinations have been 
well tolerated.   
Based on this data, it suggests that combining weekly cisplatin with pembrolizumab will be 
safe and well tolerated.  Furthermore, this cisplatin backbone is more amenable to steroid 
sparing antiemetic regimens.  It is clear that corticosteroids, including dexamethasone, are 
immunosuppressive and may negate the effect of PD-1 inhibitors [26].  High dose bolus 
cisplatin carries one of the highest emetic risks [27].  Standard antiemetic guidelines from both 

 
SH MISP203 v08/22/2018                                                                                              Page 19 
 
the NCCN and ASCO recommend the use of high dose corticosteroids on day 1 through 4 
when treating with high emetic risk chemotherapy [27, 28].  Current combination 
chemoimmunotherapy studies using PD-1 inhibitors often limit dexamethasone dose to no 
more than 4 mg at a time.  This is far below what is recommended for standard high emetic 
risk prophylaxis.  While low-dose weekly cisplatin still may pose a significant emetic risk, our 
institutional standard is to treat the regimen as moderate emetic risk.  This affords the option 
to eliminate corticosteroids from the antiemetic management.  Use of steroids sparing 
antiemetics may be effective enough to control nausea with this regimen.  
Rationale for combination regimen  
As outlined in the study schema, treatment is outlined as two separate periods:  Concurrent 
treatment and adjuvant treatment.  Pembrolizumab will be administered initially as a loading 
dose, similar to what is done with cetuximab-based CRT [29].  There are several reasons for 
this loading dose.  First, this loading dose will allow for an initial evaluation for potential 
infusion reactions and acute immune related adverse events prior to initiation of standard CRT.  
This will support the safety component of this study, in that patients with severe immune 
adverse events at the start of therapy will not have their standard treatment impacted, as further 
doses of pembrolizumab would be held and/or appropriate supportive medications could be 
initiated.   
Secondly, the rationale behind the loading dose is to allow the drug time before the initiation 
of chemoradiation to invoke an immune response.  While “flare responses” are fairly 
uncommon in head and neck cancer, these can be seen.  A loading dose of this drug will allow 
some time for recovery until standard CRT is started.  Logistically, this loading dose should 
not be an issue for routine clinical care, due to the time needed to begin radiation planning and 
initiation.  This allows for a window of time to utilize the loading dose.  Furthermore, it mirrors 
standard clinical practice when using cetuximab-based CRT.  
The rationale for doses given during concurrent treatment is based on preclinical and clinical 
literature.  High PD-L1 expression has strongly correlated with a response to pembrolizumab 
[30].  While patients with low or no PD-L1 expression can still respond to the drug, response 
rates are much higher in those with high expression.  Recent literature suggests that both 
cisplatin and radiation independently cause upregulation of PD-L1 [9, 10].  In the absence of 
PD-1 inhibition, this could lead to decreased immune clearance and may be a biomarker of 
chemoradioresistance.  Based on the predictive nature of PD-L1 expression on response to 
pembrolizumab, treatment during a period of high PD-L1 expression makes perfect sense.  
Further supporting this is a recent clinical study demonstrated that cisplatin-based CRT 
suppresses circulating immune response by upregulating PD-1 expression nearly 2.5-fold on 
circulating CD4+ T-cells [11].  Overall circulating T-cells were suppressed by the end of CRT 
and there was an increase in myeloid derived suppressor cells (MDSCs), thus creating an 
immunosuppressed phenotype by the end of therapy.  Adding PD-1 inhibition following 
standard CRT may be efficacious, however it may be equally or more efficacious to add 
treatment at the beginning and during concurrent therapy before the circulating T-cell pools 
have been depleted and prior to the emergency of the immunosuppressive environment.   

 
SH MISP203 v08/22/2018                                                                                              Page 20 
 
This regimen also consists of an adjuvant treatment period with pembrolizumab that will 
continue every 3 weeks until day 100 post-treatment imaging.   A great deal of inflammation 
will be occurring in the tumor microenvironment during this time and optimization of immune 
clearance with pembrolizumab will be important.  It is possible that the greatest amount of 
tumor clearance will occur during this time; therefore, it is vital to include this adjuvant period. 
The ultimate rationale behind this combination is to determine if this combination is as safe 
and efficacious as the gold standard of high-dose bolus cisplatin.  This current standard of care 
has significant toxicity and carries substantial acute and late morbidity for patients.  If the 
combination of pembrolizumab with weekly cisplatin and radiation is well tolerated and 
equally or more efficacious than the current standard of care, this could replace high-dose bolus 
cisplatin as the preferred treatment for LA-SCCHN.  Depending on the efficacy and analysis 
of biomarkers, the potential for “de-escalation” therapy using this chemoimmunotherapy 
backbone may be presented.   
4.2.3 Rationale for Endpoints 
4.2.3.1 Safety and Efficacy Endpoints 
Safety and efficacy are the primary endpoints for this study.  Safety is an important endpoint 
for a study like this for a number of factors.  First of all, the inflammatory events surrounding 
chemoradiation, while potentially allowing for improved immune clearance with 
pembrolizumab, may end up causing more toxicity.  The PD-1: PD-L1 pathway is important 
in normal, healthy individuals in protecting from autoimmunity during inflammatory events. 
As CRT will induce an inflammatory event in the head and neck region, one can surmise that 
PD-L1 and PD-1 upregulation may be a normal response meant to protect from autoimmune 
events.  Evaluation of safety during and following this period is paramount to understanding 
the role of PD-1 inhibitors combined with CRT.  While a certain level of toxicity is expected 
with this combination, special attention will be paid to immune-related toxicities and 
exacerbation of known CRT related toxicities.  If this combination is not felt to be safe, it 
would not be recommended to move forth with further evaluation.    
Efficacy is the co-primary endpoint for the study.  This endpoint is important to estimate the 
clinical benefit of this combination.  If there is little to no added benefit with this combination, 
it would not be recommended to move forth with additional studies utilizing this combination.  
If the treatment is efficacious, it would be reasonable to consider phase III testing of this 
combination, comparing it to high-dose bolus cisplatin.  
Complete response rate was chosen as the primary efficacy measure.  While progression-free 
survival may be a reasonable alternative to this efficacy measure, complete response rate was 
chosen based on several factors. First, this was the efficacy measure in preclinical studies that 
suggested this combination was efficacious.  Second, this outcome can be compared to the 
Intergroup Trial [13], which evaluated high-dose bolus cisplatin in a phase III setting.  In this 
study, imaging and clinical response were used to determine response rate.  The complete 
response rate in those treated with high-dose bolus cisplatin was 40.2% among 87 analyzable 
patients.  While the imaging and response criteria from that study does not directly match what 

 
SH MISP203 v08/22/2018                                                                                              Page 21 
 
is proposed in this study, we feel the response criteria documented is stricter and mirrors what 
is done in standard clinical practice today, to follow response in patients treated with CRT.  
This endpoint is supported by the fact that patients without a CR will have salvage surgery.  
This will give a true pathologic response.  A second analysis looking at pathologic and 
radiographic response will be performed.  This will give a second assessment of efficacy of 
this combination.  The main purpose for using response as an assessment is for rapid analysis 
of the efficacy of this regimen.  Due to the nature of head and neck cancer treatment and the 
interest in improving therapy, it is important to rapidly estimate efficacy and move forward 
with phase III testing if signals are present.  
Although they are not primary endpoints, important survival and response endpoints will be 
followed as secondary endpoints during this study.  These will include progression-free 
survival, overall survival, locoregional control (LRC) rate, distant metastasis (DM) rate, and 
overall response rate (ORR).  While the study is not powered for these endpoints, they will be 
compared to historical data from similar head and neck studies.  If these are found to be 
superior to historical data and the analysis is statistically sound, these endpoints may be 
considered when deciding whether to move forward with further evaluation of this 
combination.  As these data points take longer to mature, we have opted to have them serve as 
secondary endpoints and keep CR rate as the primary measure of efficacy. 
4.2.3.2 Pharmacokinetic, Biomarker, and Patient Report Outcomes Research 
There are ongoing clinical trials evaluating pembrolizumab in combination with platinum-
doublet therapy in non-small cell lung cancer and in other chemotherapy combination studies 
[31].  This will be the first study looking at pembrolizumab in combination with weekly 
cisplatin chemotherapy.  Despite this, based on data from other combination studies, the risk 
for a drug-drug interaction is extremely low.  Furthermore, pembrolizumab has been utilized 
with cisplatin at varying doses in a number of studies with accompanying pharmacokinetic 
data.  As a result, pharmacokinetic data will not be obtained during this study.  Additionally, 
as it is felt there is reasonable data available to understand the risk of anti-drug antibodies with 
this combination.  Therefore, this will also be excluded from this protocol.    
PD-L1 expression may be an important factor in efficacy.  Current data supports high PD-L1 
expression as a correlate of response to therapy.  While patients with no or low expression may 
still respond to pembrolizumab, the response rates are significantly higher for those with high 
expression.  As we venture into multimodality therapy with chemotherapy and radiation, it will 
be important to see if baseline expression of PD-L1 correlates with a response.  As previously 
mentioned, data is emerging that suggests altered PD-L1 expression during both chemotherapy 
and radiation.  While we will not be performing biopsies during therapy, the baseline PD-L1 
expression may be important to see if this biomarker maintains its predictive nature in the 
setting of chemoradiation.  There is the potential that the biomarker will not continue to predict 
response, as even non-expressers or low expressers at baseline, may develop enhanced 
responses during CRT.  It will be important to evaluate PD-L1 expression to generate 
hypotheses for future biomarker research.   

 
SH MISP203 v08/22/2018                                                                                              Page 22 
 
A final supportive outcome of importance is patient-related outcomes (PRO).  High-dose bolus 
cisplatin is highly toxic and leads to severe acute and late effects for patients.  Survivors of 
head and neck cancer experience some of the most severe late effects from therapy [32].  
During treatment, the majority of patients will require feeding tubes as they will develop severe 
mucositis, dysphagia/odynophagia, nausea/vomiting, loss of appetite, xerostomia/sialorrhea, 
and malnutrition [12].  Fatigue, difficulties with speech, and inability to eat can affect mood. 
It may take anywhere from 12-36 months for most patients to return back to an acceptable 
baseline quality of life (QOL) [33]. Some patients will never return to a self-rated acceptable 
QOL. The factors degrading QOL are complex, but include psychosocial symptoms and 
chronic somatic changes related to the disease and associated treatment [34].  Many feel that 
low-dose weekly cisplatin may be better tolerated and have improved QOL indices [17].  We 
feel that QOL is an extremely important endpoint to evaluate when developing a novel 
combination as proposed.  This is important, as even if efficacy is improved, if QOL is 
significantly degraded, it may not be worthwhile to move forward with further testing.  
Fortunately, we have QOL data, using the Functional Assessment of Cancer Therapy Head and 
Neck (FACT H&N) survey, from approximately 50 patients treated with standard of care, high-
dose bolus cisplatin in this setting for comparison at approximate time points as outlined in 
this study [35].  We propose using the same QOL survey for this study.  While it is not a head 
to head comparison in a randomized trial, it does provide insight into how this combination 
may be tolerated in a phase III comparison to standard therapy.     
4.2.3.3 Exploratory Research 
As previously mentioned, we have data from a randomized phase 2 trial in this setting, in this 
same patient population [35].  The study utilized high-dose bolus cisplatin 100 mg/m2 on days 
1, 22, and 43 with or without the agent dichloroacetate (DCA).  From this study, we have 
historically banked specimens from 40-50 patients undergoing primary CRT.  These specimens 
include tumor RNA/DNA (freshly isolated), tumor blocks of primary and metastatic nodal 
specimens, peripheral immune cells isolated to remain live and functional.  Quality of life 
analyses, response data, and survival data were also prospectively collected and can be 
correlated to outcomes.  These data will be used as a control to ascertain changes seen with the 
addition of PD-1 inhibition as proposed in this study.   This data, combined with the correlative 
studies performed during this study, can provide valuable insight into biomarkers for treatment 
response, targets for future therapy, and other potential factors that may impact efficacy and 
safety, as we enter the field of chemoimmunoradiotherapy. 
While this is still developing in this field, several of the key areas of exploratory research in 
this setting include:  circulating immune cell analysis, tumor infiltrate immune cell analysis, 
the HPV specific immune response [11], and tumor genomic alterations [36].   We have the 
capability to collect specimens and evaluate each of these factors during and following CRT.  
As previously mentioned, we have experience with these procedures from a prior study in a 
similar population.  Furthermore, our cancer biology COBRE grant funding and core facilities 
will help fund and assist in this testing.   

 
SH MISP203 v08/22/2018                                                                                              Page 23 
 
4.2.3.4 Exploratory Molecular Profiling and Analysis and its Rationale 
Genomic sequencing of tumor cells from tissue relative to non-tumor cells from whole blood 
will be profiled to identify the genomic variances that may contribute to response or disease 
progression and provide an understanding of molecular abnormalities.  RNA sequencing will 
be conducted to provide expression data and give relevance to DNA mutations; Quantitative 
proteomics analysis will be conducted to determine the exact amounts of specific proteins and 
to confirm expression of genes that are correlative of response and disease progression. Flow 
cytometry and T-cell gene analysis utilizing similar techniques will be utilized to evaluate 
peripheral blood immunocyte response during therapy.  All genomic, transcriptomic, and 
proteomic molecular analyses will be retrospective and exploratory. 
 
4.2.3.5   Preliminary Results and Rationale for Expansion Cohort 
The current study has enrolled 27 patients from November 18, 2015 to August 6, 2016.  The 
study is currently on hold for an interim safety and efficacy analysis.  As of the data lock on 
September 14, 2016,  20 (74.1%) patients with HPV positive (p16 positive) disease and 7 
(15.9%)  with HPV negative (p16 negative) disease have enrolled.  Early response data in 
imaged patients (n=9), shows a CR (CT and/or PET or pathologic CR on salvage surgery) in 
8/8 (100%) of HPV positive patients and a PR in the single HPV negative patient.  We 
anticipate easily hitting our primary endpoint of CR rate >60% in our HPV positive population 
based on these early results.  However, based on our lack of HPV negative patients, it is unclear 
what responses will be seen.   
Recent data analysis of an internal study (NCT01386632) using standard of care high-dose 
cisplatin (100 mg/m2 on days 1, 22, and 43) in a similar cohort of patients was performed.  
Distinct differences in response were seen in the HPV+ and HPV- groups, which mirror 
efficacy findings in similar studies.  This analysis has revealed that 20 of 27 (74%) of evaluable 
patients with HPV positive disease achieved a CR (based on 3-month post-radiation CT and/or 
PET or subsequent salvage surgery). In the same study, the evaluable patients in the HPV 
negative cohort had 6 of 12 (50%) achieving the same CR endpoint.   
Due to the historically good responses in HPV positive disease and the early findings in our 
current HPV positive cohort, we propose evaluation of efficacy separately in the HPV 
positive and HPV negative cohorts.  As a result, we propose adding expansion cohorts after 
the interim analysis to explore efficacy in each of these unique populations.  Addition of both 
HPV negative and HPV positive patients will provide further insight into efficacy of this 
novel combination.   

 
SH MISP203 v08/22/2018                                                                                              Page 24 
 
5.0 METHODOLOGY 
 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Male and female patients with TNM clinical stage III, IVA, or IVB squamous cell carcinoma 
of oral cavity (excluding lip), oropharynx, hypopharynx, and larynx eligible for curative-intent 
treatment. A total of 57 patients will be enrolled with 34 of those patients being HPV-positive 
and 23 patients being HPV-negative.  Enrollment to each sub-category will end when the target 
is met. 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
 
1. Have histologically or cytologically-confirmed head and neck squamous cell 
carcinoma of the oral cavity (excluding lip), oropharynx, hypopharynx, or  larynx. 
 
2. Have TNM clinical stage III, IVA, or IVB disease. Can have T0 disease if evaluation 
of pathology indicates an origin of one of the above sites. (See criteria 1) 
 
3. Be eligible for curative-intent concurrent chemoradiation therapy 
 
4. Be willing and able to provide written informed consent for the trial. 
5. Be  18 years of age on day of signing informed consent. 
6. Have a known p16 status by immunohistochemical stain 
a. HPV positivity is defined by p16 IHC staining of > 70% of tumor cells (strong 
and diffuse nuclear and cytoplasmic staining) 
b. For cases that are indeterminate or if p16 testing cannot be accurately 
performed, HPV positivity can be confirmed by high-risk HPV DNA Testing 
which covers the following HPV subtypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 
56, 58, 59, 66, 68. 
7. Have measurable disease based on RECIST 1.1 
8. Be willing to provide tissue from a recently obtained core or excisional biopsy of a 
tumor lesion.  Recently-obtained is defined as a specimen obtained up to 60 days prior 
to enrollment.  Subjects for whom recently-obtained samples cannot be provided (e.g. 
inaccessible or subject safety concern) may submit an archived specimen only upon 
agreement from Sanford Research. 
9. Have a performance status of 0 or 1 on the ECOG Performance Scale. 

 
SH MISP203 v08/22/2018                                                                                              Page 25 
 
10. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation (Day -7).   
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 
Albumin 
>2.5 mg/dL 
 
 
 
aCreatinine clearance should be calculated per institutional standard. 
 
11. 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.   
12. 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.  
13. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Patients may not be receiving any other investigational agents, chemotherapy, 
immunotherapy, radiotherapy, or molecular targeted agents within 4 weeks of the 
start of the study treatment. 

 
SH MISP203 v08/22/2018                                                                                              Page 26 
 
 
2. Prior treatment with radiation to the head and neck 
 
3. Patients with TNM Stage IVC disease 
 
4. 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. 
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
6. Has a known history of active TB   (Bacillus Tuberculosis) 
 
7. Hypersensitivity to pembrolizumab or any of its excipients. 
8. 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. 
9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy. 
10. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
11. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   
12. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
13. Has known history of, or any evidence of active, non-infectious pneumonitis. 
14. Has an active infection requiring systemic therapy. 
15. 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.   
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 

 
SH MISP203 v08/22/2018                                                                                              Page 27 
 
17. 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 
120days after the last dose of trial treatment. 
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
21. 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. 
 
 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. 
 
Table 2  Trial Treatments 
Drug 
Dose 
Dose 
Frequency 
Route 
Regimen 
Use 
Pembrolizumab 200 mg Days -7, 15, 
36, 57, 78, 
99, 120, 141   
Intravenous Every 3 weeks 
starting on day -
7 during CRT; 
then every 3 
weeks following 
CRT ending on 
day 141.  
Experimental 
Cisplatin 
40 
mg/m2 
Days 1, 8, 15, 
22, 29, 36 
Intravenous Weekly starting 
on day 1 
Standard of 
care 
Radiation 
2 Gy 
Daily 
(Monday-
Friday) 
starting on 
day 1 
3D or 
IMRT 
Day1-50 
(approximate*) 
for a total of 35 
treatments 
Standard of 
care 
*Note: If the subject experiences radiation treatment delays the active treatment phase can extend beyond 7 
weeks. 
 
Study treatment begins on day -7 with a loading dose of pembrolizumab.  Day 1 signifies the 
start date of CRT.  Both cisplatin and radiation should begin on day 1.  CRT will end on the 
last day of radiation, which is when the cumulative dose reaches 70 Gy.   

 
SH MISP203 v08/22/2018                                                                                              Page 28 
 
 
Patients will be closely monitored for treatment-related adverse events, especially 
hypersensitivity reactions, during the infusion and the post-infusion per local guidelines. For 
the duration that patients are on study therapy, adverse event monitoring will be done and 
recorded. Patients will be evaluated for adverse events at each visit and are to be instructed to 
call their physician to report any clinically significant adverse events between visits. 
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modification  
The investigator may attribute each toxicity event to the study drug (pembrolizumab), cisplatin, 
or radiation alone, if appropriate.  If a dose reduction for toxicity occurs, the dose of that agent 
may not be re-escalated.  Dose modifications for additional rounds of treatment are based on 
the most recent dose utilized previously. Dose modifications for pembrolizumab (section 
5.2.1.2.1), cisplatin (5.2.1.2.2) and radiation (5.2.1.2.3) are outlined below.  
5.2.1.2.1 Dose Modification for Pembrolizumab 
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. 
 
 
Table 3  Dose Modification Guidelines for Pembrolizumab-Related Adverse Events 

 
SH MISP203 v08/22/2018                                                                                              Page 29 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure.  
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 
5.2.1.2.2 Dose Modification for Cisplatin 
Investigators must use cisplatin for this protocol.  Substitutions to carboplatin will not be 
permitted.  If toxicities occur, dose reductions as outlined in Tables 3.1 and 3.2 should be 
performed.   
 
Cisplatin will not be given until the ANC exceeds 1000/mm3 and the platelet count exceeds 
75,000/mm3.  Myeloid growth factors can be used per local guidelines. 
 

 
SH MISP203 v08/22/2018                                                                                              Page 30 
 
Complete blood count, differential and platelets will be checked weekly during therapy.  
Cisplatin dose will be reduced for nadir WBC or platelet count as follows: 
 
 
Table 3.1 – Cisplatin modifications based on Hematology Parameters 
 
 
Cisplatin will only be given if the serum creatinine is < 1.6 mg/dl. 
Reduce cisplatin dose for transient rises in creatinine as follows: 
 
 
Table  3.2 Cisplatin modifications based on Creatinine Peak 
 
Creatinine Peak 
Cisplatin Dose to Give 
< 1.6 
100% (dose level 0) 
>1.6 – 4.0 
80%  (dose level -1) 
> 4.0 
60% (dose level -2) 
 
 
In individuals whose creatinine does not come back down to <1.6 mg/dl, cisplatin should 
continue to be held.   
 
Neurotoxicity: 
Grade 3 hearing loss in the speech frequency range is an indication to discontinue cisplatin. 
Significant (grade 3) myopathy, weakness, or neuropathy; seizure or paralysis should prompt 
discontinuation of cisplatin and contact with the principal investigator. 
Other adverse events: 
Any other grade 4 adverse events, not previously outlined above, will result in decreasing the 
next weekly dose of cisplatin to 80% (dose level -1).  If any grade 4 event persists beyond dose 
reduction to 60% (dose level -2), cisplatin will be permanently discontinued for the duration 
of the study. 
 
Dose reductions for grade 3 events, not previously outlined above, will be permitted, but are 
at the discretion of the individual treating physician.  Dose modifications should be performed 
as: Dose level -1 = 80% dose, Dose level -2 = 60% dose, dose level -3 = hold further cisplatin.  
Treatment-related grade 3 mucositis, skin toxic effects, xerostomia, dysphagia, and anorexia, 
are expected toxicities, and dose reduction is not recommended, but will be permitted.   
Dose re-escalations are not permitted. 
Nadir  
% of 100% 
ANC 
 
Platelet 
 
Cisplatin Dose to 
Give 
> 1000 
And 
>75,000 
100% (dose level 0) 
500 – 999 
Or 
50 – 75,000 
80%  (dose level -1) 
< 500 
Or 
< 50,000 
60% (dose level -2) 

 
SH MISP203 v08/22/2018                                                                                              Page 31 
 
5.2.1.2.3  Dose Modification for Radiation 
Reversible radiation mucositis is expected to develop in the majority of patients. This will 
commonly manifest as Grades I to III in severity. In those rare cases of Grade IV mucositis, 
radiation can be interrupted for up to5 consecutive radiation treatment days until the reaction 
subsides to Grade III. However, every effort should be made to keep this treatment break as 
short as possible. If Grade IV mucositis occurs, systemic chemotherapy should also be held 
until the reaction subsides to Grade III and then radiation and chemotherapy are resumed.  
 
Toxicities:  Common radiation toxicities include mucositis, fatigue, weight loss, regional 
alopecia, xerostomia, hoarseness, transient ear discomfort, hypogeusia, dysgeusia, dysphagia, 
and skin erythema and desquamation within the treatment fields. Less common long-term 
radiation toxicities include hypothyroidism, loss of hearing, chronic swallowing dysfunction 
requiring permanent feeding tube, and cervical fibrosis. Much less common radiation toxicities 
include mandibular osteoradionecrosis (<5% incidence with attention to a full dental 
evaluation as part of pre-treatment planning), and cervical myelopathy (<1% with restriction 
of spinal cord dose to < 45 Gy). 
 
5.2.1.3 Timing of Dose Administration 
Trial treatment should be administered after all procedures/assessments have been completed 
as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be administered up to 4 
days after the scheduled Day -7 treatment start date due to administrative reasons. Additional 
treatments may be delayed as outlined in Section 6.0. 
 
5.2.1.3.1 Pembrolizumab 
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). 
On days in which cisplatin is to be administered the same day as pembrolizumab, 
pembrolizumab should be administered prior to the cisplatin.  On days when pembrolizumab 
is to coincide only with radiation, pembrolizumab can be given prior to or after radiation.   
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 

 
SH MISP203 v08/22/2018                                                                                              Page 32 
 
5.2.1.3.2  Cisplatin 
Cisplatin will be administered weekly (every 7 days) starting on day 1 of CRT.  Treatment 
cannot begin until all study procedures and assessments are completed as outlined in the Trial 
Flow Chart (Section 6.0).   
 
Cisplatin is to be given as a dose of 40 mg/m2 using an infusion duration of 60 minutes (or 
infusion duration according to local practice).  
 
 
5.2.2 Radiation 
IMRT planning will be used for this study.  
 
 
5.2.2.1 IMRT 
IMRT will be given as 70 Gy in 35 fractions over approximately 7 weeks.  The primary tumor 
and involved nodes (PTVHD) will receive 2 Gy per fractions and subclinical disease sites 
(PTVID) will receive 1.8 Gy per fraction. The total doses will thus be 70 Gy and 63 Gy, 
respectively.  When desired, PTVID can receive 1.6 Gy per fractions to a total dose of 56 Gy 
(PTVLD). 
All plans must be normalized such that 95% of the volume of the PTVHD is covered with the 
prescription dose of 70Gy. Additionally: 
 No more than 20% of the PTVHD should receive ≥ 110% of the prescribed dose; 
 No more than 1% of any PTVHD or PTVID should receive ≤ 93% of the prescribed dose; 
 No more than 1% or 1 cc of the tissue outside the PTVs should receive ≥ 110% of the 
prescribed dose to the PTVHD. 
5.2.2.2 Technical Factors 
Photon beams of ≥ 4 MV and/or electron beams from 6-25 MeV are required. Treatment 
distance must be ≥ 80 cm SAD for isocentric techniques.  
IMRT: Megavoltage equipment capable of delivering intensity modulated beams using a step-
and-shoot technique with a multileaf collimator or using dynamically moving leaves. 
Additionally, a binary multileaf collimator or tomotherapy can be used to modulate the beam.  
Other techniques, e.g. physical compensators, are acceptable as long as dose specifications and 
constraints are satisfied. 

 
SH MISP203 v08/22/2018                                                                                              Page 33 
 
5.2.2.3 Immobilization, Simulation, and Localization 
5.2.2.4 Immobilization 
The use of a thermoplastic head and shoulder mask is mandatory for IMRT. The margins used 
for expansion of the CTVs to PTVs are discussed in Section 5.2.2.3.3. 
5.2.2.5 Planning CT scan 
A treatment planning CT scan is mandatory for defining target volumes (see Section 5.2.2.6). 
CT scan thickness should be at most 0.3 cm for IMRT. The treatment planning CT scan should 
be acquired with the patient in the same position and using the same immobilization device as 
for treatment. All tissues receiving irradiation should be included in the CT scan. 
5.2.2.6 Treatment Planning/Target Volumes 
CT based treatment planning is mandatory for every patient. For IMRT, the treatment plan 
used for each patient will be based on an analysis of the volumetric dose, including dose-
volume histogram (DVH) analyses of the PTV (CTV with a 5 mm margin) and critical normal 
structures. An “inverse” planning with computerized optimization should be used. 
Gross Tumor Volume (GTV) represents the region judged to contain gross primary tumor or 
involved node(s) based on clinical and endoscopic examinations, CT scan, and, when 
applicable, other imaging techniques. Grossly positive lymph nodes are defined as any lymph 
nodes > 1 cm or nodes with a necrotic center. 
Clinical Target Volume (CTV) is defined as the GTV plus areas considered at risk for 
containing microscopic disease delineated by the treating physician. CTV1 represents GTV 
plus a margin of generally 1 cm and CTV2 represents GTV with a margin of about 2 cm and 
nodal regions to receive elective irradiation. When the tumor is infiltrative (endophytic) or 
when the border is ill defined, it might be desirable to deliver an intermediate dose (e.g., 59-
63 Gy) to a volume (CTVINT) that is slightly larger than CTV1. The CTV margins can be 
narrower when GTV is in the proximity of the spinal cord or critical normal tissues. 
Planning Target Volume (PTVHD, PTVID, PTVLD) represents an additional margin around 
CTV1 and CTV2 to compensate for the variability of treatment set up and internal organ motion. 
A minimum margin of 0.5 cm around the CTV is required in all directions to define each 
respective PTV, except for situations in which the CTV is adjacent to spinal cord or other 
critical normal tissues. In such situations, the margin can be reduced judiciously. A minimum 
margin of 3 mm can be used in all directions as long as an institution implements a study to 
define the appropriate magnitude of the uncertain components of the PTV.  
5.2.2.7 Critical Structures  
Spinal cord: A margin of 0.5-1cm around the spinal cord may be added to create a Planning 
Organ at Risk Volume (PRV). The dose to any point within the spinal cord should not exceed 
48 Gy to any volume larger than 0.03 cc (approximately equivalent to a 3x3x3 mm cube). 

 
SH MISP203 v08/22/2018                                                                                              Page 34 
 
Parotid glands: When using IMRT, the objective is to limit the mean dose to at least one gland 
to ≤ 26 Gy; alternatively at least 20 cc of the combined volume of both parotid glands to < 20 
Gy or at least 50% of one gland to <30 Gy. 
Glottic larynx: In patients with oropharyngeal carcinoma without extension to the larynx, 
placing the isocenter just above the arytenoids and irradiating the lower neck with an anterior 
matching field with larynx block can minimize the dose to the glottic larynx. Alternatively, the 
dose to the larynx should be kept <45 Gy whenever feasible. 
Brachial plexus: The dose to the brachial plexus must be limited to ≤ 60 Gy in patients with 
level IV node(s).based on a dose distribution corrected for heterogeneities. 
Unspecified tissue outside the target volumes: ≤ 100% of the dose prescribed to CTV1. No 
more than 5% of the non-target tissue can receive greater than the dose to CTV1. 
5.2.2.8 Documentation Requirements 
Portal image of each field of 3-D radiotherapy or orthogonal images that localize the isocenter 
placement of IMRT must be obtained on the first day of therapy. 
Weekly verification or orthogonal images are required. 
Isodose plans for IMRT and DVHs of GTV, CTVs, and critical normal structures for IMRT.  
5.2.2.9 Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Missed treatments due to holidays or logistic reasons can be 
compensated for by delivering additional BID treatments with a minimum interfraction interval 
of 6 hours or by treating on a Saturday or Sunday. 
Treatment breaks should be allowed only for resolution of severe acute toxicity and/or for 
intercurrent illness and ideally, should not exceed 5 treatment days at a time and 10 treatment 
days in total. Any treatment break(s) exceeding two treatment days for reasons other than 
toxicity/illness will be considered a protocol deviation. 
Plan normalization should provide coverage of 95% of the volume of the PTV of the GTV 
(PTVHD) with the prescribed dose of 70 Gy. No more than 1% of the volume of the PTVHD 
should receive less than 64 Gy. Additionally, no more than 10% of the PTV of the GTV should 
receive more than 76 Gy, and no more than 5% of this volume should receive more than 79 
Gy. These numbers describe the DVH shown in the figure below with the diamond shaped 
symbols. Obviously, better DVHs (i.e., with smaller amounts of either underdose or overdose) 
are preferable. 
A region of “minor deviation” is also defined in the figure as the DVH represented by the 
square symbols. Deviations of this magnitude are not desirable, but will be deemed acceptable. 

 
SH MISP203 v08/22/2018                                                                                              Page 35 
 
That is, a DVH with at least 97% of the volume receiving 64 Gy is acceptable as a minor 
deviation. 
Additionally, as a minor deviation for the overdose region, as much as 40% of the PTVHD 
volume can receive 76 Gy and up to 10% of this volume can receive 79 Gy. DVHs for the 
PTVHD falling outside the limits for a minor deviation (i.e., increased under or overdose) will 
be scored as unacceptable “major deviations.” 
The DVHs for the other target regions should deliver the prescribed dose, as much as possible, 
to at least 95% of the volume of that PTV. 
Overall Evaluation 
Radiotherapy 
Prolongation 
Total Dose Variation 
IMRT** 
Per Protocol 
≤5 days 
See parameters in the 
figure below 
Minor Variation 
(Acceptable) 
6-10 days 
See parameters in the 
figure and table 
below 
Major Deviation 
(Unacceptable) 
>10 days 
Deviations greater 
than presented in the 
table and figure 
below 
 
**Note: For IMRT, prescription dose is the isodose surface that encompasses at least 95% of 
the planning target volume (PTV) with no more than 10% of any PTVHD receiving ≥ 110% 
of the prescribed dose and no more than 1% of any PTVHD and PTVID receiving ≤ 93% of 
the prescribed dose.  
 

 
SH MISP203 v08/22/2018                                                                                              Page 36 
 
 
 
 
Trial Blinding/Masking 
This is an open-label trial; therefore, Sanford Research, investigator and subject will know the 
treatment administered. 
 
Randomization or Treatment Allocation 
The study is non-randomized.  There is only one treatment arm.  All subjects will receive the 
study treatment. 
 
Stratification 
There are two separate cohorts of subjects in this clinical trial.  Thirty-four of the 57 subjects 
will be HPV+ while the remaining 23 subjects will be HPV-. 
. 

 
SH MISP203 v08/22/2018                                                                                              Page 37 
 
 
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 Principal Investigator.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.6.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.6.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy not specified in this protocol 
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the study Principal 
Investigator or designee. 

 
SH MISP203 v08/22/2018                                                                                              Page 38 
 
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. 
 
Rescue Medications & Supportive Care 
5.7.1 Supportive Care Guidelines for Pembrolizumab 
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 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 

 
SH MISP203 v08/22/2018                                                                                              Page 39 
 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 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 3-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 

 
SH MISP203 v08/22/2018                                                                                              Page 40 
 
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 
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). 

 
SH MISP203 v08/22/2018                                                                                              Page 41 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
5.7.2 Supportive Care Guidelines for Cisplatin 
Based on local standard practices the chemotherapy regimen is considered moderate emesis 
potential.  Prevention and/or treatment of nausea and vomiting should be managed with the 
following regimen initially: 
 
Prior to each cisplatin dose: 
1. Fosaprepitant 150 mg IV day 1 or  aprepitant  3 day pack (125 mg day 1, 80 mg days 
2 and 3) 
2. Palonosetron 0.25 mg IV day 1 
 
Additional scheduled antiemetic support can include (per investigator discretion): 
1. Ondansetron 8 mg two times a day starting 1 day following palonsetron 
2. Prochlorperazine 10 mg IV/PO 3-4 times per day 
3. Olanzapine 5-10mg PO days 1-4 
4. Granisetron transdermal patch 3.1mg/day; maximum  duration of patch is 7 days 
5. Lorazepam 0.5-2mg PO/IV every 4-6 hours 
6. H2 blocker or proton pump inhibitor 
 
Additional as needed antiemetics can be used per local standards. However, due to the 
immunologic nature of this trial, corticosteroids, including dexamethasone should not be used 
unless Grade 4 nausea occurs.  If this occurs, dexamethasone 4 mg IV/PO can be used as a 
premedication for cisplatin.  If Grade 4 nausea still occurs, despite dexamethasone 4 mg IV/PO, 
additional corticosteroid can be used after discussion with the principal investigator.  
 
Please refer to the product label or local standards of care for additional cisplatin supportive 
measures. 
 

 
SH MISP203 v08/22/2018                                                                                              Page 42 
 
Hydration and electrolyte replacement may be utilized per the discretion of the treating 
physician provided adequate pre/post cisplatin hydration is achieved and renal function 
remains adequate.  
 
5.7.3 Supportive Care Guidelines for Radiation 
Please refer to local standards of care for additional supportive measures for radiation. 
 
 
Diet/Activity/Other Considerations 
5.8.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.8.2 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), vasectomy, copper intrauterine device, sponge, or spermicide.  Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent that 
contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, 
or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to Sanford Research 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. 
5.8.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the treatment phase of the study.  The site will 
contact the subject at least monthly and document the subject’s status until the pregnancy has 

 
SH MISP203 v08/22/2018                                                                                              Page 43 
 
been completed or terminated.  The outcome of the pregnancy will be reported to Sanford 
Research and to Merck without delay and within 24 hours to Sanford Research 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 Sanford Research.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Sanford Research and to Merck and followed as 
described above and in Section 7.2.2. 
5.8.4 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. 
5.8.4.1 Pembrolizumab 
It is unknown whether pembrolizumab is excreted in human milk. 
 
5.8.4.2 Cisplatin 
Cisplatin has been reported to be found in human milk; subjects receiving Cisplatin injection 
should not breast-feed. 
 
 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be withdrawn 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 principal investigator if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other 
Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 

 
SH MISP203 v08/22/2018                                                                                              Page 44 
 
 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).  For those subjects discontinue treatment early, 
each subject will be followed for 30 days for adverse event monitoring (serious adverse events 
will be collected for 90 days after the end of treatment as described in Section 7.2.3.1).  
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed for overall survival until death, withdrawal of consent, or the end 
of the study, whichever occurs first. 
 Subject Replacement Strategy 
A subject who discontinues from the trial during the active treatment for reasons other than 
AE/SAE or progression will be replaced. 
 
 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

 
 
 
 
 
SH MISP203 v08/22/2018                                                                                              
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6.0 TRIAL FLOW CHART 
 
Screening and Concurrent Treatment Phase 
 
Screening Visit 
Treatment Days1 
 
Treatment Day 
-36 to -8 
-7 
1 
8 
15 
22 
29 
36 
43 
50 
Scheduling Window2 (days) 
 
+4 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
Administrative Procedures 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Informed consent correlative 
research 
x 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
Demographics and medical history 
x 
 
 
 
 
 
 
 
 
 
Prior and concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Disease specific details 
x 
 
 
 
 
 
 
 
 
 
Clinical Procedures and Assessments 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Full Physical Exam 
x 
 
 
 
 
 
 
 
 
 
Directed Physical Exam 
 
x 
x 
x 
x 
x 
x 
x 
x 
 

 
 
 
 
 
SH MISP203 v08/22/2018                                                                                              
Page 46 
 
 
 
Screening Visit 
Treatment Days1 
 
Treatment Day 
-36 to -8 
-7 
1 
8 
15 
22 
29 
36 
43 
50 
Scheduling Window2 (days) 
 
+4 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
Vitals and Weight19 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG PS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Study Treatments 
Pembrolizumab 
 
x 
 
 
x 
 
 
x 
 
 
Cisplatin 
 
 
x 
x 
x 
x 
x 
x 
 
 
Radiation3 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Procedures/Assessments (local laboratory testing): 
Pregnancy Test4 
x 
 
 
 
 
 
 
 
 
 
CBC with differential 
x 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Chemistry Panel5 
x 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
Uric Acid 
x 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
Magnesium, Phosphorus, LDH 
x 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
T3, FT4, TSH 
x 
 
 
 
x 
 
 
x 
 
 
 

 
 
 
 
 
SH MISP203 v08/22/2018                                                                                              
Page 47 
 
 
 
Screening Visit 
Treatment Days1 
 
Treatment Day 
-36 to -8 
-7 
1 
8 
15 
22 
29 
36 
43 
50 
Scheduling Window2 (days) 
 
+4 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
+/-2 
Urinalysis 
x 
 
 
 
x 
 
 
x 
 
 
P16 testing6 
x 
 
 
 
 
 
 
 
 
 
Imaging 
Tumor Imaging (CT  neck12, 
PET14) 
x 
 
 
 
 
 
 
 
 
 
Correlative Study Procedures 
Tumor tissue collection7 
x 
 
 
 
 
 
 
 
 
 
Blood for correlative studies10 
 
x 
 
 
x 
 
 
x 
 
 
Patient Reported Outcomes (PRO) 
FACT H&N11  
 
x 
 
 
 
 
 
x 
 
 
 
 

 
 
 
 
 
SH MISP203 v08/22/2018                                                                                              
Page 48 
 
 
 
Adjuvant Treatment Phase 
 
Treatment Days1 
Treatment End 
Treatment Day 
57 
78 
99 
120 
141 
150 
Scheduling Window (days)2 
-3/+7 
-3/+7 
-3/+7 
-3/+7 
-3/+7 
-7/+14 
Administrative Procedures 
Prior and concomitant medications 
x 
x 
x 
x 
x 
x 
Clinical Procedures and Assessments 
Adverse Events 
x 
x 
x 
x 
x 
x 
Directed Physical Exam 
x 
x 
x 
x 
x 
x 
Vitals and Weight 
x 
x 
x 
x 
x 
x 
ECOG PS 
x 
x 
x 
x 
x 
x 
Study Treatments 
Pembrolizumab17,18 
x 
x 
x 
x 
x 
 
 
 
 
 

 
 
 
 
 
SH MISP203 v08/22/2018                                                                                              
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Treatment Days1 
Treatment End 
Treatment Day 
57 
78 
99 
120 
141 
150 
Scheduling Window (days)2 
-3/+7 
-3/+7 
-3/+7 
-3/+7 
-3/+7 
-7/+14 
Laboratory Procedures/Assessments (local laboratory testing): 
CBC with differential 
x 
x 
x 
x 
x 
x 
Serum Chemistry Panel5 
x 
x 
x 
x 
x 
x 
Uric Acid 
x 
x 
x 
x 
x 
x 
Magnesium 
x 
 
 
 
 
 
Urinalysis 
x 
x 
x 
x 
x 
x 
T3, FT4, TSH 
 
 
 
x 
 
x 
Imaging 
Tumor Imaging (CT neck12, PET14 ) 
 
 
 
 
 
x 
Correlative Study Procedures 
Blood for correlative studies10 
 
x 
 
x 
 
x 
Salvage surgery collection13 
 
 
 
 
 
x 
Patient Reported Outcomes (PRO) 
FACT H&N11  
 
x 
 
 
 
x 

 
 
 
 
 
SH MISP203 v08/22/2018                                                                                              
Page 50 
 
 
6.3 
Follow-up 
 
Months Following Study Treatment End (after day 150 imaging) 
Follow-up Month 
Follow up 
visit 1 
(90 days from 
Day 150) 
Follow up 
visit 2 
(90 days from 
FU-V1) 
Follow up 
visit 3 
(180 days 
from FU-V2) 
Follow up 
visit 4 
(180 days 
from FU-V3) 
Follow up 
visit 5 
(180 days 
from FU-V4) 
Follow up 
visit 6 
(352 days 
from FU-V5) 
Follow up 
visit 7 
(352 days 
from FU-V6) 
Follow up 
visit 8 
(352 days from 
FU-V7) 
Study 
End 
Scheduling Window 
+/- 14 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
Subsequent antineoplastic 
therapy status 
x 
x 
x 
x 
x 
x 
x 
x 
Survival Status16 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical Procedures and Assessments 
Adverse Events20 
x 
x 
x 
x 
x 
x 
x 
x 
Directed Physical Exam 
x 
x 
x 
x 
x 
x 
x 
x 
Vitals and Weight (optional) 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG PS(optional) 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 

 
 
 
 
 
SH MISP203 v08/22/2018                                                                                              
Page 51 
 
 
 
Months Following Study Treatment End (after day 150 imaging) 
Follow-up Month 
Follow up 
visit 1 
(90 days from 
Day 150) 
Follow up 
visit 2 
(90 days from 
FU-V1) 
Follow up 
visit 3 
(180 days 
from FU-V2) 
Follow up 
visit 4 
(180 days 
from FU-V3) 
Follow up 
visit 5 
(180 days 
from FU-V4) 
Follow up 
visit 6 
(352 days 
from FU-V5) 
Follow up 
visit 7 
(352 days 
from FU-V6) 
Follow up 
visit 8 
(352 days from 
FU-V7) 
Study 
End 
Scheduling Window 
+/- 14 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
+/- 30 days 
 
Laboratory Procedures/Assessments (local laboratory testing): 
 
CBC with differential 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Chemistry Panel5 
x 
x 
x 
x 
x 
x 
x 
x 
T3, FT4, TSH 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
Imaging 
 
Tumor Imaging (CT neck) 
x 
x 
x 
 
x 
x 
x 
x 
Correlative Study Procedures 
Blood for correlative studies10 
 
 
x 
 
 
 
 
 
Patient Reported Outcomes (PRO) 
FACT H&N11  
 
 
x 
 
x 
 
 
 
 
 

 
 
 
 
 
SH MISP203 v08/22/2018                                                                                              
Page 52 
 
 
1. Treatment day 1 coincides with the first day of radiation therapy. Any treatment days before will be denoted with a preceding (-) symbol.   
2. The window for each visit is outlined as above.  If a treatment is delayed, the following treatment must occur with the same delay.  Additional treatment delay can occur with the 
specified scheduling window.  If treatment is delayed beyond that window, treatment for that scheduled course must be held.   Treatment can be resumed for the next scheduled 
treatment day. 
3. Radiation occurs continuously throughout therapy until the total of 35 fractions has been completed.  Therefore, the dates listed may not always have radiation treatment on that 
date.  All radiation should be completed by day 52.  
4. For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to the first dose of trial treatment.  If urine pregnancy tests cannot be confirmed 
as negative, a serum pregnancy test, performed by the local lab, will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines. 
5. The serum chemistry panel includes tests listed in Section 7.1.3, Table 5(Albumin, AST, ALT, Alkaline phosphatase, Total Bilirubin (and direct bilirubin if elevated), Total 
Protein, CO2, Calcium, Chloride, Glucose, Potassium, Sodium, Creatinine, and BUN). 
6. p16 immunohistochemistry status is required on all patients.  This can be performed by the local laboratory sites. High risk HPV DNA testing at an outside lab can be performed 
if p16 staining is indeterminate or not able to be obtained. See section 5.1.2 for details.  
7. Tumor tissue for biomarker analysis from an archival tissue sample or fresh biopsy must be provided for enrollment.  Detailed instructions for tissue collection, processing and 
shipment are included in the procedures manual.  
10. Blood for correlative flow cytometry studies will be drawn throughout treatment.  On days with corresponding treatment, this should be drawn within 24 hours prior to treatment 
with pembrolizumab or chemotherapy.  Procedures for sample collection, processing, and shipment are included in the procedures manual. 
11. Patient reported outcomes (PRO) will be assessed using the FACT H&N form (see Appendix 11.8).  PRO forms must be completed on paper or electronically by subjects prior 
to all other study procedures for that date. Patients who go off-treatment but continue follow up should be encouraged to complete PRO at the times outlined in the calendar. 
12.  Tumor imaging will be completed at baseline and after treatment has finished, on approximately day 150-157.  Baseline imaging must be completed within 42 days of enrollment.  
Required imaging for the study protocol is diagnostic quality imaging of the neck.  Additional imaging techniques can be utilized (i.e. MRI, FDG-PET, etc.), but are not required for 
study procedures.  
13. Patients with residual disease (SD, PR, or PD) on post-treatment imaging will undergo salvage surgical resection (at the discretion of the surgeon) if their disease is felt curable 
with salvage surgery.  Additionally, patients with a CR and clinical suspicion for viable residual disease will be offered salvage surgery.  Following pathology analysis, salvage 
surgical tissue will be sent for correlative studies.  Detailed instructions for tissue collection, processing, and shipment are included in the procedures manual. 
14. PET imaging at baseline and treatment end is not required for the study, but is allowed for use to determine complete response rate when tumor response on standard imaging 
cannot confirm CR based on RECIST 1.1. Please see sections 7.1.2.6.2 and 7.1.2.6.3 for details.   
15.  Screening labs completed within 7 days (168 hours) of treatment initiation (day -7) will not need to be repeated.  
16. Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the subject moves into the Survival Follow-Up Phase.  These subjects will be 
followed every 6 months to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
17.  If a subject discontinues pembrolizumab, return visit timing is left to treating physician discretion until day 150 although it is highly recommended that the subject return for 
Day 78, 120, and 150 so research specimens and QOL can be collected. 
18.  Minimum interval between pembrolizumab doses is 14 days. 
19. Vital signs and weight do not need to occur on the same day as the visit but need to be completed within the window and prior to the next treatment. 
20. Once a subject transitions to follow-up all documented AEs will be followed until resolution or to a new baseline as determined by the treating investigator.  Only new AEs that 
could be considered an ECI or irAR will be documented and followed while in follow-up. 
 
 
 

 
 
 
 
 
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7.0 TRIAL PROCEDURES 
 
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 Sanford Research 
and/or Merck for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature 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 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 informed consent will adhere to IRB/ERC 
requirements, applicable laws, regulations, and Sanford Research 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 clinically significant by the Investigator.  Details regarding the disease for 

 
 
 
 
 
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which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated, the subject will 
move into survival follow-up.  
7.1.1.6 Assignment of Screening Number 
Consented subjects will be assigned a screening number. Specific details on the screening visit 
requirements (screening/rescreening) are provided in Section 7.1.5.1.  
 

 
 
 
 
 
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7.1.1.7 Assignment of Study Subject Number 
Subjects will be assigned a subject study number at enrollment.  This number will be unique 
to this subject.  
 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for >1 week require consultation with 
the principal investigator. Written documentation of the collaborative decision is required. 
 
Missed doses of the study drug, pembrolizumab, will be monitored and tracked.  This will be 
analyzed as part of the safety and tolerability portion of the analysis. 
 
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 according to NCI 
CTCAE Version 4.0 (see Section 11.2).  Toxicities will be characterized in terms regarding 
seriousness, causality/attribution, toxicity grading, and action taken with regard to trial 
treatment.  
AEs should be assessed up to 30 days following cessation of treatment and followed for 90 
days for SAEs, even if the patient transitions to follow-up during this time. Once a subject 
transitions to follow-up all documented AEs will be followed until resolution or to a new 
baseline as determined by the treating investigator.  Only new AEs that could be considered 
an ECI or irAR will be documented and followed while in follow-up. 
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 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 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.    

 
 
 
 
 
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7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs after Day 150 will be at the discretion of the 
treating investigator. Vital signs should include temperature, pulse, weight and blood pressure.  
Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
7.1.2.6.1 Baseline Tumor Imaging 
Initial tumor imaging must be performed within 42 days prior to enrollment. Baseline imaging 
does not need to have a centralized study review to determine subject eligibility. The baseline 
imaging scan should be reviewed by each individual site prior to enrollment to confirm 
measurable disease.  
 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 42 days prior to the enrollment. 
 
The only required imaging modality for the study is a diagnostic quality CT scan of the neck. 
This should be adequate to fully include the primary tumor and involved locoregional disease. 
Additional imaging is allowed, but not required for the study. This includes, but is not limited 
to CT imaging of the head, chest, abdomen, and pelvis, MRI imaging, and FDG-PET imaging.   
 
7.1.2.6.2 Tumor Imaging During Trial 
The first imaging assessment should be performed at approximately 100 days after 
completion of radiation therapy. For the purposes of this study, this is considered the 
“treatment end” imaging study.  This will be approximately day 150 from the first dose of 
radiation.  Due to treatment variations and delays, this may be delayed by up to 14 days.  
 
Follow-up imaging will occur at scheduled intervals outlined on the Flow Chart.  At 1 year 
following completion of the study treatment  PET/CT imaging is not required, but is suggested 

 
 
 
 
 
SH MISP203 v08/22/2018 
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and is allowed so long as diagnostic quality CT images are included.   Diagnostic quality 
imaging of the primary tumor site (CT scan of the neck) should be performed annually 
thereafter for up to 5 years.  Images will be reviewed by the central radiologist at the end of 
the study to confirm disease response for purposes of study evaluation. 
 
Additional imaging should be performed per clinical guidelines and is not required the study. 
Patients with clinical signs and symptoms of progression should have follow-up imaging as 
deemed clinically necessary.  If this occurs during the study period, it should be reported to the 
study.   
 
During the follow up period, if an instance occurs where the participants insurance will not 
approve a diagnostic CT scan a clinical evaluation will be used.  No protocol deviation is 
needed but the insurance denial must be documented on the tumor assessment source 
documents. 
 
7.1.2.6.3  Assessment of Disease – RECIST 1.1, irRECIST 1.1, PET Response, Salvage 
Surgery 
7.1.2.6.3.1 RECIST 1.1 
 
RECIST 1.1 will be applied by the individual sites for assessment of tumor response. Sites 
should also assess tumor response and progression per modified RECIST 1.1 and this data will 
be collected in the clinical database. Site assessment of tumor response and progression will 
be used for all patient decision making in the trial.  See Section 11.3 and 11.4. 
 
7.1.2.6.3.2 irRECIST 1.1 
 
irRECIST 1.1 will not be used in this study.  Any patient with documented progression, partial 
response, or stable disease on post-treatment imaging will undergo salvage surgical procedures 
to confirm pathologic response (see Section 7.1.2.7.3.3). 
 
7.1.2.6.3.3 PET Response (Hopkins Criteria) 
 
Hopkins Criteria will be used to assess PET response when PET imaging is utilized.  This is 
outlined in section 11.5.  PET is not required, but is allowable to assist in determine the primary 
efficacy outcome when RECIST 1.1 data is considered not clinically representative of 
response.  Patients without a RECIST 1.1 CR, but with a Hopkins Criteria negative predictive 
value (NPV) (See section 11.5) can forgo salvage surgery and be considered as having a CR 
in terms of the primary efficacy measure.    
7.1.2.6.3.4 Salvage Surgery 
 

 
 
 
 
 
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Patients with residual disease considered resectable after all their planned therapy is completed 
may undergo a salvage surgical procedure, if that procedure is conceived as potentially 
curative.  
 
PET imaging can be used to guide post treatment surgical need.  The preference of the study 
would be to recommend no further therapy for any PET tumor avidity (CMR).  However, this 
is not a requirement and will be left up to the discretion of the treating surgical oncologist. 
 
Patients achieving a complete response who had advanced (N2 or greater) neck disease at 
presentation should be considered for an elective neck dissection after completion of all of 
their planned therapy if the post therapy imaging or clinical exam indicates persistent disease, 
despite RECIST 1.1 response. The nature of the neck dissection will be at the discretion of the 
treating head and neck surgeon. 
 
Pathologic response to therapy will be evaluated following surgery. Pathological complete 
response (pCR) is defined as the absence of residual invasive and in situ cancer on hematoxylin 
and eosin evaluation of the completely resected sites of residual disease.  Subjects who have a 
pathologic CR, but do not have a RECIST 1.1 CR will be included in the final efficacy analysis.  
This analysis will include the composite outcome of patients with RECIST 1.1 CR, Hopkins 
Criteria NPV (see section 11.5), and pathologic CR.   
 
 
Patients who show signs of clear, clinical progression prior to the treatment end imaging may 
be considered for surgery.  This will be at the discretion of the treating providers, including the 
surgeon, medical oncologist, and radiation oncologist.  Patients who undergo surgery will be 
determined to have PD in terms of analysis of the primary endpoint.  
 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
7.1.2.7.1 Tumor Tissue Collection 
All subjects will submit either a “recently obtained” core or excisional biopsy (fine needle 
aspirate not adequate) to a central lab for characterization of PD -L1 status, performed 
retrospectively. A “recently obtained” sample may be obtained up to 60 days prior to 
enrollment. Tissue beyond the 60-day window may be considered with principal investigator 
approval as long as no intervening systemic therapy has been administered.  Subjects for whom 
recently obtained samples cannot be obtained (e.g. inaccessible or subject safety concern) may 
submit an archived specimen only upon agreement from the principal investigator.  Formalin 
fixed paraffin embedded (FFPE) are allowable.    
 
Post-treatment biopsy of the primary site if tumor persists and salvage neck dissection 
specimens will be analyzed for tumor PD-L1 expression and tumor infiltrating immune 
cells. 
 
For correlative genomic analysis, an additional portion of the pre-treatment core or excisional 
biopsy will be used for analysis.   If fresh frozen tissue is available, RNA profiling studies may 

 
 
 
 
 
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be performed, but this is not a requirement for the study.  Correlative circulating tumor DNA 
may be also be analyzed.  This will be collected in addition to other correlative blood sampling.  
Details of collection and appropriate specimens are outlined in the procedures manual.     
Detailed instructions for tissue collection and appropriate specimens are provided in the 
Procedures Manual. 
 
7.1.2.7.2 Correlative Blood Sampling 
Correlative blood sampling for biomarkers of immune response will be collected at key time 
points during the study.  These are not required for all subjects, but are strongly recommended.  
Timing for correlative blood sampling is outlined in section 6 – Trial Flow Chart.  To 
summarize: 
 
Blood sampling for flow cytometry or functional immune cell analysis will be used to analyze 
peripheral blood immunocyte populations will occur on day-7, day 15, day 36, day 78, day 
120, treatment end (day 150-157), and at 12 months treatment.   
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  Laboratory tests for hematology, chemistry, urinalysis, and others are 
specified in Table 5.   
 
 

 
 
 
 
 
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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Total thriiodothyronine (T3) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
Free tyroxine (T4) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Thyroid stimulating hormone (TSH) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Blood for correlative studies 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Creatinine 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
Screening laboratory tests may be done up to 10 days prior to start of treatment but if done less 
than 7 days (168 hours) prior to the first dose of treatment on Day -7, they will not need to be 
repeated. After Day -7, 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 Tissue Collection and Evaluation 
7.1.3.1.1Tumor Collection for p16, PD-L1, and Genomic Analysis 
 
All subjects will have p16 immunohistochemical (IHC) staining (high risk HPV DNA testing  
may be used as outlined in section 5.1.2) done per institutional standard procedures prior to 
treatment.   
 
All subjects will submit a recently obtained core or excisional biopsy (within 60 days from 
enrollment).  Fine-needle aspirates (FNAs) are not adequate.  Characterization of PD-L1 will 
be performed using IHC.  Detailed instructions for processing of specimens and testing are 
outlined in the procedures manual and statistical analysis plan (SAP).   
 

 
 
 
 
 
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For correlative genomic studies, tumor tissue blocks will be micro-dissected and Tumor DNA 
and RNA will be immediately processed and stored.  Detailed instructions for processing of 
tumor specimens and testing are outlined in the SAP. 
 
For infiltrating immunocyte analysis, tumor tissue blocks will be stored in the Sanford  or 
similar UCSD facility and testing will be completed at a later date.  Detailed instructions for 
processing of tumor specimens are outlined in the SAP.  
 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to active trial completion, the subject will need 
to sign a withdrawal consent.  If the subject becomes cognitively impaired while on this study 
the subject and/or their Legal Representative will have the opportunity to sign a withdrawal 
consent. All applicable activities scheduled for the final trial visit should be performed at the 
time of discontinuation/withdrawal.  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.  After discontinuing 
treatment following completion, subjects should return to the site for a Safety Follow-up Visit 
(described in Section 7.1.5.) and then proceed to the Follow-Up Period of the study (described 
in Section 7.1.5.4). 
Subjects will have the option to withdraw from the study completely or partially which will 
allow following for progression/survival. 
7.1.4.2 Blinding/Unblinding 
There is no blinding for this trial. 
 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
Approximately 28 days prior to treatment (day-36), potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Visit requirements 
are outlined in Section 6.0 – Trial Flow Chart.   
 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 

 
 
 
 
 
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frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following: 
Laboratory tests and ECOG performance status are to be performed within 14 days 
prior to the first dose of trial treatment. 
For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment. 
Biopsy collections may be collected up to 60 days prior to enrollment as presented in 
Sections 5.1.1 and 6.1. 
 
. 
7.1.5.2 Treatment Period 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures. 
 
7.1.5.3 Post-Treatment Visits 
Subjects will be followed for up to 5-years following treatment completion.  The Trial Flow 
Chart – Section 6 outlines visit requirements and study procedures required at these visits.  
Further details are outlined in the subsections below.   
 
7.1.5.4 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first, for those subjects who do not complete active 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, return to baseline, or until the beginning 
of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of 
the end of treatment or before initiation of a new anti-cancer treatment should also be followed 
and recorded.   
7.1.5.5 Follow-up Visits 
Follow-up visits for subjects who complete study treatment are outlined in the Trial Flow Chart 
– section 6.   
 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase.  Every effort should be made to collect information regarding 
disease status until the start of new anti-cancer therapy, disease progression, death, or end of 
study.  Information regarding post-study anti-cancer treatment will be collected if new 
treatment is initiated. 
 

 
 
 
 
 
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7.1.5.6 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the Survival Follow-Up Phase.  These subjects will be followed  every 
6 months to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
 
 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient that received a 
pharmaceutical product during the course of the study, whether or not they are considered 
related to the product. This includes changes in laboratory parameters.  Any medical condition 
that is present before the subject starts study medication and does not deteriorate should not be 
reported as an AE. However, if it deteriorates at any time during the study it should be recorded 
as an AE. 
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.  Example 
of this may include, but are not limited to,  menopause occurring at a physiologically 
appropriate time. 
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. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
All acute adverse events will be recorded from the time the subject receives the first dose of 
treatment through 30 days following cessation of treatment. 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 
Sanford Research 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. 

 
 
 
 
 
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If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
Overdoses of radiation and cisplatin will be in accordance with the respective local product 
label and standard procedures. 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
Sanford Research and within 2 working days’ hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to Sanford Research 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 Sanford Research and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to Sanford Research and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is a new cancer (that is not a condition of the study); 
 Is associated with an overdose; 
 Is another important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 

 
 
 
 
 
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Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to Sanford Research 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 principal investigator and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to Sanford 
Research via email at SH-MISP@sanfordhealth.org or fax (1-605-312-3321) and to the 
Merck Global Safety facsimile number:  +1-215-993-1220. 
A copy of all 15 Day Reports and Annual Progress Reports will be submitted as required by 
FDA, Merck or other local regulators. Investigators will cross reference this submission 
according to local regulations to the Merck Investigational Compound Number (IND, CSA, 
etc.) at the time of submission.  Additionally, investigators will submit a copy of these reports 
to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to Sanford Research and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)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 Sanford Research, 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 

 
 
 
 
 
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upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
1. Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document”.  This document provides guidance regarding identification, 
evaluation and management of ECIs and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days 
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported 
within 24 hours to Sanford Research via email at SH-MISP@sanfordhealth.org or fax (1-
605-312-3321   and within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220), regardless of attribution to study treatment, consistent 
with standard SAE reporting guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related. 
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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7.2.4.1 Table 6  Evaluating Adverse Events 
An investigator, who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality/attribution noted on 
the AE form, ensures that a medically qualified assessment of causality/attribution was done. This initialed document must be retained for the required regulatory 
time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the 
adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 

 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

 
 
 
 
 
 
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7.2.5 Sanford Research Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators and 
Merck in accordance with all applicable global laws and regulations.  
 
TRIAL GOVERNANCE AND OVERSIGHT 
 
7.3.1 Study Oversight Committee 
The Study Oversight Committee (SOC) comprises members of Study Team and is led by the 
Principal Investigator. The SOC will receive and follow up on  any recommendations made by 
the Data Safety and Monitoring Board (DSMB) regarding the trial. 
 
7.3.2 Data Safety and Monitoring Board (DSMB) 
An independent DSMB will be established with experienced members, none of whom are 
participating as study investigators, to monitor and evaluate the safety of subjects, to maintain 
oversight of study data and to monitor progress of the study. The board will meet at according 
to the DSMB Charter approved at the beginning of the trial. The DSMB may also meet at 
unscheduled times according to clinical necessity.  All SAEs will be reported to the DSMB as 
soon as possible after learning of the event. 
 
The DSMB will make recommendations to the SOC regarding steps to ensure subject safety 
and the continued ethical integrity of the trial.  The DSMB will review interim study results 
and consider the overall risk and benefit to trial participants.  They will recommend to the SOC 
whether the trial should continue in accordance with the protocol.   
 
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members of the DSMB; meeting facilitation; the trial 
governance structure; and requirements for and proper documentation of DSMB reports, 
minutes, and recommendations will be described in a separate charter that is reviewed and 
approved by the DSMB.  
 
8.0 STATISTICAL ANALYSIS PLAN 
 
Statistical Analysis Plan Summary 
A brief summary of the statistical analysis plan (SAP) is outlined in the table below.  A more 
detailed description of statistical plan begins at section 8.2 and continues in the SAP 
 
 
 
 
 

 
 
 
 
 
 
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Study Design Overview 
 
Phase 
IB 
study 
of 
Pembrolizumab 
in 
combination with chemoradiotherapy (CRT) for 
locally advanced squamous cell carcinoma of 
the head and neck (SCCHN) 
Treatment Assignment. 
 
Treatment assignment is open label 
Analysis Populations 
 
Efficacy: Full Analysis Set (FAS) 
Safety: All Subjects as Treated (ASaT) 
Primary Endpoint(s) 
 
1) Safety and Tolerability 
2) Efficacy: Complete Response (CR) Rate at 
treatment end. 
Statistical Methods for Key Efficacy Analyses 
 
The key efficacy analysis is estimation of the 
treatment end CR rate using Exact method 
based on binomial distribution. There is no 
statistical hypothesis. 
Statistical Methods for Key Safety Analyses 
 
Count and percentage of AE will be provided. 
Fisher’s exact test will be used to compare the 
proportions. 
Interim Analyses 
 
Interim efficacy analysis will be performed 
when 27 subjects have enrolled in this study and 
are evaluable for response (day 150). Efficacy 
results will be reviewed by the DSMB.  
Multiplicity 
 
Not included in this study.  
Sample Size and Power 
 
Sample size is based off the efficacy endpoint. It 
is estimated that57 evaluable patients, will be 
sufficient to determine the efficacy endpoint 
with a power = 0.8 and one-sided alpha = .05.   
 
 
 
Statistical Analysis Plan (SAP) 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).   Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, along with an explanation as to when and why they 
occurred, will be listed in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. See the statistical analysis plan (SAP) for more 
information. 
 
 
Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 3. 
 
 

 
 
 
 
 
 
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Analysis Endpoints 
 
8.4.1 Efficacy Endpoints 
Radiographic Complete response (rCR) rate: proportion of subjects in the analysis population 
who have a complete response on RECIST 1.1 imaging at treatment end.  
 
PET NPV rate: proportion of subjects in the analysis population who  are considered to have 
NPV based on Hopkins Criteria scoring at treatment end.  
 
Pathologic complete response (pCR) rate:  proportion of subjects in the analysis population 
who have stable disease (SD) or partial response (PR) on RECIST 1.1 imaging at treatment 
end, who undergo salvage surgical resection and have a complete response determined on 
histologic evaluation.   
 
Overall Complete Response (CR) rate: this is a composite proportion of subjects in the analysis 
population with a rCR, PET NPV , and pCR. This is the primary measure of efficacy for the 
study.     
 
Overall Response Rate (ORR): proportion of subjects in the analysis population who have 
complete response (CR) or partial response (PR) based on RECIST 1.1 imaging at treatment 
end. 
 
Progression-Free Survival (PFS): time from Day -7 treatment administration to the first 
documented disease progression or death. 
 
Overall Survival (OS): time from Day -7 treatment administration to death due to any cause. 
 
Locoregional Control (LRC): time from day -7 treatment to date of local or regional relapse 
within the primary radiation treatment field (relapse in the head or neck region, excluding CNS 
recurrence).  
 
Rate of Distant Metastases (DM):  proportion of subjects in the analysis population who 
develop distant recurrence, as defined by recurrence outside of the primary radiation treatment 
field (head and neck region).   
 
8.4.2 Safety Endpoints 
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with head and neck cancer. The primary safety analysis will be 
based on subjects who experienced toxicities as defined by CTCAE Version 4.0 criteria. Safety 
will be assessed by quantifying the toxicities and grades experienced by subjects who have 
received pembrolizumab, including serious adverse events (SAEs) and events of clinical 
interest (ECIs). 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 72 
 
 
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific immune-related 
adverse events (irAEs) will be collected and designated as immune-related events of clinical 
interest (ECIs) as described in Section 7.2.3.2. 
 
Consider referring to Section 4.2.3 for the initial description of safety measures. 
 
8.4.2.1 Analysis Populations 
8.4.2.2 Efficacy Analysis Populations 
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population consists of all subjects who: 
 Receive at least one dose of study treatment, 
 Complete the treatment end imaging study  
 
A supportive analysis using the All Patients as Treated (APaT) population, defined as all 
enrolled subjects who receive at least one dose of study medication, will be performed for the 
primary efficacy endpoint(s). Supportive analyses in the FAS population using the site 
radiology assessment will require baseline scan with measureable disease per RECIST 1.1 
using site radiology assessment. 
 
Patients who undergo surgical resection prior to treatment end imaging will be included in the 
efficacy analysis.  These patients will be determined as having PD.   
 
Details on the approach to handling missing data are provided in Section 8.6 Statistical 
Methods. 
 
8.4.2.3 Safety Analysis Populations 
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. 
 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required. 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 73 
 
8.4.3 Statistical Methods 
8.4.3.1 Statistical Methods for Efficacy Analyses 
The efficacy endpoints, analysis population, and statistical methods (including missing data 
handling) that will be employed for the efficacy analyses are presented in Table 7. 
The primary endpoint is the total CR rate (composite outcome of rCR, PET NPV, and pCR) 
on all subjects. We have designed the study to test the hypothesis that the CR rate will be 
greater than 40.2% assuming a rate of 60.4%.  To test this, we will use a one sample, one-sided 
asymptotic equality test with the null hypothesis that the total CR rate will be 40.2%. This test 
will result in a p-value greater than 0.05 if fewer than 21 patients respond to treatment.  
Secondary endpoints will include rCR, pCR, PET NPV, PFS, OS, LRC, and DM rates.  For 
the secondary endpoints, we will only estimate confidence intervals to understand the possible 
range of values rather than doing formal hypothesis testing.  Survival curves for PFS and OS 
will be constructed using the Kaplan-Meier method and 1 and 2-year survival estimates will 
be calculated.  
 
8.4.3.2 Table 7: Statistical Methods for Key Efficacy Endpoints 
Endpoint 
 
Statistical Method 
Analysis 
Population 
Missing data 
approach 
rCR Rate 
 Exact binomial method: 
Clopper-Pearson 95% 
confidence interval 
FAS 
Subjects with missing 
data are considered 
non-responders 
pCR Rate 
 Exact binomial method: 
Clopper-Pearson 95% 
confidence interval 
FAS1 
Subjects with missing 
data are considered 
non-responders 
CR Rate 
 One sample, one-sided 
asymptotic binomial test 
FAS 
Subjects with missing 
data are considered 
non-responders 
Objective Response Rate 
(CR + PR) 
Exact binomial method: 
Clopper-Pearson 95% 
confidence interval 
FAS 
Subjects with missing 
data are considered 
non-responders 
PFS (RECIST 1.1) by 
independent radiology 
review 
Summary statistics  
using Kaplan-Meier 
method 
ASaT 
 
Censored at last 
assessment date 
OS 
Summary statistics  
using Kaplan-Meier 
method 
ASaT 
 
Censored at last 
assessment date 
LRC rate 
Exact binomial method: 
Clopper-Pearson 95% 
confidence interval 
FAS 
Subjects with missing 
data are considered as 
disease not under 
control 
DM rate 
Exact binomial method: 
Clopper-Pearson 95% 
confidence interval 
FAS 
Subjects with missing 
data are considered as 
disease not under 
control 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 74 
 
Patient Reported 
Outcomes (PRO) 
 Linear mixed model to 
compare with historical 
controls over time. 
ASaT 
Missing data will not 
be included 
1 – only those who undergo salvage surgery 
 
 
8.4.4 Statistical Methods for Safety Analyses 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs. Count and percentage of AE will be 
provided. Clopper-Pearson 95% confidence interval for the proportion of AE of clinical 
interest will be estimated using exact method based on binomial distribution.  AE rates will be 
compared, using a Fisher’s exact test to compare the proportions.  This will also be compared 
to historical data from patients treated on a similar clinical trial using high-dose bolus cisplatin 
in combination with radiation which was recently performed at the primary study site (Sanford 
Cancer Center, Sioux Falls and Sanford Roger Maris Cancer Center, Fargo).   
 
8.4.5  Summaries of Baseline Characteristics, and Demographics 
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed. Demographic variables, 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant therapies 
will be summarized by treatment either by descriptive statistics or categorical tables. 
 
8.4.6 Patient Reported Outcomes (PROs) Evaluation 
The FACT-H&N questionnaire will be will be used to assess HRQOL (See 11.7).  This 
questionnaire combines 27 questions from the FACT-G scale with 12 disease specific 
questions for head and neck cancer.  The FACT-H&N can be subdivided into five subscales 
which include the four subscales of the FACT-G (physical well-being, social/family well-
being, emotional well-being, and functional well-being) and the Head and Neck Cancer 
Subscale.  This questionnaire is widely used in head and neck cancer patients and has been 
validated within this population [22].  
The FACT-H&N questionnaire will be requested at defined time points; at baseline, end of 
treatment, 6 months, 1 year, and 1 years post treatment. The initial questionnaire must be filled 
out prior to any treatment.  
Statistical analysis of HRQOL will involve global HRQOL as well as each of the five domains 
in the FACT-H&N questionnaire.  Longitudinal analysis will be conducted using a linear 
mixed model to compare the overall score and subscales scores between the patients in this 
trial and historical controls. 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 75 
 
8.4.7  Interim Analyses 
A formal interim efficacy analysis will occur after 27 patients have enrolled in the study.  This 
analysis will be reviewed by the DSMB to determine if the study should continue to accrue to 
a total of 39 evaluable patients. A non-formal safety analysis will occur after approximately 8 
patients have completed the study treatment.  This analysis will not involve stopping the study.  
The DSMB will meet and review toxicities at that time point.  If it is felt there is risk beyond 
what is to be expected for standard CRT, the DSMB will determine if the study should be 
stopped and if a formal safety analysis is warranted.  
 
8.4.7.1 Interim Efficacy Analysis 
An interim analysis will also occur to evaluate efficacy.  The interim analysis will occur after 
27 patients are accrued to the study and have treatment end response assessments completed 
(imaging and if applicable, salvage surgical resection).  This will occur at approximately 9 
months after study initiation.  In terms of efficacy, futility will be determined if 13 or fewer 
CRs (rCR +pCR) are seen in the 27 patients. If futility is not determined, the study will continue 
to accrue to final total of 34 HPV + patients and 23 HPV - patients who are evaluable for 
treatment response.  This will be presented to and evaluated by the DSMB.   
 
8.4.7.2 Multiplicity 
No multiplicity adjustment is planned.  
8.4.7.3 Sample Size and Power Calculations 
Sample size for this study will be powered based on the co-primary outcome of efficacy.  
Efficacy will be defined by the rCR rate at the treatment end imaging evaluation.  The rCR rate 
will be defined by RECIST 1.1 criteria.  Based on the Intergroup Trial evaluating the gold 
standard of high-dose bolus cisplatin 100 mg/m2 given on days 1, 22, and 43 of radiation at 70 
cGy, the complete response rate was 40.2% [10].  This study included both HPV+ and HPV- 
patients with unresectable disease and did not differentiate response based on HPV status.  
Extrapolating on our data from the animal model, we anticipate at least a 50% improvement in 
this CR rate.  Therefore, we estimated a CR rate of 60.4% with this study regimen in all-
comers.  
For the initial sample size calculation, Simon's two-stage design with the Minimax approach 
was utilized.  The null hypothesis that the true response rate is 0.402 will be tested against a 
one-sided alternative. In the first stage, 27 patients were to be accrued. If there are 13 or fewer 
CRs in these 27 patients, the study will be stopped. Otherwise, 12 additional patients will be 
accrued for a total of 39. The null hypothesis will be rejected if 21 or more CRs are observed 
in 39 patients. This design yielded a type I error rate of 0.05 and power of 0.80 when the true 
CR rate is 0.604. 
At the time of interim analysis, 27 patients are enrolled in the study.  During this analysis, an 
internal analysis of a similar study (NCT01386632) using standard of care high-dose cisplatin 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 76 
 
(100 mg/m2 on days 1, 22, and 43) in a similar cohort of patients was performed.  Distinct 
differences in response were seen in the HPV+ and HPV- groups, which mirror efficacy 
findings in similar studies.  This analysis has revealed that 20 of 27 (74%) of evaluable patients 
with HPV positive disease achieved a CR (based on 3-month post-radiation CT and/or PET or 
subsequent salvage surgery).  
Based on this new data, we have reassessed our power calculations for our HPV positive 
cohort,   With this novel combination therapy we estimate that an improvement in efficacy of 
>20% to a CR rate of 90% would warrant future study of this regimen in HPV positive disease.  
Therefore, using a one-arm binomial design the null hypothesis that the true response rate is 
74% will be tested against a one-sided alternative. The null hypothesis will be rejected if 31 or 
more CRs are observed in 34 patients. This design yields a type I error rate of 0.05 and power 
of 80% when the true response rate is 90%.  
Reviewing the same data, the HPV negative cohort had 6 of 12 (50%) evaluable patients 
achieving a CR (based on 3-month post-radiation CT and/or PET or subsequent salvage 
surgery).  Therefore, reassessing our power calculations for the HPV negative cohort in the 
proposed expansion cohort, we estimate a CR rate of 75% (50% improvement from the 
standard of care) with the study regimen would warrant future study of this regimen in HPV 
negative disease.  Therefore, using a one-arm binomial sample size, the null hypothesis with a 
true response rate of 50% will be tested against a one-sided alternative. The null hypothesis 
will be rejected if 18 or more responses are observed in 23 patients. This design yields a type 
I error rate of 0.05 and power of 80% when the true response rate is 75%. 
At the time of the interim analysis, 20 patients with HPV + disease are enrolled and 7 patients 
with HPV – disease are enrolled.  Based on this reanalysis of sample size and power 
calculations, an additional 14 HPV positive patients and 16 HPV negative patients would need 
to be enrolled after the interim analysis.   
8.4.7.4 Subgroup Analyses and Effect of Baseline Factors 
All efficacy endpoints CR rate, ORR, PFS, OS, LRC rate, and DM rate will be evaluated and 
compared based on: 
 HPV-positive and HPV-negative status 
 PD-L1 positive and PD-L1 negative status 
 Additional correlative studies as pertinent 
 ECOG PS 0 or 1 
 Key demographic variables (i.e. age, sex, etc.) as deemed appropriate 
 
Differences in subgroups will be evaluated using appropriate statistical techniques adjusting 
for key demographic variables.  Models will include logistic regression and proportional 
hazards regression. 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 77 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
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 are as summarized in Table 8. 
Table 8 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL1 
Solution for Injection 
1-Provided by Merck 
 
 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
Clinical Supplies Disclosure 
The Pembrolizumab product that will be supplied for this trial is not an approved US 
commercial product at this time.  It is, however, filed to the Merck IND along with data 
supporting a claim of analytical comparability of this product to all other pembrolizumab 
products being used in the clinic, some of which have been approved by the US FDA for 
commercial use. 
This trial is open-label; therefore, the subject, the trial site personnel, Sanford Research and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text. 
 
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. 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 78 
 
 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 Confidentiality 
10.1.1 Confidentiality of Data 
By signing this protocol, the investigator affirms to Sanford Research that information 
furnished to the investigator by Sanford Research 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 Sanford Research (or Sanford Research 
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 Sanford Research.  See the 
procedure manual for additional information. 
 
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, 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 79 
 
may be used and disclosed for trial management purposes, as part of a regulatory submissions, 
and as required by law. This information may include: 
 
1. name, address, telephone number and e-mail address; 
2. hospital or clinic address and telephone number; 
3. curriculum vitae or other summary of qualifications and credentials; and 
4. other professional documentation. 
 
Consistent with the purposes described above, this information may be transmitted to Sanford 
Research, and subsidiaries, affiliates and agents of Sanford Research and Merck. 
 
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. 
 
As this is a multicenter trial, in order to facilitate contact between investigators, Sanford 
Research may share an investigator’s name and contact information with other participating 
investigators upon request. 
 
10.1.4 Confidentiality of IRB/IEC Information 
Sanford Research is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial. Sanford Research 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. 
 
 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is Sanford 
Research’s responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/sub investigator’s 
responsibility to comply with any such request. 
 
The investigator/sub investigator(s) agree, if requested by Sanford Research in accordance 
with 21CFR Part 54, to provide his/her financial interests in and/or arrangements with Sanford 
Research to allow for the submission of complete and accurate certification and disclosure 
statements. The investigator/sub investigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
Sanford Research or through a secure password-protected electronic portal provided by 
Sanford Research. The investigator/subinvestigator(s) also consent to the transmission of this 
information to Sanford Research for these purposes.  
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 80 
 
 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 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 Sanford Research. 
 
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 Sanford Research as 
required by this protocol or as otherwise required pursuant to any agreement with Sanford 
Research. 
 
Trial documentation will be promptly and fully disclosed to Sanford Research 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 Sanford 
Research or any regulatory authorities. The investigator agrees to promptly take any reasonable 
steps that are requested by Sanford Research 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, 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. 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 81 
 
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. Sanford Research will determine the minimum retention period and notify the 
investigator when documents may be destroyed Sanford Research 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 Sanford 
Research 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 Sanford Research 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 Sanford Research’s trials. The investigator 
will immediately disclose in writing to Sanford Research 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 Sanford Research prematurely terminates a particular trial site, Sanford Research 
will promptly notify that trial site’s IRB/IEC. 
 
 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), Sanford Research 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.     
 Quality Management System 
By signing this protocol, the principal investigator 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. 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 82 
 
 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.  
Detailed information regarding Data Management procedures for this protocol will be provided 
separately. 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 83 
 
11.0 APPENDICES 
 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. 
 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 84 
 
 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) 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 85 
 
 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
Baseline Eligibility 
 
Measurable Disease: 
Tumor lesions: Must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to 
be recorded) with a minimum size of:: 
o 10 mm by CT by computerized tomography (CT scan 
slice thickness no greater than 5 mm). 
o 10 mm caliper measurement by clinical exam (lesions 
that cannot be accurately measured with calipers should 
be recorded as nonmeasurable). 
o 20 mm by chest x-ray. 
 
Skin lesions: Documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
Malignant lymph nodes: To be considered pathologically 
enlarged and measurable, a lymph node must be > 15mm in short 
axis when assessed by CT scan.. At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
 
Non-Measurable Disease:  All other lesions, including small lesions (longest diameter <10 
mm or pathological lymph nodes with > 10 to <15 mm short 
axis) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, and lymphangitic involvement of skin or lung, 
abdominal masses, abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging 
techniques. 
 
 
Target Lesions:  
The most reproducible measurable lesions, up to a maximum of 
2 lesions per organ and 5 lesions in total, representative of all 
involved organs should be identified as target lesions and 
recorded and measured at baseline. 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 86 
 
Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), should be representative of 
all involved organs, and, in addition, should be those that lend 
themselves 
to 
reproducible 
repeated 
measurements. 
Pathological nodes which are defined as measurable and that 
may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15mm. All target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is 
added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor response. 
 
Non-Target Lesions:  
All other lesions (or sites of disease) are identified as non-target 
lesions (chosen based on their representativeness of involved 
organs and the ability to be reproduced in repeated 
measurements) 
and 
should 
be 
recorded 
at 
baseline. 
Measurements of these lesions are not required, but the presence 
or absence of each should be noted throughout follow-up.  
Lymph nodes with short axis > 10mm but < 15mm should be 
considered non-target lesions.  Nodes that have a short axis < 
10mm are considered non-pathological and are not recorded or 
followed. 
 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10mm.  Tumor marker results must have 
normalized 
 
Partial Response (PR):  
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
(nadir) sum of diameters since the treatment started. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest (nadir) sum since the 
treatment started, or the appearance of one or more new 
lesions. Requires not only 20% increase, but absolute increase 
of a minimum of 5 mm over sum. 
 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 87 
 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor markers.  All lymph nodes must be non-pathological in 
size (<10 mm short axis). 
 
Stable Disease (SD):  
Persistence of one or more non-target lesions and/or 
persistence of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. When the patient 
also has measurable disease there must be an overall level of 
substantial worsening in non-target disease such that, even in 
presence of SD or PR in the target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of 
therapy. 
 
Evaluation of Best Overall Response 
 
Target Lesions  Non-Target Lesions 
New Lesions 
Overall response 
CR: disappearance of 
all target and non-target 
lesions, 
normalization 
of tumor marker level, 
and 
reduction 
in 
pathological 
lymph 
nodes short axis to <10 
mm. 
PR: 30% decrease in 
the sum of diameters of 
the target lesions. 
PD: 20% increase in the 
sum of diameters of the 
target lesions. 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
When nodal disease is included in the sum of target lesions, and the nodes decrease to 
“normal” size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 88 
 
progression, should it be based on increase in size of the nodes. As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
* As published in the European Journal of Cancer: 
 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 89 
 
 Modified RECIST 1.1 
Modified RECIST 1.1 is RECIST 1.1 adapted as follows to account for the unique tumor 
response seen in this class of therapeutics (refer to Section 4.2.3.1). 
 
If radiologic imaging shows PD, tumor assessment may be repeated >=4 weeks later at the 
site in order to confirm PD with the option of continuing treatment for clinically stable 
subjects as discussed below. Clinically stable is defined by the following criteria: 
 
Absence of signs and symptoms indicating disease progression 
•No decline in ECOG performance status 
•Absence of rapid progression of disease 
•Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
Imaging and Treatment after 1st radiologic evidence of PD  
 
Clinically Stable 
Clinically Unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging 
at >=4 weeks at 
site to confirm 
PD 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan by site 
Repeat imaging 
at >=4 weeks at 
site to confirm 
PD per 
physician 
discretion only 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging 
required 
Discontinue 
treatment  
No additional 
imaging 
required 
N/A 
Repeat scan 
shows SD, PR, 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
Investigator’s 
discretion 
 
In determining whether or not the tumor burden has increased or decreased, investigators 
should consider all target lesions as well as non-target lesions. Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation. If radiologic 
progression is confirmed (by subsequent scan) then the subject will be discontinued from 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 90 
 
trial treatment. 
 
If radiologic progression is not confirmed, then the subject should resume/continue trial 
treatment and have their next scan at the regularly scheduled interval. Subjects who obtain a 
confirmation scan at 4 weeks do not need to undergo the next scheduled imaging assessment 
if it is due < 4 weeks later. Imaging may be performed at the next scheduled imaging 
time point if the subject remains clinically stable. 
 
NOTE: If a subject with confirmed radiographic progression (i.e. 2 scans at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and there 
is no further increase in the tumor dimensions at the confirmatory scan, an exception may be 
considered to continue treatment upon consultation with the Sponsor. 
 
Imaging during the follow-up period is to be repeated every 6 weeks (± 7 days) for the first 
year patients are on study and then every 9 weeks (± 7 days) after 1 year for subjects who 
discontinue trial treatment for reasons other than disease progression. Follow-up scans should 
be continued until the subject experiences confirmed disease progression or starts a new 
antineoplastic therapy. 
 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 91 
 
 
 Hopkins Criteria for PET Response Evaluation in Head and Neck Cancer  
Post-treatment FDG PET/CT imaging will be utilized as part of the response criteria, based 
on clinical research that showed the utility of this imaging to prevent unnecessary salvage 
surgery [Mehanna, et al]. PET response will be based on the “Hopkin’s criteria.”[Marcus et 
al.]. This is a five point scale with blood pool and liver as reference standard and 
accommodates FDG uptake due to post radiation inflammation and is outlined below.  
 
Five-Point Qualitative Post-Therapy Assessment Scoring System (Hopkins Criteria) for Head 
and Neck PET/CT [38] 
 
Score 
18F-FDG uptake pattern 
Response Category 
1 
18F-FDG uptake at the primary site and nodes less than IJV 
 
Complete metabolic response 
2 
Focal 18F-FDG uptake at the primary site and nodes great than IJV 
but less than liver 
Likely complete metabolic 
response 
3 
Diffuse 18F-FDGuptake at the primary site or nodes is greater than 
IJV or Liver 
Likely post-radiation inflammation 
4 
Focal 18F-FDGuptake at the primary site or nodes greater than 
liver 
Likely residual tumor 
5 
Focal and intense 18F-FDG uptake at the primary site or nodes 
 
Residual tumor 
 
Scores 1, 2, and 3, which represent complete metabolic response, likely complete metabolic 
response, and likely post-radiation inflammation, respectively, were considered negative for tumor 
and have a Negative Predictive Value (NPV).  
 
Scores 4 and 5, which represent likely residual tumor and residual tumor, respectively, were 
considered positive for tumor and have a Positive Predictive Value (PPV). New lesion would be 
considered as progressive disease. 
Salvage surgery decisions will be left the treatment team and should not be dictated by the 
PET imaging findings.   
 
 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 92 
 
 Events of Clinical Interest Guidance Document 
See separate ECI Guidance Document 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 93 
 
 Preclinical data (unpublished) 
PD-1 BLOCKADE SYNERGIZES WITH CISPLATIN RADIATION THERAPY 
AIDING IN CLEARANCE OF HPV+ OROPHARYNGEAL CARCINOMA 
 
VERMEER DW1, POWELL S1, SPANOS WC1,2 AND LEE JH1,2 
 
 
1Sanford Cancer Research Center, Sanford Research, Sioux Falls SD. 
2Department of Otolaryngology/Head and Neck Surgery, Sanford Research, Sioux Falls, 
South Dakota, 57104 USA 
 
 
Squamous cell carcinomas of the head and neck (SCCHN) are the 6th most common 
malignancy world-wide with approximately 650,000 diagnoses per year.  Human 
papillomavirus (HPV) causes up to 80% of oropharyngeal (tonsil/base of tongue) SCCHN.  
Despite presenting at an advanced stage, multiple studies show that HPV+ SCCHN are more 
curable relative to their HPV- counterparts. Clearance of SCCHN during treatment with 
cisplatin radiation therapy (CRT) is not only related to direct cytotoxicity, but is also dependent 
on immune mediated clearance.  This immune clearance is strongly dependent on an intact 
CD4+ and CD8+ cellular response to tumor cells harboring these viral oncogenes.  
Furthermore, the immune system recognizes and clears HPV + SCCHN only after the start of 
CRT.  The immunologic tolerance to these cancers prior to treatment could be explained by 
immune checkpoints aimed at preventing unregulated immune activity.  The programmed 
death 1 receptor (PD-1) and its ligand, PD-L1, are one such checkpoint axis.  Recent data 
suggests that the PD-1:PD-L1 pathway may play an important role in immune resistance in 
head and neck cancer.  We evaluated PD-1 in combination with CRT in an immune competent 
HPV+ SCCHN mouse model.  HPV + mouse SCCHN cells were injected subcutaneously into 
immune competent mice and tumors were treated after growing to palpable size.  Using the 
mouse analog to the human PD-1 blocker pembrolizumab, we determined that while single-
agent therapy does not have significant activity on primary disease or distant metastasis, PD-1 
blockade strongly synergizes with CRT.  An overall survival of  58% was evident in mice 
treated with combination PD-1 and CRT versus 8% in mice treated with isotype control (IgG1) 
in combination with CRT (p = 0.006). These studies provide the impetus for future work 
investigating less toxic induction of immune responses in combination with blockade of 
immune checkpoint pathways.  
 
 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 94 
 
 Patient Reported Outcomes (PRO) – FACT H&N 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 95 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 96 
 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 97 
 
 List of Abbreviations 
AE  
 
 
Adverse Event 
ADA   
 
Anti-Drug Antibodies 
ALT      
 
Alanine Aminotransferase 
ANC  
 
Absolute Neutrophil Count 
APaT/ASaT   
All Patients/Subjects as Treated Population 
ASCO  
 
American Society of Clinical Oncology 
AST   
 
Aspartate Aminotransferase 
ß-HCG  
 
Beta Human Chorionic Gonadotropin 
CBC   
 
Complete Blood Count 
CFR 
 
 
Code of Federal Regulations 
CI  
 
 
Confidence Interval 
CNS  
 
Central Nervous System 
CR  
 
 
Complete Response 
CrCl   
 
Calculated Creatinine Clearance 
CRF   
 
Case Report Form 
CRT 
 
 
Chemo radiotherapy 
CSR   
 
Clinical Study Report 
CT  
 
 
Computed Tomography 
CTCAE  
 
Common Toxicity Criteria for Adverse Events 
CTLA-4  
 
Cytotoxic T-Lymphocyte-Associated Antigen-4 
CTV  
 
Clinical Target Volume 
DCA  
 
Dichloroacetate 
DKA  
 
Diabetic Ketoacidosis 
DLT 
 
 
Dose Limiting Toxicity 
DM 
 
 
Distant Metastases 
DNA   
 
Deoxyribonucleic acid 
DSMB  
 
Data Safety Monitoring Board 
ECI  
 
 
Events of Clinical Interest 
ECOG  
 
Eastern Cooperative Oncology Group 
ERC   
 
Ethics Review Committee 
EU 
 
 
European Union 
FACT H&N  
Functional Assessment of Cancer Therapy Head and Neck 
FAS   
 
Full Analysis Set 
FDA   
 
Food and Drug Administration 
FDAAA  
 
Food and Drug Administration Amendments Act 
FDAMA 
 
Food and Drug Administration Modernization Act 
FFPE   
 
Formalin-fixed Paraffin Embedded 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 98 
 
FNA  
 
Fine-Needle Aspirate 
GCP   
 
Good Clinical Practice 
GFR   
 
Glomerular Filtration Rate 
GTV  
 
Gross Tumor Volume 
Gy 
 
 
Gray 
HCV   
 
Hepatitis C 
HIV   
 
Human Immunodeficiency Virus 
HPV  
 
Human Papilloma Virus 
IB 
 
 
Investigator Brochure 
ICF  
 
 
Informed Consent Form 
ICH   
 
International Conference on Harmonization 
IEC 
 
 
Institutional Ethics Committee 
IHC   
 
Immunohistochemistry 
IMRT  
 
Intensity-modulated radiation therapy 
irAEs   
 
Immune-related Adverse Events 
IRB  
 
 
Institutional Review Board 
irRECIST  
 
Immune-related RECIST 
ITIM  
 
Immunoreceptor Tyrosine-based Inhibition Motif 
ITSM  
 
Immunoreceptor Tyrosine-based Switch Motif 
IV  
 
 
Intravenous 
LA-SCCHN  
Locally Advanced-Squamous Cell Carcinoma of the Head and Neck 
LDH  
 
Lactate dehydrogenase 
LRC 
 
 
Loco regional Control 
mAb   
 
Monoclonal Antibody 
MDSCa 
 
Myeloid-Derived Suppressor Cells 
MEL   
 
Melanoma 
mg  
 
 
Milligram 
mg/kg  
 
Milligram per Kilogram 
mL  
 
 
Milliliter 
mm  
 
 
Millimeters 
MRI 
 
 
Magnetic Resonance Imaging 
MSD   
 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
MTD  
 
Maximum Tolerated Dose 
NA or N/A  
 
Not Applicable 
NCCN  
 
National Comprehensive Cancer Network 
NCI   
 
National Cancer Institute 
NPV  
 
Negative Predictive Value 
NSAID  
 
Non-Steroidal Anti-inflammatory Drug 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 99 
 
OAR  
 
Organs At Risk 
ORR   
 
Overall Response Rate 
OS  
 
 
Overall Survival 
OTC   
 
Over-the-counter 
pCR 
 
 
Pathologic Complete Response 
PD  
 
 
Progressive Disease 
PET 
 
 
Positron emission tomography 
PFS  
 
 
Progression Free Survival 
PK  
 
 
Pharmacokinetic 
PK/PD  
 
Pharmacokinetic-Pharmacodynamic 
PO  
 
 
Oral Administration 
PPV 
 
 
Positive Predictive Value 
PR  
 
 
Partial Response 
PRO  
 
Patient Reported Outcomes 
PS 
 
 
Performance Status 
PTV 
 
 
Planning Target Volume 
QOL  
 
Quality of Life 
rCR 
 
 
Radiographic Complete Response 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
RNA  
 
Ribonucleic Acid 
RTOG  
 
Radiation Therapy Oncology Group 
Q2W   
 
Every 2 Weeks 
Q3W  
 
Every 3 Weeks 
SAE   
 
Serious Adverse Events 
SAP   
 
Statistical Analysis Plan 
SCCHN 
 
Squamous Cell Carcinoma of the Head and Neck 
SD 
 
 
Stable Disease 
SGOT   
 
Serum Glutamic Oxaloacetic Transaminase 
SGPT   
 
Serum Glutamic Pyruvic Transaminase 
SOC   
 
Standard of Care 
SOP 
 
 
Standard Operating Procedures 
T1DM  
 
Type 1 Diabetes Mellitus 
TB 
 
 
Bacillus Tuberculosis 
TIL  
 
 
Tumor-Infiltrating Lymphocytes 
TNM  
 
Tumor, node, and metastasis 
TSH   
 
Thyroid Stimulating Hormone 
ULN   
 
Upper Limit of Normal 
WBC  
 
White Blood Cell 
 

 
 
 
 
 
 
SH MISP203 v08/22/2018                                                                                            Page 100 
 
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SH MISP203 v08/22/2018                                                                                            Page 101 
 
 
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SH MISP203 v08/22/2018                                                                                            Page 102 
 
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SH MISP203 v08/22/2018                                                                                            Page 103 
 
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SH MISP203 v08/22/2018                                                                                            Page 104 
 
13.0 SIGNATURES 
INVESTIGATOR’S STATEMENT 
I agree to conduct the study as outlined in the protocol entitled “Phase IB study of 
Pembrolizumab in combination with chemo radiotherapy (CRT) for locally advanced 
squamous cell carcinoma of the head and neck (SCCHN)” in accordance with the 
guidelines set forth and all applicable government regulations. 
 
READ AND ACKNOWLEDGED: 
 
 
 
PRINCIPAL INVESTIGATOR 
 
 
Date